Further Possible MS Drugs and Treatments

Researchers have uncovered a potent class of small molecules that selectively turn on the S1P1 receptor, a type of receptor in cells that can be targeted in the design of new treatments for diseases such as multiple sclerosis. These findings are reported in the Feb. 17 issue of the journal Science. The research was supported by the National Institutes of Health Common Fund and the National Institute of General Medical Science (NIGMS).

Structural biology is a field of study aimed at determining the molecular structure of biological molecules, such as proteins, and how alterations in their structures affect their function. The ability to determine how well different drugs bind to a protein receptor to turn on or turn off the receptor provides a powerful way to design new drugs that selectively target certain receptors and not others, a major stumbling block to drug development.

"This work is an excellent example of how structural studies can reveal insights into basic principles of protein function and how this may lead to smarter, safer drugs,” said NIH Director Francis S. Collins, M.D., Ph.D. "This approach could be used to design better therapies for a variety of adverse health conditions."

G-protein coupled receptors (GPCRs) comprise a highly diverse class of protein receptors that are common targets of therapeutic interventions due to their central roles in multiple normal and pathological processes. GPCRs reside on the surface of cells and are activated by binding select molecules. The sphingosine 1-phosphate 1 (S1P1) receptor is a GPCR that is activated by certain fat molecules. Its role in the immune response has made it an attractive therapeutic target for multiple sclerosis, a disease where the body's own immune system attacks and damages nerve cells. However, S1P1 is so similar to several other GPCRs that modifying its function selectively without affecting other receptors has proven difficult.

Using technology developed through the Structural Biology Program of the NIH Common Fund, established through the NIH Reform Act to support innovative, trans-NIH programs, along with the NIGMS-funded Protein Structure Initiative (PSI), the research teams of Drs. Raymond Stevens, Ph.D., and Hugh Rosen, M.D., Ph.D., of The Scripps Institute teamed up to take molecular snapshots of S1P1 bound to different activators and inhibitors developed through the Common Fund's Molecular Libraries and Imaging Program. The snapshots revealed that S1P1 has structural features that allow it to bind activators in two ways. One of these structural features varies subtly between related GPCRs, such that molecules can be designed to activate S1P1 selectively. Such molecules may prove to be effective therapies for multiple sclerosis with fewer side effects than current therapies.

“The potential impact of this research is far-reaching, since members of the GPCR family have been implicated in a wide range of diseases, including heart disease, allergy and multiple sclerosis,” said James M. Anderson, M.D., Ph.D., director of the Division of Program Coordination, Planning, and Strategic Initiatives that guides the NIH Common Fund’s programs. “Using the results from this study, investigators may be able to design drugs that selectively activate or inhibit other important GPCRs.”

“This innovative work reflects the deep integration of chemistry and biology at The Scripps Research Institute,” said Michael A. Marletta, Ph.D., president of Scripps Research. “The close collaboration among our scientists in different disciplines makes studies with far-reaching results like this possible.”

The NIH Common Fund supports a series of exceptionally high impact research programs that are broadly relevant to health and disease. Common Fund programs are designed to overcome major research barriers and pursue emerging opportunities for the benefit of the biomedical research community at large. The research products of Common Fund programs are expected to catalyze disease-specific research supported by the NIH Institutes and Centers. The Common Fund's Structural Biology Program is developing novel approaches to isolate membrane proteins and characterize their 3D structure while the Molecular Libraries and Imaging Program supports large-scale screening efforts to identify small molecules that facilitate studies of biological processes in health and disease.

“This fundamental advance would not have been possible without NIH Common Fund’s far-sighted vision and support of these two programs,” said Rosen, who is principle investigator of the Scripps Research Molecular Screening Center, part of the NIH Molecular Libraries and Imaging Program. “The programs have come together to contribute to a more efficient data-enabled approach to therapeutics. One compound resulting from the NIH Molecular Library is already in clinical trials for the treatment of multiple sclerosis and other autoimmune diseases.”

The PSI is a continuing effort to improve the efficiency of three-dimensional protein structure determination, especially the structures of difficult targets such as membrane proteins. It is funded by NIGMS, a part of NIH that supports basic research to increase our understanding of life processes and lay the foundation for advances in disease diagnosis, treatment, and prevention.

Source: PharmaPro Copyright ©2012 Advantage Business Media (17/02/12)

Summary

Background
Monoclonal antibody therapy against α4β-integrin is efficacious in patients with multiple sclerosis (MS) with some safety concerns. We assessed the safety and efficacy of firategrast, a small oral anti-α4β-integrin molecule, in patients with relapsing remitting MS.

Methods
We did a multicentre, phase 2, randomised, double-blind, placebo-controlled, dose-ranging study in participants with clinically definite relapsing-remitting MS. A 24-week treatment period was followed by 12 weeks of core follow-up and 40 weeks of extended follow-up. Participants were randomly assigned, via computer-generated block randomisation in a 1:2:2:2 ratio, to receive one of four treatments twice a day: firategrast 150 mg, firategrast 600 mg, or firategrast 900 mg (women) or 1200 mg (men), or placebo.

Brain scans were obtained at 4-week intervals to the end of core follow-up. The primary outcome was cumulative number of new gadolinium-enhancing brain lesions during the treatment phase and was analysed using a generalised linear model with an underlying negative binomial distribution, adjusted for sex, baseline number of new gadolinium-enhancing lesions, and country.

Findings
Of 343 individuals enrolled, 49 received firategrast 150 mg, 95 received firategrast 600 mg, 100 received firategrast 900 mg or 1200 mg, and 99 received placebo. A 49% reduction (95% CI 21·2—67·6; p=0·0026) in the cumulative number of new gadolinium-enhancing lesions was seen for the 900 mg or 1200 mg firategrast group (n=92, mean number of lesions 2·69 [SE 1·18]) versus the placebo group (90, 5·31 [1·18]). In the 600 mg group (86, 4·12 [SE 1·19]), a non-significant 22% reduction (95% CI −21·3 to 49·7; p=0·2657) occurred in mean number of new gadolinium-enhanced lesions relative to placebo; for the 150 mg group (47, 9·51 [SE 1·24]), a 79% increase (95% CI 4·1—308·1; p=0·0353) occurred relative to placebo.

Firategrast was generally well tolerated at all doses. The frequency of all adverse events was similar across all treatment groups except for an increased rate of urinary tract infections in the high-dose firategrast group. No cases of progressive multifocal leukoencephalopathy or evidence of reactivation of JC virus were identified.

Interpretation
This study showed efficacy on imaging endpoints for firategrast at the highest dose tested, and suggests that further investigation of oral short-acting α4β integrin blockade therapies is warranted.

Funding
GlaxoSmithKline.

Prof David H Miller FMedSci, Prof Thomas Weber MD, Richard Grove MSc, Claire Wardell PhD, Joseph Horrigan MD, Ole Graff MD, Gillian Atkinson PhD, Pinky Dua PhD, Prof Tarek Yousry MD, David MacManus MSc, Prof Xavier Montalban MD

Full Article

Source: The Lancet Neurology Copyright © 2011 Elsevier Limited (12/01/12)

MorphoSys AG announced today that a phase 1b clinical trial evaluating MOR103, a human monoclonal antibody to GM-CSF (granulocyte macrophage-colony stimulating factor), in patients with multiple sclerosis (MS) is now open for enrollment, thereby adding a second indication to the development program.

A phase 1b/2a trial in patients with active rheumatoid arthritis is ongoing and is on track to report data by mid of 2012. Additionally, a phase 1 pharmacokinetic (PK) study in healthy volunteers to evaluate a subcutaneous formulation of MOR103 will commence shortly.

"Our proprietary portfolio has made significant progress this year," commented Dr. Arndt Schottelius, Chief Development Officer of MorphoSys AG. "These two new studies further increase the value of our lead proprietary drug MOR103. GM-CSF is strongly implicated in the pathogenesis of inflammatory diseases, including rheumatoid arthritis and multiple sclerosis. Recent in vivo data generated in animal models for MS demonstrate that inhibition of GM-CSF improves disease scores, which further substantiates the decision to choose MS as the second indication for MOR103. My team and I are thus very excited that the phase 1b study in multiple sclerosis has been initiated."

The phase 1b dose-escalation study in multiple sclerosis will determine the safety of three doses of MOR103. In total, 30 patients will be enrolled in the study which is planned to be conducted at sites in Germany, the UK and Poland. Data for this trial is expected to be available in 2013.

The PK study will evaluate the pharmacokinetics, bioavailability, safety and tolerability of subcutaneously administered MOR103 in 32 healthy volunteers. Subcutaneous injection represents a more convenient way of administration for patients and the data will help guide dosing regimens for future clinical trials for MOR103. Enrollment for this trial is expected to be completed in 2012.

Source: Reuters (c) Thomson Reuters 2011 (21/12/11)

Innate Immunotherapeutics today announced that the dose confirmation part of the company's Phase 2A trial of drug candidate MIS416 in patients with the progressive form of MS will commence in early January 2012.

The announcement follows the successful conclusion of a dose escalation study in 16 patients with either primary progressive or secondary progressive MS conducted at Primorus Clinical Trials (Christchurch, NZ). The upcoming dose confirmation study will test a potentially therapeutic dose level of MIS416 in 15 patients with secondary progressive MS over a three month period.

Both parts of the 2A study are designed to establish the safety and tolerability of Innate Immunotherapeutics' immune modulating microparticle and to also establish a dose level to be trialed in a larger scale Phase 2B clinical trial in late 2012.

The current trial is being partly sponsored by the U.S. National MS Society Fast Forward programme in collaboration with Merck Serono and has also attracted significant support from the New Zealand Government's Ministry of Science and Innovation.

Innate Immunotherapeutics' CEO, Simon Wilkinson, said the Company was delighted to have successfully completely the first part of the study and paid tribute to the patients and trial centre staff. "This study commenced just two weeks after the major earthquake that struck Christchurch on September 4th last year. Since that time there have been over 8,000 aftershocks including major quakes on Feb 22nd and June 13th. Despite the significant disruption caused to the Christchurch infrastructure and people's lives, both patients and staff have soldiered on and been unwavering in their support of the study. We are indebted to them."

About MIS416

Source: Scoop Health © Scoop Media 2011 (15/11/11)

An investigational biologic drug that deactivates antibody-producing B cells reduced gadolinium-enhancing T1 lesions in multiple sclerosis patients, potentially offering yet another treatment approach to the disease, researchers said.

After 24 weeks of the phase II trial, lesion burden as measured by MRI was reduced by 89% in 55 patients treated with a low dose ocrelizumab relative to the 54-patient placebo group (95% CI 68% to 97%), according to Ludwig Kappos, MD, of University Hospital in Basel, Switzerland, and colleagues.

Lesions were reduced by 96% in 55 patients receiving a high dose of the drug (95% CI 89% to 99%), the researchers reported online in The Lancet.

The randomized trial also included a fourth arm in which 52 patients received intramuscular interferon-beta-1a (Avonex), a standard treatment for MS. Mean lesion counts during the trial in this group were similar to those seen in the placebo group.

"Our study shows the effectiveness of B-cell depletion with both ocrelizumab doses in reducing MRI and clinical disease activity, combined with a favorable short-term safety profile," Kappos and colleagues wrote.

Ocrelizumab is a humanized monoclonal antibody against the CD20 protein that marks activated B cells. It shares this target with rituximab (Rituxan), which has also shown promise in MS and is sometimes used off-label in the condition.

But rituximab is a chimeric mouse-human globulin and hence potentially more prone to development of neutralizing antibodies. Kappos and colleagues cited data suggesting that ocrelizumab has increased antibody-dependent cell-mediated cytotoxic effects that may make it a better drug for MS.

The current study is the first to compare ocrelizumab with placebo and interferon-beta in a controlled trial.

The 218 patients had relapsing-remitting MS with mean duration of about 6 years and mean EDSS disability scores of about 3.3.

Mean gadolinium-enhancing T1 lesion counts at baseline were 1.6 in the placebo group, 3.9 in the low-dose ocrelizumab group, 2.2 among those assigned to high-dose ocrelizumab, and 2.3 in the interferon group.

Ocrelizumab was given in two infusions separated by two weeks. The low-dose group received 300 mg in each infusion and the high-dose group was given 1,000 mg per infusion.

The placebo was given by infusion as well, providing blinding. Interferon, however, was given weekly by intramuscular injection at the standard 30-µg dose and therefore was open-label.

Primary efficacy outcomes were evaluated after 24 weeks. At that point, all patients received another cycle of treatment with ocrelizumab. The original placebo and interferon groups received two infusions, 14 days apart, of 300 mg of ocrelizumab. The initial low-dose group received a single infusion of 600 mg and the high-dose group received a single dose of 1,000 mg.

Kappos and colleagues reported safety and limited efficacy data for weeks 24 to 48 in addition to the primary analyses based on the first 24 weeks of treatment.

Whereas mean gadolinium-enhancing T1 lesion counts -- the study's primary outcome measure -- remained stable through the first 24 weeks in the placebo and interferon groups, they dropped nearly to zero in both ocrelizumab groups (mean 0.6 low dose, 0.2 high dose).

About 80% of both ocrelizumab groups had lesion counts of zero over weeks 12 to 24, compared with 35% of the placebo group and 48% of the interferon-treated patients.

A similar pattern was seen for other MRI outcomes, including new gadolinium-enhancing lesions, volume of T2 lesions, and total number of new or enlarging T2 lesions.

Kappos and colleagues also assessed clinical relapses at week 24 and again at week 48. During the first half of the study, annualized relapse rates were as follows:

Placebo: 0.64 (95% CI 0.43 to 0.94)
Interferon: 0.36 (95% CI 0.22 to 0.60)
Low-dose ocrelizumab: 0.13 (95% CI 0.03 to 0.29)
High-dose ocrelizumab: 0.17 (95% CI 0.05 to 0.35)
Annualized relapse rates from week 24 to 48 (at which point all patients were receiving ocrelizumab) ranged from 0.09 to 0.28 with no clear difference between the original assignment groups.

With one exception, ocrelizumab appeared to have a "benign" safety profile in the study, the researchers indicated.

But the exception was major -- a woman in the high-dose group developed a systemic inflammatory reaction at week 12 that was ultimately fatal. Whether the drug was directly to blame is not yet clear.

Safety concerns were already lingering over ocrelizumab because of a high rate of opportunistic infections seen in trials of the drug in rheumatoid arthritis. Ocrelizumab's developer, Genentech, stopped that program as a result.

No opportunistic infections were seen in the current study. Kappos and colleagues noted that their patients were generally younger, in better overall health, and not taking concomitant treatment with steroids or immunosuppressants.

There have also been no cases of progressive multifocal leukoencephalopathy in the ocrelizumab trials for MS or rheumatoid arthritis, the researchers indicated.

In an accompanying editorial, two British neurologists argued that all disease-modifying therapies for MS are likely to pose safety concerns.

Natalizumab (Tysabri), fingolimod (Gilenya), alemtuzumab (Lemtrada), and cladribine each have their own rare but serious side effects that have given clinicians and regulators pause, according to Jeremy Chataway, MD, and David H. Miller, MD, both of University College London.

"Therapeutic potency will have to be balanced against early or late risk, both known and unknown. The equation is difficult to solve," they wrote.

Chataway and Miller also highlighted the completely unmet clinical need for therapies that slow or halt progressive MS, noting that clinical trials will be difficult from a pragmatic standpoint.

They argued that the two- to three-year clinical trial now typical for novel MS drugs will have to be extended to at least five years if the endpoint is -- as it eventually should be -- delay in conversion from relapsing-remitting to progressive disease.

The trial was funded by Genentech (Roche) and Biogen Idec.

Kappos reported relationship with Acorda Therapeutics, Actelion Pharmaceuticals Ltd, Advancell, Allozyne, Barofold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, Boehringer Ingelheim, CSL Behring, Geneuro, Genmab, GlaxoSmithKline, Glenmark, Merck Serono, MediciNova, Novartis, sanofi-aventis, Santhera Pharmaceuticals, Shire Plc, Roche, Teva, UCB, Wyeth, the Swiss MS Society, the Swiss National Research Foundation, Europen Union, Gianni Rubato, Roche, and Novartis. Several authors were employees of Genentech/Roche.

Chataway reported relationships with Novartis, Teva, and Biogen Idec. Miller reported relationships with Biogen Idec, Novartis, GlaxoSmithKline, and Bayer Schering.

Primary source: Lancet
Source reference:
Kappos L, et al "Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial," Lancet 2011; doi:10.1016/S0140-6736(11)61649-8.

Additional source: Lancet
Source reference:
Chataway J, et al "Multiple sclerosis -- quenching the flames of inflammation," Lancet 2011; doi:10.1016/S0140-6736(11)61133-1.

Source: Medpage Today © 2011 Everyday Health, Inc (01/11/11)

Roche Holding AG said Thursday that a phase II showed its experimental drug ocrelizumab maintained significant reduction in disease activity for multiple sclerosis patients for almost two years. Roche said phase III trials underway to investigate ocrelizumab in two forms of MS

96-week results from a phase II study of ocrelizumab in patients with relapsing-remitting multiple sclerosis (RRMS), the most common clinical form of the disease. The study showed that the significant reduction in disease activity as measured by the total number of active brain lesions and relapses previously reported for 24 weeks, was maintained through 96 weeks.

The data is being presented today at ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) the world's largest annual international conference devoted to basic and clinical research in multiple sclerosis.

People with RRMS suffer from relapses and disabling symptoms caused by damage to the central nervous system (the brain, spinal cord and optic nerves) which can significantly affect their quality of life. Symptoms are unpredictable and vary between patients. Most people experience their first symptoms between the ages of 20 and 40.

Results from the trial showed that during the 24-96 week treatment period no patient who received a dose of 600mg ocrelizumab developed a new or enlarging brain lesions (as measured by MRI). The annualised relapse rate (ARR), the rate of clinical attacks or flare-ups per patient-year, was less than 0.2 attacks per patient per year across the 96-week period. The data also showed that, of the patients who completed the study, two-thirds of the patients in the 600mg group were free of any disease activity (as measured by MRI, relapses or neurological progression) over the 96-week treatment period.

"This demonstration of long-term efficacy of ocrelizumab confirms the compelling benefit demonstrated in the first 24-week treatment period", said Hal Barron, M.D., Head of Global Development and Chief Medical Officer for Roche. "These results indicate a high likelihood of success of the ongoing Phase III program in patients with relapsing-remitting multiple sclerosis. Additionally, a study is underway to evaluate the potential benefit of ocrelizumab in patients with primary progressive multiple sclerosis."

The safety profile of ocrelizumab over the 96 weeks of the study was consistent with that demonstrated in the earlier 24-week data. No opportunistic infections were reported and the rate of infections (and serious infections) did not increase over the treatment period. Serious infection rates were similar for ocrelizumab 600mg (1.97 events/100 patient/years) and ocrelizumab 1000 mg (1.93 events/100 patient/years) and did not increase with time on ocrelizumab treatment.

Source: Fox Business ©2011 FOX News Network, LLC (20/10/11)

Merck KGaA said its Merck Serono unit will develop and market a pill for multiple sclerosis with Japan's Ono Pharmaceutical Co. to compete with a similar product made by Novartis AG.

The experimental therapy, ONO-4641, is in the second of three stages of clinical trials usually required for regulatory approval, Merck said Tuesday.

The companies will also collaborate in Japan on the development and marketing of Merck's Stimuvax, a cancer treatment in the final stage of trials, according to the statement.

ONO-4641 is Merck's second attempt to develop a tablet for MS after it decided not to seek approval of its cladribine pill in June. Novartis' Gilenya, the first oral drug for MS, was approved last year, and Israel's Teva Pharmaceutical Industries Ltd. is developing a competing Laquinimod pill.

"There's a huge unmet clinical need," said Gustav Ando, a London analyst at consulting company IHS Global Insight. With a pill, "the patient doesn't have to go to the hospital for monthly injections, which significantly impedes quality of life."

Novartis has 13,000 patients on Gilenya, the company said in July. The drug may reach $1.2 billion in sales by 2013 and $2.1 billion by 2015, according to analysts' estimates compiled by Bloomberg.

"It's a very lucrative market," Ando said.

Source: SF Gate © 2011 Hearst Communications Inc.(05/10/11)

Merck Serono acquired worldwide exclusive rights to a Phase II-ready multiple sclerosis candidate, PI-2301, originally developed by Peptimmune, the Cambridge, MA-based peptide therapeutics firm that reportedly filed for Chapter 7 bankruptcy earlier this year after it failed to complete a $35 million fundraising round.

PI-2301 is a second-generation peptide copolymer derived from a similar compound class as Teva Pharmaceuticals’ Copaxone®. PI-2301 is believed to work by enhancing the regulatory response of the immune system, and dampening immune responses that drive autoimmune diseases such as multiple sclerosis. Merck will evaluate the product for autoimmune diseases including multiple sclerosis.

Merck Serono’s marketed MS drug, Rebif® (interferon beta-1a) is a disease-modifying therapeutic used to treat relapsing forms of multiple sclerosis. The drug was approved in Europe in 1998 and in the U.S. in 2002, and is now registered in more than 90 countries worldwide. Studies are in progress to evaluate Rebif in related indications such as clinically isolated syndrome (CIS), which manifests as intermittent neurological attacks that resemble those of multiple sclerosis. An extended release formulation of interferon beta-1a is separately undergoing Phase I clinical development.

The firm’s Phase I stage pipeline includes two additional MS candidates: ARX 424 is a long-acting interferon, and ATX-MS-1467 is an immune-tolerizing agent. Merck Serono is also collaborating with Bionomics on the development of MS therapeutics that target the potassium ion channel Kv1.3, a key modulator of the immune system and a target found on human immune cells associated with nerve cell damage in patients with multiple sclerosis.

Source: GEN © 2011 Genetic Engineering & Biotechnology News (19/09/11)

Actelion announced today that the primary endpoint - reduction in the number of new active inflammatory lesions in the brain - has been met with its selective S1P1 receptor agonist, ponesimod, in a Phase IIb dose-finding study in patients with relapsing-remitting multiple sclerosis.

The study assessed efficacy, safety and tolerability of three ponesimod doses (10 mg, 20 mg or 40 mg) versus placebo, administered orally once daily for 24 weeks. With 464 patients enrolled, this is the largest ever dose-finding study conducted in this autoimmune disorder of the central nervous system.

In this study, ponesimod significantly reduced the cumulative number of new active lesions on monthly magnetic resonance imaging (MRI) brain scans performed from weeks 12 to 24, with the most effective dose at p<0.0001.

Martine Clozel, M.D. and Chief Scientific Officer at Actelion commented: "This is the first report of a selective S1P1 receptor agonist reporting a statistically significant treatment effect in patients suffering from relapsing multiple sclerosis. The relationship between lymphocyte count reduction and efficacy will be an important topic for further scientific scrutiny. The rapid reversibility of lymphocyte count observed upon treatment discontinuation already highlights a key differentiation attribute of this selective S1P1 receptor agonist and its pharmacokinetic profile."

As in previous healthy volunteer studies with ponesimod, average lymphocyte counts in patients with relapsing multiple sclerosis were reduced in a dose-dependent fashion. Average lymphocyte counts returned to baseline values within a week in patients who discontinued treatment with ponesimod.

Guy Braunstein, M.D. and Head of Clinical Development at Actelion commented: "I am very pleased to observe that this large study shows a clear dose response relationship. This gives us confidence that we can identify the appropriate dosing regimen for the upcoming Phase III program."

Despite the small overall number of confirmed relapses in this study, there was also a clinically meaningful effect observed on annualized relapse rate, an important secondary endpoint. Multiple sclerosis is most commonly diagnosed in young adults and is associated with diverse recurrent neurological symptoms.

Ponesimod exhibited an adverse event pattern in this study that, if confirmed in the upcoming Phase III program, would give ponesimod a competitive safety and tolerability profile.

Jean-Paul Clozel, M.D. and Chief Executive Officer commented: "This large Phase IIb study highlights the efficacy of ponesimod and provides us with key information on the potential differentiation of this agent from all other oral MS agents, either marketed or in development. I am very pleased that our drug discovery and development efforts have resulted in such a promising compound."

Once full data analysis has been concluded, Actelion will discuss the details of the upcoming Phase III program with health authorities worldwide. At a later stage, Actelion will discuss and present the findings of this Phase IIb study as well as the Phase III program in scientific presentations and publications.

About S1P receptors

Sphingosine-1-phosphate (S1P) is a phospholipid released by erythrocytes, platelets, mast cells and other cell types. It is currently established that S1P stimulates at least five different cell surface resident G-protein coupled receptors (GPCRs) - S1P1,2,3,4, and 5. Activation of these GPCRs mediates a complex variety of biological responses such as lymphocyte migration, endothelial cell proliferation, blood vessel constriction and heart rate modulation.

About the selective S1P1 agonist ponesimod

Ponesimod is an orally active, selective sphingosine 1-phosphate receptor 1 (S1P1) agonist. Ponesimod prevents lymphocytes from leaving lymph nodes, thereby reducing circulating blood lymphocyte counts and preventing infiltration of lymphocytes into target tissues. The lymphocyte count reduction is rapid, dose-responsive, is sustained with continued dosing and quickly reversed upon discontinuation. Ponesimod does not cause lymphotoxicity: it does not destroy lymphocytes or interfere with their cellular function. Other blood cells of the innate immune system are unaffected and remain available to fight off infection. Ponesimod is therefore considered a promising new oral agent for the treatment of a variety of autoimmune disorders.

Source: Actelion Pharmaceuticals Ltd (02/08/11)

The biotechnological companies Advancell and Neurotec Pharma, both based in Barcelona Science Park (PCB), Spain, have announced the initiation of a clinical Phase IIa study with NT-KO-003, an innovative oral therapy for multiple sclerosis (MS). NT-KO-003 was codeveloped by both companies and its mechanism of action is completely different from the drugs currently used to treat this disease.

The clinical trial, called NeuroAdvan, will be conducted in 105 patients from 11 hospitals in Spain (4 of them in Catalonia) and 3 in Germany, and will be led by Dr Pablo Villoslada, director of Neuroimmunology at IDIBAPS, Hospital Clínic de Barcelona, Spain. The project is being conducted in collaboration with the MRI Analysis and Research Center in Neuroimaging and Multiple Sclerosis (CARM) at the Hospital Vall d'Hebron, Barcelona, led by Dr. Alex Rovira, and also with advice from Dr. Rafael Arroyo at the San Carlos Cinical Hospital, Madrid, Spainm and Dr. Xavier Montalban from Hospital Vall d'Hebron, Spain. Results from the study are expected in late 2012.

MS affects about 30,000 people in Spain according to the Spanish Association of Multiple Sclerosis, and about 2.5 million worldwide, according to World Health Organization (WHO). MS mainly affects young adults (mostly women), aged between 20 and 50. The drugs currently used to treat MS are immunomodulators with significant side effects, limited effectiveness and require parenteral administration (intravenous or subcutaneous), thus making adherence to the therapies difficult.

In animal models during the preclinical phase, NT-KO-003 has demonstrated an anti-inflammatory and neuroprotective effect, rather than an immunosuppressive effect. Consequently, NT-KO-003 can be combined with other drugs when necessary without increasing toxicity and can be administered to nearly all patients affected by the disease. It is also one of the first oral treatments that can potentially slow the progression of MS and reduce the neurological damage caused by the disease.

Because of its neuroprotective mechanism of action, Advancell and Neurotec are exploring the possibility of using NT-KO-003 in the treatment of other neuromuscular diseases, such as amyotrophic lateral sclerosis, which mainly affects men aged between 40 and 70 and causes the death of 50% of patients it in the first three years after the onset of symptoms.

According to the project managers at Advancell, Mercè de Frias, and Neurotec Pharma, Javier Bustos, "the promising results of NT-KO-003 in animals convinced us to start clinical trials in MS patients. We managed to involve doctors and patients' associations in the design of the trial protocol and we believe the study meets the current needs of MS patients"

"At present, the main concern of MS patients is to maintain a good quality of life. They need to stop the progression of the disease, or at least to slow down, and if possible to recover from the serious side-effects. Since MS is a chronic disease that affects young people who are working and have families, new treatments should be easy to manage and should have no side effects, so as not to interfere with patients lives. NT-KO-003 holds great great promise because of its safety and ease-of-use, which are very good, and unlike current drugs it does not alter patients' quality of life, and also because it's mechanism of actionis new and complementary to existing treatments", says Dr. Villoslada. "Furthrmore, all the neurologists participating in this study are really motivated because this treatment has arisen from basic research done by colleagues from our country and may be beneficial to our patients. This is an example of real innovation".

An investment of EUR 2.2 million will be made in this clinical trial, and Advancell and Neurotec Pharma will receive funding support from the Catalan Local Government, through the Nuclis of Technological Innovation Program of ACC1Ó, and from the Ministry of Science and Innovation, through the subprogram INNPACTO, which is part of the National Plan for Scientific Research, Technological Development and Innovation 2008-2011 (IPT-010000-2010-035). Both programs are financed by the European Regional Development Fund (FEDER). The total cost of NT-KO-003 development is about EUR 4 million, with an estimated potential market of around EUR 5.3 billion.

This project will lead to clinical proof of concept of the first molecule arising from Neurotec's research and Advancell reaffirms its business model of developing new drugs to Phase II,. Once the trial has been successfully completed, both companies plan to license the drug to a pharmaceutical company, which will continue its development and bring it to market.

According to the director of the Advancell's Therapeutics Unit, Clara Campàs and Advancell´s CEO, Kenneth Weissmahr, "with this project, Advancell demonstrates its know-how in drug development and shows its commitment to develop projects with significant social and economic return in addition to responding to a difficult disease with significant therapeutic needs "

According to the CEO of Neurotec Pharma, Marco Pugliese, "this clinical trial is the proof that projects born in the universitary environment can be successfully translated to the business world and quickly arrive to the patients thanks to a reprofiling strategy, which is increasingly used to develop new therapies".

Source: Advancell (19/07/11)

A drug used in over-the-counter cough medicine may treat symptoms of multiple sclerosis -- offering inexpensive therapy for a disease with few treatment options, according to UC Davis researchers.

In tests using mice, the drug, dextromethorphan, was found to significantly reduce the loss of myelin, the fatty sheath surrounding nerve fibers in the central nervous system. It also minimized the development of paralysis during MS attacks.

The finding provides an opportunity to pursue a new treatment strategy "with a drug that is widely available, inexpensive and known to be safe," said Wenbin Deng, principal investigator of the study and a UC Davis assistant professor.

MS affects about 400,000 people in the United States and 2.5 million worldwide. It is caused by cells of the immune system attacking the myelin.

Symptoms of the disease vary and often involve periods of motor problems, including paralysis of a limb or poor coordination. It may either go away or become permanent.

As the disease progresses, it causes increased disability and has no known cure, according to a UC Davis Health System press release.

Researchers induced mice to have moderate or severe MS and treated them with either very low or high doses of dextromethorphan. Investigators found that very low amounts given to mice with moderate disease signficantly reduced the loss of myelin and the development of paralysis during acute attacks. High doses didn't help at all.

"Finding that a chemical like dextromethorphan might be useful for treating multiple sclerosis is especially significant because we already know it is safe," said David E. Pleasure, director of research at the Institute for Pediatric Regenerative Medicine at Shriners Hospitals for Children Northern California in Sacramento and one of the authors of the study. "Normally, a possible new treatment must first undergo years of clinical trials to prove this."

Source: The Sacramento Bee Copyright © The Sacramento Bee 2011 (08/07/11)

People suffering from multiple sclerosis may benefit if patent-pending research conducted at Purdue University shows that a decades-old drug approved by the FDA to treat hypertension also delays the onset and reduces the severity of MS symptoms.

Purdue professor Riyi Shi is examining the effects of hydralazine on acrolein, a compound that can affect the central nervous system and damage nerve cells. Acrolein reacts with proteins and lipids that make up cells, including neurons. Hydralazine sequesters acrolein and acrolein-protein compounds, leading to their expulsion from the body.

Shi's research focuses on discovering the effective dosage levels to combat acrolein.

"Hydralazine usage in paediatric patients is 7.5 mg per kg of body weight, but we began testing at a much lower ratio: 1 mg per kg of body weight, which has turned out to be effective in delaying the onset of symptoms and lowering their severity in an animal model of MS," he said. "We have discovered that this dosage level does not cause a significant blood pressure drop or other side effects associated with using higher dosage levels for extended periods of time. We expect that potential use in human MS patients would be at significantly lower doses than the treatment for hypertension."

Hydralazine therapy for MS is not ready for clinical usage said Shi, a medical doctor and a professor of neuroscience and biomedical engineering in Purdue's Department of Basic Medical Sciences, School of Veterinary Medicine, Center for Paralysis Research and Weldon School of Biomedical Engineering.

Shi's first study, published in the journal Neuroscience, tested hydralazine's effectiveness before MS symptoms developed. He will follow up with studies to identify optimal treatment timing and dosage.

"We currently are testing to see if hydralazine can reduce symptoms if treatment starts after they begin," he said. "If the drug continues to prove effective, we have good reason to think it might be useful in human MS patients."

Source: Medical News Today © 2011 MediLexicon International Ltd (16/03/11)

Receptos, Inc., announced that their highly selective sphingosine-1-phosphate receptor 1 (S1P1) agonist, RPC1063, has been administered to the first subject in a single-ascending and multiple-ascending dose design Phase 1 clinical safety study.

The study is being conducted in healthy male and female volunteers at a single site in the United States under an Investigational New Drug (IND) application recently allowed by the FDA. Receptos is developing RPC1063 as a potential treatment for multiple sclerosis.

The study will generate data to confirm that the characteristics of RPC1063 meet pre-specified pharmacokinetic (PK), pharmacodynamic (PD), and safety criteria. These include half-life determination to support once-per-day dosing, and measures that will focus on extent and speed of reversibility of lymphopenia. Safety features will also include observation of cardiovascular, hepatic, lung, and ocular events. The goal of the Phase 1 study will be to utilize the PK-PD relationship of RPC1063 to accurately select dose levels for Phase 2 evaluation.

“The progression of RPC1063 into Phase 1 development marks the evolution of Receptos into a clinical stage organization. The exceptional performance of the development team at Receptos has been demonstrated by their ability to initiate clinical trials for our lead compound within 14 months of our Series A funding round,” said Faheem Hasnain, President and Chief Executive Officer of Receptos. “Clearly our forward focus in the RPC1063 clinical program will be to provide meaningful product candidate differentiation to serve the multiple sclerosis market with this potentially best-in-class S1P1 agonist.”

The Phase 1 study is anticipated to conclude in 2011, paving the way for a Phase 2 Proof of Concept (PoC) study in 2012. In addition, RPC1063 may be investigated in other immune-mediated disorders. The Receptos portfolio of proprietary S1P1 agonist compounds also contains candidates that exhibit diverse molecular and therapeutic profiles that may be used to fully exploit the therapeutic potential of the class.

About S1P1 Agonists and RPC1063

S1P1 is a G protein-coupled receptor (GPCR) that binds the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P is a circulating lipid that binds to five GPCRs termed S1P1-5. S1P1 selectively regulates physiological functions in the immune and cardiovascular systems, including immune cell trafficking and the maintenance of endothelial integrity.

In the disease state of multiple sclerosis, S1P1 agonism works by selectively sequestering circulating lymphocytes, blunting the underlying autoimmune cause of multiple sclerosis. RPC1063, developed in the labs of Receptos, is a novel, highly selective S1P1 agonist exhibiting picomolar potency that is effective in rodent models of multiple sclerosis, and possesses an excellent safety profile in non-clinical toxicology studies. In addition to selectivity, which reduces the likelihood of “off target” side effects, RPC1063 has an appropriately short half-life to promote rapid reversibility of lymphopenia. Patents supporting RPC1063 were exclusively licensed to Receptos from The Scripps Research Institute (TSRI). The discoveries originated in the NIH Molecular Libraries Probe Production Center at TSRI, which is part of the NIH Common Fund Molecular Libraries initiative.

About Receptos

Receptos is a biopharmaceutical company developing best- and first-in-class G protein-coupled receptor (GPCR) therapeutic candidates through information-driven drug discovery, including GPCR structure determination. The company’s lead program is a best-in-class S1P1 small molecule agonist candidate for autoimmune indications, including multiple sclerosis, which has begun Phase 1 clinical testing.

The S1P1 program is supported by the company's proprietary high resolution protein crystal structure of the S1P1 receptor. In November 2009, Receptos completed a $25 million Series A financing and is supported by a seasoned venture capital syndicate including ARCH Venture Partners, Flagship Ventures, Lilly Ventures and Venrock. Receptos has established partnerships on its GPCR structure determination technology platform with Eli Lilly and the Ortho-MacNeil-Janssen subsidiary of Johnson and Johnson.

Source: Business Wire ©2011 Business Wire (28/01/11)

Trophos SA a clinical stage pharmaceutical company developing innovative therapeutics from discovery to clinical validation for indications with under-served needs in neurology and cardiology, announced that Trophos and partners in the MS-Repair consortium delivered an oral presentation detailing Trophos' novel approach in multiple sclerosis (MS) at the recent Society for Neuroscience (SfN) Meeting. The data presented demonstrate that olesoxime, Trophos' lead compound, is a promising candidate for neuroaxonal repair and remyelination in white matter diseases, notably multiple sclerosis. The MS-Repair project is supported by the French Agence Nationale pour la Recherche (ANR).

"Disease progression in MS may reflect chronic and progressive neurodegeneration while relapses only reflect acute focal inflammation of the CNS. Hence, despite recent advances in treating relapses, therapeutic strategies promoting remyelination and providing neuroprotection are now the key needs in MS," said Rebecca Pruss, CSO at Trophos. "We are very pleased to present with our academic partners this important work, which demonstrates the potential for olesoxime to bring a new treatment approach in multiple sclerosis through neuronal protection and remyelination aimed at addressing the long term progression and disability associated with the disease."

The oral presentation of results was: Novel compounds to promote axon repair and remyelination in multiple sclerosis, Bordet et al. It showed that Olesoxime dose-dependently promoted oligodendrocyte maturation and myelination in several in vitro (oligodendrocyte progenitor cells, oligodendrocyte - neuron co-cultures, organotypic brain slice cultures) and two in vivo models (cuprizone and lysophosphatidyl choline induced demyelination).

The results were obtained by a collaboration supported by the ANR project MS-Repair awarded to Trophos and two academic partners in Marseille, Dr Pascale Durbec at the Institut de Biologie du Développement de Marseille Luminy CNRS - Université de la Méditerranée UMR6216 and Dr Angèle Viola at the Centre de Résonance Magnétique Biologique et Médicale CNRS - Université de la Méditerranée UMR6612, in February 2009.

Olesoxime (TRO19622) is the lead compound of Trophos' proprietary cholesterol-oxime compound family of mitochondrial pore modulators, developed for their ability to promote the function and survival of neurons and other cell types under disease-relevant stress conditions through interactions with the mitochondrial permeability transition pore (mPTP). The data announced today show that olesoxime also has the ability to promote remyelination in addition to providing neuroprotection. Olesoxime is currently in two pivotal clinical efficacy studies, the first in over 500 patients with Amyotrophic Lateral Sclerosis with results expected in the fourth quarter of next year (see releases of May 9 2009 and March 17 2010) and the second a recently started pivotal clinical study in Spinal Muscular Atrophy (see release of October 15 2010).

"These data on olesoxime in MS highlight the further strong potential of Trophos' cholesterol oxime mitochondrial pore modulators in neurodegenerative diseases. Multiple sclerosis is one of the more common neurodegenerative diseases with an estimated 1.5 - 2.5 million sufferers globally," added Damian Marron, CEO of Trophos. "We will continue this work to provide a complete package of data that will clearly demonstrate the value and therapeutic positioning of our compounds in multiple sclerosis."

Source: Medical News Today © 2010 MediLexicon International Ltd (26/11/10)

Successfully treating and reversing the effects of multiple sclerosis, or MS, may one day be possible using a drug originally developed to treat chronic pain, according to Distinguished Professor Linda Watkins of the University of Colorado at Boulder.

Watkins and her colleagues in CU-Boulder's department of psychology and neuroscience discovered that a single injection of a compound called ATL313 -- an anti-inflammatory drug being developed to treat chronic pain -- stopped the progression of MS-caused paralysis in rats for weeks at a time.

Lisa Loram, a senior research associate who spearheaded the project in Watkins' laboratory, presented the findings at the Society for Neuroscience's annual meeting held in San Diego this week.

MS is an inflammatory disease where the body's immune system attacks a protective sheath called myelin that encompasses nerves in the spinal cord and brain. As the disease progresses, the myelin develops lesions, or scars, that cause permanent neurological problems.

"What happens now with MS drugs is they slow or stop the progression of MS, but they don't treat it," Watkins said. "They don't take people back to normal because the lesions caused by MS don't heal."

Watkins, Loram and their colleagues hope to use spinal cord and brain-imaging technology to extend their studies to determine if lesions are being healed in rats that received an ATL313 injection.

"If we have a drug that is able to heal these lesions, this treatment could be a major breakthrough in how we treat the symptoms of MS in the future," she said.

The new findings were quite a surprise to Watkins. The team had originally wanted to look at the drug's potential in treating pain associated with MS, because about 70 to 80 percent of MS patients suffer from chronic pain that is not treatable.

"What we had originally thought about this class of compounds is that they would calm down glial cells in the spinal cord because their pro-inflammatory activation is what causes pain," she said.

Under normal circumstances glial cells are thought to be like housekeepers in the nervous system, Watkins said, essentially cleaning up debris and providing support for neurons. Recent work by Watkins and others has shown that glial cells in the central nervous system also act as key players in pain enhancement by exciting neurons that transmit pain signals.

"What's become evident is that glial cells have a Dr. Jekyll and Mr. Hyde personality," Watkins said. "Under normal circumstances they do all these really good things for the neurons, but when they shift into the Mr. Hyde formation they release a whole host of chemicals that cause problems like neuropathic pain and other chronic pain conditions."

They discovered that ATL313 appears to reset the glial cells from an angry activated state to a calm anti-inflammatory state that may heal MS lesions.

Contributing to the findings presented at the Society for Neuroscience annual meeting were Watkins, Loram, Keith Strand, Derick Taylor, Evan Sloane and Steven Maier of CU-Boulder; Jayson Rieger of the company PGxHealth, a division of Clinical Data Inc. based in Newton, Mass.; and Natalie Serkova of the University of Colorado Denver's Anschutz Medical Campus.

The study was funded by PGxHealth and grants from the state of Colorado's CO-Pilot program, the National Institutes on Drug Abuse and the National Institute on Neurological Disease and Stroke.

Source: Science News (19/11/10)

Provid Pharmaceuticals, Inc, a drug discovery company, and Fast Forward, LLC, the National Multiple Sclerosis Society's subsidiary devoted to bridging the gap between research and drug development, today announced an expansion of their partnership to support Provid's preclinical studies of their candidate MS drug, PV-267. 

This novel, highly selective small molecule is designed to block a critical step in the autoimmune process of MS, which leads to the destruction of the body's protective myelin in the central nervous system and to the ultimate accumulation of disability. 

The expanded partnership will enable Provid to enhance knowledge of the immune mechanisms involved in the activity of PV-267, paving the way for future development and clinical studies.  The biological studies will be carried out by Dr. Thomas Forsthuber, Provid's collaborator and a leading immunologist at the University of Texas San Antonio. 

"The partnership between Fast Forward and Provid was begun in May 2009 and helped fund important research," noted Dr. Gary Olson, Provid's President and CEO.  "In these studies, PV-267 was shown to be active in an animal model of MS in transgenic mice that carry the human gene for HLA-DR2, a disease-associated molecule that is involved in the attack of the immune system on myelin, the insulating protein on nerves that are damaged in MS."  Dr. Olson added, "DR2 is present in about 60% of the MS population and PV-267 was designed to be a potent and selective blocker of DR2.  This specificity suggests that PV-267 could have a better safety profile compared with immune-modifying therapies since it will not affect other, normal immune responses." 

The partnership with Provid is one of a series of partnerships between Fast Forward and early stage biotechnology companies. "The results of our initial funding of the PV-267 project are very encouraging, which prompts us to extend our partnership with Provid to continue development of this promising new approach to treating MS," said Dr. Timothy Coetzee, Fast Forward's President. 

The National Multiple Sclerosis Society funds research in a wide range of scientific areas including immune mechanisms, genetics, nerve regeneration, and symptom managements.  The agreement with Provid is a part of the Society's Fast Forward initiative through which Fast Forward will partner with early stage biotechnology and pharmaceutical companies to develop treatments, diagnostics, medical devices, and related technologies to treat, reverse, and ultimately cure MS.  Under terms of the agreement, Fast Forward will provide Provid with funds to support pre-clinical studies with PV-267.  In addition, Fast Forward will receive warrants for purchase of shares in the company.

Source: Provid Pharmaceuticals, Inc. (18/11/10)

Roche Holding AG Friday said mid-stage trials of a experimental multiple sclerosis medicine ocrelizumab showed the drug to significantly reduce disease activity in patients with relapsing-remitting multiple sclerosis, raising hopes the medicine could make it to the market and eventually turn into a blockbuster.

Developed by U.S.-based Biogen Idec Inc (BIIB) and Roche unit Genentech, ocrelizumab was recently abandoned in treating patients suffering from rheumatoid arthritis due to an unfavourable risk profile, raising concerns the drug could be discarded in other indications, a step that would have weakened Roche’s pipeline.

Roche said that a 24 week phase II trial showed a substantial reduction of brain lesions and the relapse rate of multiple sclerosis patients. When administered at a dose of 2,000 milligrams, the reduction of brain lesions was 96% and at 89% at a dose of 600 milligram when compared to placebo.

“These efficacy results are amongst the most remarkable seen in a phase II … study, and show that ocrelizumab may have the potential to offer benefits to patients with this disease,” said Professor Ludwig Kappos, lead investigator of the study, from the Department of Neurology, University Hospital Basel, Switzerland.

The study involved 220 patients, comparing ocrelizumab to placebo in patients with relapsing-remitting multiple sclerosis, the most common form of this autoimmune disease that affects around 1.5 million people worldwide.

“We are strongly encouraged by these data and the possibility that ocrelizumab could become a new option for patients with multiple sclerosis,” said Hal Barron, Roche’s Chief Medical Officer. “We believe in the potential of ocrelizumab and look forward to exploring it further in the final phase of clinical development.”

Given these study results, chances for a potential approval are rising and could give Roche a sizable stake in the $10 billion multiple-sclerosis market even though ocrelizumab is administered via infusions, albeit only about twice a year depending on the treatment methodology. Earlier this year, cross-town rival Novartis AG  received approval to market its multiple sclerosis drug Gilenya, which is administered orally in pill form.

Given this easy regime, Gilenya is expected to reach peak sales of more than $ 3 billion, and could, according to analysts, give Novartis a lead over competitors such as Irish drug maker Elan Corp. PLC, U.S.-based Biogen Idec Inc. and Germany’s Merck KGaA, whose drugs have to be administered more often via injections and infusions.

“The data still lacks a few missing pieces, but if it is what it looks like … ocrelizumab has a … strong efficacy profile, especially in relapse rates,” said Vontobel pharma analyst Andrew Weiss.

Source: Adjmediator's Blog (13/11/10)

Biogen Idec Inc. and Genentech said Thursday they amended their development agreement on a potential multiple sclerosis treatment.

Genentech, a unit of Swiss drug developer Roche, will now have responsibility for the further development of ocrelizumab in multiple sclerosis and will fund all the costs going forward. Biogen will receive tiered, double-digit royalties on U.S. sales that will approximate its current 30 percent interest in the compound.

Ocrelizumab recently completed a midstage study with positive results.

The companies are already partners on the drug Rituxan and said the sale of ocrelizumab will not impact that current profit-sharing deal.

Also, Biogen will increase its share of the losses and profits related to the development and sales of GA101 in the US to 35 percent from 30 percent. GA101 is aimed at treating chronic lymphocytic leukemia and non-Hodgkin lymphoma. Once that drug reaches certain sales milestones, Biogen's share of the profits of Rituxan will decrease to 35 percent from 40 percent.

Source: Bloomberg ©2010 Bloomberg L.P. (22/10/10)

Biotest has obtained positive pre-clinical data
indicating the potential of BT-061 for the treatment of multiple sclerosis
(MS).

Current scientific publications by respected academic research groups show that the regulatory T-cells in particular play a central part in the development and progression of MS; impairment of their function in the patient appears to be causally linked with the disease. The monoclonal antibody BT-061 specifically activates regulatory T-cells. The pre-clinical data that have now been obtained show that BT-061 reinforces the function of regulatory T-cells derived from MS patients.

´We are very pleased that the data now available confirm our expectations that the immunomodulatory mechanism of action of BT-061 has considerable potential in the indication MS, ´ comments Dr. Frank Osterroth, director of the Biotherapeutics Division at Biotest, on the data. ´Particularly in MS, there is still a significant medical need for effective and better tolerated and safe active agents despite modern approved products´.

Further pre-clinical analyses are now aimed at preparing for the clinical
trial of BT-061 in the indication MS. Evidence is to be sought on which
patient populations might respond particularly well to therapy with BT-061.
The analyses will be conducted in collaboration with leading academic study
groups working in this area.

To deal with this and other questions, Biotest has joined the ´New active
agents for neurological diseases´ consortium (Neu² Konsortium). This is a
consortium of institutes and pharmaceutical companies that work on the
development of new active agents to treat neurological diseases, supported
by the German Federal Ministry of Education and Research (BMBF). The
consortium represents an optimal platform for further studies focused on
clinical development.

The decision-making body of the Neu² Konsortium voted unanimously to
support the development programme of BT-061 in MS and this decision has now been confirmed by the BMBF.

The approved support programme extends over a three-year period and may also include a phase IIa clinical trial, which will investigate the
potential of BT-061 in patients with MS (proof-of-concept trial).

BT-061 reinforces one of the body´s natural functions to prevent extreme
immune reactions. It is therefore being developed for the treatment of
diseases due to an over-reaction of the immune system. Three clinical
studies are currently underway in the lead indications rheumatoid arthritis
and chronic plaque psoriasis. Based on the data available so far, promising
efficacy and generally good safety and tolerability have been shown for
both indications.

Source: Biotest AG (21/10/10)

Roche Holding AG and Biogen Idec Inc reported data from a mid-stage trial of their experimental multiple sclerosis drug ocrelizumab on Friday that showed one patient died of an inflammatory condition.

Data presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) showed that the drug reduced disease activity by a significant amount as measured by the number of brain lesions and relapse rate. But some side effects were greater in the ocrelizumab arm than in the placebo arm.

In May, Roche of Switzerland and Biogen of Cambridge, Massachusetts, said they would discontinue studies of the drug as a treatment for rheumatoid arthritis after a safety monitoring board ruled that the risk outweighed the benefit in the RA population.

The decision followed reports of serious infections, some of which were fatal, as well as opportunistic infections -- or infections that do not normally occur in healthy people.

The companies said that in the latest 220-patient MS trial no opportunistic infections were reported, and they said no causal link had been established between ocrelizumab and the patient death from systemic inflammatory response syndrome (SIRS). Roche said exhaustive analysis showed the condition in this case was not sparked by an infection, even though it sometimes can be.

There were no cases of SIRS in the placebo group or among patients who received the lower of the two doses of ocrelizumab. However, 1.8 percent of patients -- or one out of 55 -- who took the higher dose developed the condition.

Infusion-site reactions such as swelling were higher in the ocrelizumab group than in the placebo group -- with 34.5 percent of those taking the lower dose and 43.6 percent taking the higher dose experiencing a reaction compared with 9.3 percent in the placebo group. The reactions were in general mild to moderate, the companies said, and the reports decreased during the second infusion.

In general, the companies said, the serious side effect profile was similar in all treatment groups, with the drug showing strong efficacy.

The total number of brain lesions detected by magnetic resonance imaging (MRI) in the study was reduced by 96 percent in the higher-dose group and 89 percent in the lower-dose group compared with placebo.

"We are strongly encouraged by these data and the possibility that ocrelizumab could become a new option for patients with MS," said Dr. Hal Barron, chief medical officer at Roche. "We believe in the potential of ocrelizumab and look forward to exploring it further in the final phase of clinical development."

Patients will be treated for up to 96 weeks, receiving ocrelizumab infusions every 24 weeks.

Source: Reuters © Copyright 2010 Thomson Reuters (20/10/10)

Roche and Biogen Idec announced 24-week results from a phase II study of ocrelizumab in patients with relapsing-remitting multiple sclerosis (RRMS), the most common form of the disease.

Ocrelizumab demonstrated a significant reduction in disease activity as measured by brain lesions and relapse rate. Patients with RRMS suffer from relapses and disabling symptoms caused by nerve damage which can significantly affect their quality of life.

“These efficacy results are amongst the most remarkable seen in a phase II RRMS study, and show that ocrelizumab may have the potential to offer benefits to patients with this disease”

Reductions in total number of brain lesions detected by magnetic resonance imaging (MRI) scans (the primary endpoint of the study) were highly significant at 96% for 2000mg ocrelizumab and 89% for 600mg ocrelizumab compared to placebo. Disease activity was also measured by reduction in annualized relapse rate (ARR), the rate of attacks or flare-ups per patient-year. At week 24, ARR was significantly lowered versus placebo with a reduction of 73% for ocrelizumab 2000mg and 80% for ocrelizumab 600mg.

"These efficacy results are amongst the most remarkable seen in a phase II RRMS study, and show that ocrelizumab may have the potential to offer benefits to patients with this disease," said Professor Ludwig Kappos, lead investigator of the study, from the Department of Neurology, University Hospital Basel, Switzerland.

"We are strongly encouraged by these data and the possibility that ocrelizumab could become a new option for patients with MS," commented Hal Barron, M.D., executive vice president, Product Development and chief medical officer. "We believe in the potential of ocrelizumab and look forward to exploring it further in the final phase of clinical development."

Both ocrelizumab doses were generally well tolerated and no opportunistic infections were reported. Serious adverse events (SAEs) were similar in all treatment groups. Infusion-related events during first infusion, predominantly mild to moderate, were more common with ocrelizumab (34.5% and 43.6%) than placebo (9.3%). However, these reports decreased during the second ocrelizumab infusion and were comparable to those initially reported with placebo.

Source: Roche Inc. and Biogen Idec (16/10/10)

Innate Therapeutics today announced that the company has begun treating patients in a Phase 2a clinical study of its lead molecule, MIS416, in patients with progressive multiple sclerosis (MS).

“MIS416 is believed to work through a combination of mechanisms involving the down regulation of chronic inflammation, reduction of autoimmune factors, and the repair of damaged tissue,” said Simon Wilkinson, Innate Therapeutics chief executive officer.

“MS is the most common progressive and disabling neurological condition in young adults. More than half of the patients initially diagnosed with the relapsing-remitting form of the disease go on to develop progressive MS, for which there currently are no approved therapies. Thus, there is an obvious and important unmet medical need for new treatments.”

Mr. Wilkinson noted that Innate Therapeutics had chosen MS as its initial disease target because of encouraging results of testing of MIS416 in a small number of New Zealand patients who had early access (under the NZ Medicines Act) to the drug on compassionate grounds, and because of US$550,000 funding received from the US not-for-profit, Fast Forward.

Established by the United States National Multiple Sclerosis Society and part funded by EMD Serono, Inc., an affiliate of Merck KGaA, Darmstadt, Germany, Fast Forward is committed to providing support to accelerate the development of research discoveries into new or improved therapies for people with MS. Innate has additionally received NZ$600,000 in support of the development of MIS416 from the NZ Foundation for Research, Science and Technology (FRST).

The study, to be conducted at the Primorus clinical trial unit in Christchurch, New Zealand, will enroll a total of 24-30 patients. The initial stage of the trial, involving the first 12-18 patients, will examine the safety, tolerability and pharmacokinetics of intravenously administered MIS416 to determine a recommended therapeutic dose and dosing interval for the confirmatory portion of the trial. The dose confirmation portion of the study will treat patients weekly at the recommended dose level for a period of six months. Besides safety and tolerability, the end point for this confirmatory portion of the study will be to document any changes in MS clinical status, as determined by several standard MS scales for clinical evaluation, as well as frequency of relapses and signs of clinical activity on serial brain MRI scans. Innate Therapeutics expects to complete the study around the end of 2011.

Innate Therapeutics is additionally conducting preclinical studies with MIS416 in other applications, including as a potential co-therapy with other treatments for cancer, and in the treatment of infectious diseases.

About MIS416

MIS416 is the lead product from Innate Therapeutics’ proprietary microparticle immune stimulant (MIS) technology. In addition to its potential use in MS, the company is conducting preclinical studies of MIS416 in other applications, including oncology co-therapy and the treatment of infectious diseases. MIS technology is based on the use of a bacterially derived, therapeutic microparticle incorporating multiple naturally occurring ligands, which when administered can activate synergistic innate immune signaling pathways. By activating and/or regulating important innate system mechanisms, Innate Therapeutic’s microparticle immunomodulator technology presents a new way to fight infections and certain cancers, and to treat select autoimmune diseases.

Source: Innate Therapeutics Limited (11/10/10)

GlaxoSmithKline PLC and Genmab A/S will end the development of an intravenous form of a drug intended to treat autoimmune diseases like lupus and multiple sclerosis, and focus on an injectable version.

The companies said an injectable version of Arzerra (ofatumumab) should be more convenient for patients and have fewer side effects. The drug can also be used to treat rheumatoid arthritis.

Based on from a recent study of Arzerra in multiple sclerosis, GlaxoSmithKline will start a new trial of the drug in 2011. The results from that study were announced Friday. GlaxoSmithKline is solely responsible for developing the drug as a treatment for autoimmune disorders. The companies are codeveloping the drug as a treatment for cancer.

Arzerra is approved as a treatment for chronic lymphocytic leukemia in patients who have received at least one previous therapy. The companies are also testing it as a treatment for newly diagnosed chronic lymphocytic leukemia, and lymphoma.

Source: Bloomburb Business Weak ©2010 Bloomberg L.P (17/09/10)

A clinical trial to test a promising new multiple sclerosis therapeutic gets underway in Christchurch later this month.

The therapeutic, developed by Auckland biopharmaceutical company Innate Therapeutics, also has the potential to fight certain cancers and infectious diseases.

The trial will test MIS416, a naturally occurring agent derived from bacteria, in people with progressive multiple sclerosis (MS). The trial has begun recruiting patients and will be conducted at the Primorus Clinical Trials purpose-built unit in Christchurch.

Innate Therapeutics has sourced New Zealand and American funding for the trial. The Foundation for Research, Science and Technology (FRST) is investing NZ$600,000 through TechNZ, its business assistance programme. This is being matched with US$550,000 from the US not-for-profit, Fast Forward. Established by the United States National Multiple Sclerosis Society, Fast Forward is committed to providing support to accelerate the development of research discoveries into new or improved therapies for people with MS.

US and New Zealand MS specialists say MIS416 has the potential to change the landscape for people living with MS. It is understood to work by a combination of mechanisms involving down-regulation of chronic inflammation, reduction of autoimmune factors, and damaged tissue repair. There are currently no drugs specifically approved to treat the progressive forms of MS in New Zealand.

Innate Therapeutics’ CEO, Simon Wilkinson, said the company had chosen MS as its initial disease target because of very encouraging signs in a small number of patients who had early access (under the Medicines Act) to the drug on compassionate grounds and because of the funding from Fast Forward.

“We are delighted to gain the substantial funding invested by TechNZ and Fast Forward, which has allowed us to begin this important trial. The ongoing difficulty for small biotechs anywhere is funding and the mechanism that the US MS Society has established with Fast Forward encourages researchers and developers, such as ourselves, to come forward with candidates,” he said.

“However, as we have already found, the involvement with Fast Forward is more than about the dollars. We now have access to their networks and clinical expertise. MS is an exciting field to be in. For a therapeutic to be able to stop the progression of this debilitating condition is exciting. The wow factor would be seeing the partial reversal of symptoms.”

The Foundation for Research, Science and Technology’s General Manager Manufacturing and High Growth Firms, Richard Bentley, says the TechNZ investment was awarded with two key benefits in mind – for people living with MS and for New Zealand’s clinical trials sector.

“We think this investment has the potential to make a huge difference to developing a new therapy. Local clinical trial teams will also gain invaluable experience through working with international experts and other companies. This type of experience is hugely beneficial when it comes to building national capability. And the potential of economic gains to come with a successful trial, through licensing deals, is very exciting,” Mr Bentley said.

Fast Forward’s President Timothy Coetzee says: “The promise of current research like that undertaken by Innate Therapeutics to change the MS landscape is exciting and we are delighted to provide this support to speed the development of this new therapy that has the potential to help people living with MS”.

The Multiple Sclerosis Society of New Zealand’s National Director, Rosie Gallagher, says the society is extremely excited about the prospect of a new medication for those with progressive MS.

“There has been very little progress in terms of disease therapies for those with this type of MS and the fact that it is being developed by a Kiwi company and trialled within New Zealand is a great highlight for us. We offer our full support to this venture and hope for an outcome which will benefit those who are struggling with the effects of this devastating condition.”

Co-principal investigators for the Phase 2A trial are Primorus’ Medical Director and clinical trials specialist Dr Alison Luckey and Professor Tim Anderson. Professor Anderson is a consultant neurologist with the Canterbury District Health Board; Professor in the Department of Medicine, University of Otago, Christchurch; and Acting Director at the Van der Veer Institute for Parkinsons and Brain Research.

The initial stage of the trial aims to establish the recommended therapeutic dosage level of MIS416 administered weekly over a four week period in 12 to 18 patients. A dose confirmation stage will follow when 12-18 patients will be treated with the recommended dosage level weekly for a six month period.

With trials proceeding according to schedule, Innate Therapeutics estimates the drug could be on the market by 2016.

The company confirms it is also conducting preclinical studies using MIS416 in other applications, including oncology co-therapy and the treatment of infectious diseases.

About Innate Therapeutics

Innate Therapeutics Limited is a public unlisted biopharmaceutical company based in Auckland. The company is focussed on the development of a new generation of immune response modifiers for potential use in the treatment of MS and other autoimmune diseases, a range of infectious diseases, certain cancers, and as a novel cellular and humoral adjuvant.

Source: Scoop Independent News - Health (16/09/10)

A medication used to treat asthma and COPD has been found to improve clinical outcomes for patients with multiple sclerosis, especially during the first year following diagnosis.

The asthma drug decreases blood levels of interleukin 12 that also promotes a type of helper T cell thought to destroy the myelin sheath in multiple sclerosis patients.

Multiple sclerosis is associated with high levels of interleukin 12, found in patients with the chronic inflammatory disease. Albuterol sulfate relaxes the airways for asthma patients and is also thought to lower levels of interleukin.

In a new study, patients given a combination of Albuterol and glatiramer acetate experienced improvement in symptoms of the disease at 6 and 12 months, compared to a group given placebo plus glatiramer. No benefit was seen at 24 months. Interleukin 12 levels declined after one year.

Asthma Drug Delays MS Relapse
Another benefit found in the two year study, that included 39 patients, was longer time before relapse of multiple sclerosis symptoms. Of the 39 patients, 3 experienced significant side effects of leg weakness, chest tightness and reaction at the site of glatiramer injection.

All of the patients received a neurological exam at the start of the study and again at six, 12, 18 and 24 months. Blood samples were also collected during the study, at three, six and 12 months. The researchers used MRI to evaluate brain response at the beginning of the study, at 12 months and again at two years.

The study authors concluded Albuterol, used to treat respiratory disorders, improves symptoms in patients with multiple sclerosis, combined with glatiramer injections, during the first year of therapy.

Arch Neurol. 2010;67[9]:1055-1061

Source: Emax Health Copyright eMaxhealth.com 2005-2010. (14/09/10)

XenoPort, Inc. announced that it plans to move arbaclofen placarbil (AP), also known as XP19986, into Phase 3 development as a potential treatment of spasticity in multiple sclerosis (MS) patients.

Following discussions with the U.S. Food and Drug Administration (FDA), XenoPort intends to conduct a single placebo-controlled Phase 3 efficacy clinical trial and an open-label, long-term, safety study of AP in patients with MS.

Favourable results from these studies could lead to the filing of a new drug application (NDA) with the FDA under Section 505(b)(2) seeking approval of AP for the treatment of spasticity.

Ronald W. Barrett, chief executive officer of XenoPort, stated, "In our previous Phase 2 clinical trial in spinal cord injury patients with spasticity, AP was well tolerated and demonstrated dose-dependent improvement in muscle tone that was maintained throughout the twelve-hour dosing interval. We hope to demonstrate similar results in our Phase 3 trial of AP in MS patients with spasticity."

Randall Schapiro, M.D., Clinical Professor of Neurology at the University of Minnesota and President of the Schapiro Multiple Sclerosis Advisory Group, stated, "Available treatments do not fully address the needs of MS patients with spasticity. Baclofen is often used in these patients, but its short duration of action and central nervous system side effects can result in sub-optimal therapy. A new oral medicine that could maintain efficacy with limited adverse events would be a welcome addition to the spasticity treatment armamentarium."

XenoPort intends to initiate this Phase 3 clinical program in the first half of 2011. The pivotal trial would be a multi-center, randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of AP as a treatment for spasticity in MS patients.

Patients who complete this study would have the option to enter a long-term study to evaluate the safety of AP in MS patients.

Following successful outcomes from these studies, XenoPort would file an NDA with the FDA using the 505(b)(2) application process. The 505(b)(2) application would enable XenoPort to reference published literature and the FDA's previous finding of safety and effectiveness for baclofen, a drug that has been approved by the FDA for the alleviation of signs and symptoms of spasticity resulting from MS.

About Arbaclofen Placarbil (AP)

AP is a patented new chemical entity that is a Transported Prodrug of R-baclofen designed to engage natural nutrient transport mechanisms found on intestinal cell membranes, thereby gaining efficient entrance into the bloodstream. AP is then rapidly converted by high-capacity enzymes to the parent compound and natural substances with favourable safety characteristics. R-baclofen is an agonist of the target known as gamma amino-butyric acid(B), or GABA(B), receptor. Baclofen, which is a mixture of the R- and S-isomers, is an approved treatment for spasticity that is administered three or four times a day.

XenoPort has completed a successful Phase 2 clinical trial of AP in patients with spasticity due to spinal cord injury. AP treatment was associated with statistically significant differences from placebo at all time points in the 20 mg and 30 mg twice-a-day AP dose cohorts. AP was well tolerated at all dose levels.

Source: MarketWatch Copyright © 2010 MarketWatch, Inc. (13/09/10)

Genmab announces 48 week results from a Phase II study of ofatumumab in RRMS.

Genmab A/S announced encouraging results from an ofatumumab Phase II safety and pharmacokinetics study in patients with relapsing-remitting multiple sclerosis (RRMS).

A total of 38 patients were included in this double-blind, dose escalation trial. Patients were randomized to receive two infusions of 100 mg, 300 mg or 700 mg of ofatumumab or placebo. After 24 weeks, the patients randomized to placebo were treated with ofatumumab and patients who were treated with ofatumumab received placebo. All patients were then followed for an additional 24 weeks.

In the study, there were no dose limiting toxicities, no unexpected safety findings, and no patients tested positive for human anti-human antibodies. Efficacy was assessed by MRI (magnetic resonance imaging) as a secondary endpoint. Repeated MRI scans showed a sustained reduction in the number of brain lesions up to week 48 in patients (n=26) who were treated with ofatumumab followed by placebo. Patients who received placebo followed by ofatumumab (n=12) showed similar 24 week results to those who were treated with ofatumumab followed by placebo.

About ofatumumab

Ofatumumab is a novel human monoclonal antibody. It targets a part of the CD20 molecule on B-cells encompassing an epitope in the small loop.

Ofatumumab is being developed under a co-development and commercialization agreement between Genmab and GlaxoSmithKline. Ofatumumab is not yet approved in any country for relapsing-remitting multiple sclerosis.

Source: Market Watch Copyright 2010 GlobeNewswire, Inc (13/09/10)

Genentech Inc. is licensing a human monoclonal antibody for autoimmune diseases.

Financial terms and other aspects of the deal between the South San Francisco-based unit of Swiss drug maker Roche and NovImmune of Switzerland were not disclosed.

Genentech will get access to an anti-IL-17 fully humanized monoclonal antibody and backup antibodies, the companies said. The antibody is in late-stage development by NovImmune researchers, the company said.

IL-17, or Interleukin 17, is a protein molecule secreted by immune system cells that appears to promote inflammation by advancing the production of more cytokines. That pathway could be used to treat diseases like rheumatoid arthritis, multiple sclerosis and asthma.

“We are hopeful that (the antibody) has the potential to benefit patients across a range of autoimmune diseases,” James Sabry, vice president of Genentech partnering, said in a news release.

Source: San Francisco Business Times © 2010 American City Business Journals, Inc (27/07/10)

BACKGROUND: Partial blockade of voltage-gated sodium channels is neuroprotective in experimental models of inflammatory demyelinating disease. In this phase 2 trial, we aimed to assess whether the sodium-channel blocker lamotrigine is also neuroprotective in patients with secondary progressive multiple sclerosis.

METHODS: Patients with secondary progressive multiple sclerosis who attended the National Hospital for Neurology and Neurosurgery or the Royal Free Hospital, London, UK, were eligible for inclusion in this double-blind, parallel-group trial. Patients were randomly assigned via a website by minimisation to receive lamotrigine (target dose 400 mg/day) or placebo for 2 years. Treating physicians, evaluating physicians, and patients were masked to treatment allocation. The primary outcome was the rate of change of partial (central) cerebral volume over 24 months. All patients who were randomly assigned were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT00257855.

FINDINGS: 120 patients were randomly assigned to treatment (87 women and 33 men): 61 to lamotrigine and 59 to placebo. 108 patients were analysed for the primary endpoint: 52 in the lamotrigine group and 56 in the placebo group. The mean change in partial (central) cerebral volume per year was -3.18 mL (SD -1.25) in the lamotrigine group and -2.48 mL (-0.97) in the placebo group (difference -0.71 mL, 95% CI -2.56 to 1.15; p=0.40). However, in an exploratory modelling analysis, lamotrigine treatment seemed to be associated with greater partial (central) cerebral volume loss than was placebo in the first year (p=0.04), and volume increased partially after treatment stopped (p=0.04). Lamotrigine treatment reduced the deterioration of the timed 25-foot walk (p=0.02) but did not affect other secondary clinical outcome measures. Rash and dose-related deterioration of gait and balance were experienced more by patients in the lamotrigine group than the placebo group.

INTERPRETATION: The effect of lamotrigine on cerebral volume of patients with secondary progressive multiple sclerosis did not differ from that of placebo over 24 months, but lamotrigine seemed to cause early volume loss that reversed partially on discontinuation of treatment.

Future trials of neuroprotection in multiple sclerosis should include investigation of complex early volume changes in different compartments of the CNS, effects unrelated to neurodegeneration, and targeting of earlier and more inflammatory disease.

Kapoor R, Furby J, Hayton T, Smith KJ, Altmann DR, Brenner R, Chataway J, Hughes RA, Miller DH.

Department of Neuroinflammation, National Hospital for Neurology and Neurosurgery and the Institute of Neurology, Queen Square, London, UK.

Source: Lancet Neurol. 2010 Jul;9(7):647-8. Copyright 2010 Elsevier Ltd. & Pubmed PMID: 20621711 (14/07/10)

Angiotensin II sustains brain inflammation in mice via TGF-β

The renin-angiotensin-aldosterone system (RAAS) is a key hormonal system regulating blood pressure. However, expression of RAAS components has recently been detected in immune cells, and the RAAS has been implicated in several mouse models of autoimmune disease.

Here, we have identified Ang II as a paracrine mediator, sustaining inflammation in the CNS in the EAE mouse model of MS via TGF-β. Ang II type 1 receptors (AT1Rs) were found to be primarily expressed in CNS-resident cells during EAE.

In vitro, astrocytes and microglia responded to Ang II treatment by inducing TGF-β expression via a pathway involving the TGF-β–activating protease thrombospondin-1 (TSP-1).

TGF-β upregulation in astrocytes and microglia during EAE was blocked with candesartan (CA), an inhibitor of AT1R.

Treatment of EAE with CA ameliorated paralysis and blunted lymphocyte infiltration into the CNS, outcomes that were also seen with genetic ablation of AT1Ra and treatment with an inhibitor of TSP-1.

These data suggest that AT1R antagonists, frequently prescribed as antihypertensives, may be useful to interrupt this proinflammatory, CNS-specific pathway in individuals with MS.

Full article - http://www.jci.org/articles/view/41709?key=8f0637504b7a09b96526

Tobias V. Lanz^1,2, Zhaoqing Ding¹, Peggy P. Ho¹, Jian Luo¹, Ankur N. Agrawal¹, Hrishikesh Srinagesh¹, Robert Axtell¹, Hui Zhang¹, Michael Platten², Tony Wyss-Coray^1,3 and Lawrence Steinman¹

¹Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
²Department of Neurooncology, University Hospital Heidelberg, and German Cancer Research Center, Heidelberg, Germany.
³Geriatric Research Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, USA.

Authorship note: Tobias V. Lanz, Zhaoqing Ding, and Peggy P. Ho contributed equally to this work.

Source: The Journal Of Clinical Investigation  Clin Invest. doi:10.1172/JCI41709 © 2010, The American Society for Clinical Investigation. (13/07/10)

Genmab A/S announced today positive interim results from an ofatumumab Phase II safety and pharmacokinetics study in patients with relapsing-remitting multiple sclerosis (RRMS).

A total of 38 patients were included in the trial, of which 12 patients received placebo and 26 patients received ofatumumab intravenously. Patients were treated with ofatumumab at the dose levels of 100 mg, 300 mg or 700 mg and followed for 24 weeks.

There were no dose limiting toxicities, no unexpected safety findings and the rates of infection were comparable between the groups. Efficacy was assessed as a secondary endpoint. Although the study included a small number of patients, statistically significant reductions in the number of brain lesions (gadolinium-enhancing T1 lesions and new/enlarging T2 lesions) as measured on serial MRI scans from week 8 to week 24 were seen on ofatumumab as compared to placebo and the reductions were seen in all dose groups.

“We are encouraged by the first results from this initial Phase II study of ofatumumab in RRMS, and are looking forward to seeing the full study results later this year,” said Prof. Jan G.J. van de Winkel, Ph.D., Chief Executive Officer of Genmab.

About the study
This double blind, randomized, dose-escalation trial includes patients with RRMS with demonstrated disease activity as evidenced by recent occurrence of relapses and/or MRI activity. Patients are randomized to receive two infusions of 100 mg, 300 mg or 700 mg of ofatumumab or placebo.

After 24 weeks, the patients randomized to placebo will be treated with ofatumumab and patients who received ofatumumab will receive placebo. Thus, each patient will receive two administrations of ofatumumab with 24 weeks follow-up, resulting in a total treatment period of 48 weeks duration.

The objective of the study is to evaluate the safety of three doses of ofatumumab in patients with RRMS. The primary endpoints of the study were safety and pharmacokinetics.

About ofatumumab
Ofatumumab is a novel human monoclonal antibody. It targets a part of the CD20 molecule on B-cells encompassing an epitope in the small loop.

Ofatumumab is being developed under a co-development and commercialization agreement between Genmab and GlaxoSmithKline. Ofatumumab is not yet approved in any country for RRMS.

Source: Drugs.com  © 2000-2010 Drugs.com (07/07/10)

Japanese scientists used mice to show that bortezomib, currently used to treat cancers that affect white blood cells, induces cell death only in harmful (active and proliferating) T cells, leaving the rest unharmed.

If the results prove true in humans, it offers hope that this drugs or others similar to it might be used to treat inflammatory diseases without the side effects of current drugs that affect all T cells equally.

"Unfortunately, there are a lot of people who are suffering from autoimmune and inflammatory disease," said Koichi Yanaba, a scientist from the Department of Dermatology at Nagasaki University Graduate School of Biomedical Sciences who was involved in the research.

"We believe that this new-type remedy for autoimmune and inflammatory disease could successfully treat them in the near future," Yanaba added.

To make this discovery, scientists used two groups of mice—the first treated with bortezomib and the second with saline. Researchers induced contact hypersensitivity reaction with oxazolone, a chemical allergen used for immunological experiments and found that bortezomib significantly inhibited the contact hypersensitivity responses.

Results strongly suggest that bortezomib treatment enhanced T cell death by inhibiting NF-kappa B activation, which plays a key role in regulating the immune response to infection.

This in turn led to the suppression of inflammatory responses in immune cells by reducing interferon-gamma production.

The study has been published in the July 2010 print issue of the Journal of Leukocyte Biology.

Source: The Times Of India  © 2010 Bennett, Coleman & Co. Ltd. (01/07/10)

Compugen Ltd. announced today that administration of CGEN-15001 in an animal model of multiple sclerosis (MS) has been shown to completely abolish spontaneous relapses.

In addition, administration of this novel molecule prior to disease onset demonstrated a pronounced delay of disease onset and a significant decrease in disease symptoms.

These results, together with complementary results from earlier studies, strongly support a significant potential therapeutic utility for CGEN-15001 in the treatment of multiple sclerosis and other autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and type 1 diabetes.

CGEN-15001 is a soluble recombinant fusion protein comprised of the extracellular region of a Compugen discovered B7/CD28 family member, designated CGEN-15001T. CGEN-15001T, which itself has potential medical utilities - such as serving as a target for antibody therapeutics - was discovered by Compugen through the use of its LEADS platform and a proprietary algorithm designed to predict novel members of known protein families. Patents have been filed for both CGEN-15001 and CGEN-15001T.

The recently completed study of CGEN-15001 utilized the relapsing-remitting autoimmune encephalomyelitis mouse model. This well-recognized animal model of multiple sclerosis manifests an autoimmune CNS demyelinating disease with clinical and pathologic similarity to human relapsing-remitting multiple sclerosis.

Relapsing/Remitting multiple sclerosis is the most common form of MS affecting approximately 85% of the 2.5 million people worldwide diagnosed with MS. Relapses in multiple sclerosis patients result in recurring attacks of clinical symptoms which lead to a worsening of existing symptoms or to the appearance of new symptoms. Thus, prevention of relapses is a major goal in the development of treatments for multiple sclerosis, and the demonstrated therapeutic effect of CGEN-15001 in the presence of this established disease, as demonstrated in this animal model, is highly relevant for its potential use in human therapy.

Professor Stephen Miller from Northwestern University, a leading scientist in this field who supervised the studies, stated, "The capacity of CGEN-15001 to prevent the development of disease in this well-recognized animal model for multiple sclerosis, and more significantly to ameliorate its progression when administered in the presence of pre-existing disease is quite dramatic. Furthermore, these beneficial effects were shown to be long lasting and persisted through the study, indicating that CGEN-15001 may prevent disease progression as efficiently as immune tolerance induction, a process whereby the immune system no longer attacks the self antigens that cause the disease. These findings, together with those demonstrated in our earlier studies, are unique among the molecules targeting the B7 family of co-stimulatory molecules that have been published to date."

Compugen's VP R&D, Dr. Zurit Levine stated, "In addition to being an extremely exciting discovery, this is a good example of how our extensive infrastructure of predictive capabilities can be utilized for 'discovery on demand' purposes. In this case, we were interested in finding a new member of the B7 protein family, a family of proteins that are widely believed to have substantial therapeutic potential. However, it was our belief that relying only on commonly used discovery approaches, such as sequence and functional homology, which underlie most such efforts by others, would be unlikely to yield all unknown members for this family."

Dr. Levine continued, "We utilized, therefore, a different predictive discovery approach combining certain components of our LEADS infrastructure platform with a proprietary algorithm that had been developed to predict in silico novel members of a known protein family based on genomic information, protein structure and additional characteristics. This led to the prediction and selection of a number of novel proteins, including CGEN-15001T, and the discovery of CGEN-15001T led to the identification of the CGEN- 15001 protein."

About the B7/CD28 protein family

Members of the B7/CD28 family have been intensively studied over the past decade and have brought much excitement to the field of immune regulation. The activation and development of an adaptive immune response is initiated by the engagement of a T-cell antigen receptor with an antigenic peptide-MHC complex. The outcome of this engagement is determined by both positive and negative co-stimulatory signals, generated mainly by the interaction between the B7 family and their receptor CD28 family. A growing body of evidence indicates that the dysfunction of immune regulation contributes to the development of autoimmune diseases.

Positive and negative co-stimulatory pathways play critical roles in immune regulation and are considered potential targets for modulating chronic inflammation in autoimmune diseases. To date, one soluble recombinant fusion protein, that selectively blocks the co-stimulatory signal mediated by the B7/CD28 pathway, has been cleared for marketing in the U.S. for the treatment of moderate to severe rheumatoid arthritis, and is in clinical trials for other autoimmune indications. In addition, a number of clinical and preclinical studies of this protein family are underway at various companies.

About LEADS

The LEADS platform provides a comprehensive predictive view of the human transcriptome, proteome and peptidome, and serves as a rich infrastructure for the discovery of novel genes, transcripts and proteins. It includes extensive gene information and annotation, such as splice variants, antisense genes, SNPs, novel genes and RNA editing. At the protein level, LEADS provides full protein annotation, including homologies, domain information, subcellular localization, peptide prediction and novelty status.

Source: Compugen Ltd. (01/07/10)

The Multiple Sclerosis Research Center of New York (MSRCNY), together with the International Multiple Sclerosis Management Practice (IMSMP), today announced that results from its Intrathecal Methotrexate Treatment in Multiple Sclerosis study have been published in this month's issue of Journal of Neurology. 

This study reports on the feasibility of using intrathecal methotrexate (ITMTX) in treatment unresponsive multiple sclerosis (MS) patients with progressive forms of the disease.

A retrospective, open-label, chart review analysis was conducted following patients with MS for up to eight treatments. Patients were considered for ITMTX treatment if they were unresponsive to or intolerant of FDA approved treatments.

There was a one year follow-up after their eighth or last treatment.

Patients underwent neurological assessments and Expanded Disability Status Scale (EDSS) evaluations.

In 87 secondary progressive MS patients, EDSS scores were stable or improved in 89%, with significantly improved mean EDSS post-treatment compared to baseline. Of 34 primary progressive patients, EDSS scores were stable in 82%, with no significant progression in EDSS post-treatment compared to baseline.

ITMTX may have a beneficial role in progressive forms of MS and is well tolerated with no serious adverse events.

"We have opened an avenue of treatment for an otherwise untreatable form of MS," said Dr. Saud A. Sadiq, Director of the IMSMP/MSRCNY and the study's lead author.  "This is exciting news because it's the first time a treatment has been shown to be effective in the late stages/progressive forms of MS."

About Methotrexate

Methotrexate (MTX), an antimetabolite, has been in clinical use since 1948 when it was found to produce temporary remission of acute childhood leukemia.  Because of its indirect immunosuppressive effects, MTX is used in treating autoimmune conditions such as rheumatoid arthritis and psoriasis.

About the IMSMP & MSRCNY

The International Multiple Sclerosis Management Practice and the Multiple Sclerosis Research Center of New York is a leader in MS healthcare and research.  As a center of excellence, it establishes an unparalleled level of care for individualized, compassionate attention to patients' needs and well-being.  Patients receive in-depth assessments and management plans with on-site physical therapists, social workers and neuropsychologists for cognitive rehabilitation.

Appointments may be scheduled with a naturopathic physician, urologist/urogynecologist, pain specialist or massage therapist.  The on-site infusion suite is open 7 days a week for intravenous medications, and a physician is accessible 24 hours a day/7 days a week. 

Patients benefit from the research lab by investigation into the cause of MS, disease mechanisms and treatment discoveries.  As an international MS center, patients throughout the United States and from more than 30 countries on 5 continents rely on and visit the IMSMP for care.

Source: International Multiple Sclerosis Management Practice (28/06/10)

Seattle biotech company Kineta is betting that a toxin from a Caribbean Sea anemone can stop autoimmune diseases, including type 1 diabetes and multiple sclerosis.

The compound shows promise in animals. But in a tough market, where does a small startup find the kind of money and patience to support lengthy clinical trials to determine whether it works in humans?

The heart, it turns out, is a strong motivator. Kineta's latest investor is a charitable foundation created by a famous executive who lost his wife to diabetes.

Kineta is announcing a new partnership with the family foundation of Lee Iacocca, the former Chrysler chairman who is funding diabetes research in honor of his first wife, Mary. The Iacocca Family Foundation is investing in Kineta to spur its efforts to develop the new drug, called ShK-186.

"They want a drug," said Shawn Iadonato, Kineta's chief scientist. "The financial consideration is secondary.

"A venture capitalist is ultimately indifferent," he said. "They want a return on investment."

The foundation is not releasing the amount of its investment but says the deal with Kineta is structured like a program-related investment and is less than $1 million. In 2008, the foundation made a $3 million equity investment in Silicon Valley biotech company Bayhill Therapeutics for work on type 1 diabetes. That infusion paved the way for Bayhill to attract additional matching funds.

The partnership is an example of how foundations are recasting the model of philanthropy, investing in promising work to advance treatments, both from the commercial sector and academic research. With an equity stake, there's the potential for a double payoff if the company succeeds.

Funding from nonprofits is unusual for a biotech company, says Kineta Chief Executive Charles Magness. But it helps Kineta build a more stable and diverse funding base.

"We're broadening our options so we don't get stuck relying on any one funding source," Magness said.

Founded in 2007

Magness and Iadonato founded Kineta in 2007 after working together to develop an anti-hepatitis C drug at Illumigen Biosciences, which they later sold to Cubist Pharmaceuticals. Kineta has raised about $15 million so far, including private equity, government grants and contracts, and investments by corporate partners.

Kineta is focusing its science on enhancing the human immune system and its business model on bridging the gap between basic research and commercialization. It's acquiring and advancing potential drugs through the pipeline, channeling new compounds that have worked well in animals through the first stage of clinical trials.

"It's what the big companies think is very risky," Magness said. The earliest stage of clinical trials is the farthest from being able to help their bottom line, so pharmaceutical companies are less willing to do the work themselves.

"Critical turning point"

However, for drug development "it's a critical turning point," he said. "If it's successful, it will reduce anxiety that some toxicity will torpedo the program."

Once the initial viability has been demonstrated, Kineta will look for a larger commercial partner to do the more advanced trials needed for FDA approval.

Type 1 diabetes usually strikes people at a young age, and unlike type 2, it can't be managed with diet or exercise. Type 1 affects about 3 million Americans, who require injections of insulin; no new treatments have been developed for more than two decades.

"We have all these new technologies, telecom and the Internet, but no new technologies in the disease area where people are being treated the same way they were 20 or 30 years ago," Iodonato said.

Kineta licensed the ShK-186 technology last July from Airmid, a private pharmaceutical company, and the University of California, Irvine, based on research by UCI professor K. George Chandy. Kineta plans to take ShK-186 into the first phase of human trials later this year.

It works by blocking some of the white blood cells that trigger inflammation in autoimmune diseases. With type 1 diabetes, the body attacks cells in the pancreas that produce insulin. In people with MS, the body attacks the myelin sheath that protects nerves.

Narrower focus

If ShK-186 is successful, it may have fewer side effects than existing drugs because its focus is narrower. It targets a specific kind of blood cell — effector memory T-cells — without causing general immune suppression.

That means other immune functions can proceed as normal, allowing the body to fight viruses, infections and cancer.

Source: The Seattle Times Copyright © 2010 The Seattle Times Company (07/06/10)

Hard to Treat Diseases, Inc. announced today that researchers from its Slavica BioChem division in Belgrade have made great progress in the experimental findings to aid in the suppression or ultimately cure of Multiple Sclerosis which are comparable with investigations of other MS-Research groups around the world.

Researchers in Belgrade are making progress in suppression of immune response in MS using an immunomodulatory approach that involved application of purine nucleoside analogues: Ribavirin (FDA approved drug used in human clinical practice for 20 years) and Tiazofurin (orphan-drug).

These drugs act primarily by inhibition of Inosine Monophosphate Dehydrogenase (IMPDH), a rate limiting enzyme in de novo purine synthesis pathway causing interruption of cell metabolism.

Importantly, this exhaustion of purine pools had a more potent effect on activated lymphocytes than on the other cell types, since salvage pathways for the production of guanine nucleosides do not operate in T- and B cells. In this way, Ribavirin and Tiazofurin also work by selectively targeting activated T-cells.

Prof Mirjana Stojiljkovic, the leader of IBISS research team, and Medical Advisor of Slavica BioChem division said: "We have shown promising results in decreasing severity of clinical symptoms and duration of MS induced in experimental animals, and radical reduction of mortality and degree of disability.

Administration of ribavirin and tiazofurin attenuated proliferation of autoreactive T lymphocytes and their infiltration into the nervous tissue, and thereby prevented myelin destruction.

Similarly to our colleagues from Switzerland we have observed that the severity of treatment side effects of used substances was low and disappeared after cessation of drug application. These results are encouraging for the future of MS therapy."

Source: Hard to Treat Diseases (03/06/10)

A small research company developing a promising treatment for multiple sclerosis has won a prestigious award to pay for further research.

Cognosci will use the $330,000 grant to continue evaluating an experimental compound that shows potential in helping rebuild the central nervous system, rather than just blocking damage from MS.

It's not a lot of money for a seven-employee company that's attracted more than $18 million, mostly in federal grants, since it was founded in May 2000. But the award does elevate Cognosci's reputation and could help its leaders land new partnerships.

The money was one of two initial grants handed out by Fast Forward, a nonprofit organization set up by the National MS Society to accelerate the development of promising treatments, and EMD Serono, the subsidiary of a German drug maker that's also working on MS drugs.

The other grant was given to a New Zealand company.

"The promise of current research to change the MS landscape is exciting," said Fast Forward president Timothy Coetzee. "We are proud to be able to provide resources for those working to end MS and look forward to seeing the results stemming from these projects."

Cognosci's grant also includes a license option for EMD Serono. That means that if Cognosci's early testing continues to be successful, EMD could invest more money to help test the drug in patients and commercialize it, said Dale Christensen, Cognosci's vice president of research and business development.

The treatment is still being tested on animals, and it could take eight or nine years before it's approved and on the market. But Cognosci could start doing clinical trials on humans within a couple of years.

"It's really not that long before patients could start seeing benefits," said Christensen, whose father died from MS. "That helps keep our energy up."

Cognosci was started by Mike Vitek, a neurobiologist at Duke University. The company is also working on treatments for Alzheimer's disease and traumatic brain injury.

In recent years, company officials had sought venture capital money to pay for further research. But venture capitalists who were interested "wanted us to shut down everything but our MS work and move the company to San Diego," Christensen said.

Instead, officials continued to attract federal grants from the National Institutes of Health and Department of Defense. The company also received $143,317 in funding from the N.C. Biotechnology Center.

And now Cognosci is pursuing partnerships with larger drug companies that want to invest in promising products, Christensen said. "You retain a lot more scientific control," he added.

Source: Newsobserver.com © Copyright 2010, The News & Observer Publishing Company (02/06/10)

Five Prime Therapeutics, Inc., a leader in the discovery and development of innovative biologics, and Fast Forward, LLC, a subsidiary of the National Multiple Sclerosis Society, announced an alliance to fund the development of a FivePrime pre-clinical stage therapeutic candidate for treatment of Multiple Sclerosis (MS).

Fast Forward will commit up to $1 million to fund the advancement of the therapeutic candidate.

Under the terms of the agreement Fast Forward will provide funds to enable pre-clinical testing of a proprietary and innovative biological molecule discovered at FivePrime. This biologic targets specific cells of the innate immune system, a mechanism that differentiates this potential therapy from the approved treatments for MS. The innate immune system is a component of the body's immune system and recent research has suggested that it contributes to disease activity in both relapsing-remitting and progressive forms of MS.

"We are delighted to be able to work with Fast Forward in order to bring new treatments to people with MS. MS is an important area of innovation and focus at FivePrime," said Brian Wong, MD, PhD, vice president, immunology and discovery research at FivePrime. "Fast Forward's support provides important validation of FivePrime's powerful discovery engine and the company's growing pipeline of first-in-class therapeutic biologics."

"We are pleased to partner with FivePrime to accelerate the development of new treatments for people with MS. Their high-caliber scientists have identified a new treatment strategy which should be explored further," adds Dr. Timothy Coetzee, president of Fast Forward. "Five Prime's approach fits well with our strategy of supporting innovative and promising new treatments for MS."

Source: Fast Forward, LLC & The National Multiple Sclerosis Society (28/05/10)

Swiss drugmaker Roche AG and Biogen Idec Inc. are discontinuing development of ocrelizumab in patients with rheumatoid arthritis (RA), after an infection-related safety signal was observed in Phase III testing, resulting in the death of some patients.

Results from the program will be made available at a medical forum, the companies said, without divulging the specific type of infection or the number of affected study patients.

Roche and Biogen have said that the infections were serious, some of which were fatal, and others were opportunistic infections.

The FDA had placed a clinical hold on the studies prior to the companies' ultimate decision to stop development in RA. Last year Biogen had stopped its Phase III program of ocrelizumab in lupus patients.

Despite the severe safety concerns a Phase II study of ocrelizumab is ongoing in patients with relapsing-remitting multiple sclerosis, and data from that study will be submitted for presentation this autumn at the European Committee for the Treatment and Research in Multiple Sclerosis conference in Sweden.

Roche was taking the lead on the development of ocrelizumab in RA, while Biogen Idec was contributing financial support.

Biogen Idec spokeswoman Amy Reilly said the company has not disclosed the costs of the ocrelizumab RA program.

Roche representatives in Basel, Switzerland, could not be reached immediately for comment.

Ocrelizumab, which was discovered by Biogen, was in four Phase III studies known as SCRIPT, FILM, FEATURE, and STAGE.

The most recent analysis included available safety and efficacy data from the SCRIPT Phase III study in patients with previous inadequate response to TNF-inhibitors and safety data from the Phase III FILM study in patients who were methotrexate-naïve.

The troubles in the ocrelizumab RA program surfaced in March, when Roche and Biogen Idec suspended treatment.

That decision came after an independent RA and lupus data and safety monitoring board for ocrelizumab concluded that the safety risk outweighed the benefits observed in those patient populations, based on an infection-related safety signal.

Source: Bioworld copywrite AHC Media LLC (21/05/10)

Innate Therapeutics today announced funding support from Fast Forward, LLC, a not-for-profit organization established by the U.S. National Multiple Sclerosis Society and EMD Serono, an affiliate of Merck KGaA, Darmstadt, Germany.

The award of funds will help support the conduct of a Phase 2A clinical trial in patients with progressive forms of MS using MIS416, a naturally occurring agent derived from bacteria. “We are delighted to gain this substantial funding as well as to be able to work with Fast Forward and their collaborative partner, EMD Serono,” said Simon Wilkinson, the Chief Executive Officer of Innate Therapeutics.

The award from Fast Forward and EMD Serono, which provides US $550,000 over 15 months is one of the first given in the Accelerating Commercial Development category from a funding program designed to accelerate the development of research discoveries into new or improved therapies for people with multiple sclerosis.

“We are pleased to announce the 2009 funding recipients who will work to advance promising early- and late-stage projects in MS that could ultimately help patients,” said Bernhard Kirschbaum, PhD, Executive Vice President, Global Research and Development at Merck Serono, an affiliate of Merck KGaA, Darmstadt, Germany. “EMD Serono is committed to advancing scientific and medical knowledge and to furthering key research that has the potential to help people living with MS.”

“The promise of current research like that undertaken by Innate Therapeutics to change the MS landscape is exciting, and it fuels the collaboration between Fast Forward and EMD Serono in advancing science in key areas of focus to speed the development of new therapies and innovations to benefit people living with MS. We are proud to be able to provide resources for those working to end MS and look forward to seeing the results stemming from these projects,” said Dr. Timothy Coetzee, President of Fast Forward.

About MIS416

MIS416 is the lead product from Innate Therapeutics’ proprietary microparticle immune stimulant (MIS) technology. In addition to its potential use in MS, the company is conducting preclinical studies of MIS416 in other applications, including oncology co-therapy and the treatment of infectious diseases. MIS technology is based on the use of a bacterially derived, therapeutic microparticle incorporating multiple naturally occurring ligands, which when administered can activate synergistic innate immune signaling pathways. By activating and/or regulating important innate system mechanisms, Innate Therapeutic’s microparticle immunomodulator technology presents a new way to fight infections and certain cancers, and to treat select autoimmune diseases.

About Fast Forward, LLC

Fast Forward, LLC, established by the National Multiple Sclerosis Society as part of a comprehensive approach to MS research and treatment, focuses on speeding promising research discoveries towards commercial drug development. Fast Forward accelerates the development of treatments for MS by connecting university-based MS research with private-sector drug development and by funding small biotechnology/pharmaceutical companies to develop innovative new MS therapies and repurpose FDA-approved drugs as new treatments for MS.

About Innate Therapeutics Limited

Innate Therapeutics Limited is a public unlisted biopharmaceutical company based in Auckland, NZ. The company is focused on the development of a new generation of immune response modifier for potential use in the treatment of multiple sclerosis and other autoimmune disease, a range of infectious diseases, certain cancers, and as a novel cellular and humoral adjuvant.

Source: Innate Therapeutics Limited (07/05/10)

Kineta, Inc. announced receipt of a Phase 1 Small Business Innovation Research (SBIR) grant from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH).

Awarded under the NIAID’s expanded Phase 1 program, the $600,000, two-year grant will help finance IND-enabling studies of ShK-186, Kineta’s first-in-class therapeutic for type 1 diabetes mellitus, multiple sclerosis and other autoimmune diseases.   The award includes a subcontract to George Chandy, M.D., Ph.D. of the University of California at Irvine for mechanistic studies. Kineta intends to begin human clinical trials on the investigational drug in the second half of 2010.  

“This SBIR award is great validation of the importance and novelty of Kineta’s autoimmune program.    The funding adds to Kineta’s financial horsepower as we conclude preclinical studies and move into man later this year,” said Charles L. Magness, Ph.D., President and Chief Executive Officer of Kineta, Inc.

"It is very gratifying to see the high level support for ShK-186, and to witness its steady momentum through the development pipeline," added Dr. Chandy.

ShK-186 is a potent and highly specific Kv1.3 potassium channel blocker. It is designed to suppress activation of effector memory T cells, which are important mediators of inflammation and tissue damage in MS, type 1 diabetes mellitus and other autoimmune diseases. The drug candidate has been shown to significantly reverse disease in animal models of MS and rheumatoid arthritis. Animal models also have demonstrated that efficacy is achieved without the generalized immunosuppression that occurs with competing therapies.

The synthetically manufactured compound was originally isolated from the Caribbean sea anemone, Stichodactyla helianthus, and subsequently optimized by Dr. Chandy’s laboratory.

Source: Kineta, Inc. (30/03/10)

Antisense said on Wednesday that global pharmaceutical company Teva had ended its licensing agreement for the lead compound, ATL1102, with Antisense.

Shares in Antisense fell 1.9 cents, or 40.43 per cent, to 2.8 cents on Wednesday as nearly 34 million of the company's shares changed hands.

"Teva advised Antisense that after performing certain steps in the development process, ATL1102 was determined to no longer be in line with Teva's preferred product profile," Antisense said in a statement to the Australian Securities Exchange.

"Antisense understands that business considerations or factors contributing to Teva's decision include issues with one of the long-term toxicological studies that may require repeat of the study, lengthening the development time and time to market of the drug in light of the competitive landscape."

Antisense said it would evaluate its options in relation to further development of ATL1102.

"ANP intends to move forward as quickly as possible with this evaluation," Antisense said.

"However, a timeline for its completion cannot be advised at this point until the company has fully analysed and assessed its options with respect to ATL1102 and once details of the licence termination are finalised."

An injectable version of ATL1102 had completed a Phase IIa efficacy and safety trial in patients with multiple sclerosis.

Antisense licensed ATL1102 to Teva in February 2008.

The licence included potential milestone payments of up to $US100 million ($A108.81 million) which was contingent upon completion of research and development and successful commercialisation.

Source: The Sydney Morning Herald © 2010. Fairfax Digital (24/03/10)

Peptimmune, Inc. a privately held biotechnology company, announced the grant of US Patent Number 7,655,221 (the '221 patent) which protects the target product profile for its PI-2301 peptide copolymer for the treatment of multiple sclerosis, and other autoimmune diseases.

The '221 patent claims important treatment modalities for PI-2301 and related compounds. "The '221 patent enhances the exclusivity for what we believe may become a very important therapy for the treatment of multiple sclerosis and other autoimmune diseases," stated Thomas P. Mathers, President & CEO of Peptimmune.

Peptimmune recently completed a Phase Ib multiple-ascending dose, double-blind, placebo-controlled randomized study in subjects with SP-MS. The Company plans to continue developing PI-2301 by initiating a Phase II study in multiple sclerosis patients later this year.

PI-2301 is a second-generation peptide copolymer from a similar compound class as Copaxone® (Teva Pharmaceuticals). PI-2301 works through immune modulation by enhancing the regulatory response of the immune system and thereby controlling the pathogenic autoimmune response observed in some diseases.

PI-2301 has been optimized using Peptimmune's novel platform peptide chemistry. In preclinical studies, PI-2301 has shown to be more potent and effective than Copaxone in treating disease models for multiple sclerosis. PI-2301 has also shown efficacy in preclinical models of autoimmune diseases where immune modulation may be effective, such as Crohn's disease, rheumatoid arthritis, and autoimmune uveitis. Peptimmune has put in place high-quality synthesis and analytical methods that provide a superior level of batch-to-batch reproducibility in the manufacturing of PI-2301.

Over 400,000 Americans have multiple sclerosis (MS), and MS may affect over 2.5 million individuals worldwide. MS is an autoimmune disease in which the individual's immune system responds against multiple components of nerve-insulating myelin. The effects of these immune-mediated attacks can range from relatively benign to somewhat disabling to devastating, as communication between the brain and other parts of the body is disrupted.

Peptimmune Presentation at the upcoming meeting of the American Society for Experimental NeuroTherapeutics

Dr. Eric Zanelli, Vice President Research, will make a presentation entitled "Induction of an anti-inflammatory immune response toward toxic species of alpha-synuclein; Immunomodulatory therapy for Parkinson's Disease" in the Oral Pipeline Session on March 5, 2010 from 2:00 pm - 6:00 pm in the Haverford Suite of the Crystal Ballroom of the Hyatt Regency Bethesda, Bethesda Maryland.

Dr. Zanelli will discuss the application of Peptimmune's DEEP technology to the development of a first-line disease modifying treatment for Parkinson's Disease.

About DEEP

DEEP is a peptide copolymer technology that anticipates antigenic diversity while preserving specificity for the epitope of interest. DEEP takes advantage of Peptimmune's know-how in the solid-phase manufacturing of complex peptide mixtures. The technology combines the epitope specificity of a fixed-sequence peptide with the randomness of a broadly immune-interactive copolymer.

Source: Medical News Today © 2010 MediLexicon International Ltd (10/03/10)

Compugen Ltd.  announced today the discovery and
experimental validation of CGEN-15001 for the treatment of autoimmune
disorders. CGEN-15001 is the extracellular region of a previously
unknown membrane protein in the B7/CD28 family. The existence and
potential utility of the newly discovered parent protein from which
CGEN-15001 is derived was predicted in silico utilizing Compugen’s LEADS Platform and other proprietary algorithms.

Autoimmune diseases develop when defects in the immune system lead the
body to attack its own cells, tissues, and organs and include more than
80 chronic, and often disabling, illnesses. Among the most common
autoimmune diseases are rheumatoid arthritis, systemic lupus
erythematosus, multiple sclerosis, inflammatory bowel disease, and type
1 diabetes. Collectively, autoimmune diseases are among the most
prevalent diseases, affecting an estimated 25 million people in the U.S.

CGEN-15001 is a novel soluble recombinant fusion protein corresponding
to the extracellular region of the Compugen discovered parent protein.
The discovery of the parent protein, which is a membrane protein, was
accomplished through the incorporation in Compugen’s LEADS Platform of
additional algorithms specifically designed to predict novel members of
the B7/CD28 family of co-stimulatory proteins. This approach relied on
Compugen’s proprietary understandings and modeling of genomic structure,
gene expression, protein structural domains, and cellular localization.
Compugen has filed for patent coverage on both the parent protein, which
potentially has other medical uses such as a target for antibody
therapeutics, and CGEN-15001.

The in vivo validation of CGEN-15001 utilized a mouse model of
multiple sclerosis, relapsing-remitting experimental autoimmune
encephalomyelitis (R-EAE). In this model, administration of CGEN-15001
resulted in potent amelioration of the disease state. These results
indicate that CGEN-15001 could have therapeutic utility for the
treatment of multiple sclerosis and other autoimmune diseases, such as
rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel
disease, and type 1 diabetes. Earlier in vitro studies validated
the predicted functional activity of CGEN-15001 as a new member of the
B7/CD28 family proteins.

Professor Stephen Miller from Northwestern University, a leading
scientist in this field who supervised the studies, stated, “Our studies
have indicated robust disease suppressing activity for CGEN-15001 in the
SJL R-EAE model, a recognized mouse model for multiple sclerosis. These
studies have also demonstrated that CGEN-15001 has the unique ability
to inhibit proliferation, differentiation, and cytokine production of
pro-inflammatory Th1 and Th17 responses while at the same time sparing
or actually promoting regulatory Th2-derived cytokines. As far as I am
aware, this potentially very beneficial pattern of inhibiting Th1/Th17
while promoting Th2 responses is unique among the reagents targeting the
B7 family of co-stimulatory molecules that have been published to date.”

Compugen’s VP R&D, Dr. Zurit Levine stated, “We are extremely pleased by
this further demonstration of the unique discovery capability that has
been created at Compugen. In view of its recognized potential in the
largely unmet and critical field of immune regulation, the B7/CD28
co-stimulation protein family has been an area of extensive research for
a number of years. In our opinion, in addition to providing Compugen
with a very attractive product candidate, the predictive discovery and
experimental validation of a previously unknown member of this
extensively researched protein family represents a major milestone in
the transition from experimentally based therapeutic discovery to in
silico prediction and selection.”

Source: Compugen Ltd. (03/02/10)

Biogen Idec Inc. has begin human testing of an experimental drug, dubbed BIIB033, that it hopes will take the revolutionary step of repairing some of the damage done by multiple sclerosis.

Although it is a major step to begin testing in humans, drug development is always risky and it will take years to measure the drug's effectiveness and potential side effects.

Multiple sclerosis, or MS, is a chronic, inflammatory condition that occurs when the body attacks its own myelin, the protective insulation surrounding the nerve fibers, or axons, in the central nervous system. The debilitating disease affects an estimated 400,000 people in the U.S., according to the National MS Society, but current treatments only aim to slow the disease's progression and cannot help repair damage.

Research that focuses on ways to help the body regenerate myelin is growing and scientists around the world are taking several different approaches. Damage to myelin can distort or block messages carried by axons and result in a wide variety of MS symptoms such as vision problems, limb numbness and paralysis.

BIIB033 is an antibody designed to turn off Lingo-1, a molecule that the company believes prevents myelin production in adults after axons are well covered. Blocking Lingo-1 may encourage myelin regeneration, something that occurs in healthy adults, after damage from MS occurs.

The antibody has been shown to be effective in mouse models that are accepted as being useful for mimicking the properties of MS.

The small Phase I study will include 64 healthy volunteer adults in the Netherlands, with the main goal of assessing safety and tolerability, and is expected to be completed in 2011.

The placebo-contolled study will give patients a single dose of the drug and different groups will get different amounts, a standard practice in such early trials that helps determine the optimal dose for later investigation.

The secondary goals of the trial relate to how the body processes the drug and there is no measure of its effectiveness, which is not surprising in such an early study that doesn't actually include MS patients.

MS is an attractive area of drug makers as its often requires lifelong treatment, and MS drugs brought in more than $8.7 billion in 2009 revenue worldwide, according to projections from Bernstein Research.

Biogen is mostly focused on selling MS treatments, including Tysabri and Avonex, which are expected to bring sales of more than $3 billion for 2009.

Source: Dow Jones Newswires (c) 2010 Dow Jones & Company, Inc. (27/01/10)

BTG Plc said it commenced dosing in a European multicentre Phase IIa study of Pleneva, a novel orally administered compound under development as a potential treatment for multiple sclerosis.

According to the company, the study, in 166 patients with the relapsing-remitting form of the disease, comprises an initial 24 week double-blind, placebo-controlled dosing period followed by a 24 week open-label extension. The primary endpoint of the study is a reduction in the number of new T1 gadolinium enhanced lesions on MRI at weeks 12, 16, 20 and 24 when compared to placebo.

Source: RTT News © 2010 RTTNews (21/01/10)

Roche and Biogen Idec announced that the experimental monoclonal antibody ocrelizumab, given intravenously, significantly reduced disease activity as measured by MRI (magnetic resonance imaging) scans in a phase II study of 220 people with relapsing-remitting MS. 

Ocrelizumab binds to a molecule (CD20) on the surface of B cells and depletes them from the circulation. B cells are immune cells that make antibodies and may play a role in the immune attack on brain and spinal cord tissues in multiple sclerosis. The drug is a humanized version of rituximab, a mouse antibody to CD20 that has previously shown benefit in people with relapsing-remitting MS.

In the aspects of this phase II study participants were randomly assigned to receive one of two treatment regimens and observed for 24 weeks, with plans for observing them for up to 96 weeks. Participants received repeated intravenous infusions of one of three different dose regimens of ocrelizumab or inactive placebo) or intramuscular injections of Avonex®.

The main objective of this study was to determine whether ocrelizumab was effective in reducing MS disease activity compared with placebo, as observed on MRI at 12, 16, 20, and 24 weeks. The companies report that ocrelizumab "showed a strong effect with a highly statistically significant reduction" in signs of disease activity.

The companies are continuing to analyze the data, and plan to provide a full report at an upcoming medical meeting, including the results of secondary endpoints - which include relapse rate and the appearance of new disease activity - and safety information. Since this was a phase 2 study, additional research will be needed to further determine this drug's safety and efficacy.

Source: MSS Canada (10/12/09)

Researchers have shown how an experimental drug might restore the function of nerves damaged in spinal cord injuries by preventing short circuits caused when tiny "potassium channels" in the fibers are exposed.

The chemical compound also might be developed as a treatment for multiple sclerosis.

Because nerves usually are not severed in a common type of spinal cord trauma, called "compression" injuries, the drug offers hope as a possible treatment, said Riyi Shi, a professor in Purdue University's Department of Basic Medical Sciences, School of Veterinary Medicine, Center for Paralysis Research and Weldon School of Biomedical Engineering.

"Compression is responsible for most spinal cord injuries, including many resulting in paralysis," Shi said. "Since the nerves are not severed, this type of drug represents a potential golden opportunity to treat spinal cord injuries."

The experimental compound, 4-aminopyridine-3-methyl hydroxide, has been shown to restore function to damaged axons, slender fibers that extend from nerve cells and transmit electrical impulses in the spinal cord.

Findings, based on experiments with guinea pig spinal cord tissue, appeared online in the Journal of Neurophysiology. The work was led by Department of Basic Medical Sciences doctoral student Wenjing Sun.

Shi said the findings were made possible by the interdisciplinary nature of the work, which also involves researchers Richard Borgens, director of Purdue's Center for Paralysis Research and the Mari Hulman George Professor of Neurology in the School of Veterinary Medicine; Stephen Byrn, the Charles B. Jordan Professor of Medicinal Chemistry, and Daniel Smith, a research assistant professor, both in the Department of Industrial and Physical Pharmacy; and Ji-Xin Cheng, an associate professor in the Weldon School of Biomedical Engineering and Department of Chemistry.

Researchers have shown how an experimental drug might restore the function of nerves damaged in spinal cord injuries by preventing short circuits caused when tiny "potassium channels" in the fibers are exposed by trauma. The compound also might be developed as a treatment for multiple sclerosis. This diagram illustrates how the drug functions as a "channel blocker," meaning it permits the conduction of signals even though the protective myelin insulation has been damaged.

(Photo Credit: Purdue University, Department of Basic Medical Sciences)

The researchers subjected spinal cord tissue to stresses that mimic what happens in a compression injury, which stretches nerves. Then they treated the damaged axons with 4-aminopyridine-3-methyl hydroxide.

The compound is a derivative of the drug 4-aminopyridine, used primarily as a research tool and also to manage symptoms of multiple sclerosis.

The axons of each nerve are sheathed in a thick insulating lipid layer, called myelin, which enables the transmission of signals without short circuiting, much like the insulation surrounding electrical wires. Spinal cord trauma damages the myelin sheath, exposing "fast potassium channels" that are embedded in the axons and are critical for transmitting nerve impulses.

The researchers confirmed previous circumstantial evidence suggesting injury causes the myelin insulation to recede, exposing the channels and impairing signal transmission. Laboratory and imaging techniques revealed the exposed channels in damaged axons.
The researchers also discovered that 4-aminopyridine-3-methyl hydroxide is a "potassium channel blocker," using a sophistic laboratory technique called "patch clamp" to measure signal conduction. Findings confirmed that the compound prevents the exposed channels from leaking electrical current and enhances nerve conduction in segments of the damaged spinal cord.

The compound could make it possible to sidestep spinal cord damage by enabling axons to transmit signals as though they were still sheathed in myelin, Shi said.

Nerves transmit signals through a series of rapid electrical pulses, or "action potentials." For proper nerve function, the time gap between pulses must be as brief as possible. However, 4-aminopyridine has been shown to lengthen the gap, or "refractory period," between pulses. The researchers found that 4-aminopyridine-3-methyl hydroxide restores function without affecting the refractory period. As a result, the damaged nerves perform more like healthy nerves than those treated with other drugs, he said.

Another key advantage of the new compound is that it's about 10 times more potent than 4-aminopyridine, meaning lower doses can be used to reduce the likelihood of serious side effects.

Because myelin also is damaged in multiple sclerosis, the same drug might be used to restore nerve function in people stricken with the disease, Shi said. Since the newer drug can be used in lower doses, it might be more effective than 4-aminopyridine in treating multiple sclerosis, which affects more than 350,000 people in the United States and 2.5 million worldwide, he said.

Source: Science Codex (20/11/09)

Belgian biotech company Galapagos said it would start a Phase II clinical study to evaluate the effectiveness of its product Nanocort in treating flares in multiple sclerosis (MS).

Galapagos, which specialises in bone and joint diseases such as rheumatoid arthritis and osteoporosism, said Nanocort combined less frequent treatment with lower dosage and potentially more effective delivery than other flare treatments.

The trial follows a Phase I/II study concluded in 2008, which demonstrated safety as well as faster and more pronounced decrease in rheumatoid arthritis flare symptoms, Galapagos said.

"After the positive outcome of the Phase I/II study last year, we have evaluated Nanocort's product profile and decided to pursue MS as a first indication," chief executive Onno van de Stolpe said.

Multiple sclerosis is an autoimmune disease where the body's immune system mistakenly attacks the nervous system. The World Health Organisation estimates that over 2.5 million people suffer from multiple sclerosis worldwide.

The Phase II trial will involve 90 MS patients experiencing flares, episodes of increased neurological dysfunction. The study will take place in Belgium and Germany over a period of one to two years.

Source: Reuters © Thomson Reuters 2009 (17/11/09)

Actelion Ltd announced that the selective S1P1 receptor agonist ACT-128800/ RG3477 has achieved an important clinical milestone. Actelion's first-in-class selective S1P1 (Sphingosine-1-phosphate) receptor agonist has entered into a Phase IIb dose-finding study in patients suffering from multiple sclerosis. This triggers a milestone payment by Roche to Actelion of USD 20 million.

Guy Braunstein, M.D., Ph.D. and Head of Clinical Development at Actelion, commented: "Together with our partner Roche, we are committed to the rapid development of our selective S1P1 receptor agonist for patients suffering from autoimmune disorders. With the start of this dose-finding study in patients with multiple sclerosis, we have made an important step forward."

About the Actelion / Roche alliance Actelion and Roche entered into an exclusive worldwide collaboration in July 2006 to jointly develop and commercialize Actelion's selective S1P1 receptor agonist, an immunomodulator with the potential for once-a-day oral dosing. The two companies plan to jointly develop and commercialise this novel compound for multiple autoimmune disorders. For the current selective S1P1 receptor agonist, Actelion will fully fund all development activities up to the end of Phase II for the first two indications. All subsequent development and commercialisation costs will be shared equally between Roche and Actelion. Both companies will co-promote any product resulting from this collaboration and will equally share profit.

This S1P1 collaboration covers both the current selective S1P1 receptor agonist in clinical development, as well as any other selective S1P1 receptor agonists resulting from Actelion's research efforts in the field. Actelion received an upfront payment of USD 75 million in July 2006. In the case of future development and approval milestones being achieved, Actelion will be eligible to receive further payments of up to USD 535 million for the first compound for all targeted indications. Further development and approval milestone payments are due for additional compounds. Roche will pay Actelion undisclosed royalties on all product sales.

Selective S1P1 receptor agonists Sphingosine-1-phosphate (S1P) is a phospholipid released by platelets, mast cells and other cells. It is currently established ^[1,2] that S1P stimulates at least five different G-protein coupled receptors (GPCRs): S1P1,2,3,4, and 5. Activation of these GPCRs mediates a complex variety of biological responses, such as lymphocyte migration, endothelial cell proliferation, blood vessel constriction and heart rate modulation.

Actelion's efforts in the field of selective S1P1 receptor agonists started in 1999 by focusing on GPCRs found on the endothelium, the inner lining of blood vessels. The result of these research efforts is Actelion's orally active selective S1P1 receptor agonist.

References ^[1] Huwiler A, Pfeilschifter J. Biochem Pharmacol. 2008 May 15;75(10):1893-900. Review. ^[2] Rivera J, Proia RL, Olivera A.Nat Rev Immunol. 2008 Oct;8(10):753-63.

Source: Actelion Pharmaceuticals Ltd (09/10/09)

RegeneRx Biopharamceuticals Inc. have announced that researchers at the Henry Ford Health System in Detroit, Michigan, demonstrated for the first time that Tβ4 treatment of EAE (experimental autoimmune encephalomyelitis – an animal model for multiple sclerosis) significantly improves neurological functional recovery.

In addition to this neurological benefit, the researchers reported a significant reduction of inflammation and induction of oligodendrogenesis (maturation of central nervous system cells associated with the formation of the nerve sheath), the control of which are important therapeutic goals.

The study entitled, “Neurological Functional Recovery after Thymosin Beta 4 Treatment in Mice with Experimental Auto Encephalomyelitis,” was published online ahead of print in Neuroscience, 2009 September 24. The publication highlights the statistically significant effects of Tβ4 treatment in EAE mice, including improvement of neurological functional recovery, reduction of inflammatory infiltrates in the brain, and increase of oligodendrocyte progenitor cells (a type of stem cell) and mature oligodendrocytes in the brain.

The research team was led by Jing Zhang, MD, PhD; Zheng Gang Zhang, MD, PhD; Dan Morris, MD; Yi Li, MD; Cynthia Roberts, Stanton B. Elias, MD, and Michael Chopp, PhD of the Departments of Neurology and Emergency Medicine at the Henry Ford Health System in Detroit, Michigan and the Department of Physics at Oakland University in Rochester, Michigan.

Tβ4 and RGN-352

Tβ4 peptide is a synthetic version of a naturally occurring peptide present in virtually all human cells. It is a first-in-class multi-faceted molecule that promotes endothelial cell differentiation, angiogenesis in dermal tissues, keratinocyte migration, collagen deposition, and down-regulates inflammation. RegeneRx has identified several molecular variations of Tβ4 that may affect the aging of skin, among other properties, and could be important candidates as active ingredients in pharmaceutical and consumer products.

Researchers at the National Institutes of Health, and at other academic institutions in the U.S., have published scientific articles indicating Tβ4’s in vitro and in vivo efficacy in accelerating wound healing and tissue protection under a variety of conditions. Abstracts of scientific papers related to Tβ4's mechanisms of action may be viewed at RegeneRx's web page: www.regenerx.com.

RGN-352 is an injectable formulation of Tβ4 that has just completed Phase I clinical trials and has been shown to be safe and well-tolerated. The product candidate has been developed to address medical indications where systemic administration is warranted. RegeneRx is currently planning a Phase II clinical trial to evaluate RGN-352 in post-acute myocardial infarction (heart attack) patients, although other indications such as stroke, ischemic renal disease, and certain ulcerative and autoimmune conditions have been identified as potential targets.

Source: RegeneRx Biopharamceuticals Inc. (30/09/09)

Biovista Inc. today announced that BVA-201, its drug targeting Multiple Sclerosis (MS), has shown significant positive results in the MOG-induced Experimental Allergic Encephalomyelitis (EAE) murine model of MS. BVA-201 is an existing drug that Biovista repositioned in MS and is aimed at neuroprotection. It was shown to have both efficacy in reducing symptoms and no toxic effects in this well established model of MS.

"This is our second success in MS in a period of 6 months, with BVA-201 showing efficacy levels closely comparable to those of dexamethasone," said Aris Persidis, Ph.D., President of Biovista. "Histology results are also encouraging, since they seem to confirm our expectations regarding the compound's mechanism of action. What is even more important is that BVA-201 has a known and very favourable safety profile and is already approved for chronic use," Dr. Persidis added.

About Biovista's BVA-201 trial in the MS EAE-MOG model

MS is a chronic inflammatory neurological disease. It is the most frequent non-traumatic disabling neurologic disease among young adults, with over 2.5 million patients worldwide.

In the animal proof-of-concept trial, BVA-201 was compared to dexamethasone, a potent anti-inflammatory and immunosuppressive drug that is efficient in accelerating the recovery from MS relapses but too toxic for chronic use. BVA-201 induced a statistically significant reduction of EAE severity, the magnitude of which was directly comparable to that caused by dexamethasone.

Furthermore, BVA-201 protected neural axons and myelin against degeneration, as shown in the histology analysis performed. This analysis provided strong evidence that the compound works as a neuroprotective agent as opposed to most currently approved drugs that target the immune system.

Source: Biovista Inc. (10/09/09)

SuppreMol GmbH, a privately held biopharmaceutical company developing novel therapeutics for the treatment of autoimmune diseases, today announced it has been awarded research funding from the federal program "KMU-Innovativ" by the German Federal Ministry of Education and Research (BMBF). The grant covers an R&D program of EUR 1 million to explore the therapeutic potential of SM101 in previously unaddressed indications and to develop novel diagnostic tools to stratify patients with Multiple Sclerosis (MS).

At present, SuppreMol's lead candidate SM101 is being developed for the treatment of Idiopathic Thrombocytopenic Purpura (ITP), an autoimmune disease characterised by a low count of thrombocytes. A Phase I trial in about 42 male volunteers to assess the safety and tolerability of intravenously administered SM101 is ongoing, with final results expected in early 2010. In parallel, the company has filed for a Phase Ib/IIa trial in ITP which is scheduled to start by the end of 2009.

The grant will enable SuppreMol to explore additional formulations of SM101 for subcutaneous and pulmonal administration as well as novel indications, e. g. Systemic Lupus Erythematosus (SLE pulmonitis). This research is performed in close collaboration with the Institute for Pharmaceutical Technology and Biopharmaceutics of the University of Munich.

A second project covered by the grant focuses on the development and evaluation of a new assay for the stratification of B-cell dependent Multiple Sclerosis (MS) patients. This diagnostic tool could help to significantly reduce treatment costs in MS. The project is a collaboration between SuppreMol and the Max Planck Institute of Neurobiology in Munich.

"We are very pleased about the funding," commented Peter Buckel, CEO of SuppreMol. "It will enable us to develop new marketing opportunities for SM101, e. g. in novel indications and by alleviating the administration of SM101 so that it can be applied by general practitioners or the patients themselves. In addition it will help us to develop a diagnostic tool to identify patients with Multiple Sclerosis who might be eligible for treatment with SM101.

"SM101 is addressing a very general mechanism involved in the onset of most autoimmune diseases," said Peter Sondermann, CSO of SuppreMol. "Rather than blocking the entire immune system, SM101 suppresses the specific antibody-dependent part of the immune response only, which we expect to lead to a lasting decrease of the level of pathogenic antibodies in the patient. Therefore, the compound has a huge potential for a broad range of autoimmune diseases."

In 2007, the European Commission granted orphan medicinal product designation for SM101 for the treatment of ITP.

SuppreMol's lead product SM101 is a recombinant, soluble, non-glycosylated version of the Fc-receptor FcγRIIb. It binds to autoantibody/autoantigen complexes and blocks the triggering of Fc-receptors on the surface of immune cells. As a result, the immune response is downregulated and the activation of the inflammation cascade typically seen in autoimmune diseases is prevented.

SM101 targets autoimmune disease specific B cells. Non-target B-cells (i.e., B-cells participating in regular immune reactions) are not affected, so that possible side-effects such as increased susceptibility to infections are not expected.

SM101 has been validated in relevant animal models and has shown strong efficacy in terms of decrease in inflammation and immune reaction.

Source: PharmaLive ©2009 Canon Communications Pharmaceutical Media Group (07/09/09)

Peptimmune, Inc.announced the completion of a clinical trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PI-2301 in subjects with Secondary Progressive Multiple Sclerosis (SP-MS). PI-2301 is a novel peptide copolymer for the treatment of multiple sclerosis and other autoimmune diseases.

The Phase Ib multiple-ascending dose, double-blind, placebo-controlled, randomized study enrolled 50 subjects with SP-MS. A total of 36 subjects received PI-2301 once weekly for 8 weeks followed by an open label extension of an additional 4 weeks. The doses ranged from 1 to 60 mg. Safety at all doses, including potentially therapeutic doses, was established. The most frequent adverse events (AEs) were dose-dependent site reactions which were mild to moderate, transient, and resolved without specific therapy. Dose-dependent increases in serum levels of anti-inflammatory markers were consistent with PI-2301 exposure as measured using the Company's proprietary pharmacokinetic assay. The Company plans to continue developing this promising compound by initiating a Phase II study in multiple sclerosis patients later this year.

"PI-2301 has now shown safety and pharmacologic activity in two clinical studies, the first in healthy volunteers, and this second in patients with multiple sclerosis. As we look forward to the Phase II, we are excited about the observed pharmacologic effects of PI-2301 in patients suffering from secondary progressive MS," stated Thomas P. Mathers, President and CEO of Peptimmune.

Data from this Phase Ib study will be presented at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Eric Zanelli will make a poster presentation titled "Clinical and biological results of a 12-week, double-blind, multiple ascending dose study evaluating the safety and tolerability of peptide copolymer PI-2301 in patients with the secondary progressive form of multiple sclerosis." The poster (P-422) will be presented within Topic 15 - Immunomodulation - 1 during the Poster Session I taking place on Thursday, September 10, 2009, between 2:30 and 5:00 p.m.

About PI-2301

PI-2301 is a second-generation peptide copolymer from a similar compound class as Copaxone(R) (Teva Pharmaceuticals). PI-2301 works through immune modulation by enhancing the regulatory response of the immune system and thereby controlling the pathogenic autoimmune response observed in autoimmune diseases such as multiple sclerosis. PI-2301 has been optimized using Peptimmune's novel platform peptide chemistry and, in preclinical studies, has shown to be more potent and effective than Copaxone in treating disease models for multiple sclerosis and other autoimmune diseases where immune modulation may be effective, such as Crohn's disease, rheumatoid arthritis, and autoimmune uveitis. Peptimmune has high-quality synthesis and analytical methods that provide a superior level of batch-to-batch reproducibility in the manufacturing of PI-2301.

In January 2009 Peptimmune granted Novartis an exclusive option to obtain exclusive worldwide rights to develop and commercialize PI-2301.

Source:  Peptimmune, Inc.(26/08/09)

Amplimmune, Inc., a Maryland-based biotechnology company, and Fast Forward, LLC, the National Multiple Sclerosis Society's subsidiary devoted to bridging the gap between research and drug development, today announced a collaboration to support the development of Amplimmune's AMP-110 therapeutic candidate. This novel and proprietary biological molecule, or biologic, is specifically designed to target and prevent the abnormal immune responses associated with multiple sclerosis and other autoimmune diseases.

The agreement with Amplimmune is the third in a series of growing partnerships between Fast Forward and emerging biotechnology companies. "We are pleased to partner with Amplimmune to advance the development of new treatments for MS," said Dr. Timothy Coetzee, President of Fast Forward. "AMP-110 represents an important inventive approach to inhibiting inflammatory responses in multiple sclerosis." Adds Dr. Coetzee, "Modulating the immune system by using costimulatory and coinhibitory biologics is an active area of research and has significant potential in developing new therapies for MS. AMP-110 fits our profile for supporting innovative and promising new treatments for MS."

"Fast Forward's support provides a strong, independent and scientific validation for developing Amplimmune's AMP-110 for treating MS," said Mr. Michael Richman, President and CEO of Amplimmune. "Building on the exciting discovery of one of Amplimmune's founders, Dr. Lieping Chen, at The Johns Hopkins University, we are pleased to form this collaboration with Fast Forward which will help accelerate AMP-110 into clinical testing."

The National Multiple Sclerosis Society funds research in a range of scientific areas including immune mechanisms, genetics, nerve regeneration and symptom managements. The agreement with Amplimmune is a part of the Society's Fast Forward initiative through which Fast Forward will partner with young innovative biotechnology and pharmaceutical companies to develop treatments, diagnostics, medical devices, and related technologies to treat, reverse and ultimately cure MS. Under the terms of the agreement, Fast Forward will provide Amplimmune with funds to support preclinical development of AMP-110. In consideration, Fast Forward will receive warrants to purchase shares of the company.

Source: PRWeb (25/08/09)

Turning serendipity into science, researchers at the Stanford University School of Medicine have found a link, in mice and in human brain tissue, between high blood pressure and multiple sclerosis. Their findings suggest that a safe, inexpensive drug already in wide use for high blood pressure may have therapeutic value in multiple sclerosis, as well.

While neurology professor Lawrence Steinman, MD, senior author of the new study, cautioned that extensive clinical trial work is needed to determine if the drug, known as lisinopril, can do in humans what it does in mice, he is excited that "we were able to show that all the targets for lisinopril are there and ready for therapeutic manipulation in the multiple-sclerosis lesions of human patients. Without that, this would be just another intriguing paper about what's possible in the mouse."

The paper was published online on Aug. 17 by the Proceedings of the National Academy of Sciences.

The genesis for the paper can be traced to about seven years ago, when Steinman learned he had high blood pressure. His doctor put him on lisinopril, which is used by millions of people all over the world and has an excellent safety profile. Chagrined, Steinman went home and, researcher that he is, immediately did a Google search on the drug. (Steinman is a renowned multiple sclerosis investigator whose earlier work on the inflammatory features of the disease spurred development of a blockbuster class of anti-inflammatory multiple-sclerosis therapeutics. The drug natalizumab, marketed under the trade name Tysabri, is one.)

Long ago, a glitch crept into Steinman's home computer: No matter what keywords he types into the search field, the computer automatically inserts the additional term, "multiple sclerosis." Thus, to his surprise, a list of medical literature popped up offering tantalizing, if vague, hints of a possible connection between multiple sclerosis and a fast-acting hormone, angiotensin, whose receptors abound on blood-vessel walls throughout the body.

In response to, say, a change in posture, angiotensin immediately causes blood vessels to constrict. "That raises your blood pressure so when you stand up to get out of a chair, you don't fall down and faint," said Steinman, who is also the George A. Zimmerman Professor in the medical school. But angiotensin overactivity causes chronic hypertension. Lisinopril controls blood pressure by blocking an enzyme that converts angiotensin's precursor into the active hormone. The drug also appears to have certain anti-inflammatory properties.

Multiple sclerosis is a chronic and occasionally lethal autoimmune disease in which the body's immune system mounts recurring assaults on the myelin sheathing of nerve cells in the brain. This causes nerves to malfunction and can lead to blindness and paralysis. Both multiple sclerosis and atherosclerosis involve inflammatory processes.

Eventually, Steinman and his colleagues decided to test the angiotensin/multiple-sclerosis relationship using modern scientific techniques. First, they examined the multiple-sclerosis lesions of brain samples from autopsied patients. In those lesions, well-established molecular-detection methods turned up significantly elevated levels of both the angiotensin receptor and the angiotensin-producing enzyme blocked by lisinopril.

Next, the investigators turned to an equally well-established animal model: a laboratory-bred strain of mouse that, after being immunized with a particular chemical, develops brain lesions very similar to those observed in multiple sclerosis. When, before immunization with the disease-triggering chemical, mice got lisinopril dosages equivalent to those prescribed for humans with high blood pressure, they didn't develop the paralysis characteristic of disease progression. Strikingly, if it was given after the mice developed full-blown symptoms, lisinopril reversed their paralysis.

The team also found that lisonopril administration reduced numerous molecular measures of inflammation that accompany multiple sclerosis in humans and its analog in the animal model. But, importantly, the drug didn't inhibit the mice's overall immune competence.

An additional observation was that lisinopril administration triggered proliferation of an important class of immune cells, called regulatory T cells, that prevent autoimmune diseases by dialing down the activity of other immune cells erroneously targeting cells and tissues that should be left alone. It's likely, Steinman said, that this proliferation was a key component in the protection provided by the drug, as an infusion of regulatory T cells from mice that had been given lisinopril was sufficient to prevent or reverse the disease process in mice that had been given none.

Steinman's results have major public-health implications, said Marc Feldmann, an Imperial College London immunologist who is familiar with the study but did not participate in it. He noted that the current therapies for multiple sclerosis (including Tysabri) are pricey monoclonal antibodies, costing tens of thousands of dollars annually for each patient treated. "If multiple-sclerosis patients can be treated with lisinopril at something like 1 percent of the price of treatment with Tysabri, then far more patients will receive adequate therapy, at a substantially lower cost to those paying for it," Feldmann said.

Commenting on the study, Helen Yates, Multiple Sclerosis Resource Centre Chief Executive said, “This new piece of research could be very exciting news indeed.  If the researchers can progress this work into a human model with similar results to those shown in mice, it could prove to be a very cost effective treatment for MS.  The possibility that lisinopril could prevent lesion development is, of course, an even more exciting prospect.  Let’s hope that the researchers can take this work to the next level soon”

Source: Stanford University Medical Center (18/08/09)

GTC Biotherapeutics, Inc. has obtained exclusive worldwide rights to the development and commercialisation of recombinant human alpha-fetoprotein (rhAFP), including the recombinant, non-glycosylated version of rhAFP known as MM-093, for the treatment of autoimmune diseases from Merrimack Pharmaceuticals. GTC will receive an initial inventory of bulk drug substance suitable for use in clinical studies. GTC will also assume control of the transgenic goats that express rhAFP in their milk, which were originally developed by GTC for Merrimack and are cared for in GTC’s facilities. GTC intends to further develop rhAFP through commercial partnering.

“This product opportunity represents an exceptional strategic fit for GTC and we are excited to add a drug that has great potential as a treatment for multiple sclerosis and myasthenia gravis to our proprietary pipeline of recombinant human plasma proteins,” stated Geoffrey F. Cox, PhD, GTC’s Chairman and CEO. “The already established safety data and production capability, the published animal disease models, and access to sufficient drug substance make rhAFP an attractive candidate for partnering discussions to support further development and commercialisation, potentially as a phase II product candidate.”

Published studies of rhAFP and AFP derived from cord blood indicate that the recombinant form could be as effective in treating multiple sclerosis as the native form that occurs during pregnancy. With a strong dosing and safety profile and supportive preclinical evaluations of efficacy, further studies of rhAFP in multiple sclerosis or myasthenia gravis may begin at the proof of concept phase II level of clinical evaluation. Preclinical models of myasthenia gravis support the use of rhAFP as a treatment for this unmet medical need.

Human AFP is an immunomodulatory blood protein normally produced at very high levels during pregnancy. Research on AFP suggests that it plays a role in modulating the mother’s immune system to protect the fetus. The presence of high levels of AFP in the mother’s blood has long been associated with remission of many autoimmune diseases. AFP is difficult to express in recombinant systems other than in transgenic mammals and is not available as a blood fractionation product due to very low levels except during pregnancy.

Source: GTC Biotherapeutics, Inc. (08/07/09)

First Drug Derivative of Caribbean Sea Anemone Peptide Scheduled for Clinical Trials in 2010

Kineta, Inc. of Seattle and Airmid Incorporated of Redwood City, CA jointly announce an agreement in which a Kineta subsidiary has acquired exclusive commercial rights to a portfolio of novel therapeutic compounds from Airmid. The array of compounds holds extraordinary potential for the treatment of multiple sclerosis, type 1 diabetes mellitus and numerous other autoimmune diseases.

“This transaction is a significant milestone for Airmid. It places our peptidic Kv1.3 blockers into the very capable hands of Kineta’s drug development team, sets Airmid on a path to provide substantial return-on-investment for our shareholders, and provides funding to enhance the value of Airmid’s retained assets,” said George Miljanich, Ph.D., CEO of Airmid. Under the terms of the deal, Airmid will receive upfront payments, development, regulatory and commercial milestones as well as sales royalties.

Airmid founder, K. George Chandy, MD, Ph.D., also applauded the announcement: “Kineta possesses both the scientific capacity and the track record of success necessary to advance these promising therapeutics toward the goal of conquering multiple devastating autoimmune diseases.”

Following today’s agreement, Kineta One, LLC (a subsidiary of Kineta, Inc.) will aggressively pursue additional preclinical studies on a lead compound. The company intends to file an investigational new drug (IND) application with the FDA and begin clinical trials in 2010. “We are very excited to move forward. Dr. Chandy is an extraordinary scientist who has made an exceptional contribution to the scientific field of autoimmune disease. He will remain an integral advisor to our scientific team,” said Kineta President and CEO, Charles Magness, Ph.D.

Dr. Chandy, Airmid co-founder Dr. Michael Cahalan and their colleagues at the University of California have spent more than two decades identifying and characterizing ion channels and their role in immune cell function under normal conditions and in autoimmune diseases. Dr. Chandy and his collaborators—Dr. Michael Pennington, Dr. Christine Beeton, Dr. Heike Wulff and Dr. Ray Norton—are credited with discovering an array of novel autoimmune compounds which were later patented. Together they founded Airmid Incorporated. A professor of physiology and biophysics at the University of California, Irvine, Dr. Chandy is an internationally recognized authority on mechanisms of autoimmunity and the role of ion channels in autoimmune disease.

The novel class of compounds acquired by Kineta One, LLC today includes potent and highly specific Kv1.3 potassium channel blockers derived from venom of the Caribbean sea anemone. They are designed to suppress activation of effector memory T cells which are important mediators of inflammation and tissue damage in MS, type 1 diabetes and other autoimmune diseases. These compounds have been shown to significantly reverse disease in animal models of multiple sclerosis and rheumatoid arthritis, and also have potential against a number of other autoimmune diseases controlled by effector memory T cells. Animal models also have demonstrated that efficacy is achieved without the generalized immunosuppression that occurs in competing therapies.

Source: Kineta, Inc.(07/07/09)

Hard To Treat Diseases (HTDS) Chief Scientist with its Slavica BioChem subsidiary, Dr. Sanja Pekovic provided updates on recent clinical trials with animal subjects in regards to the use of Ribavirin And Tiazofurin for the potential treatment of Multiple Sclerosis (MS).

Dr. Pekovic reported; "It is now well accepted that axonal injury begins at an early stage in MS, and likely accounts for clinical progression seen later in the disease course, suggesting that early, aggressive treatment is critical in order to suppress long-term disability progression. Researchers from IBISS group (a related research group) tested the effect of combined treatment with ribavirin (R) and tiazofurin (T) administrated during the effecter phase of disease."

Dr. Pekovic added: "We are hopeful, that with additional funding, we will be able to continue along this promising path, and continue researching the potential applications of a combination of ribavirin and tiazofurin in the treatment of MS."

Source: Medical News Today © 2009 MediLexicon International Ltd (03/07/09)

Biogen Idec Inc. and Belgian biopharmaceutical company UCB SA discontinued a Phase II clinical trial of a treatment for relapsing-remitting multiple sclerosis, saying there was no clinically relevant benefit for patients.

The companies said a preliminary interim analysis showed patients enrolled in the clinical trial didn't benefit as expected from the treatment, CDP323, compared with placebo after a six-month treatment period.

Source: Biogen Idec Inc. & UCB SA (01/07/09)

Santhera Pharmaceuticals announced today a collaboration with the US National Institutes of Health (NIH) to investigate Catena^® as potential treatment of Primary Progressive Multiple Sclerosis (PPMS). An estimated 150,000 to 300,000 patients worldwide suffer from this rare but devastating form of Multiple Sclerosis. The Phase I/II trial consists of a one-year observational and a two-year interventional period.

The IPPoMS (Idebenone in Patients with Primary Progressive Multiple Sclerosis) trial is a Phase I/II study with a 12-month pre-treatment baseline period followed by a double-blind, randomized, placebo-controlled treatment of 24 months duration investigating the safety and efficacy of one dose of Catena^® (INN: idebenone) versus placebo. During the baseline period up to 80 patients will be enrolled to collect patient-specific biomarkers of disease progression as well as longitudinal neuroimaging and clinical data. Selection of the primary outcome measure as well as potential adjustments of the sample size will be based on the analysis of data from pre-randomization baseline period for the first 30 patients. The adaptive trial design allows for the selection of the most sensitive measures of tissue destruction of the central nervous system as key outcome parameters. In addition, this specific design was selected to reduce the number of patients usually required for clinical studies in MS.

The IPPoMS study is performed as collaboration between the US National Institute of Neurological Disorders and Stroke (NINDS) at the NIH and Santhera. Under the collaboration, the NIH will conduct the clinical trial while Santhera will supply study medication.

Bibiana Bielekova, Chief of the Neuroimmunological Diseases Unit at the NINDS and principal investigator of the study, declared: "PPMS is a debilitating disease for which no effective treatment is approved. Lack of demonstrated efficacy of immunomodulatory or immunosuppressive treatments suggests that alternative mechanisms, such as mitochondrial dysfunction and oxidative damage may underlie development of clinical disability in these patients. Previous studies have suggested that idebenone can increase the cellular energy production in the mitochondria and protect cells from oxidative stress. By conducting this study, we want to investigate the drug's potential as first efficacious therapy to treat patients suffering from PPMS."

Thomas Meier, Chief Scientific Officer of Santhera, commented: "We are very pleased to be collaborating with Dr. Bielekova and her colleagues at the NIH in this intervention study in PPMS. There is a compelling scientific rationale that suggests that Catena^® may protect from neuronal damage in patients suffering from PPMS. This is based on the principal mode of action of Catena^® as an ATP production modulator and powerful antioxidant which is generally considered as safe and well tolerated in the dose that the NIH will use in the IPPoMS-study."

Catena^® is a trademark of Santhera Pharmaceuticals.

Source: Santhera Pharmaceuticals (24/06/09)

A drug derived from the hydrangea root, used for centuries in traditional Chinese medicine, shows promise in treating autoimmune disorders, report researchers from the Program in Cellular and Molecular Medicine and the Immune Disease Institute at Children's Hospital Boston (PCMM/IDI), along with the Harvard School of Dental Medicine. In the June 5 edition of Science, they show that a small-molecule compound known as  inhibits the development of Th17 cells, immune cells recently recognized as important players in autoimmune disease, without altering other kinds of T cells involved in normal immune function. They further demonstrate that halofuginone reduces disease pathology in a mouse model of autoimmunity.

Currently there is no good treatment for autoimmune disorders; the challenge has been suppressing inflammatory attacks by the immune system on body tissues without generally suppressing immune function (thereby increasing risk of infections). The main treatment is antibodies that neutralize cytokines, chemical messengers produced by T cells that regulate immune function and inflammatory responses. However, antibodies are expensive, must be given intravenously and don't address the root cause of disease, simply sopping up cytokines rather than stopping their production; patients must therefore receive frequent intravenous infusions to keep inflammation in check. Powerful immune-suppressing drugs are sometimes used as a last resort, but patients are left at risk for life-threatening infections and other serious side effects.

Through a series of experiments, the researchers show that halofuginone prevents the development of Th17 cells in both mice and humans, halts the disease process they trigger, and is selective in its effects. It also has the potential to be taken orally. "This is really the first description of a small molecule that interferes with autoimmune pathology but is not a general immune suppressant," says Mark Sundrud, PhD, of the PCMM/IDI, the study's first author.

Recognized only since 2006, Th17 cells have been implicated in a variety of autoimmune disorders including inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, eczema and psoriasis. They are genetically distinct from the other major categories of T-cells (Th1, Th2 and T-regulatory cells).

Th17 cells normally differentiate from "naïve" CD4+ T cells, but when Sundrud and colleagues cultured mouse CD4+ T-cells along with cytokines that normally induce Th17 development, there was a pronounced decrease in Th17 cells -- but not in Th1, Th2 or T regulatory cells -- when halofuginone was added. Similarly, in cultured human CD4+ T-cells, halofuginone selectively suppressed production of IL-17, the principal cytokine made by Th17 cells.

And in mice with experimental autoimmune encephalitis (EAE), an artificially-induced immune disease resembling multiple sclerosis in humans, and marked by infiltration of Th17 cells into the central nervous system, low-dose halofuginone treatment significantly reduced both the development of EAE and its severity. (In mice with another form of EAE that doesn't involve Th17 cells, halofuginone had no effect.)

Wondering how halofuginone works, the researchers did microarray studies of the halofuginone-treated cells to examine patterns of gene expression in response to the drug. Unexpectedly, many genes involved in stress responses were turned on. Eventually, they found that halofuginone acts by activating a biochemical pathway known as the "amino acid starvation response," or AAR, which typically protects cells when amino acids, essential building blocks of proteins, are in short supply. When excess amino acids were added to cultured T-cells exposed to halofuginone, the AAR didn't switch on, and Th17 cells were able to develop. Conversely, the researchers were able to inhibit Th17 differentiation simply by depleting amino acids, thereby inducing the AAR.

Why would the AAR prevent Th17 cells from forming? The researchers propose that the AAR has an energy-saving function, slowing down a cell's building activities to conserve amino acids. "When a cell senses amino acid deprivation, it tries to conserve amino acids by preventing specific types of responses that are energetically expensive," says Sundrud. "In inflamed tissues, a lot of cells are producing a lot of protein, so it would make sense that a cell with amino acid deprivation would want to block signals that promote inflammation."

Halofuginine is one of the 50 fundamental herbs of traditional Chinese medicine, and has been used as an antimalarial agent. Decades ago, the U.S. Army tried to improve upon its antimalarial properties, without success. It has been in clinical trials for scleroderma, but because it is now in the public domain, the pharmaceutical industry has not shown interest in further developing it therapeutically.

But halofuginone, or some yet-to-be developed derivative compound, could potentially be used to address any autoimmune or inflammatory disease related to Th17 cells by activating the AAR, the researchers say.

"Remarkably, halofuginone evokes the AAR in all cells but selectively inhibits T-cell inflammatory responses," says Anjana Rao, PhD, of the PCMM/IDI, a senior investigator on the study. "This recalls the actions of cyclosporin A and FK506, two other immunosuppressive drugs that block the activity of calcineurin. Calcineurin is present in all cells, but selectively prevents the rejection of heart, lung, liver and bone marrow transplants when given to patients. These drugs revolutionized transplant medicine when they were introduced over 20 years ago, and halofuginone may herald a revolution in the treatment of certain types of autoimmune/inflammatory diseases."

Malcolm Whitman, PhD and Tracy Keller, PhD, of the Harvard School of Dental Medicine, and Anjana Rao, PhD, of the PCMM/IDI, were the study's senior investigators. The study was funded by grants from the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the Cancer Research Institute.

Source: ScienceBlog Copyright, Science Blog.2009 (05/06/09)

U.S. medical researchers say they've found a drug used to treat diabetes shows protective effects in the brains of some multiple sclerosis patients.

Researchers at the University of Illinois-Chicago College of Medicine say they conducted a small, double-blind clinical trial involving patients with relapsing remitting multiple sclerosis. The patients were assigned to take pioglitazone -- a type 2 diabetes drug commercially known as Actos -- or a placebo. Patients continued their normal course of therapy during the trial.

The scientists said patients taking pioglitazone showed significantly less loss of grey matter during the course of the one-year trial than patients taking placebo. Of the 21 patients who finished the study, patients taking pioglitazone had no adverse reactions.

"This is very encouraging," said Professor Douglas Feinstein. "Grey matter in the brain is the part that is rich in neurons. These preliminary results suggest the drug has important effects on neuronal survival."

The scientists also tested pioglitazone in an animal model of MS and found the drug "can significantly reduce the clinical signs in mice with an MS-type disease," said Feinstein.

"More importantly, when mice who are already ill are treated with pioglitazone, the clinical signs of the disease go away," he said.

The study is reported in the online edition of the Journal of Neuroimmunology.

Source: Media dis&dat (29/05/09)

Biovista Inc. today announced that BVA-101, its drug targeting Multiple Sclerosis (MS), has shown significant positive results in the MOG-induced Experimental Allergic Encephalomyelitis (EAE) murine model of MS. BVA-101, an existing drug that Biovista repositioned in MS and is aimed at neuroprotection, was shown to have both efficacy in reducing symptoms and no toxic effects in this well established model of MS.

"We are excited about these early results that confirm the predictive capability of our repositioning platform technology and encourage us to further develop this compound in a disease area where there is a significant need for new therapies" said Aris Persidis, Ph.D., President of Biovista. "What is also encouraging is that we reached this stage just 4 months after deciding to work in MS. At the present time we are exploring all options available to us, including the further co-development with a pharmaceutical company and the licensing of the IP to a generics company" Dr. Persidis added.

About Biovista's BVA-101 trial in the MS EAE-MOG model

MS is a chronic inflammatory disease of the CNS with unknown etiology. It is the most frequent non-traumatic disabling neurologic disease among young adults, with 12,000 new diagnoses per year in the US alone, and over 2.5 million patients worldwide. In the animal proof of concept trial, BVA-101 was compared to dexamethasone, a potent anti-inflammatory and immunosuppressive drug that is efficient in accelerating the recovery from MS relapses but too toxic for chronic use. BVA-101 induced a statistically significant reduction of EAE severity, the magnitude of which was statistically similar to that caused by dexamethasone.

Source: Biovista Inc.(02/04/09)

Epiphany Biosciences announced today that the company plans on filing an IND with the Food and Drug Administration (FDA) to study the potential impact of using the antiviral medication valomaciclovir (EPB-348) as an adjunctive therapy in the treatment of multiple sclerosis.

Valomaciclovir has been shown to possess potent antiviral activity in vitro against a number of herpes-related viruses, including herpes simplex (HSV), Epstein-Barr virus (EBV), herpes zoster (HZV), and human herpes virus 6 (HHV-6). The drug is currently being tested in a phase 2b study in patients with acute herpes zoster infection (shingles) and in a phase 2a study in patients with acute infectious mononucleosis.

"There has been accumulating evidence that MS may be the result of multiple contributing factors, including infection by the Epstein-Barr virus," stated Fred Volinsky, MD, CEO of Epiphany. "Based on these data, we feel this is the right time to explore the potential use of valomaciclovir to help manage this illness that can affect young adults as well as children."

Multiple sclerosis is a chronic, and often progressive demyelinating illness of the central nervous system, occurring with a noted predominance among women. "MS affects approximately 2.5 million people worldwide and appears to result from an interplay between genetic and environmental factors which taken together, increase a person's likelihood of developing the disease. MS is also increasing in frequency worldwide. Some progress in managing the symptoms of MS has been achieved with the use of immunomodulatory therapies. This program would be the first foray into potentially augmenting immunomodulatory therapeutics with a medicine specifically targeted at a suspected infectious cause, the Epstein-Barr virus," commented Stephen Hauser, MD, Chair of the Department of Neurology at the University of California, San Francisco and recent recipient of John Dystel Prize awarded jointly by the American Academy of Neurology and the National MS Society for his work in the field of MS research.

"We plan to conduct viral and pharmacokinetic studies prior to the use of valomaciclovir in longer term studies in patients with MS. Valomaciclovir has exhibited a sound safety profile to date with dosages ranging from one gram to three grams daily," reports Brian Murphy, MD, Chief Medical Officer of Epiphany. "We feel that ultimately, a combination approach, especially one that would involve antiviral pharmacologic pressure on the suspected viral component of the disease, could provide patients with better long-term management, especially if coupled with immunomodulatory agents that may cause transient leukopenia."

About Epiphany Biosciences

Epiphany Biosciences is a privately-held company developing therapeutic products and diagnostic technologies that treat or help prevent the spread of pathogenic viruses, including varicella virus (VZV), Epstein-Barr Virus (EBV) and hepatitis C virus (HCV).

Source: Epiphany Biosciences (24/03/09)

Ambrx Inc, and Merck Serono, a division of Merck KGaA, Darmstadt, Germany, today announced a global strategic collaboration to develop and commercialize Ambrx's ARX424 preclinical product candidate for the treatment of multiple sclerosis.  ARX424 was created by Ambrx through the application of its proprietary protein optimization technology, ReCODE(TM).

This second collaboration between the two companies follows a previous agreement announced in 2007 to develop ARX201, Ambrx's long-acting growth hormone product, currently in Phase II of clinical development.

Under the terms of the agreement, Merck Serono will receive worldwide exclusive development and commercialization rights for ARX424. Merck Serono will make an initial payment to Ambrx, and Ambrx is eligible to receive undisclosed clinical, regulatory and commercial milestone payments based upon the successful development and commercialization of potential products resulting from this collaboration, as well as undisclosed royalties on the associated worldwide net sales. Ambrx also retains the option to convert its right to receive royalties in the U.S. to a profit and loss sharing option. If the option is exercised, Ambrx and Merck Serono will share global development expenses, US commercialization expenses as well as profit. In addition, Merck Serono will make an undisclosed equity investment in Ambrx.  Additional terms of the collaboration were not disclosed.

"This second collaboration with Ambrx not only demonstrates their robust research and development capability, it also strengthens our partnership to deliver innovative products to the market to help improve the quality of life of patients," said Vincent Aurentz, Executive Vice President Portfolio Development at Merck Serono.

"We are pleased to expand our productive relationship with Merck Serono, a company ideally suited to harness the potential of our growth hormone and multiple sclerosis product candidates given their franchises in these areas," said Stephen Kaldor, Ph.D., Ambrx President and Chief Executive Officer.  "While we are operating from a strong cash position, we felt it appropriate that Merck Serono make an equity commitment as part of this transaction to further strengthen and align our interests going forward."

Source: PR Newswire © 2008 PR Newswire (24/02/09)

Hard to Treat Diseases (HTDS) announced the results of preliminary testing of a potential treatment for Multiple Sclerosis.

Testing involved the use of a combination of drugs; ribavirin and tiazofurin on animal test subjects. Administration of ribavirin and tiazofurin in combination attenuated or weakened the proliferation of autoreactive T lymphocytes and their infiltration into the nervous tissue that are involved in the destruction of myelin, oligodendrocytes and axons associated with MS. The tests succeeded in decreasing clinical symptoms and duration of the disease induced in experimental animals. These results are encouraging for the future MS therapy.

Also encouraging is the fact that the two drugs in question are currently used in treatment or undergoing clinical trials in relation to the treatment of other diseases. In particular, ribavirin is already in use in human clinical practice as an antiviral drug (VIRAZOL), and is very successful in treatment of respiratory syncicial virus in children, hepatitis C, SARS and HIV. Tiazofurin is in phase II of clinical trials as an anticancer drug.

Multiple sclerosis is a chronic disease with severe neurological symptoms, which often leads to disability. To date there is no suitable therapy for this heavy neurological disorder.

The company will provide further details as they become available.

Source: Hard to Treat Diseases (03/02/09)

A century-old drug that failed in its original intent to treat tuberculosis but has worked well as an anti-leprosy medicine now holds new promise as a potential therapy for multiple sclerosis and other autoimmune diseases. "We never expected that an old antibiotic would hit this target that has been implicated in multiple sclerosis, psoriasis and type 1 diabetes," says Johns Hopkins pharmacologist Jun O. Liu "People have been working for years and spending tens of millions of dollars on developing a drug to inhibit a specific molecular target involved in these diseases, and here, we have a safe, known drug that hits that target,"

The finding about , a synthetic compound made in the 1890s, is reported in Public Library of Science (PLoS One) by Johns Hopkins researchers, who uncovered the drug's latest potential during an ongoing and exhaustive screening of FDA-approved drugs designed to identify new uses for them. The Hopkins team was specifically hunting for immune system control agents within the Johns Hopkins Drug Library, a collection assembled over the past seven years by Liu and colleagues of more than 3,000 drugs in pharmacies or being tested in phase II clinical trials.

The Johns Hopkins scientists say they were surprised to discover that clofazimine interferes with a molecular pathway important in orchestrating the human body's immune response.

"Until now, clofazimine's presumed target was not human cells, but bacteria," says Liu, professor of pharmacology and molecular science, Johns Hopkins University School of Medicine. "But we discovered the drug has a tremendous effect on human immune cells that are heavily involved in both the initiation and execution of an effective immune response."

More specifically, Liu's team sought drugs that stop the molecular signaling pathway that leads from the surface of an immune system cell to the cell's interior, where the signal turns on genes important in activating the immune response, Liu says. In autoimmune diseases, a person's own white blood cells, meant to fight infection or disease, are misguided to target and attack the body's own cells, damaging or destroying them.

To search for such compounds, the team first engineered cells to mimic an immune cell's natural signaling pathway, a complex and circuitous route from the cell surface to the genetic switch inside. They then subjected these specialized cells to the Drug Library, one at a time, and identified more than 200 hits — drugs that inhibited the signaling system significantly, by more than 50 percent.

When they compared the potency of the 200 with each other, "clofazimine was the hit with the highest inhibitory activity," Liu says.

Next, by systematically studying the multistep signaling process, the researchers pinpointed clofazimine's molecular target, a protein "pore" called ion channel Kv1.3, which plays an essential role in the complicated signaling process.

One of the key steps involved in turning on the immune response is the prolonged accumulation of calcium inside of immune cells, Liu explains. When the researchers stimulated an immune cell, setting the signaling event in motion, they noticed that lots of calcium flushed into the cell and lingered there. However, when they pretreated the immune cells with clofazimine, the calcium rush was much less and it didn't hang around as long.

"This let us conclude that clofazimine was blocking the calcium influx into the immune cells," Liu says. "Without enough calcium getting inside a cell, the signaling pathway that turns on the immune response was short-circuited." The Johns Hopkins group also showed that clofazimine tamps down the presence of free calcium in immune cells by disrupting a potassium channel. The combined effect is to shut down a signaling pathway involved in autoimmune disease.

Source: Johns Hopkins Medical Institutions (01/02/09)

Peptimmune, Inc. announced that it has granted Novartis an exclusive option to obtain exclusive worldwide rights to develop and commercialize PI-2301, Peptimmune's multiple sclerosis drug candidate.

In the event that Novartis exercises the option to PI-2301, Novartis would assume the global clinical development, manufacturing, and marketing of PI-2301 and all associated costs. Peptimmune would receive payments upon the option exercise and upon successful completion of certain development, regulatory, and commercial milestones. These payments together could total more than $500 million. In addition, Peptimmune shall be eligible to receive royalties on product sales. Additional terms were not disclosed.

"We believe that Novartis represents an outstanding future partner for Peptimmune and the global development of PI-2301. This option agreement provides Peptimmune with access to both Novartis' world class development expertise and the necessary capital to invest in this proprietary product," said Thomas P. Mathers, President and CEO of Peptimmune.

Todd Foley, Managing Director at MPM Capital commented, "Peptimmune and its world-leading expertise in peptide copolymers represent an attractive investment opportunity."

About PI-2301

PI-2301 is a peptide copolymer developed using Peptimmune's novel platform peptide chemistry. PI-2301 is designed to enhance the regulatory response of the immune system, thereby controlling the pathogenic autoimmune response in certain diseases. PI-2301 is currently in Phase 1b development by Peptimmune.

Source: Peptimmune, Inc.(19/01/09)

Reversing the damage done by multiple sclerosis would be a dream come true for patients of the debilitating disease, and there is some promising research working toward that goal.

The condition is thought to occur when the body literally attacks itself and current therapies only seek to slow or stop that situation. But Biogen Idec Inc. (BIIB) is developing a drug that may repair the damage to the nervous system from the disease, a prospect that could also aid victims of other neurological conditions.

"This is the first entry into our clinical pipeline, or really in anyone else's pipeline that we are aware of, for a truly restorative therapy for MS," said Ken Rhodes, vice president of discovery neurobiology at Biogen.

Though the Cambridge, Mass., biotech company is hopeful for the drug's development, it is yet to be tested in humans and, assuming success, it wouldn't be available to patients for many years.

Much remains unknown about multiple sclerosis, but it is thought to be an autoimmune disease that occurs when the body attacks myelin, the protective insulation surrounding the nerve fibers called axons in the central nervous system. The myelin damage can distort or block messages carried by the axons and result in a wide variety of symptoms such as vision problems, limb numbness and paralysis.

Though the cause is a mystery, MS is thought to develop from some degree of genetic predisposition working in combination with environmental triggers earlier in the life. It is more common in women and tends to develop between the ages of 20 and 50, according to the National Multiple Sclerosis Society.

Current treatments for the disease all involve trying to alter the immune system's ability to attack the nervous systems, notes John Richert, executive vice president of research and clinical programs for the MS Society.

A popular group of drugs are the beta-interferons, which reduce disease flare ups and are similar to proteins that play a role in the immune system. Those are Biogen's Avonex, Bayer AG's (BAY.XE) Betaseron, and Rebif, marketed by Pfizer Inc. (PFE) and Germany's Merck KGaA (MRK.XE).

Teva Pharmaceuticals Industries Inc. (TEVA) makes Copaxone, which seems to fight the nerve-attacking immune cells by acting as a myelin decoy. Biogen and partner Elan Plc (ELN) also sell Tysabri, which prevents those immune cells leaving the blood stream so that they can't get to the brain or spinal cord.

Early Success

The focus of much of Biogen's current discovery research in MS is focused on restorative therapy, but its most advanced program is led by biologist Sha Mi, who joined the company in 2000 and studied why the axons in MS lesions weren't generating new myelin.

Research found that cells called oligodendrocytes were being prevented from undergoing the needed differentiation for them to build new myelin.

Furthermore, Mi found that the so-called LINGO molecule was inhibiting that differentiation and that using an antibody to block LINGO's function could allow myelin to regenerate.

"When we block LINGO function, we can see robust oligodendrocyte differentiation, and they interact with the axon for remylination," said Mi.

The antibody has been shown to be effective in mouse models that are accepted as being useful for mimicking the properties of MS.

The antibody helped the mice grow new myelin, and it also helped with the integrity of the nerve fibers, in comparison to untreated mice, thus aiding nerve function. More myelin growth occurred closer to the site of the antibody application, also suggesting its responsibility for the effects.

The research showed that the antibody didn't prevent the loss of myelin in an animal model, but it did reduce the effects of disease progression.

Though the development is clearly exciting, the antibody is only in toxicity studies that are expected to be completed later this year. Biogen expects to file an Investigational New Drug application with Food and Drug Administration in the fourth quarter and begin human studies starting shortly thereafter.

Rhodes noted that the next goal is to conduct proof-of-concept studies to determine if the drug inhibits LINGO function in humans with the same positive effects.

Hopeful Future

The possibility of repairing damage done by MS and reducing symptoms of the disease would be revolutionary for MS patients, but Dr. Richert believes that currently used therapies are likely to continue as the best treatment for new patients who may not have a lot of nerve damage.

Regeneration would be used on patients who already have neurological deficits, he said, as well as those whose disease continues to progress regardless of treatment.

In order to provide the best benefit, Dr. Rhodes said that the anti-LINGO antibody would likely be used in combination with one of the more traditional immunosupressive approaches.

"As you dampen the immune response, you treat with anti-LINGO to try and actually facilitate recovery and repair," he said.

If successful, the antibody could have a future in treating other neurological disease such as Parkinson's, or even help repair damage done to the spinal cord.

Biogen has a number of programs to explore the antibody's use in other diseases but is cautious on any of those prospects.

"The preclinical data supporting the utility of those indications isn't as well developed yet as it is with MS," Dr. Rhodes said.

Source: CNN Money.com © 2009 BigCharts.com Inc. (14/01/09)

Allozyne will find out soon whether it has a disruptive technology for treating multiple sclerosis. The fledgling Seattle biotech company plans to start its first clinical trial within the next six months, which will give it an early glimpse into whether it can do something that giant companies have been unable to do. It plans to develop an MS drug that works better, lasts longer, has fewer side effects, and requires less-frequent injections than the current standard of care.

Allozyne bears watching as one of the “graduates” of the Accelerator, the Seattle-based startup incubator affiliated with Leroy Hood’s Institute for Systems Biology. Almost exactly a year ago, it raised $30 million from MPM Capital, OVP Venture Partners, Amgen Ventures, Arch Venture Partners, and Alexandria Real Estate Equities. While that deal was getting done, the venture capital backers recruited Meenu Chhabra from her no-doubt lucrative job as a top dealmaker at Switzerland-based pharmaceutical giant Novartis to be the founding CEO. Hood himself, MIT biologist Harvey Lodish, and Nobel Laureate K. Barry Sharpless of the The Scripps Research Institute serve as scientific advisers, so this idea seems to have a little more shine to it than your average startup in town.

The concept has major implications for patients. Without getting too deep into the science (more on that later), Allozyne thinks it has discovered an improved treatment for multiple sclerosis. It’s a disease in which the immune system goes haywire, attacking nerve cells, and ultimately robbing patients of their vision, speech, and walking ability. More than 400,000 patients in the U.S. have this disease (including a disproportionate percentage in the Northwest).

The staple drugs for these patients are from a class of drugs called interferon beta products, which tamp down the part of the immune system that attacks nerves. The drugs are marketed as Biogen Idec’s Avonex, Merck KGaA’s Rebif, and Bayer’s Betaseron. These medicines are huge moneymakers, generating more than $3.5 billion a year in annual sales. But they are far from perfect. The drugs cause flu-like symptoms, have to be taken by injection at least once a week, and sometimes as often as daily, and don’t stop the progressive decline patients have to endure.

Allozyne’s technology aims to be the first to enable what is known as “pegylation” of an interferon beta drug. That means scientists can attach a polymer that helps the drug remain stable for a longer period of time in the bloodstream to do its job. Instead of weekly injections, Allozyne thinks its candidate can be given every other week, or even once a month, Chhabra says. By avoiding the peaks and valleys in bloodstream concentration between injections, the drug might offer improved effectiveness at reducing brain lesions in MS patients, Chhabra says.

“This can supplant interferon beta,” Chhabra says.

Of course, Allozyne isn’t the only company trying to come up with a more convenient way to treat MS. Cambridge, MA-based Biogen is developing an oral pill called BG-12, and Chhabra’s former employer, Novartis, has another oral pill in the works called FTY-720. These drugs are further along in clinical trials, so if they succeed, they could beat Allozyne to the punch with a more convenient MS treatment.

“If the oral drugs in the pipeline fizzle out, there might be a significant market for Allozyne’s product because of its reduced frequency of administration,” says John Richert, executive vice president of research and clinical programs for the National MS Society in New York.

So how is this technology really supposed to work? Allozyne has licensed technology from the lab of Caltech chemists William Goddard and David Tirrell. They discovered a way to essentially snip out a certain amino acid found in the backbone of protein drugs (methionine), and replace it with a genetically modified amino acid that can stick like Velcro to other molecules.

This means that Allozyne should be able to efficiently attach the polymer in exactly the same place on the protein, providing the kind of consistency the FDA likes to see in a product, says Hans van Houte, Allozyne’s vice president of finance and administration. Biogen and other companies have tried to add such polymers to their interferon beta drugs, without success, Chhabra says.

But if this concept can be proven in MS, then the implications could be profound for other diseases, because the method from Goddard and Tirrell can be applied to attach polymers to any number of genetically engineered drugs to improve their properties, Chhabra says.

Besides attaching polymers to drugs, Allozyne’s technique can also be used to attach potent toxins onto genetically engineered drugs, sort of like how Seattle Genetics is developing a souped-up antibody drug for Hodgkin’s disease. If the MS trial shows promise, I’d expect Allozyne to move forward with one of these more novel products, rather than another new-and-improved version of an existing drug. “We don’t want to be seen as just a pegylation company,” van Houte says.

When I met Chhabra over lunch at Joey’s Restaurant a couple weeks ago in South Lake Union, she was eager to tell me about a meeting the company had recently had with the FDA about clinical trial preparations. She expects the trial to get underway before the end of March, in healthy volunteers. She’s busy keeping big drugmakers apprised about partnership possibilities with this drug, because in order to win approval, Allozyne will have to do clinical trials that are way too big for a venture-backed company to do alone. The question is how far it should go alone, building value in the program, so it can get the best terms for a deal.

There’s no rush to sell the baby away. Allozyne currently has about 20 employees and enough cash to carry out its current plans to the end of 2010, Chhabra says. By then, she expects to have the MS drug in Phase II clinical trials, one other drug candidate in human testing, and two to four drugs teed up to enter the clinic. If she can deliver on all of that, then she’ll be holding a pretty strong hand of cards when it’s time to deal with her old friends in Big Pharma.

Source: Xconomy Seattle © 2007-2008 Xconomy (16/10/08)

ISIS Pharmaceuticals Inc. and Australia-based Antisense Therapeutics Ltd. said that the investigational multiple sclerosis drug ATL/TV1102 met the primary endpoint of a significant reduction in disease activity in patients with Relapsing Remitting Multiple Sclerosis, or RRMS, in a mid-stage trial.

ATL/TV1102 is an antisense drug discovered by Isis Pharma and licensed to Antisense Therapeutics. It is an antisense inhibitor of CD49d, a subunit of Very Late Antigen 4 (VLA-4), which plays a key role in cell adhesion to vessel walls. VLA-4 blockade prevents activated lymphocytes from migrating into the CNS (central nervous system) and reduces disease activity in multiple sclerosis.

The Phase II randomized, double-blind, placebo-controlled study evaluated ATL/TV1102 for its effectiveness in reducing multiple sclerosis - related brain lesions as detected by magnetic resonance images. The study was conducted on a total of 77 patients across six European countries.

The patients were either injected with 200mg of ATL/TV1102 over 8-weeks or given placebo subcutaneous injections twice a week and were evaluated for 16 weeks. MRI scans were performed during the screening, and then once a month for 16 weeks. The study showed a considerable decrease of 54.4% in cumulative number of new active lesions in the ATL/TV1102 treated patients compared to placebo.

Antisense Therapeutics noted that the effectiveness of ATL/TV1102 in the phase II study in patients with RRMS shows the potential of the drug in other disease settings such as autoimmune, inflammation and cancer. Also, it validates the application of second-generation antisense drugs for diseases such as cholesterol and diabetes.

Source: RTT News © 2008 RTTNews (22/09/08)

In patients with relapsing-remitting multiple sclerosis (MS), IVIG was shown to reduce the relapse rate and progression of disability. In patients with chronic progressive MS, a beneficial effect of IVIG was not documented in placebo controlled studies.

This trial investigated the influence of IVIG in primary (PPMS) and secondary (SPMS) chronic progressive MS. Two-hundred and thirty-one patients stratified for PPMS (n=34) and SPMS (n=197) were randomly assigned to IVIG 0.4 g/kg per month or to placebo for 24 months. Primary endpoints were 1) the time to sustained progression of disease identified as worsening of the expanded disability status scale (EDSS) sustained for 3 months, and 2) the improvement of neurological functions defined by a patient's best EDSS score.

Secondary endpoints were the proportion of patients with sustained progression, the relapse rate, the assessment of fine motor skills, visual evoked potentials, contrast sensitivity, depression and quality of life. Analysis of the intention-to-treat (ITT) population of combined PPMS and SPMS patients showed that the mean time to sustained progression was 74 weeks in the IVIG compared with 62 weeks in the placebo group (P=0.0406). When PPMS and SPMS patients were analysed separately, the time to sustained progression was also longer in the IVIG group, but the difference was not significant.

There was no IVIG-mediated improvement in neurological functions.In the combined per protocol (PP) treated patients, IVIG treatment prolonged time to sustained progression by 13 weeks (P=0.0396). PPMS patients, but not SPMS patients showed a slight favourable IVIG effect on the best EDSS score.In the combined ITT population there were less patients with sustained progression in the IVIG than in the placebo group (P=0.028). The difference was significant in PPMS (P=0.016), but not in SPMS patients.

In the combined PP population, there was a trend for a favorable IVIG effect on the rates of patients with sustained progression. In patients with PPMS, this IVIG effect reached significance (P=0.036). Other secondary endpoints did not show significant differences between treatment groups. Eighteen patients with PPMS and 102 patients with SPMS withdrew from the study for various reasons.

Treatment was generally well tolerated. It was concluded that monthly IVIG infusion could delay progression of disease in patients with PPMS, and that there was a trend in favour of IVIG treatment in patients with SPMS.

PÃhlau D, Przuntek H, Sailer M, Bethke F, Koehler J, KÃnig N, Heesen C, SpÃth P, Andresen I.
Department of Neurology, Multiple Sclerosis Center, Kamillus-Klinik Asbach, Germany.

Source: Pubmed PMID: 17623736 (01/09/08)

Biogen Idec has made a lot of its money on Avonex and Tysabri, drugs that slow down the rate of flare-ups for people with multiple sclerosis. Now the Cambridge, MA-based biotech company is pursuing a loftier goal. It is working on the first experimental drug that may reverse the symptoms of the neurodegenerative disease.

The drug, being tested in animals and prepped for its first human trial, is designed to block a protein called Lingo-1 that interferes with body’s production of myelin, the fatty protective coating around nerve fibers. People with multiple sclerosis have an overactive immune system that eats away at the myelin layer, and they have no ability to regenerate myelin in the brain or spinal cord, says Sha Mi, a Biogen researcher. That means nerve impulses that control speech, vision, and movement get short-circuited, sort of like when an electrical wire is stripped of its insulation. Biogen thinks it now has engineered a drug that can stop Lingo-1 from doing its dirty work, allowing the body to regenerate myelin coating around nerves. That could restore normal functions, like walking.

“People around the company are very excited about this,” says Kenneth Rhodes, Biogen’s vice president of discovery neurobiology. “It’s potentially a transformational therapy.” Sha Mi, the Biogen scientist who discovered the molecular switch that paved the way for the program, put it this way, “As a scientist, I came all the way from China. If we can create a new medicine to affect patients, that is my dream.”

The drug hasn’t even entered clinical trials yet, and it’s already been an eight-year odyssey. Sha Mi (who goes by the name Misha) joined the company in 2000 from Wyeth’s Genetics Institute unit in Cambridge, MA. Not long after joining Biogen, she found the Lingo-1 protein in a database and learned it was expressed solely in the central nervous system and, then, only in neurons. Later experiments showed that when scientists delete the gene that makes Lingo-1 in mice, those altered mice would recover from a disease in which the immune system eats away at myelin, called autoimmune encephalomyelitis. The same recovery was seen in mice when they were given an antibody drug designed to block the Lingo-1 protein. There were no side effects or dangers seen from producing too much myelin, because the body will only produce the amount needed to cover nerves, Sha Mi says. The combination of experiments, conducted by Biogen scientists and collaborators in China, made the cover of Nature Medicine last October.

Other researchers are working on myelin repair, such as a group led by Bruce Trapp at the Cleveland Clinic, says Rhodes, the Biogen vice president. Madison, NJ-based Wyeth has attempted to develop conventional small molecule drugs against Lingo, but hasn’t been successful, he says.

Biogen is developing a genetically engineered antibody against Lingo because that approach should do a better job of binding with the Lingo protein target on the surface of cells, Rhodes says. The first version, however, wasn’t quite “optimal,” and a newer one is being engineered with better properties, he says. The latest version is made with fully human DNA, instead of partial mouse DNA, because researchers want to be confident that the drug won’t spark the immune system to reject it, especially if it needs to be given chronically. The company is planning to ask the FDA for permission to start its first human clinical trials, although he wouldn’t say when.

No details are available yet on how the trials will be crafted, but Rhodes made clear that the company’s vision is for Lingo to be used in combination with Avonex or Tysabri. The idea is that those drugs can reduce the immune system’s assault on neurons, quieting the storm. That would give an opportunity for the anti-Lingo-1 drug to step in and regenerate myelin around the nerves.

Since 400,000 people in the U.S. suffer from MS, and there’s nothing else quite like this program poised for clinical trials, it seems unlikely that Biogen will have much trouble recruiting patients in the first study. If they show they can regenerate myelin in even a few people, Biogen will be a few steps closer to fulfilling Sha Mi’s dream.

Source: Xconomy © 2007-2008 Xconomy (27/08/08)

Pluristem Therapeutics Inc. announced that the Company’s PLacental eXpanded (PLX-MS) cells have demonstrated in vivo efficacy in the prevention of Multiple Sclerosis (MS). PLX cells are Pluristem’s placental-derived mesenchymal stromal cells (MSCs) that have been expanded in the Company’s proprietary PluriX™ 3-D bioreactor.

In a further analysis aiming to demonstrate the in vivo efficacy of PLX-MS cells for the prevention of MS, Experimental Autoimmune Encephalitis (EAE) was induced in mice via immunization with the MOG_35-55 protein on day 0.

EAE is an autoimmune inflammatory disease of the CNS that represents the paradigmatic model for MS. The animals then received, on day 8, intravenously either PLX-MS or PlasmaLyte, which served as a control. PLX-MS administration prevented the appearance of clinical symptoms and signs associated with MS throughout the 35-day study period compared to those animals receiving the control. Additionally, the beneficial effects were similar to when Zappia et. al. used MSCs that were non-placental in origin in this EAE animal model^†.

Mr. Zami Aberman, Pluristem’s President and CEO, commented: “This trial’s remarkable results demonstrated our PLX-MS cells’ ability to prevent the appearance of multiple sclerosis symptoms and showed the potential for our PLX cells to treat global autoimmune diseases. As a cellular therapy, our PLX cells, which are derived from human placenta, a non-controversial, non-embryonic, adult stem cell source, and stored ready-to-use, could prove to be a readily available preventive therapeutic alternative for these disorders."

Pluristem is initiating repeated sets of EAE experiments at the Berlin-Brandenburg Center for Regenerative Therapy (BCRT) at Charité - University Medicine Berlin, one of the largest independent clinical research centers in Europe.

^†Zappia et. al. Mesenchymal stem cells ameliorate experimental autoimmune encephalitis inducing T cell anergy. Blood. 2005;106: 1755-1761

Source: Pluristem Therapeutics Inc.(11/08/08)

Researchers at SUNY Downstate Medical Center have developed a substance that inhibits the progress of multiple sclerosis (MS) in an animal model. The agent, a novel calpain inhibitor, can be administered orally.

Calpains are a family of proteolytic enzymes naturally found in the human body. Inappropriate activation of calpain is associated with a number of neurodegenerative and autoimmune diseases such as multiple sclerosis. It is known to destroy the myelin sheath that coats and protects the nerves.

In a paper published in the Journal of Neuroimmunology, SUNY Downstate and Maimonides Medical Center researchers described the use of the calpain inhibitor for the treatment of a mouse model of MS. Whether administered by injection or by mouth, the inhibitor produced an almost complete cessation of the disease’s progress.

The calpain inhibitor, developed at Downstate, was shown to reduce clinical illness signs and prevent demyelination and inflammatory infiltration in a dose- and time-dependant manner, and holds promise in treating both the acute and chronic phases of MS. The inhibitor may also prove beneficial for treating other degenerative illnesses, such as Alzheimer’s, Huntington’s and Parkinson’s disease.

Source: Health Article © 2008 - Health Article News (05/08/08)

Peptimmune, Inc. announced today the grant of US Patent Number 7,381,790 (the '790 patent) which protects the composition of matter for its PI-2301 peptide copolymer for the treatment of autoimmune diseases.

PI-2301 is currently in a Phase Ib multiple-ascending dose, double-blind, placebo-controlled randomized study in subjects with multiple sclerosis. Following establishment of safety at potentially therapeutic doses and proof of pharmacologic mechanism, the Company plans to initiate its Phase II study in relapsing remitting multiple sclerosis patients in early 2009.

"This patent represents an important component in the development of our intellectual property in peptide copolymers, including PI-2301," stated Thomas P. Mathers, President and CEO of Peptimmune. "The '790 patent protects what we believe may become a very important therapy for the treatment of multiple sclerosis and other autoimmune diseases."

PI-2301 is a second-generation peptide copolymer from a similar compound class as Copaxone(R) (Teva Pharmaceuticals). PI-2301 has been designed to be more efficacious and more convenient (weekly versus daily dosing) than Copaxone for the treatment of multiple sclerosis. PI-2301 works through immune modulation by enhancing the regulatory response of the immune system and thereby controlling the pathogenic autoimmune response observed in some diseases. In a Phase I single ascending dose, double blind placebo controlled randomized study, all doses of PI-2301 were safe and well tolerated, and no serious adverse events were observed. Pharmacodynamic assays demonstrated evidence of immune exposure consistent with the pharmacologic mechanism of action for PI-2301, and dose-dependent pharmacokinetics was observed.

PI-2301 has been optimized using Peptimmune's novel platform peptide chemistry and, in preclinical studies, has shown to be more potent and effective than Copaxone in treating disease models for multiple sclerosis. PI-2301 has also shown efficacy in preclinical models of autoimmune diseases where immune modulation may be effective, such as Crohn's disease, rheumatoid arthritis, and autoimmune uveitis. Peptimmune has put in place high-quality synthesis and analytical methods that provide a superior level of batch-to-batch reproducibility in the manufacturing of PI-2301.

Over 400,000 Americans have multiple sclerosis (MS), and MS may affect over 2.5 million individuals worldwide. MS is an autoimmune disease in which the individuals' immune system responds against multiple components of nerve-insulating myelin. The effects of these immune-mediated attacks can range from relatively benign to somewhat disabling to devastating, as communication between the brain and other parts of the body is disrupted.

The '790 patent claims "A linear random copolymer YFAK comprising amino acids tyrosine (Y), phenylalanine (F), alanine (A), and lysine (K)," )." which was licensed from Harvard University. The copolymer technology was developed in conjunction with Professor Jack L. Strominger M.D., Higgins Professor of Biochemistry, Department of Molecular and Cellular Biology, at Harvard University. Peptimmune is the exclusive worldwide licensee of the '790 patent.

Source: PR Newswire (C) 2008 PR Newswire. (31/07/08)

OBJECTIVE:

Several studies have reported a reduction of relapses after the long-term administration of IV immunoglobulin (IVIG) to patients with relapsing-remitting multiple sclerosis (RRMS), but they were mostly small and differed in terms of predefined outcome variables and treatment regimen. We therefore set out to test two different doses of a new formulation of immunoglobulin termed IGIV-C 10% for suppression of both clinical and MRI disease activity as well as safety.

METHODS:

One hundred twenty-seven patients with RRMS participated in this multicenter, randomized, double-blind, placebo-controlled trial. Forty-four and 42 patients received treatment with 0.2 and 0.4 g/kg of IGIV-C 10%, and 41 patients received an equal volume of placebo (0.1% albumin) every 4 weeks for 48 weeks. The primary endpoint was the proportion of relapse-free patients. The main secondary endpoint was lesion activity assessed by 6-weekly MRI.

RESULTS:

Baseline variables were similar in IVIG- and placebo-treated groups. After 1 year, the proportion of relapse-free patients did not differ statistically according to treatment (IVIG 0.2 g/kg: 57%; IVIG 0.4 g/kg: 60%; placebo: 68%), and there was no difference regarding the cumulative number of unique newly active MRI lesions (median numbers: IVIG 0.2 g/kg: 8.0; IVIG 0.4 g/kg: 5.0; placebo: 7.2) after 48 weeks. There were no significant between-group differences in the rates of adverse events.

CONCLUSION:

Although IV immunoglobulin (IVIG) treatment was well tolerated, this study did not substantiate a beneficial effect of IVIG in doses ranging from 0.2 to 0.4 g/kg. This result seriously questions the utility of IVIG for the treatment of relapsing-remitting multiple sclerosis.

Fazekas F, Lublin FD, Li D, Freedman MS, Hartung HP, Rieckmann P, Sørensen PS, Maas-Enriquez M, Sommerauer B, Hanna K; PRIVIG Study Group; UBC MS/MRI Research Group.
Collaborators (42)

Rice G, Duquette P, Freedman MS, Panitch H, Coyle P, Vollmer T, Jefferey D, Strasser-Fuchs S, Rektor I, Stourac P, Havrdová E, Meluzínová E, Haas J, Hartung HP, Wolfgang H, Oschmann P, Kiefer R, Haller P, Tumani H, Gold R, Papadimitriou A, Komoly S, Jakab G, Harcos P, Vécsei L, Miller A, Wajgt A, Selmaj K, Stelmasiak Z, Kotowicz J, Constantinescu C, Cheng Y, Faber R, Han J, Lagroix L, Li D, Medina M, Riddehough A, Traboulsee A, To A, Yu R, Zhao G.

Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, A-8036 Graz, Austria.

Source: Neurology. 2008 Jul 22;71(4):265-71 (28/07/08)

Teva Pharmaceutical Industries Ltd. and Antisense Therapeutics Ltd. announced that anti-sense drug, ATL/TV1102, significantly reduced disease activity in patients with relapsing-remitting multiple sclerosis.

The companies noted that their Phase IIa study met its primary endpoint showing a significant reduction by 54.4% in cumulative number of new active lesions in patients taking ATL/TV1102, compared to placebo. In general, ATL/TV1102 was well tolerated.

Based on these encouraging results, Teva said it intends to conduct additional pre-clinical and clinical research before continuing to a Phase III study with ATL/TV1102.

Antisense Therapeutics has two drugs in development and two drugs in pre-clinical research. ATL/TV1102 (injection) is in the advanced stages of a Phase IIa trial as a potential treatment of multiple sclerosis. ATL/TV1102 (inhaled) is at the pre-clinical research stage as a potential treatment for asthma. ATL/TV1102 has been licensed to Teva.

Teva is responsible for funding and performing future development activities for ATL/TV1102.

Teva's decision to move forward with the development of ATL/TV1102 will earn a US$4 million milestone payment under the license agreement between Teva and Antisense Therapeutics.

Source: RTTNews © 2008 RTTNews (30/06/08)

Peptimmune, Inc. announced that physicians have treated the first participant in a clinical trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PI-2301 in subjects with Secondary Progressive Multiple Sclerosis (SP-MS). PI-2301 is a novel peptide copolymer for the treatment of multiple sclerosis and other autoimmune diseases.

The Phase Ib multiple-ascending dose, double-blind, placebo-controlled randomized study will involve up to fifty-three subjects with SP-MS who will receive the drug once weekly in four escalating-dose cohorts. Following establishment of safety at potentially therapeutic doses and proof of pharmacologic mechanism, the Company plans to initiate its Phase II study in multiple sclerosis patients in early 2009.

"While the primary goal of this study is to demonstrate safety of PI-2301 in multiple sclerosis patients, we believe that this clinical trial is one of the most comprehensive looks at the pharmacologic effects of any immunomodulator in patients suffering from autoimmune diseases," stated Thomas P. Mathers, President and CEO of Peptimmune.

PI-2301 is a second-generation peptide copolymer from a similar compound class as Copaxone® (Teva Pharmaceuticals). PI-2301 works through immune modulation by enhancing the regulatory response of the immune system and thereby controlling the pathogenic autoimmune response observed in some diseases.

In a Phase I single ascending dose, double blind placebo controlled randomized study, all doses of PI-2301 were safe and well tolerated, and no serious adverse events were observed. Pharmacodynamic assays demonstrated evidence of immune exposure consistent with the pharmacologic mechanism of action for PI-2301, and dose-dependent pharmacokinetics was observed.

PI-2301 has been optimized using Peptimmune's novel platform peptide chemistry and, in preclinical studies, has shown to be more potent and effective than Copaxone in treating disease models for multiple sclerosis. PI-2301 has also shown efficacy in preclinical models of autoimmune diseases where immune modulation may be effective, such as Crohn's disease, rheumatoid arthritis, and autoimmune uveitis. Peptimmune has put in place high-quality synthesis and analytical methods that provide a superior level of batch-to- batch reproducibility in the manufacturing of PI-2301.

Source: Peptimmune, Inc (17/06/08)

BaroFold Inc. announced that it has initiated a two-stage Phase 1, repeat dosing, single-center, double-blinded study in up to sixty healthy volunteers to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of escalating doses of BaroFeron^(TM) (IFN beta-1b).

In published preclinical studies BaroFeron demonstrated enhanced pharmacological properties, both pharmacokinetics and pharmacodynamics, when compared to commercial interferon beta products. BaroFeron has the potential to offer significant benefits to multiple sclerosis patients as these properties have been demonstrated to correlate with lesion formation by MRI measurements and clinical exacerbations.

"BaroFeron is posed to set a new standard for biologics incorporating our novel PreEMT(TM) technology that produces a product with biopharmaceutical properties that may be superior to conventionally produced proteins," stated Jeffrey L. Cleland, Ph.D., Vice President of Therapeutic Development. "We believe that MS patients will ultimately benefit from the unique properties of BaroFeron."

"This is the Company's first clinical milestone and demonstrates our ability to advance product programs from concept to the clinic in less than 18 months," stated Lyndal Hesterberg, President and CEO. "The tremendous team at BaroFold, combined with the utilization of our unique technology to improve existing biopharmaceutical products, provides us with the ability to rapidly generate multiple product candidates that address large markets. Our goal is to have BaroFeron for multiple sclerosis in late-stage clinical trials and advance two additional two pipeline products targeting allergic asthma and rheumatoid arthritis in the clinic by the end of 2010."

About BaroFeron

BaroFeron is a proprietary recombinant human interferon beta being developed for the treatment of multiple sclerosis. Interferon beta products are considered the "gold" standard for first line treatment options for managing the progression of multiple sclerosis. However, clinical evidence and physician surveys indicate the need to improve upon the efficacy and safety of currently available therapies. BaroFeron is produced using BaroFold's proprietary PreEMT(TM) technology to yield a formulation essentially free of protein aggregates. BaroFeron could potentially be differentiated from other interferon-beta products by improved safety and greater bioavailability enabled by BaroFold's proprietary PreEMT(TM) technology.

Source: BaroFold Inc. (16/06/08)

The Phase I single-ascending dose, double-blind placebo, controlled-randomized study involved fifty-six healthy volunteers who received the drug in eight escalating dose cohorts. All doses were safe and well tolerated (0.035 - 60mg), and there were no serious adverse events. Pharmacodynamic assays demonstrated evidence of immune exposure (tritium uptake, IL-13 in recall responses) consistent with the pharmacologic mechanism of action for PI-2301, and dose-related pharmacokinetics were observed (proprietary antibody-based assay). The Company plans to initiate its first repeat-dose study in multiple sclerosis patients in Q2/2008.

Peptimmune also presented data that details significant differences in the bioavailability, mechanism of action, and pharmacodynamic effects between PI-2301 and Copaxone(R) (Teva Pharmaceuticals). The Company demonstrated four-fold greater bioavailabilty of PI-2301 than Copaxone, and a significantly greater regulatory immune response than Copaxone.

"We are pleased to see that PI-2301 was well tolerated and that this trial has provided evidence of PI-2301's immunomodulatory effects. These data, along with the significant improvements on bioavailability and pharmacodynamic effects with PI-2301, provide further evidence that PI-2301 may replace Copaxone as first-line therapy in relapsing remitting multiple sclerosis," stated Thomas P. Mathers, President and CEO of Peptimmune. "We have designed PI-2301 to maximize the therapeutic benefit of a proven, safe compound class in multiple sclerosis as well as increasing patients' convenience."

PI-2301 is a second generation peptide copolymer from a similar compound class as Copaxone. PI-2301 works through immune modulation by enhancing the regulatory response of the immune system to control the pathogenic autoimmune response in certain diseases. PI-2301 has been optimized using Peptimmune's novel platform peptide chemistry and in pre-clinical studies, has shown to be more potent and effective than Copaxone in treating disease models for multiple sclerosis. PI-2301 has also shown efficacy in pre-clinical models of autoimmune diseases where immune modulation may be effective, such as Crohn's disease, rheumatoid arthritis and autoimmune uveitis. Peptimmune has also introduced highly reproducible manufacturing methods that allow very strict control and characterization of PI-2301 and should provide a superior level of batch to batch consistency.

Source: Peptimmune, Inc.

Multiple sclerosis is the first of four autoimmune diseases that HGS and its partner GlaxoSmithKline want to treat using LymphoStat-B. The companies are still working on the details of the trial, said HGS spokesman Jerry Parrott.

Source: The Washington Post © Copyright 1996-2008 The Washington Post Company (29/05/08)

The research team randomly allocated 40 patients with the relapsing remitting form of MS to treatment with either 20 mg daily of fluoxetine (Prozac) or an inactive substance (placebo) for a period of 24 weeks.

Detailed brain scans (magnetic resonance images or MRI) every four weeks were used to check for new areas of neurological inflammation, a hallmark of active disease.

In total, 38 patients—19 in each group—completed the study. The scans showed that those in the placebo group had more new areas of inflammation than those treated with Prozac.

The effects began to become evident after eight weeks, which corresponds to the time the selective serotonin reuptake inhibitor (SSRI) class of drugs, of which Prozac is one, start to work on relieving depression.

The average number of new areas affected was more than five in the group given the placebo compared with just under two in the group given Prozac.

One in four scans from patients treated with Prozac showed new areas of inflammation compared with four out of 10 of those taking placebo.

During the last 16 weeks of treatment, almost two thirds of patients (63%) in the group given Prozac had no new areas of inflammation compared with only one in four (26%) in the group given placebo.

The authors caution that their study was small, and larger studies would be needed before firm conclusions could be drawn.

But they conclude that their results are “sufficiently encouraging to justify further studies with fluoxetine in patients with MS,” adding that higher doses and treatment combinations with other drugs that alter the immune response, should be considered.

Source: Newswise Medical News © 2008 Newswise. (01/05/08)

ZymoGenetics, Inc. announced that its development partner Merck Serono, a division of Merck KGaA, Darmstadt, Germany, has initiated a Phase 2 clinical trial to evaluate the safety and efficacy of atacicept in patients with relapsing multiple sclerosis (RMS).

"Patients with multiple sclerosis need more treatment options," said Nicole Onetto, M.D., Senior Vice President and Chief Medical Officer of ZymoGenetics. "Our preclinical models have shown biological activity of atacicept in multiple sclerosis and, because of the growing body of supporting data in the literature indicating the importance of B cells and antibodies in the pathology of multiple sclerosis, we believe there is strong rationale for the clinical testing of atacicept in patients with RMS."

The four-arm randomized, double blind, placebo controlled, multicenter study will evaluate the safety and efficacy of atacicept in patients with RMS over 36 weeks of treatment. The primary objective of the study is to evaluate the efficacy of atacicept in reducing central nervous system inflammation in subjects with RMS as assessed by frequent MRI measures.

Approximately 300 RMS patients meeting the eligibility criteria will be randomly assigned to receive one of three subcutaneous doses of atacicept or placebo for 36 weeks. Patients will have follow-up visits at 48 weeks.

About Atacicept

Merck Serono and ZymoGenetics are developing atacicept (formerly referred to as TACI-Ig) as a potential treatment of autoimmune diseases, such as systemic lupus erythematosus (SLE), lupus nephritis (LN), rheumatoid arthritis and multiple sclerosis, as well as B-cell malignancies.

Atacicept contains the soluble TACI receptor that binds to the cytokines BLyS and APRIL. These cytokines are members of the tumor necrosis factor family that promote B-cell survival and autoantibody production associated with certain autoimmune diseases such as systemic lupus erythematosus. Current data indicates that levels of BLyS and APRIL are elevated in patients with rheumatoid arthritis, lupus erythematosus, B-cell malignancies and multiple sclerosis. Atacicept has been shown to affect several stages of B-cell development and may inhibit the survival of cells responsible for making antibodies.

Source: ZymoGenetics, Inc.(30/04/08)

The treatment was found to be safe, with no adverse side effects. It was also shown to have a clear modulatory effect on the immune system. Data demonstrated that there was an increase in the regulatory cells that control the immune response in the body. In addition, there was a decrease in the cytokines that induce inflammation. The results enabled the clinical team to identify the mechanism of the effects as well as to determine which cells in the immune system are involved in the process of defense.

The Phase I trial, which included 18 healthy male subjects, in their 20's and 30's, investigated dosing, safety and the immunological effects of the drug, which was given orally, once daily, for a week. The study was conducted at the Hadassah Hospital, Jerusalem. The drug is based on monoclonal antibody (Anti-CD3) and a glyco lipid given separately and together. The Phase II studies are anticipated to begin during the second half of 2008. Indications under consideration include multiple sclerosis, hepatitis C, diabetes Type II and fatty liver disease.

Source: Pharamaceutical Business Review ©2008 Business Review Ltd (20/04/08)

Antisense Therapeutics reported that it has completed its Phase IIa clinical trial of ATL1102 in patients with relapsing-remitting multiple sclerosis (RR-MS). The trial results are expected to be reported to the market in mid 2008.

Source: Yahoo! Finance Copyright © 2008 Yahoo! (17/04/08)

Using the experimental autoimmune encephalomyelitis (EAE) model, the effect of Symadex was evaluated during both the acute and chronic phases of EAE in the mouse models. A partial, concentration-dependant decrease in clinical signs was observed in the acute prevention experiment, and chronic treatment resulted in a dose-dependent reduction of clinical scores. Plasma titers in a combined treatment group versus disease controls showed significant changes with a trend towards restoring baseline levels of biomarkers found in naïve controls. Symadex has previously shown therapeutic benefit in both the acute and chronic stages of the guinea pig EAE model as well as a similar effect on innate cell biomarkers.

“This study adds to the growing body of work supporting the ability of Symadex to potentially prevent and reverse chronic disease in animal models of multiple sclerosis,” said Dr. Karlik. “The evidence that Symadex targets innate immune cell function in the treatment of MS is encouraging and is a foundation for the Company’s continued work on Symadex in autoimmune models.”

About Symadex™

Symadex (formerly C-1311) is the lead compound in clinical development from a new series of agents, the imidazoacridinones, which have shown in vitro to be potent and selective FLT3 receptor tyrosine kinase inhibitors. Xanthus is exploring the use of Symadex and follow-on compounds for the treatment of a number of autoimmune diseases, such as multiple sclerosis and inflammatory bowel disease. Early preclinical data has shown encouraging signs of activity in models of autoimmune disease. Given the compound's safety profile and oral availability, Xanthus believes Symadex represents an exciting drug opportunity.

Source: Xanthus Pharmaceuticals, Inc. (17/04/08)

A potential treatment for multiple sclerosis (MS), developed by University of Greenwich in association with Kings College, London, has begun clinical trials.

The life sciences company BTG plc, which has licensed the research, is running the trials on a new compound, known as BGC20-0134.

Dr Laurence Harbige and Dr Mike Leach, from the Biomedical & Drug Discovery Research Group in the University of Greenwich School of Science, developed the new treatment following many years of research.

Dr Laurence Harbige explains: "Although the cause of multiple sclerosis is unknown, there is strong evidence that it involves the regulation of the immune system through molecules in our bodies called cytokines. In MS, the balance of these cytokines is altered, leading to inflammation in the brain which can result in serious disability."

Dr Mike Leach adds: "This new treatment should encourage the immune system to rebalance itself, by inhibiting the production of inflammatory cytokines while promoting the production of helpful anti-inflammatory ones."

These initial trials, in volunteers, will look at how the new treatment works in the body and whether it leads to an increase in the helpful cytokines. A pilot study of a prototype treatment developed by the University of Greenwich team, which is related to this compound, has already shown promising results. It demonstrated clinical benefits in patients with a common form of multiple sclerosis, called relapsing-remitting. It led to decreases in relapse rates, disability and pain, along with improvements in quality of life. Preclinical research on the new compound, BGC20-0134, indicates that it may be three times as potent as this prototype.

Professor Tom Barnes, Pro Vice-Chancellor for Research & Enterprise at the University of Greenwich, congratulates the team behind the discovery: "It is very good news that this research is now in clinical trials. Our university aims to carry out work which is useful to society and this discovery is a classic example of that. It highlights the excellence of the research staff at Greenwich and also the business orientation of the university, through this partnership with BTG plc. Drs Harbige and Leach are to be congratulated on this important milestone."

Louise Makin, BTG's Chief Executive Officer, comments: "The effective treatment of multiple sclerosis remains a significant unmet need. We are pleased to have started clinical development of BGC20-0134, which has the potential to address different forms of the disease and has the advantage of being an oral product."

Source: Medical News Today © 2008 MediLexicon International Ltd (14/04/08)

The Indian pharmaceutical company said it intends to file an IND (investigational new drug) application with the U.S. Food and Drug Administration by August 2008 for initiation of phase I trials.

It expects to complete phase I in this fiscal year immediately followed by a proof of concept phase IIa study.

Glenmark has already manufactured sufficient antibody for conducting phase I and phase IIa clinical studies, the company said in a press release.

Source: Forbes.com © 2008 Forbes.com (11/04/08)

• Patient dosing completed
• Patient monitoring phase to be completed this month
• Results of trial on track to be reported in mid 2008

Antisense Therapeutics Ltd. provided the following update on the Phase IIa clinical trial in patients with relapsing-remitting multiple sclerosis.

The dosing phase of the study has now been completed. All patients enrolled into the study have received either ATL1102 or placebo injections. The next step in the study is the completion of the 8 week monitoring phase of the trial. The last patient is scheduled to complete their final monitoring visit by the middle of this month. This will mark the end of the trial, after which the entry of the clinical trial data into the trial database will be finalised and the database locked for statistical analysis. The results of this analysis will then be reported to the market. The trial remains on track with results to be reported in mid 2008.

As announced last month, ANP has licensed ATL1102 to Teva Pharmaceutical Industries Ltd (Teva). As per the licence agreement, ANP is responsible for the completion of the current Phase IIa trial with Teva to fund and perform all future development of ATL1102 beyond the current trial.

Background Information
ATL1102 Phase IIa trial is a randomised double-blind, placebo-controlled clinical trial of ATL1102. Patients received either ATL1102 or placebo injections over 8 weeks, and were monitored with monthly MRI (magnetic resonance imaging) brain scans during treatment, and for the 8 weeks following treatment. 77 patients were enrolled in the trial, which was conducted at multiple trial sites across six European countries The goal of the trial is to obtain preliminary evidence of ATL1102’s effectiveness in reducing the number of MS-related brain lesions as detected by MRI.

ATL1102 is a second generation antisense inhibitor of CD49d, a subunit of VLA-4 (Very Late Antigen-4), and is currently in Phase IIa clinical trials as a treatment for MS. In inflammation, white blood cells (leukocytes) move out of the bloodstream into the inflamed tissue, for example, the CNS in MS, and the lung airways in asthma. The inhibition of VLA-4 may prevent white blood cells from entering sites of inflammation, thereby halting progression of the disease. VLA-4 is a clinically validated target in the treatment of MS. Antisense inhibition of VLA-4 has demonstrated positive effects in a number of animal models of inflammatory disease including MS (Myers et al. J Neuroimmunol 160, p12-24, 2005).

Source: Antisense Therapeutics (01/04/08)

T-cells are a form of white blood cell which assists the body's immune system attack specific pathogens and researchers have had success when they have administered the drug to mice.

"We know that it generates t-cell lines that are regulatory for auto immune diseases and that the same t-cell line will suppress three different auto immune diseases in mice," said study author Jack Strominger of Harvard University.

"It is also effective in several other auto immune diseases in mice, so it's possible this class of molecules could be more broadly used than simply for multiple sclerosis," he added.

Multiple sclerosis or MS is a disease which affects the central nervous system, consisting of the brain and spinal cord. The cause of the disease is still yet to be discovered despite it being the most common neurological condition afflicting young adults.

Strominger told AFP news agency he and his team developed a relative of the drug Copaxone which is currently used to treat the condition. The team tested the new drug on mice directly before generating a T-cell line from the treated mice.

"Whether this relative or another one is going to replace Copaxone, I don't know but there are certain to be second or third generation drugs in this category," he said. "Mice are not man and the only way to find out whether FYAK is more effective than Copaxone is to do a clinical trial."

The study has been reported in the Proceedings of the National Academy of Sciences.

Source: The Tech Herald © 2008 The Tech Herald.com (25/03/08)

The Phase I single ascending dose, double blind placebo controlled randomized study involved 56 healthy volunteers who received the drug in eight escalating dose cohorts. All doses were safe and well tolerated, and there were no serious adverse events. Pharmacodynamic assays demonstrated evidence of immune exposure consistent with the pharmacologic mechanism of action for PI-2301, and dose related pharmacokinetics were observed. The Company plans to initiate its first repeat dose study in multiple sclerosis patients in Q2/2008.

"We are pleased to see that PI-2301 was well tolerated and that this trial has provided evidence of single dose priming of healthy subjects. This effect is important as repeated doses in multiple sclerosis patients should lead to therapeutic immune modulation," stated Thomas P. Mathers, President and CEO of Peptimmune. "We have designed PI-2301 to maximize the therapeutic benefit of a proven, safe compound class in multiple sclerosis as well as increasing patients' convenience."

PI-2301 is a second generation peptide copolymer from a similar compound class as Copaxone(R) (Teva Pharmaceuticals). PI-2301 works through immune modulation by enhancing the regulatory response of the immune system to control the pathogenic autoimmune response in certain diseases. PI-2301 has been optimized using Peptimmune's novel platform peptide chemistry and in pre-clinical studies, has shown to be more potent and effective than Copaxone in treating disease models for multiple sclerosis. PI-2301 has also shown efficacy in pre-clinical models of autoimmune diseases where immune modulation may be effective, such as Crohn's disease, rheumatoid arthritis and autoimmune uveitis. Peptimmune has also introduced highly reproducible manufacturing methods that allow very strict control and characterization of PI-2301 and should provide a superior level of batch to batch consistency.

Source: Peptimmune, Inc (19/03/08)

The authors of the study therefore suggested that agents similar to the one they characterised might provide a new approach to treating individuals with MS and other neurodegenerative disorders.

Multiple sclerosis (MS) is a chronic inflammatory disease of the brain and spinal cord. Individuals with MS develop progressive neurological disability, and this is thought to be caused by degradation of the nerve cells. It is therefore hoped that treatments that protect nerve cells might help individuals with the progressive form of MS.

Data to support this hypothesis has now been generated using a chronic progressive EAE mouse model of MS by Howard Weiner and colleagues at the Brigham and Women's Hospital, Harvard Medical School, Boston.

In the study, treatment of mice after the onset of disease with a water-soluble agent known as ABS-75, which has antioxidant properties and blocks the stimulation of the subset of nerve cells that express the NMDA receptor, markedly reduced disease progression.

This beneficial effect was associated with decreased nerve cell degradation, and a similar protective effect was observed for ABS-75 when it was added to cultured nerve cells exposed to damaging reagents. These data led the authors to suggest that agents similar to ABS-75 might provide a new approach to treating individuals with MS and other neurodegenerative disorders.

Journal reference: Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. Journal of Clinical Investigation. March 12, 2008.

Source: Science Daily © 1995-2008 ScienceDaily LLC (14/03/08)

Sirtris Pharmaceuticals, Inc, announced today that drug candidate SRT501, when orally administered, suppressed neurological dysfunction in a preclinical model of multiple sclerosis. Kenneth Shindler, MD, PhD, Assistant Professor of Ophthalmology at the University of Pennsylvania Scheie Eye Institute and lead investigator, will present the data today at the North American Neuro-Ophthalmology Society annual meeting.

The new data builds on earlier work by Dr. Shindler in the same preclinical model showing that activation of the SIRT1 enzyme with SRT501 is neuroprotective for optic neuritis (inflammation of the optic nerve that can cause a complete or partial loss of vision) by reducing the loss of retinal ganglion cells. Optic neuritis is common in patients with multiple sclerosis and can be an early warning sign for the disease. Sirtris Pharmaceuticals Senior Vice Present for Development, Peter Elliott, PhD, was a co-author of this work published in the August 2007 issue of Investigative Opthalmology & Visual Science.

In the new work, Dr. Shindler’s team used mice with experimental autoimmune encephalomyelitis (EAE), which causes the autoimmune system to attack the eye and central nervous system. These effects on the central nervous system mirror symptoms observed in patients with multiple sclerosis.

The mice were observed for clinical signs of EAE, measured by the strength and duration of tail and limb paralysis. Mice were given daily oral doses of SRT501 at 1000 mg/kg beginning at day 10 through day 14, the peak day of the autoimmune system attack. The paralysis scores of the treated mice improved more completely than the untreated mice following the first clinical episode of EAE.

“We have previously established that we can reduce the loss of retinal ganglion cells during acute optic neuritis in EAE mice with SRT501 when injected into the vitreous layer of the eye,” said Dr. Shindler. “This work shows oral SRT501 exerts similar effects in optic neuritis and leads to suppression of observed dysfunction in the first clinical episode of EAE, suggesting added neuroprotective benefits of SIRT1 activation.”

Source: Sirtris Pharmaceuticals, Inc. (10/03/08)

BTG plc, the life sciences company, announces that dosing has commenced in a Phase I clinical study of BGC20-0134, a potential treatment for multiple sclerosis.

The randomised, double-blind, placebo-controlled study will assess the pharmacodynamic, pharmacokinetic and safety profiles of single and multiple oral doses of BGC20-0134 in healthy volunteers.

Louise Makin, BTG's chief executive officer, commented: "The effective treatment of multiple sclerosis remains a significant unmet need. We are pleased to have started clinical development of BGC20-0134, which has the potential to address different forms of the disease and has the advantage of being an oral product."

Although the cause of multiple sclerosis is unknown, there is strong evidence that autoimmune mechanisms are involved in its development. T-cell infiltration into the central nervous system and resultant dysregulation of key pro-inflammatory cytokines leads to myelin loss, neuronal damage and the onset of symptoms and disability. BGC20-0134 is a novel structured lipid designed to restore the balance between pro-inflammatory (e.g. IL-1b and TNFá) and anti-inflammatory (e.g. TGFb1) cytokines.

In a pilot study of a prototype compound, patients with the relapsing-remitting form of multiple sclerosis experienced clinical benefits including decreases in both relapse rates and EDSS scores (a standard measure of disability in multiple sclerosis), together with improvements in pain and cognitive endpoints. In preclinical models of multiple sclerosis, the potency of BGC20-0134 was shown to be three times that of the prototype compound.

Source: BTG Ltd (06/03/08) 

"Despite the availability of newer biologic agents, drugs such as mitoxantrone remain an important therapy in relapsing MS. Long term cardiotoxicity remains a major drawback to treating multiple sclerosis with mitoxantrone and imposes a limitation both for selection of patients and for the duration of the treatment," said R.E. Gonsette, M.D., Chairman Fondation Charcot Stichting and principal investigator of the study. "In addition to the potential for lower cardiac toxicity, preclinical studies suggest that pixantrone may provide more effective immune regulation than mitoxantrone, the only currently approved cytotoxic agent for treating MS."

The investigator-sponsored trial (IST) will enroll 20 patients in Belgium, France and Germany.

About the Study

Twenty patients with aggressive RR MS or SP MS who failed to respond to approved immunomodulatory agents (interferons, glatiramer acetate) will be included. The objectives of the study are to determine the efficacy of pixantrone as an immunosuppressive agent based on its ability to decrease the lymphocyte count and to evaluate efficacy in MS based on gadolinium enhanced magnetic resonance imaging. This trial is an open-label, multi-center, non-comparative study of pixantrone administered at a dose of 120 mg/m2 once every 21 days (3 weeks). Four consecutive three-week courses of pixantrone will be administered in order to determine if this regimen results in lymphopenia of less than or equal to 1000/mm3. The doses and the number of infusions will be adapted to leukocyte, granulocyte and thrombocyte counts and possibly reduced.

About Pixantrone

Pixantrone (BBR 2778) is a novel DNA major groove binder that contains an aza-anthracenedione molecular structure, differentiating it from anthracycline chemotherapy agents. A new chemical compound for the treatment of non-Hodgkin's lymphoma (NHL), and various other hematologic malignancies, solid tumors, and immunological disorders, pixantrone is being developed by CTI to improve the activity and safety in treating cancers usually treated with the anthracycline family of anti-cancer agents. Anthracyclines have been shown to be very active clinically in a number of tumor types, such as lymphoma, leukemia, and breast cancer. For these diseases, anthracycline-containing chemotherapy regimens are effective in first-line (initial) treatment. However, they may cause cumulative heart damage that limits lifetime dosage and does not allow for retreatment. Pixantrone has been designed to reduce the potential for heart damage compared to currently available anthracyclines or anthracenediones without a loss in anti-tumor or immunomodulatory activities.

Source: Earthtimes © 2008 www.earthtimes.org (06/03/08)

This is with approval from the Medicines and Healthcare Products Regulatory Agency [MHRA] in the U.K. The company intends to develop GRC 4039 for Rheumatoid Arthritis.

Glenmark expects to complete Phase I trials for GRC 4039 by October 2008 and initiate Phase II by January 2009.

Source: The Hindu Business Line © 2008, The Hindu Business Line (21/02/08)

Yissum Ltd., the technology transfer company of the Hebrew University of Jerusalem, today announced that it has licensed an orally-available small molecule for several biological indications including the treatment of neurodegenerative diseases to Eucalyptus Ltd. The molecule is an antioxidant that overcomes the blood-brain barrier.

"This invention, by Professor Daphne Atlas, jointly developed with Dr. Daniel Offen and Professor Eldad Melamed, is a breakthrough in the treatment of oxidative stress, which plays a major role in CNS disorders," stated Nava Swersky Sofer, CEO of Yissum. "We are delighted to collaborate with Professor Ashley Bush, CSO, Eucalyptus, a leading expert in Alzheimer's research to take our invention into the clinic for the benefit of patients."

Under the terms of the agreement, Eucalyptus has acquired worldwide exclusive rights to develop and commercialize the molecule and Yissum together with Ramot, the technology transfer company of Tel Aviv University, and Mor Research Applications, the technology transfer company of Clalit Health Services, will receive upfront payments, milestone payments in accordance with development progress and royalties from sales of final products.

The molecule, N-acetylcysteine amide (AD4), is an antioxidant for the prevention and treatment of Parkinson's, Alzheimer's, multiple sclerosis and other neurodegenerative diseases that are linked to oxidative stress, and also has broader applications in biology. Oxidative stress, induced by free radicals, plays an important role in the progression of neurodegenerative and age-related diseases, causing damage to proteins, DNA, and lipids. For example, increasing evidence correlates Parkinson's disease with the accumulation of oxidative damage in specific neurons in the brain. AD4 is administered orally, and is able to cross the blood-brain barrier, thus overcoming a major obstacle of central nervous system (CNS) directed drugs.

Pre-clinical data showed the ability of AD4 to protect cells in culture from oxidative damage. Furthermore, the molecule was shown to protect neuronal cells from damage in rodent models of both Parkinson's disease and multiple sclerosis. The low toxicity of AD4, as evidenced in the lab, together with its neuroprotective function and high bioavailability make it highly suitable for the treatment of CNS disorders.

The molecule was invented by Daphne Atlas, Ph.D., Professor of Neurochemistry at the Hebrew University of Jerusalem, Israel. The work was performed in collaboration with Dr. Daniel Offen, Ph.D. from the Tel Aviv University, Israel and Eldad Melamed, MD, Professor and Chairman of the Department of Neurology at the Rabin Medical Center, Petah Tiqva, Israel.

"In our aging society, in which neurodegenerative diseases have become more common, there is a growing need for safe and effective drugs for age-related diseases. AD4 which overcomes the blood-brain barrier, is an excellent candidate for both the prevention and treatment of various neurodegenerative disorders," commented Prof. Daphne Atlas.

Professor Ashley Bush, CSO, Eucalyptus, added "We are excited to be able to progress the pioneering work of our Israeli collaborators towards commercialization. I am very confident that AD4 will be therapeutically useful for several major neurological disorders, certain major psychiatric conditions as well as several other biological applications. I expect this to be a rapid development project."

About Yissum

Yissum was founded in 1964 to protect the Hebrew University's intellectual property and commercialise it. $1 Billion in annual sales are generated by products based on Hebrew University technologies licensed out by Yissum. Ranked among the top technology transfer companies in the world, Yissum has registered 5000 patents covering 1400 inventions; licensed out 400 technologies and spun out 60 companies. Yissum's business partners span the globe and include companies such as Novartis, Microsoft, Johnson & Johnson, Merck, Intel, Teva and many more.

Source: Yissum Ltd (14/01/08)

Ofatumumab is an investigational, fully human, next generation monoclonal antibody that targets a unique epitope of the CD20 receptor on the surface of B-cells. Other anti-CD20 antibodies currently available or in development bind to a different epitope on the CD20 receptor. Ofatumumab is being developed under a co-development and commercialization agreement between Genmab and GlaxoSmithKline.

"Multiple sclerosis is a debilitating disease for which there are currently few treatments," said Lisa N. Drakeman, Ph.D., Chief Executive Officer of Genmab. "We hope our fully human antibody, ofatumumab, may offer another potential treatment option for patients suffering from this incapacitating disease."

About the trial

The double blind randomized trial will consist of two parts. Part A will include approximately 36 patients in one of three increasing dose cohorts (100 mg, 300 mg or 700 mg of ofatumumab) randomized to receive ofatumumab or placebo. An independent data monitoring committee (IDMC) will evaluate the safety of each sequential cohort prior to progression to the next cohort. When all patients in Part A have had their week 4 MRI scan, the IDMC will evaluate the data before Part B of the study begins.

Part B will consist of a 48 week treatment period of approximately 288 patients. Patients will be randomized to treatment with 100 mg, 300 mg, or 700 mg of ofatumumab or placebo. After week 24, patients on an active dose will receive re-treatment with the same dose of ofatumumab or placebo. Patients on placebo will receive ofatumumab at the highest tolerated dose from Part A.

The objective of the study is to determine the safety and tolerability of three doses of ofatumumab and the dose response of ofatumumab on disease activity on MRI in patients with RRMS. The primary endpoints are safety and cumulative number of new Gd-enhanced lesions from week 8 to week 24.

Source: Genmab A/S (14/12/07)

Xanthus Pharmaceuticals, Inc. today presented preclinical data further supporting the potential for Symadex™ to reverse the clinical and pathological signs of multiple sclerosis (MS), including new data demonstrating increased spinal cord remyelination. The study was presented by Dr. Stephen J. Karlik, Ph.D., Professor of Diagnostic Radiology at the University of Western Ontario, London, Ontario and researchers from Xanthus at a meeting of the Multiple Sclerosis Society of Canada in Banff, Canada.

Using an animal model of experimental autoimmune encephalomyelistis (EAE) designed to replicate MS, Dr. Karlik studied the efficacy of Symadex in both acute and chronic phases of the disease. While treatment with Symadex in this study attenuated acute EAE, it prevented chronic disease. Importantly, in chronic disease Symadex also demonstrated a statistically significant ability to reverse clinical signs of EAE, including perivascular inflammation, myelitis (inflammation of the spinal cord resulting in a loss of its ability to transmit nerve impulses) and demyelination (the loss of myelin, a protective coating of the nerve fibers, that can lead to impaired bodily functions).

Of significant note, Symadex also increased spinal cord remyelination (the repair of damaged myelin) in the study. Myelin repair occurs spontaneously in MS, but happens very slowly. Identifying ways to speed the healing process is an important component in finding an effective treatment for MS. In the study, remyelination was determined after four weeks of treatment by a blinded observer who measured the size of all lesions and the amount remyelinated in all sections of the animal.

The study also builds on prior data demonstrating Symadex’s novel mechanism of action, which is believed to directly target macrophages and monocytes, key cells responsible for driving the autoimmune response.

“This study adds to the growing body of work supporting the ability of Symadex to prevent and reverse chronic disease in the animal model of multiple sclerosis,” said Dr. Karlick. “The newly observed evidence of remyelination is noteworthy and warrants additional study.”

“Repeated studies of Symadex continue to support the promise of the candidate,” said Richard T. Dean, Ph.D, Xanthus’s Chief Executive Officer. “We remain on track to initiate a human proof-of-concept study in autoimmune disease in 2008 and believe the data on remyelination enhances the partnering opportunities for Symadex™.”

About Symadex™

Symadex (formerly C-1311) is the lead compound in clinical development from a new series of agents, the imidazoacridinones, which have shown in vitro to be potent and selective FLT3 receptor tyrosine kinase inhibitors. Symadex is currently in a Phase 2 study for women with metastatic breast cancer, and has the potential to be active in hematological malignancies. Xanthus is also exploring the use of Symadex and follow-on compounds for the treatment of a number of autoimmune diseases, such as multiple sclerosis and inflammatory bowel disease. Early preclinical data has shown encouraging signs of activity in models of autoimmune disease. Given the compound's safety profile and oral availability, Xanthus believes Symadex represents an exciting drug opportunity. Further preclinical studies are currently being conducted, after which the Company expects to enter clinical development.

Source: Xanthus Pharmaceuticals, Inc. (12/12/07)

Treatment of active or passive EAE with RTL551 after disease onset significantly reduced clinical signs and spinal cord lesions. Moreover, RTL551 treatment strongly and selectively reduced secretion of interleukin-17 and tumor necrosis factor by transferred green fluorescent protein-positive (GFP+) MOG-35-55-reactive T-cells and almost completely abrogated existent GFP+ cellular infiltrates in affected spinal cord sections.

Reduced inflammation in spinal cords of RTL551-treated mice was accompanied by a highly significant downregulation of chemokines and their receptors and inhibition of VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) expression by endothelial cells.

Thus, RTL therapy cannot only inhibit systemic production of encephalitogenic cytokines by the targeted myelin oligodendrocyte glycoprotein-reactive T-cells but also impedes downstream local recruitment and retention of inflammatory cells in the CNS.

These findings indicate that targeted immunotherapy of antigen-specific T-cells can result in a reversal of CNS lesion formation and lend strong support to the application of the RTL approach for therapy in MS.

Sushmita Sinha,^1,2 Sandhya Subramanian,¹ Thomas M. Proctor,^1,7 Laurie J. Kaler,¹ Marjorie Grafe^,3,4 Rony Dahan,^2,3 Jianya Huan,^2,7 Arthur A. Vandenbark,^1,2,5,7 Gregory G. Burrows,^2,6,7 and Halina Offner^1,2,4,7

¹Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, and Departments of ²Neurology, ³Pathology, ⁴Anesthesiology and Perioperative Medicine, ⁵Molecular Microbiology and Immunology, and ⁶Biochemistry and Molecular Biology and ⁷Tykeson MS Research Laboratory, Oregon Health & Science University, Portland, Oregon 97239

Source: The Journal of Neuroscience Copyright © 2007 by Society for Neuroscience. (15/11/07)

Amiloride was found to reduce degeneration of nerve tissue in mice and the team at Oxford University are now planning a trial in MS patients.

It works by blocking the build up of high levels of calcium in nerve cells, which can lead to nerve damage.

There are about 100,000 people with MS in the UK.

The condition is caused by a defect in the body's immune system, which turns in on itself, and attacks the fatty myelin sheath which coats the nerves.

This damage to nerve cells is caused in part by a build up of calcium.

Professor Lars Fugger and colleagues investigated the effects of a specific channel, ASIC1, which controls the entry of calcium molecules into cells.

In mice with a condition that mimics MS, they found that when the channel remains open, calcium can flood into nerve cells in higher than normal proportions and cause damage.

Inflammation like that found in MS leads to acidic conditions, which would lead to the channel opening and too much calcium accumulating in nerve cells, Professor Fugger said.

Treatment

Amiloride, a drug used for many years to treat high blood pressure and heart failure, was found to stop calcium entering through the ASIC1 channel and prevent degeneration of nerve tissue in mice, the journal Nature Medicine reported.

Professor Fugger from the Medical Research Council Human Immunology Unit said the fact the drug was already licensed would speed up the process of getting the treatment to patients should it be prove effective.

He is currently working out what the appropriate dose would be in humans and plans to start a clinical trial next year.

"To develop a drug from scratch takes 10-15 years and a billion dollars and some of them are abruptly halted by unexpected side effects," he said.

"It was known that calcium is not good for nerve cells but it's not been appreciated how simple it is to block it."

Dr Laura Bell, from the MS Society, said: "Protection of nerve fibres is a promising and vital area of research and this is why the MS Society is currently spending half a million pounds on a clinical trial investigating this type of nerve protection in people with MS.

"The early stage results from Oxford are interesting and we look forward to seeing the findings of future studies."

The research is published in Nature Medicine.

Source BBC News © BBC 2007 (12/11/07)

Principal investigator Simon Broadley, MD, PhD, Associate Professor of Neurology, Department of Medicine, Griffith University, Gold Coast City, United States, discussed the findings of the study in a presentation.

"Chaperonin 10 was originally known as an early pregnancy factor, as it was discovered as one of the factors in pregnancy that was thought to induce immune tolerance during pregnancy. And it was then found to improve the outcome in experimental models of multiple sclerosis."

Subsequently, it was shown to be identical to heat-shock protein Hsp10, and it is now known as chaperonin 10. In its role as a chaperone, chaperonin 10 is thought to be involved in the mitochondrial protein folding. Furthermore, it has a protective effect in experimental autoimmune encephalomyelitis, with suppression of the proinflammatory cytokines and chemokines, and it has been safely given to healthy subjects and patients with MS.

This randomised, double-blind, placebo-controlled, phase 2 study consisted of a 4-week lead-in, a 12-week treatment period, and a 4-week exit evaluation after completion of treatment. Clinical assessments, including Expanded Disability Status Scale (EDSS), and magnetic resonance imaging (MRI) were undertaken every 4 weeks.

Of 73 patients with relapsing-remitting (RRMS) or secondary progressive (SPMS) who were screened, 11 patients were randomized to receive placebo twice weekly and 20 received IV chaperonin 10 at a dose of 5 mg twice weekly, and 15 patients received chaperonin 10 at a dose of 5 mg once weekly plus placebo once weekly, both IV.

Chaperonin 10 was well tolerated and safe when administered at these doses.

No significant changes were seen in mean EDSS scores comparing the baseline score with the 12-week score in the placebo group (3.8 vs 3.8, respectively), placebo/chaperonin 10 group (3.2 vs 3.3) and chaperonin 10 group (3.8 vs 3.8). Similarly, there were no significant differences in relapse rate and MS impact scale (MSIS)-29 across the three treatment groups.

Dr. Broadley noted, however, "We saw this very slight hint of reduced Gd-enhancing lesions in the two treatment arms versus a slight increase in the placebo group, although it was not statistically significant."

Thus, although there were no significant differences seen in the clinical outcome measures across the three treatment groups, the researchers observed the expected pattern of changes in cytokine profiles in the active-treatment arms.

Therefore, intravenous chaperonin 10 appears to be safe and well tolerated, and shows a trend towards a reduction in MRI activity. Dr. Broadley also noted that a recent investigation of chaperonin 10 as rescue therapy in patients with rheumatoid arthritis showed promising results, with improvements in clinical measures of disease activity.

With this early promise for chaperonin 10, it now appears likely that investigations for patients with MS should continue, making use of improved dosing and administration routes that should arise from continued trials of chaperonin 10 for patients with rheumatoid arthritis, according to the researchers.

Funding for this study was provided by C-Bio.

Source: Presentation title: A Multicentre, Phase 2a Clinical Trial of chaperonin 10 in Multiple Sclerosis. Abstract P554 (19/10/07)

These findings were presented here on October 13 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Treosulfan, a cytostatic bifunctional alkylating agent, has been available for the treatment of ovarian cancer for several years, and more recently it has been shown to reduce the severity of autoimmune encephalomyelitis in an animal model. At the same time, it is known to reduce proliferative capacity and increase apoptosis in human peripheral blood mononuclear cells, and to inhibit migration of immune cells.

Heinz Wiendl, MD, Coordinating Investigator and Head, Clinical Research Group, Department of Neurology, University of Wuerzburg, Wuerzburg, Germany, and colleagues evaluated the safety and efficacy of treosulfan in patients with SPMS who have failed or do not qualify for treatment with conventional immunomodulatory agents.

After patient screening, the study design provided an initial induction phase of 3 months with monthly pulses of treosulfan starting at 7 g/m2, with dose escalation to 8 g/m2. This was accompanied by clinical evaluations every 4 weeks, with magnetic resonance imaging (MRI) at baseline and at the end of this induction phase.

This phase was followed by a maintenance phase for 1 year, with 3-monthly pulses of treosulfan, and accompanied by 3-monthly clinical and MRI analyses. In both induction and maintenance, the clinical assessments included expanded disability status scale (EDSS) and MS Functional Composite (MSFC), along with blood and urine analyses.

A total of 21 patients with confirmed SPMS participated in the study, divided according to the safety (n = 11) and efficacy (n = 20) sets. These patients were in a phase of secondary progression of the disease, as seen from the mean duration of SPMS of 4.3 and 4.6 years, respectively. Their mean MS durations since the first manifestation were 16.6 and 17.2 years, respectively, and they were still under active disease according to the number of attacks they had in the previous year (means, 1.4, 1.4). Their mean EDSS scores were 4.95 and 5.05, respectively.

"All of the patients either stabilized or even improved over the observation period of 1 year," Dr Wiendl indicated. The annual relapse rate of 1.5 prior to study entry decreased significantly to 0 by the end of the study year (P <.016).

Within the MRI analyses, there was a trend for a reduction in Gd-enhancing lesions, although, as Dr. Wiendl said, "What we saw by the end of this study was that some of these patients seemed to be having recurring activity, which could be an indication that the 3-monthly maintenance pulses are not sufficient to be anti-inflammatory."

Therefore, the researchers concluded that not only was treosulfan safe and well tolerated, but nine of the 11 patients remained on treosulfan for the complete study period, during which they showed clinical stabilization or improvements, as judged by their EDSS and MSFC scores. Furthermore, no clinical relapses were seen during the treatment period, and the mean numbers and volumes of their T2 and T1 lesions did not change during the year of treatment.

These results have thus moved things forward with the establishing of a randomised phase 2 study, which is currently in recruitment, Dr. Wiendl said.

Funding for this study was provided by Medac GmbH.

Source: Presentation title: Treatment of Active Secondary Progressive Multiple Sclerosis With Treosulfan. Abstract 75A (19/10/07)

The study, which was conducted by Jop P. Mostert, MD, and colleagues at the University of Groningen, the Netherlands, shows a trend toward a reduction in new enhancing lesions with fluoxetine treatment in patients with relapsing-remitting or relapsing secondary progressive MS.

Why Fluoxetine?

Fluoxetine, a selective serotonin reuptake inhibitor, was approved by the US Food and Drug Administration in 1987 and is frequently prescribed for the treatment of various psychiatric disorders, including major depression. However, fluoxetine also has a number of immunomodulatory effects, and previous studies have indicated that it might be beneficial for patients with MS, Dr. Mostert said in his presentation.

One of these earlier studies, which was first presented at the 1997 Annual Meeting of the American Association of Neurology, showed that fluoxetine reduced disease activity in experimental autoimmune encephalomyelitis, the animal model of MS, Dr. Mostert noted. "Furthermore, psychiatrists already reported in 1991 reduced MS in patients using fluoxetine," he added.

Previous research has also found that astrocytes in patients with MS lack beta-2 adrenergic receptors, and this leads to decreased cyclic adenosine monophosphate (cAMP) production, which in turn contributes to the initiation of the inflammatory cascade that eventually results in demyelination, Dr. Mostert explained. Because fluoxetine is able to increase the amount of cAMP in the astrocyte, the researchers hypothesized that the drug could help compensate for the loss of beta-2 adrenergic receptors and thus, reduce the amount of inflammation in MS.

Fewer New Lesions

To test their hypothesis, Dr. Mostert's team enrolled 40 patients (age 18 - 65 years) with relapsing-remitting or relapsing secondary progressive MS in a randomized, double-blind, placebo-controlled trial, with a duration of 24 weeks. Half of the patients were given fluoxetine (20 mg/day), whereas the remaining subjects received placebo.

The primary end point was the cumulative number of new gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (MRI) of the brain performed at weeks 4, 8, 16, and 24. Secondary outcome measures included changes in the Expanded Disability Status Scale (EDSS) and in the Multiple Sclerosis Self-Efficacy Scale (MSSE) from baseline to week 24.

The investigators found that the study drug was generally well tolerated, with only 1 patient dropping out because of adverse effects (nausea) in the treatment group. One patient also dropped out from the placebo group, leaving 19 completers in each group.

Regarding the primary end point, the results show that there was a trend toward a reduction in the number of new enhancing lesions in patients treated with fluoxetine. The mean (SD) cumulative number of new enhancing lesions during the 24 weeks of treatment was 1.84 (2.9) in the fluoxetine-treated patients and 5.16 (8.6) in the control subjects (P = .15).

At week 4, the cumulative number of new enhancing lesions was "quite comparable" in the two 2 groups, pointed out Dr. Mostert. He emphasized, however, that in the latter part of the trial, there was a steady increase in new lesions in the placebo group, while the number of lesions in the fluoxetine-treated patients remained relatively stable. Restricting the analysis to the last 16 weeks showed a "nearly significant" reduction in the cumulative number of new enhancing lesions and a higher number of patients without new enhancing lesions (63% vs 26%; P = .02).

Commenting on the study, session cochair Roland Liblau, MD, PhD, from Toulouse University Hospital in France, noted that the researchers used "a very interesting approach," because fluoxetine has a very good safety profile.

"It has been used in hundreds of thousands of patients, so we know it's safe," he told Medscape Neurology and Neurosurgery. "The possibility that it has even a slight effect in multiple sclerosis would be very interesting," he added. "The data showed a trend toward efficacy in MS, and I would strongly encourage further trials involving more patients."

This study was an investigator-initiated trial, with no pharmaceutical industry funding.

Source: Medscape Medical News 2007. ©2007 Medscape (18/10/07)

Dr. Karlik, together with researchers from Xanthus, conducted several studies to investigate the immunomodulatory effects and kinase activity of Symadex using a model of experimental autoimmune encephalomyelitis (EAE) that is designed to represent multiple sclerosis. Researchers examined Symadex-treated versus control animals for changes in several circulating biomarkers known to be relevant to autoimmune disease. Symadex was found to bring elevated levels of monocyte- and macrophage-related biomarkers associated with disease back to normal. MRI imaging showed that macrophage function was inhibited in areas of inflammation. In vitro studies supporting this mode of action show that Symadex is an inhibitor of FLT3, a receptor tyrosine kinase known to regulate dendritic cells, as well as CSF-1R, a related receptor expressed particularly on macrophages.

"We observed that Symadex exhibits a distinctive targeted effect on macrophage and monocyte function. These cell types play a key role in driving the autoimmune response, and the ability of Symadex to specifically interfere with their function makes this candidate a potentially unique therapeutic opportunity for MS and other autoimmune diseases," said Dr. Karlik.

"We believe that the targeted mechanism of action observed with Symadex in these studies has opened the door for Xanthus to explore multiple autoimmune and oncology indications for this compound and our series of related agents. We are preparing to initiate a human proof-of-principle trial with Symadex in autoimmune disease in 2008 to support our partnering objective for the FLT3 autoimmune program, and we are exploring the potential of additional oncology studies that may leverage Symadex’s targeted kinase activity," stated Richard T. Dean, Ph.D., Xanthus' Chief Executive Officer.

About Symadex™

Symadex (formerly C-1311) is the lead compound in clinical development from a new series of agents, the imidazoacridinones, which have shown in vitro to be potent and selective FLT3 receptor tyrosine kinase inhibitors. Symadex is currently in a Phase 2 study for women with metastatic breast cancer, and has the potential to be active in hematological malignancies. Xanthus is also exploring the use of Symadex and follow-on compounds for the treatment of a number of autoimmune diseases, such as multiple sclerosis and inflammatory bowel disease. Early preclinical data has shown encouraging signs of activity in models of autoimmune disease. Given the compound's safety profile and oral availability, Xanthus believes Symadex represents the potential for a large-scale drug opportunity. Further preclinical studies are currently being conducted, after which the Company expects to enter clinical development.

Source: Xanthus Pharmaceuticals, Inc. (15/10/07)

Peptimmune, Inc. a privately held biotechnology company, announced that physicians have treated the first participant in a clinical trial to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of PI-2301, a novel peptide copolymer for the treatment of multiple sclerosis and other autoimmune diseases.

The Phase I single ascending dose, double blind placebo controlled randomised study will involve 56 healthy male volunteers who will receive the drug in eight escalating dose cohorts. Following establishment of safety at potentially therapeutic doses, the Company will initiate its first repeat dose study in multiple sclerosis patients in early 2008.

PI-2301 is a second generation peptide copolymer from a similar compound class as Copaxone® (Teva Pharmaceuticals). PI-2301 works through immune modulation by enhancing the regulatory response of the immune system to control the pathogenic autoimmune response in certain diseases. PI-2301 has been optimized using Peptimmune's novel platform peptide chemistry and in pre-clinical studies, has shown to be more potent and effective than Copaxone® in treating disease models for multiple sclerosis. PI-2301 has also shown efficacy in pre-clinical models of autoimmune diseases where immune modulation may be effective, such as Crohn's disease, rheumatoid arthritis and autoimmune uveitis. Peptimmune has also introduced highly reproducible manufacturing methods that allow very strict control and characterisation of PI-2301 and should provide a superior level of batch to batch consistency.

"The commencement of this clinical trial is an important milestone for the development of PI-2301 and for the Company," stated Thomas Mathers, President and CEO of Peptimmune. "The goal for PI-2301 is to enhance the therapeutic benefit of a proven compound class in multiple sclerosis and give neurologists a new weapon as a primary treatment for patients with this debilitating disease."

Over 400,000 Americans have multiple sclerosis (MS), and worldwide MS may affect over 2.5 million individuals. MS is an autoimmune disease in which the individuals' immune system responds against multiple components of nerve-insulating myelin. The effects of these immune-mediated attacks can range from relatively benign to somewhat disabling to devastating, as communication between the brain and other parts of the body is disrupted.

Source: Peptimmune, Inc.(03/10/07)

Hollis-Eden Pharmaceuticals, Inc. is presenting new data this week showing that its drug candidate HE3286, a novel orally bio-available small molecule compound that has previously demonstrated significant benefit in rodent models of rheumatoid arthritis (RA), also provided benefit in an animal model of multiple sclerosis (MS). The Company is presenting data this week at the 2nd International Congress on Immune-Mediated Diseases being held in Moscow, Russia. In addition the Company is presenting preclinical data demonstrating that HE3286, along with other novel compounds under investigation, HE3413 and HE3177, appear to act by limiting the activation of the pro-inflammatory transcription factor NF-kappaB.

In the data presented, HE3286 showed marked benefit in a SJL/J female mouse model of experimental autoimmune encephalitis (EAE), a model widely used in industry and academia to test agents as potential treatments for multiple sclerosis. In the study, mice were treated orally at disease onset with either HE3286 or placebo for approximately 20 days. HE3286-treated mice, at doses as low as 4 mg/kg, had markedly reduced disease scores in comparison to placebo-treated animals. Importantly, benefit was maintained for over two weeks, even after treatment was discontinued. The Company also presented previously reported data showing that HE3286 could provide significant benefit in the DBA mouse model of rheumatoid arthritis, even when treatment was delayed until disease was well established.

Additional data presented this week at the conference demonstrate that recently identified compounds in the Company's library, HE3413 and HE3177, appear to limit NF-kappaB activation in preclinical models. Many pro-inflammatory signals, such as TNF-alpha and IL-6, are controlled by NF-kappaB. In these studies, mice were challenged with LPS (bacterial products) and levels of NF-kappaB activation in spleen were measured. Both HE3413 and HE3177 reduced levels of LPS driven NF-kappaB activation compared to placebo-treated animals. The Company believes both compounds are adrenal steroid hormones that occur naturally in man, and which appear to be potent endogenous regulators of inflammation. HE3413, a newly discovered natural hormone, appears in preclinical models to be a particularly potent anti-inflammatory agent and to have good oral bio-availability in mice.

Dr. Halina Offner, Professor of Neurology at Oregon Health Science Center, who presented the data and is a leading expert on animal models of autoimmune diseases, stated, "We continue to be excited about researching these new steroid hormones because of their apparent ability to regulate critical inflammatory targets such as NF-kappaB and T-regulatory cells. Previous research we conducted demonstrated that HE3286 has potent anti-inflammatory properties in models of RA, and we wanted to see this drug candidate tested in models of multiple sclerosis. These data suggest that HE3286 is regulating critical pathways that are dysregulated not only in RA and MS, but also in multiple autoimmune disorders and diseases of inflammation. We remain excited about the future role adrenal steroid hormones may play in offering patients relief from these life altering diseases."

"We are pleased that HE3286 continues to perform well in pre-clinical models of diseases of inflammation," said Richard Hollis, Chairman and CEO of Hollis-Eden Pharmaceuticals. "To date, HE3286 has demonstrated anti-inflammatory activity in animal models of rheumatoid arthritis, multiple sclerosis, lupus, ulcerative colitis and cystic fibrosis. Importantly, our recently concluded Phase I clinical study showed that the same blood levels of HE3286 that were effective in our animal models appear to be achievable in man. These observations are leading us to consider initiating pilot Phase I/II clinical studies testing HE3286 in one or more acute inflammatory conditions in the near future. If we are successful in initiating and completing these clinical studies, there may be an opportunity to potentially demonstrate the anti-inflammatory activity of HE3286 in man before the end of this year. With this in mind, we intend to file an IND to support a Phase I/II clinical trial with HE3286 in diseases of inflammation this month. This IND would enable us to potentially test HE3286 not only in RA but in additional diseases of inflammation."

Anti-inflammatory treatments are among the most frequently prescribed drugs today. Approximately 67 million prescriptions are written each year for glucocorticoid steroids to treat many inflammatory conditions despite their well-known side effects that include immune suppression and bone loss. To date, HE3286 and other Hollis-Eden compounds have demonstrated in preclinical models of inflammatory diseases, the anti-inflammatory activity associated with glucocorticoids, but without these side effects. Unlike glucocorticoids that act through the glucocorticoid receptor to completely block NF-kappaB activation which may cause immune suppression and bone loss, HE3286 does not interact with the glucocorticoid receptor and only partially inhibits NF-kappaB.

Source: Hollis-Eden Pharmaceuticals, Inc.(12/09/07)

The Company is currently conducting this 80 patient trial to assess the safety and efficacy of ATL1102 in relapsing-remitting MS patients in Poland, Czech Republic, Bulgaria, Romania, Slovak Republic and Germany.

As previously reported the Company had made an application to conduct the clinical trial in Russia. The Company is pleased to advise that approval for the clinical trial has been granted by the regulatory authorities in Russia.

The Company’s ability to receive approval from the regulatory authorities in 7 countries to conduct this study is a reflection of the quality of the ATL1102 clinical trial application.

Screening and enrollment of patients is on-going at all active trial sites. 58 patients have now been enrolled into the study. More than half the enrolled patients have completed the dosing phase of the trial.

The study continues under the supervision of a Data and Safety Monitoring Board -an independent group of neuroscience experts who oversee a strict safety protocol for the conduct of the trial.

About ATL1102 for MS
ATL1102 is a second generation antisense inhibitor of CD49d, a subunit of VLA-4 (Very Late Antigen-4), and is currently in Phase IIa clinical trials as a treatment for MS. In inflammation, white blood cells (leukocytes) move out of the bloodstream into the inflamed tissue, for example, the CNS in MS, and the lung airways in asthma. The inhibition of VLA-4 may prevent white blood cells from entering sites of inflammation, thereby halting progression of the disease. VLA-4 is a clinically validated target in the treatment of MS. Antisense inhibition of VLA-4 has demonstrated positive effects in a number of animal models of inflammatory disease including MS, the MS animal data having been published in a peer reviewed scientific journal.

ATL1102 Phase IIa Study Design Summary
The study is a multi-centre, randomised, double-blinded, placebo-controlled clinical trial, in approximately 80 patients with relapsing-remitting MS. Patients receive either ATL1102 or placebo over eight weeks. The goal of the Phase IIa trial is to obtain preliminary evidence of the drug’s effectiveness. This is assessed by using MRI (magnetic resonance imaging) indices. MRI’s are conducted at monthly intervals over the 8 week dosing period and at monthly intervals for a further 8 weeks following completion of dosing.

Source: Antisense Therapeutics (12/09/07)

The Adelaide company's head of MS drug development, Jorgen Mould, told the World Congress of Neuroscience in Melbourne yesterday that preclinical data showed the drug BNC245 was effective in a rat model of MS.

The studies showed BNC245, given over several days, had no side effects and was as effective as one of the common steroid anti-inflammatory drugs.

MS is the result of damage caused to a fatty layer known as the myelin sheath that surrounds neurons in the brain and the spinal cord.

This damage slows down or blocks messages between the brain and the rest of the body.

Dr Mould said the most common MS treatments were a class of drugs called interferons which are administered by injection.

However, these MS drugs generally had side effects such as flu-like reactions and reactions at the site of the injection like redness, inflammation and pain.

As well, patients who were on these drugs for long terms sometimes developed resistance.

Dr Mould said BNC245 could be developed into a tablet which would have a huge advantage over current injectable drugs.

Because BNC245 acts specifically on cells linked to auto-immune disease and could be taken orally by patients, it would not have the side effects of site reactions or flu-like symptoms, he said.

"We carried out a number of preclinical tests which showed that BNC245 was as effective as a common anti-inflammatory drug used to treat MS symptoms, but it did not have the negative side effects," Dr Mould said. "We are . . . targeting a novel pathway that underlies MS and a number of other auto-immune diseases."

Source: Adelaide Now Copyright 2007 News Limited. (14/07/07)

UCB and Biogen Idec today announced the initiation of a Phase II study of CDP323 - an oral VLA-4 antagonist - under development for relapsing-remitting multiple sclerosis (MS). The double-blind, randomised Phase II study commenced this week with dosing of the first patient.

The study is designed to enroll over 200 patients with relapsing-remitting MS who have failed earlier treatment with a beta-interferon. Last October the companies entered an agreement to co-develop and co-commercialise this small molecule compound.

The trial compares the safety and efficacy of two doses of CDP323 monotherapy to placebo over a period of six months. This is the first time that patients with MS will be exposed to CDP323. Approximately 50 medical centers in Europe and the U.S. are expected to participate in this study. The results of this Phase II study are expected by the end of 2008.

"Multiple sclerosis affects more than a million people worldwide and so far, no oral treatment has been available. An oral therapy would represent a significant advance for patients as it could provide them with a new, non-invasive option of drug delivery," said Professor Chris Polman, Professor of Neurology, VU Medical Centre, Amsterdam, the Netherlands, Lead Investigator for this study.

About CDP323

CDP323 is an orally active small molecule VLA-4 antagonist. The safety, tolerability and pharmacokinetic profile of CDP323 have been evaluated in healthy volunteers in three separate Phase I studies. Data from these studies were reported at the 2006 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The data from these early studies supports further development of CDP323.

Source: UCB and Biogen Idec (26/06/07)

Antisense Therapeutics announced that it has now enrolled 40 patients into its Phase IIa Multiple Sclerosis trial with half the quota of patients anticipated for this trial.

The company advised further that it has recently received approval in Poland to initiate new trial sites. The company is currently enrolling 80 patients into the trial to assess the safety and efficacy of ATL1102 in relapsing-remitting MS patients in 6 countries (Poland, Czech Replubic, Bulgaria, Romania, Slovak Replubic and Germany).

Source: Yahoo Finance Copyright © 2007 Yahoo! Australia & NZ Pty Limited. All rights reserved. (22/06/07)

Under the terms of the agreement, Micromet will receive an upfront license fee of euro 5 million (approximately US$7 million), and is eligible to receive R&D reimbursements and payments upon the achievement of development milestones of more than euro 120 million (approximately US$160 million) in the aggregate. In addition, Micromet is eligible for royalties on worldwide sales of MT203 and other products that may be developed under the agreement. Micromet will be primarily responsible for performing preclinical development, process development and manufacturing of MT203 for early clinical trials, whereas Nycomed will be responsible for clinical development and commercialisation on a worldwide basis. Nycomed will bear the cost of development activities and reimburse Micromet for its expenses incurred in connection with the development program.

"We are delighted to enter into a collaboration for the development of MT203 with our new partner Nycomed. We are excited about this collaboration as both parties' expertise and capabilities complement each other," said Christian Itin, President and Chief Executive Officer of Micromet.

"Neutralising GM-CSF presents a new biology concept in inflammatory processes and may have the potential to improve the lives of patients suffering from severe chronic inflammatory and autoimmune diseases. Furthermore, this deal is the first example of Nycomed's strong commitment towards external collaborations across all development stages as a key component of our new R&D strategy. MT203 also highlights our strategic interest in inflammatory research," said Anders Ullman, Executive Vice President R&D of Nycomed.

Source: Press Portal (25/05/07)

The agreements cover patents held by UC Davis and UC Irvine on two novel compounds that could be used to treat autoimmune diseases, in which the body's own immune system attacks healthy tissue. The agreements allow Airmid to pursue further testing and commercial development of the compounds.

"Airmid is the latest of the startup companies emerging from the UC campuses -- in this case from both UC Davis and UC Irvine. I'm delighted we've concluded this license with the company, and look forward to their growth and success," said David McGee, executive director of UC Davis InnovationAccess.

"We at Airmid are extremely excited about the prospect of working with the University of California and its world-renowned researchers to bring these potential therapies to the millions of sufferers of autoimmune diseases, who so desperately need safer and more effective treatments," said Airmid CEO George Miljanich.

The first compound, ShK(L5) is a synthetic version of a component of sea anemone venom. It prevents the activity of human immune cells that are implicated in conditions such as multiple sclerosis and is effective in animal models of multiple sclerosis and rheumatoid arthritis.

The second, PAP-1, is derived from a shrub, the common rue. In the laboratory, it can suppress skin inflammation in rats. It could have potential as a treatment for psoriasis.

Both compounds act to block channels that allow potassium ions to flow in or out of cells. These ion channels appear to play an important role in regulating the activity of cells in the immune system and are especially abundant on a type of immune cell implicated in diseases such as multiple sclerosis and psoriasis.

"This could be a completely new mechanism of immune suppression for patients who do not respond to or have side effects from current therapies," said UC Davis' Heike Wulff, assistant professor of medical pharmacology and toxicology.

The compounds were discovered by Wulff and George Chandy, professor of physiology and biophysics at UC Irvine, as a result of work in Chandy's laboratory going back more than two decades. Chandy and Wulff are also among the co-founders of Airmid.

Both compounds have been tested in the laboratory but not yet studied in humans. UC Davis' InnovationAccess unit negotiated the licensing agreements on behalf of both campuses.

About Airmid
Airmid is a privately held pharmaceutical company based in Redwood City, Calif. Airmid is focused on developing its novel potassium ion channel blockers as safer and more effective medicines for a variety of autoimmune diseases that are inadequately treated by current therapies. These diseases include multiple sclerosis, psoriasis, type 1 diabetes and rheumatoid arthritis.

About UC Davis InnovationAccess
UC Davis InnovationAccess actively manages a patent portfolio of 841 inventions reflecting the diversity of the campus's research base, and seeks opportunities to commercialise these via licensing, with 485 currently active licensees. UC Davis has also seen an upsurge in startup companies emerging from campus research and technologies, with nearly 20 companies founded since 2005. The UC Davis InnovationAccess team is comprised of more than 20 professionals with PhDs, JDs, and MBAs with significant private-sector experience.

Source: UC Davis News and Information (24/05/07)

"We're thrilled that Dr. Siahaan has joined the movement to a world free of MS," said Kay Julian, president of the Mid America Chapter of the National Multiple Sclerosis Society. "Research by scientists like Dr. Siahaan will one day find the cause and the cure for multiple sclerosis, a debilitating disease that affects more than 400,000 individuals nationwide."

It is believed that MS affects the central nervous system, consisting of the brain, spinal cord and optic nerves. In patients with MS, the immune system mistakenly attacks myelin, a fatty tissue that insulates nerve fibres and helps them to conduct electrical impulses.

"How the myelin sheath gets destroyed is the focus of our work," said Siahaan. "We're trying to change the mind of the immune system's attackers. Instead of attacking myelin cells, we want the attackers to be tolerant of the cells."

The $217,595 grant will support Siahaan's work on a compound called PLP-BPI, which contains myelin proteins and molecules that stop immune cells from damaging the nervous system. Siahaan developed PLP-BPI himself.

"It's actually a piece of protein we form using an automated synthesiser in our lab," said Siahaan of the new compound.

Siahaan has shown that PLP-BPI halts the progress of EAE, a disease similar to MS that affects mice.

"We induce the mice to get EAE and then we challenge them with a very small amount of the molecule that we've discovered," said Siahaan. "We basically suppress the progression of the disease compared with animals that get injected with the control molecule."

With the National Multiple Sclerosis Society grant, Siahaan will examine the effects of PLP-BPI on mice already suffering the onset of EAE symptoms. He will also attempt to shed light on the compound's mechanism for fighting the disease. Eventually, the grant-funded work could lead to therapies for people with MS.

"If we can, we'll move to humans in the future with clinical trials," said Siahaan. "First, we'll look at the stability of the molecule and its side effects. Because it has to be safe."

A committee of more than 70 eminent scientists who peer review hundreds of research proposals each year awarded the grant to Siahaan.

Source: Kansas City Infozine © 1994-2007 INFOZINE(15/05/07)

Xanthus Pharmaceuticals, Inc today presented data demonstrating that Symadex(TM) reversed the clinical and pathological signs of chronic disease in an animal model for multiple sclerosis. The presentation was made by Stephen J. Karlik, Ph.D., Professor of Diagnostic Radiology at the University of Western Ontario, London, Ontario, together with researchers from Xanthus in a poster session at the 59th American Academy of Neurology Meeting in Boston, MA.

Using a model of experimental autoimmune encephalomyelitis (EAE) that is designed to represent multiple sclerosis, Dr. Karlik tested Symadex for its effect on both acute and chronic disease. In the acute EAE model, animals treated with Symadex substantially recovered while in control animals the disease symptoms and damage remained unchanged. In chronic EAE disease models, clinical and pathological disease reversal and tissue recovery were observed with Symadex treatment. At the same time, Symadex did not affect circulating immune cell numbers, suggesting that it does not act as a general immunosuppressant.

"Symadex' ability to reverse chronic autoimmune disease in this animal model is notable. The study results suggest this activity may result from inhibiting macrophage function rather than inhibiting T cell function. This mechanism is novel in my experience," said Dr. Karlik.

"We now have a significant body of promising preclinical data supporting the use of Symadex in multiple autoimmune indications. We believe this represents a strong partnering opportunity for our Company, and we are preparing to initiate a human proof-of-principle trial with Symadex in autoimmune disease," stated Richard T. Dean, Ph.D., Xanthus' Chief Executive Officer.

About Symadex(TM)

Symadex (formerly C-1311) is the lead compound from a new series of agents, the imidazoacridinones, which have been shown to be potent and selective FLT3 receptor tyrosine kinase inhibitors in vitro. Symadex is currently in Phase 2 clinical trials in oncology indications. Xanthus is also exploring the use of Symadex for the treatment of a number of autoimmune diseases, where early preclinical data has shown encouraging signs of activity.

Source: Xanthus Pharmaceuticals (03/05/07)

OBJECTIVE: To study the safety and efficacy of treosulfan, a cytotoxic alkylating agent, in patients with active secondary progressive multiple sclerosis.

BACKGROUND: Treosulfan (L-threitol-1,4-bis(methanesulfonate)) is a bifunctional alkylating agent with a favourable profile of side effects, approved for the treatment of ovarian cancer. Treosulfan has previously been shown to reduce the severity of experimental allergic encephalomyelitis under pre-therapeutic and therapeutic conditions. In human peripheral blood mononuclear cells, treosulfan reduces proliferative capacity and increases apoptosis.

STUDY DESIGN: This was a nonrandomised, open label study conducted in two centers. Eleven patients with active secondary progressive MS that failed to or did not qualify for approved disease modifying drugs were treated with treosulfan for 1 year. Patients received intravenous infusions of 7 g/m(2) every 4 weeks for 3 months (cycles 1-4, induction phase) with a predefined one-step dose escalation, thereafter every 3 months for the following 9 months (cyles 5-7, maintainance phase). Cranial MRI was performed every 3 months, EDSS and MSFC as well as physical examination were assessed at each clinical visit.

RESULTS: Treatment with treosulfan was safe and well tolerated. Nine of 11 patients remained on study drug over the complete treatment period and showed clinical stabilisation or improvement as determined by EDSS and MSFC. Two patients discontinued study drug because of leukocytopenia and withdrawal of consent, respectively. No clinical relapses were observed during the treatment period. Thus, the median number of relapses per year was reduced significantly by 1.5 (range -3 to 0), p < 0.016, compared to pre-study. Therapy with treosulfan lead to a clear reduction of MRI activity as revealed by a reduced number of Gd + enhancing lesions on T1 weighted images. The mean number and volume of T2 lesions remained unchanged over 1 year. Four out of 9 patients under treosulfan showed no detectable disease activity (no Gd enhancing lesions, no new or newly enlarging T2 lesions).

CONCLUSIONS: Application of treosulfan in MS was safe and well tolerated. Further studies are warranted to evaluate the efficacy of this treatment in secondary progressive MS.

Wiendl H, Kieseier BC, Weissert R, Mylius HA, Pichlmeier U, Hartung HP, Melms A, Kuker W, Weller M. Dept. of Neurology, University of Wuerzburg, Josef-Schneider-Str. 11, D-97080, Wuerzburg, Germany

Source: J Neurol. Apr 20 2007. (23/04/07)

Novosom plans to target CD40 for indications such as Crohn's disease, transplant, rheumatoid arthritis, cancer and multiple sclerosis. If acquired, the license from Isis would include rights to the target and to oligonucleotides targeting CD40 and incorporating Isis' second generation antisense chemistry, 2' MOE oligonucleotides in exchange for an upfront exercise fee, milestone payments and royalties. Preclinical studies of the already conducted support a favourable safety profile of the CD40 program.

Novosom is using its Smarticles technology to enable systemic delivery of antisense targeting CD40. This encapsulated antisense approach has demonstrated targeted delivery to specific cell types with a rapid onset of action and greater efficacy than the anti-inflammatory blockbuster Remicade.

"We plan to further extend our pipeline with antisense and siRNA programs while taking advantage of the targeted properties of our Smarticles technology in oncology and inflammation," commented Elias Papatheodorou, CEO of Novosom.

Source: Pharmaceutical Business Review ©2007 Business Review (12/04/07) 

Critical Outcome Technologies Inc. (COTI) has been monitoring the synthesis of its first four MS compounds through regular meetings with its synthetic chemistry partner, Dalton Pharma Services (Dalton). "The COTI MS compounds are novel and therefore have not been made before. Each of the first four COTI MS compounds has required the research and development of some entirely new chemistry. As a result, this new chemistry will strengthen our patent position and add to the value realised by future customers" said Dr. Wayne Danter, President and Chief Scientific Officer of COTI.

Dalton has manufactured small amounts of the lead MS compound COT601-M06.1, but has encountered difficulty with scaling up production. Dalton will continue its work synthesising the lead MS compound COT601-M06.1 and is confident that they will be successful in scaling up production.

Since the November 2006 start of the MS molecule synthesis, COTI has broadened its synthetic chemistry resource base in recognition of the complexity and issues surrounding compounds requiring new chemistry. Delmar Chemicals (Delmar)of Montreal has consulted since February 2007 to synthesise the second two MS compounds starting with the lead MS compound COT604-M06.2. Delmaris are also confident that they will be successful in scaling up production.

"COTI together with our synthetic chemistry partners remain confident that these novel compounds will be successfully synthesised in the near future" said Dr. Wayne Danter. "We will continue our pursuit of seeking an effective treatment for acute MS and we will remain focused on engaging prospective partners and customers with this library of novel, optimised lead compounds."

About Critical Outcome Technologies Inc.

COTI is formed around a unique computational platform technology called CHEMSAS®, which allows for the accelerated identification, profiling and optimisation of targeted small molecules potentially effective in the treatment of human diseases for which current therapy is either lacking or ineffective. COTI's business is focused on the discovery and pre-clinical development of libraries of novel, optimised lead molecules for the treatment of specific cancers, HIV and multiple sclerosis. Currently, five targeted libraries of lead compounds (small cell lung cancer, multiple sclerosis, HIV integrase inhibitors, colorectal cancer, and acute myelogenous leukemia in adults) are under active development.

Source: Critical Outcome Technologies Inc.(30/03/07)

"CD83 has shown promising activity as an efficient immunosuppressant and Argos is leveraging its expertise in immune system function and dendritic cells in the development of this compound," said John Bonfiglio, Ph.D., President and CEO of Argos. "This patent further extends our CD83-related intellectual property portfolio and protects our continued development of this exciting, novel asset."

CD83 is a glycoprotein expressed on the cell surface of mature dendritic cells (DCs), the most potent stimulators of immune responses. The strong upregulation of this protein during DC maturation suggests that it plays an important functional role in the induction of immune responses. Experimental data demonstrate that soluble CD83 can potently down-regulate immune responses, indicating that it can be developed to treat transplantation rejection and variety of autoimmune disorders. Importantly, data from animal models demonstrate that soluble CD83 exerts its effects without a requirement for chronic administration and does not leave the subject globally immunosuppressed. In April 2006, Argos obtained exclusive therapeutic use rights for CD83 from Beckman Coulter.

"Argos plans to build on this positive data and has planned additional studies in transplantation and autoimmune models, the results of which will help drive our clinical development strategy for this candidate," said Dr. Charles Nicolette, Chief Scientific Officer and Vice President of Research and Development of Argos.

About Argos Therapeutics, Inc.

Argos Therapeutics is developing breakthrough immunotherapies that target the unique features of a patient's disease. This new generation of personalised cancer and infectious disease therapeutics trains the immune system to recognise and attack the disease. Argos' scientific leadership in RNA-loaded dendritic cells and advanced manufacturing processes provide a platform to tackle virtually all forms of cancers and infectious diseases.

Argos is a private biotechnology company headquartered in Research Triangle Park, NC. The Company has clinical trial programs in cancer and human immunodeficiency virus (HIV) and has an ongoing co-development and commercialisation alliance with the Pharmaceutical Division of Kirin Brewery Company, Limited.

Source: Argos Therapeutics(22/03/07)

MultiCell Technologies, Inc, developing first-in-class drugs based on advanced immune system modulation technologies, has announced its patented recombinant immunoglobulin peptide (IgP) technology creates a highly specific and superior antibody therapeutic. MultiCell's patented IgP antibody therapeutics are a new class of human antibody therapeutics engineered using recombinant DNA technology to contain disease-associated, T-cell responsive, therapeutic peptides.

MultiCell's IgP antibody therapeutics have shown a superior ability to more specifically target key immune system regulators, and elicit cytokine production compared to traditionally administered peptide therapeutics. In preclinical animal models for relapsing-remitting multiple sclerosis and juvenile diabetes, MultiCell's IgP antibody therapeutics eradicated the disease and prevented death in the treated population, while all of the control animals died as a result of the disease. In preclinical animal models, MultiCell's IgP antibody therapeutics have been shown to eradicate cancer and prevent recurrence when co-administered with MCT-465, MultiCell's Toll-like receptor (TLR) agonist.

"When a person's T-cells are activated in autoimmune disease, they produce antibodies which attack specific targets such as pancreatic islet cells, or the protective myelin sheath surrounding nerves resulting in diabetes or multiple sclerosis,'' explained Dr. Stephen Chang, President and CEO of MultiCell Technologies. "Our IgP antibody therapeutics contain T-cell responsive therapeutic peptides that bind only to the autoimmune disease-producing T-cells, causing the cells to self destruct and the disease to be eradicated,'' added Dr. Chang. "In cancer, our IgP antibody therapeutics work synergistically with our TLR agonist, MCT-465, to kill tumor cells by immune system activation, specific cellular targeting, and cell death,'' said Dr. Chang. "In both autoimmune disease and cancer, our IgP antibody therapeutics prevent recurrence of the disease by sensitising the immune system in a manner similar to how a vaccine immunises against future attack.''

"T-cells are only responsive to small peptides, so the antibody therapeutic must be engineered with the therapeutic peptide portion displayed in the most optimal location for maximum efficacy,'' stated Dr. Chang. "Taken together, we believe we have developed the next-generation antibody therapeutic having the best attributes of today's therapeutic antibodies such as specificity and the ability to modulate the immune system. At the same time, our IgP antibody therapeutics minimise the short in vivo half-life and non-specific targeting of traditional peptide therapeutics.''

MultiCell is an innovator in the science of modulating the human immune system, focusing on the development of breakthrough drugs to treat serious diseases, including chronic fatigue-associated with multiple sclerosis, relapsing-remitting multiple sclerosis, juvenile diabetes, influenza, and cancer.

Source: MultiCell Technologies Inc. (21/03/07)

Enkorten, a drug for Multiple Sclerosis and Asthma, which is produced by Farmacija from Tuzla, which recently has successfully finished clinical trials, is the first original patented drug from Bosnia and Herzegovina.

In the clinical trials of the drug, which were done after the first phase of testing at the Faculty of Medicine in Sarajevo, it was proved that the drug is very effective and safe, reported by Federal television.

If the third phase of testing goes as expected, it will be a significant contribution to the health of the sick.

Source: Javno Copyright © 2006-2007 Javno.com All rights reserved.(07/03/07)

Under the agreement, Israel-based Teva will make an equity investment in Vaccinex and pay undisclosed fees, development milestone payments and royalties on product sales to acquire an exclusive license for the development and commercialization of the antibody VX15 in multiple sclerosis and other disease indications. Antibodies are molecules produced by the body’s immune system to battle disease and infection.

Teva and existing Vaccinex investor, Pan Atlantic Bank and Trust Ltd., are lead investors in the local firm’s third major financing round, anticipated to exceed $25 million.

“This transaction demonstrates Vaccinex’s evolution from an antibody discovery company to a product-based company with a growing pipeline and increasing product development capabilities,” said Maurice Zauderer, Vaccinex’s president and CEO, in a statement.

The antibody VX15 represents a new targeted therapy that has the potential to improve efficacy in treating multiple sclerosis by both suppressing the body’s autoimmune response and blocking damage to the central nervous system, Vaccinex officials said. It also has shown the ability to destroy tumors in animal studies by inhibiting blood flow and starving cancer cells of nutrients and energy.

Vaccinex retains rights to oncology indications for VX15. It will continue to conduct all pre-clinical development activities, which will be funded by Teva, company officials said. Teva will have an option to join as a co-development partner in oncology after Vaccinex completes Phase I clinical trials. VX15 is one of four Vaccinex antibodies in pre-clinical development.

Zauderer called Teva a “tremendously valuable partner” for the antibody, due to its expertise in the multiple sclerosis market.

Vaccinex’s technology can generate functional antibodies against difficult targets. The firm employs 48 staffers at its Mount Hope Avenue site.

Source: Rochester Business Journal (c) 2007 Rochester Business Journal.(27/02/07)

The licensing agreement involves the study of C243, a compound that prevents leukocyte infiltration. Leukocytes are white blood cells that help defend the body against infection. Leukocyte infiltration is strongly linked to tissue injury in chronic autoimmune and inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and atherosclerosis.

Under the terms of the agreement, SRI will fund and conduct preclinical and toxicology studies directed at supporting an Investigational New Drug (IND) application filing for C243 with the U.S. Food and Drug Administration, as well as develop GMP-compliant sources for C243 manufacturing. Telik will have the option to re-acquire C243 rights in the future. In North and South America, Telik has exclusive commercialisation rights to C243. Sanwa Kagaku Kenkyusho, Co., Ltd. and Telik share commercialisation rights to the compound in Europe, and Sanwa has exclusive commercialisation rights in Asia. The license agreement covers territories where Telik has exclusive rights.

"SRI has a decades long history of drug discovery and development for cancer and infectious disease. The addition of C243 to our portfolio of CNS therapeutics is a tremendous opportunity to develop a drug to help people afflicted with inflammatory and autoimmune disease," said Edward Spack, Ph.D., senior director of business development, SRI Biosciences Division.

"SRI's exceptional track record in drug development makes them an appropriate organisation to partner with and determine the efficacy of this promising drug candidate, which was discovered through our proprietary TRAP small molecule drug discovery technology," said Marc L. Steuer, senior vice president of business development at Telik.

Source: PR Newswire (08/02/07)

The drug, T-0047, was placed on clinical hold by the FDA in response to the reports that progressive multifocal leukoencephalopathy (PML), a rare nerve disorder, was associated with Tysabri. Tysabri is marketed by Biogen Idec and Elan Pharmaceuticals and is a monoclonal antibody with a similar receptor target to T-0047.

Tanabe and GlaxoSmtihKline have been waiting to resume the study of T-0047 after the FDA and the EU approved the marketing of Tysabri in 2006. Tysabri was approved with the condition that it must be administered at registered infusion centers.

The resumed clinical trial is being conducted in Europe, Canada, Australia and New Zealand.

Source: Datamonitor (30/01/07)