TYSABRI® Ongoing Research

Tysabri (Natalizumab) is a class of drug known as selective adhesion molecule (SAM) inhibitors. You can find out more about this drug on our Tysabri page.

Abstract

Objective To explore cell subsets and molecules that changed specifically in patients with multiple sclerosis (MS) who had an optimal response to natalizumab. Natalizumab is a monoclonal antibody that inhibits the migration of activated immune cells to the central nervous system. It shows high efficacy in modifying the natural history of MS and induces freedom of disease activity in about 40% of treated patients with MS.

Design Prospective study of intrathecal immunoglobulin synthesis and cerebrospinal fluid lymphocyte subsets in patients with MS before and 1 year after beginning treatment with natalizumab. We monitored clinical and magnetic resonance imaging activity during a median time of 2 years.

Setting Two tertiary hospitals from the Spanish National Health Service.

Patients A total of 23 patients with MS.

Main Outcome Measures The differences between patients free of disease activity and patients with active disease during treatment.

Results Of the 23 patients, 10 (43.5%) remained free of disease activity during follow-up. The remaining 13 patients (56.5%) had relapses or new lesions despite natalizumab therapy. We did not find differences in demographic variables or clinical data between both groups prior to natalizumab therapy. All patients showed a decrease in cerebrospinal fluid CD4+ cells regardless of their response to treatment. Conversely, only patients free of disease activity showed a decrease in local IgM and, to a lesser extent, in IgG synthesis. They also showed lower percentages of B cells, particularly of CD5+ and plasmablast subsets that virtually disappeared after treatment with natalizumab.

Conclusion These data indicate that inhibition of intrathecal antibody synthesis is associated with a complete therapeutic response to natalizumab in patients with aggressive MS.

Luisa M. Villar, PhD; María I. García-Sánchez, PhD; Lucienne Costa-Frossard, MD; Mercedes Espiño, PhD; Ernesto Roldán, PhD; Dolores Páramo, MD; Miguel Lucas, PhD; Guillermo Izquierdo, MD; José C. Álvarez-Cermeño, MD

Source: Arch Neurol. 2012;69(2):191-197. doi:10.1001/archneurol.2011.971 © 2012 American Medical Association (14/02/12)

Abstract

Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS).

Treatment with natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV).

We searched PubMed and used current data from the natalizumab global safety database to assess risk factors and quantify the risk of PML.

Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in natalizumab-treated patients.

With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV.

The availability of this assay provides an additional option for risk stratification of PML in patients using or considering natalizumab therapy.

Recommendations for clinical management of patients with MS and use of natalizumab are provided based on the presence of these three risk factors.

The identification of risk factors that increase the likelihood of PML in natalizumab-treated patients can facilitate benefit–risk discussions between health care professionals and patients.

Continued research and data collection will further develop our understanding of PML and the mechanisms by which these risk factors contribute to its development.

Full Text

Per Soelberg Sørensen, Antonio Bertolotto, Gilles Edan, Gavin Giovannoni, Ralf Gold, Eva Havrdova, Ludwig Kappos, Bernd C Kieseier, Xavier Montalban, Tomas Olsson

Source: Multiple Sclerosis Journal Copyright © 2012 by SAGE Publications (13/02/12)

Biogen Idec today announced a global Phase 3b study, ASCEND, that is being conducted to evaluate the effectiveness of Tysabri as a treatment for secondary-progressive multiple sclerosis (SPMS). According to the National Multiple Sclerosis Society, approximately half of all people initially diagnosed with relapsing-remitting multiple sclerosis (RRMS) - the most common form of multiple sclerosis (MS) - will transition to SPMS within 19 years.

Patients with RRMS typically experience unpredictable relapses; the time between relapses is characterised by full or partial recovery and a lack of disease progression. SPMS is characterized by a steady progression of nerve damage, symptoms and disability, but the exact reasons for the progression are unknown. The potential for greater disease burden in SPMS typically includes decreased mobility, impaired activities of daily living, loss of independence and reduced quality of life.

"There are limited treatment options available to people living with SPMS and there is a high unmet need for effective therapies," said Aaron Miller, M.D., member of the ASCEND advisory board; Medical Director, Corinne Goldsmith Dickinson Center for Multiple Sclerosis; and Co-Director of the Multiple Sclerosis Care Center at Maimonides Medical Center in Brooklyn, New York. "The ASCEND trial is investigating whether treatment with Tysabri may prevent worsening in walking, hand movement and daily functioning in these patients."

"One hypothesis behind the development of SPMS is that disease progression is a result of chronic inflammation in the brain tissue trapped behind the blood-brain-barrier. This causes destruction of the myelin sheath which protects the coating around nerve fibres, as well as the progressive loss of nerve cells, which can lead to disability in MS patients," said Professor Richard Reynolds, Professor of Cellular Neuroscience, Imperial College, London; and Scientific Director of the UK Multiple Sclerosis Society Tissue Bank. "Preliminary data suggest that Tysabri may hinder this inflammation in the brain and reduce SPMS-related disease progression; therefore, further investigation of this hypothesis is warranted."

The ASCEND study is part of the ongoing commitment of both Biogen Idec and Elan to find ways to improve the well-being of patients with multiple sclerosis.

About the ASCEND Study

ASCEND (A Study to Characterise the Efficacy of Natalizumab on Disability in SPMS) is a double-blind, placebo-controlled study with SPMS patients being randomized to receive either Tysabri 300 mg or placebo intravenously every four weeks for 96 weeks. A global study, ASCEND is expected to enroll approximately 850 patients in 15 countries.

Study participants will be between the ages of 18 and 58, inclusive, with a diagnosis of SPMS for at least two years; an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5, inclusive; MS Severity Score of 4 or higher; documented, confirmed evidence of disease progression, independent of clinical relapses during the one-year prior to enrollment; and naive to Tysabri treatment.

The primary endpoint is to investigate whether treatment with Tysabri slows the accumulation of disability not related to relapses in subjects with SPMS.

Secondary endpoints are:

-- The proportion of subjects with consistent improvement in Timed 25-foot Walk (T25FW);

-- The change in subject-reported ambulatory status as measured by the 12-Item MS Walking Scale (MSWS-12);

-- The change in manual ability based on the ABILHAND questionnaire;

-- The impact of Tysabri on subject-reported quality of life using the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical);

-- The change in whole brain volume between the end of study and week 24 using MRI; and

-- The proportion of subjects experiencing progression of disability as measured by individual physical EDSS system scores.

ASCEND is ongoing and actively enrolling patients.

Source: Biogen Idec and Elan Corporation, plc (26/01/12)

Background: In the pediatric Multiple Sclerosis (MS) population large and controlled studies on safety and efficacy of Natalizumab have not yet been performed. In literature there have been no cases of Natalizumab-related Progressive Multifocal Leukoencephalopathy (PML) reported in paediatric population with MS.

Case Report: A 14-year-old girl presented in October 2009 diplopia, gait ataxia, vomiting and impaired mentation, preceded by asthenia, fever and left sensory loss lasting for 3 days, 1 month earlier. MRI showed a diffuse leukoencephalopathy with large lesions in brainstem, semioval centers and spinal cord with diffuse gadolinium enhancement. The IgG Index was increased. After treatment with i.v. Methylprednisolone (MP) she improved.

Initial diagnosis was ADEM. In December 2009 she presented behavioural changes, ataxia, strabismus and urinary incontinence. Brain MRI showed new large lesions with ring enhancement. She was treated with MP and high dose i.v. immunoglobulins for 5 days without efficacy. She underwent 3 Mitoxantrone (8 mg/sqm) monthly infusions and then 8 plasma exchanges, with partial recovery only in mental function. MRI showed new demyelinating areas with ring enhancement. A 10 d MP course was followed by improvement in motor and mental functions; apraxia and urinary incontinence persisted.

Final diagnosis was of malignant MS. She was treated with monthly Natalizumab infusions from May 2010 to December 2010, with partial efficacy. Antibodies against Natalizumab were negative. Her parents refused autologous bone marrow transplantation.

In February 2011 the girl had a clinical relapse with stable MRI. She was treated with Natalizumab (one infusion) and i.v. MP. Brain MRI in March 2011 showed new areas in left frontal lobe, some subcortical with enhancement. The girl had further deterioration in cognitive function. Test for JC virus antibodies was positive. Assuming a diagnosis of PML Natalizumab was stopped and lumbar puncture was performed. PCR for JC virus DNA revealed over 140 copies and diagnosis of PML was confirmed.

Conclusions: This case of paediatric MS is extremely aggressive and no treatment was really effective to stabilize the disease. The girl had a cognitive impairment from the beginning of the disease and worsening of it is the only signal of PML. Further studies are needed to assess the efficacy and safety of Natalizumab in paediatric MS population and to identify clinical and radiological parameters for early diagnosis of PML.

M di Ioia, D. Farina, G. De Luca, D. Travaglini, V. Di Tommaso, E. Pietrolongo, A. Lugaresi (Chieti, IT)

Maria Di Ioia is involved in clinical trials of Merck Serono S.A – Geneva and Teva Neuroscience Deborah Farina has received researcher grant from: Merck Serono S.A. – Geneva, Biogen-Dompè and is involved in clinical trials of the same company, plus GlaxoSmithKline, Biogen-Dompé, Bayer Schering, Novartis and Teva. Giovanna De Luca has received a researcher grant from: Merck Serono S.A. – Geneva and is involved in clinical trials of the same company, plus GlaxoSmithKline, Biogen-Dompé, Bayer Schering, Novartis and Teva. Daniela Travaglini is involved in clinical trials of GlaxoSmithKline, Biogen-Dompé, Bayer Schering, Merck-Serono, Novartis and Teva. Valeria Di Tommaso is involved in clinical trials of GlaxoSmithKline, Biogen-Dompé, Bayer Schering, Merck-Serono, Novartis and Teva. Erika Pietrolongo is involved in clinical trials of Merck-Serono, Novartis, Sanofi-Aventis and Teva. Alessandra Lugaresi has received research and travel support or speaker fees from Biogen-Dompé, Bayer Schering, Merck-Serono, Novartis, Sanofi-Aventis and Teva.

Source: 5th Joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis Amsterdam, The Netherlands 19.10.2011 - 22.10.2011 (31/10/11)

In patients with relapsing-remitting multiple sclerosis (MS), interrupting treatment with natalizumab (Tysabri, Biogen) often leads to relapse, a new study shows.

The findings "confirm a high rate of recurrence" of magnetic resonance imaging (MRI)-defined and clinical MS disease activity starting at approximately week 12, during a 24-week interruption of natalizumab therapy, a study team notes.

"Clearly, the risk of return of disease activity during treatment interruption is notable, even with the alternative immunomodulatory therapies used in this study," Robert J. Fox, MD, neurologist and medical director of the Mellen Center for MS at the Cleveland Clinic, Ohio, and leader of the study team, said in his presentation here at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

If an interruption is still desired, the researchers recommend monthly MRIs starting 3 months, or certainly 4 months, after the last natalizumab dose could be considered, "although the practicality of monthly MRI obviously needs to be factored in," he added. "Rescue therapy if gadolinium lesions appear or the patient has a clinical relapse could be considered as well."

The RESTORE Study

Natalizumab is a monoclonal antibody that inhibits leukocyte migration across the blood–brain barrier. It is thought to reduce inflammation in the central nervous system and has been approved worldwide for the treatment of relapsing-remitting MS.

After US Food and Drug Administration approval in 2004, natalizumab was temporarily withdrawn from the market in 2005 after being linked with progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the central nervous system associated with the John Cunningham (JC) virus. The drug was reintroduced in the United States in 2006 with stricter safety warnings and monitoring programs.

A test for antibodies for the JC virus is currently in development. In addition to JC virus positivity, an increasing time receiving natalizumab has also emerged as a risk factor for PML, leading researchers to hypothesize that a temporary interruption of natalizumab treatment might decrease PML risk. "However, that needs to be balanced out with the risk of return of the underlying MS disease activity," Dr. Fox points out.

The Randomized Treatment Interruption of Natalizumab (RESTORE) trial is a randomized, partially placebo-controlled study designed to evaluate the effect of a 24-week interruption in natalizumab treatment. Presented here were preliminary data from an interim analysis of the study focusing on MS disease activity.

The aims were, first, to determine the relative time course of return of MS disease activity during natalizumab interruption, and second, to determine whether an alternative immunomodulatory treatment could modify disease activity after a temporary treatment interruption. "It's important to recognize that RESTORE was not designed, nor was it powered, to detect the effect of a temporary natalizumab treatment interruption on the development of PML," Dr. Fox noted.

The trial compares continued natalizumab treatment with placebo or with switching therapy to interferon beta-1a, glatiramer acetate, or methylprednisolone. The first 2 groups were double-blind, whereas in the third group, the preferred alternative agent could be chosen by the neurologist in consultation with the patient. After 24 weeks, all patients returned to treatment with natalizumab and were followed-up to week 52.

If disease activity occurred, including clinical relapse and/or new gadolinium-enhancing lesions, rescue treatment with high-dose corticosteroids and/or natalizumab could be initiated. Clinical disease activity was defined by the blinded neurologist, but "the bar was set relatively low," Dr. Fox said, as either an increase in the overall Expanded Disability Status Scale or an increase in any other functional system subscale. MRI disease activity also qualified as a return of disease activity, defined as 1 gadolinium-enhancing lesion of 0.8 cm3 or larger, or 2 gadolinium lesions of any size.

Eligible patients were relapse-free during natalizumab treatment for the preceding 12 months or longer before randomization, and did not have gadolinium-enhancing lesions on screening brain MRI.

The 175 patients enrolled in the study were randomly assigned to the treatment groups in a 1:1:2 ratio. They were also stratified by country and by disease activity before the start of natalizumab therapy, and dichotomized into high (≥2 relapses in the year before natalizumab therapy) or low (0 or 1 relapses) groups. Of those randomly assigned to receive the other therapy, about half of the patients chose methylprednisolone, and the rest were split between interferon-beta-1a and glatiramir acetate. Dr. Fox emphasized, however, that the study was also not powered to detect differences between these other therapies.

Of patients who continued to receive natalizumab, none met the criteria for return of MRI disease activity compared with 44% of the patients receiving placebo, 7% of patients receiving interferon-beta-1a, 40% of patients receiving methylprednisolone, and 53% of patients receiving glatiramir acetate. Perhaps not surprisingly, those with high disease activity before starting natalizumab were more likely to have it return after interruption.

Kaplan-Meier curves suggested that first return of MRI-defined disease activity occurred at around 12 weeks, "and around weeks 16 to 20, we really see the up-tick in patients who were going to have return of disease activity, and then it flattened out somewhat after week 20," Dr. Fox noted.

Despite no MRI activity, 2 of the patients who had continued to receive natalizumab had a clinical relapse during the trial. Relapses occurred in 17% of patients receiving placebo, and in between 15% and 29% of patients receiving the other therapies. Again, relapses were more common in those with higher disease activity before natalizumab therapy.

Kaplan-Meier curves on time to relapse showed that relapses occurred later in the randomized period for patients receiving natalizumab compared with those receiving other therapies or placebo. Several patients randomly assigned to receive the other therapies had early return of disease activity clinically, despite not yet having a return of MRI-defined disease activity, Dr. Fox noted. "And to me this suggests that perhaps there was a reverse placebo or nocebo effect in at least a portion of the patients."

When the researchers combined time to first clinical relapse or meeting MRI criteria for return of disease activity, curves again showed an increase between weeks 16 and 20.

There was a sense of some delay in the return of disease activity among those receiving interferon-beta-1a as an alternative therapy, Dr. Fox noted, "although the sample sizes are very small." Those patients receiving interferon also tended to have lower disease activity before natalizumab therapy. Monthly methylprednisolone, in contrast, appeared not to be effective in suppressing disease activity, at least at the doses used here, he noted.

Rescue therapy with natalizumab tended not to be used for early signs of disease activity return, and the 2 patients who had relapses despite receiving natalizumab did not return to open-label therapy until the end of the trial. "But again, it was in the area of 20 weeks when patients opted for the rescue therapy," Dr. Fox said.

Patients Rescued With Natalizumab

"Not Surprising"

Reached for comment, David M. Clifford, MD, from the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, who was not involved in the study, said he is not surprised that interrupting natalizumab led to relapse.

"This is exactly what was expected. It has been my view that treatment interruption was not rational, and indeed might well put patients at risk for disease progression with no real expectation on my part that it would reduce risk of PML," Dr. Clifford told Medscape Medical News.

"While these data are suboptimal in number, they certainly seem to confirm that interruption will often result in recurrent MS in a relatively short time frame," he added.

Ralf Gold, MD, professor and chair, Department of Neurology, St. Josef-Hospital, Ruhr-University, Bochum, Germany, gave a talk on the last day of the conference on the clinical highlights presented, and touched on these results from RESTORE.

Natalizumab is an important agent for patients with active disease, but given the potential risks with longer treatment duration, he said, "it's clear some patients who are stable may like to discontinue after 2 years, and maybe switch, and this was addressed by this study."

The main result "doesn't come as a surprise," he said. "All of us know in active patients after 3 months, it starts again, and those on natalizumab remained stable." Although the numbers were small, Dr. Gold noted, "surprisingly, the interferon patients also stayed stable."

This finding raises an interesting hypothesis, he said: If disease is "silenced" for 1 or 2 years by natalizumab, it may be possible that alternative therapies could then be used. "At least it's important, and we'll learn a lot about this study from further biomarkers."

The study was supported by Biogen Idec Inc and Elan Pharmaceuticals, Inc. Several of the study authors have disclosed financial relationships with Biogen Idec and Elan and other pharmaceutical companies. Four of the authors are employed by Biogen Idec. Dr. Clifford has disclosed no relevant financial relationships.

5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS): Abstract 150. Presented October 22, 2011.

Source: Medscape Today Copyright © 1994-2011 by WebMD LLC. (24/10/11)

Objective: To report on a case of progressive multifocal leukoencephalopathy (PML) after natalizumab (NTZ) treatment discontinuation.

Case report: She is a 24-years-old woman who developed a very active multiple sclerosis in 1999 when she was 12. Between 2000 and 2004 she was treated with immunomodulants (GA and interferon) and XX underwent 3 cycles of Mithoxantrone for a cumulative dose of 45 mg. Then for continuous clinical and MRI activity she started natalizumab treatment in May 2007. During this therapy she did not have any disease activity and she had a very good quality of life.

In September 2010 she was tested for anti-JCV antibodies resulting positive.

In October 2010 the treatment was interrupted after 44 doses due to her high risk of developing PML In fact she had all risk factors: duration of treatment, previous use of IS and JCV antibodies seropositivity.

She was asymptomatic until middle of January 2011 when she developed seizures and changes in personality. She was admitted to hospital and the first MRI showed a right frontal subcortical lesion extending to lateral ventriculus with enhancement compatible with PML and initial IRIS. She undergone two lumbar punctures and qualitative PCR showed a mild positivity for JCV in both samples.

Then at the middle of February she was admitted to our neurological department were the neurological examination revealed only dysphoric and hypocritic behavior (EDSS: 2,0 and Karnoksfki 80); she underwent a third lumbar puncture and a quantitative PCR assay was negative. MRI scan showed an extension of the frontal lesion with increased T1 hypointensity and gadolinium enhancement as well as reactivation of many MS lesions.

The patient was treated with monthly iv steroid courses. Both clinical condition (EDSS: 1,0 and Karnoksfki 100) and neuroradiological features improved.

Conclusions: We report this case to emphasize the importance of close clinical and neuroradiological follow up after natalizumab discontinuation since an indolent PML could develop during the phase of immunoreconstitution.

Morevover we remark the relevance of stratifying the risk of PML especially in patients with long duration of treatment and previous use of immunosuppressant drugs.

L. Moiola, F. Sangalli, M. Radaelli, G. Di Maggio, P. Preziosa, S. Gerevini, V. Martinelli, G. Comi (Milan, IT)

Prof Comi received personal compensation for activities such as advisory board and consultant with the following companies: Novartis, Teva., Sanofi-Aventis, Merck Serono and Bayer Schering and for speaking with the following companies: Novartis, Teva, Sanofi-Aventis, Merck Serono, Biogen-Dompè and Bayer Schering. Dr Martinelli received travel supports and speaker fees for activities with Biogen Dompe, Merck/Serono, Bayer Schering, TEVA and Sanofi Aventis as a speaker. Dr. L. Moiola received personal compensation for speaking activity from Biogen Dompè and Sanofi-Aventis. In the last year Dr. S. Bucello received personal compensation for speaking activity from Biogen Dompè. Dr. F. Sangalli, Dr. M. Radaelli, Dr. G. Di Maggio, P. Preziosa and S. Gerevini have nothing to disclose.

Source: 5th Joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis Amsterdam, The Netherlands(21/10/11)

Biogen Idec and Elan Corporation, plc today announced 28 company-supported Tysabri ® (natalizumab) presentations at the 5 th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS), held in Amsterdam, the Netherlands.

Key data indicated patients on Tysabri experienced reduced annualized relapse rates (ARR), particularly in those treated with Tysabri early in the course of their disease. Data also indicated a long-term benefit for patients who had achieved freedom from disease activity early in their treatment course. Data from a separate study showed Tysabri-treated patients experienced improved incontinence-related quality of life (QOL). Additional data sets were presented further supporting Biogen Idec´s and Elan´s efforts to stratify the risk of progressive multifocal leukoencephalopathy (PML) in Tysabri-treated patients.

"Continued study of patient experience with Tysabri has shown it can potentially improve the lives of people with MS by delaying disease progression and improving incontinence-related quality of life," said Douglas E. Williams, Ph.D., Executive Vice President, Research and Development at Biogen Idec. "The efficacy data from TOP and STRATA have shown the potential benefits of Tysabri treatment early in the course of the disease, and these benefits were maintained over time. These, coupled with our data-driven approach to risk stratification, help us confidently position Tysabri for the treatment of many patients who previously may not have considered this important therapy."

"Further study of anti-JCV antibody status continues to support its utility for risk stratification, enabling a personalized discussion of benefit/risk for each individual patient," said Ted Yednock, Ph.D., Executive Vice President, Head of Global Research at Elan. "Our five years in-market experience, along with information resulting from our ongoing study of the efficacy and safety of Tysabri in MS, enables physicians and patients to make decisions on therapeutic approaches for treating this debilitating disease."

Data supporting early use and long-term benefit of Tysabri

Long-term outcomes in natalizumab-treated patients who were free of disease activity over the 2-year AFFIRM study - Poster 513

This analysis compared patients in the long-term Safety of Tysabri Re-dosing and Treatment (STRATA) study who were disease activity free (DAF) to patients who were not disease activity free (NDAF) over two years in the AFFIRM trial. At STRATA baseline, there were 177 DAF patients and 415 NDAF patients. Ninety four percent of the patients free of disease activity and 60 percent of the patients not free of disease activity were originally randomized to Tysabri in AFFIRM. AFFIRM randomized patients in a 2:1 ratio (Tysabri:placebo).

At three years of Tysabri treatment in STRATA, the DAF patients had less disability and significantly lower ARR than the NDAF patients. Mean Expanded Disability Status Scale (EDSS) scores were 2.34 for DAF and 3.23 for NDAF patients (p<0.0001) and the unadjusted ARRs was 0.08 in DAF patients and 0.16 in NDAF patients (p<0.0001).

These data show Tysabri-treated patients who achieve freedom from disease activity over the short term may experience longer-term benefits, as well as early treatment is preferable to delayed treatment.

This poster will be available for viewing on Thursday, 20 October between 15:30 and 17:00 CEST.

Updated safety and efficacy of natalizumab in the ongoing STRATA study - Poster 981This study evaluated the safety and efficacy of Tysabri in the ongoing Safety of Tysabri Re-dosing and Treatment Study (STRATA) in which participants represented 3,198 patient-years of Tysabri exposure. STRATA is an ongoing, open-label, multinational study currently in its long-term extension phase in patients who completed feeder studies and their open-label extensions.

This study showed that for patients in the overall population, ARR remained low at .17 during Tysabri treatment, which is consistent with rates observed in the AFFIRM study and was maintained over 240 weeks. In addition ARR was lower in patients originally randomized to Tysabri compared with patients who were originally randomized to placebo in the feeder studies: 0.15 (95% confidence interval (CI): 0.14-0.17) vs 0.22 (95% CI: 0.19-0.24). Mean EDSS scores were either stable or improved throughout STRATA and were lower in patients who originally received TYSABRI compared with those who originally received placebo in the feeder studies. The proportion of patients with sustained disability progression during STRATA remained low and stable, regardless of original treatment assignment. Overall these data suggested early treatment may be preferable to late treatment.

Further, data showed that the safety profile of Tysabri in STRATA is consistent with the overall post-marketing safety profile of the drug.

This poster will be available for viewing on Friday, 21 October between 15:30 and 17:00 CEST.

Assessment of annualized relapse rate and Expanded Disability Status Scale score changes over time in the Tysabri (Natalizumab) Observational Program - Poster 509

This analysis evaluated the association between baseline treatment history and ARR in the Tysabri Observational Program (TOP). TOP assesses long-term outcomes in 3,484 Tysabri-treated RRMS patients in five treatment-history groups: therapy naïve (n=337); interferon (IFN) only (n=1626); glatiramer acetate (GA) only (n=288); switched between IFN and GA in either direction (n=595), and prior immunosuppressant (IS) use (n=487).

Post-baseline ARR was significantly reduced and remained low after three years of Tysabri therapy. Mean ARRs in Tysabri patients were lowest in patients who were therapy naïve at baseline (0.16) and highest in patients who were previously treated with IS therapy (0.34) or who switched between GA and IFN (0.25). EDSS scores remained stable over three years in patients treated with Tysabri. The proportion of patients with sustained improvement of EDSS scores was higher than the proportion of patients with sustained worsening (progression) of EDSS scores.

These findings indicated a potential benefit of Tysabri treatment early in the course of the disease.

This poster will be available for viewing on Thursday, 20 October between 15:30 and 17:00 CEST.

TRUST study results: effects of natalizumab on bladder function - Poster 1040In the TRUST (EvaluaTion of Bladder Function in Relapsing Remitting Multiple Sclerosis Patients Treated with natalizumab) study, investigators evaluated the potential effects of Tysabri on bladder control as measured by the Urogenital Distress Inventory short form (UDI-6) score compared with baseline. The change in the Incontinence Impact Questionnaire short form (IIQ-7) was used as a secondary endpoint. At week 24, 28 patients completed the study.

Mean UDI-6 and IIQ-7 scores were both significantly lower than baseline beginning at week four and up to week 24. At week 24, 85.7 percent and 78.6 percent of patients demonstrated improvements from baseline in UDI-6 and IIQ-7 scores (p=0.0001 and p=0.0011, respectively).

According to data from this open-label, single-arm, 24-week proof-of-concept study, the magnitude of the effect shows that Tysabri may be capable of decreasing the impact of incontinence on QOL from moderate to mild. Other endpoints are currently being analyzed; final data will be presented upon study completion.

Tysabri significantly improved incontinence-related QOL as measured by mean improvements in UDI-6 and IIQ-7 scores. Patients with worse (higher) UDI-6 or IIQ-7 scores at baseline showed greater initial improvement in scores and maintained improvement over time while receiving Tysabri. The magnitude of this effect suggests that Tysabri may be capable of decreasing the impact of urinary incontinence on QOL from moderate to mild. Further studies are needed to support these analyses.

This poster will be available for viewing on Friday, 21 October between 15:30 and 17:00 CEST.

Additional Data Supports Risk Stratification Initiatives

Data from two studies further support the risk stratification initiatives undertaken by Biogen Idec and Elan.

JCV epidemiology in MS: epidemiology of anti-JC virus antibody prevalence in multiple sclerosis patients - Poster 801This cross-sectional, multicenter, multi-national, epidemiological study of more than 2,600 patients was designed to confirm the rate of anti-JCV antibodies in the MS patient population. This preliminary analysis showed a prevalence rate of anti-JCV antibodies of 57.0 percent in this group, which is consistent with previous studies. In addition, no significant associations were observed between anti-JCV antibody status and MS disease duration, MS type, MS therapy use, IS use, or MS treatment duration.

Contribution of natalizumab treatment duration, prior immunosuppressant use, and anti-JC virus antibody status to the risk of progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis patients - Poster 995This analysis evaluated PML risk in MS patients based on three risk factors.

Tysabri treatment duration, prior immunosuppressant (IS) use and anti-JCV antibody serostatus. Patient blood samples and clinical data were obtained from Tysabri post-marketing sources, clinical studies and an independent Swedish registry representing 165,500 patient-years of Tysabri experience.

Anti-JCV antibody status, combined with prior IS and Tysabri treatment duration can stratify patients at lower and higher risk for PML.
Patients who were anti-JCV antibody negative were at lowest risk.
Patients who had all three risk factors were at greatest risk.

Further, poster 981 showed the three factors had a relationship with PML since they occurred in patients who received between 33 and 58 doses of Tysabri, were anti-JCV antibody positive, and three of the eight PML patients from the study had prior IS use. In the study, as of July 20, 2011, reported SAEs also included infections and infestations (3 percent), gastrointestinal disorders (2 percent) and neoplasms (2 percent).

Posters 801 and 995 will be available for viewing on Friday, 21 October between 15:30 and 17:00 CEST.

Source: Biogen Idec and Elan Corporation, plc (19/10/11)

Patients with multiple sclerosis (MS) who took the new generation anti-inflammatory medication natalizumab for two years had a lower risk of experiencing relapses and progression of their disability, according to a new study.

MS experts say the research is useful because it confirms results from earlier trials.

Natalizumab (NTZ), which is also known by its brand name Tysabri, is recommended for use in the NHS for patients with severe relapsing-remitting MS which is deteriorating quickly. It is administered by intravenous infusion once a month.

Relapsing-remitting MS

The National Institute for Health and Clinical Excellence (NICE), which gives advice on which treatments should be available on the NHS, says natalizumab is only recommended for severe, relapsing-remitting MS (RRMS) that is getting rapidly worse.

The medication works by stopping a type of white blood cell in the immune system from passing into the brain and nervous system and causing inflammation. The theory is that blocking these cells from crossing the blood-brain barrier will reduce the symptoms of RRMS.

Relapsing-remitting MS is the most common type of multiple sclerosis, affecting around 85% of everyone diagnosed with the condition. It means that symptoms appear during the relapsing stage and then fade away, either partially or completely, during the remitting phase.

Reducing risk

In the latest study, researchers from Italy and the UK examined evidence from three trials involving a total of 2,223 patients. They found that NTZ reduced the risk of patients experiencing a relapse during a two year period by about 40% and the risk of the disease progressing by about 25% compared to a control group.

Magnetic Resonance Imaging (MRI) brain scans also showed evidence that NTZ had reduced disease activity.

Safety

As part of their study, the researchers also carried out a review of the safety of the medication.

Natalizumab has a number of side-effects including the serious and often fatal condition called progressive multifocal leukoencephalopathy (PML) which is caused by a viral infection in the brain. In the trials included in the review, there were two cases of PML among the 2,223 cases. One of these was in a patient who had received 29 doses of NTZ and the second, fatal case was in a patient who had received 37 doses.

Writing in the latest edition of The Cochrane Library, the researchers say they were unable to provide a definitive assessment of the safety of natalizumab because of the limited two year period of the trials they looked at. However, study leader Eugenio Pucci of the neurological unit in Macerata, Italy, says in a statement: "Our analysis indicated that NTZ is well tolerated and safe over a period of up to two years."

Pucci and his colleagues recommend that NTZ only be used only by skilled neurologists in MS centres under national or international surveillance programmes.

Pucci adds that, because of these safety concerns and the high cost of the medication, more research should be carried out into which MS patients would most benefit from natalizumab.

Commenting on the research, Dr Doug Brown, Head of Biomedical Research at the MS Society, said in an emailed statement: "Natalizumab is a licensed treatment for MS in the UK and we have known for some time that it reduces relapse rates and progression of disability in people with relapsing remitting MS; it’s nice to see these findings confirmed in this review.”

Pam Macfarlane, Chief Executive of the Multiple Sclerosis Trust, tells us: "The Cochrane review of natalizumab (NTZ)/(Tysabri) is useful and supports what we know about the drug so far.

“Natalizumab is an important treatment option for people with highly active relapsing remitting MS, but as the report highlights it is not without risk. People considering this treatment need full information and specialist support to assess the risks and benefits for themselves. We would also agree with the author’s comment that NTZ should only be used in specialist MS centres with a comprehensive monitoring programme."

Source: Boots WebMD © 2011 WebMD, LLC (05/10/11)

Abstract

Background: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML).

Objectives: We present a patient study through therapy, the diagnosis of PML (after 29 infusions), plasma exchange (PE) and development of immune reconstitution inflammatory syndrome (IRIS).

Methods: Routine diagnostics, magnetic resonance imaging (MRI), immunological status (flow cytometry, T-cell migration assays and T-cell repertoire analysis), and brain biopsy with immunohistological analysis.

Results: CD49d decreased after 12months of treatment. At PML diagnosis, CD49d expression and migratory capacity of T cells was low and peripheral T-cell receptor (TCR) complexity showed severe perturbations. The distribution of peripheral monocytes changed from CCR5+ to CCR7+. After PE some changes reverted: CD49d increased and overshot earliest levels, migratory capacities of T cells recovered and peripheral TCR complexity increased. With no clinical, routine laboratory or cerebrospinal fluid (CSF) changes, MRI 2 months after PE demonstrated progressive lesion development. Brain histopathology confirmed the presence of infiltrates indicative of IRIS without clinical signs, immunologically accompanied by CCR7/CCR5 recovery of peripheral monocytes.

Conclusion: Natalizumab-associated immunological changes accompanying PML were reversible after PE; IRIS can occur very late, remain asymptomatic and be elusive to CSF analysis. Our study may provide insights into the changes under treatment with natalizumab associated with JC virus control.

Full Article

Nicholas Schwab, Karin G Höhn, Tilman Schneider-Hohendorf, Imke Metz, Max-Philipp Stenner, Samantha Jilek, Renaud A Du Pasquier, Ralf Gold, Sven G Meuth, Richard M Ransohoff,
Wolfgang Brück, Heinz Wiendl

Source: Multiple Sclerosis Journal Copyright © 2011 by SAGE Publications (20/09/11)

ABSTRACT

Objective: To study the outcome of patients with multiple sclerosis (MS) and with natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution inflammatory syndrome (IRIS).

Methods: MedWatch reports from Biogen-Idec (manufacturer of natalizumab, Tysabri®) were reviewed which comprised all 42 cases of natalizumab-related PML cases since its reintroduction until March 2010.

Results: All except 2 patients with natalizumab-related PML were managed by discontinuation of natalizumab and plasmapheresis/immunoadsorption (PLEX/IA). Seventeen patients had contrast enhancement of PML lesions on neuroimaging at the time of diagnosis before withdrawal/removal of natalizumab (early-PML-IRIS) and 23 patients developed contrast enhancement only after withdrawal/removal of natalizumab (late-PML-IRIS). All patients developed IRIS. IRIS was defined as worsening of neurologic deficits during the immune reconstitution following discontinuation of natalizumab, corroborated by inflammatory changes on neuroimaging.

Following PLEX/IA, JC viral load in CSF increased by >10 fold in those with early-PML-IRIS but <2 fold in late-PML-IRIS. IRIS developed earlier and was more severe in early-PML-IRIS (p < 0.05). At the last follow-up, all patients had worse EDSS scores but this was higher in patients with early-PML-IRIS compared to those with late-PML-IRIS (p > 0.05). Mortality was comparable between the 2 groups, 29.4 ± 11% vs 21.7 ± 8.8%. Corticosteroid therapy during IRIS was associated with better Expanded Disability Status Scale outcome, p < 0.05.

Conclusion: Early immunologic rebound in natalizumab-associated PML has worse survival and neurologic outcome. PLEX/IA may accelerate IRIS and its impact on the final outcome is unclear. Corticosteroid therapy provides a modest benefit and needs to be systemically studied in a controlled manner in the management of natalizumab-associated PML-IRIS.

Full Article

Source: Neurology Copyright © 2011 by AAN Enterprises, Inc. (19/09/11)

Abstract
OBJECTIVE:
To study the outcome of patients with multiple sclerosis (MS) and with natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution inflammatory syndrome (IRIS).

METHODS:
MedWatch reports from Biogen-Idec (manufacturer of natalizumab, Tysabri®) were reviewed which comprised all 42 cases of natalizumab-related PML cases since its reintroduction until March 2010.

RESULTS:
All except 2 patients with natalizumab-related PML were managed by discontinuation of natalizumab and plasmapheresis/immunoadsorption (PLEX/IA). Seventeen patients had contrast enhancement of PML lesions on neuroimaging at the time of diagnosis before withdrawal/removal of natalizumab (early-PML-IRIS) and 23 patients developed contrast enhancement only after withdrawal/removal of natalizumab (late-PML-IRIS). All patients developed IRIS. IRIS was defined as worsening of neurologic deficits during the immune reconstitution following discontinuation of natalizumab, corroborated by inflammatory changes on neuroimaging. Following PLEX/IA, JC viral load in CSF increased by >10 fold in those with early-PML-IRIS but <2 fold in late-PML-IRIS. IRIS developed earlier and was more severe in early-PML-IRIS (p < 0.05). At the last follow-up, all patients had worse EDSS scores but this was higher in patients with early-PML-IRIS compared to those with late-PML-IRIS (p > 0.05). Mortality was comparable between the 2 groups, 29.4 ± 11% vs 21.7 ± 8.8%. Corticosteroid therapy during IRIS was associated with better Expanded Disability Status Scale outcome, p < 0.05.

CONCLUSION:
Early immunologic rebound in natalizumab-associated PML has worse survival and neurologic outcome. PLEX/IA may accelerate IRIS and its impact on the final outcome is unclear. Corticosteroid therapy provides a modest benefit and needs to be systemically studied in a controlled manner in the management of natalizumab-associated PML-IRIS.

Tan IL, McArthur JC, Clifford DB, Major EO, Nath A.

From the Department of Neurology (I.L.T., J.C.M., A.N.), Johns Hopkins School of Medicine, Baltimore, MD; Department of Neurology (D.B.C.), Washington University, St Louis, MO; and Laboratory of Molecular Medicine and Neuroscience (E.O.M.), NINDS, NIH, Bethesda, MD.

Source: Neurology. 2011 Aug 10 & Pubmed PMID: 21832229 (17/08/11)

Inhibikase Therapeutics, Inc., an emerging leader in infectious disease, announced today that it has received FDA clearance to commence a Phase II proof-of-concept trial for its lead compound IkT-001. IkT-001, a host-directed kinase inhibitor, is intended to clear JC polyomavirus (JCV) infection, the causative agent of Progressive Multifocal Leukoencephalopathy (PML).

This proof-of-concept trial will be conducted in multiple sclerosis (MS) patients on natalizumab (Tysabri®), a patient group that is at significant risk for developing the potentially fatal PML disease. JCV progresses to PML only in patients with chronic or drug-induced immune suppression, to include patients diagnosed with clinical AIDS or who are receiving monoclonal antibody treatment for MS, lupus, rheumatoid arthritis, leukemia or lymphoma.

The Phase II trial will be a four-week, open-label, sequential-dose-ranging study of the compound's safety and its antiviral effects against JCV in 48 patients with a relapsing form of MS who receive Tysabri® infusion therapy. In addition to closely monitoring the safety and pharmacokinetic profile of IkT-001, the study also will determine the potential antiviral effect of IkT-001 against JCV as measured by the suppression of urinary excretion of JCV. Led by Jeffrey English, MD, of the Multiple Sclerosis Center of Atlanta, the study will be performed at three to five U.S. treatment centers for MS. All participating centers must be registered with the TOUCH Program for the prescription and infusion of Tysabri® to patients with MS.

"The launch of this study is a pivotal event for Inhibikase Therapeutics, just 23 months into operations, as we advance a new approach to treating bacterial and viral infectious diseases into the clinic," said Milton H. Werner Ph.D., Chief Executive Officer and President of Inhibikase Therapeutics. "If IkT-001 proves to be efficacious at suppressing JCV in MS patients on Tysabri®, then a much broader population of patients at potential risk of contracting PML could benefit from this approach to preempting the virus from reaching the brain and causing the disease. The common mechanism of action utilized by IkT-001 enables treatment for bacterial and viral infectious disease, thus an efficacious outcome for this Phase II study could clear a path for multiple indications using the same pharmaceutical approach."

About JC Virus and Progressive Multifocal Leukoencephalopathy (PML)

The John Cunningham virus (JCV) is a type of human polyomavirus. It was isolated in 1971 from a patient with progressive multifocal leukoencephalopathy (PML). Human polyomaviruses, like JC and BK, cause PML and other diseases only in the context of immunodeficiency, as in AIDS, or drug-related immune suppression, either for treatment of autoimmune disease, cancer or for solid organ transplant maintenance. JCV infection is very common in the general population, with roughly 60 percent of adult humans likely to have been exposed to the virus; most people acquire JCV in childhood or adolescence.⁽¹⁾ When immunodeficiency or immunosuppression allows JCV to 'reactivate', the virus preferentially migrates to the brain, destroying oligodendrocytes and astrocytes. This lytic infection leads to cognitive and motor dysfunction (the syndrome PML) and is fatal in 50 percent or more of patients. The best approach to treating the disease is to attack the virus in its quiescent state before it enters the brain. IkT-001 blocks viral entry into host cells, and therefore could suppress an active JCV infection in at risk patients prior to virus migration into the brain. There is no currently approved treatment for PML.

About Inhibikase Therapeutics

Founded in 2008, Inhibikase Therapeutics is a private biopharmaceutical company developing novel, small-molecule compounds to treat bacterial and viral infectious diseases through a know-risk development strategy, one that advances a compound against a clinically validated target to proof-of-concept stage on an accelerated timeline. Its pipeline of validated targets utilizes known chemical entities, as well as novel chemical entities, to treat diseases therapeutically and prophylactically. By inhibiting human pathways used by multiple bacteria and viruses for reproduction in the patient, the Company's compounds block viral and bacterial reproduction with a lower likelihood of stimulating resistance. Inhibikase Therapeutics is also developing a broad-spectrum antiviral specific for enveloped viruses, opening new avenues for vaccine development and biodefense.

⁽¹⁾ Padgett, B.L. and Walker, D.L. (1973). "Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multifocal leukoencephalopathy". J. Infect. Dis. 127 (4): 467-470.

Source: Digital Journal copyright © 1998-2011 digitaljournal.com (16/08/11)

Younger age, faster diagnosis, and undergoing treatment in Europe were among the factors associated with greater likelihood of survival in cases of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis patients treated with natalizumab (Tysabri), a researcher reported here.

Analysis of the first 79 cases of PML in patients receiving natalizumab found that these were the strongest survival predictors, according to John Foley, MD, of the Rocky Mountain Multiple Sclerosis Clinic in Salt Lake City.

Others included distribution of MS lesions and titers of JC virus -- the actual cause of PML -- in cerebrospinal fluid at diagnosis, he told attendees at the annual meeting of the Consortium of Multiple Sclerosis Centers.

PML is a rare but extremely serious side effect of natalizumab treatment. Its emergence led to the drug's removal from the U.S. market just a few months after it was launched, but development of a strict risk evaluation and mitigation strategy led the FDA to approve the drug again.

At this point, the rate of PML appears to be just over one per 1,000 patients treated.

The drug inhibits leukocyte migration and may also alter the balance of CD4- and CD8-positive T-cells, increasing vulnerability to infections within the brain.

JC virus is widespread. Studies by natalizumab's manufacturer, Biogen Idec, indicate that roughly half of MS patients are seropositive for infection. In most people, the latent infection is harmless, but when they become immunocompromised, as in AIDS, it can become active and deadly.

A total of 124 patients have been diagnosed with PML worldwide following treatment with natalizumab. Foley said the most recent data indicated that about 80% have survived, a rate that has grown since the first cases were seen.

The study he reported here was a follow up to an analysis by the same group of researchers, published last month in Neurology, covering the first 35 PML patients.

The same general patterns were generally seen with the addition of more patients but, not surprisingly, the specific numbers differed somewhat.

Foley and colleagues obtained patient information from the treating physicians as well as from Biogen Idec's registry, comparing characteristics of survivors with those of fatal cases.

Median duration of follow up for the survivors was 9.6 months (range 1.2 to 29.1 months). Among the fatal cases, the median time from PML diagnosis to death was 2.1 months.

Most of the deaths and much of the morbidity in the PML cases were actually attributable to immune reconstitution inflammatory syndrome (IRIS) following withdrawal of natalizumab, Foley indicated.

Comparisons of survivors with fatal cases revealed the following differences:

Median age: 43 in survivors, 53 in fatalities
Median time from symptom onset to PML diagnosis: 27 days in survivors, 41 days in fatalities
Median JC virus loads in cerebrospinal fluid (CSF) at diagnosis: 132,000 copies/mL in survivors, 287,000 copies/mL in fatalities
Moreover, while patients in the U.S. represented 43% of the worldwide PML total, they accounted for 81% of the fatalities.

The survival rate in the U.S. was 62% versus 93% in Europe, Foley said.

Differences in practice patterns

Foley said the reasons for the disparity were uncertain, but he speculated that several differences between the U.S. and Europe in practice patterns may help explain it.

He said that U.S. patients receiving natalizumab were older and had more widespread disease than their European counterparts. Also, physicians in the U.S. may be more reluctant to treat aggressively with steroids when IRIS develops, he said.

"A lot of the U.S. cases probably are dying more during the IRIS phase when there is a lot of cell necrosis," he said. He also indicated that U.S. physicians may have been slower to diagnose PML after symptoms develop.

It is possible that more virulent JC virus strains are endemic in the U.S., he said, although much remains to be learned about the virology of JC virus.

Foley also identified several factors that were virtually identical in the survivors and fatal cases. These included the gender balance, median duration of natalizumab treatment, and prior immunosuppressant therapy.

The latter two have been found in Biogen Idec's analyses to be powerful predictors of PML development, along with JC virus infection status.

Another finding in the new study was that most patients surviving PML appear to need a long time to recover. Among 38 patients with Karnofsky performance ratings by their physicians at least six months after PML diagnosis, only five were in the "mild" disability category.

Half were rated as moderately impaired, and 37% were severely disabled and required custodial care.

One implication of the study, Foley said, is that it may be advisable to begin natalizumab treatment earlier in the disease in patients negative for JC virus. That may improve the survival chances in those extremely rare patients who still go on to develop PML.

At this point, according to Biogen Idec's data, no patient shown to be seronegative for JC virus exposure has developed PML.

But Robert Fox, MD, of the Cleveland Clinic, told MedPage Today that there is some risk that a seronegative patient will become infected during natalizumab treatment. Early data appear to indicate that the annual risk is on the order of 1% to 2% annually, he said.

The serological test now being studied for assessing JC virus status in MS patients also seems to have a false-negative rate of about 2.5%, he said.

Consequently, Fox said, it is likely that patients on natalizumab will need regular retesting every six months to confirm their continued negativity.

The study was supported by Biogen Idec.

Foley reported consulting fees from Biogen Idec, Genzyme, and Teva. Several co-authors were Biogen Idec employees.

Fox reported consulting fees from Biogen Idec, Teva, Genentech, and Novartis.

Source: Medpage Today © 2011 Everyday Health, Inc. (06/06/11)

A follow-up study of 35 MS patients with Tysabri-associated progressive multifocal leukoencephalopathy provides a somewhat encouraging survival rate of about 70%.

This percentage is more than twice the quoted survival rate of other patient types with PML (eg, those with HIV infection or following transplantation), and the authors speculate that the improved survival in Tysabri-related cases may be due (partially) to the ability to reconstitute the immune system more easily in these cases.

Factors that appeared to improve the chances of survival among Tysabri-treated patients specifically were generally not surprising: relative youth, less MS-related disability, a shorter time between symptom onset and the diagnosis of PML, and less extensive disease (ie, unilobar PML vs global disease).

The provided overall risk of PML with Tysabri treatment remains within the ranges observed during the clinical development of the drug (1/1000) and the postmarketing experience (0.9/1000). However, the risk of PML is acknowledged to increase substantially as the duration of treatment increases*:
•from 0.01/1000 during months 1-12,

•to 0.39/1000 during months 13-24,
•to 1.46/1000 during months 25-36.
The risk of PML reapproaches the overall risk when treatment extends 37-48 months.

The authors, 3 of whom work for Biogen Idec, the maker of Tysabri, admit that one major deficiency of their follow-up report is the lack of long-term data. Only 12 of 25 PML survivors had follow-up data beyond 6 months at the time of the analysis. However, most Tysabri-treated patients with PML who died did so within 2 months of diagnosis; so the authors predict that the ~70% survival rate will be maintained as the data continue to accumulate.

Source: Pathophilia © Barbara J. Martin, MD. (19/05/11)

Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.

In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.

A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.

Antibodies Precede PML

In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.

"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.

In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.

The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.

Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.

Serum Concentration Predicts Risk

The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.

For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.

In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.

Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.

Higher Survival With Early Diagnosis

Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.

In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.

Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.

The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.

Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.

The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.

Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.

PML Presentation Can Be Subtle

PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.

After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.

He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.

The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.

Immunosuppressant History Is Relevant

A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.

The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.

Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.

The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.

The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).

The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.

Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.

Source: International Medical News Copyright © 2011 International Medical News Group, LLC. (17/05/11)

Summary
Patients of African descent often experience a more aggressive disease course, with more frequent relapses, faster progression to a secondary progressive stage, and less robust response to Beta-interferon. In this paper a post hoc analysis was performed on two pivotal trials of Natalizumab: AFFIRM and SENTINEL trials. Forty nine patients of African descent were evaluated.

It was found that Natalizumab therapy significantly reduced the relapse rate in this population, as well as T2 lesions and gadolinium-enhancing lesions on MRI. As there is limited information on people of African descent with MS this paper would support its use as a second line therapy for those with ongoing disease activity despite treatment with Beta-interferons or glatiramer acetate.

Abstract
BACKGROUND:
Patients with multiple sclerosis (MS) who are of African descent experience a more aggressive disease course than patients who are of white race/ethnicity. In phase 3 clinical trials (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]), natalizumab use significantly improved clinical and magnetic resonance imaging outcomes over 2 years in patients with relapsing MS. Because patients of African descent may be less responsive to interferon beta treatment than patients of white race/ethnicity, the efficacy of natalizumab therapy in this population is clinically important.

OBJECTIVE:
To evaluate the efficacy of natalizumab use in patients of African descent with relapsing MS.

DESIGN:
Post hoc analysis.

SETTING:
Academic research. Patients Patients of African descent with relapsing MS who received natalizumab or placebo in the phase 3 AFFIRM study and those who received natalizumab plus intramuscular interferon beta-1a or placebo plus intramuscular interferon beta-1a in the phase 3 SENTINEL study. Main Outcome Measure Efficacy of natalizumab use in patients of African descent with relapsing MS who participated in the AFFIRM or SENTINEL trial.

RESULTS:
Forty-nine patients of African descent participated in AFFIRM (n = 10) or SENTINEL (n = 39). Demographic and baseline disease characteristics were similar between patients treated with natalizumab (n = 21) or placebo (n = 28). Natalizumab therapy significantly reduced the annualized MS relapse rate by 60% (0.21 vs 0.53 in the placebo group, P = .02). Compared with placebo use, natalizumab therapy also significantly reduced the accumulation of lesions observed on magnetic resonance imaging over 2 years: the mean number of gadolinium-enhancing lesions was reduced by 79% (0.19 vs 0.91, P = .03), and the mean number of new or enlarged T2-weighted lesions was reduced by 90% (0.88 vs 8.52, P = .008).

CONCLUSION:
Natalizumab therapy significantly improved the relapse rate and accumulation of brain lesions in patients of African descent with relapsing MS.

Cree BA, Stuart WH, Tornatore CS, Jeffery DR, Pace AL, Cha CH.
MCR, UCSF Multiple Sclerosis Center, University of California, San Francisco, 350 Parnassus Ave, Ste 908, San Francisco, CA 94117

Full Artice

Source: Arch Neurol. 2011 Apr;68(4):464-8. & Pubmed PMID: 21482925 (03/05/11)

Biogen Idec Inc.  has identified high-risk patients taking its multiple sclerosis drug Tysabri who have a 1 in 100 chance of developing a potentially deadly brain infection from the medicine.

By analyzing risk factors including the length of time taking Tysabri, previous treatments and results of a blood test for antibodies to the virus that causes the infection, doctors may also spot patients with less than a 1 in 10,000 chance of developing the disease known as progressive multifocal leukoencephalopathy, or PML, a study showed. The drug’s U.S. label says the risk of PML is about 1 in 1,000 after two years of treatment.

The test for the JC virus should boost use of Tysabri over time, with peak sales of as much as $3 billion, said Corey Davis, an analyst at Jefferies & Co. in New York.

“If you test negative right now, you have a zero percent chance of getting PML,” since everyone who has the brain disease was previously infected, Davis said today in a telephone interview. “To better delineate the risk is going to be a very powerful tool for Tysabri.”

Tysabri generated $1.2 billion last year for Biogen and its partner, Dublin-based Elan Corp. Knowing the odds of getting PML may reassure patients taking the medicine and help doctors in their treatment decisions.

“We have to tell patients at this point it’s not an entirely proven test, but it certainly will affect our decision making,” said Jack Ratchford, assistant professor of neurology at Johns Hopkins University in Baltimore. “What is done when someone tests positive depends on the individual. Often it is enough of a concern that the possible risk outweighs the benefit” and they stop Tysabri treatment, he said.

Study Results

Results of the analysis of 102 Tysabri patients who developed the brain disease through March 4, including 21 who died, were presented at the American Academy of Neurology meeting in Honolulu. A closer look at 25 patients found all those who developed PML were previously positive for the virus, said Alfred Sandrock, senior vice president of development for Weston, Massachusetts-based Biogen.

Some patients, particularly those with hard-to-control disease, elect to stay on the drug, Ratchford said in a telephone interview. The risk of disability from MS is higher than the risk of the infection for those patients, he said.

Up to half of patients who test negative for the virus may get Tysabri after failing other medicines, and about 14 percent of people with the virus also may be treated, said Michael Yee, an analyst at RBC Capital Markets in San Francisco, in a note to investors last month. About 57,000 patients worldwide take Tysabri, according to a Jan. 11 presentation by Biogen at the J.P. Morgan Healthcare Conference.

Over Time

Studies have shown that after two years of Tysabri, 37 percent of patients taking the drug were free from active disease, including relapses and worsening disability, compared with 7 percent of those given a placebo.

Multiple sclerosis is neurological disorder that robs people of muscle coordination and balance, sometimes leading to damaged vision and paralysis. More than 400,000 Americans and 2.5 million people worldwide have the condition, which is thought to develop when a person’s immune system goes awry and attacks healthy cells in the central nervous system, according to the National Multiple Sclerosis Society.

The risk of PML emerged after Tysabri was on the market, leading Biogen and Elan to suspend sales in February 2005. The drug returned to the market in June 2006 with a risk management program for patients who didn’t benefit from rival medications after research showed it was twice as effective as other MS therapies.

Positive Test

Fifty percent to 60 percent of patients taking Tysabri test positive for antibodies to the JC virus, according to Biogen research. Doctors may think twice before starting patients who are positive for the virus on Tysabri, Ratchford said.

Even testing negative isn’t completely reassuring because patients can be subsequently exposed to the virus, he said.

“We can’t tell them their risk is zero, but it’s considerably lower” if they test negative, he said. “One feels very reassured continuing them on Tysabri.”

There also is a 1 in 25 rate of false negatives with the test, Sandrock said when presenting the results during a poster session at the Neurology meeting. That means some patients with multiple sclerosis who test negative and take Tysabri may develop PML because the test failed to accurately assess their exposure to the virus, he said.

PML Risk

The risk of PML increases after the first year of treatment with the drug, and many doctors consider switching their patients after two years. A question remains about what medicine to use following Tysabri. Stopping treatment appears to trigger flares of the disease and may be detrimental, ruling out the idea of taking a patient off the medication temporarily to reduce the risk, studies at the meeting showed.

One new choice is Novartis AG’s Gilenya, the first pill to treat multiple sclerosis. It is almost twice as effective as Biogen’s Avonex, said Gordon Francis, head of Novartis’s neuroimmunology clinical science unit. It also reduced the risk of worsening disability by 30 percent in previously treated patients, a study presented at the meeting showed.

The company, based in Basel, Switzerland, is considering a study of patients who want to start Gilenya after coming off Tysabri, Francis said. The goal would be to determine short-term risks and see how long patients must be off Tysabri, which can remain in the body for two months or more, before starting another treatment, he said.

Gilenya Oversight

Sales of Gilenya will increase as doctors become more comfortable with it, Francis said. Patients need to be monitored for a slow heart rate for six hours after their first dose, and then checked for vision changes a few months later.

Ultimately, the long-term safety of the drug will be what matters to doctors, he said. The older injected drugs such as Avonex, Bayer AG’s Betaseron, German drugmaker Merck’s Rebif and Teva Pharmaceutical Industries Ltd.’s Copaxone will be favored “until the dust settles,” in perhaps three to five years, he said in an interview.

“There hasn’t been the stampede of the first Tysabri launch, and that is appropriate,” Francis said. “Neurologists are a conservative group, and they are even more conservative than they were five years ago because of Tysabri,” he said.

Source: Bloomberg (c) 2011 BLOOMBERG L.P (15/04/11)

Biogen Idec Inc. has halted enrollment in a large, long-term clinical trial aimed at testing the earlier use of multiple sclerosis drug Tysabri, citing a slower-than-expected pace of finding participants.

The Surpass study aims to test the effectiveness of Tysabri, sold with Elan Corp, when patients switched from more widely used drugs. Tysabri has proved to be highly effective; however, because of a link to a rare brain infection, the patients taking the drug tend to be those who have stopped responding to other drugs or have aggressive cases of MS.

The study started a year ago and had aimed to enroll 1,800 patients to be followed for about two years, yielding data in 2013 or 2014. Enrollment was stopped last month, but participating patients will continue in the trial.

Biogen spokeswoman Kate Weiss declined to comment on the number of patients enrolled, citing policy. The company has decided to devote its resources toward "risk stratification" efforts for the drug and remains dedicated to studying its effectiveness, she said.

Tysabri has been linked in a small number of patients to a serious brain infection called progressive multifocal leukoencephalopathy, or PML. Global sales rose 16% to $1.2 billion last year, although growth has been lower than originally expected in recent years because of the risks of the infection.

Biogen is developing a blood test that may better determine the chances of patients contracting PML. The test recently received CE Mark approval in Europe and the companies are conducting large studies of its effectiveness.

The Surpass trial was designed to measure Tysabri's effectiveness in patients with active MS that have switched from either Teva Pharmaceutical Industries Ltd.'s Copaxone or Rebif, sold by Pfizer Inc. and Germany's Merck KGaA.

The goal of the Surpass trial is to get physicians to use Tysabri when patients aren't responding to their current therapy, rather than switching them to more mainstream therapies and using Tysabri as a last resort.

But the design of the trial meant that patients weren't assured that they would switch treatments at all, something that proved to be a hurdle, Weiss said.

The difficulty comes as many new MS treatments are in development, and Novartis AG (NVS) recently launched Gilenya, the first oral treatment for the condition.

"The MS environment is changing and we need to adapt to that change," Weiss said. "This made it challenging to enroll in light of the current clinical trial landscape and the trial itself."

Source: Dow Jones Newswires Copyright (c) 2011 Dow Jones & Company, Inc. (16/03/11)

Summary: This paper comparing evoked potential measurements (visual [VEP], somatosensory [SEP] and motor evoked potentials [MEP] in 44 patients with MS, 1 year prior to treatment with natalizumab and after 6-12 month follow up found that a significant proportion of patients showed improvements in VEPs and SEPs following initiation of treatment but that no similar changes were seen with MEP results.

These results support previous findings that natalizumab treatment can improve visual outcomes. The authors suggest that these findings demonstrate that natalizumab can stabilize and improve the functional capability of nervous system conduction and that evoked potentials may be a useful tool for evaluating drug effects but that further prospective analysis is required.

Abstract
Background and Objective: The objective of this study was to examine the effects of natalizumab on functional parameters assessed by evoked potentials (visual [VEP], somatosensory [SEP] and motor evoked potentials [MEP]) in a cohort study in relapsing-remitting multiple sclerosis patients.

Methods: EP data of 44 patients examined 12 months prior to natalizumab treatment, at the timepoint of treatment initiation and 1 year later were compared. Sum scores (VEP, MEP, SEP) were evaluated and correlated with the Expanded Disability Status Scale.

Results: Improvement of the VEP sum score was found in 33% of natalizumab-treated patients but only in 9% of the same patients prior to treatment (p = 0.041). A comparable situation was found for SEP (improvement: 32% versus 5%; worsening: 11% versus 37%; p = 0.027). For MEP no significant differences were seen (improvement: 10% versus 18%; worsening: 5% versus 29%; p = 0.60). EP recordings (VEP = SEP > MEP) have the capacity to demonstrate treatment effects of natalizumab on a functional level.

Conclusions: Natalizumab therapy increases the percentage of patients showing stable or even ameliorated electrophysiological parameters in the investigated functional systems.

Full Text - http://msj.sagepub.com/content/17/2/198.long

Meuth SG, Bittner S, Seiler C, Göbel K, Wiendl H.¹

¹University of Wuerzburg, Germany.

Source: Mult Scler. 2011 Feb;17(2):198-203. & PubMed PMID: 21135021 (02/03/11)

Cytheris Announces Publication of Clinical Case Study Combining Recombinant Human Interleukin-7 (CYT107) with Antiviral Agent CMX001 as Potential Treatment for Progressive Multifocal Leukoencephalopathy (PML)

Combination Therapy with Two Investigational Agents, Cytheris’ CYT107 and Chimerix’s CMX001, Indicates Potential for Clearing the JC Virus that Causes PML, a Rare and Usually Fatal Neurological Disease

Cytheris SA, a clinical-stage biopharmaceutical company focused on research and development of new therapies for immune modulation, today announced the publication of a case study report based on successful treatment of Progressive Multifocal Leukoencephalopathy (PML) with combination therapy consisting of two investigational agents, Cytheris’ recombinant human interleukin-7 (CYT107) and CMX001, an investigational, oral broad-spectrum antiviral drug (Chimerix, Research Triangle Park, NC) in the Journal of Antimicrobial Chemotherapy. The combination therapy succeeded in eradicating the polyomavirus JC, the virus that causes PML, in less than two weeks following initiation of CYT107 treatment, and four weeks following the introduction of CMX001.

Progressive Multifocal Leukoencephalopathy (PML) is a rare and usually fatal neurological disease caused by the polyomavirus JC. The virus, first identified in 1971, multiplies in and destroys oligodendrocytes, which are cells of the brain that produce the myelin sheath surrounding neurons. Symptoms include loss of vision, impaired speech, paralysis, cognitive decline and weakness. There is no known cure for PML.

“The combination of CYT107 with a powerful antiviral agent to treat PML follows the same therapeutic regimen that Cytheris is investigating in clinical studies of HCV and HBV, where interferon or antiviral therapy is employed to drop the viral load and is then followed by added treatment with CYT107 to clear the virus, a process accompanied by an increase in CD4 and CD8 T cell counts”, said Michel Morre, DVM, President and Chief Executive Officer of Cytheris. “In responding patients, comparison of the resulting trend lines in decreased viral load and increased CD4 count over time shows an almost identical pattern when the PML case described in Dr. Patel’s report is compared to CYT107-treated patients who have cleared the HCV virus. We believe the same pattern will soon emerge as we reach the higher dose range in our HBV CONVERT study, currently being conducted in France and Italy.”

The paper, "A case of progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia," published in the Journal of Antimicrobial Chemotherapy (Patel A, et al, 2010, Dec., Vol. 65(12): 2489-92), is a case study that provides an overview of the treatment of a single adult patient with PML, a rare and usually fatal disease caused by the human polyomavirus JC. The patient, an adult female admitted to The Methodist Hospital, Houston, Texas, was treated by a medical team under the direction of Julie Y. Patel, MD, of the Immunology, Allergy & Rheumatology Department of Texas A&M Health Science Center College of Medicine.

“Though both experiential and experimental data in the treatment of PML have grown quite considerably in recent years, it is important to keep in mind that there still are no known interventions that can reliably prevent or adequately treat PML”, stated Dr. Patel. “To my knowledge, this is the first case report to demonstrate the use of combination therapy, in this instance two investigational medications, as a possible therapeutic strategy for the treatment of PML.”

About the Case Study
The patient in the reported case study is a 69 year-old female who first presented with mouth numbness. Over the next few months her symptoms progressed to right arm and leg weakness and she eventually developed slurred speech. A brain biopsy showed PML and her cerebrospinal fluid PCR was positive for the JC virus. In addition, her absolute CD4 count was 87 and she was subsequently diagnosed with idiopathic CD4 lymphocytopenia (ICL), a rare disease characterized by abnormally low CD4 T cell counts without evidence of human immunodeficiency virus (HIV) infection.

Prior to IL-7 therapy, she was started on CMX001. Given the risk of deterioration of her condition in the setting of immunodeficiency, Dr. Patel applied for and received an additional Emergency Investigational New Drug Application (EIND) from the U.S. Food and Drug Administration for administration of CYT107 in combination with CMX001, an orally-administered, broad-spectrum antiviral agent with demonstrated in vitro activity against multiple double-stranded DNA (dsDNA) viruses, including cytomegalovirus, adenovirus, JC virus and variola.

Under development by Chimerix, Inc. CMX001 is in Phase 2 clinical studies in immunocompromised transplant and cancer patients for the treatment of life-threatening viruses, including cytomegalovirus and adenovirus. It has also been administered to more than 120 patients under investigator-held Emergency Investigational New Drug applications (EINDs) for the treatment of a wide range of life-threatening infections caused by dsDNA viruses for which there are either no approved treatments or where patients have failed the available treatment.

A treatment cycle of CYT107 includes three administrations of the drug, one subcutaneous injection per week for three weeks. The standard dose is 20µg/kg but to be cautious 10µg/kg was prescribed in this first patient with PML. Shortly after the first administration of CYT107 on March 15, the viral load of this patient dropped to an undetectable level. The patient received the remaining two injections on March 22 and March 29. In September 2010, following submission of the case study for publication, the patient received another cycle of CYT107 to further boost her CD4 T cell count. Blood samples taken during this second cycle of CYT107 administration indicate that the patient remains free of any detectable trace of the JC virus and that her CD4 T cell count continues to increase.

About PML
PML is a rare, progressive, demyelinating disease of the central nervous system that leads to death or severe disability. PML is caused by activation of the John Cunningham (JC) virus. The JC virus resides in latent form in up to 90 percent of healthy adults, typically only causing PML in immunocompromised patients.

When patients are immunosuppressed – for organ transplantation, as a consequence of HIV infection, or by treatment with drugs such as TYSABRI® (natalizumab – Biogen Idec) or RITUXAN® (rituximab - Genentech) that dampen the host immune response – the JC virus may multiply unchecked and cause PML. These observations suggest that the immune system is important in regulating the asymptomatic nature of human JC virus infections.

The factors leading to activation of the latent infection are not fully understood, though abnormalities in T-cells may be important for reactivation and PML. PML has been reported in the published literature in HIV-positive patients, as well as immunosuppressed cancer patients (including patients with hematologic malignancies), organ transplant recipients, and patients with autoimmune diseases. There are no known interventions that can reliably prevent or adequately treat PML.

About Recombinant Human Interleukin-7 (CYT107)
Recombinant human interleukin-7 (CYT107) is a critical immune-modulator for immune T-cell recovery and enhancement. As a growth factor and cytokine physiologically produced by marrow or thymic stromal cells and other epithelia, IL-7 has a critical and, at some steps, a non-redundant stimulating effect on T lymphocyte development, notably on thymopoiesis and, downstream from the thymus, on homeostatic expansion of peripheral T-cells.

Clinical trials conducted on more than 160 patients in Europe, North America, South Africa and Taiwan have demonstrated the potential of IL-7 to expand and protect CD4+ and CD8+ T-cells. Currently, Cytheris is conducting multiple international investigations of IL-7 in HIV, HCV, HBV, post-BMT and cancer. Additional studies include a NIAID/NIH-sponsored trial in idiopathic CD4 lymphocytopenia (ICL) and a cancer vaccine study in children with Ewing's sarcoma family of tumors or similar genetic tumors sponsored by US National Cancer Institute.

Source: Business Wire ©2010 Business Wire (30/11/10)

Fatigue is one of the hallmark symptoms of MS and is associated with severe impairment of quality of life, noted Norman Putzki, MD, Cantonal Hospital, St. Gallen, Switzerland, on October 15.

In the study, 49 patients with RRMS who were treated with natalizumab were compared with 53 matched patients who had been treated with IFNb or GA. Some of the patients treated with natalizumab had previously been treated with IFN, GA, or mitoxantrone, and others had received no previous treatment.

Treatment efficacy was based on the Fatigue Severity Scale (FSS), Modified Fatigue Impact Scale (MFIS) score, and WHO-Five Well-Being Index (WHO-5) scores.

Mean FSS was 3.7 in natalizumab -treated patients and 4.9 IFNb- or GA-treated patients (P =.012), with 51.0% of natalizumab patients no fatigue versus 13.2% of patients receiving the other treatments reporting. The prevalence of borderline and severe fatigue was lower with natalizumab than with IFNb or GA.

Mean total MFIS was 32.6 during treatment with natalizumab and 47.8 with IFNb or GA (P <.001). Fatigue was significantly lower on all subscales of the MFIS (physical, cognitive, and psychosocial) during treatment with natalizumab than with IFNb or GA (P <.001 for all comparisons).

The mean WHO-5 score was 56.7 during treatment with natalizumab. According to the WHO-5 scale, patients with a score <28 are considered to have depression, 28-50 is a sign of possible depression, and a >50 indicates no depression.

The researchers conclude that natalizumab may have a more potent effect on central inflammatory activity relative to the other treatments and that this property may account for its greater beneficial effects on fatigue in patients with MS.

[Presentation title: Multiple Sclerosis-Associated Fatigue During Disease-Modifying Treatment With Natalizumab, Interferon Beta and Glatiramer Acetate. Abstract P925]

Source: Doctor's Guide Channel Copyright (c) 1995-2010 Doctor's Guide Publishing Limited (20/10/10)

Biogen Idec and Elan Corporation, plc announced data further supporting the potential clinical utility of an investigational assay that detects anti-JC virus (JCV) antibodies in human plasma or serum.

The detection of anti-JCV antibodies may provide a means to segment, or stratify, multiple sclerosis (MS) patients considering or receiving treatment with TYSABRI® (natalizumab) and assess their risk for developing progressive multifocal leukoencephalopathy (PML), a rare, but serious, brain infection. These data have been presented at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Gothenburg, Sweden.

This two-step, analytically-validated, enzyme-linked immunosorbant assay (ELISA) to detect anti-JCV antibodies is currently being evaluated in large-scale, prospective clinical studies (>10,000 patients) to determine the utility of the assay in stratifying the risk of PML in TYSABRI-treated patients. Infection with JCV is one of a number of factors required for the development of PML. Detection of anti-JCV antibodies may be a useful tool to identify prior or ongoing JCV infection, helping physicians better assess a patient’s potential risk for developing PML.

“When treating a debilitating, chronic disease such as MS, patient safety is of the utmost importance. At Biogen Idec, we are committed to improving the lives of people with MS. Understanding and mitigating potential treatment risk factors further support our commitment,” said Alfred Sandrock, M.D., Ph.D., Senior Vice President of Neurology Research and Development at Biogen Idec. "We are committed to better understanding PML and have embarked on a number of risk mitigation efforts. The anti-JCV antibody assay is one of our most advanced initiatives and has the potential to provide physicians a tool to help them assess patients’ risk for developing PML."

Overview of Data

Late Breaking News – Factors associated with anti-JCV antibody prevalence in a large cohort of natalizumab-treated MS patients – Platform Presentation 138

The two-step ELISA was used to detect anti-JCV antibodies in blood from patients enrolled in the TYSABRI Global Observation Study (TYGRIS), Safety of TYSABRI Re-dosing and Treatment (STRATA) study, and JCV Antibody Program in Patients with Relapsing Multiple Sclerosis Receiving or Considering Treatment with TYSABRI (STRATIFY-1) study. A chi-square test was used to assess associations between factors and prevalence of anti-JCV antibodies. Together, these data represent one of the largest cohorts of MS patients evaluated for the presence of anti-JCV antibodies, demonstrating an overall prevalence of anti-JCV antibodies of approximately 50 to 60 percent and delineating the prevalence by factors such as age and gender. There was an increasing prevalence of anti-JCV antibodies in men compared to women. There was also an increasing prevalence with age, regardless of gender. TYSABRI use and prior treatment with immunosuppressants did not appear to affect the prevalence of anti-JCV antibodies in this cohort.

Assessment of the incidence of anti-JCV antibodies in a cohort of natalizumab-treated patients with multiple sclerosis – Poster P873

This study, which used the ELISA to evaluate more than 800 serum samples, was designed to assess the prevalence of anti-JCV antibodies in TYSABRI-treated MS patients and evaluate the possible utility of anti-JCV antibodies as a means to segment, or stratify, MS patients and assess their risk for developing PML. Of the more than 800 patients evaluated, 54 percent tested positive for anti-JCV antibodies.

Additionally, anti-JCV antibodies were detected in 20 out of 20 (100 percent) of TYSABRI-treated PML patients at least six months prior to the diagnosis of PML. Further clinical studies are being conducted to determine whether the presence or absence of anti-JCV antibodies may be useful to stratify PML risk.

Late Breaking News – Multi-site cross-validation of the assay to detect anti-JCV antibodies in human serum and plasma – Poster P992

In this study, cross-validation of the ELISA was performed by three laboratories (Focus Diagnostics, Quintiles Laboratories, and Biogen Idec) by evaluating intra- and inter-assay precision, including specificity, sensitivity, selectivity and matrix interference, robustness, and reagent stability. A panel of 100 serum and plasma samples was evaluated at each laboratory. The ability of the ELISA to detect anti-JCV antibodies in human serum and plasma was robust and cross-validated by all three laboratories. The assay is now being used in two global clinical trials to evaluate the potential clinical utility of anti-JCV antibody status for stratifying PML risk.

Late Breaking News – Anti-JCV antibody prevalence in a Swedish cohort of MS patients and non-MS controls – Poster P983

In this study from Sweden, the ELISA was used to detect anti-JCV antibodies in plasma from 2772 untreated or treated MS patients, as well as non-MS controls. A chi-square test was used to assess the association between demographic factors and prevalence of anti-JCV antibodies. Based on the data analyzed to date, it is estimated that the prevalence of anti-JCV antibodies in the Swedish MS population to be 61 percent, which is lower than the prevalence observed in the non-MS control population (67 percent) in the study.

Source: Financial Post © 2010 National Post Inc. (16/10/10)

Some multiple sclerosis (MS) patients who discontinue natalizumab therapy may experience a rebound of disease activity, according to research published online Oct. 11 in the Archives of Neurology.

Augusto Miravalle, M.D., of the University of Colorado Denver, and colleagues observed 32 MS patients who had received at least 12 consecutive infusions of natalizumab to assess the effect of temporary suspension of the treatment during a three- to four-month treatment holiday.

Relapses were experienced during interruption of natalizumab therapy or shortly after resumption of therapy by 38 percent of patients with relapsing-remitting MS (nine of 24) and secondary progressive MS (three of eight); magnetic resonance imaging revealed widespread evidence of inflammatory activity in some patients with secondary progressive MS who had greater inflammatory disease activity before starting therapy. Relapses tended to occur more frequently in younger patients who had received fewer treatments before suspension of therapy. Restarting natalizumab therapy resulted in resumption of prior disease control in all patients.

"In this cohort of patients with MS who had disease refractive to multiple therapeutics before starting natalizumab treatment, magnetic resonance imaging and clinical disease activity returned, often aggressively, following discontinuation of natalizumab therapy. These findings suggest we should consider strategies to minimize the risk of immune reconstitution inflammatory syndrome after natalizumab discontinuation," the authors write.

Two authors disclosed financial relationships with pharmaceutical companies, including Biogen Idec, which markets natalizumab.

Source: Doctors Lounge Copyright © 2001-2010 Doctors Lounge.(13/10/10)

Biogen Idec and Elan Corporation, plc have announced six-month results of an ongoing, one-year longitudinal, observational, patient-reported outcomes study showing multiple sclerosis (MS) patients taking Tysabri® (natalizumab) experienced an improvement in both their physical function and psychological well-being.

Findings from the study, which was performed in conjunction with HealthCore Inc., a health-outcomes research company, are the first attempt to assess patient experiences with Tysabri in usual-care settings. The data, presented at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), shows patients report Tysabri has an impact in improving their overall quality of life.

“The symptoms that an MS patient deals with on a daily basis result in significant psychological and physical effects that can adversely impact their quality of life,” said William Stuart, M.D., medical director of the Multiple Sclerosis Center of Atlanta. “In a previous pivotal trial, Tysabri not only showed a reduction in relapse rates and disability progression, but also improved quality of life. Results from this observational study further demonstrate the impact of Tysabri on improving MS patients’ well-being as reported by patients who live with this disease every day.”

About the study

The study is assessing health outcomes from patients’ perspectives before starting Tysabri and after the third, sixth and 12th infusions of Tysabri. A majority of the patients in the study are female (76.3%) with mean age of 46.6 years and mean disease duration of 10 years.

After six Tysabri infusions, patients reported statistically significant improvement in:

•Disease-specific quality of life (QoL), as measured by the Multiple Sclerosis Impact Scale-29 (MSIS-29), which measures the physical impact of MS in terms of mobility and self care, as well as the psychological impact of MS in terms of anxiety/depression, with lower scores indicating better QoL; and

•General health-related QoL, as measured by the 12-item Short Form Scale (SF-12) health survey, which assesses the physical and mental health, with higher scores indicating better QoL.

Both scales assess patient experience of the physical and psychological aspects of QoL. For the MSIS-29 subscales, there were statistically significant improvements over time for both the physical (baseline 46.87; third infusion 39.60; sixth infusion 39.27 (p< 0.001)) and psychological (baseline 41.56; third infusion 33.77; sixth infusion 33.20 (p< 0.001)) impact scores.

SF-12 physical component summary (baseline 34.20; third infusion 36.05; sixth infusion 36.34 (p< 0.001)) and the SF-12 mental component summary score (baseline 43.25, third infusion 47.35, sixth infusion 47.92 (p< 0.001)) showed statistically significant improvements over time.

Source: Discuss Pharmacy  Copyright 2010 Copyright 2009 (08/10/10)

A new study may help clinicians balance the risks and potential benefits of suspending natalizumab dosing in patients with relapsing multiple sclerosis (MS), according to research presented here at the 135th Annual Meeting of the American Neurological Association (ANA).

There is no clear answer, said Timothy West, MD, University of California San Francisco (UCSF) Multiple Sclerosis Center, San Francisco, California, on September 15. Continuing dosing appears to increase the risk for developing progressive multifocal leucoencephalopathy (PML). Suspending dosing to reduce the risk of PML may contribute to an increased risk for MS flares.

"There is a clear risk to these patients for developing PML from continuing use of natalizumab," Dr. West said. "But if you suspend dosing, about 30% of your patients will flare. Some of them will have an uncharacteristically severe flare."

Natalizumab is a humanised monoclonal antibody that is effective in treating relapsing MS. It has been shown to decrease the relapse rate, reduce TC and gadolinium-enhancing (Gd+) lesions on magnetic resonance imaging (MRI), and slow the progression of disability. The problem is that longer treatment is associated with an increased risk for developing PML. The estimated risk for developing PML is 1 in 50,000 after 12 infusions, 1 in 3,000 after 24 infusions, and 1 in 750 after 36 infusions.

Many clinicians use planned dosing interruptions of 3 to 6 months to reduce the cumulative risk for PML. During a phase 2 trial of the natalizumab, patients on active drug and placebo showed no difference in Gd+ lesions 3 months after discontinuation. Another observational cohort showed an increase in cerebrospinal fluid oligoclonal bands and intrathecally synthesised immunoglobulin G 6 months after cessation of natalizumab. No data show that treatment suspension can restore immunological function to the degree needed to influence the risk of PML, Dr. West noted, but it has become common practice.

Researchers conducted an observational study through chart review of all patients at the UCSF MS Center who had received at least 12 natalizumab infusions. Patients were identified via the Tysabri Outreach United Commitment to Health (TOUCH) program mandated by the US Food and Drug Administration and implemented by the manufacturer. Observational data were censored at 6 months because patients whose treatment was interrupted typically have restarted natalizumab or some other disease-modifying treatment in place of natalizumab by then.

The researchers identified 187 patients who had received natalizumab, of whom 84 met the inclusion criteria. Within the inclusion group, 68 patients had a treatment interruption and 16 did not. Of the 68 patients who had a drug holiday, 4 received another disease-modifying therapy during the natalizumab dosing suspension. None of the 4 patients had a clinical flare or an observed increase in MRI activity during the observation period. Patients had a median of 18 infusions before dosing suspension.

Among the 16 patients who did not have a dosing interruption, none had a clinical flare during the observation period. Of the 68 patients who had a drug holiday, 19 (28%) had a clinical relapse within the 6-month period (P = .017). The median time from dosing interruption to flare was 3 months (range 1-6 months). Seven of the 19 patients (10.3%) who flared had unusually severe flares, Dr. West said. These patients had nearly a 3-point increase in median Expanded Disability Status Scale score, many Gd+ lesions, and limited recovery of neurological function.

"You want to exercise extra vigilance with patients if you suspend dosing," Dr. West said. "Most of our flares happened at 3 months or later, so you may want to consider an extra clinic visit around that time. You may also want to consider some other disease-modifying therapy during dosing suspension. The reality is that nobody knows for sure."

[Presentation title: Natalizumab Dosage Suspension: Are We Helping or Hurting? Abstract WIP-27]

Source: Doctors Guide Channels (c) 1995-2010 Doctor's Guide Publishing Limited (20/09/10)

Abstract
OBJECTIVE: To describe the effect of natalizumab in the treatment of subjects with active multiple sclerosis (MS) treated before the age of 18 years.

METHODS: Nineteen paediatric subjects with MS (mean age 14.6 +/- 2.2 years, mean number of attacks 5.2 +/- 1.9 during the pretreatment phase of 27.7 +/- 19.7 months, median pretreatment Expanded Disability Status Scale score [EDSS] 2.5, range 1.0-5.0) were treated with natalizumab at the dose of 300 mg every 28 days. After treatment initiation, patients were reassessed clinically every month; brain MRI was performed at baseline and every 6 months.

RESULTS: Patients received a median number of 15 infusions (range 6-26). A transient reversible worsening of preexisting symptoms occurred in 1 subject during and following the first infusion. All the patients remained relapse-free during the whole follow-up. The median EDSS decreased from 2.5 to 2.0 at the last visit (p < 0.001). EDSS remained stable in 5 cases, decreased by at least 0.5 point in 6 cases, and decreased by at least 1 point in 8 cases. At baseline, the mean number of gadolinium-enhancing lesions was 4.1 (range 1-20). During the follow-up, no gadolinium-enhancing lesions were detected (p = 0.008); 3 patients developed new T2-visible lesions at month 6 scan but the overall number of T2 lesions remained stable during the subsequent follow-up. Transient and mild side effects occurred in 8 patients.

CONCLUSIONS: Natalizumab was well-tolerated in all subjects. A strong suppression of disease activity was observed in all subjects during the follow-up. Classification of evidence: This study provides Class IV evidence that natalizumab, 300 mg IV once every 28 days, decreased EDSS scores in paediatric patients with MS over a mean treatment period of 15.2 months.

Ghezzi A, Pozzilli C, Grimaldi LM, Brescia Morra V, Bortolon F, Capra R, Filippi M, Moiola L, Rocca MA, Rottoli M, Sarchielli P, Zaffaroni M, Comi G.

Centro Studi Sclerosi Multipla, Via Pastori 4, Ospedale di Gallarate, Gallarate, Italy.

Source: Neurology. 2010 Sep 7;75(10):912-7 & Pubmed PMID: 20820002

Biogen Idec and Elan Corporation, plc announced data has been published in the Annals of Neurology on an investigational, two-step assay to detect anti-JC virus (JCV) antibodies in human serum and plasma.

This assay is currently being evaluated in clinical studies as a potential tool for risk stratification in TYSABRI® (natalizumab)-treated patients. Data from this preliminary analysis have been released online and will be published in the journal’s September issue.

Detection of anti-JCV antibodies may provide a means to segment patients into groups at higher risk or lower risk for developing progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection. In order to develop PML, it is believed that a person must experience a convergence of viral and environmental factors, one of which is being anti-JCV antibody positive.

The publication describes the development and validation efforts undertaken to date, as well as preliminary findings on the prevalence of anti-JCV antibodies in multiple sclerosis (MS) patients from the Safety of TYSABRI Redosing and Treatment (STRATA) study. Plasma and serum samples were also analyzed from 17 TYSABRI-treated patients who were later diagnosed with PML. These data showed that all 17 patients were anti-JCV antibody positive prior to the onset of PML.

“We believe an assay with the ability to detect anti-JCV antibodies will be useful in our efforts to stratify patients for the risk of developing PML. It also has the potential to change the clinical management of MS patients,” said Alfred Sandrock, M.D., Ph.D., senior vice president of neurology research and development at Biogen Idec. “These data support our ongoing clinical studies to assess the clinical utility of this assay and our commitment to further mitigating the rare risk of PML in TYSABRI-treated patients.”

About the study

The study was undertaken to develop an enzyme-linked immunosorbent assay (ELISA) to detect JCV-specific antibodies in MS patients and to evaluate its potential utility in identifying patients at higher or lower risk of developing PML.

A two-step assay for detecting and confirming the presence of anti-JCV antibodies in human serum and plasma was developed and demonstrated to be both sensitive and specific. ELISA cutpoints were statistically established using plasma and serum samples obtained from a total of 831 patients with relapsing MS from the STRATA study. STRATA is an open-label, single-arm, multinational study in which all patients receive TYSABRI every four weeks for 48 weeks. Subsequently, the assay was used to determine the presence of anti-JCV antibodies in TYSABRI-treated PML patients where serum samples were collected 16-180 months prior to the diagnosis of PML.

In the evaluation, 53.6 percent of MS patients in the STRATA study tested positive for anti-JCV antibodies, with a 95 percent confidence interval of 49.9 to 57.3 percent. The false-negative rate was calculated as 2.5 percent. Notably, all pre-PML serum samples from 17 TYSABRI-treated patients who were later diagnosed with PML were anti-JCV antibody positive. This was significantly different from the 53.6 percent seropositivity observed in the analysis of the STRATA study (p<0.001).

The article, entitled “Anti-JC Virus Antibodies: Implications for PML Risk Stratification,” can be found online and will be published in the Annals of Neurology September print issue, Volume 68, Issue 3.

Source: Business Wire © Business Wire 2010 (31/08/10)

Abstract

It has been suggested that natalizumab-associated progressive multifocal leukoencephalopathy may be prevented by structured interruptions of treatment.

Evidence supporting such a drug holiday is not yet available.

Here we present initial observations in 10 multiple sclerosis patients who were stringently monitored up to 6 months after discontinuation of the infusions.

Cumulatively, a combination of clinical relapse and new and/or enhanced lesions on magnetic resonance imaging had occurred in 7 of 10 patients.

Although numbers are small, our data suggest that in patients who were switched to natalizumab because of disease activity despite first-line treatment, a natalizumab drug holiday without reinstatement of alternate disease-modifying therapy is poorly tolerated.

Killestein J, Vennegoor A, Strijbis EM, Seewann A, van Oosten BW, Uitdehaag BM, Polman CH.

Department of Neurology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.

Source: Ann Neurol. 2010 Jul 26 & Pubmed PMID: 20661928 (29/07/10)

DESIGN: Case report.

SETTING: University hospital. Patient A 41-year-old woman with relapsing-remitting multiple sclerosis developed PML after 29 natalizumab infusions.

INTERVENTIONS: Immediate plasma exchange was combined for removal of natalizumab with application of mefloquine and mirtazapine to limit viral replication and oligodendrocyte infection. A subsequent IRIS was treated with glucocorticosteroids.

RESULTS: After 3 months of treatment, cerebrospinal fluid tested negative for JC virus. There was a favourable outcome, and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML.

CONCLUSIONS: In the setting of early diagnosis and consequent treatment, natalizumab-associated PML can be well managed in some cases. This situation differs from the course of PML in other conditions, eg, after the application of depleting monoclonal antibodies, in which irreversible cellular effects are associated with very high mortality.

Schröder A, Lee DH, Hellwig K, Lukas C, Linker RA, Gold R;

Specialists Explore Options for Treating Natalizumab-Associated PML

A new case report suggests that natalizumab-associated progressive multifocal leukoencephalopathy (PML) may be successfully treated in a patient with multiple sclerosis, if caught early.

This differs from the course of PML in other conditions, point out investigators led by Alexandra Schröder, MD, from Ruhr-University in Bochum, Germany. In the case of PML after depleting monoclonal antibodies, irreversible cellular effects are associated with very high mortality.

"In the setting of early diagnosis and consequent treatment, natalizumab-associated PML can be well managed in some cases," the study authors report in an online article published July 12 in the Archives of Neurology.

"We used to think PML was always fatal," Kate Weiss, a spokesperson for Biogen Idec, said during an interview. "But now we are learning that it might not always be."

Asked by Medscape Medical News to comment, Jeffrey Cohen, MD, from the Cleveland Clinic Mellen Center for Multiple Sclerosis in Ohio, said, "PML continues to be the main concern with natalizumab." But he adds that with early detection and treatment, the benefits may still outweigh the risks for carefully selected patients.

PML is a rare, but serious and often fatal adverse effect of natalizumab (Tysabri) that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations. It is caused by the JC virus, which is normally present and kept under control by the immune system. Immunosuppressive drugs prevent the immune system from controlling the virus.

Biogen Idec reports 58 cases of natalizumab-associated PML. Of these, 12 people died. Those who survived experienced varying degrees of disability, with half reporting severe consequences.

Table 1. Cases of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy

Location  No. of Cases 
United States 22
European Union 32
Rest of the world 4

Table 2. Disability Rates

Disability  Rate, % 
Mild 15
Moderate 35
Severe 50

Earlier this year, the US Food and Drug Administration (FDA) notified healthcare professionals and patients that the risk of developing PML increases with the number of natalizumab infusions. There is no established treatment for PML and associated complications.

In the current report, investigators treated a 41-year-old woman with relapsing-remitting multiple sclerosis who developed PML after 29 natalizumab infusions.

Dr. Schröder and colleagues treated her with immediate plasma exchange, and she received 5 courses to accelerate the removal of natalizumab.

The patient then received 60 mg/day of the antidepressant mirtazapine. She also received a loading dose of 250 mg of the antimalarial mefloquine for 3 days. Clinicians then continued administration of the drug weekly.

A week after plasma exchange, the patient experienced progressive cognitive decline with somnolence and a slowing of psychomotor function. A new cranial magnetic resonance imaging scan revealed an increase of the left frontal lesion associated with mass effect and compression of the anterior horn of both lateral ventricles and persistent contrast enhancement compatible with an immune reconstitution syndrome.

Clinicians administered methylprednisolone at a dose of 500 mg for 5 days. They also treated cerebral edema with mannitol at a dose of 4 × 125 mL for 4 days.

During this regimen and with intensive care unit monitoring, the patient rapidly improved with only mild residual signs of frontal inhibition. Follow-up cranial magnetic resonance imaging scans revealed a residual left frontal demyelinating lesion with persistent marginal contrast enhancement but no mass effect.

After 1 month of treatment, polymerase chain reaction copy numbers for the JC virus in the cerebrospinal fluid had significantly decreased to 169/mL, whereas numbers in the plasma were unchanged.

After 3 months of treatment, the JC virus was undetectable in the cerebrospinal fluid, plasma, and urine. Clinicians discontinued administration of mefloquine and mirtazapine, and the patient started receiving immunomodulatory therapy with glatiramer acetate.

"There was a favorable outcome," report investigators, "and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML."

Dr. Cohen said this is very exciting. "This is a general approach that has been talked about in most of the field, but the 2 new aspects of treatment include using an antidepressant and an antimalarial." It has been hypothesized that an antidepressant may block the receptor of the JC virus, and clinicians have long wondered whether the antiviral effects of antimalarials could prove useful.

The investigators acknowledge that additional study is needed and regulators continue to monitor for new cases of PML.

"We recommend stringent monitoring as outlined by the Tysabri Outreach Unified Commitment to Health (TOUCH) program in the US," Weiss said. Only prescribers and patients enrolled in the program can use natalizumab, and only certain pharmacies and infusion sites are authorized to dispense the drug.

The FDA is also monitoring for herpes virus infections with natalizumab and cases of pericarditis.

Senior author Dr. Ralf Gold reports receiving grant support, speaker, and consulting honoraria from Biogen Idec. Dr. Cohen is an investigator on company-sponsored clinical trials.

Sources: Archives of Neurology (Jul 2010) © 2010 American Medical Association. (21/07/10) Medscape Medical News  © 2010 WebMD, LLC (21/07/10)

Treatment with natalizumab (Tysabri, Biogen Idec and Elan) leads to improved language processing and retrieval of newly learned verbal material in patients with multiple sclerosis (MS).

The researchers compared the effects of natalizumab with treatment with other disease-modifying therapies in patients with MS. The study included 46 patients taking natalizumab (mean ± SD age, 43.2 ± 9.1 years; mean ± SD years of education, 15.1 ± 2.5 years; 76% female; mean ± SD intertest interval, 14.9 ± 3.9 months; mean ± SD Expanded Disability Status Scale [EDSS] score, 3.8 ± 2.2; and disease duration <5 years, 9%; 5 – 10 years, 50%; and >10 years, 41%).

Investigators with South Shore Neurologic Associates of Patchogue, New York, and NeuroTrax Corporation of Newark, New Jersey, tested patients with a 30- to 60-minute computerized test designed to assess mild cognitive impairment (Mindstreams, NeuroTrax Corp). Patients were tested once, either before treatment or early in the treatment cycle (0-3 infusions), and again after the completion of more extended treatment (>9 infusions).

The comparison group included 37 stable patients, of whom 10 were receiving Avonex, 5 Betaseron, 5 Rebif, 5 CombiRX, 4 Copaxone, and 8 no treatment. In this group, mean ± SD age was 45.8 ± 10.8 years; mean ± SD years of education was 14.9 ± 3.6 years; 78% were female; mean ± SD intertest interval was 18.3 ± 5.0 months; mean ± SD EDSS score was 2.8 ± 1.8; and disease duration was less than 5 years for 32%, 5 to 10 years for 43%, and more than 10 years for 24%.

The researchers used repeated-measures analysis of variance (ANOVA) to assess improvements in EDSS, age- and education-adjusted cognitive domain scores, and raw data from individual tests. To measure effect size, the researchers computed Cohen's d (<.05 [1-tailed] was considered significant). The team used mixed-model ANOVA, controlled for EDSS, to analyze change over time between the groups.

There was improvement in the natalizumab group (P = .04, d = 0.21) but not the comparison group (P = .15, d = 0.11) in memory function, particularly verbal memory (natalizumab: .001 < P < .004; 0.43 < d < 0.55; comparison: .18 < P < .62; 0.02 < d < 0.14). The natalizumab group also showed improvement in verbal function (P = .005, d = 0.41), with no improvement seen in the comparison group (P = .31, d = 0.07). The improvements were seen in tests of matching (natalizumab: P = .01, d = 0.38; comparison: P = .17, d = 0.20) and rhyming (natalizumab: P = .01, d = 0.45; comparison: P = .94, d = 0.01). Similarly, EDSS scores improved (natalizumab: P = .03, d = 0.11; comparison: P = .26, d = 0.05).

"We did not expect to see improvements in cognition in this short period of time," Myassar Zarif, MD, a neurologist at South Shore Neurologic Associates who presented the research, told Medscape Medical News.

Dr. Zarif added that the NeuroTrax Mindstreams test, which was used in the study, proved useful. "Cognitive dysfunction is very difficult to assess in patients with MS. This test gives us data that is easy to apply, it's short, and it doesn't fatigue the patient," Dr. Zarif added.

"These quantitative neurologic tools give us a better idea as to what treatment failure is and what treatment success is. Tysabri is one of the treatments likely much more effective in suppressing [central nervous system] inflammation, and maybe it gives the brain a chance to recover. Maybe they will continue to get better as you shut down disease progression," Mark Gudesblatt, MD, director of the Comprehensive MS Care Center at South Shore Neurologic Associates, a coauthor of the research, told Medscape Medical News.

Dr. Gudesblatt was critical of the EDSS that is commonly in use, calling NeuroTrax a major improvement. "We're still using caveman neurology techniques to determine how we treat people."

Others were skeptical of the new technique. "I'd be interested in seeing further validation of NeuroTrax before it is put to wider use. It's relatively new, and we just don't know how accurate or sensitive it is," Keith Edwards, MD, director of the MS Center of Northeastern New York in Latham, who attended the session, told Medscape Medical News.

Dr. Edwards expressed skepticism about the fact that the study found improvements in language processing. "The conclusions of the study were surprising. Language issues are not the problem with MS. Usually, it's relatively preserved compared to processing speed and working memory, so the conclusions of the study strike me as possibly not valid."

The study was supported in part by NeuroTrax Corporation, Newark, New Jersey. Dr. Zarif, Dr. Gudesblatt, and Dr. Edwards have disclosed no relevant financial relationships.

Source: Medscape Today © 1994-2010 by WebMD LLC (09/07/10)

Abstract
We investigated the role of adhesion molecule VLA-4 in CD34+ blood stem-cell mobilization. Therefore, we examined 20 patients with multiple sclerosis (MS) who were treated with the anti-VLA-4 antibody natalizumab.

Treated patients had received a median number of 4 natalizumab infusions (range: 2-9 infusions). Blood samples were taken 4 weeks following the last infusion.

With a median proportion of 7.6 CD34+ cells/microL (range: 2.2-30.4 cells/microL), these patients had a significantly higher (P=.003) amount of circulating CD34+ cells compared with 5 healthy volunteers (median: 1.4/microL; range: 0.6-2.4/microL) and 5 untreated MS patients (median: 1.0/microL; range: 0.5-1.7/microL) (P=.001). Serial measurements in 4 patients receiving their first natalizumab infusion showed a maximal significant increase in circulating CD34+ cells from 3.3/microL (range: 1.6-4.8/microL) to 10.4/microL (range: 7.5-12.04/microL) 72 hours following natalizumab infusion (P=.001), including pluripotent cells in colony-forming assays.

This mobilizing ability of natalizumab might be useful for patients with poor response to granulocyte colony-stimulating factor (G-CSF)-based protocols.

Zohren F, Toutzaris D, Klärner V, Hartung HP, Kieseier B, Haas R.

Department of Haematology, Oncology and Clinical Immunology, Heinrich Heine-University, Düsseldorf, Germany.

Source: Pubmed PMID: 18235044 (11/05/10)

Abstract
Therapeutic application of natalizumab, an anti-CD49d Ab, in patients with multiple sclerosis (MS) has been associated with increased levels of circulating CD34+ progenitors.

We analyzed the frequency, phenotype and functional activity of CD34+ HSC in blood and BM of patients with MS who were treated with natalizumab.

Compared with healthy controls and untreated MS patients, natalizumab treatment increased CD34+ cells in the peripheral blood 7-fold and in BM 10-fold. CD34+ cells derived from blood and marrow of natalizumab-treated patients expressed less of the stem cell marker CD133, were enriched for erythroid progenitors (CFU-E) and expressed lower levels of adhesion molecules than G-CSF-mobilized CD34+ cells.

The level of surface CXCR-4 expression on CD34+ cells from patients treated with natalizumab was higher compared with that of CD34+ cells mobilized by G-CSF (median 43.9 vs 15.1%).

This was associated with a more than doubled migration capacity toward a chemokine stimulus. Furthermore, CD34+ cells mobilized by natalizumab contained more mRNA for p21 and less for matrix metallopeptidase 9 compared with G-CSF-mobilized hematopoietic stem cell (HSC).

Our data indicate that G-CSF and CD49d blockade mobilize different HSC subsets and suggest that both strategies may be differentially applied in specific cell therapy approaches.

Jing D, Oelschlaegel U, Ordemann R, Hölig K, Ehninger G, Reichmann H, Ziemssen T, Bornhäuser M.

Department of Hematology and Oncology, University Hospital Dresden, Dresden, Germany.

Source: Pubmed PMID: 20098455 (11/05/10)

Biogen Idec and Elan Corporation, plc have announced results from a one-year, longitudinal health outcomes study (n=324) in which patients with multiple sclerosis (MS) who received 12 infusions of Tysabri (natalizumab) reported improvements in quality of life (QoL) measures, as well as reduced fatigue and overall improved cognitive function, as measured by validated tools.

The goal of the study, which was performed in conjunction with HealthCore Inc., a health-outcomes research company, was to assess patient experiences with Tysabri in a real-world setting. This research was presented in three posters at the American Academy of Neurology's (AAN) 62nd Annual Meeting in Toronto, April 10 - 17, 2010. The AAN Annual Meeting is the world's largest gathering of neurologists.

"Because MS is such a debilitating disease that affects patients physically, cognitively, psychologically and socially, it can have a significant impact on their quality of life," said William Stuart, M.D., Medical Director of the Multiple Sclerosis Center of Atlanta. "These analyses, based on patient-reported outcomes, are critical to understanding the benefits of treatment with Tysabri over the long term and in a real-world setting."

The one-year longitudinal study assessed health outcomes from the perspective of the patient using validated patient-reported outcome (PRO) measures prior to treatment initiation and after the third, sixth and 12th infusion with Tysabri in a real-world setting. A majority of the patients in the study were female (77.8%) with mean age of 46.7 years and mean years since diagnosis of nine years.

Quality of Life Study Results

After one year of treatment, patients reported statistically significant improvement in:

•general health-related QoL, as measured by the 12-item Short Form Scale (SF-12v2), with higher scores indicating better QoL
•MS-specific QoL, as measured by the 29-item Multiple Sclerosis Impact Scale (MSIS-29), with lower scores indicating better QoL

Both scales report the physical and psychological aspects of QoL in two summary scores. For both scales changes in mean scores from baseline through the 12th infusion were evaluated after adjusting for baseline patient-level and treatment characteristics.

SF-12v2 Physical Component Summary (PCS) scores improved significantly from baseline (BL 34.25, 12th 36.66; p<0.001). Similar improvements were observed in the Mental Component Summary (MCS) scores, which also improved significantly from baseline (BL 43.13, 12th 46.77; p<0.001).

After controlling for covariates, a statistically significant improvement was also observed in MSIS-29 physical impact scores (BL 47.38, 12th 40.43; p<0.001). Similarly, MSIS-29 psychological impact scores showed statistically significant improvements (BL 42.01, 12th 34.09; p<0.001) over time.

The results of these findings are consistent with results from pivotal clinical trials and show the beneficial impact of Tysabri on QoL in MS patients. Results show that improvements were seen as early as three months and were sustained for 12 months.

Fatigue and Cognition Study Results

After one year of treatment, patients reported:

•improvement in cognitive function
•lower impact of fatigue on daily functioning

Cognitive function was measured by the six-question Medical Outcomes Study Cognitive Functioning Scale (MOS-Cog Scale, score range 6-36) with higher scores indicating better reasoning skills, memory, concentration, ability to start several actions at one time and ability to react. Fatigue was measured by the five-question Modified Fatigue Impact Scale-5 (MFIS-5, score range 0-20), with lower scores indicating lower impact of fatigue on physical, cognitive and psychosocial functioning.

After controlling for covariates, on average MOS-Cog scores increased significantly over time (BL 25.12; 12th infusion score 26.19, p=0.0006), indicating improvement in cognitive function, and MFIS-5 scores decreased significantly (BL 12.36; 12th infusion score 11.16, p<0.001), suggesting lower impact of fatigue on daily functioning.

The poster titled Improvement in Patient-Reported Fatigue and Cognitive Function over Time with Natalizumab Treatment (P06.167) was made available for viewing on April 15 from 3-7:30 p.m. EDT.

Dr. Stuart serves as a paid consultant for Biogen Idec.

Source: Science Blog Copyright, Science Blog 2010 (16/04/10)

An early check of registry data from women with multiple sclerosis who became pregnant while taking natalizumab (Tysabri) does not appear to raise concerns of miscarriages or abnormalities, researchers said here.

"We have to emphasize that these are preliminary findings," said Lynda Cristiano, MD, medical director of drug safety at Biogen Idec, Cambridge, Mass., who presented data at a poster presentation at the annual meeting of the American Academy of Neurology.

The prospective Tysabri Pregnancy Exposure Registry has enrolled 179 women, of whom 125 have completed outcomes as of Nov. 23, 2009, Cristiano said.

She said 20 miscarriages occurred among those 125 outcomes -- about 16%, similar to the estimated 15% rate reported in the general population, according to the March of Dimes. Six other women elected to terminate their pregnancies. No ectopic pregnancies or stillbirths were recorded.

Of the 99 live births, 78 of the pregnancies were full term, Cristiano reported. Eight malformations were reported in six pregnancies -- two which involved twin births. The average maternal age in these cases was 29 years.

"As this is an internal and preliminary analysis, birth defects have not yet been classified as major or minor," she said.

"In addition, the sample size of enrolled patients is small and has limited power to detect an increased risk of major birth defects." For those reasons, Cristiano said the rate of birth defects was not calculated for her report.

However, she said the cases have no patterns related to the disease-modifying therapy. 

The registry data reflect the fact that about two-thirds of patients with multiple sclerosis are women, and that the average age of onset of multiple sclerosis coincides with childbearing years. Therefore, disease-modifying agents such as natalizumab are likely to be used by women of childbearing age, Cristiano noted.

Of the 64,600 patients who were exposed to natalizumab through December 2009, about 73% were women, and their average age was 44 years.

"There are no adequate and well-controlled studies of natalizumab in pregnant women," she said.

Animal studies suggested treatment with natalizumab might have adverse impacts on fetal outcomes.

"Doctors tell their patients who are going on disease modifying therapy that none of these drugs are approved for women who are pregnant," said Rosalind Kalb, PhD, vice-president of the professional resource center of the New York-based National MS Society.

"This registry and those that were established for the interferon therapies are designed to capture information on outcomes of women who become pregnant by accident while they are taking these drugs," she explained.

Kalb said registries are the only way to determine safety of these drugs because controlled clinical trials are unlikely to be conducted.

She said the preliminary results presented at AAN do not raise alarms, but don't prove natalizumab is safe for pregnant women, either.

Cristiano is an employee of Biogen Idec. Kalb has no financial disclosures.

Primary source: American Academy of Neurology
Source reference:
Cristiano L, et al "Preliminary evaluation of pregnancy outcomes from the TYSABRI (Natalizumab) pregnancy exposure registry" AAN 2010; Abstract P01.185

Source: MedPage Today © 2004-2010 MedPage Today, LLC. (15/04/10)

Biogen Idec Inc. wants to take the fear out of prescribing its multiple sclerosis treatment Tysabri with a test that can tell patients their odds of getting a deadly brain illness from the drug.

The screening tool could be marketed as early as 2011 if clinical trials involving 9,000 people, set to start this year, show a low rate of false findings, said Naomi Aoki, a spokeswoman for the Cambridge, Massachusetts-based biotechnology company. The test is designed to detect the JC virus that causes progressive multifocal leukoencephalopathy, or PML, a brain-cell destroyer that can lead to disability and death.

Tysabri, which generated $1.1 billion in sales in 2009, has been linked to 42 PML cases, the company has reported. While it's approved for use only after other drugs fail, 61 percent of 285 neurologists surveyed by RBC Capital Markets in San Francisco said Tysabri's ability to slow MS progression would make it their first choice if they could assess the risk of PML.

If the test works, it is "absolutely a game changer," said Patricia O'Looney, vice president of biomedical research at the New York-based National Multiple Sclerosis Society, in a telephone interview. "If Biogen can validate it, that takes out the guessing game."

Tysabri was removed from the market on Feb. 28, 2005, after three patients developed PML, and two died. A year later, the U.S. Food and Drug Administration allowed Biogen and Dublin- based Elan Corp., its marketing partner, to resume selling the treatment after an advisory panel determined it was twice as effective as other drugs in slowing MS progression.

'Longer-Term Positive'

It's too early to set a dollar amount on the potential gain in drug sales based on such a test until the clinical trials are completed said Geoffrey Meacham, an analyst for J.P. Morgan in New York, in a telephone interview. A successful test that determines Tysabri is safe to use in some patients would be "a longer-term positive" for the company, he said.

Biogen's shares, which sold for $67.28 on the last trading day before Tysabri was removed from the market, plunged 43 percent on the withdrawal. Shares have fallen 16 percent since Feb. 27, 2005, closing at $56.43 in Nasdaq Stock Exchange composite trading yesterday.

Biogen first tested their assay using blood samples taken from 11 patients who later developed PML, said Al Sandrock, senior vice president of neurology research and development. The findings from that study and research on the prevalence of JC virus will be presented next week at the American Academy of Neurology meeting in Toronto.

Behind Goal

Since the therapy returned to the market in 2006, the company hasn't reached its goal to have 100,000 patients use it by the end of 2010. Tysabri is used by about 48,800 patients as of the end of 2009, according to Biogen. The company backed away from the goal last year, after a fifth patient developed PML.

About 200 new cases of multiple sclerosis are diagnosed weekly in the U.S., according to the National Institutes of Health. Patients, at first diagnosis, typically are prescribed Biogen's Avonex; Rebif, made by Darmstadt, Germany-based Merck KGaA; Betaferon, made by Bayer AG, of Leverkusen, German; and Copaxone, by Israel-based Teva Pharmaceutical Industries Ltd.

While less effective than Tysabri, these drugs all carry fewer side-effects, Meacham said.

Biogen plans two clinical trials to determine the rates of false positives and false negatives. For patients who test positive, the risk of PML will be about 1 in 500, said Robert Fox, a neurologist at the Cleveland Clinic in Ohio. For those who test negative, though, the risk is "quite low," Biogen's Sandrock said.

MS Millions

About 400,000 Americans and 2.5 million people worldwide have multiple sclerosis, according to the National Multiple Sclerosis Society, a patient group.

The disease destroys neurons, leading to blurred vision, poor balance and coordination, problems with speaking, tremors, fatigue and paralysis. The malady is caused when the immune system mistakenly attacks myelin, a protective coating on nerve fibers, disrupting the brain's communication with the body.

PML occurs when a common germ, called JC virus, mutates, then evades the body's immune defenses and penetrates the brain, causing irreversible damage. Researchers theorize that Tysabri may subdue defenses meant to keep the virus out of the brain.

In February, the FDA updated Tysabri's labeling to clarify its risks. The number of infections and deaths from PML remains about 1 in 1,000 overall. The rate is higher outside the U.S., with 2 of every 1,000 patients contracting the illness. The reason for the difference is unknown, the FDA said.

Antibody Presence

The test is designed to detect the presence of an antibody to the JC virus in the blood of patients, signaling that the patient has been infected.

With a false-negative rate of 2 percent, patients who are free of the virus would lower their risk of getting the brain disorder PML to 1 in 25,000 for the first three years of their Tysabri therapy, wrote analyst Joshua Schimmer of Leerink Swann, in a March 25 note to investors.

Since a patient may become infected with the JC virus at any time (it is passed through the air), part of Biogen's task in its clinical trials is to determine how many patients become infected over time. This determination changes the odds that any one patient may get the disease.

Probably about 1 to 2 percent of patients will be infected yearly, Sandrock said.

Antibody Reliability

Eugene Major, a researcher at the National Institutes of Health in Bethesda, Maryland, said that when the NIH and others tested for the presence of the virus, rather than antibodies, they found that at least 70 percent of the population probably is infected. The company, based on antibody testing, has put that number at 50 percent.

"They're underestimating the number of people who've been exposed," Major said in a telephone interview. "We have strong evidence that the overwhelming majority, especially after the third and fourth decade, have been exposed."

Biogen is looking at other biological signs of PML risk that may be incorporated to improve the test, Sandrock said. In those who test positive, Biogen is testing for markers to further determine which patients are at high risk, Sandrock said. Those markers may include certain genes that increase the risk of a brain infection, or viral mutation that allows JC virus to live in brain tissue.

"We know a lot about the benefits of Tysabri, and we know something about the risk," said Sandrock. "If we can be specific about an individual's risk versus an individual's benefit, that would help patients make better-informed treatment decisions. Patients want to know, 'what's my risk?'"

Source: SFGate © 2010 Hearst Communications Inc. (09/04/10)

Biogen Idec and Elan Corporation, plc today announced enrollment of the first patient in a global Phase IIIb, randomized, rater-blinded, active-controlled study designed to evaluate switching to Tysabri(R) (natalizumab) from Copaxone(R) (glatiramer acetate) or Rebif(R) (interferon beta-1a) in patients with relapsing-remitting multiple sclerosis (RRMS).

The study, called SURPASS, is expected to enroll 1,800 patients in 27 countries and provide direct comparative data of different treatment options for RRMS patients who experience breakthrough disease activity.

"Despite being on therapy, many MS patients still experience disease progression, resulting in loss of physical abilities and permanent damage to the central nervous system," said Richard Rudick, M.D., chair of the SURPASS trial advisory committee and director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic. "Currently, there is limited data to inform decisions about how to switch in patients who have disease activity while on therapy. The goal of the SURPASS study is to provide that data so physicians can improve treatment decisions and outcomes for their MS patients."

A significant number of MS patients continue to experience clinical relapses and disease progression despite treatment with disease-modifying therapies such as Copaxone and Rebif. The SURPASS study, a large, well-controlled comparative trial of MS treatments, will evaluate switching to TYSABRI versus staying on or switching between Copaxone and Rebif and determine whether early use of Tysabri in the treatment algorithm ultimately leads to better outcomes.

"Tysabri is a compelling treatment option that is bringing hope to many MS patients," said Alfred Sandrock, M.D., M.P.H., senior vice president of neurology research and development at Biogen Idec. "By evaluating Tysabri against other MS treatments, our goal is to provide the data needed to make better treatment decisions and improve patients' lives."

"We believe the SURPASS study has the potential to improve the way MS is treated," said Carlos Paya, M.D., Ph.D., president at Elan. "Despite significant advances in treatment, the unmet medical need for many MS patients remains great and this study supports our commitment to continuing to advance the standard of care in MS."

About SURPASS

SURPASS is a global, Phase IIIb, multicenter, randomized, rater-blinded, parallel-group, active-controlled trial designed to provide direct comparative data to inform patients and physicians of the relative benefits of different treatment options when faced with breakthrough disease activity. The large, well-controlled comparative study assessing Tysabri, Copaxone and Rebif is expected to enroll 1,800 patients with RRMS, ages 18 to 60 years old, with a baseline Expanded Disability Status Scale (EDSS) score from 0.0 to 5.5. Patients must have been treated with a stable regimen of either Copaxone or Rebif as their principal first therapy for MS for six to 18 months prior to randomization. Patients must also have had disease activity within 12 months prior to screening defined as one or more clinical relapses or two or more new MRI lesions (Gd+ and/or T2 hyperintense lesions).

The primary endpoint of the study is the annualized relapse rate. Secondary endpoints include the change from baseline to 48 weeks in T2 lesion volume and the proportion of subjects who remain free of disease activity -- defined as no clinical relapses, no new Gd+ lesions, no new or newly-enlarging T2 lesions, and no sustained progression on EDSS. Additional study objectives will evaluate the safety and tolerability of switching to Tysabri.

Participants will be randomized in a 2:1:1 ratio to one of the following groups:

-- Group 1: 900 patients will receive Tysabri 300 mg intravenous (IV) every four weeks;

-- Group 2: 450 patients will receive interferon beta-1a 44 mcg subcutaneous (SC) three times per week; and

-- Group 3: 450 patients will receive glatiramer acetate 20 mg SC once daily.

Source: Biogen Idec and Elan Corporation, plc (25/03/10)

Biogen Idec Inc. is planning the first clinical trial that could lead to use of controversial multiple sclerosis treatment Tysabri, sold with Elan Corp, at earlier stages of the disease.

The long-term trial, dubbed Surpass, will measure the effectiveness of Tysabri in patients with active MS that have switched from either Teva Pharmaceutical Industries Ltd.'s Copaxone or Rebif, sold by Pfizer Inc. and Germany's Merck KGaA.

Tysabri is considered a highly effective therapy for MS, and its growth is important to the future of both Elan and Biogen. But its sales have been slower than originally hoped amid concerns about the risk of a rare brain infection that led to its 18-month market withdrawal beginning in 2005. The study comes after Tysabri brought in more than $1 billion in 2009, and it is part of Biogen's push to accelerate Tysabri's growth.

It also comes amid increased competition in MS treatments. Novartis AG and Germany's Merck KGaA could launch oral treatments for the disease this year, a notable advance compared to the injections and infusions required with current drugs.

The goal of the Surpass trial is to get physicians to use Tysabri when patients aren't responding to their current therapy, rather than switching them to more mainstream therapies.

Beside Copaxone and Rebif, other common options include Biogen's Avonex and Bayer AG's Betaseron, while Tysabri is generally reserved for patients with very aggressive disease or have no other options.

"We are trying to establish that there is no use in switching around [prior to using Tysabri]," Biogen spokeswoman Naomi Aoki. The company is signing up sites for the trial and has yet to enroll the first of an estimated 1,800 patients.

The study will follow participants for about two years and isn't likely to yield data until 2013 or 2014. If successful, the result should allow Biogen to update Tysabri's label and allow it to market the earlier use to physicians.

Source: ADVFN III Copyright 1999-2010 ADVFN PLC (07/02/10)

Biogen Idec and Elan Corporation today announced data presented at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) showing the potential of Tysabri^® (natalizumab) to redefine successful multiple sclerosis (MS) therapy. These data were from observational studies and retrospective analyses of the Phase III AFFIRM clinical trial, demonstrating that Tysabri^®:

Significantly improves measures of physical and cognitive disability using the Multiple Sclerosis Functional Composite (MSFC) in patients from the AFFIRM trial with baseline impairment;
Promoted regeneration or stabilization of damage to the myelin sheath, which can cause some of the symptoms seen in MS patients, as measured by advanced MRI technology; and
Shows improvement in quality of life as reported by patients.
"MS patients should expect more from an MS therapy and studies such as these demonstrate the potential for Tysabri^® to satisfy their expectations," said Michael Panzara, M.D., M.P.H., vice president and chief medical officer of neurology, Biogen Idec. "These data presented at ECTRIMS show that, for many MS patients, Tysabri^® may lead to improvement in a broad range of physical and cognitive symptoms.”

"The strong efficacy profile demonstrated in clinical trials is enhanced further from these and other important Tysabri^® data presented at ECTRIMS," said Carlos Paya, M.D., Ph.D., president, Elan Corporation. "Tysabri^® is the first approved MS therapy with reported data suggesting some signs of the progression of MS can be stopped, whether measured by clinical, radiological or patient-reported measures.”

Tysabri^®significantly improves physical and cognitive function

This post-hoc analysis from the Phase III AFFIRM trial was conducted using the MSFC, a measure of disability that assesses aspects of neurologic dysfunction in MS not captured by Expanded Disability Status Scale (EDSS), to evaluate the effects of Tysabri^® on disability improvement in patients with baseline impairment. Baseline impairment was defined when a patient experienced at least one of the following:

Taking more than five seconds on the timed 25-foot walk (T25FW; ambulation);
Taking more than 21 seconds on the 9-hole peg test (9-HPT; upper extremity function); or
Providing fewer than 55 correct sums on the paced auditory serial addition test (PASAT-3; cognitive function).
The MSFC was administered to patients every 12 weeks; change from baseline to two years was a prespecified secondary endpoint. In the study, 460 patients received Tysabri^® and 225 received placebo.

Results showed that Tysabri^® significantly increased the proportion of patients who improved from baseline to two years on the T25FW (p=.023), 9-HPT (p=.001) and PASAT-3 (p=.012) compared with placebo. The effect of Tysabri^® remained significant for the T25FW, 9-HPT and PASAT-3 compared with placebo when improvement was defined as an improved change from baseline sustained for at least six, seven, or eight out of ten planned study visits.

"This data showing the ability of Tysabri^® to improve both physical and cognitive function represents a new paradigm for defining success in MS therapies,” said Frederick E. Munschauer, III, M.D., Irvin and Rosemary Smith professor, University of New York, Buffalo, New York.

Natalizumab improves disability on the Multiple Sclerosis Functional Composite in a randomized, double-blind, placebo-controlled study of patients with relapsing multiple sclerosis (poster P434).

Tysabri^®stabilizes and restores damage to the myelin sheath

Results from the study showed Tysabri^® promoted regeneration and stabilization of damage done to the myelin sheath, as measured Voxel-Wise MTR (VWMTR), an advanced MRI technology, when compared with those receiving interferon beta-1a IM and healthy subjects.

In the study, 77 MS patients who received Tysabri^® were followed for 12 months along with 21 MS patients who received interferon beta-1a IM and 17 age-matched and sex-matched healthy volunteers. Tysabri^® significantly promoted remyelination when compared to patients treated with interferon beta-1a IM and healthy volunteers. There was no significant difference in decreasing VWMTR NABT volume over the follow-up between Tysabri^®-treated patients and healthy volunteers. Relapsing-remitting patients on both therapies showed higher remyelination potential and less evident demyelination than relapsing secondary progressive MS patients.

Evolution of Voxel-Wise magnetization transfer ratio in natalizumab and interferon beta-1a IM treated patients with multiple sclerosis. A case-control study (poster P721).

Tysabri^® patients report improvement in physical and psychological well-being

This ongoing, one-year longitudinal observational study assesses health outcomes from patients’ perspectives before the start of Tysabri^® treatment and after the third, sixth and 12th infusions. The Multiple Sclerosis Impact Scale-29 (MSIS-29) will be used to assess the impact of Tysabri^® on disease-specific quality of life. Over a six-month period, the study showed patients receiving Tysabri^® experienced a consistent improvement in both their physical and psychological well-being, suggesting that Tysabri^®may improve overall quality of life of MS patients over time.

What do multiple sclerosis patients experience? Effect of natalizumab on disease-specific quality of life over time (poster P872).

Source: Welt Online Copyright 2009 Axel Springer AG (11/09/09)

The multiple sclerosis drug Tysabri awakens a virus that causes a rare brain disease, not only suppressing the body's ability to fight it but making the virus stronger, U.S. researchers have reported.

But these changes take place even in patients who show no symptoms of the infection -- a finding that suggests scientists still do not fully understand why 13 patients taking Tysabri have developed the potentially fatal brain infection.

Tysabri, known generically as natalizumab, is designed the suppress the immune system which mistakenly attacks nerves in MS patients.

Made by Biogen Idec Inc and marketed with Irish drugmaker Elan Corp Plc, Tysabri was temporarily withdrawn from the market in 2005 after it was linked with progressive multifocal leukoencephalopathy or PML. It was brought back in 2006 with stricter safety warnings.

Dr. Igor Koralnik of Harvard Medical School and Beth Israel Deaconess Medical Center and colleagues studied 19 multiple sclerosis patients just starting Tysabri.

They were looking for a virus called JC virus.

'This virus, the JC virus named for the initials of a patient, is found in about 90 percent of the population,' Koralnik said in a statement.

'But in healthy individuals the virus lies dormant in the kidneys and causes no problems.'

Urine samples from the 19 patients showed levels of the JC virus shot up after a year of taking Tysabri, Koralnik and colleagues reported in the New England Journal of Medicine.

The virus infected the blood cells of 60 percent of the patients after 18 months, they found.

They confirmed that Tysabri was affecting immune cells called T cells. 'It further tells us that reactivation and transformation of the virus may first occur in the kidney and that once the activated virus spills into the blood it can easily spread to the brain,' Koralnik said.

None of the 19 patients developed any symptoms or brain lesions suggestive of PML, so the researchers do not suggest that patients should stop taking Tysabri.

Tysabri is one of several immune system suppressing therapies that have been linked to PML, including Rituxan, sold by Biogen with Roche Holding  AG unit Genentech, and Raptiva, a psoriasis drug Genentech pulled from the market.

More than 56,500 MS patients take Tysabri.

Evan Beckman, Biogen's senior vice president of Immunology Research and Development, said the biotechnology company has not found any correlation between the level of JC virus in the blood or urine and the likelihood of a patient developing the rare brain infection progressive multifocal leukoencephalopathy, or PML. "We haven't seen any predictive value of this even in patients who have developed PML."

Beckman noted that the study in the NEJM report was very small and that none of the patients developed PML. He called the results "interesting," but said he is not sure to what extent they can be generalized.

Source: Forbes.com Copywrite 2009 Forbes.com LLC (10/09/09)

According to a post hoc analysis presented at the 19th Meeting of the European Neurological Society (ENS), patients with highly active multiple sclerosis (MS) have significant improvement in their physical and mental quality of life (QOL) after 2 years of treatment with natalizumab.

In the phase 3 Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study and the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) study, natalizumab significantly improved QOL as measured by the Medical Outcomes Study Short Form-36 (SF-36) and a visual analogue scale (VAS) of well-being in patients with relapsing MS.

In AFFIRM, patients received natalizumab or placebo for up to 116 weeks. In SENTINEL, treatment consisted of natalizumab added to interferon (IFN) beta-1a or placebo plus IFN beta-1a for up to 116 weeks.

"We performed a post hoc analysis to assess QOL in the subgroup of patients with highly active disease," explained Robert Hyde, PhD, Biogen Idec, Inc., Cambridge, Massachusetts, on June 22.

The researchers pooled data from AFFIRM and SENTINEL to evaluate the effects of natalizumab on QOL at 2 years in this patient group (n = 378).

At baseline, patients with highly active disease had worse QOL than the general United States population. Their mean physical component summary (PCS) score was 43.2, and their mean mental component summary (MCS) score was 45.8, according to SF-36.

"This is quite a poor QOL compared with heart disease and oncology indications," Dr. Hyde pointed out.

In AFFIRM, natalizumab significantly improved the mean QOL from baseline to 2 years compared with placebo. The mean score change with natalizumab and placebo, respectively, was 1.6 vs -2.2 for PCS (P = .019), 3.4 vs -1.3 for MCS (P = .030), and 3.7 vs -7.6 for VAS (P = .013).

In SENTINEL, treatment with natalizumab plus IFN beta-1a significantly improved mean changes in PCS scores (0.7 vs -0.9 with IFN beta-1a alone; P = .032) and VAS scores (1.0 vs -3.5 with IFN beta-1a alone; P = .044) at 2 years.

Dr. Hyde indicated that the distribution of patients who experienced a clinically important change in MCS scores in AFFIRM was significantly more favourable with natalizumab treatment than with placebo (P = .018). More patients on treatment experienced improvement or no change compared with the placebo group, in which a greater percentage of patients was subject to worsening.

"Even in this small group of patients, natalizumab improved the QOL on the physical and mental level, whereas the placebo group experienced a deterioration," Dr. Hyde summarised.

Funding for this study was provided by Biogen Idec, Inc., and Elan Pharmaceuticals, Inc.

[Presentation title: Natalizumab Improves Quality-of-Life Outcomes in Patients With Highly Active Multiple Sclerosis. Abstract P351]

Source: Doctor's Guide (c) 1995-2009 Doctor's Guide Publishing Limited (26/06/09)

Biogen Idec and Elan Corporation, plc have announced interim results from an ongoing, one-year longitudinal health-outcomes study in which patients reported significantly higher levels of treatment satisfaction after three infusions with TYSABRI® (natalizumab) when compared to multiple sclerosis (MS) therapies used previously.

The findings from the study, which were reported by patients on therapy, further demonstrate the benefits of TYSABRI in treating MS and are helping to redefine successful treatment of the disease. The study, which was performed in conjunction with HealthCore Inc., a health-outcomes research company, is being presented in a poster today during the 23rd Annual Meeting of the Consortium of Multiple Sclerosis Centers.

"The patients in this study reported significantly greater satisfaction with TYSABRI when compared to their previous MS treatments, which makes these data even more compelling for patients who may not be satisfied with their current treatment," said William Stuart, M.D., medical director of the Multiple Sclerosis Center of Atlanta. "When coupled with previously reported data from this ongoing study that showed overall improvement in quality of life measures, we have a clearer picture of the real-world impact of TYSABRI on MS patients' lives. The success of TYSABRI over the past three years should be an encouragement to move this drug to the forefront of treatment options in many select MS patients."

About the Study

This ongoing study, which is the first attempt to evaluate patient experiences with TYSABRI in usual-care settings, will continue to assess health outcomes from the patients' perspectives, with subsequent data collections, after the sixth and 12th TYSABRI infusions. A total of 1,275 patients were enrolled in the study. Of these patients, 702 completed the third infusion assessment at the time of the analysis. Of the 1,275, there were 224 patients who were still being contacted or had not yet reached their third infusion. Of the initial 1,275; 43 chose to no longer participate in the study, 60 had already received a fourth infusion, 53 were unable to be contacted and 193 discontinued or had never started TYSABRI treatment.

These patient-reported outcomes paint a broad picture of MS patients' ongoing treatment experience, which helps us to measure the effectiveness of MS treatments and expand our understanding of their everyday impact. A majority of the patients in the study are female (78.4%) with a mean age of 45.3 years and mean disease duration of 10 years. Almost all (97%) patients had used at least one MS drug prior to receiving TYSABRI.

Patient satisfaction with treatment was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM) with higher scores indicating higher satisfaction.

In the study, patients' attitudes towards MS drugs, with respect to effectiveness, convenience and overall satisfaction, at baseline (n=681) were compared to their attitudes to the same measures after three TYSABRI infusions.

As compared to other MS drugs, patients reported statistically significant higher levels of satisfaction after three infusions of TYSABRI with respect to: effectiveness of treatment (baseline 43.9 vs. 63.5 at the third infusion; p< 0.001); convenience of treatment (baseline 58.9 vs. 80.0 at the third infusion; p< 0.001); and global satisfaction (baseline 61.5 vs. 73.8 at the third infusion; p< 0.001).

Source: Medical News Today © 2009 MediLexicon International Ltd (30/05/09)

Oral herpes virus (HSV-1) eruptions were 3 times more likely in patients with multiple sclerosis who were taking natalizumab than in multiple sclerosis patients on no therapy, according to research presented at the American Academy of Neurology (AAN) 61st Annual Meeting.

Nicoline Schiess, MD, Johns Hopkins Medical Center, Baltimore, Maryland, and colleagues evaluated the activity of various herpes viruses in 34 patients with multiple sclerosis taking natalizumab and 34 age- and gender-matched healthy controls, as well as 20 patients with multiple sclerosis on no therapy and 20 patients with multiple sclerosis on interferon therapy.

All participants responded to a questionnaire regarding previous exposure and activation of herpes viruses: HSV-1 (oral), HSV-2 (genital), varicella zoster (VZV), and Epstein-Barr virus (EBV; indicating a history of infectious mononucleosis).

Saliva and blood virus samples were collected in 12 patients and 10 healthy controls.

Based on the questionnaire results, patients with multiple sclerosis were significantly more likely to report a history of infectious mononucleosis (EBV) (P = .05) and a history of genital herpes (HSV-2) than were healthy controls (P < .05). Natalizumab-treated patients were significantly more likely than healthy controls (P = .005) and untreated multiple sclerosis patients (P < .05) to develop oral herpes. Natalizumab-treated patients were less likely to report genital herpes, however, than were untreated MS patients (P < .05). In addition, natalizumab-treated patients were more likely than healthy controls to report an EBV recurrence (P = .05).

There was no significant difference in the history of VZV or shingle recurrence in multiple sclerosis patients or healthy controls.

Prior to natalizumab infusion, 6 of the 12 patients with multiple sclerosis had elevated VZV titres in their blood compared to 1 healthy control (P = NS). One week after the natalizumab infusion, VZV titres increased in the saliva, approaching statistical significance (P = .06).

Patients with multiple sclerosis are more likely to report a history of infectious mononucleosis than healthy controls as well as a history of genital herpes, Dr. Schiess concluded. In addition, reactivation of herpes virus infections may occur with natalizumab treatment resulting in symptoms such as herpes labialis or mononucleosis. In addition, virus reactivation may be asymptomatic, but detectable in saliva, as was seen with VZV virus.

Dr. Schiess plans to continue to study the pathophysiology of virus reactivation in the setting of treatment-induced immunosuppression.

Source: Presentation title: Reactivation of Herpes Viruses in Multiple Sclerosis Patients on Natalizumab Therapy. Abstract P03.163 (05/05/09)

Biogen Idec and Elan Corporation, plc have announced results from an ongoing, one-year longitudinal health outcomes study (n=1275) in which patients who received three infusions of TYSABRI(R) (natalizumab) reported reduced fatigue, as well significant improvements in general and disease-specific measurements of quality of life (QoL) and cognitive function.

Findings from the study, which was performed in conjunction with HealthCore Inc., a health-outcomes research company, are the first attempt to assess patient experiences with TYSABRI in usual-care settings. The results from this study are being presented today in two separate posters at the 61st Annual Meeting of the American Academy of Neurology.

"MS is a debilitating disease that significantly reduces the quality of patients' lives. In this study, a majority of patients said they were less tired, thought more clearly, and had a better overall quality of life," said Dr. William Stuart, M.D., medical director of the Multiple Sclerosis Center of Atlanta. "Data from the pivotal trial has shown that TYSABRI not only results in a significant reduction in relapses, but also showed an improvement in quality of life. These new patient-reported outcomes expand our understanding of the real-world impact of TYSABRI on different aspects of the lives of MS patients."

The ongoing one-year follow-up study will assess health outcomes from patients' perspectives before starting TYSABRI and after the third, sixth, and 12th infusions of TYSABRI, respectively. A majority of the patients in the study are female (78.4%) with mean age of 45.3 years and mean disease duration of 10 years.

Quality of Life Study Results

As early as after the third infusion of TYSABRI, patients reported statistically significant improvement in:

General health-related QoL, as measured by the 12-item Short Form Scale (SF-12), with higher scores indicating better QoL.

MS-specific QoL, as measured by the 29-item Multiple Sclerosis Impact Scale (MSIS-29), with lower scores indicating better QoL.

Both scales report the physical and psychological aspects of QoL in two summary scores. SF-12 physical component summary (baseline 34.03 vs. 36.02 at the 3rd infusion; p<0.001) and the SF-12 mental component summary score (baseline 43.17 vs. 47.22 at the 3rd infusion; p<0.001) showed statistically significant improvements from baseline.

For the MSIS-29 subscales, there were statistically significant improvements from baseline for both the physical (baseline 48.25 vs. 40.19; p<0.001) and psychological (baseline 43.70 vs. 34.80; p<0.001) impact scores.

The results of the current study are consistent with those reported in clinical trials and an earlier cross-sectional study in which patients reported significant improvements in functional status, disability and overall QoL after three TYSABRI infusions. The cross-sectional study also found that TYSABRI patients who had the disease for less than five years had higher magnitudes of improvement in functional status and overall QoL as compared to patients who had the disease for more than five years. Findings from this study will also be reported in the peer-reviewed journal The Patient: Patient-Centered Outcomes Research later this quarter.

Cognition and Fatigue Study Results

After three infusions of TYSABRI, patients reported both:

Improvements in cognitive functioning

Lower impact of fatigue on daily functioning

Cognitive functioning was assessed by Medical Outcomes Study Cognitive Functioning Scale (MOS-Cog Scale) with higher scores indicating improved cognition. Impact of fatigue on daily functioning was assessed by short version of Modified Fatigue Impact Scale (MFIS-5) with lower scores indicating lower fatigue.

On average, MOS-Cog scores increased by statistical significance from baseline (baseline score 24.48; 3rd infusion score 26.29, p<0.001) and MFIS scores decreased by statistical significance from baseline (baseline score 12.46; 3 rd infusion score 10.29, p<0.001).

Source: Science Blog Copyright, Science Blog.(30/04/09)

Biogen Idec and its partner, Elan, catch a lot of heat because their fastest-growing drug for multiple sclerosis is associated with a rare, potentially fatal brain infection called PML. But today they are pushing back a bit with a study that suggests the drug may provide an important benefit to balance against the risk—the potential ability to help promote healing around the frayed nerves of MS patients.

The finding is preliminary, from a small study of 62 patients who took natalizumab (Tysabri), and 26 patients in a control group followed for a year, according to research presented today at the American Academy of Neurology annual meeting in Seattle. Researchers at the Jacobs Neurological Institute in Buffalo, NY, led by Robert Zivadinov, found that natalizumab promoted re-myelination and stabilized de-myelination in lesions and brain tissue that appeared normal.

If this can be proven in larger studies, it’s the sort of finding that could change the risk/benefit equation for the drug. More than 400,000 people in the U.S. suffer from multiple sclerosis, a disease in which the immune system goes haywire and starts attacking the fatty coating around nerve fibers, called myelin. Existing MS drugs mostly work by tamping down the excess inflammation that that harms the myelin coating, but they don’t really stop the short-circuiting of nerve signals that gradually robs people of their balance, and ability to walk. Scientists have not observed that older drugs work well enough to allow myelin to naturally regenerate, but that’s one possibility for what was happening with patients in this study on natalizumab, says Al Sandrock, Biogen’s senior vice president for neurology R&D.

“It’s hard to be absolutely sure you have re-myelination going on,” Sandrock says. “Perhaps by decreasing inflammation you allow normal healing processes to take place.”

The study, sponsored by Biogen Idec, used an imaging technique known as magnetization transfer ratio (MTR). Generally, if researchers see an increase in MTR signal, that suggests the nerves may be re-myelinating, and a decreasing signal is associated with losing myelin, Sandrock says.

“What we have seen in these MRI data suggest that Tysabri may have the capacity to repair and possibly restore some of the damaged myelin sheath that protects nerve fibers. Results from this study support the continued investigation of the potential effects of Tysabri on this process,” Zivadinov said in a Biogen statement.

The finding is intriguing, but would need to be confirmed in subsequent studies, Sandrock says. Other imaging techniques may be more specific for spotting re-myelination, and even then, “the resolution is not where I’d like it,” Sandrock says.

Still, Biogen has to be hoping this could shift the focus away from PML fears, and perhaps revive the slowing growth rate of Tysabri sales. The drug generated $227 million in worldwide first quarter sales, a long shot from the $246 million that Wall Street analysts had been expecting.

Whether this can help revive Tysabri in the near-term or not, seeking ways to regenerate myelin for MS patients are clearly on Biogen’s research agenda. The company plans to move the first drug specifically designed to induce re-myelination into clinical trials later this year. Biogen hopes to bring that drug into human trials in late 2009 or early 2010, Sandrock says. He didn’t cite any new natalizumab trials that the company has planned to test the idea that it is able to spur re-myelination.

Source: Xconomy © 2007-2009 Xconomy (29/04/09)

A possible treatment for a potentially fatal side effect of multiple sclerosis therapy, Tysabri, and other immuno-modulating drugs is currently under investigation.

Biogen Idec, Elan’s partner in the development and sale of Tysabri, is testing the efficacy of a malaria pill developed during the Vietnam war in treating progressive multifocal leukoencephalopathy (PML), the brain infection that has been tied to use of Tysabri, according to Al Sandrock, Biogen’s head of neurology research.

Tysabri was pulled from the market in 2005 after three PML cases were reported. It was reintroduced a year later when US regulators said the medication’s effectiveness, twice that of other MS drugs, outweighed its risks.

However, the threat of PML has affected sales of the treatment which, although a successful drug in commercial terms, is well short of the figures initially expected.

The companies have reported five new PML cases since July 2008, reigniting concerns of patients who believe a safer Tysabri would be their best treatment option, said John Richert of the US National Multiple Sclerosis Society.

Tysabri, a laboratory-engineered antibody, is designed to suppress the immune attack that leads to MS.

PML occurs when a common germ, called JC virus, mutates, evades the body’s immune defences and penetrates the brain, causing irreversible damage.

Biogen has been seeking a PML treatment since 2005, screening about 2,000 compounds known to fight brain infections.

The drug showing the most promise in laboratory tests was the commonly used malaria pill mefloquine.

A clinical trial is now testing mefloquine in 40 patients with PML from any cause, whether drug-related or from HIV.

The goal is to see whether mefloquine, sold by Roche Holding under the name Lariam, can treat PML when it occurs. The trial is expected to be completed by the end of the year.

Helen Yates, Chief Executive of the Multiple Sclerosis Resource Centre (MSRC) said: "We truly hope that the research leads to a treatment for this very worrying and potentially life threatening condition. 

It is important that people affected by MS that are undergoing treatment with Tysabri have as much reassurance as possible about the potential side effects and the ability to treat them should they arise."
 

Source: The Irish Times  © 2009 irishtimes.com and MSRC (25/03/09)

OBJECTIVE: To evaluate the safety and tolerability of natalizumab when added to glatiramer acetate (GA) in patients with relapsing multiple sclerosis. The primary outcome assessed whether this combination would increase the rate of development of new active lesions on cranial MRI scans vs GA alone.

METHODS: This phase 2, randomized, double-blind, placebo-controlled study included patients aged 19 to 55 years who were treated with GA for at least 1 year before randomization and experienced at least one relapse during the previous year. Patients received IV natalizumab 300 mg (n = 55) or placebo (n = 55) once every 4 weeks plus GA 20 mg subcutaneously once daily for < or = 20 weeks.

RESULTS: The mean rate of development of new active lesions was 0.03 with combination therapy vs 0.11 with GA alone (p = 0.031). Combination therapy resulted in lower mean numbers of new gadolinium-enhancing lesions (0.6 vs 2.3 for GA alone, p = 0.020) and new/newly enlarging T2-hyperintense lesions (0.5 vs 1.3, p = 0.029). The incidence of infection and infusion reactions was similar in both groups; no hypersensitivity reactions were observed. One serious adverse event occurred with combination therapy (elective hip surgery). With the exception of an increase in anti-natalizumab antibodies with combination therapy, laboratory data were consistent with previous clinical studies of natalizumab alone.

CONCLUSION: The combination of natalizumab and glatiramer acetate seemed safe and well tolerated during 6 months of therapy.

Goodman AD, Rossman H, Bar-Or A, Miller A, Miller DH, Schmierer K, Lublin F, Khan O, Bormann NM, Yang M, Panzara MA, Sandrock AW; GLANCE Investigators. -

CDepartment of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.

Source: Neurology. 2009 Mar 3;72(9):806-12. (11/03/09)

Background: Natalizumab affects systemic cytokine expressions and clinical course in relapsing-remitting multiple sclerosis (RRMS). We analyzed levels of inflammatory cytokines in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs), levels of matrix metalloproteinase (MMP)-9 and osteopontin (OPN) in CSF, and clinical outcome measures in 22 natalizumab-treated RRMS patients.

Methods: mRNA levels of cytokines in cells were detected with real-time RT-PCR. Protein levels of OPN and MMP-9 were measured by ELISA.

Results: Natalizumab reduced CSF cell counts (P < 0.0001). Tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) mRNAs were significantly increased in PBMCs. In contrast, expressions of IFN-gamma and interleukin (IL)-23 were decreased but IL-10 increased in the CSF cells. OPN and MMP-9 were reduced in the CSF. Patients being in remission at baseline showed the same deviations of mediators as those in relapse after natalizumab treatment. The open label clinical outcome measures were either stable or improved during therapy.

Conclusions: Natalizumab attenuates pro-inflammatory mediators intrathecally and the reduced pro-inflammatory milieu may allow increased production of the anti-inflammatory mediator IL-10. The increased systemic cytokines may impede the improvement of certain clinical measures like fatigue. The affected mediators seem to be sensitive to an immune-modifying treatment which could be used as biomarkers for this therapy.

Khademi M, Bornsen L, Rafatnia F, Andersson M, Brundin L, Piehl F, Sellebjerg F, Olsson T.

Neuroimmunology Unit, CMM, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Source: Pubmed PMID: 19220425 (20/02/09)

A retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study.

BACKGROUND: The efficacy of natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has prompted the investigation of whether natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity.

METHODS: Post-hoc analyses of data from the AFFIRM study were done to determine the effects of natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two.

FINDINGS: 383 (64%) of 596 patients taking natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25.4%, 95% CI 18.7-32.1%, p<0.0001); 342 (58%) of 593 and 42 (14%) of 296 were free of radiological disease activity (43.5%, 37.9-49.1%, p<0.0001); and 220 (37%) of 600 and 22 (7%) of 304 were free of combined activity (29.5%, 24.7-34.3%, p<0.0001) over 2 years. The effect of natalizumab versus placebo was consistent across subgroups of patients with highly active or non-highly active disease at baseline.

INTERPRETATION: Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies.

FUNDING: Biogen Idec.

Havrdova E, Galetta S, Hutchinson M, Stefoski D, Bates D, Polman CH, O'Connor PW, Giovannoni G, Phillips JT, Lublin FD, Pace A, Kim R, Hyde R.

Charles University in Prague, First Faculty of Medicine, Prague, Czech Republic.

Source: Pubmed PMID: 19201654 (19/02/09)

Biogen Idec Inc. and Elan Corp. announced five-times as many multiple sclerosis (MS) patients taking TYSABRI® (natalizumab) were free from disease activity versus placebo in the overall patient population. Results from this retrospective analysis showed that two years after beginning treatment with TYSABRI, 37 percent of patients remained free of disease activity, compared to seven percent of placebo-treated patients. Sixty-four percent of patients showed no sign of relapse or sustained disability progression and 58 percent were free of radiological disease activity. Both of these measures were used to define freedom from disease activity in this analysis of the AFFIRM clinical trial. These data were published online today and in the March 2009 issue of The Lancet Neurology.

The analysis also suggests that the efficacy of TYSABRI may increase over time. The data show the proportion of MS patients who were free of disease activity in the TYSABRI group were greater in the second year than in the first year, while the number of MS patients in a placebo group free of disease activity stayed about the same in the second year.

"Natalizumab is the first therapy to show a robust effect on a composite of disease measures for a two-year time period. These data are encouraging because they suggest that disease remission might become an increasingly attainable goal in MS treatment," said one of the study's authors, Steven Galetta, M.D., professor of neurology, University of Pennsylvania School of Medicine. "The ultimate treatment goal in MS, as with many other autoimmune diseases, is to help patients remain symptom free for as long as possible."

MS is a disease that attacks the central nervous system. In the United States, there are approximately 400,000 people with MS; 200 people are diagnosed with the disease each week.

"The significant efficacy of TYSABRI allows us for the first time to describe response to an MS therapy in terms of freedom from disease activity, as opposed to simply a reduction in relapse rate or change in a disability scale," said Michael Panzara, MD, MPH, vice president, chief medical officer of neurology, Biogen Idec. "It is a change in thinking that raises the bar on what should be considered successful treatment of this devastating disease."

"Since we first discovered TYSABRI in our labs, we have been confident in the product's efficacy and the impact it can have on improving the lives of patients," said Carlos V. Paya, MD, PhD, president of Elan.

About the Study

The retrospective analysis examined the results of the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study at two years to determine the effects of TYSABRI in increasing the proportion of patients who were free of disease activity over two years, when compared with patients receiving placebo. AFFIRM was a multicenter, randomized, double-blind, placebo-controlled study. The primary endpoints were rate of clinical relapse at one year and the cumulative probability of sustained disability progression at two years. In the study, patients were randomly assigned, two to one, to receive TYSABRI 300 mg or placebo by intravenous infusion once every four weeks for up to 116 weeks.

The analysis showed that 383 of 596 patients (64 percent) taking TYSABRI were free of clinical disease activity over two years compared to 117 of 311 taking placebo (39 percent). Additionally, the proportion of patients who were free of disease activity based on the composite of clinical and radiological measures in the TYSABRI group was greater in the second year than in the first year (68 percent vs. 47 percent) but was similar for placebo (13 percent vs. 15 percent). Absence of disease activity was defined as no activity in clinical measures (no relapses and no sustained disability progression as defined by > or = 1.0-point increase in Expanded Disability Status Scale (EDSS) score from a baseline score of > or =1.0, or a > or =1.5-point increase from a baseline score of 0.0, sustained for 12 weeks), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions), or a composite of both measures.

Steven Galetta, M.D., professor of neurology, University of Pennsylvania School of Medicine is a co-author of the study. He has served as a consultant for Biogen Idec and has received research support from the company.

Source: Medical News Today © 2009 MediLexicon International Ltd (10/02/09)

A blood-washing treatment may remove Tysabri from the bloodstreams of patients with multiple sclerosis, potentially neutralizing a rare side effect before it turns deadly.

Tysabri was pulled from the market in February 2005 by Biogen and its marketing partner, Elan Corp., after three patients developed a viral brain disease called progressive multifocal leukoencephalopathy, or PML, and two of them died.

Since U.S. regulators allowed the companies to resume selling the drug in July 2006, four new cases of the brain disease have been reported among Tysabri users. All four patients were treated with the blood-washing method and only one of them died, said Robert Fox, medical director of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. A study led by Fox, funded by Biogen, and published in the journal Neurology showed that blood-washing reduced Tysabri to acceptable levels within two weeks.

“If you decide that a patient needs to get rid of the drug, you want to do it as fast as you can,” Fox said in a telephone interview today. “We were able to reduce Tysabri levels by 92 percent” with the treatment.

Tysabri, Biogen’s second-best-selling medicine, is approved to treat multiple sclerosis patients who aren’t helped by other drugs. Tysabri generated $597 million in sales in the first nine months of 2008, and sales growth slowed in the fourth quarter, Chief Executive Officer James Mullen told investors on Jan. 13 at the JPMorgan Healthcare Conference in San Francisco.

Purifying Plasma

The blood-washing method, known to doctors as plasmapheresis or plasma exchange, draws blood from a patient’s arm. Purified plasma, the liquid component of blood, is then returned to the other arm during a two- to three-hour process. In Fox’s study, 12 Tysabri users who didn’t have the brain disease had three blood- washing sessions to see if the approach could work. In all 12, Tysabri levels were lowered by an amount that Fox said may stop the progression of the brain illness if they had it.

Because Fox and his colleagues had presented early results from the study at medical meetings in 2007 and 2008, doctors used the technique on the four patients who developed the brain disease last year.

The technique could improve clinical outcomes for Tysabri patients who develop PML, said Shannon Altimari, a Biogen spokeswoman.

Medical consultants advising Leerink Swann & Co. said they believe the report “could make physicians more comfortable with prescribing Tysabri,” said William Tanner, a Leerink analyst, in a note to investors today. The decline in the number of new patients starting Tysabri may have stabilized, “perhaps providing an opportunity for regrowth in the next few quarters,” he said.

Source: Bloomberg.com © 2009 Bloomberg L.P. (03/02/09)

A drug used to treat multiple sclerosis might make some patients vulnerable to brain infection by reducing the number of immune cells there, researchers at UT Southwestern Medical Center have found.

The findings also suggest that the drug, natalizumab, might be safer and more effective when given with treatment "holidays" instead of continuously over long periods, the researchers said.

"Natalizumab is very effective in keeping pro-inflammatory cells out of the brain to reduce damage from MS," said Dr. Olaf Stuve, the assistant professor of neurology at UT Southwestern and senior author of the study, which appears in the December issue of Archives of Neurology.

But the potential downside is interference with immune surveillance against infection, he said. Thus, infections of the brain or spinal cord may go undetected until they become a serious problem.

"However, our study has limitations because of the small number of autopsies that were involved,"

"Whether or not treatments other than prolonged, uninterrupted dosing may benefit patients with MS should be tested in controlled clinical trials," Dr. Olaf Stuve said.

Natalizumab was introduced in 2004 and almost immediately withdrawn after three people developed a brain infection called progressive multifocal leukoencephalopathy, or PML. Two of those patients died.

The drug, known as Tysabri, returned to the market in 2006 under stricter monitoring guidelines and label warnings about the risk of developing PML. Only five other drugs are approved for treating MS.

"It's a very effective drug, and it's clear that the vast majority of patients are greatly benefiting from its use."

MS is an autoimmune disease in which a person's own body attacks the fatty coating surrounding nerve cells. Natalizumab is designed to prevent that autoimmune attack.

"Unlike other immunosuppressant drugs, natalizumab was specifically designed to interfere with the migration of immune cells into organs," said Dr. Olaf Stuve. Most MS experts believe that these cells play a major role in the disease and that their ability to enter the central nervous system should be reduced.

 "This type of infection has also been reported with several other types of immunosuppressant drugs that are being used to treat MS," he said.

About 43,000 people have taken natalizumab since it was reintroduced in 2006, with three more people having developed PML. Because of the increased monitoring, these cases of PML were detected relatively early, Dr. Stuve said.

The researchers previously have shown that natalizumab significantly reduces the number of immune cells in the cerebrospinal fluid, which bathes and protects the spine and brain. In particular, the number of CD4 T cells dropped 10 times more than the other types of immune cells. Activation and rapid division of CD4 T cells are vital for many immune responses.

In the current study, the researchers focused on the number of immune cells within the open spaces of the brain itself, known as cerebral perivascular spaces. Cells around these spaces are believed to be crucial in mounting autoimmune attacks on the body.

They examined postmortem brain tissue from one of the patients with MS who had died while taking natalizumab. Controls included tissue from patients with MS who were not treated with natalizumab, and from patients with PML who had not been treated with natalizumab.

Natalizumab caused a significant reduction in immune-related cells in the perivascular spaces of the person with MS, including a total depletion of CD4 T cells and the cells that activate them.

"The challenge will be to identify biomarkers that will help patients at risk for breakdown of immune surveillance," Dr. Stuve said

Other UT Southwestern researchers involved in the study were Dr. Maria del Pilar Martin, a former postdoctoral fellow; Dr. Petra Cravens, instructor of neurology; Ryan Winger, summer student; Dr. Elliot Frohman, professor of neurology; Dr. Todd Eagar, assistant professor of neurology; and Dr. Nitin Karandikar, associate professor of pathology.

Researchers from Ohio State University Medical Center; the University of California, San Francisco; Klinkim Rechts der Isar in Munich, Germany; and the University of Colorado, Denver, also participated.

The study was funded by the Dallas Veterans Affairs Research Corp., the Department of Veterans Affairs, the National Multiple Sclerosis Society, the Viragh Family Foundation, the Deutsch Forschungsemeinschaft and Teva Neuroscience.

Source: News-Medical.Net © 2008 News-Medical.Net (19/12/08)

Background  Natalizumab, a humanized monoclonal antibody raised against 4 integrins, is approved for treatment of active relapsing-remitting multiple sclerosis (RRMS) in adult patients.

Objective  To determine the safety, effectiveness, and tolerability of natalizumab use in pediatric patients with MS.

Design  Case report.

Setting  Center for MS in childhood and adolescents, Göttingen, Germany.

Patients  Three pediatric patients with RRMS having a poor response to other immunomodulatory therapies or having intolerable adverse effects.

Interventions  Natalizumab given every 4 weeks at a dosage of 3 to 5 mg/kg of body weight.

Main Outcome Measures  Cranial magnetic resonance (MR) imaging before treatment and every 6 months thereafter.

Results  During 24, 16, and 15 months of treatment, no further relapses occurred in the 3 pediatric patients; all reported significant improvement in their quality of life. Follow-up MR imaging showed no new T2-weighted lesions or gadolinium-enhancing lesions. No adverse events were seen when dosage was adjusted to body weight.

Conclusions  Natalizumab treatment was effective and well tolerated in our paediatric patients with RRMS who did not respond to initial immunomodulatory treatments. Therefore, it is a promising second-line therapy for paediatric patients with RRMS.

Peter Huppke, MD; Wiebke Stark, MD; Claudia Zürcher, MD; Brenda Huppke, MD; Wolfgang Brück, MD; Jutta Gärtner, MD

Author Affiliations: Departments of Pediatrics and Pediatric Neurology (Drs P. Huppke, Stark, Zürcher, B. Huppke, and Gärtner) and Neuropathology (Dr Brück), Faculty of Medicine, Georg August University, Göttingen, Germany.

Source: Arch Neurol. 2008;65(12):1655-1658. (09/12/08)

Objective  To extend our studies on the prolonged and differential effect of natalizumab on T lymphocyte numbers in the cerebrospinal fluid, we investigated the number and phenotypes of leukocytes and the expression of major histocompatibility complex (MHC) classes I and II in cerebral perivascular spaces (CPVS). We hypothesized that natalizumab reduces the number of antigen presenting cells in CPVS.

Design  A case-control study in which inflammatory cell numbers in the CPVS of cerebral tissue were assessed by immunohistochemical staining.

Subjects  A patient with multiple sclerosis (MS) who developed progressive multifocal leukoencephalopathy (PML) during natalizumab therapy. Controls included location-matched cerebral autopsy material of patients without disease of the central nervous system, patients with MS not treated with natalizumab, and patients with PML not associated with natalizumab therapy.

Results  The absolute number of CPVS in the patient with MS treated with natalizumab was significantly lower than in the control groups owing to extensive destruction of the tissue architecture. The expression of MHC class II molecules and the number of CD209+ dendritic cells were significantly decreased in the CPVS of the patient with MS treated with natalizumab. No CD4+ T cells were detectable.

Conclusions  Our observations may explain the differential and prolonged effects of natalizumab therapy on leukocyte numbers in the cerebrospinal fluid.

Maria del Pilar Martin, PhD; Petra D. Cravens, PhD; Ryan Winger; Elliot M. Frohman, MD, PhD; Michael K. Racke, MD; Todd N. Eagar, PhD; Scott S. Zamvil, MD, PhD; Martin S. Weber, MD; Bernhard Hemmer, MD; Nitin J. Karandikar, MD, PhD; B. K. Kleinschmidt-DeMasters, MD; Olaf Stüve, MD, PhD

Author Affiliations: Departments of Neurology (Drs Martin, Cravens, Frohman, Eagar, and Stüve and Mr Winger), Ophthalmology (Dr Frohman), Immunology (Drs Eagar, Karandikar, and Stüve), and Pathology (Dr Karandikar), University of Texas Southwestern Medical Center at Dallas; Departments of Neurology, The Ohio State University Medical Center, Columbus (Dr Racke), University of California, San Francisco (Drs Zamvil and Weber), and Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany (Drs Weber and Hemmer); Departments of Pathology, Neurology, and Neurosurgery, University of Colorado, Denver (Dr Kleinschmidt-DeMasters); and the Neurology Section, Veterans Affairs North Texas Health Care System, Medical Service, Dallas (Dr Stüve).

Source: Arch Neurol. 2008;65(12):1596-1603 (09/12/08)

Natalizumab (Tysabri) significantly increases the proportion of disease-free patients with relapsing multiple sclerosis (MS) compared with placebo over 2 years, according to study results presented at the World Congress on Treatment and Research in Multiple Sclerosis (WCTRMS).

The study, led by Eva Havrdova, MD, General Teaching Hospital, Prague, Czech Republic, evaluated the effects of natalizumab on the proportion of MS patients who were disease free as measured by clinical and magnetic-resonance-imaging (MRI) outcomes in the phase III Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study.

The study randomised 627 patients to receive intravenous natalizumab 300 mg and 315 patients to placebo once every 4 weeks for up to 116 weeks.

The post hoc analyses, presented by Dr. Havrdova and colleagues, found the proportion of disease-free patients was significantly higher in the natalizumab group compared with the placebo group.

Criteria for clinical disease-free status were no relapse and no disability progression for 12 weeks, free of MRI disease activity, no gadolinium-enhancing (Gd+) lesions, and no new or enlarging T2-hyperintense lesions.

Based on clinical outcomes, 70.6% of natalizumab patients had no relapse over 2 years compared with 43.3% of the placebo group. Progression-free status was achieved in 83.6% of natalizumab and 71.7% of placebo patients, and 64.3% of natalizumab and 38.9% of placebo patients were clinically disease-free (P < .0001, for all outcomes).

Natalizumab monotherapy significantly increased the proportion of patients with no Gd+ lesions (94.9% natalizumab vs 56.6% placebo), the proportion with no new or enlarging T2 lesions (58.3% vs 14.9%), and the proportion of patients with no MRI lesion activity (57.7% vs 14.2%) over 2 years compared with placebo (P < .0001, for all outcomes).

The proportion of patients who were free of clinical and MRI disease activity was significantly greater with natalizumab than placebo over 2 years (36.7% vs 7.2%, P < .0001).

Dr. Havrdova said the disease-free concept has not been well considered by the MS community, but should be discussed "because this goal is potentially within reach as more effective therapies are introduced."

Funding for this study was provided by Biogen Idec, Inc. and Elan Pharmaceuticals, Inc.

Source; PeerView Media Bar (c) 1995-2008 Doctor's Guide Publishing Limited (22/09/08)

Biogen Idec and Elan Corporation, plc announced that a post-hoc analysis showed TYSABRI(R) (natalizumab) treatment increases the probability of achieving sustained improvement in physical disability over two years when compared to placebo. This post-hoc analysis provides the first evidence that TYSABRI is associated with a significant improvement in functional outcome, rather than only slowing or preventing progression of disability, in those living with relapsing multiple sclerosis (MS).

These findings were derived from a subset analysis of the Phase III AFFIRM trial and were presented as a poster presentation at the World Congress on Treatment and Research in Multiple Sclerosis in Montreal, Canada. 

"These results show that TYSABRI treated patients are significantly more likely to experience a sustained improvement in disability compared to placebo patients. This finding from a post-hoc analysis of the pivotal AFFIRM trial supports both the earlier findings from the AFFIRM trial that TYSABRI is associated with an improvement in quality of life as well as anecdotal evidence of recovery of function in some patients." said Frederick E. Munschauer, MD, Smith Professor and Chair, Department of Neurology, State University of New York at Buffalo. "While, like TYSABRI, other therapies have shown a slowing of progression in disability, this analysis represents the first evidence supporting a sustained improvement in function associated with an approved disease modifying therapy."

Post-hoc Disability Analysis of Phase III AFFIRM Study

The proportion of patients exhibiting sustained improvements in physical disability in the AFFIRM study was determined based upon the Expanded Disability Status Scale (EDSS) over two years in patients with relapsing MS. EDSS is one of the oldest and most widely utilized methods of quantifying disability in MS.

Post-hoc analysis of AFFIRM patients assessed sustained improvement in disability among patients with a baseline EDSS score > or = 2.0. Improvement in disability was defined as a one-point decrease in EDSS score sustained for 12 weeks. The cumulative probabilities of 12-week sustained improvement in disability at two years were estimated using the Kaplan-Meier method. Treatment effects were analyzed using the Cox proportional hazards model adjusted for baseline EDSS score. The distribution of sustained improvement by baseline EDSS score for each treatment group was also examined.

TYSABRI produced significant results on the cumulative probability of sustained improvement in disability in those treated over two years compared with placebo. In patients with a baseline EDSS score > or = 2.0, the probability of achieving sustained improvement was 29.6% with TYSABRI (n=417) compared with 18.7% with placebo (n=203) (p=0.006). In patients with an EDSS score > or = 2.0 and highly active disease at baseline, the difference between groups was even greater, 35.5% for TYSABRI (n=103) and 15.4% for placebo (n=40) (p=0.045).

Source: Biogen Idec and Elan Corporation, plc (22/09/08)

I report a 31-year-old woman with relapsing remitting MS of 12 years duration who developed aggressive demyelinating disease four months after the initiation of natalizumab. The clinical worsening was accompanied by a significant increase in new large T2-hyperintense signal abnormalities and in both solid and C-shaped contrast-enhancing lesions. Neither the clinical severity nor the striking MRI abnormalities had been noted earlier in her disease course. Neutralizing antibodies to natalizumab were not detected.

She subsequently responded to combination therapy of pulsed methylprednisolone and daily glatiramer acetate.

JR Berger
Department of Neurology, University of Kentucky College of Medicine, Lexington, KY, USA

Source: Multiple Sclerosis, Vol. 14, No. 5, 708-710 (2008) DOI: 10.1177/1352458507087135 © 2008 SAGE Publications (20/06/08)

Study Shows Increased Proportion of Patients Achieve Disease-Free Status with TYSABRI - Separate Study Demonstrates Plasma Exchange May Be an Effective Tool to Accelerate TYSABRI Removal.

Biogen Idec and Elan Corporation, plc announced that TYSABRI® (natalizumab) treatment significantly increases the proportion of disease-free patients with multiple sclerosis (MS) according to a post hoc analysis of the Phase III AFFIRM study to be presented on Saturday, October 13, 2007 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Prague, Czech Republic. Also to be presented on Saturday will be findings from the PLEX study which suggest that plasma exchange may be an effective means of accelerating the removal of TYSABRI from the circulation.

Post Hoc Analysis of Phase III AFFIRM Study

The proportion of disease-free patients in the AFFIRM study was determined based upon clinical and MRI criteria. The proportion of disease-free patients over two years was significantly higher in the TYSABRI-treated group compared with the placebo group regardless of how disease free was defined.

Clinically, disease free was defined as no relapses and no progression of disability (as defined by > or =1.0-point increase in Expanded Disability Status Scale (EDSS) score from a baseline score of > or =1.0, or a > or =1.5-point increase from a baseline score of 0.0, sustained for 12 weeks) over two years. MRI disease free was defined as no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions.

Using clinical and MRI disease-free criteria combined, the most stringent definition of disease free, 36.7% of TYSABRI-treated patients had no relapses, disability progression or MRI activity compared with 7.2% of placebo patients (p<0.0001). In the clinical analysis, 64.3% of TYSABRI-treated patients vs. 38.9% placebo-treated patients(p<0.0001) were disease free or without relapses and disability progression. Using MRI measures, 57.7% of TYSABRI-treated patients vs. 14.2% placebo-treated patients (p<0.0001); were disease free, or without gadolinium-enhancing lesions and new or enlarging T2-hyperintense lesions.

"These data demonstrate the dramatic effect TYSABRI can have on critical measures of multiple sclerosis. In addition to the impact on individual clinical and MRI outcomes, it is striking that more than one-third of patients were free of relapses, disability progression and MRI activity after two years of treatment. This suggests that TYSABRI may offer patients freedom from many of their MS symptoms," said Eva Havrdova, MD, PhD, Director of the Center for Demyelinating Diseases at the First School of Medicine, General University Hospital, Charles University, Prague, Czech Republic.

PLEX Plasma Exchange Study

Results from the PLEX study also to be presented suggest that plasma exchange may be an effective means of accelerating the removal of TYSABRI from blood serum. Plasma exchange is one of several research efforts the companies have underway to learn more about potential interventions or treatments for progressive multifocal leukoencephalopathy (PML), a rare side effect of TYSABRI.

"These data from the PLEX study are encouraging as they show the removal of TYSABRI is faster following plasma exchange. Time will tell whether plasma exchange develops as an effective treatment approach for PML," said Bhupendra O. Khatri, MD, Medical Director of the Regional MS Center, Aurora St. Luke's Medical Center, Milwaukee, WI.

PLEX is an open-label, single-arm, multicenter exploratory study involving 12 patients with relapsing-remitting MS designed to explore whether plasma exchange could significantly reduce the concentration of TYSABRI in blood serum and alpha 4-integrin receptor saturation. Based on the PLEX findings, plasma exchange was effective at accelerating the normal decline of serum TYSABRI concentrations.

Plasma exchange was generally well tolerated with no increase in MS disease activity following plasma exchange. There were no study discontinuations due to adverse events and all patients returned to TYSABRI treatment without complications. Further investigations are needed to determine whether plasma exchange holds promise as an intervention in the setting of PML

Source: Biogen Idec and Elan Corporation, plc (12/10/07)

The study involved 21 people who had MRI scans of their brains taken before taking natalizumab and again an average of 15 months after receiving the last infusion of the drug. The drug is given by IV infusion once a month. The participants were divided into two groups: one group took the drug for an average of three years, and the other group took the drug for an average of two months.

The participants developed more than three times as many brain lesions, or areas of damage in the brain that are a marker of MS disease activity, in the 15-month period after discontinuing the drug than they had developed before they started taking the drug. The results were most pronounced for those who took the drug for only a short time; they developed five times as many brain lesions after stopping the drug than they did before they started taking it.

More research needs to be done with larger numbers of patients before any recommendations can be made about use of the drug, according to study author Machteld Vellinga, MD, of VU University Medical Center in Amsterdam, the Netherlands. "For now the recommendations remain the same-patients and their doctors should choose the most applicable treatment for them," she said.

Vellinga said it's not clear why discontinuing the drug would lead to increased disease activity, although an earlier animal study showed a similar result when rats with an animal model of multiple sclerosis were given a drug that suppresses the immune system.

The study came about because use of natalizumab was suspended in 2005 after three people participating in clinical trials for the drug developed a rare, often fatal brain disease called progressive multifocal leukoencephalopathy.

"All of our patients had an MRI shortly after the drug was suspended, and our neuroradiologist noticed that in some patients a considerable number of new lesions developed on their MRIs in the following year," said Vellinga. "We decided to do a formal analysis to see if this was actually the case." Vellinga noted that the results need to be confirmed in independent groups of patients.

The drug was reintroduced in 2006 with specific guidelines for its use and to monitor patients for signs of progressive multifocal leukoencephalopathy.

Source: News-Medical.Net ©2007 News-Medical.Net (13/09/07)

Objective  To report a significant, delayed, serum sickness–like, type III systemic allergic reaction to natalizumab.

Design  Case report describing clinical follow-up and the serial measurement of antinatalizumab antibodies.

Patient  A 23-year-old man with relapsing-remitting multiple sclerosis developed a fever, arthralgias, urticarial exanthema, and a swollen lower lip during several days after his second infusion of natalizumab.

Results  The patient developed a delayed, serum sickness–like, type III systemic allergic reaction to natalizumab. Five weeks after initiation of this therapy, he tested positive for antinatalizumab antibodies and exhibited persistent antibody titers 8 and 12 weeks later. His symptoms completely resolved with a short course of oral glucocorticosteroids.

Conclusion  Clinicians and patients should be alert not only to immediate but also to significantly delayed substantial allergic reactions to natalizumab.

Author Affiliations: Institute for Clinical Neuroimmunology, Ludwig Maximilian University, Munich, Germany (Drs Krumbholz, Pellkofer, Hoffmann, Hohlfeld, and Kümpfel); and Department of Neurology, St Josef-Hospital, Ruhr University, Bochum, Germany (Dr Gold).

Source: Arch Neurol. 2007;64:1331-1333. © 2007 American Medical Association. All Rights Reserved.(11/09/07)

“These data showed that patients treated with TYSABRI were more likely to experience statistically important improvement in the quality-of-life measures used to assess meaningful disease improvement or progression. These findings have not been previously observed in clinical studies involving MS patients,” said Richard Rudick, MD, Director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, the lead investigator of the study.

These two-year, randomized, double-blind, placebo-controlled, multicenter, Phase III clinical trials (AFFIRM and SENTINEL) were conducted in 2,113 patients with relapsing forms of MS. The objective was to assess the relationship between disease activity and HRQoL in relapsing forms of MS, and the impact of TYSABRI on these measures.

In the studies, HRQoL was assessed using two different measures at baseline and weeks 24, 52 and 104:

• The Short Form-36 (SF-36), a standardized, well-validated survey that has been used extensively in many disease areas, including MS to review health status. The SF-36 is comprised of 36 questions designed to assess physical (Physical Component Summary or PCS) and mental (Mental Component Summary or MCS) well-being from the perspective of the patient.
• The Visual Analogue Scale (VAS), a measure of well-being as assessed by the patient and marked on a scale of 0 to 100, with 0 indicating “poor” and 100 indicating “excellent.”

Results from the AFFIRM monotherapy trial include:

• A statistically significant improvement in SF-36 PCS beginning at week 24 and all subsequent time points compared with a decline in the placebo-treated group.
• A statistically significant improvement in SF-36 MCS at week 104 compared with a decline in the placebo-treated group.
• Statistically significant benefits using the VAS when compared with placebo at week 52 and at week 104.
• Patients showed sustained improvement from baseline quality-of-life measures, not just a slowing down of quality-of-life deterioration.
• HRQoL measures correlated with common measures of MS severity, including EDSS, sustained disability progression, relapse number, MSFC and volume of T2-hyperintense and T1-hypointense lesions.

Improvements on quality-of-life measures were also observed in the SENTINEL study, in which TYSABRI was added to AVONEX^® (Interferon beta-1a). This publication is in addition to a presentation of preliminary results from the same study presented at the 2006 American Academy of Neurology Annual Meeting.

Source: Biogen Idec and Elan Corporation, plc (20/08/07)

Natalizumab has recently been re-approved by the FDA, and a comprehensive article published in the latest issue of CNS Drug Reviews provides a timely overview of the drug, its pharmacological properties, clinical efficacy, safety and toxicology.

MS is a disorder that affects the central nervous system, with leukocytes (inflammatory cells) attacking the body's neurons and causing serious damage. A highly effective immunosuppressive treatment, natalizumab is an antibody that prevents leukocytes from crossing blood vessel walls into tissues such as the brain and spinal cord. The drug may also benefit secondary lymphoid organs, such as lymph nodes and the spleen, and inhibit reactivation in the central nervous system. It has been shown to significantly reduce leukocyte cell numbers in spinal fluid, with benefits continuing for six months after treatment.

"The release of natalizumab ushers in a new era in the treatment of MS," says Dr. Olaf St've , author of the study, noting, however, that while the short-term risk-benefit ratio appears positive, the long-term risks remain unknown. "As therapy with natalizumab resumes worldwide, the neurologic community will garner more information about the long-term risks and benefits of this powerful therapeutic medication," but for now natalizumab use is being strictly monitored.

Both the FDA and TOUCH, a special distribution program designed to prevent patients not qualified for the treatment from receiving the drug, are working to make sure that any potential infectious complications are identified as early as possible.

News-medical.net(29/05/07)

Biogen Idec and Elan Corporation, plc announced today that new data from the TOUCH Prescribing Program(TM) and TYGRIS safety study confirm the safety profile from previous clinical studies of TYSABRI(R) (natalizumab). Also presented at the 59th annual meeting of the American Academy of Neurology in Boston, MA were extension study data that showed that TYSABRI has a sustained treatment effect on clinical relapses and the risk of disability progression in multiple sclerosis (MS) patients treated for up to three years. The companies recently reported that as of mid-April 2007 approximately 12,500 patients have been prescribed TYSABRI worldwide. The companies estimate that in both commercial use and clinical trials, there are currently over 10,000 patients on TYSABRI therapy worldwide.

"The findings from the safety update combined with the data showing the sustained effect of TYSABRI in patients treated for up to three years, contribute to our evolving understanding of the utilisation of this therapy as an important treatment option for people living with the debilitating effects of MS," said Paul O'Connor, MD, St. Michael's Hospital, Toronto, Ontario, Canada, lead investigator of the TYSABRI extension study.

TYSABRI Update

TYSABRI is available in the US through the TOUCH Prescribing Program. All prescribers, infusion sites and patients receiving TYSABRI are required to enroll in TOUCH. Safety information is also collected through ongoing clinical trials and registries, including STRATA, TYGRIS and the pregnancy registry. According to data available to the companies as of April 23, 2007, there have been no new reports of confirmed cases of progressive multifocal leukoencephalopathy (PML) or other serious opportunistic infections (OIs). The data confirm the safety profile from previous clinical studies of TYSABRI and will continue to expand the knowledge of the long-term safety and tolerability of TYSABRI.

The combination of TOUCH, TYGRIS and the pregnancy registry will be the largest long-term follow-up undertaken for an MS therapy, and the companies plan to continue to provide similar updates at upcoming medical meetings.

The companies recently announced that as of mid-April, approximately 12,500 patients have been prescribed TYSABRI worldwide. In both commercial use and clinical trials, there are currently over 10,000 patients on TYSABRI therapy worldwide.

• In the US, approximately 6,600 patients are on TYSABRI therapy commercially. Approximately 10,000 patients have enrolled in the TOUCH program and 1,500 physicians have enrolled patients.
• In the EU, approximately 2,500 patients internationally have received TYSABRI infusions commercially, mostly in Germany and the Nordic countries.
• In clinical trial settings, over 1,000 patients are on TYSABRI therapy

TYSABRI Efficacy Sustained through Three Years.

Patients who participated in the Phase III TYSABRI program were eligible to enroll in an open-label extension study that evaluated the therapy's long-term effects. Included in this were patients from AFFIRM, a randomised, double-blind, placebo-controlled, two-year monotherapy study of TYSABRI that enrolled 942 patients (627 patients on TYSABRI, 315 on placebo). In AFFIRM, TYSABRI reduced the annualised relapse rate in patients with MS by 67% (p(less than)0.001) and the risk of 12-week sustained disability progression by 42% (p(less than)0.001) compared with placebo. In the intent to treat analysis, the annualised relapse rate for patients treated with TYSABRI over the three-year period was 0.23, translating into an average of one relapse every 4.3 years. The relapse rate also continued to remain low over the three-year treatment period with TYSABRI: 0.27 during the first year; 0.20 during the second year; and 0.15 during the third year (based on 531 patients who entered the extension study, which includes approximately 250 patients with nearly three years of continuous therapy).

In addition, TYSABRI also decreased the cumulative probability of disability progression sustained for six months compared to placebo. The estimated proportion of patients who had 24-week sustained disability progression at two years was 11% in patients treated with TYSABRI compared to 23% in patients treated with placebo, a 54% relative reduction.

This effect was maintained in patients treated with TYSABRI for up to three years with 13% showing 24-week sustained disability progression.

About TOUCH and TYGRIS

Before initiating treatment, all US patients, prescribers and infusion sites must be enrolled in the TOUCH Prescribing Program (TYSABRI Outreach: Unified Commitment to Health). TOUCH is designed to determine the incidence of and risk factors for serious OIs, including PML, and to monitor patients for signs and symptoms of PML while promoting informed benefit/risk discussions prior to initiating TYSABRI treatment. Physicians report on PML, serious OIs, deaths and discontinuation of therapy on an ongoing basis.

TYGRIS (TYSABRI Global ObseRvation Program In Safety) is expected enroll 5,000 patients worldwide, including approximately 3,000 patients from TOUCH. Patients in TYGRIS are evaluated at baseline and every six months thereafter for five years. Researchers will evaluate data including medical/MS history; prior TYSABRI use; prior use of immunomodulatory, antineoplastic, or immunosuppressive agents; and all serious adverse events, including PML and other serious OIs, and malignancies.

Source: Biogen Idec and Elan Corporation, plc (03/05/07)

The analyses were performed on data from the AFFIRM and SENTINEL studies, which involved 2,138 men and women with relapsing multiple sclerosis from clinics in Europe, North American, Australia, and New Zealand. More than half of the people received the drug natalizumab every four weeks for two years. The rest of the group received placebo. Researchers used eye charts of low contrast letters to test the vision of the participants every 12 weeks.

The study found vision loss, defined as a worsening in score by two rows of letters on the eye chart, was reduced by as much as 47 percent among people taking natalizumab compared to those taking placebo.

"Not only does natalizumab prevent the worsening of vision loss in people with relapsing MS, we also found the drug was associated with significant reductions in the likelihood of sustained vision loss," said study author Laura J. Balcer, MD, MSCE, with the University of Pennsylvania School of Medicine in Philadelphia, PA, and member of the American Academy of Neurology. "Specifically, this drug may have implications for preventing further sustained vision loss due to inflammatory demyelination of nerve fibres that connect to the eye, which is common in MS."

However, Balcer said the potential benefits of natalizumab treatment must be weighed with the drug's potential risks or complications, including the rare, often lethal brain disease progressive multifocal leukoencephalopathy (PML), of which three confirmed cases have been reported.

In addition, data from AFFIRM and SENTINEL studies showed that low-contrast letter acuity eye chart testing is effective for assessing visual outcomes in future MS clinical trials, which have not typically included visual testing components despite vision loss being a main disability of MS.

Source: American Academy of Neurology (16/04/07)

Speaking on an investor telephone conference call, Elan Chief Executive Kelly Martin said this figure gives some indication of the "potential future market structure" for Tysabri sales.

Chief Financial Officer Shane Cooke added that the 75% figure also applies to the E.U., where "Around three-quarters of the patients are coming (to use Tysabri) from existing treatments."

"They're coming from all products," Cooke said, "not any particular one."

Cooke said Tysabri's "compelling efficacy will play an important and significant role in the treatment of multiple sclerosis," or MS, but said sales forecasts "will take a few quarters to bed down."

Elan also said that Tysabri should be available in Canada by year-end. It estimates there are between 55,000 and 75,000 MS patients in Canada - where Tysabri was approved for use earlier this month.

Elan and its partner Biogen Idec PLC suspended Tysabri in the U.S. on Feb. 28 last year after two patients using combination therapy there contracted a rare neurological disease called progressive multifocal leukoencephalopathy, or PML. A third case was confirmed later.

Tysabri was reintroduced in the U.S. and launched in Europe in the third quarter, for use primarily as a monotherapy for relapsing and remitting MS patients. However Elan has said the complete rollout will take six months to a year.

To date in the third quarter, 1,700 patients have received their first dose in the U.S. and 500-600 patients in the E.U. 

Tysabri is thus far available in Germany, Sweden, the U.K., Ireland, Denmark, the Netherlands, Austria, Finland and Norway, as well as the U.S.

In the U.S., the drug is prescribed, distributed, and infused only by infusion centers and pharmacies registered with the "Touch" Tysabri program.

Source: TherapeuticsDaily.com ©2005 PharmaLive.com

Cambridge, Mass.based Biogen presented the data with research partner, Dublin-based Elan Corp.

Data presented from the Phase III study also demonstrates the positive impact of Tysabri on a number of health-related quality of life of measures and the cost-effectiveness of MS therapies, and also that a greater percentage of treated patients had no disease activity, meaning no additional relapses or disability progression the company said.

Specifically, data from the phase III study showed treated patients saw a 69-percent relative reduction in the annualised rate of relapses requiring steroids, compared to those on placebo, and a 65-percent relative reduction in the annualised rate of MS-related hospitalisations over two years.

The companies said they would present the findings along with data on improved quality of life and cost-effectiveness measures in Tysabri patients at the Academy of Managed Care Pharmacy's 2006 Educational Conference in Chicago.

Tysabri was recalled briefly three months after approval in November 2004 because of links to a fatal brain disease called progressive multifocal leukoencephalopathy. Patients died in two of three cases found.

Tysabri was cleared to return to the United States in July with restrictions on how it is prescribed. Earlier this week, Tysabri was also approved for use in Canada as a treatment for relapsing-remitting multiple sclerosis.

Source: Boston Business Journal © 2006 American City Business Journals, Inc and Red Orbit © 2002-2006 redOrbit.com. All rights reserved

Biogen Idec Canada and Elan Corporation, plc announced today that following a priority review process, Health Canada has granted approval to TYSABRI(TM) (natalizumab) for the treatment of relapsing-remitting multiple sclerosis (MS). TYSABRI is the first in a new therapeutic class of MS treatments (called selective adhesion molecule inhibitors) and has been shown to significantly reduce the rate of MS relapses as well as the progression of disability associated with the illness.

"TYSABRI has demonstrated a major reduction in relapses - by more than two-thirds - in clinical trials," said Dr. Paul O'Connor, AFFIRM Principal Investigator and Chief of Division of Neurology, St Michael's Hospital, Toronto. "Clinical trials that have looked at TYSABRI provide us with impressive evidence that it is a highly effective treatment for patients with MS."

A two-year, randomised, multi-centre, placebo-controlled, double-blind study (called AFFIRM) enrolled 942 patients and evaluated the effect of TYSABRI on the rate of clinical relapses and the progression of disability. The results found that TYSABRI reduced the rate of clinical relapses by 68 per cent relative to placebo (p less than 0.001), and the risk of sustained disability progression associated with MS by 42 per cent relative to placebo (p less than 0.001). Treatment with TYSABRI also resulted in sustained and statistically significant reductions in brain lesion activity as measured by magnetic resonance imaging (MRI) scans.

In Canada, TYSABRI is indicated as monotherapy i.e. single disease-modifying agent for the treatment of patients with the relapsing-remitting form of MS to reduce the frequency of clinical relapses, to delay the progression of disability and to decrease the number and volume of active brain lesions identified on magnetic resonance imaging (MRI) scans. TYSABRI is administered once every four weeks by intravenous infusion.

"TYSABRI's administration every four weeks also offers an additional benefit compared to the currently available MS therapies, some of which are injected as often as daily," said O'Connor.

MS attacks the protective myelin covering of the central nervous system, causing inflammation and often destroying the myelin in patches. In its most common form, relapsing-remitting MS, the illness is characterised as having well defined attacks followed by complete or partial recovery. Relapsing-remitting MS makes up 75% of all MS cases in Canada.

TYSABRI works by preventing the body's affected immune cells from migrating from the bloodstream into the brain where they can cause inflammation and potentially damage nerve fibres and their insulation.

"Canada has one of the highest rates of MS in the world. The approval of TYSABRI represents an important step forward for Canadians living with this disease," said Deanna Groetzinger, vice president of government relations and policy at the Multiple Sclerosis Society of Canada. "We are pleased there is another approved treatment option for Canadians with relapsing-remitting MS."

Paulette O'Leary, 36, has been living with MS for over half of her life. At one point a relapse left her without the use of her legs and numbness across the left side of her body. After other therapy options failed to help her, O'Leary opted to travel to the United States to receive TYSABRI treatments when it was approved by the Food and Drug Administration (FDA) in the US.

"My particular experience with MS was really terrible. The illness hit me very hard, and I went from my normal, everyday life, to feeling awful physically and emotionally. After one relapse I was left in a wheelchair," said O'Leary. "I eventually recovered, but did not escape some permanent residual disability. I tried several other therapies, but when I was on TYSABRI the results were quite impressive. For the first time in a long time, I could walk, I could do the things that I love to do - I could actually live my life again."

Independent safety evaluation published

Biogen Idec and Elan Corporation, plc voluntarily suspended TYSABRI from the US market and from all clinical trials in 2005. This was based on three cases of progressive multifocal leukoencephalopathy (PML).

A comprehensive, independent safety evaluation of more than 3,000 patients treated with TYSABRI was completed.

The detailed safety analysis of the data yielded no new confirmed cases of PML beyond the three previously reported. The results of this safety evaluation were published in the March 2006 issue of the New England Journal of Medicine.

"The safety data analysis that was carried by an independent panel of experts is reassuring. And getting an understanding of the benefit-risk profile of TYSABRI is an important step towards bringing this medicine to Canadian MS patients with confidence," said Dr. O'Connor. "Any treatment decision should carefully evaluated by patients and their physicians."

Patients who are prescribed TYSABRI should enroll in the TYSABRI Care Program. The program ensures that appropriate physicians and infusion centres are able to prescribe or infuse the product. The TYSABRI Care Program is a comprehensive program that will support the safe and effective use of TYSABRI by physicians and patients on an ongoing basis. It will optimise treatment through improved compliance, will standardise infusion treatment at clinics, will support safety through rigorous education and on-going surveillance, and, through support in areas like reimbursement and patient support, will ease the administrative burden of physicians and patients, allowing patients and their treatment team to focus on treating the illness.

AFFIRM and SENTINEL Phase III study design and adverse events

AFFIRM is a two-year, randomised, multi-center, placebo-controlled, double-blind study of 942 patients conducted in 99 sites worldwide (including ten sites in Canada with 101 MS patients), evaluating the effect of TYSABRI on the progression of disability as measured by at least a one-point increase on the Expanded Disability Status Scale (EDSS) sustained for three months, and the rate of clinical relapses. Progression of disability is a sustained change that has a long-term impact on a patient's functional and ambulatory performance. Patients in AFFIRM were randomised to receive either a 300 mg IV infusion dose of TYSABRI (n=627) or placebo (n=315) every four weeks.

SENTINEL is a two-year, randomised, multi-center, placebo-controlled, double-blind study of 1,171 AVONEX®-treated patients in 123 clinical trial sites worldwide. AVONEX-treated patients who continued to experience disease activity were randomised to add TYSABRI (n=589) or placebo (n=582) to their standard regimen.

The two-year adverse event profile in AFFIRM and SENTINEL were consistent with previously reported one-year results. Common events included headache, fatigue, urinary tract infection, depression, lower respiratory tract infection, limb and joint pain, and pharyngitis. The rate and incidence of infections in patients treated with TYSABRI and placebo-treated patients were similar. Serious infections occurred in 3.2 percent and 2.6 percent of patients treated with TYSABRI and placebo-treated patients, respectively.

Use of TYSABRI has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML). PML can cause severe disability or death.

Cases of PML included patients who were treated with TYSABRI for over two years or who received intermittent doses of TYSABRI over an 18-month period. In clinical trials, two cases of PML were observed in 1869 patients with multiple sclerosis treated for a median of 120 weeks; the third case occurred among 1043 patients with Crohn's disease after the patient received 8 doses. These patients were concomitantly exposed to immunomodulators (e.g. interferon beta) or were immunocompromised due to treatment with immunosuppressants (e.g. azathioprine).

TYSABRI has also been associated with hypersensitivity reactions, including serious systemic reactions that occurred at an incidence of less than 1 percent of patients

Source: Elan Corporation, plc

Patients who participated in the Phase III TYSABRI program were eligible to enroll in an open-label extension study that evaluated the therapy's long-term effects. Approximately 1,900 patients and over 200 sites worldwide participated in the extension study. Approximately 250 of these patients remained on TYSABRI monotherapy for nearly three years. The annualised relapse rate for these patients over the three-year period was 0.23, translating into an average of one relapse every 4.3 years. This was consistent with the 0.23 annualised relapse rate seen in the two-year AFFIRM study, which represented a 68% relative reduction when compared to the two-year placebo annualised relapse rate of 0.73, as published in the New England Journal of Medicine.

"Data from this long-term follow-up study show that TYSABRI has a sustained and compelling effect on relapse rates beyond two years of treatment. The efficacy benefit of TYSABRI when considered with the management of its known risks, offers an important therapeutic option for many patients living with the debilitating effects of MS," said Paul O'Connor, MD, St. Michael's Hospital, Toronto, Ontario, Canada, lead investigator of the extension study.

Source: Biogen Idec and Elan Corporation, plc (29/09/06)

Drug developers Biogen Idec Inc. and Elan Corp. said Thursday data from a late-stage study of Tysabri showed it was effective in reducing cognitive degeneration in multiple sclerosis patients.

The drug was relaunched in June, 17 months after being pulled from the market after three cases of a rare and often fatal brain inflammation occurred in three  patients. Two of the patients died. The drug is now prescribed by doctors in a program called Touch Prescribing, and patients are monitored for the brain inflammation.

In the latest study, which included 942 patients worldwide, treatment with Tysabri reduced the risk of sustained cognitive worsening by 43 percent when compared to placebo.

The drug has previously shown a 68 percent reduction in the relapse rate of patients and a 42 percent reduction in the relative risk of disability progression.

Areas affected by cognitive dysfunction include memory, ability to process information and learning. The drug reduced the risk of cognitive dysfunction by 43 percent, the study showed.

The company presented the data at the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis in Madrid, Spain.

Source: Biogen Idec (29/09/06)

Tysabri was initially approved by the FDA in November 2004, but was withdrawn by the manufacturer in February 2005 after three patients in the drug's clinical trials developed progressive multifocal leukoencephalopathy (PML), a serious and rare viral infection of the brain. Two of the cases were fatal. Based on this information, FDA put clinical trials of the drug on hold in February 2005. FDA allowed a clinical trial to resume in February 2006, following a re-examination of the patients who had participated in the previous clinical trials, confirming that there were no additional cases of PML.

The Peripheral and Central Nervous Systems Drugs Advisory Committee recommended a risk-minimisation programme with mandatory patient registration and periodic follow-up. Natalizumab will only be prescribed, distributed, and infused by prescribers, infusion centres, and pharmacies registered with the programme.

Source: WHO Drug Information (c) 2006 WHO Drug Information

The Multiple Sclerosis Center of Atlanta (MSCA) has announced it is now administering TYSABRI® (natalizumab), the drug recently re-released by the U.S. Food and Drug Administration (FDA). TYSABRI, manufactured by Biogen Idec and Elan Corp., treats relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical relapses. TYSABRI is the first humanized monoclonal antibody approved for the treatment of MS.

TYSABRI was withdrawn from the market in February 2005 when three patients out of nearly 3,000 were found to have Progressive Multifocal Leukoencephalopathy (PML), a serious and potentially fatal virus which affects the brain. After an extensive safety study in which no further cases of PML were found, the FDA approved the re-release of the medication in July 2006. To minimise risks to patients, all patients who receive TYSABRI are required by the FDA to participate in a risk management program called TouchTM. The MSCA is registered with the Touch program and its physicians and staff are well prepared to discuss and follow the program’s guidelines.

In its early stages of development, the MSCA was the only site in Georgia to be involved in the pivotal international clinical trials for TYSABRI, and the center has more than three years of experience in managing patients on TYSABRI therapy. Research suggests the drug works by preventing immune cells from migrating from the bloodstream into the brain where they can cause inflammation and potentially damage nerve fibres and their insulation. Studies found that TYSABRI reduced the formation of new, enhancing lesions of MS by 92 percent and reduced the number of MS attacks by 68 percent.

The MSCA provides this additional treatment option to patients with relapsing forms of MS. The drug is administered intravenously once every four weeks and studies show that the medication initially begins working after the first dose, and is even more effective after the second dose.

Source: Atlanta dBusinessNews.com Copyright @ 2005, dBusinessNews.

Biogen Idec and Elan Corporation, plc today (24th July) announced the commercial availability of TYSABRI® (natalizumab) for the treatment of relapsing forms of multiple sclerosis (MS) in the U.S.

As previously announced, the U.S. Food and Drug Administration (FDA) approved the supplemental Biologics License Application (sBLA) for the reintroduction of TYSABRI as a monotherapy treatment for relapsing forms of MS to slow the progression of disability and reduce the frequency of clinical relapses.

The FDA granted approval for reintroduction based on the review of TYSABRI clinical trial data; revised labeling with enhanced safety warnings; and a risk management plan (TOUCH Prescribing Program) designed to inform physicians and patients of the benefits and risks of TYSABRI treatment and minimize potential risk of progressive multifocal leukoencephalopathy (PML). Because of the increased risk of PML, TYSABRI is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, alternate MS therapies.

Under the TOUCH Prescribing Program, only prescribers, infusion centers and pharmacies associated with infusion centers registered in the TOUCH program are able to prescribe, infuse or distribute TYSABRI. Elan has contracted with a single distributor, ICS, a division of AmerisourceBergen Specialty Group, and 12 specialty pharmacies: Caremark, CuraScript, PharmaCare, PrecisionRx Specialty Solutions, Medmark, BioScrip, McKesson Specialty, Option Care, Cigna Tel-Drug Specialty Pharmacy, Aetna Specialty Pharmacy, Prescription Solutions, and Accredo NovaFactor. ICS and the 12 specialty pharmacies have been trained on the TOUCH Prescribing Program and are obligated to follow the requirements of the program in order to purchase and distribute TYSABRI to authorised infusion sites and central pharmacies.

In addition, following the recent approval by the European Commission, the companies have introduced TYSABRI in several countries in Europe.

Source: Biogen Idec and Elan Corporation, plc

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