Glatiramer acetate and interferon beta-1a for intramuscular administration: a study of outcomes among multiple sclerosis intent-to-treat and persistent-use cohorts.

Abstract
Objective: To study outcomes of multiple sclerosis (MS) patients treated with either glatiramer acetate (Copaxone * ) or interferon beta-1a for once-weekly, intramuscular administration (Avonex dagger ).

Methods: An 'intent-to-treat' (ITT) cohort (n = 1282) was established, consisting of patients diagnosed with MS who began therapy on either glatiramer acetate (GA) or intramuscular interferon beta-1a (IFN beta-1a-IM) and had continuous insurance coverage from 6 months before to 24 months after the date when they began taking the medication.

A 'persistent use' (PU) cohort (n = 639) was also constructed, consisting of individuals who, in addition to the criteria listed above, had a claim for GA or IFN beta-1a-IM within 28 days of the end of the 2-year post-period.

Data were obtained from the i3 InVision Data Mart Database from July 2001 to June 2006. Multivariate regressions were used to examine both the 2-year total direct medical costs and the likelihood of relapse associated with the use of each of these alternative MS medications.

A relapse was defined as either being hospitalized with a principal diagnosis of MS or having an outpatient visit with a MS diagnosis followed within 7 days by a claim for a corticosteroid. All regressions controlled a wide range of factors that may potentially affect outcomes.

Results: In the ITT cohort, patients who started therapy on GA had a significantly lower 2-year risk of relapse (10.01 vs. 5.18%; p = 0.0034) as well as significantly lower 2-year total medical costs ($44,201 vs. $41,121; p = 0.0294). In the PU cohort, patients who used GA also had a significantly lower 2-year risk of relapse (7.25 vs. 2.16%; p = 0.0048) as well as significantly lower total medical costs ($67,744 vs. 63,714; p = 0.0445).

Limitations: The analyses relies on an administrative claims database of an insured population and hence, may not be generalizeable to other populations. In addition, such a database precludes measurement of lost work time, unemployment, caregiver burden or other costs associated with MS.

Conclusions: Results from this study indicate that the use of GA is associated with significantly lower probability of relapse as well as significantly lower 2-year total direct medical costs than IFN beta-1a-IM.

Castelli-Haley J, Oleen-Burkey MA, Lage MJ, Johnson K.

Teva Neuroscience, Kansas City, MO, USA.

Source: Pubmed PMID: 20662760 (30/07/10)

Teva Pharmaceutical Industries Ltd. announced positive results from a study assessing a new lower-volume injection of Copaxone(R) (glatiramer acetate) containing the currently approved dose in half the injection volume.

The SONG study ('Study of New Glatiramer Acetate Formulation') explored the safety and tolerability of a 20mg/0.5mL injection of Copaxone(R) versus the current formulation of 20 mg/1.0mL.

These findings were presented at the 24th Annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC) in San Antonio, Texas.

"Copaxone(R) has proven long-term efficacy, safety and tolerability with more than one million patient years of treatment," said Dr. Ronald Murray, FAAN, a lead study investigator and Director of the MS Clinic of Colorado. "We are encouraged by these data as they suggest that a 0.5mL dose of glatiramer acetate may enhance patients' experience with the most frequently prescribed MS therapy."

The SONG study enrolled 148 relapsing-remitting MS patients (RRMS) at 21 sites in the United States. Data demonstrated that both the 1.0mL and 0.5mL products were safe and well tolerated. Patients receiving the lower-volume injection reported significantly less pain immediately following and five minutes after administration (p<0.0001). Although the presence of injection site reactions (swelling, redness, itching, lumps) was not high for either group, patients reported fewer and less severe reactions within five minutes (p<0.0001) and 24 hours (p<0.0001) post-administration with the 20mg/0.5mL product. No serious adverse events were reported in the study.

"Copaxone(R) is the global market leading RRMS treatment, and Teva is continuously pursuing research focused on further enhancing the patient treatment experience with the product," said Moshe Manor, Teva's Group Vice President, Global Branded Products. "Our investment in research has already translated to increased benefits for Copaxone(R) patients, including an expanded indication to treat early-stage MS-like symptoms in patients at risk of progression to an MS diagnosis, as well as device improvements such as a thinner needle to reduce injection discomfort and an auto inject device to better facilitate treatment delivery."

About the Study

Patients (N=148) enrolled in an open-label randomized two-arm single crossover study. Half of the patients (n=76) were randomized to inject 20mg/1.0mL daily for the first 14 day period (Period 1); the other half of the patients (n=72) injected 20mg/0.5mL daily during Period 1. During the second 14 day period (Period 2), the groups switched their injection volume formulation.

Patients completed a daily diary reporting pain occurring immediately and at 5 minutes post injection, as well as the presence and severity of injection site reactions within 5 minutes and 24 hours of injection. Safety, tolerability, clinical and laboratory assessments occurred during the course of the study.

Adverse events were reported by 12.5 percent of patients when injecting 20mg/1.0mL and by 18.1 percent of patients when injecting 20mg/0.5mL. Overall, the AE profile of Copaxone in patients treated with either formulation was consistent with Copaxone's observed safety profile in placebo-controlled pivotal trials and post-marketing experience.

Source: Teva Pharmaceutical Industries Ltd (07/06/10)

BACKGROUND: Glatiramer acetate is an immunomodulatory drug that is widely prescribed for the treatment of multiple sclerosis. It is frequently associated with local injection site reactions and generalized urticaria. It is also associated with immediate postinjection systemic reactions in approximately 10% of patients. To our knowledge, no desensitization protocols for glatiramer acetate have been published to date.

OBJECTIVES: To evaluate the safety and efficacy of glatiramer acetate desensitization in a series of patients with multiple sclerosis.

METHODS: Six patients with multiple sclerosis and glatiramer acetate-associated local or systemic reactions underwent a 4-hour outpatient desensitization procedure at Cleveland Clinic between 2003 and 2008. Beginning with 20 ng, we administered subcutaneous glatiramer acetate suspension in increasing dosages every 15 minutes. Patient outcomes were monitored by return clinic visit and telephone follow-up.

RESULTS: No episodes of anaphylaxis or serious adverse reactions occurred during or immediately after desensitization. One patient suspended therapy after 14 months due to persistent local injection site reactions. All other patients successfully continued glatiramer acetate therapy.

CONCLUSION: Glatiramer acetate offers significant benefit to patients with multiple sclerosis. Our experience suggests that patients who suspend its use owing to local or systemic reactions can be successfully and safely desensitized and can resume medication use. To our knowledge, this is the first report of successful desensitization to glatiramer acetate in patients with multiple sclerosis.

Source: PMID: 20408342 (26/04/10)

Multiple sclerosis patients who don't respond to or cannot tolerate treatment with interferon beta disease-modifying therapy can be safely and effectively switched to treatment with glatiramer acetate (Copaxone), researchers reported here.

"Patients who had discontinued interferon beta treatment because of side effects seemed to tolerate glatiramer acetate well," said Celia Oreja-Guevara, MD, coordinator of the Group for the Study of Demyelinating Diseases of the Neurological Society of Spain. "A switch to glatiramer acetate in this kind of patients must be considered."

In a study reported at the annual meeting of the American Academy of Neurology, Oreja-Guevara and her colleagues recruited 60 consecutive patients -- 41 women and 19 men -- who were diagnosed with the relapsing-remitting form of multiple sclerosis. All had all been treated with interferon beta therapies for at least six months.

The patients were switched to glatiramer acetate because of either suboptimal clinical efficacy (21 patients) or intolerable toxicity (39 patients) with interferon-based therapy.

The patients who were switched to glatiramer acetate because of ineffectiveness had 0.52 relapses per year, compared to 1.39 per year while on interferon. Such finding could reflect the drug's effectiveness or a case of regression toward the mean, a clinical phenomenon that can occur among patients with active disease.

Patients who discontinued for adverse events maintained a nearly identical, low relapse rate: 0.35 relapses a year with interferon versus 0.36 per year with glatiramer acetate.

"Glatiramer acetate can be considered as an alternative for multiple sclerosis patients who have a suboptimal response or adverse events with interferon beta," Oreja-Guevara suggested.

She also suggested that because patients were able to control multiple sclerosis with glatiramer acetate when interferons had failed "supports the idea of different mechanisms of action for both types of drugs."

Oreja-Guevara disclosed a financial relationship with Teva Neuroscience. Her co-authors had no disclosures. 

Primary source: American Academy of Neurology

Source reference:
Oreja-Guevara C, et al "Characteristics of switching from interferon beta to glatiramer acetate in non respondent relapsing remitting multiple sclerosis" AAN 2010; Abstract P06.162. 

Source: Medpage Today © 2004-2010 MedPage Today, LLC(19/04/10)

Multiple sclerosis patients treated with glatiramer acetate (Copaxone) reported a trend to lessening of the fatigue caused by the disease, researchers said here at the annual meeting of the American Academy of Neurology.

After six months, 59.1% of the patients given the immunomodulator had experienced an improvement of fatigue severity as measured with the total Modified Fatigue Impact Scale score compared with baseline, Norman Putzki, MD, of the Klinik fur Neurologie und Neurophysiologie in St. Gallen, Switzerland, and colleagues reported.

"Fatigue is one of the most frequent and most debilitating symptoms of multiple sclerosis," Putzki and his noted in their poster presentation. "Its origin is poorly understood, but immunologic mechanisms may play a role."

The researchers scrutinized outcomes with glatiramer acetate because the drug is thought to modulate T-cell activation. Glatiramer acetate is also believed to favourably impact the Th1 to Th2 ratio -- the subsets of T cells that produce different cytokine activity, which characterizes different immunologic responses.

However, other recent work also suggests that GA may exhibit its primary clinical effect via modulation of antigen presentation on monocytes and B cells and not by changing T cell activity.

Putzki and colleagues enrolled 29 patients diagnosed with the relapsing-remitting form of multiple sclerosis. They had been diagnosed for a mean of 34 months and their mean Expanded Disability Status Scale score was 2.2 -- indicating minimal to mild disability.

These patients -- 20 of whom were women -- were naïve to multiple sclerosis treatment when they were started on glatiramer acetate. Their scores on the Modified Fatigue Impact Scale at baseline were compared with similar scores at the end of six months in this prospective, observational study.

"The majority of patients who initiate GA experience a mild decrease of fatigue severity while fatigue worsening is rare," Putzki reported.

The mean scores of the physical subscore of the scale showed a tendency to decrease from baseline to month 6 while the other subscores and the total scores did not show significant changes during the investigational period.

Mean Functional System Scores decreased from 4.4 to 4.1 (P=0.06).

Only a few patients scored worse six months after treatment initiation with glatiramer acetate, the researchers reported.

A limitation of the study is that it is difficult to draw definitive conclusions from very small open label trials such as this one.

The study was supported by Teva, Germany.

Putzki disclosed financial relationships with Biogen Idec, Merck Serono, Schering, Teva Neuroscience, sanofi-aventis, Allegan, Ipsen and Novartis. Other authors disclosed financial relationships with Antisense Therapeutics, Bayer, GlaxoSmithKline and Pfizer.

Primary source: Neurology (Supplement) 2010 Annual Meeting Program

Source reference:
Nowack M, et al, "Course of Multiple Sclerosis Associated Fatigue during Treatment with Glatiramer Acetate," [P05.055]Neurology 74, March 5, 2010 (Suppl 2) p. A421.

Source: Medpage Today © 2004-2010 MedPage Today, LLC(19/04/10)

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)

Teva Pharmaceutical Industries Ltd. announced the publication of data from the 15-year clinical study with Copaxone(R) (glatiramer acetate injection), which is the longest prospective and continuous evaluation ever conducted in relapsing-remitting multiple sclerosis (RRMS) patients. The data were published in the February issue of the journal Multiple Sclerosis.

The 15-year clinical study demonstrated that more than 80 percent of patients were still walking without assistance despite a mean MS disease duration of 22 years, and two-thirds of patients have not transitioned to secondary progressive MS. Patients who remained in the study over a mean of 15 years showed a reduction in annualized relapse rate (ARR) from baseline as well as minimal increase in Expanded Disability Status Scale (EDSS). On average, the ARR in the ongoing cohort declined from 1.12 ± 0.82 to 0.25 ± 0.34 at the 15-year analysis.

Additionally, the study reinforces the established long-term safety profile associated with Copaxone(R). The most common adverse events associated with Copaxone(R) were local injection-site reactions and immediate post-injection reactions. No other immune-mediated disorders, infections or malignancies were reported.

"This study is important for the MS community as it further confirms the benefits of continuous long-term use of Copaxone(R) and its ability to effectively slow the natural progression of this disease," said Corey Ford, M.D., Ph.D., primary investigator in the study and Professor of Neurology, Director of the Multiple Sclerosis Specialty Clinic and Assistant Dean for Research at the University of New Mexico Health Sciences Center. "It is encouraging to see such long-term results that further support the well-established benefit-to-risk profile of this treatment relevant to a life-long disease."

"We are pleased to see that results from this study reinforce the long term efficacy and safety of Copaxone(R)," said Moshe Manor, Teva's Group Vice President, Global Branded Products. "The longest term study extension further demonstrates Teva's investment in Copaxone(R) and our ongoing commitment to improve the disease course of MS."

This study represents the only prospective, open-label follow-up study designed to evaluate continuous immunomodulatory therapy in RRMS patients. The study, currently in its 19th year, was extended to 20 years based on the positive results seen thus far and the interest of the MS community in the long term outcomes of treatments for this life-long disease.

About the Study

The study "Continuous Long-Term Immunomodulatory Therapy in Relapsing Multiple Sclerosis: Results from the 15-Year Analysis of the U.S. Prospective Open-label Study of Glatiramer Acetate," a follow-up to the pivotal, Phase III trial, followed 100 ongoing Copaxone(R) (glatiramer acetate injection) patients starting in 1991. Patients' EDSS scores were evaluated every six months. Confirmed disability progression was defined as greater-than or equal to 1.0 EDSS point increase sustained for six months. Patients were classified as "stable/improved" if EDSS score changes were less or equal to 0.5 points. Proportions of patients who reached confirmed thresholds of EDSS 4, 6, or 8 while on Copaxone(R), and Kaplan-Meier (KM) estimates of median times to these thresholds, were obtained.

Fifty-seven percent of patients experienced either stabilized or improved EDSS scores, while 65 percent has not yet transitioned to Secondary-Progressive Multiple Sclerosis (SPMS). While being treated with Copaxone(R), the mITT patients' ARR declined from 1.18+/-0.82 to 0.43+/-0.58/year.

Source: Teva Pharmaceutical Industries Ltd. (25/02/10)

While inflammation often causes damage to the nerves of multiple sclerosis (MS) patients, a group of HBI researchers has been studying how neuroinflammation can instead be harnessed to repair the damage caused by this disease.

Dr. V.W. Yong’s laboratory set out to test whether a drug that is used to treat MS symptoms, Copaxone or glatiramer acetate (GA), could also play a role in repairing the covering of nerves that have been damaged by MS. 

“We know the drug is safely used around the world but we wanted to know if GA offered any reparative benefits,” said Claudia Silva, laboratory manager for the Yong lab.

In MS, axons (the wiring between cells) lose their protective covering, otherwise known as myelin. The myelin helps nerve cells transmit signals and without it axons cannot carry information as quickly or efficiently, which can lead to the short or jerky movements demonstrated by some MS patients.

Yong’s team attempted to enhance the body’s ability to re-cover axons with myelin, by stimulating cells in the immune system to produce beneficial growth factors.  The researchers isolated a specific immune cell, the TH2 helper cell, and found that GA caused these TH2 cells to secrete several growth factors. Those growth factors in turn caused cells in the nervous system that are responsible for making myelin, oligodendrocytes, to grow. 

In various models of MS, the team saw that the application of GA led to an increase in both the number of new oligodendrocytes being created and to positive indicators that damaged nerves were being remyelinated. 

“Our study demonstrated a neuronal repair capacity induced by glatiramer acetate therapy, further extending both an anti-inflammatory and neuroprotective mechanism associated with this treatment, and suggesting that long-term benefits of GA in MS patients may be, in part, due to remyelination,” said Dr. Yong.

The results of this work were published this week in the Proceedings of the National Academy of Sciences(PNAS), one of the world’s most-cited scientific journals.  HBI members Drs. Sam Weiss, Andrew Chojnacki and Axinia Döring also contributed to the project, along with Dr. Viktor Skihar, a former postdoctoral fellow in Dr. Yong’s laboratory who recently finished his training at the HBI and has returned to the University of Saskatchewan.

Further research and clinical trials could lead to an understanding that GA can not only treat the symptoms of MS for patients but that it may also provide protection or repair for the nerve damage caused by this devastating disorder.

Source: Scientific Blogging © 2009 ION Publications LLC (19/10/09)

Summary
Minocycline is proposed as an add-on therapy to improve the efficacy of glatiramer acetate in relapsing-remitting multiple sclerosis. The effect of minocycline plus glatiramer acetate was evaluated in this double-blind, placebo-controlled study.Mult Scler. 2009 Sep 23 epub ahead of print

Details
Canadian researchers, lead by Dr. Luanne Metz of Calgary,aimed to investigate the efficacy of combined glatiramer acetate(GA) plus minocycline treatment in people with relapsing-remitting MS, by comparing a group receiving GA plus minocycline with another receiving GA plus placebo. Forty-four participants were randomized to either minocycline 100 mg twice daily or matching placebo for 9 months as add-on therapy. They were assessed at screening and months 1, 3, 6, 8 and 9. Forty participants completed the study.

Compared with glatiramer acetate/placebo, glatiramer acetate/minocycline reduced the total number of T1 gadolinium-enhanced lesions by 63%, the total number of new and enlarging T2 lesions by 65%, and the total T2 disease burden.  A higher number of gadolinium-enhanced lesions were present in the glatiramer acetate/minocycline group at baseline; this was incorporated into the analysis of the primary endpoint but makes interpretation of the data more challenging. The risk of relapse tended to be lower in the combination group.

Treatment was safe and well tolerated. The authors conclude that results showed a consistent trend favouring combination treatment.

As minocycline is a relatively safe oral therapy, The authors conclude that further study of this combination is warranted in relapsing-remitting multiple sclerosis.

Source: Multiple Sclerosis Society of Canada (14/10/09)

Among patients who show early signs of multiple sclerosis, treatment with Copaxone (glatiramer acetate) appears to halve the risk that they will develop full-blown disease, new research suggests.

About 85 percent of patients who are diagnosed with multiple sclerosis first show signs of a "clinical event" that goes away. But many people who have this happen -- about one-third -- don't go on to develop the disease, and most of the rest won't be severely disabled, research has shown.

In the new study, published in Oct. 6 online edition of The Lancet, 481 people who showed possible signs of multiple sclerosis were assigned to receive either a placebo or glatiramer acetate for up to 36 months. The dosage for those who received the active drug was 20 milligrams per day.

The researchers found that glatiramer acetate reduced the risk of developing the disease by 45 percent compared to the placebo, and it took longer for some patients to develop the disease -- it was an average of about two years for those who took the drug compared to about one year for those who didn't.

Injection-related side effects were common: more than half of those who were given glatiramer acetate developed problems around the site of their injections, and about 19 percent had reactions right after receiving the treatment. By comparison, 24 percent of those who were given the placebo had reactions at the site of their injections, and only 5 percent had problems immediately after the treatment, according to the study authors.

"This study establishes glatiramer acetate as an option for patients with clinically isolated syndrome who choose to start treatment early to improve control of the underlying disease process," the researchers concluded.

Commenting on the study, Helen Yates, Multiple Sclerosis Resource Centre Chief Executive said, "This research further emphasises the need for treating early with Copaxone.  It is also positive to see that a treatment is being shown to be worth starting after just one clinically isolated event."

Some doctors may now urge treatment with Copaxone or beta interferon therapies in an effort to give patients a better long-term prognosis, neurologists David Miller and Siobhan Leary wrote in a comment accompanying the Lancet study.

“Others will adopt a wait-and-see approach, noting that many such patients remain well for a long time,” Miller and Leary wrote, adding that the biggest need is for treatments that can help repair disability for multiple sclerosis patients.

Currently glatiramer acetate is only recommended for 'confirmed' NHS patients under guidance issued by the National Institute for health and Clinical Excellence.

The drug was only approved for NHS use after its manufacturers agreed to a 'risk sharing' scheme, promising to reimburse some of the cost if the medicine failed to prove effective enough.

Treating one patient with glatiramer acetate for a year costs around £6,650.

U.S. regulators accepted an application for a generic version of the injected therapy last month from U.S. generic- drug maker Mylan Inc. and its partner Natco Pharma Ltd., an Indian drugmaker. U.S. biotech Momenta Pharmaceuticals Inc. is also seeking approval to sell a generic version of the medicine.

Source: Various (07/10/09)

Teva Pharmaceutical Industries Ltd. has presented data that demonstrates patients treated for 10 and 15 years with Copaxone(R) (glatiramer acetate injection) had significant reduction in disease severity. These data, generated from the longest continuous prospective study of any disease-modifying therapy in relapsing-remitting multiple sclerosis (RRMS), were presented at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Dusseldorf, Germany.

The long-term analysis utilized the universal MS Severity Score (MSSS) to evaluate the accumulation of disease severity in long-term Copaxone(R) patients actively on therapy and those who withdrew early from the 15 year ongoing Copaxone(R) clinical trial⁽¹⁾. Results demonstrated that 51 percent of long-term Copaxone(R) treated patients shifted to lower severity grades (p<0.0001). In contrast, 41 percent of patients who withdrew from Copaxone(R) showed a deterioration in MSSS grades, when compared to their baseline severity grades. Patients remaining on long-term treatment (treatment exposures of 10.12±1.32 years and 13.6±1.3 years), had improved median MSSS scores of 1.84 and 1.69 at 10 and 15 years, compared to MSSS scores at start, 3.62 and 3.50, respectively. Median MSSS score for withdrawn patients worsened to 6.01 at long-term follow-up versus 4.30 at treatment initiation.

"This study, along with other MSSS studies, is paving the way to enable neurologists to predict the progression of disease severity in MS patients," said Joseph Herbert, M.D., associate professor, NYU Department of Neurology and principal investigator of the study. "The demonstrated positive impact of long-term Copaxone(R) treatment on slowing disease progression provides hope to MS patients and further emphasizes the importance of early treatment initiation."

About the Analysis

The modified intention-to-treat cohort (mITT, N=232) included all study patients receiving greater-than or equal to 1 Copaxone(R) dose. Of mITT, 108 and 100 patients were ongoing in the trial at 10 and 15 years, respectively. Of the 124 patients who withdrew by the 10th year of the study, 50 patients returned for a long-term follow-up. MSSS scores were generated at the onset of Copaxone(R) treatment, at last patient observation for all those who were on Copaxone(R) and withdrew, at 10 and 15 year visits for ongoing patients and at 10 year long-term follow-up for withdrawn patients who returned.

At the 10 year long-term follow-up, mean disease duration for withdrawn patients was 18.54 ± 5.91 years and mean time since leaving study for the withdrawn patients was 5.44±2.89 years. Median MSSS scores for ongoing patients were 1.84 and 1.69 at 10 and 15 years, compared to MSSS scores at Copaxone(R) (glatiramer acetate injection) therapy start, 3.62 and 3.50, respectively. For 50 withdrawn patients, median MSSS score was 6.01 at LTFU vs. 4.30 at Copaxone(R) treatment initiation.

During the study, there was a significant difference between ongoing patients at 10 and 15 years and those who eventually withdrew, in the shift toward lower disease severity categories from Copaxone(R) start to last patient observation on Copaxone(R) (p<0.0001). There was a significant difference in disease severity between ongoing patients at 10 years and withdrawn patients at 10 year long-term follow up. Only 11 percent of ongoing, compared with 41 percent of withdrawn patients, had shifted to higher severity scores; while 51 percent of ongoing, compared to only 24 percent of withdrawn, had shifted to lower severity scores (p<0.0001).

^1. Continuous Long-Term Immunomodulatory Therapy in Relapsing Multiple Sclerosis: Results from the 15-Year Analysis of the U.S. Prospective Open-label Study of Glatiramer Acetate, C. Ford et al.

The study was supported by Teva Neuroscience.

Source: Teva Pharmaceutical Industries Ltd. (11/09/09)

New data presented at the 61st Annual Meeting of the American Academy of Neurology provided evidence that long-term treatment with Copaxone® (glatiramer acetate injection) may offer sustained protection from neuronal/axonal injury. This protective effect was reflected biologically by a significant increase in N-acetylaspartate (NAA), a specific marker of neuronal mitochondrial function, in treated versus non-treated relapsing-remitting multiple sclerosis (RRMS) patients. These six-year results augment previously published findings suggesting that treatment with Copaxone® may provide a neuroprotective effect in RRMS patients ^{1, 2}.

The study, “Six-Year Prospective Multi-Voxel Brain MRS Study of Two Cohorts in RRMS To Examine the Effect of Glatiramer Acetate on Neuronal/Axonal Metabolic Injury,” is the largest (n=46) and longest study of its kind to date. In the study, patients taking Copaxone® for six years experienced an improvement in neuronal mitochodrial function, as quantified by an increase in neuronal NAA levels and evaluated by 1H- Magnetic Resonance Spectroscopy (1H-MRS). Decreased neuronal NAA levels are reflective of neuronal/axonal injury.

“The potential ability to prevent or repair brain tissue damage in RRMS patients is an important treatment consideration given the degenerative pathology of this life-long condition,” said Omar Khan, M.D., Professor of Neurology, Director, Multiple Sclerosis Center, Wayne State University and lead investigator of the study. “These data further substantiate our previous research into the potential neuroprotective effect of Copaxone®, as well as the use of NAA measures as a reliable marker for assessing a patient’s disease progression and response to treatment.”

Similar results were reported from a different study examining the effect of Copaxone® in Clinically Isolated Syndrome (CIS) patients. The study demonstrated patients who received Copaxone® improved in their cerebral neuroaxonal integrity relative to patients treated with placebo. Patients on placebo showed a decline in NAA consistent with that demonstrated in historical control studies.

^1. Khan, O. (2008). Long-Term Study of Brain 1H-MRS Study in Multiple Sclerosis: Effect of Glatiramer Acetate Therapy on Axonal Metabolic Function and Feasibility of Long-Term 1H-MRS Monitoring in Multiple Sclerosis. Neuroimaging 2008.
 
^2.Arnold, D. et al. (2008, September). Treatment with Glatiramer Acetate Protects Axons in Patients with Clinically Isolated Syndromes: Evidence from the PreCISe trial. Presented at ECTRIMS, Montreal, Canada. Multiple Sclerosis 2008 14 (Suppl 1): S5.
 

About the Study

Forty-nine patients, divided into two cohorts of previously treatment-naïve RRMS patients, underwent serial brain 1H-MRS scanning. Group 1 (n=22) included patients who started Copaxone® therapy at enrollment (n=18) and during the course of the study (n=4). Mean age, disease duration and Expanded Disability Status Scale (EDSS) were 43.5 years, 8.2 years and 2.77, respectively. Mean NAA/Cr at baseline was 1.97 + 0.24 and 2.20 + 0.16 (+11.6 percent) at year 6 (p<0.05). Group 2 (n=31) included patients who started GA therapy at enrollment. Mean age, disease duration and EDSS were 35.1 years, 5.8 years and 2.53, respectively. Mean NAA/Cr at baseline was 1.99 + 0.1 and 2.12 + 0.08 (+6.53 percent) at year 6 (p<0.05).

Twelve untreated RRMS patients were also scanned for two years and showed a significant decline in NAA/Cr over the two years of follow-up. Additionally four untreated patients initiated Copaxone® during the course of the study and demonstrated considerable improvement in the mean NAA/Cr ratio, as well as clinical stability during total study observation. Finally, nine healthy volunteers were scanned annually for controls. Further analysis is ongoing. The study was in part supported by Teva Neuroscience.

Source: Teva Pharmaceutical Industries Ltd.(28/04/09)

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)

Glatiramer acetate has been shown to be efficacious in several outcomes among patients with relapsing-remitting multiple sclerosis (RRMS) when a scale other than the Expanded Disability Status Scale (EDSS) was used, according to research presented at the World Congress on Treatment and Research in Multiple Sclerosis (WCTRMS).

A study of 251 patients was presented by investigator Joseph Herbert, MD, New York University, New York, New York, who described the EDSS as not truly reflective of clinical patient outcomes.

In the pivotal study, glatiramer acetate resulted in a 29% decrease in relapse rates compared with placebo. While patients treated glatiramer acetate did show improvement in their EDSS score, Dr. Herbert described the scale as an insufficiently sensitive measure of disease progression.

In this study, Dr. Herbert employed a Multiple Sclerosis Severity Score (MSSS) algorithm that relates MS disability as measured by EDSS to disease duration from the time of first symptom.

"This measure is a more useful outcome measure, because it corrects for certain flaws in the EDSS," said Dr. Herbert in an interview. "It accounts for duration of disease. The EDSS needs to be considered in the context of duration of disease."

This study enrolled patients who had EDSS scores of between 0 and 5. The researchers randomised 125 patients to subcutaneous injections of glatiramer acetate at 20 mg/day and 126 to placebo. Patients were followed for approximately 35 months.

Subjects in this study were divided into 6 groups according to their disease severity, explained Dr. Herbert. At study entry, the median MSSS scores for patients treated with glatiramer acetate and those treated with placebo were similar (4.59 vs 4.29; P = .1). At the end of the study, the median MSSS change from study entry was significantly greater in patients treated with glatiramer acetate compared with those treated with placebo (-0.73 vs -0.19; P = .0019).

With the revised grading of patients according to the MSSS, fewer patients who received glatiramer acetate were categorised as having severe disease. Specifically, more patients treated with glatiramer acetate were reclassified as having less severe illness (49% vs 31%) and fewer patients were reclassified as having more severe illness (16% vs 26%; P < .0014).

"There was a significant drop in severity for the treated patients," said Dr. Herbert. "There was a reassignment toward the higher grades with placebo patients."

The data support the use of the MSSS scale to measure changes in disability in patients with RRMS.

"We are suggesting that, since EDSS and duration of disease must be collected to begin with, that [MSSS] should be used as an outcome measure," said Dr. Herbert. "There is a true change in the intrinsic severity of the disease over 3 years, which is quite dramatic."

Funding for this study was provided by Teva Pharmaceutical Industries Ltd.

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

Teva Pharmaceutical Industries Ltd. revealed that a prospective study on Copaxone or glatiramer acetate injection in the treatment of relapsing-remitting multiple sclerosis confirmed the efficacy and safety of the drug.

Results from the study reaffirmed the benefits of long-term, daily use of Copaxone for the treatment of multiple sclerosis and confirmed the safety profile of the therapy.

Petach Tikva, Israel-based Teva presented the data from the study at the World Congress on Treatment and Research in Multiple Sclerosis. Copaxone is indicated for the reduction of the frequency of relapses in multiple sclerosis and is approved in 51 countries worldwide.

Results from the clinical trial, the longest ever study in treatment of multiple sclerosis, showed that after 15 years of treatment and average disease duration of 22 years, more than 80% of the patients were able to walk without help. Most of the patients demonstrated either stable or improved disability rates and experienced 78% reduction in annualized relapse rate from baseline.

The study, a follow up to the Phase III trial, evaluated both patients who received Copaxone treatment ongoing for an average of 13.6±1.3 years and patients in a modified intention-to-treat cohort, who received at least one dose of Copaxone, with average treatment duration of 8.6±5.2 years.

Source: RTT News © 2008 RTTNews (19/09/08)

The 40mg dose did not demonstrate increased efficacy in reducing the relapse rate; however, the higher dose maintained the favourable safety and tolerability profile of COPAXONE® 20mg.

Seventy-eight percent (78%) of COPAXONE® 20mg treated patients remained relapse-free throughout the study. Moreover, patients that completed one year of treatment with COPAXONE® 20mg experienced a very low annualised relapse rate of 0.27. This robust effect was also reflected in a remarkable reduction of inflammatory activity as measured by MRI. "While the trial did not demonstrate an enhanced efficacy at the higher dose level, the study reaffirms that COPAXONE® 20mg, the leading multiple sclerosis therapy, remains the optimal treatment dose with unmatched long term efficacy confirmed over 10 years,” said Moshe Manor, Group Vice President – Global Innovative Resources. "Teva is committed to ongoing research in the field of multiple sclerosis and will continue to move forward towards providing additional treatment options to multiple sclerosis patients”.

Teva will continue to analyse the study results to better understand the effect of GA 40mg on patients. The Company is also evaluating the use of GA for additional indications.

About the Study

A randomized, double-blind study, designed to assess the efficacy, safety and tolerability of 40mg glatiramer acetate, as compared to the currently approved COPAXONE® (glatiramer acetate) 20mg dose. The study was conducted in 136 centers in North America, Argentina, Europe and Israel, and included 1,155 patients with RRMS. The trial’s primary clinical outcome measure was rate of confirmed relapses.

Source: Teva Pharmaceutical Industries Ltd (07/06/08)

Teva Seeks Approval for the Extension of its Indication to Include the Treatment of Patients with a First Clinical Event Suggestive of MS.

 Teva Pharmaceutical Industries Ltd. announced new results from the PreCISe study, which demonstrated that early treatment with COPAXONE^® (glatiramer acetate injection) significantly reduced the risk of developing clinically definite multiple sclerosis (CDMS) by 45 percent compared to placebo (hazard ratio 0.55, p=0.0001). These data were presented as late-breaking science at the 60^th Annual Meeting of the American Academy of Neurology (AAN) in Chicago.

Based on the PreCISE results, an application for marketing authorization in Europe to the Medicines and Healthcare products Regulatory Agency (MHRA) for the extension of its indication to include the treatment of patients with a first clinical event suggestive of MS, was submitted and is currently under review. A similar application requesting an expanded label for COPAXONE^® will also be submitted shortly with the U.S. Food and Drug Administration (FDA).

“Clinically isolated syndrome, or CIS, is a first neurologic episode, usually caused by inflammation or demyelination, which is indicative of possible development of multiple sclerosis,” said Giancarlo Comi, M.D., University Vita-Salute San Raffaele, Scientific Institute San Raffaele, Milan, Italy, and principal investigator. “The PreCISe study results clearly demonstrate that early treatment with COPAXONE^®, as early as CIS, reduces the risk of developing MS” he added.

COPAXONE^®, currently indicated for RRMS, is a unique disease modifying treatment with a dual mode of action that has over 10 years of prospective clinical trial data demonstrating long-term clinical treatment benefits and good safety profile. The PreCISe results now extend COPAXONE^® effect to CIS patients, demonstrating a reduced risk of developing Clinically Definite MS (CDMS). Furthermore, the safety profile of COPAXONE^® in the PreCISe study was consistent with the well-established safety profile of the product based on many years of post-marketing surveillance and over 100,000 patients treated globally with COPAXONE^®.

Moshe Manor, Group Vice President, Global Innovative Resources of Teva Pharmaceutical Industries, Ltd., said, “These impressive results clearly demonstrate the potency of COPAXONE^® in treating early phases of multiple sclerosis. Along with its lasting efficacy, confirmed over 10 years, it positions COPAXONE^® as the preferred treatment option for multiple sclerosis patients."

About the Study

The multi-national, multi-center, prospective, double-blind, randomized, Phase III study was conducted in approximately 100 centers located in the U.S., Europe, Argentina, Israel, Nordic countries, Australia and New Zealand. It included a total of 481 patients presenting with a single clinical episode and MRI suggestive of MS. Patients included were those who had a unifocal disease manifestation (i.e., clinical evidence of a single lesion). Patients received either COPAXONE^® 20mg/day or placebo as a subcutaneous injection and continued treatment for up to 36 months, unless a second attack was experienced and they were diagnosed with CDMS. Patients who converted to CDMS continued the trial on active treatment for an additional two years. The primary efficacy outcome was time to CDMS, based on a second clinical attack.

COPAXONE^® (glatiramer acetate injection) was also demonstrated to be very well tolerated in the PreCISe study, with only 16 percent overall dropouts during the up to three-year study period, similar to that observed in RRMS patients treated with COPAXONE^®. All patients in the study participated in a follow-up study with COPAXONE^® to prospectively assess the impact of early versus delayed treatment with COPAXONE^® on the long-term course of the disease for a total observation time of up to five years.

A pre-planned interim analysis was performed on data accumulated from approximately 80 percent of the three-year placebo-controlled study exposure. Results of the interim analysis, announced in December 2007, demonstrated the proportion of patients developing CDMS was reduced from 43 percent in the placebo group to only 25 percent in the COPAXONE^® group (p< 0.0001). The PreCISe study also demonstrated that the 25^th percentile of number of days to conversion to CDMS has more than doubled by COPAXONE^® from 336 days to 722 days (hazard ratio 0.55, p=0.0005) compared with placebo.

At the time of this analysis, the data monitoring committee (DMC) stopped the placebo arm of the study, as COPAXONE^® successfully met the efficacy endpoint of the study.

Source: Teva Pharmaceutical Industries Ltd. (17/04/08)

The three-year study showed patients who switched to Teva's Copaxone after failing treatment with a standard interferon drug experienced 77 percent fewer relapses of their disease. Patients switched among different interferon drugs also had fewer relapses, but patients who switched to Teva's drug also showed slowed disability progression.

The study enrolled 114 patients at eight centers in Argentina

Teva's Copaxone passed the $1 billion sales mark for the first time last year. It competes with Tysabri, made by Biogen Idec Inc. and Elan Corp.

Source: Yahoo! Finance © 2008 Yahoo! Inc. (11/04/08)

The Petach Tikva, Israel-based company said that the outcome indicated that treatment with Copaxone, or glatiramer acetate injection, lowered the risk of developing clinically definite MS by 44% compared to placebo, and prolonged the quartile time to disease conversion to 722 days compared to 336 days, +386 days, +115%, in those patients receiving placebo.

During the interim analysis, the proportion of patients who had developed Clinically Definite Multiple Sclerosis, or CDMS, was cut to only 25% in the Copaxone group from 43% in the placebo group. Following these results, Teva intends to file a request for marketing authorization of Copaxone in Europe, the United States and Canada for the treatment of patients with a first clinical event suggestive of MS.

Commenting on the results, Professor Paul O'Connor, chairman of the study's independent data monitoring committee, stated, "After analyzing the data from the PreCISe study at the interim analysis, the DMC recommended that the placebo arm of the trial be stopped, as Copaxone successfully met the efficacy endpoint of the study."

O'Connor added, "all placebo patients will now be given the opportunity to receive active treatment with Copaxone for two years."

Teva noted that the study further established the beneficial effect of early treatment with Copaxone on disease activity and burden, also in its early stages, as measured by both short-term clinical and magnetic resonance imaging, or MRI, disease outcomes. Copaxone is the only relapsing-remitting MS, or RRMS, treatment with data from a long-term, prospective, ongoing study, which indicated that in those patients adhering to therapy, 92% still walk unassisted after a mean of 10 years of therapy and 18 years of disease duration.

Moshe Manor, Group Vice President of Global Innovative Resources of Teva, said "The interim results of this study, which showed that early treatment with Copaxone delayed progression to CDMS, together with the unmatched long-term efficacy, tolerability and favorable safety profile supporting Copaxone, position it now also as the outstanding treatment option for patients with a first clinical event suggestive of MS and RRMS patients."

Source: Trading Markets.com © 2007 The Connors Group, Inc. (03/12/07)

A retrospective study comparing outcomes of relapsing-remitting multiple sclerosis (RRMS) patients treated either with COPAXONE^® (glatiramer acetate injection) or high-dose interferon beta-1a (Rebif^®) demonstrated that patients continuously treated with COPAXONE^® had a significantly lower risk of relapse (p=0.0049) and experienced significantly lower two-year total medical costs (p<0.0001) than those continuously treated with interferon beta-1a (Rebif^®).

The results of the study, “A Comparison of Outcomes Among Multiple Sclerosis Patients Treated with Glatiramer Acetate Injection or High-Dose Interferon Beta-1a,” were presented at the 10^th European International Society for Pharmacoeconomics and Outcomes Research (E-ISPOR) meeting, in Dublin, Ireland. The study analyzed medical claims of patients (n=845) from United Healthcare to examine the association between use of a drug and two-year direct medical costs and risk of relapse.

“Medical costs are an increasingly important factor in treating a chronic disease such as multiple sclerosis,” said MerriKay Oleen-Burkey, PhD, director of Outcomes Research at Teva Neuroscience and study investigator. “Findings of this study not only indicated that COPAXONE^® provided patients with a significant treatment benefit by lowering risk of relapse, but lowered the financial burden associated with the disease, in terms of medical costs,” Oleen-Burkey added.

About the Study

In the retrospective database analyses of United Healthcare medical claims for the time period from September, 2001 to June, 2006, multivariate regressions were used to examine the association between the use of COPAXONE^® and interferon beta-1a (Rebif^®) and two-year direct medical costs and relapses. The study analyzed both intent-to-treat (ITT) (n=845) and continuous use (CU) (n=410) patient cohorts. The ITT cohort included patients with an RRMS diagnosis who initiated therapy on either COPAXONE^® or interferon beta-1a (Rebif^®), and had continuous insurance overage from 6 months prior to drug initiation through 24 months after drug initiation.

The CU cohort consisted of patients who used the medication of interest within 28 days of the end of the two-year period. Patients who initiated treatment with COPAXONE^® (glatiramer acetate injection) in the ITT cohort experienced a significantly lower risk of relapse (odds ratio = 0.543, p=0.0305) and lower two-year direct medical costs ($7,244, p=0.0002) compared to those who began treatment with interferon beta-1a (Rebif^®). Patients who were treated with COPAXONE^® in the CU cohort experienced a significantly lower risk of relapse (odds ratio=0.213, p=0.0049) and significantly lower two-year total medical costs ($12,098, p<0.0001).

Source: Teva Neuroscience, Inc.(26/10/07)

"Comprehensive exams were negative in the search of the etiology of EN, which spontaneously resolved despite treatment continuation. GA treatment is known to generate reactive polyclonal antibodies that can cross-react with myelin epitopes, like MBP. These antibodies may also be implicated in allergenic reactions and auto-immune adverse events, such as anaphylactic shock, lymphadenopathy, livedo-like dermatitis, or lymphocytic infiltration. EN is an unspecific skin reaction occurring in several disorders and induced by many treatments," wrote E. Thouvenot and colleagues, .

The researchers concluded: "As EN can result from a polyclonal antibody response or type I hypersensitivity mechanisms, we hypothesize that GA treatment could be responsible for the occurrence of EN."

Thouvenot and colleagues published their study in Multiple Sclerosis (Erythema nodosum and glatiramer acetate treatment in relapsing-remitting multiple sclerosis. Multiple Sclerosis, 2007;13(7):941-4).

Source: NewsRX Copyright © 2007 NewsRx (19/10/07)

A group of Israeli scientists from the Technion – Israel Institute of Technology, the Weizmann Institute of Science and Teva Pharmaceutical Industries have recently identified genes responsible for the positive response of many multiple sclerosis patients to the drug Copaxone®. These findings may contribute to the development of personalised medicine for multiple sclerosis sufferers.

Copaxone® was the first original Israeli drug to be approved by the U.S. Food and Drug Administration (FDA), and is today marketed in over 40 countries worldwide, including the U.S.A., Europe, Australia, Latin America and Israel.

The drug molecule was the fruit of research by Prof. Michael Sela, Prof. Ruth Arnon and Dr. Dvora Teitelbaum of the Weizmann Institute’s Immunology Department. It was developed for the treatment of multiple sclerosis (MS) by Teva, which produces and markets Copaxone® today.

‘Until now, medical treatments for all kinds of diseases have relied on trial and error methods to determine dosage and treatment protocols,’ says Prof. Ariel Miller of the Ruth and Bruce Rappaport Faculty of Medicine at the Technion, and Head of the Multiple Sclerosis and Brain Research Center, Carmel Medical Center, Haifa. ‘But the process of fixing the correct dosage affects the efficacy of the treatment and can lead to complications in some cases.’ In the past few years, it has been shown that many drugs are not equally effective for every patient, and this variability is due, at least in part, to genetic differences. Finding medications and doses to suit the genetic make-up of each individual patient is likely to be more successful and to cause fewer side effects.

The new research, which deals with the genetic components of the response to Copaxone®, was recently published in the journal Pharmacogenetics and Genomics. It represents a significant step toward realizing this medical vision. In the collaborative study, Teva supplied DNA samples from drug-treated patients, and the genetic tests were performed at the Crown Human Genome Center of the Weizmann Institute, headed by Prof. Doron Lancet of the Institute’s Department of Molecular Genetics.

The scientists used state-of-the-art equipment – the first of its kind in Israel –which allows for the rapid and accurate scanning of variations in the human genome. The scientists then examined the links between the genetic markers they found and the response of MS patients to Copaxone®. They identified several genes that are tied to a positive response to the drug. ‘We analyzed the DNA sequences in 27 candidate genes from each patient participating in the trial,’ said Lancet, ‘and we identified two genes with a high potential for determining the response to Copaxone®. In the future, it may be possible to use this method to scan the genome of MS sufferers, to predict the response levels in advance, and to optimise the dosage and treatment protocol to suit each patient personally.’

Also participating in the research were Prof. Jacques Beckmann (formerly at the Weizmann Institute); Drs. Liat Hayardeny and Dan Goldstaub of Teva; and Iris Grossman, a joint research student at the Technion and the Weizmann Institute.

Source: The Weizmann Institute of Science (11/10/07)

"The number of events (relapses) was insufficient to establish a statistically significant difference between the two products, despite a trend advantage for Rebif," the report said.

The 96-week Phase IV study involving almost 800 patients will be presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Prague.

Merck inherited Rebif through its recent 10.2 billion-euro ($14 billion) acquisition of Swiss biotech company Serono.

Serono had hoped to gain market share from Copaxone in the case of a positive outcome from the head-to-head study.

Source: Reuters (C) Reuters 2007. All rights reserved

"Like other peptide antigens, GA induces an antibody response in all patients. In contrast to biologically active agents, such as the recombinant interferon beta drugs, GA is a peptide antigen that lacks intrinsic biological activity. In vitro and in vivo data have shown that GA-reactive antibodies are not neutralizing. Antibodies do not alter the principal immunological effects of GA, including binding to MHC Class 11 molecules, activation and proliferation of GA-reactive T cells, and the release of anti-inflammatory Th2 cytokines. Higher antibody titres do not appear to be associated with a deterioration in clinical endpoints, such as relapse rate, EDSS progression or the occurrence of side effects in MS patients treated with GA," they continue.

The researchers concluded: "The presence of GA-reactive antibodies may promote remyelination and enhance the immunological and clinical effects of GA, indicating that they may be part of GA's mechanism of action."

Source: Multiple Sclerosis (Clinical significance of glatiramer acetate antibodies. Multiple Sclerosis, 2007;13(Suppl. 1):S28-S35). (26/09/07)

Researchers at UCSF and Stanford University have discovered a key mechanism responsible for the activity of a commonly prescribed drug for treating multiple sclerosis (MS), which they hope will spur better therapies for the disease.

The study was conducted on the drug glatiramer acetate (marketed as Copaxone), in mice with experimental autoimmune encephalomyelitis (EAE), the standard MS animal model. Findings appear in the August 5, 2007 online edition of the journal “Nature Medicine.”

The discovery could signal a new direction in the search for an effective therapy for MS, according to Scott Zamvil, MD, PhD, UCSF associate professor of neurology whose laboratory led the study.

Until now, he said, scientists believed this drug acted primarily on a class of white blood cells called lymphocytes, which are known to cause tissue damage in MS. This study found that, instead, the drug targets a different blood cell, called a type II monocyte. It now appears that the monocyte instructs the lymphocyte to change course. When treated with glatiramer acetate, monocytes were found to reverse paralysis in mice with EAE, an experimental disease that closely resembles multiple sclerosis.

“These results represent a major change in our understanding of how this MS drug works,” Zamvil said. “What we’ve shown, for the first time, is that the drug actually works by targeting monocytes and also that drug-activated monocytes can be transferred to an affected animal and reverse the disease.”

The next step, he said, is to assess whether they can reproduce the immunologic findings in humans.

MS is an autoimmune disease in which lymphocytes attack and damage myelin, the tissue that surrounds and protects the nerves in the brain and spinal cord. This causes a variety of symptoms, ranging from mild muscle weakness to partial or complete paralysis. The primary human symptom of the disease, which is a recurring temporary paralysis in the limbs, also occurs in mice with EAE.

Roughly 400,000 Americans acknowledge having MS, which may affect 2.5 million people worldwide, according to the National Multiple Sclerosis Society. Another 200 people are diagnosed nationwide each week, the society said.

Zamvil said about one-third of the U.S. patients who are currently being treated for MS receive glatiramer acetate, which reduces inflammation and tissue damage. How that occurs was not understood.

The UCSF-Stanford team observed that when the drug was administered daily, as it is in MS treatment, monocytes underwent a molecular switch. Before treatment, the monocytes secreted toxic cytokines, which are chemicals that promote lymphocytes to cause tissue damage. After treatment with glatiramer acetate, the monocytes switched to instead secrete protective cytokines that reduce inflammation and tissue damage.

When the researchers transferred the activated monocytes into mice with EAE, they were able to reverse both paralysis and tissue damage by causing the mice’s native lymphocytes to switch from secreting detrimental cytokines to secreting protective ones.

These findings provide an incentive to develop an “adoptive immunotherapy” for MS, that is, a therapy based on injecting drug-induced type II monocytes into patients, rather than the drug itself, Zamvil said. However, it is unclear whether this approach would be more effective.

Although Zamvil emphasized that the new findings will not alter current patient care, they could lead to important changes in the future.

“Our work in mice does not make glatiramer acetate a better drug,” he said.

Rather, the study’s significance is in developing a new entry point to targeting MS, noted Martin Weber, MD, the paper’s lead author and a post-doctoral fellow in Zamvil’s lab.

“The importance is that we have created a new approach to studying how a drug’s activity on monocytes influences other parts of the immune system,” Weber said. “This should facilitate development of better drugs for treating MS and possibly other autoimmune diseases, such as rheumatoid arthritis or type I diabetes.”

Several biotechnology and pharmaceutical companies have been looking for ways to improve on Copaxone. The new data could shift their focus from the lymphocytes to the monocytes, giving them a new target for drug development, he said. It could also provide important insights into combining glatiramer acetate with other drugs currently approved for MS therapy.

This work was supported by the National Institutes of Health, National Multiple Sclerosis Society, Dana Foundation, Maisin Foundation and Teva Neuroscience Inc., the maker of Copaxone.

Co-authors on the study include Lawrence Steinman, professor of neurology and director of the Stanford University Program in Immunology, and members of his laboratory, including Sawsan Youssef and Shannon Dunn.

Additional co-authors are Thomas Prod’homme, Cynthia Rundle, Linda Lee and Juan Patarroyo, all of UCSF; Raymond Sobel of Stanford University; and Olaf Stüve, formerly a postdoctoral fellow in the Zamvil lab and now at the Veterans Affairs North Texas Health Care System.

Source: The University of California, San Francisco Copyright 2007 (06/08/07)

The study, called Betaseron vs Copaxone in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (BECOME), is the first investigator-initiated, randomised, prospective, rater-blinded trial to directly compare these 2 agents in the treatment of MS. The study was supported in part by a grant from Berlex/Schering AG.

Diego Cadavid, MD, associate professor in the department of neurology and neurosciences, New Jersey Medical School, in Newark, and the Multiple Sclerosis Center at Holy Name Hospital, in Teaneck, New Jersey, reported the findings here during the Whitaker Research Track presentations of the Consortium of Multiple Sclerosis Centers 21st Annual Meeting.

Seventy-five patients with MS were randomly assigned to treatment groups: 36 with interferon beta-1b and 39 with glatiramer acetate. Combined active lesions (CAL) were monitored monthly for 2 years using 3-tesla MRI with triple-dose gadolinium and a 40-minute delay to maximise enhancement. Clinical indications of relapse, cognition, and disability were also monitored. A total of 2754 CALs were identified during the study.

After 15 months of treatment, a similar number of lesions occurred in both treatment groups, but the occurrence of lesions varied considerably between patients. "Approximately half the MRIs in each group showed new lesions and half did not," he said.

Dr. Cadavid then reclassified the 75 patients by CAL pattern: no CALs for 2 years (n=15), episodic CALs (n=44), and frequent CALs (n=16). The occurrence of these patterns in the 2 treatment groups was not significantly different (Χ2, P = .7).

Disease activity continued to some extent in 77% to 83% of the patients, again with no significant difference between the 2 drug therapies.

Sensitive Technique

Michael Racke, MD, chair of the department of neurology of Ohio State University and moderator of this session, focused his comments to Medscape on the unusually sensitive MRI technique. "In terms of clinical applicability, nobody's going to do monthly triple-dose gadolinium 3-tesla MRI. But the real problem is, we don't have a histologic correlate."

"Dr. Cadavid's data do suggest that the 2 drugs compared are very similar," continued Dr. Racke. However, he thinks the unusual MRI technique used in this study is measuring something different than an MRI with, for instance, a 1.5-tesla magnet after single-dose gadolinium. "Basically, since Berlex funded the study, they thought that Betaseron would beat Copaxone — and it didn't. So the issue becomes: Why is that? With a typical MRI, would you have seen what was anticipated? This technique is very sensitive, but we don't know exactly what we're measuring with that increased sensitivity."

CAL Patterns

Dr. Cadavid also analysed the results of the behavioural and cognitive tests for the 3 CAL pattern groups, including the 25-foot walk test, a test of response speed, and the cognitive skills index (CSI). In nearly every test, the group with frequent CALs scored lower than other groups in baseline testing and continued to do more poorly throughout the study.

Talking with Medscape, Dr. Cadavid said he had been very surprised to find that patients in the frequent-CAL group scored more poorly from the beginning of the assessments. As to why their impairment had not been noticed earlier, he commented: "It's a matter of how the relapse presents. If they lost vision in 1 eye, they'd be picked up right away. But if they have a subtle problem with balance, gait, or cognition, they may not be picked up. People tend to assign the symptoms to something else."

Regarding clinical utility of the 3 CAL patterns, Dr. Cadavid emphasised: "You cannot assume that just because you put [patients] on therapy you've got them under control. You have to be careful, especially with the group with frequent lesions, because they seem to already carry some loss of function when you first see them." Based on the results of this study, he added, "Even though you put them on the drug, you are not really controlling them. They're getting disabled in front of you."

The point is, he added, "after 10 or 12 years of these first-level drugs, we are entering a phase of what seem to be more powerful drugs with more serious side effects. We cannot put everybody in the same basket. It's time to become more selective and target the patients with more frequent lesions with what may be more powerful drugs with a higher risk."

Source: Consortium of Multiple Sclerosis Centers 21st Annual Meeting. John Whitaker Research Track. (16/06/07)

These data were presented at the 59th Annual Meeting of the American Academy of Neurology (AAN) in Boston, MA, April 28 -- May 5, 2007.

"The results of this study indicated that further exploration of this combination is warranted, as the established effect of COPAXONE^® on disease activity may be boosted when used in combination with minocycline for the treatment of active relapsing-remitting patients," said Luanne Metz, M.D., professor at the Department of Clinical Neuroscience of the University of Calgary, and principal investigator. "In these patients, the combination was safe and well tolerated," she added.

Minocycline is a broad-spectrum antibiotic, which is used to treat pneumonia, acne, and infections of the skin, genital and urinary systems, and the central nervous system. In a small proof-of-concept trial of 10 RRMS patients, minocycline demonstrated an 84 percent relative reduction in mean total Gd-enhancing lesions and was well tolerated, and data published in the Journal of Neuroimmunology indicated that the combination of minocycline and COPAXONE^® decreased neuron-inflammation, axonal loss and demyelination in an animal model of MS.

"COPAXONE^® is one of the most frequently used RRMS therapies due to its proven efficacy and safety and unique presumed mechanism of action," said Metz. "In previous studies, COPAXONE^® has shown efficacy and safety both in combination with intravenous steroids and after induction with the immunosuppressant mitoxantrone; its compatibility with other compounds may make it unique among the disease modifying class of drugs and a treatment of interest for the future study of combination therapies for MS," Metz added.

About the Study

This double-blind, randomised study evaluated the safety, tolerability and efficacy of the combination of COPAXONE^® plus oral minocycline in the treatment of RRMS patients with active disease.

Patients in this study (n=44) with one or more T1-enhancing lesions on their screening MRI were randomised to receive either COPAXONE® 20 mg daily plus minocycline 100 mg twice daily or COPAXONE^® plus placebo for nine months. Patients were assessed clinically and by MRI scans at screening and months 1, 3, 8 and 9. The primary outcome was the total number of T1-enhancing lesions at months 8 and 9.

Forty patients completed the study. Groups were balanced at baseline except for greater T1-enhancing lesion number in the COPAXONE^® plus minocycline group (median 3 versus 2; mean 7.62 versus 2.43 (p=0.07)). Despite this imbalance, treatment trended toward significance in the COPAXONE^® plus minocycline group. At months 8 and 9, the number of T1-enhancing lesions was reduced by 63 percent (mean 1.47 versus 2.95; p=0.08) and the number of new T2 lesions was reduced by 65 percent (mean 1.84 versus 5.14; p=0.06), compared to COPAXONE^® alone. Relapse risk rate was also non-significantly reduced in the COPAXONE^® plus minocycline group (0.19 versus 0.41; p=NS).

Source: Red Orbit © 2002-2007 redOrbit.com. All rights reserved (05/05/07)

Generic drug developer Teva Pharmaceutical Industries Ltd. said Tuesday it saw positive results from a mid-stage study for a higher dose of its already-approved multiple sclerosis drug.

The Phase II clinical trial showed a 40-milligram dose of Copaxone delivered a 38 percent greater reduction in inflammatory disease activity compared with the standard 20-milligram dose. Patients taken the 40-milligram dose also experienced a 77 percent reduction in relapse rate compared with 62 percent taking the 20-milligram dose.

Source: Teva Pharmaceutical Industries

A comparison of the long-term economic outcomes of four immunomodulatory drug therapies combined with symptom management versus symptom management alone revealed that COPAXONE^® (glatiramer acetate injection) was the most cost-effective treatment strategy for relapsing-remitting multiple sclerosis (RRMS).

The study provides the first pharmacoeconomic evaluation of the cost-effectiveness of multiple sclerosis (MS) therapies that includes long-term treatment outcomes and costs associated with missed days from work.

The study also evaluated the impact of neutralizing antibody (NAb) development in pharmacoeconomic measures among patients treated with the interferon beta (IFN-(beta)) class of drugs. The findings of the study, "Cost-effectiveness of Four Immunomodulatory Therapies for Relapsing-Remitting Multiple Sclerosis: A Markov Model Based on Long-term Clinical Data," were published in the April issue of the Journal of Managed Care Pharmacy.

"The recent availability of data demonstrating the long-term treatment outcomes of immunomodulatory therapies in MS allowed us to assess the cost-effectiveness of various RRMS treatment strategies. Findings of this study indicated that of the four therapies used to manage MS and in comparison with symptom management alone, the use of COPAXONE^® was the best strategy in terms of outcomes and costs," said Kenneth Johnson, M.D., professor of Neurology and director of the Maryland Center for Multiple Sclerosis, School of Medicine, University of Maryland. "A treatment that reduces relapses or slows the progression of disability, as measured by the Expanded Disability Status Scale (EDSS), may assist in lowering resource utilisation and in turn help to offset the cost of therapy," Johnson added.

Cost-effectiveness and cost-utility analyses are useful tools for assessing the relationship between added costs and potential benefits (e.g., improved patient outcomes) of therapies. Previous economic models made assumptions regarding the impact of IFN-(beta) on treatment effects (e.g., constant treatment effects over time) because of data limitations, which also made it difficult to examine the impact NAbs have on cost-effectiveness, as they may inhibit the effectiveness of IFN-(beta) treatment. The model used in the present analysis assumed that NAbs would impact the probability of relapse only after the second year of continuous interferon treatment and therefore potentially negatively affect treatment cost and outcomes for therapies susceptible to the development of NAbs.

"The development of NAbs have been shown to reduce the efficacy of IFN-(beta) therapies on magnetic resonance imaging (MRI) outcomes, relapse rate and disability progression, which in turn may affect the cost and outcomes associated with these therapies," Johnson said. "Although the results of this study provide decision makers with relevant data to evaluate the cost-effectiveness of immunomodulatory treatments versus symptom management in treating RRMS, it is important to consider the results in context, given that head-to-head randomised clinical trials comparing the immunomodulatory therapies are necessary to validate the projections from the pharmacoeconomic analyses."

About the Study

A literature-based Markov model was developed to estimate the economic outcomes of five treatment strategies: symptom management (e.g., physical therapy/exercise and pharmacological treatment) alone and symptom management combined with COPAXONE^® (glatiramer acetate injection), IM-IFN(beta)1-a (Avonex^®), SC-IFN(beta)1-a (Rebif^®), or SC-IFN(beta)1-b (Betaseron^®) in patients diagnosed with RRMS. This is the first economic model in MS to incorporate long-term data on treatment effects, account for differences among clinical trial designs of the immunomodulatory therapies and present the results in terms of cost-utility and cost-effectiveness. The model design took into account disease modifying therapy (DMT) acquisition costs, state-specific MS-related medical costs and the cost of lost worker productivity.

The analysis found that the total cost per patient over the time horizon of a patient's lifetime for COPAXONE^® was estimated to be 34.7 percent, 16.8 percent and 14.5 percent less than Rebif^®, Betaseron^® and Avonex^®, respectively. Sensitivity analyses showed the results to be sensitive to changes in health state utilities, the percentage reduction in disease progression rates as measured by EDSS in the first two years of therapy used to estimate immunomodulatory therapy treatment effects, model time horizon and immunomodulatory therapy acquisition costs.

The authors of this study note that limitations included reliance on clinical trial data, no inclusion of cost and utilities associated with adverse events, assumptions surrounding the discontinuation and switching of therapies and estimation of clinical outcomes, lack of sufficient head-to-head clinical trials and clinical trial relapse rate criteria associated with this analysis.

Source: Teva Pharmaceutical Industries Ltd

Data from the full cohort of the PROMiSE study showed that treatment with COPAXONE^® (glatiramer acetate injection) did not reach a significant effect on the primary endpoint of accumulated delay to disability versus placebo in the entire population of patients with primary progressive multiple sclerosis (PPMS) (39.6 percent versus 45.2 percent respectively, p = 0.1753). However, post-hoc analyses demonstrated that COPAXONE^® significantly delayed time to progression of accumulated disability in male patients in the study (n=455) who received treatment versus those who received placebo (p = 0.0193). Results of the randomised, double-blind study of over 900 patients were published in a recent issue of Annals of Neurology.

In the study, treatment differences in male patients emerged early and were maintained over time; 61.6 percent of male patients receiving COPAXONE^® remained progression-free as opposed to only 49.1 percent of those in the placebo group. Data from the entire population also showed that COPAXONE^® reduced the burden and activity of lesions in the brain as measured by T2-weighted and gadolinium (Gd)-enhanced magnetic resonance images (MRI).

"COPAXONE^® in this trial demonstrated a trend towards slowed disease progression versus those patients left untreated, which was only statistically significant in male patients in the post hoc analysis," said Dr. Jerry Wolinsky, Bartels Family and Opal C. Rankin Professor of Neurology, interim Dean, The University of Texas Health Center at Houston and the lead investigator of the trial.

PPMS is a degenerative form of multiple sclerosis (MS), a chronic, progressive, degenerative disorder that affects nerve fibres in the brain and spinal cord. PPMS patients experience near continual progression of disease over their lifetimes without any discernable relapses or remission of neurologic disability. Compared with relapsing-remitting multiple sclerosis (RRMS) patients, PPMS affects a higher proportion of men than women, and data suggest that men with PPMS may progress faster than women. Currently, there are no proven effective treatments for PPMS.

"The results of the PROMiSe study may warrant additional trials surrounding the effect of COPAXONE^® on PPMS, given the fact that there are no other treatments currently available. The lack of a statistically significant treatment response in women in the study does not mean that COPAXONE^® doesn't hold promise for further study in this population," said Wolinsky.

About the Study

The PROMiSe trial followed 943 patients who were randomised for treatment with COPAXONE® (n=627) or placebo (n=316) in a two-to-one ratio. A pre-planned interim analysis of 935 patients, of whom 757 had completed at least two years or had terminated the study early, projected that no significant treatment effect could be reached for the primary endpoint, which was time to progression of Expanded Disability Status Scale (EDSS) scores (defined as change of 1.0 EDSS point or greater for entry EDSS of 3.0 - 5.0, or 0.5 for entry EDSS of 5.5 - 6.5). As a result, the study was terminated prematurely and study medication was discontinued.

Despite the termination of the PROMiSe study, patients were offered the opportunity to continue to be followed. An intent-to-treat (ITT) analysis at three years was conducted to determine whether different outcomes occurred in subgroups of patients because of an unexpected on-trial slow rate of disease progression among participants and abbreviated exposure to COPAXONE^® (glatiramer acetate injection) therapy, both of which made detecting a treatment effect challenging. The post-hoc analysis demonstrated a trend toward delaying disease progression which was significant in the male subgroup of patients (n=455) who experienced a slowing disease progression to sustained disability in favour of COPAXONE^®. Post-hoc analyses are intended to re-examine an existing data set to determine potential patterns or trends that may not have been apparent based on the initial review of the data as set forth by the study design. The Kaplan Meier survival curve indicated delayed disease progression for males assigned to COPAXONE^® diverged from a placebo-assigned patient curve within a year of study entry, and the gap widened over time.

"Currently there have been no clinical trials in PPMS as large or comprehensive as the PROMiSe trial, nor are there any comparable sized studies currently being undertaken," said Wolinsky. "Because of this trial, we probably know more about the natural history of PPMS than we did before, which is of immeasurable value to the field."

Initial data from the PROMiSE trial were previously reported at the 2004 Annual Meeting of the American Academy of Neurology.

Source: Teva Pharmaceutical Industries Ltd.

The findings were presented at the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

"Glatiramer treatment not only has a positive impact on relapse rate and disease progression but we found that the effect increases over time, out to 5 years," said lead presenter Paul Hradilek, MD, neurologist, University Hospital, Ostrova, Czech Republic. "The drug is very effective on both fronts in relapsing-remitting MS patients."

The study cohort consisted of 96 women and 12 men diagnosed with relapsing-remitting multiple sclerosis who began glatiramer treatment in1999. For 95 patients glatiramer was their first disease-modifying drug. Thirteen had been treated previously with interferons.

For study entry, participants were required to have at least 2 relapses per year or 3 relapses every 2 years and magnetic resonance imaging finding confirming an MS diagnosis.

Average time from diagnosis to initiation of treatment with glatiramer was 6.75 years (1-30).

Investigators evaluated relapse rate and Expanded Disability Status Scale (EDSS) change in subgroups treated at least 1, 3 or 5 years.

Average relapse rate before treatment was 1.5. After 1 year of glatiramer treatment the rate decreased to 0.68. With glatiramer treatment, it continued to decrease after 3 years to 0.51. In the subgroup treated for at least 5 years the relapse rate was 0.31.

A majority of subjects showed stable EDSS scores, with an average change in EDSS of 0.1 point after 5 years.

The authors noted that 5 patients discontinued treatment. There were 2 skin allergic reactions leading to discontinuation, but no other major side effects.

Eleven patients became pregnant during glatiramer treatment, "which was interrupted the day the subjects knew about their pregnancy," Dr. Hradilek said. There were 3 spontaneous abortions and 8 normal deliveries. The researcher did not observe any foetal abnormalities.

Copaxone is approved in much of the world for relapsing-remitting MS. It acts as both immunomodulatory and neuroprotective agent.

[Presentation title: Treatment of Relapsing-Remitting Multiple Sclerosis With Glatiramer-Acetate: Our 7-Year Clinical Experience. Abstract P368]

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Teva Pharmaceutical Industries Ltd., the world's largest producer of generic drugs, said Friday two clinical studies showed its branded drug Copaxone, when used in combination with other drugs, significantly reduced brain lesions in multiple sclerosis patients.

In one study, patients who took Copaxone and steroids over six months experienced an average reduction in brain lesions of 65 percent, which was sustained for another six months when patients were given Copaxone without the steroids.

The other study showed that patients given Copaxone along with the chemotherapy mitoxantrone over 15 months saw an 89 percent greater reduction of brain lesions than those patients given Copaxone alone.

Source: Teva Pharmaceutical Industries Ltd (29/09/06)

A new study showed that very active patients who received COPAXONE^® (glatiramer acetate injection) therapy alone following short-term induction treatment with mitoxantrone experienced an 89 percent greater reduction (P less than0.0001) compared to those receiving COPAXONE^® alone, in Magnetic Resonance Imaging (MRI)-disease activity as measured by Gadolinium (Gd) enhancing lesions of the brain. This initial benefit achieved early on in the study was maintained over the entire 15-month study period. In addition, no adverse events outside of those associated with either treatment when used as monotherapy were observed.

These data were presented today at the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Madrid, Spain.

"These new data represent a promising development in the scientific community's effort to identify additional effective treatment strategies for those patients who have particularly aggressive forms of RRMS, many of whom do not respond optimally to traditional disease modifying therapies," said Tim Vollmer, M.D., chairman, Division of Neurology, Barrow Neurological Institute at St. Joseph's Hospital and Medical Center and the primary investigator in this study. "By putting patients on COPAXONE® after a brief induction period with mitoxantrone, we were able to significantly reduce MRI-disease activity in the brain of active RRMS patients and to sustain this benefit throughout the study."

About the Study

This randomised, double-blind study looked at the safety, tolerability and efficacy of COPAXONE^® (glatiramer acetate injection) used after short-term induction therapy with mitoxantrone versus COPAXONE^® alone. Relapsing-remitting multiple sclerosis (RRMS) patients in this study (n=40) were randomised to receive either COPAXONE^® for one year following three months of mitoxantrone (M-GA; n=21), or COPAXONE^® alone for 15 months (GA; n=19). The study included patients aged 18-55, who had a Gd-enhancing lesion at the time of an initial screening MRI scan and an EDSS

Results showing a reduction of Gd-enhancing lesions in the M-GA patient cohort compared with the GA cohort were observed as early as six months into the trial (p less than 0.0001) and were maintained throughout the duration of the study (p = 0.0147). The efficacy demonstrated in the GA cohort increased over the entire 15-months trial; a 46 percent reduction in Gd-enhancing lesions was achieved at nine months and at month 15, patients demonstrated a 67 percent reduction compared to entry.

A relapse was experienced on average eight months prior to baseline in all study participants; after 15 months, the majority of these patients had not experienced a relapse. Patients who received COPAXONE^® after mitoxantrone showed a trend in experiencing fewer relapses over the study period. Mean relapse rate during the study period was 0.16 in the M-GA group and 0.32 in the GA group, reflecting a 46 percent greater reduction in relapses in M-GA patients than of those that did not receive mitoxantrone (p=0.31). There was no difference in time to first relapse between the patient cohorts.

Within study participants, the most frequent adverse events (AEs) associated with the M-GA group were infection, nausea and vomiting, menstruation irregularities and alopecia, and were consistent with known effects of mitoxantrone therapy. Injection site erythema was the most common AE in the GA group.

"Mitoxantrone carries certain risks which limit its use to a maximum recommended lifetime dose. These difficulties make mitoxantrone an option that is generally reserved for only a small group of patients who have a poor disease prognosis or whose disease does not respond to first-line treatment," said Tim Vollmer, M.D., chairman, Division of Neurology, Barrow Neurological Institute at St. Joseph's Hospital and Medical Center and the primary investigator in this study. "When used after short-term induction with mitoxantrone, COPAXONE® minimised exposure to mitoxantrone while maintaining treatment effects ongoing, making it a viable treatment option for a broader proportion of the MS population."

Source: Teva Pharmaceutical Industries Ltd.

Studies have shown that neutralizing antibodies (Nabs) develop in 5 percent to 45 percent of all MS patients treated with interferon beta (IFN-β). The presence of Nabs to IFN-β may negatively alter the therapeutic effectiveness of this class of disease modifying drugs which includes IFN-β-1a SC (Rebif^®), IFN-β-1b SC (Betaseron^®), and IFN-β-1a IM (Avonex^®). Patients who test positive for NAbs are more likely to have reduced therapeutic benefits from their interferon beta treatment (measured by the reduction in relapse rate, the reduction in disability progression and the disease activity as evidenced by brain magnetic resonance imaging (MRI).

"Neutralizing antibodies against IFNs are therefore an important issue for MS management, as their development appear to diminish their clinical efficacy," said Professor Dimitrios Karussis, Department of Neurology, Hadassah University Hospital, Ein-Karem, Jerusalem. "Our data confirms that antibodies to COPAXONE® which develop in all patients do not neutralize the drug's biological activity and do not compromise its established sustained long term effectiveness." he added.

Recent guidelines on Nabs to beta interferons, produced by the European Federation of Neurological Societies (EFNS), recommend that all people with MS being treated with IFN-β be screened after 12 and 24 months of treatment to determine the existence of anti-IFN-β Abs, and that those who have persistently high levels of NAbs after re-testing 3-6 months after the first results, should have their interferon beta treatment discontinued. Furthermore, it is recommended that since NABs are cross-reactive, switch from one IFN preparation to another is of no clinical benefit.

About the Study

Patients in this study (n=126) who had received COPAXONE^® (glatiramer acetate injection) from 2 years to 15 years were surveyed to determine levels and types of antibodies to COPAXONE^® and to correlate these parameters with treatment outcomes. Serum samples were collected from study participants, and were analysed for the presence of antibodies to COPAXONE^® using ELISA E (enzyme-linked immunosorbent assay) methodology. Clinical data, including the current and previous Expanded Disability Status Scale (EDSS) scores, and the relapse rates, were also collected at the time the serum samples were taken.

Over the mean COPAXONE^® treatment period of 6.65 years, sera from only six patients demonstrated minimal in vitro neutralizing activity. In addition, patients were clinically stable for the whole COPAXONE^® treatment period, showing a minimal mean increase in EDSS score of 0.65 (mean annual increase = 0.10 per patient). Despite mean disease duration of 10.75 years, the majority of patients (77 percent) surveyed had an EDSS score of less than 4.0, a stage at which they were still fully ambulatory.

In order to further study the subject of NABs to IFNs, Teva Neuroscience, Inc., recently initiated the first-ever study designed to examine how the implementation of regularly scheduled IFN-β NAbs tests in MS patients receiving high-dose IFN-β therapy ultimately affects treatment patterns, versus the usual care of IFN-β patients. The study, called the NAbs Count Study, began enrolment in July, 2006, in approximately 130 centers across the United States.

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A retrospective analysis of multiple sclerosis (MS) patients comparing patients treated with immunomodulatory agents with untreated patients revealed that only treatment with COPAXONE^® (glatiramer acetate injection) was associated with significantly fewer days missed from work compared to untreated patients. Neither treatment with Avonex^® (Interferon beta-1a IM) nor Betaseron^® (Interferon beta-1b) was associated with significantly fewer days missed from work in comparison to untreated patients. The findings of this study, "Effect of immunomodulatory therapy and other factors on employment loss time in multiple sclerosis," were published in the September issue of the journal WORK.

"Being able to pursue a satisfying work life is an important part of life for most people, yet the symptoms of relapsing-remitting multiple sclerosis (RRMS) and the up and down nature of the disease can make this a challenge for many patients," said MerriKay Oleen-Burkey, PhD, director of Outcomes Research at Teva Neuroscience and a study investigator. "After diagnosis, an estimated 70 to 80 percent of MS patients in the United States leave the workforce. A major goal in the treatment of RRMS is to reduce disease relapses and to provide patients the ability to go on with their lives despite the disease."

Disease relapses in MS can be associated with hospitalisation, interference with employment and accumulated disability, leading researchers to suggest that reducing relapse rates may be associated with a reduction in lost work time.

"The results of this study suggest that COPAXONE^® might be a contributor in helping to keep MS patients participating in the workplace for as long as possible," said Oleen-Burkey. "It is important to consider the results of this study in context given various study limitations, including the retrospective design and a relatively small sample size. It is also important to continue searching for the optimal combination of factors for preserving the working life of MS patients."

About the Study

The purpose of the study was to examine the factors that potentially affect time missed from work for individuals diagnosed with MS. The study observed the impact of patient demographics, prior medical history, comorbid diagnoses, medications and the use of and type of immunomodulatory treatment on work attendance.

The study analyzed two MedStat databases - Health and Productivity Management (HPM) and MarketScan Commercial Claims and Encounters (CCE). Patients followed in the study included those diagnosed with MS between 2000 and 2002, who were continuously insured six months prior to the year of diagnosis and throughout the year following diagnosis, and with work records containing days missed from work, short-term disability and worker's compensation data (n=284).

Comparing work attendance of patients treated with the immunomodulatory agents COPAXONE^® (glatiramer acetate injection, n=28), Avonex® (interferon beta-1a IM, n=74) or Betaseron® (interferon beta-1b, n=16) to those who did not receive immunomodulatory therapy (n=166), only patients taking COPAXONE^® had significantly fewer missed days of work for short-term disability (18.24 fewer days, P less than 0.03), worker's compensation (29.50 fewer days, P less than 0.04) or any reason (53.70 fewer days, P less than 0.003) compared to untreated patients.

Source: Teva Neuroscience, Inc.

Teva Pharmaceutical Industries announced today the initiation of a large Phase III study designed to confirm the positive results from the Phase II study which compared a new higher dose of 40 mg/day dose of glatiramer acetate (GA) to the currently approved COPAXONE^® (GA) 20 mg/day, whose efficacy and safety have been well established by three pivotal trials and over a decade of experience and clinical research. The study, called FORTE - FORTy mg Efficacy of glatiramer acetate - is beginning the enrollment of approximately 1,000 patients in 160 centers across North America, Europe, Argentina and Israel.

The results of the initial nine-month, randomised, double-blind, parallel-group Phase II study were presented at the 58th Annual Meeting of the American Academy of Neurology (AAN) in San Diego, CA, April 1-8, 2006. Patients taking the higher dose of GA had a 38 percent greater reduction in mean cumulative number of gadolinium (Gd)-enhancing lesions as measured by magnetic resonance images (MRI) of the brain compared with those taking the COPAXONE^® (GA) 20 mg/day dose. In addition, compared to annual relapse rate prior to entry, patients taking GA 40 mg/day experienced a reduced mean on-trial relapse rate of 77 percent whereas patients taking COPAXONE^® (GA) 20 mg/day experienced a 62 percent reduction. GA 40 mg/day was well-tolerated with a safety profile similar to the currently COPAXONE^® (GA) 20 mg/day.

"The Phase II study results are very promising and suggest that the established efficacy of COPAXONE^® can be increased even further with this next generation of GA," said Israel Makov, President and Chief Executive Officer of Teva Pharmaceutical Industries Ltd. "The initiation of the FORTE study is part of our commitment to MS patients to develop improved therapies that combine superior efficacy and excellent safety," Makov added.

About the Study

The FORTE study is a 12-month, multinational, multicenter, randomised, parallel-group, double-blind study. Patients will be equally randomised into one of two groups: 40 mg GA once daily or COPAXONE^® (GA) 20 mg once daily. The study objectives include comparing the efficacy and safety of daily subcutaneous injections of 40 mg/day GA to that of COPAXONE^® (GA) 20 mg/day in RRMS patients. Confirmed relapses and adverse events will be monitored throughout the study. Patients completing the 12-month phase will continue in the study for an additional 12-month, open-label phase in which all subjects will receive 40 mg/day GA.

Source: Teva Pharmaceutical Industries Ltd.

The treatment regime, consisting of a limited course of mitoxantrone (an immunosuppressant normally used to treat cancer) followed by long-term glatiramer acetate (Copaxone - one of two classes of disease modifying drugs for use in relapsing-remitting multiple sclerosis), has proven so successful in this early trial that a full controlled study is now being initiated at 10 centres across the UK to examine the combination further. Investigators are now looking to enrol suitable patients with MS.

In this 'open' trial the combination was found to provide a rapid and sustained suppression of relapses in MS patients experiencing frequent, recurrent and disabling attacks (90% reduction in annualised relapse rate maintained, to date, for a mean of 36 months). It was also shown to improve, or at least stabilise, existing levels of disability in the 27 patients who had extremely active forms of the disease. Follow up in early patients now extends to over 5 years.

The patients treated with this new protocol, developed by a research team at the Walton Centre for Neurology and Neurosurgery in Liverpool, had all been diagnosed with Relapsing Remitting MS for less than 5 years and showed clear signs that their disease was likely to progress quickly producing early and severe disability.

Dr Mike Boggild, Consultant Neurologist at the Walton Centre and principal investigator of this research commented: "This novel treatment regime has proved remarkably effective in a group of patients with early MS and a poor prognosis. Though there are certain risks, associated particularly with the use of Mitoxantrone, we have been able to limit these by using this agent for just a short 'induction' period and, balanced against the high risk of early disability for these patients, the outcomes we have seen appear to justify this approach. The effect is so striking that we suspect the two drugs may be acting synergistically"

Karen Ayres, 28 from Warrington is a patient who has benefited from the new treatment protocol. She said: "Lying paralysed in hospital, I truly believed that I would never get the chance to travel again, let alone go back to university to study. Without mitoxantrone and Copaxone treatment, I simply don't think it would have been possible - it is not an exaggeration to say that I feel as though the treatment has given me my life back. I have been able to take up my beloved backpacking again and I am currently studying for a PhD. MS really doesn't spell the end of your life"

Mitoxantrone, the first immunosuppressant to be approved by the United States Food and Drug Administration (FDA) for use in MS, has previously been shown in randomised controlled studies in the US to reduce relapses in MS, but due to its potential toxicity its use is limited. Previous attempts to extend its effectiveness with subsequent use of interferon-beta have been disappointing, so researchers at the Walton Centre decided to use the alternative class of disease modifying drug, glatiramer acetate (Copaxone).

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In the study, which appears in the current edition of Acta Neurologica Scandinavica, about three quarters of the patients in both groups saw their annual relapse rates reduced by Copaxone.

In addition, 69.5 percent of the new patients and 68.4 percent of those who had previously taken Betaseron remained relapse free for the study's entire 3 1/2-year duration, researchers said.

The relapse rates of the Copaxone patients were compared to their reported relapse rates over the two years prior to entering the study.

"This study showed that it would be a very good idea to switch patients to Copaxone if they are not doing well on Betaseron for whatever reason, be it tolerability or efficacy," Dr. Howard Zwibel, medical director of the Baptist Health Doctors Hospital Multiple Sclerosis Center in Coral Gables, Florida, said in an interview.

Zwibel, who was the study's lead investigator, cautioned that the study did not demonstrate the superiority of one drug over another. But if patients are not doing well on the interferon drug Betaseron, "about three quarters are going to do exceedingly well" on Copaxone, he said.

The 247 patients in the study who had failed on Betaseron received Copaxone for an average of 14.8 months, while the 558 new, or treatment-naive patients, were treated for 20.3 months.

"The 247 patients who had been on Betaseron and stopped, when they were changed over they did as well as the new patients who were placed on Copaxone," Zwibel said.

Copaxone, known chemically as glatiramer, does not have many of the side effects associated with interferon drugs, such as flu-like symptoms, headaches and potential liver toxicity issues.The most common side effect in the Copaxone study was mild or moderate local injection-site reactions.

Copaxone, Teva's most important branded drug, saw sales jump 29 percent to $329 million in the first quarter of 2006.

Relapsing-remitting multiple sclerosis is the most common form of the disease in which patients have attacks demonstrated by physical symptoms that can then improve with medication.

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Israel-based Teva said the study of patients with relapsing-remitting MS found that Copaxone reduced their annual relapse rate by an additional 57 percent over Avonex, and that neurologic disability did not worsen in 86 percent of patients.

Officials at Biogen Idec, based in Cambridge, Massachusetts, could not be immediately reached for comment.

Both drugs are approved to treat relapsing-remitting MS, the most common form of the disease, which causes a progressive disability that can include blurred vision, weakness, poor muscle coordination and loss of memory and mental function as nerves lose their insulating sheath.

The study involved 85 patients who had been treated with Avonex for at least 18 months before relapsing or experiencing intolerable toxicity. They were then switched to Copaxone and followed for an additional 36 to 42 months.

The results were published in the June issue of the European Journal of Neurology.

Dr. Omar Khan, associate professor of neurology at Detroit's Wayne State University and senior author of the study, said the results suggest that observation of relapse rates, patient tolerability, and toxicity assessment are valuable for determining when therapy should be switched.

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This study represents the only prospective, open-label follow-up of more than 10 years' duration designed to evaluate continuous immunomodulatory therapy in RRMS patients. The study has been extended to 15 years.

"COPAXONE(R) provides RRMS patients with a treatment option that has demonstrated long-term efficacy and safety," said Corey Ford, M.D., PhD, Associate Professor of Neurology, Director of the Multiple Sclerosis Specialty Clinic and Medical Director of Pharmacy at the University of New Mexico Health Sciences Center and an investigator in the study. "Results of the study are consistent with the presumed mechanism of action of COPAXONE(R), which appear to treat inflammation and neurodegeneration, the underlying pathologies of multiple sclerosis."

Patients who remained in the study and were on COPAXONE(R) had a relapse rate reduction of more than 80 percent over a mean of 10 years in the trial. On average, patients experienced only one relapse every five years compared to an average of 1.18 attacks a year before entering the study.

A favourable safety profile was maintained over the course of the study. The most common adverse events associated with COPAXONE(R) were local injection-site reactions and immediate post- injection reactions. No other immune- mediated disorders, infections, or malignancies were reported.

This study of COPAXONE(R) (glatiramer acetate injection) in 251 RRMS patients began in 1991 as a double-blind, placebo-controlled trial in which patients were randomised to receive either COPAXONE(R) 20 mg or placebo by subcutaneous injection daily for a mean of 30 months. A total of 232 patients (125 COPAXONE(R) and 107 placebo, the modified intent-to-treat cohort, or mITT) were evaluated in this analysis.

After double-blind treatment, all patients were offered COPAXONE(R) as part of an ongoing, prospective, open- label study. All of the original 11 U.S. study sites participated, and these patients were evaluated every six months. Patients were also examined, usually within seven days, if they experienced symptoms suggestive of a relapse. After 10 years, 108 patients of the 232 remained in the study on COPAXONE(R).

Investigators looked at the percentage of patients who progressed to Kurtzke Expanded Disability Status Scale (EDSS) 4 -- a stage at which they were still ambulatory despite moderately severe disability; EDSS 6 -- a level at which a cane, crutch or brace is required for mobility; and EDSS 8 -- a state in which the patient is wheelchair-bound.

At the start of COPAXONE(R) treatment, patients had an average EDSS score of 2.79. At 10 years, the ongoing patient group on COPAXONE(R) showed significantly decreased accumulation of disability, with 24 percent of patients reaching EDSS 4, eight percent reaching EDSS 6 and only one percent reaching EDSS 8 compared with 68 percent, 50 percent and 10 percent respectively in the withdrawn with long-term follow-up visit (LTFU) cohort.

The 50 patients who withdrew from the trial and returned for the 10-year LTFU showed significantly increased disability compared with ongoing patients treated with COPAXONE(R). The mean increase in EDSS score was 2.24 points in those patients who withdrew compared with a 0.50 point increase in patients remaining on COPAXONE(R) (p<0.0001). Similarly, 62 percent of the ongoing COPAXONE(R) patients had stable or improved EDSS scores.

"The results from this trial and the fact that patient safety was maintained over time make these data clinically useful for the MS community," said Ford. "No other immunomodulatory agents used to treat multiple sclerosis have been followed continuously for as long as COPAXONE(R)."

After a mean of 10 years, patients who continued COPAXONE(R) treatment showed significantly less disability than those who withdrew from the study and returned for the long-term follow-up visit. This was evaluated using the EDSS.

"COPAXONE(R) was shown to maintain efficacy over the long term. As a group, the patients who remained in the study had no significant changes in EDSS -- even after 10 years of treatment," said Ford.

Source: Teva Pharmaceutical Industries Ltd.

According to study chairman, Fred D. Lublin, M.D., Saunders Family Professor of Neurology at Mount Sinai School of Medicine-Corinne Goldsmith Dickinson Center for Multiple Sclerosis, "This is a very important trial because, if effective, combination therapy will allow us to take advantage of these agents that have different and complementary mechanisms of action to slow or halt progression of MS."

An estimated 400,000 Americans suffer from MS, a chronic neurological disease that affects the central nervous system. MS is most commonly diagnosed in young adults. Relapsing-remitting MS, the most common form of new cases of the disease, is characterized by episodes of attacks of neurologic dysfunction, which occur over many years.

Approximately 130,000 MS patients are receiving either FDA-approved interferon beta-1a weekly (Avonex^®) or glatiramer acetate daily (Copaxone^®) to treat relapsing forms of MS. However, because these agents provide only a partial amelioration of the risk for additional attacks and development of disability, there is a major and continuing need for better therapies. As yet, there is no cure for MS.

CombiRx will determine whether the combination of these treatments is more effective than either treatment alone. This trial is unique among placebo controlled studies, in that none of the participants will receive placebo alone. All participants will receive at least one active, FDA-approved treatment. Specifically, 50% will receive the combined investigational therapy, 25% will receive interferon beta 1-a weekly plus a daily placebo, and 25% will receive glatiramer acetate daily plus a weekly placebo.

In addition to CombiRx, participants will be offered the opportunity to volunteer for another study known as Biomarkers in MS. This study is designed to determine if there are specific genes and proteins that can predict the course and progression of MS. More importantly, this study may allow identification of markers that may be useful in distinguishing which MS patients may respond to specific treatments. According to Dr. Henry McFarland, Clinical Director, NINDS, "As with the data from the CombiRx Trial, the implications of the Biomarkers in MS Study could be enormous, both for the individual patient as well as for the costs associated with MS treatment and hence the health care providers and the general public."

One thousand patients are being recruited for these studies at approximately 80 sites across the US and Canada.

Men and women between 18 and 60 years of age who have been diagnosed with relapsing-remitting MS and who have not previously taken interferon beta-1a weekly (Avonex^®) or glatiramer acetate daily (Copaxone^®) may be eligible to participate in both studies. Participants will be randomly assigned to one of the three study groups and will receive treatment over 36 months. Clinic visits will be scheduled every three months throughout the treatment period to assess the impact of treatment.

Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

A new, higher dose of Copaxone^® (glatiramer acetate injection) showed promising results in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). A 9-month, randomized, double-blind, parallel-group phase II study of 90 patients comparing a 40 mg dose of Copaxone® to the currently approved 20 mg dose showed a 38% greater reduction in mean cumulative number of gadolinium (Gd)-enhancing lesions as measured by magnetic resonance images (MRI) of the brain in patients taking the higher dose compared with those taking the 20 mg dose. In addition, patients taking Copaxone® 40 mg experienced a reduced mean on-trial relapse rate of 77% when compared to annual relapse rate prior to entry, as compared to 62% with Copaxone^® 20 mg.

These study results were announced as a Late Breaking Science platform presentation at this year's 58th Annual Meeting of the American Academy of Neurology (AAN) in San Diego, CA, April 1-8, 2006.

"These results suggest that a 40 mg dose of Copaxone® may provide even better control of disease activity within the central nervous system than the currently approved 20 mg dose," said Jeffrey A. Cohen, Director of the Experimental Therapeutics Program at the Cleveland Clinic's Mellen Center for MS Treatment and Research and Coordinating Principal Investigator of the study. "The higher dose showed promise in terms of providing additional treatment benefits to RRMS patients, paving the way for additional research on this increased therapeutic dose of Copaxone^®."

Data from this study demonstrated that Copaxone^® 40 mg was well-tolerated with a safety profile similar to the currently available 20 mg dose. The efficacy and safety of the approved 20 mg dose of Copaxone® have been well established by three pivotal trials and over a decade of experience and clinical research.

"Following these results, we are planning to conduct a large-scale Phase III study designed to confirm the higher efficacy of Copaxone^® with the increased dose. The Phase III study is expected to be launched in the second half of 2006," said Israel Makov, President and Chief Executive Officer of Teva Pharmaceutical Industries Ltd. "This study is part of our strong clinical development program in MS - a program designed to help MS patients and improve their quality of life."

Study Design and Results

The study was a randomized, double-blind, parallel-group study conducted at 18 centers in the U.S. in 90 patients with RRMS. The study evaluated the effect of 40 mg of Copaxone^® versus 20 mg of Copaxone® on disease activity as measured by MRI and clinical relapses, as well as the safety and tolerability of the 40 mg dose over a period of 9 months. Patients that qualified for this study had clinically-definite MS, had experienced a relapse in the previous year, had at least one Gd-enhancing lesion at screening visit, and had a Kurtzke Expanded Disability Status Scale (EDSS) score of 0-5. Patients were randomized in equal numbers to receive either 40 mg or 20 mg of Copaxone®. All patients underwent an MRI at baseline, and then at months 3, 7, 8 and 9. Neurological examinations were performed at screening, baseline, and again at months 3, 6 and 9, and suspected on-trial relapses were confirmed at an unscheduled visit within 7 days. The difference between the two treatment arms was assessed using a Poisson regression model accounting for potential differences in study-site and in baseline gadolinium (Gd)-enhancing lesion counts.

Copaxone^® 40 mg showed a 38% greater reduction of inflammatory disease activity as measured by mean cumulative number of Gd-enhancing T1 MRI lesions versus Copaxone® 20 mg (p=0.0898). The benefit of the 40 mg dose was observed in as soon as 3 months (p=0.005) through MRI measurement. When compared to baseline numbers, the risk of having MRI activity (Gd-enhancement) in the 40 mg group at months 7, 8 and 9 was reduced by 75% (p less than 0.0001), compared to 65% in patients receiving the 20 mg dose (p less than 0.0001).

Relapse rates were also lower in patients who received the 40 mg dose of Copaxone^®, when compared to those who received 20 mg dose (0.34 versus 0.57, respectively). Patients on 40 mg dose of Copaxone® experienced a reduced on-trial mean relapse rate of 77% when compared to the annual relapse rate prior to entry, versus patients who received the 20 mg dose (62% reduction). The time to the first relapse was significantly delayed from 80 days in the 20 mg group to 213 days in the 40 mg group (p=0.0367).

Source: Teva Pharmaceutical Industries Ltd.

For many years, multiple sclerosis (MS) patients have been waiting for a more convenient drug delivery method. To date, these medicines, which reduce and relieve the symptoms of MS, were delivered intravenously, which is not a pleasant process.

In 2000, it looked like Teva was going to change the situation when it embarked on clinical trials for an oral version of its MS therapy, Copaxone (glatiramer acetate).

Today, Teva announced that results of the oral drug trials, carried out in 2000-2004, did not yield results as significant as those for the existing version of the injectable drug. For this reason, Teva and its development partner, Danish company H. Lundbeck A/S, have decided to stop tests of oral Copaxone. The final results of the clinical trials that led to this decision were submitted to the companies only this month.

Copaxone is currently Teva's only blockbuster ethical drug, though this may change, as Agilect (rasagiline) for treatment of Parkinson's disease will be released shortly. Copaxone sales crossed the $1 billion mark for the first time in 2005, and it continues to be Teva's most profitable drug.

It should be noted that Teva is not completely shutting down development of alternate deliver forms for Copaxone. Teva's cooperation with Sweden's Active Biotech for the development and marketing of oral MS therapy Laquinmod is still ongoing. This partnership was formed in June 2004, and various clinical trials of the drug were conducted in 2005.

Source: globes Online © Copyright of Globes Publisher Itonut (1983) Ltd. 2006

Clinical research data, published in the journal Multiple Sclerosis, provided evidence that Copaxone ( Glatiramer ) may offer protection from axonal injury and induced neuronal metabolic recovery in patients with relapsing remitting multiple sclerosis ( RRMS ).

In a pilot study of 18 RRMS patients using brain imaging techniques, Copaxone was found to produce significant increases in n-acetylaspartate/creatine ( NAA/Cr ) ratio, an indicator of neuron and axon integrity, compared to four untreated control patients after one year of treatment.

This increase was maintained at two years of follow-up.
Additionally, patients treated with Copaxone showed a significant 50 percent reduction in relapses compared to baseline ( p<0.001 ) while relapse rate in the untreated group remained unchanged.

"The increases in NAA/Cr ratios with Copaxone suggested sustained beneficial effects on cerebral axonal recovery. We believe this indicates a potential for improved electrical conduction pathways in the brain, supporting the emerging concept that, centrally, Copaxone may be acting as a neuroprotective agent," said Omar Khan, director of Multiple Sclerosis Center, Wayne State University.

"This data is of critical significance because axonal transection is a well-known feature of active multiple sclerosis lesions and represents an irreversible stage of the disease process," said Khan.

Twenty-two treatment-naïve RRMS patients were included in the study.

Baseline neurological assessments and magnetic resonance spectroscopy imaging ( MRSI ) scans were performed.
Eighteen patients were treated with Copaxone ( Glatiramer ) and followed for two years with neurological assessments every six months and MRSI scans annually.

Due to needle phobia, four patients elected to remain untreated and were followed using the same assessment and MRSI schedule.

NAA/Cr ratio measurements were obtained in a selected volume of interest ( VOI ) within the brain and included normal-appearing white matter ( NAWM ) within the VOI.

In the Copaxone group, the NAA/Cr levels within the VOI were significantly increased by 9.1 percent at year one and by 10.7 percent at year two, compared to baseline ( p=0.03 for both assessments ).

Conversely, in the untreated group, a 5.5 percent decrease in NAA/Cr levels was observed in the VOI at year one ( p=0.04 ) and an 8.9 percent decrease at year two ( p=0.03 ).
Copaxone patients also demonstrated a 5.4 percent and 7.1 percent increase in NAA/Cr ratios within the NAWM at years one and two, respectively ( p=0.04 for both ).

Untreated patients had a two percent ( p=n.s. ) and 8.2 percent ( p=0.03 ) decrease in NAA/Cr ratios within the NAWM at year one and two, respectively.

"We recognize our study contains limitations, such as the number of patients, open-label design, and the MRS technique of evaluating NAA levels," stated Khan. "However, our three-year data showed sustained improvements in NAA/Cr ratios which clearly demonstrated a long-term clinical benefit and showed that Copaxone treatment may lead to neuronal recovery," said Khan.

Copaxone is a selective MHC class II modulator.

Copaxone is indicated for the reduction of the frequency of relapses in relapsing remitting multiple sclerosis.

The most common side effects of Copaxone are redness, pain, swelling, itching, or a lump at the site of injection, weakness, infection, pain, nausea, joint pain, anxiety, and muscle stiffness.

Source: Teva Pharmaceutical, 2005

Glatiramer acetate (Copaxone) treatment of children with multiple sclerosis is safe, with a safety profile similar to that found among adults, researchers reported here on September 29^th at the 21^st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

"Children get multiple sclerosis, and we found in this study children can be treated with multiple sclerosis in the same way adults can be treated," said lead investigator Lauren Krupp, MD, Professor of Neurology and Director, National Pediatric Multiple Sclerosis Center, State University of New York Medical Center, Stony Brook, New York.. "We found that they can be treated equally safely with Copaxone, or glatiramer acetate."

The investigators conducted a retrospective chart review of 16 girls and 11 boys with a mean age of 12.2 years at onset of relapsing remitting multiple sclerosis (RRMS) who were diagnosed at or before age 18 years. They included subjects from five North American sites.

Subjects received off-label treatment with glatiramer acetate 20 mg/day, injected subcutaneously daily for a mean of 20.0 months (range, 2.0 to 60.0 months). Patients started glatiramer acetate treatment at mean age of 14.1 years and at a mean of 13.2 months post-diagnosis.

Sixty-four adverse events were reported among 17 patients. Less than 6% of reported adverse events resulted in temporary or permanent discontinuation of therapy after a mean of 14.8 months on glatiramer acetate.

Most frequently reported adverse events were comparable to the adult data, and they included injection site reactions in 8 patients (23.4%), skin reactions in 2 patients (12.5%), bronchitis in 4 patients (6.3%), and dyspnea in 3 patients (4.7%).

There was no evidence of abnormal laboratory values or vital signs.

"In summary," the authors wrote in their abstract, "[glatiramer acetate] was extremely well tolerated."

The researchers calculated the annual relapse rate for the patients who had at least 12 and 24 months of pre- and post-treatment data. They observed a 56% decrease in the frequency of relapse in the first 12 months and a 58 % decrease in relapse frequency was seen for the smaller subset in the patients for whom 24-months post-treatment data was available.

Dr. Krupp concluded, "This medication, which is safe in adults, is equally safe in children. The clinical implication is that it's safe, so use it."


Presentation title: Safety and Tolerability of Copaxone(R) in Paediatric Patients With Relapsing-Remitting Multiple Sclerosis. Poster 332

Study represents extensive, continuous clinical experience with immune modulating therapy

Clinical experience and study data with COPAXONE® (glatiramer acetate injection) in relapsing-remitting multiple sclerosis (RRMS) patients with active disease (mean annual relapse rate of 2.9) now span more than a quarter of a century. In a long-term, open-label, compassionate use study of up to 26 years (prior to any immune modulating therapies approved by the Food and Drug Administration (FDA)), presented at the 21st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), clinical efficacy and safety data demonstrated reductions in relapse rates, slowed disease progression, and continued tolerability of COPAXONE®.

"To see the long-term positive impact on disease progression in these patients on COPAXONE®, is very helpful for clinicians and patients making treatment decisions, especially since long-term data with other therapies are scarce," said Dr. Aaron Miller, professor of neurology, Department of Neurology, Mount Sinai School of Medicine, New York, and lead investigator on the study. "Long-term data reinforcing the clinical utility, such as this experience with COPAXONE®, can be reassuring for patients and physicians when making treatment choices."

The author reported the long-term clinical experience in 46 RRMS patients treated with COPAXONE® for 1-26 years (average 10.5 years). Assessment of clinical effectiveness included annual relapse rates and Extended Disability Status Scale (EDSS) scores.

Safety was determined by reports of adverse effects. Patients were seen every six months. Of the original 46 patients, 18 remain active in the study, and of the 28 who withdrew, patient decision to withdraw was the most common reason (54 percent).

At entry, based on a patient's entire history, mean annual relapse rate was 2.9 +/- 1.4 (range: 1-7). At last clinical observation, mean annual relapse rate for 24 of 42 patients on COPAXONE® (glatiramer acetate injection) was reduced (0.1 +/- 0.2, p less than 0.0001). In terms of EDSS, 24 of 42 (57%) patients had improved or unchanged EDSS scores at last observation compared to pretreatment entry of 3.0 +/- 1.8 (range: 0-6.5). Over the long course of the study, a non-significant change in average EDSS score was observed (3.0 +/- 1.8 at entry vs. 3.8 +/- 2.5 at last observation). Only 8 of 34 (23.5%) patients with entry EDSS scores less than six, progressed to an EDSS score of six or more with average disease duration of greater than 17 years. For those patients remaining in the study (at the time of data cut-off for this abstract, n=18) with average disease duration greater than 24 years, only 26.7 percent progressed to EDSS greater than or equal to six. This compares favorably to a natural history cohort, which shows 50 percent progressing to six or greater at 15 years after disease onset. Long-term COPAXONE® therapy was well tolerated, and patients reported adverse events similar to those experienced in short-term trials.

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