Multiple Sclerosis Franchise

Product	Indication	Status
Copaxone® (glatiramer acetate for Injection)	Relapsing-Remitting MS (R-R MS)	Approved world-wide. Phase IIIb/IV studies on-going, including a study with a daily 40mg dose and various combination/induction protocols. Study in CIS patients was completed successfully and is waiting for approval
Laquinimod	Relapsing MS	Phase III
TV-1102	Relapsing-Remitting MS (R-R MS)	Phase II
Various other programs		Research

Copaxone® (glatiramer acetate for injection)

Copaxone®, Teva's largest product and its first major innovative drug, is a leading multiple sclerosis ("MS") therapy. Copaxone®, indicated for reduction of the frequency of relapses in patients with relapsing-remitting multiple sclerosis ("RRMS"), is a class of modifying therapy with a dual mode of action that offers MS patients a different treatment concept.

Multiple sclerosis is a chronic disease of the central nervous system characterized by both inflammation and neurodegeneration, which are both interrelated and independent of each other. In the majority of patients, the disease is of the relapsing-remitting form, which is manifested by acute attacks (relapses) followed by recovery (remission). This recovery may be incomplete at times, resulting in a disability progression which is measured by the Expanded Disability Status Scale ("EDSS").

The science behind Copaxone® has been developed over many years, and three clinical trials (prospective, randomized and controlled) have established its efficacy and safety in RR-MS patients. The three studies include two two-year studies conducted in the U.S., which demonstrated Copaxone®'s efficacy in reducing relapses. The third study, conducted in Europe and Canada, also established Copaxone®'s efficacy in reducing inflammation as measured by the number of brain lesions, as detected through magnetic resonance imaging ("MRI"). In addition, one of the two-year studies was extended as an open-label trial to 20 years � making it the longest continuous study ever of patients with relapsing-remitting multiple sclerosis. Results published after the first 10 years showed that in patients who continue to inject Copaxone® for an average of 10 years, the number of attacks was reduced to an average of one attack every five years, and nine out of ten patients continue to be able to walk unaided. In addition, no additional safety concerns other than those reported in the pivotal studies were detected in these long-term treated patients. Results of 15 years will be presented in the 2008 ECTRIMS meeting.

An additional study was conducted in patients with Clinical Isolated Symptoms (CIS). Pre-planned interim analysis of the PreCISe trial in patients showed that treatment with Copaxone® reduced the risk of developing clinically definite MS by 45% versus a placebo, and prolonged the quartile time to disease conversion. Based on these results, Teva submitted a fine in Europe and applied for a new indication in the U.S. and Canada and file a request for marketing authorization of Copaxone® for the treatment of patients with a first clinical event suggestive of MS. Finally, data suggests that Copaxone® is beneficial not only for mild to moderate MS patients but also for aggressive recurrently relapsing patients. Several studies published in 2006 and 2007 showed that patients with rapidly deteriorating MS who received Copaxone® alone following short-term induction treatment with an immunosuppressant (mitoxantrone), or following six months of combination therapy with monthly intravenous steroids, had a pronounced and sustainable reduction in relapses and MRI-measured enhancing lesions of the brain.

In 2007, results from three direct comparative studies of high dose interferon beta and Copaxone® sponsored by third parties were presented: the BECOME study involving 75 patients; the BEYOND study involving 2,200 patients (both sponsored by Bayer-Schering); and the REGARD study involving 764 patients (sponsored by Merck-Serono). The studies measured clinical parameters such as time to first or multiple relapses, progression on the EDSS scale and various MRI measures of disease activity. All three studies, which involved nearly 3,000 RRMS patients, failed to demonstrate superiority of interferon beta over Copaxone®. They provided evidence that Copaxone® was as good as interferons in controlling the disease in the short term.

Three further studies were presented in 2007 comparing the efficacy of interferons and Copaxone® in controlling neurodegeneration in the short term. All three studies showed that Copaxone® was significantly more beneficial.

A large Phase III study entitled FORTE is being conducted to explore the greater efficacy of a new higher dose of Copaxone® (40mg/day), following positive results obtained in the Phase II study. The Phase II study showed that patients treated with the higher dose of Copaxone® had a 38% greater reduction in the mean cumulative number of brain lesions as measured by MRI compared with those treated with a 20 mg/day dose of Copaxone®, with a safety profile similar to Copaxone® 20 mg/day.

This Phase III study compares 40mg Copaxone® to 20mg Copaxone® for 12 months in 1,150 RRMS patients. Based on consultation with the FDA and the MHRA (U.K. Medicine and Healthcare Regulatory Agency), a submission for approval of the 40 mg dose, with similar labeling as that of the 20mg dose, may be based on this one-year Phase III study, with an additional one-year open-label extension where all patients will be treated with the higher dose. This study is ongoing in 20 countries, and results are expected in the third quarter of 2008.

Significant efforts have been made to investigate Copaxone®'s mode of action. The current understanding suggests that it has a dual mechanism of action both outside and within the central nervous system (where MS is active) to regulate inflammation at the site of brain lesions. In addition, it has been demonstrated in animal models as well as in MS patients using unconventional MRI techniques that Copaxone® controls neurodegeneration and enhances repair. Copaxone® reduces the number of brain lesions that evolve into permanent black holes, slows brain shrinkage (atrophy) and increases the production of factors that enhance neuronal repair. Recently, it has been demonstrated that Copaxone® slows the reduction in the concentration of the metabolite NAA (N-acetyl aspartate), a marker that is highly correlated with progression of disability in MS.

To date, Copaxone® has been approved for marketing in 51 countries worldwide, including the United States, Canada, Israel, 27 European Union countries, Switzerland, Australia, Russia, Turkey, Mexico, Brazil and Argentina. Copaxone® was first launched in Israel in December 1996, followed by the launch in the United States in March 1997 and European Union approval in 2001 through the European mutual recognition procedures. Teva is the licensee of pending patent applications directed to methods of treating MS by administering 40mg dosage forms of Copaxone®. If granted, the patents would expire in 2027.

Selected publications:

Johnson, K. et al.:Neurology (1995); 45: 1268-1276
Johnson, K. et al.:Neurology (1998); 50: 701-708
Comi,G. and Filippi,M.:Ann. Neurol. (2001); 49:290-297
Riven-Kreitman R. and Blanchette F., Multiple Sclerosis (2004);10:S81-S89
Johnson KP, Ford CC, Lisak RP, Wolinsky JS. Neurologic consequence of delaying glatiramer acetate therapy for multiple sclerosis: 8-year data. Acta Neurol Scand. (2005); Jan;111(1):42-7.
Johnson KP, Brooks BR, Ford CC, Goodman AD, Lisak RP, Myers LW, Pruitt AA, Rizzo MA, Rose JW, Weiner LP, Wolinsky JS. Glatiramer acetate (Copaxone): comparison of continuous versus delayed therapy in a six-year organized multiple sclerosis trial. Mult Scler. (2003); Dec;9(6):585-91.
Clive Hawkins, FRCP, Massimo Filippi, MD, and Nicola De Stefano, MD PhD (and the 9011 study group) Short-Term Combination of Glatiramer Acetate with IV Steroid Treatment Preceding Treatment with GA Alone Is Associated with early Suppression of MRI-disease activity in Patients with Relapsing Remitting Multiple Sclerosis (2007) submitted
Ramtahal J, Jacob A, Das K, Boggild M. Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis (2006) J Neurol.;253(9):1160-4
M. Rovaris, J. Cohen, A. Goodman, G. Comi, M. Filippi on behalf of the 9006 Study Group Results of a randomized, double-blind, parallel group study assessing safety and efficacy of 40mg vs 20mg glatiramer acetate on MRI-measured disease activity in relapsing-remitting MS (2006) abstract ENS
For further information on Copaxone®: http://www.copaxone.com/

Multiple sclerosis remains an important focus of Teva's development efforts, as Teva continues to investigate potential improvement of Copaxone® and explore other molecules as future therapies for MS.

Laquinimod

In June 2004, Teva acquired from Active Biotech the exclusive rights to develop, register, manufacture and commercialize laquinimod worldwide, with the exception of the Nordic and Baltic countries (where Active Biotech will retain all commercial rights). Laquinimod is a novel, orally bioavailable immunomodulatory compound. Teva will conduct and fund the further clinical development of laquinimod.

Two global Phase III studies, Allegro and Bravo, have been initiated in centers in the U.S., Europe, and other clinical centers worldwide. The recruitment of patients for both studies has begun. These studies have been initiated following encouraging results of two Phase II studies and after discussions with the FDA and the European Medicines Agency:

A Phase II study performed by Active Biotech showed that laquinimod, at a dosage of 0.3 mg daily, is well-tolerated and effective in suppressing development of active MRI lesions in patients with relapsing MS. Treatment over six months with 0.3 mg of laquinimod daily resulted in a 44% decrease in MRI disease activity. Patients with disease activity at the start of the study showed a decrease of more than 50%. The study also confirmed laquinimod's acceptable safety profile.
An additional Phase IIb study, conducted by Teva, completed in 2006 confirmed the efficacy and favorable safety profile of laquinimod and showed significant reduction in the rate of inflammatory disease activity and a considerable reduction in the number of clinical relapses compared to placebo at a daily dose of 0.6 mg. The majority of the patients who participated in the study continued treatment with laquinimod in an extension study. The data from the extension study further confirmed and strengthened the results from the Phase IIb study.

Selected publications:

Brunmark C. et al (2002); J Neuroimmunology ; 130 : 163-172
Polman C. et al (2005); Neurology ; 64: 987-91
Comi G. et al (2008) Lancet- in press

TV-1102

TV-1102 is a second generation antisense inhibitor of CD49d, a subunit of VLA-4 (Very Late Antigen-4) originally developed by ISIS pharmaceuticals inc (Carlsbad US) and licensed to Teva by Antisense Therapeutics Limited (Australia).

VLA-4 is a clinically validated target in the treatment of MS inhibiting the trafficking of inflammatory cells to the site of inflammation . Antisense inhibition of VLA-4 has demonstrated positive effects in a number of animal models of inflammatory disease including MS (Myers et al. J Neuroimmunol 160, p12-24, 2005).

A Phase IIa studying the safety and efficacy of TV-1102 in RR-MS patients was completed. The study showed a significant reduction of 54.4% in cumulative number of new active lesions in patients taking TV1102 for 8 weeks, compared to placebo, as measured by magnetic resonance images (MRI).