COPAXONE® - the leading Multiple Sclerosis Therapy

What is COPAXONE®?

COPAXONE®, Teva's first major innovative drug, is the leading multiple sclerosis treatment.

COPAXONE® (glatiramer acetate) is a standardized, randomized mixture of synthetic polypeptides consisting of the four naturally occurring amino acids�L-alanine, L-glutamine, L-lysine, and L-tyrosine.(The GLAT of glatiramer is made up from the first letter of these four amino acids). It was originally discovered by Professor Sela, Professor Arnon and Dr. Teitelbaum at the Weizmann Institute of Science in Israel. Teva was granted world-wide exclusive license for COPAXONE® and became the developer of the product.

What is Multiple Sclerosis?

Multiple sclerosis (MS) 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").

Worldwide, MS is thought to affect more than 2.5 million people. MS is most often diagnosed in people between the ages of 20 and 40, and women are almost two to three times more likely to develop it as men. The progress, severity, and specific symptoms of MS are unpredictable and vary from one person to another.

COPAXONE® is a once daily, subcutaneous injection available as a pre-filled syringe. COPAXONE® is indicated for the treatment of patients who have a experienced a well defined first clinical episode and are determined to be at high risk of developing clinically definite MS, as well as for reduction of the frequency of relapses in patients with relapsing-remitting multiple sclerosis ("RRMS"). It is a class of modifying therapy with a dual mode of action that offers MS patients a different treatment concept.

Clinical efficacy of COPAXONE®

COPAXONE® is the first, and currently the only, non-interferon immunomodulator available for the treatment of RRMS. The science behind COPAXONE® has been developed over many years.

In three pivotal clinical trials it has been demonstrated that daily subcutaneous injection of COPAXONE® significantly reduces the relapse rate, Magnetic Resonance Imaging (MRI)-activity and burden of disease.

In the first trial, a single center, double-blind, placebo controlled trial with 50 patients, led by Professor M. Bornstein in the US, a 75% reduction in relapses was observed for COPAXONE® treated patients versus placebo.

The second trial was a 2-year, multi-center, randomized, double-blind, placebo controlled trial and was performed in eleven US centers involving 251 patients. This study was led by Professor Kenneth Johnson, Chairman of the Department of Neurology, University of Maryland Medical Center, Baltimore. In this trial, the mean relapse rate over 2 years was significantly reduced in the COPAXONE® group (29%) compared to the placebo group.

The third trial, a double-blind, multi-center, multi-country MRI study, involved 29 MS Centers in six European countries and Canada, with the participation of 239 patients. This study was led by Professor G. Comi, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, the University of Milan. This study also established COPAXONE®'s efficacy in reducing inflammation as measured by the number of brain lesions, as detected through magnetic resonance imaging ("MRI"). Treatment with COPAXONE® showed a significant reduction (29%) in the total number of enhancing lesions compared with placebo and 33% reduction in relapse rate was also observed for the COPAXONE® group versus placebo.

Results recently presented from the U.S. pivotal trial - Johnson trial, extended as an open-label trial to 15 years (making it the longest continuous study ever of patients with RRMS) demonstrate that in patients who continue to inject COPAXONE® for an average of 15 years, the number of attacks was reduced to an average of one attack every five years, and more than 80% of patients continue 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.

In 2007, results from three studies directly comparing the clinical and MRI outcomes of high dose interferon beta and COPAXONE® sponsored by manufacturers of interferon beta products were presented in Lancet (October 2008). The BECOME, BEYOND and REGARD studies, which collectively involved over 3,000 RRMS patients, were designed to demonstrate the superiority of interferon beta over COPAXONE®, but failed to do so in any of the various primary endpoints. Moreover, the REGARD study comparing COPAXONE® and Rebif® 44mcg showed that COPAXONE® was superior to Rebif® 44mcg in slowing the rate of brain shrinkage (atrophy).

The PreCISe study, a phase III, randomized, placebo-controlled, double-blind Teva-sponsored study, showed that clinically isolated syndrome patients treated early with Copaxone® had a 45% reduction in the risk of developing clinically definite MS. Of the patients who developed clinically definite MS, the time to clinically definite MS was more than doubled, from 336 days for patients given a placebo to 722 days for patients treated with Copaxone®. Based on the results of the PreCISe study, the FDA approved in March 2009 an expanded indication for Copaxone® to include the treatment of patients who have experienced a first clinical episode and have magnetic resonance imaging features consistent with MS. The FDA's approval followed a similar decision by the United Kingdom's Medicines and Healthcare Products Regulatory Agency in February 2009 to expand the label for Copaxone® to include the treatment of CIS patients suggestive of MS. This approval also includes 24 European countries that take part in the MHRA mutual recognition procedure. Approval for an expanded label for Copaxone® was also granted by the Australian Health Authority in December 2008.

Unique Mechanism of Action of COPAXONE®

The current understanding of COPAXONE®'s mode of action 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 and increases the production of factors that enhance neuronal repair. It has also been demonstrated that COPAXONE® increases the concentration of the metabolite NAA (N-acetyl aspartate), a marker that correlates with integrity of the axons, and that this effect is sustained over six years.

Marketing and Distribution

COPAXONE® was first launched in Israel in December 1996, followed by the United States in March 1997 and gained European Union approval in 2001. To date, COPAXONE®has been approved for marketing in 52 countries worldwide, including the United States, all member states of the European Union, Argentina, Australia, Brazil, Canada, Israel, Mexico, Norway, Switzerland and Russia.

In North America, COPAXONE® is marketed and distributed by TEVA Neuroscience, Inc. Patients continue to benefit from the many resources available from Teva Neuroscience, including the COPAXONE® and Shared Solutions websites. These provide individuals with disease information on Relapsing Remitting Multiple Sclerosis (RRMS), the impact it can have on lives and the opportunity to connect with an MS Peer or an MS certified Nurse for support and answers.

In Europe, a strategic alliance was formed between Teva and sanofi-aventis in the marketing of COPAXONE®. Under the terms of this agreement, COPAXONE® is co-promoted with sanofi-aventis in Germany, the U.K., France, Spain, the Netherlands and Belgium and is marketed solely by sanofi-aventis in other major European markets, Australia and New Zealand. As of February 2012, Teva expects to gradually take over marketing responsibilities for COPAXONE® in territories covered under this agreement.

In the remaining markets where COPAXONE® is approved in Europe, Russia, Turkey, South America, Asia and South Africa, the product is marketed either by a Teva subsidiary or a Teva appointed distributor.

COPAXONE® - Global Market Leader

Global in-market sales of COPAXONE®for 2008 totaled $2,262 million, with U.S. in-market sales of $1,378 million and non-U.S. sales of $884 million. Sales for 2009 continue to increase, with record global in-market sales of COPAXONE® of $776 million for the third quarter of 2009. COPAXONE® also continues to be the leading MS therapy worldwide with a global market share of 29.8% for Q3 2009.

Towards a cure for MS

Teva's commitment to address patient needs is evident in the Company's continuous research and development of innovative, safe, effective and tolerable treatments.

Teva is committed to research and innovation to offer the best possible experience with COPAXONE® therapy. The introduction of the thinner COPAXONE® 29G needle is just one of the ways that Teva is striving to meet patients' needs for improved convenience of treatment and enhanced comfort.

The Company is also currently involved in clinical trials with Laquinimod, a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease-modifying treatment for RRMS. The ability to provide a safe and effective oral treatment option would be a significant advancement for the treatment of MS.

Teva and its marketing partners recognize that multiple sclerosis encompasses more than drug therapy alone. The company is dedicated to working with the multiple sclerosis community to develop solutions that address the far-reaching implications of the disease. As part of this commitment, Teva currently supports a variety of programs and services for the multiple sclerosis community.