Multiple sclerosis (MS) is a chronic debilitating disease of the central nervous system with a variable disease course. MS is characterized by inflammatory, demyelinating plaques in the central nervous system (CNS) that lead to neurological deficits. The disease is the most frequent cause of disability in young adults after car accidents with an estimated 2.5 million people worldwide affected by the disease. The disease typically occurs in people in their 20s and 30s with a mean onset at 31 years of age and women are two times more likely to have the disease than men.

Historically, MS treatment consisted of symptom control but in 1993, the first therapeutic agent that can modify the course of disease was approved (Betaseron; interferon beta-1b). Two other interferon beta formulations soon followed, Avonex and Rebif, and together with Copaxone, a drug with a different mechanism of action, these agents have revolutionized the treatment of some forms of MS from symptom control to more effective disease control. Tysabri is the latest disease-modifying drug to join the MS armamentarium. These agents have all shown that they can reduce MRI measures of disease activity, reduce the relapse rate and delay the progression of disability in a major subset of MS patients.

Although these agents have clearly demonstrated clinical benefits in patients with MS, there remains an unmet need for agents that are better tolerated and less cumbersome to administer. In addition, while currently available therapies are effective in reducing the relapse rate and slowing disease progression, they do not cure the disease nor prevent neurological damage and clinical disability in MS patients. Thus, there is a great need for more effective disease control, especially for preventing or halting neurodegeneration.

SUMMARY OF DRUGS IN DEVELOPMENT

A new wave of immunomodulatory agents are currently in clinical development for MS. Some of these are orally available while others still require injections or infusions but far less frequently. As expected, the majority of agents are being evaluated for relapsing remitting MS (RRMS) or relapsing forms of MS (which includes RRMS and secondary progressive MS or SPMS patients who are still experiencing relapses) as these are much more drug-sensitive.

As the novel oral agents come onto the market, we believe that they will erode market share from interferon beta (IFN beta), Copaxone and Tysabri. While we believe that some patients currently on IFN beta or Copaxone therapy will stay on treatment because of familiarity and observed clinical benefits, others will switch over to more user friendly agents. We believe that the pool of patients who have not responded to current therapies, estimated to be 50,000, will be coaxed to try the newer agents while newly diagnosed, or patients with clinically isolated syndromes (CIS), are far more likely to try agents that have a more patient friendly dosing regimen.

Of the novel agents in development for RRMS or relapsing forms of MS, we believe that Fingolimod will become the most dominant oral agent, although we also project that Panaclar, and to a lesser extent, Laquinimod will be used in these patients. Fingolimod is a once-daily oral agent that has shown good efficacy in reducing MRI measures of disease activity as well as significantly reducing the relapse rate. The drug has demonstrated a good safety profile thus far although the risk for infections and immunosuppression with long-term treatment is unclear. However, the reduction in relapse rate suggests that the drug is more active than IFN beta and Copaxone, and given the once-daily oral administration, the drug is projected to become widely adopted in patients with RRMS.

Of the number of injectable agents in development for RRMS, we believe that Campath will be the most widely used immunomodulator for patients with RRMS. Campath is not only the most clinically advanced but also appears to be the most effective, demonstrating impressive reductions in relapse rate and disease progression when compared against Rebif. Furthermore, since Campath is only given once a year, the delivery profile is highly advantageous and should improve patient compliance substantially. Campath however, does increase the risk for immunosuppression and was also found to increase the risk of a bleeding disorder called immune thrombocytopenic purpura (ITP) and thus, these risks need to be better defined. Despite these risks, the efficacy of Campath is likely to ensure that the drug will become an important treatment option for RRMS patients.

A novel agent called MBP8298 is currently being evaluated in SPMS patients, including those not experiencing relapses, to determine whether the drug can reduce disability of progression in these patients. The drug has shown an impressive reduction in the risk for disability progression in chronic progressive patients with the HLA-DR2 or -DR4 haplotypes in a very small phase II study. Thus, while it is still too early to tell whether the drug can delay disease progression in these patients, the possibility for a treatment of SPMS patients without relapses is exciting.

With regards to primary progressive Multiple Sclerosis (PPMS), the most difficult-to-treat subtype of MS for which no treatment is available, the inhibition of B cell activity may be an effective therapeutic strategy since there is increasing evidence to suggest that B cells play an important role in axonal death. Rituxan is in phase III studies for these patients and while Rituxan showed impressive activity in RRMS patients, it remains to be seen whether Rituxan can reduce disability progression in PPMS patients. We project a wide uptake of Rituxan in PPMS patients should the drug show that it can significantly reduce the risk of disability in these patients.

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