Rituxan in MS: Positive Phase 2 Results, But Phase 3 Study Stalled

Making the news rounds this morning are the favorable phase 2 efficacy results of rituximab (Rituxan; Genentech, Biogen Idec) in relapsing-remitting multiple sclerosis (RRMS). These data, published in this week’s NEJM, were originally presented in May at the 2007 annual meeting of the American Academy of Neurology by the article’s first author, Stephen Hauser, MD. So for the practicing neurologist, there is little that is actionable news here.

Nevertheless, to provide a very abbreviated Cliff Notes version of the data, rituximab—when compared with placebo—significantly reduced the mean number of active lesions on brain MRI* and the percentage of individuals who experienced clinical relapses during a 24-week period. The data compare favorably with those for the monoclonal antibody natalizumab (Tysabri; Biogen Idec, Elan) in relapsing disease, although the development of Biogen's other comarketed mAb in MS has reached postmarketing phases (Miller DH et al. Neurology. 2007;68:1390-1401; O'Connor PW et al. AAN 2007. Poster P06.082). Adverse events associated with rituximab use were not unexpected and included predictable infusion-related events, which subsided with repeated administration of the drug—also predictably.

Yet despite these positive phase 2 results with rituximab, no phase 3 trials of the mAb in RRMS are listed in the NIH clinical-trials database. The evident stalling of the phase 3 investigation of rituximab in RRMS appears to have everything to do with disagreements between Genentech and Biogen Idec regarding the continued clinical development of rituximab and another anti-CD20 mAb—specifically, ocrelizumab or "son of Rituxan."

According to a May 2007 report by thestreet.com, operating profits for rituximab are split 60-40 between Genentech and Biogen Idec, respectively. But profits for ocrelizumab will be split 70-30 in Genentech's favor, which accounts for Genentech’s enthusiasm to move ahead with the development of ocrelizumab in MS, at the expense of rituximab. Obviously Biogen has less of a financial incentive to promote the development of the second-generation mAb. Moreover, approval of a product that is considerably more effective in MS than Biogen's formulation of interferon beta (Avonex) and that is potentially as effective as rituximab or natalizumab could eat into the company's considerable profits from all 3 drugs. Avonex sales made up a whopping 60% of Biogen’s sales in 2007, while rituximab sales accounted for approximately 30% of revenue (and natalizumab, 7%).

Genentech comments on its development dispute with Biogen Idec at the pipeline web page for ocrelizumab:

Our collaborator Biogen Idec disagrees with certain of our development decisions under our 2003 collaboration agreement related to humanized anti-CD20 products. We continue to pursue a resolution of our differences with Biogen Idec. The disputed issues were submitted to arbitration in San Francisco, California. Resolution of the arbitration could require that both parties agree to certain development decisions before moving forward with humanized anti-CD20 antibody clinical trials, and possibly clinical trials of other collaboration products, including Rituxan, in which case we may have to alter or cancel planned trials in order to obtain Biogen Idec's approval.