It's an exciting time for MS drug development and an even more exciting time for our patients and future MS patients. In the past year, oral BG00012 was catapulted from a niche place in the MS treatment landscape to a highly prominent international position. DEFINE data presented at ECTRIMS 2011 highlighted BG00012 as a safe, effective and mostly tolerable oral medication for the reduction of MS relapses and disability. The enthusiasm generated at ECTRIMS was still spreading at the point when top line results from the second Phase III trial (CONFIRM) were released. In CONFIRM, BG00012 was not only compared to placebo, but there was also an additional arm of subjects treated with Glatiramer Acetate. BG00012's superiority over placebo in DEFINE was confirmed by CONFIRM, and while CONFIRM was not designed to compare BG00012 head-to-head to Glatiramer Acetate, it is difficult not to make the natural conclusion that BG00012 probably performed better than Glatiramer Acetate as well. While performing better than Glatiramer Acetate is a significant accomplishment, especially in light of the disappointing performance of the high-dose high-frequency interferons compared to Glatiramer Acetate in the BEYOND and REGARD studies. In CONFIRM, however, BG00012 did not have a significant effect on sustained disability as compared to placebo; this raises the question, not of whether BG00012 will be FDA approved for the treatment of MS, but rather whether it will be approved for delaying MS disability in addition to reduction of relapses. Further exploration of prespecified subgroups and post hoc analyses will be quite useful.
Race of the orals
While large amounts of new data on Terflunomide were not released, it remains in the running as an oral, mostly safe MS medication. The safety will be further characterized by release of more data from the expansive list of Sanofi sponsored trials for this medication.
Head-to-head
Alemtuzumab is the most exciting medication in the MS pipeline for the foreseeable future.The combination of a quantum leap in efficacy (50% better than Rebif) and the infrequent dosing schedule (only 5 days in a row in the first year and not again until the second year when it is given for 3 days, and then some perhaps it will not need to be re-dosed in most people), makes Lemtrada an attractive option for many physicians and patients. In the CARE--MS-1 study Alemtuzumab was found to be significantly better (55%) than Rebif in reducing relapses, but the results for disability were not significant -- probably because the Rebif treated subjects did better than in prior studies of Rebif. The results of CARE-MS-2 confirm this assumption as Alemtuzumab was superior in terms of reducing relapses (49%) as well as sustained disability (42%) as compared to Rebif (not to be mistaken for trials comparing medications to placebo). We look forward to Genzyme, a Sanofi company, releasing more information on the annualized relapse rates in the two groups and we suspect that further investigation of patient subgroups will help clinicians understand in which patients there will be ~50% reduction as compared to Rebif as opposed to ~70% reduction compared to Rebif (as suggested in prior Phase II trials).
The decision tree for newly diagnosed patients may evolve to a question of how risk averse the individual patient is. For those wanting a medication with a very long safety record (at least in psoriasis), BG00012 may be first line, while in others who want the medication with the strongest efficacy, but with some potential for the development of humoral autoimmune diseases, Alemtuzumab may be the right choice.
Beyond T cells
Ocrelizumab is a humanized version of Rituximab, a monoclonal antibody directed against B cells -- a fairly new treatment paradigm for MS. Ocrelizumab will be dosed 4 times a year with the goal of reducing relapses as well as disability. Roche is studying Ocrelizumab for relapsing MS in the mirror OPERA 1 and 2 studies, while also studying Ocrelizumab in primary progressive MS.
Daniel Kantor, MD
Medical Director
Neurologique
President
Florida Society of Neurology
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