Emerging new treatmentsFriday, September 30, 2005, 14:00 - 14:30
Review of new immunomodulatory agents in the treatment of multiple sclerosisP.W. O'Connor (Toronto, CAN)
This past year has seen dramatic developments in the Phase-3 clinical trials of Natalizumab in relapsing-remitting multiple sclerosis. The two trials of monotherapy and combination therapy demonstrated robust clinical and radiologic efficacy with few side effects and a favorable impact on quality of life. Nonetheless, the development of two cases of progressive multifocal leukoencephalopathy (PML) resulted in removal of the medication from the United States market, cessation of all administration of this or similar agents and the launch of an extensive search for any other possible cases . As of this writing, the search continues. The two cases of PML were originally identified from individuals with MS treated in the combination therapy trial. A third case originally incorrectly diagnosed with a malignant brain tumor was retrospectively identified from a Crohn's disease study involving natalizumab and other immunosuppressants.
The search for an effective oral therapy in the treatment of relapsing-remitting MS continues. Four immunomodulatory agents being assessed include Laquinomod, Teriflunomide, Cladribine and FTY-720. Preliminary safety and efficacy data are in hand and all are currently in or near a Phase-3 trial. However, there exists a heightened sensitivity to the safety of these putative therapies in light of the natalizumab story.
Several novel agents are in Phase-2 development including monoclonal antibodies to IL-2, IL-12, CD-20, and chemokine receptors. However, it has become increasingly difficult to enroll patients into placebo - controlled Phase 2 studies because of concerns over the ethics of placebo arms, as well as safety. The practice of requiring enhancing lesions on entry MRI scans in Phase 2 trials, while methodologically sound, further hinders, if not cripples, recruitment in today's environment.
The results of separate ongoing Phase 3 trials of interferon beta-1b and glatiramer acetate vs. placebo in clinically-isolated syndromes are awaited with great interest. The findings of these studies may provide further proof of the hypothesis that treating milder (earlier) MS patients with immunomodulatory therapy provides for greater relative efficacy as compared to waiting for more advanced disease.
Other studies of note include normal vs. double dose interferon beta-1b , Campath vs. interferon beta-1a, combination therapy with interferon beta-1a and glatiramer acetate , and autologous stem cell transplantation with high-dose immunosuppression.
Finally, steroids have emerged as a potential disease-modifying agent in relapsing-remitting MS although further study is needed. The optimal dose and route of steroids for the symptomatic treatment of acute relapse is also under review.
Patients with progressive MS represent an under-studied population that has significant and increasing disability. Whether immune modification of any sort will be helpful in these patient groups is an open question. The results of the ongoing studies of rituximab in primary-progressive and myelin basic protein fragment in secondary-progressive MS are much anticipated.
1. It is possible that one cannot attain high efficacy through immunosuppression in MS without the risk of major adverse events, ie, there could be no 'free lunch' immunologically- speaking.
2. Going forward, the safety of putative therapies in MS will be of much greater concern than was previously the case to patients, their neurologists and regulatory agencies.