Two New S1P Receptor Modulators Pass Phase 2 Test in MS

May 7, 2012 (New Orleans, Louisiana) — Data on 2 new investigational oral agents with a mechanism similar to that of fingolimod (Gilenya, Novartis) show the drugs were well tolerated and reduced lesions related to relapsing-remitting multiple sclerosis (MS). However, both were still associated with cardiovascular effects, such as bradycardia.

Fingolimod, the first oral agent approved for use in MS, is an effective treatment, but some concerns about cardiovascular effects, particularly bradycardia and atrioventricular (AV) block after the first dose, have led torecent label changes in the United States and Europe.

The new agents, siponimod (BAF312, under development by Novartis, makers of fingolimod) and ONO-4641 (being developed by ONO Pharmaceutical), are oral selective modulators of the sphingosine-1-phosphate (S1P) receptor subtypes 1 and 5. The goal of this increased selectivity is to maintain or improve upon the efficacy seen with fingolimod while simultaneously trying to improve the safety profile.

New phase 2 results with these agents, plus additional analysis of a dose-titration strategy to reduce cardiac effects with siponimod, were presented at the American Academy of Neurology’s 64th Annual Meeting.

In the phase 2 DreaMS trial, presented during the AAN’s Emerging Science session, 407 patients with relapsing-remitting MS were randomly assigned to placebo or 1 of 3 doses of ONO-4641: 0.05 mg, 0.10 mg, or 0.15 mg once daily for 26 weeks. Patients were included if they had Expanded Disability Status Scale scores of up to 5.5, had had 2 or more relapses during the 2 years before the trial or 1 or more in the previous year, or 1 or more gadolinium-enhancing lesions within the previous 3 months.

“S1P-1 receptors are more selectively expressed in the immune system, and the goal was to try to decrease activation of other members of the S1P receptor family that are involved in cardiac, pulmonary and other functions,” said lead author Timothy Vollmer, MD, from the University of Colorado, Denver.

The primary endpoint was the number of T1 gadolinium-enhancing lesions on magnetic resonance imaging (MRI); secondary endpoints included new and enlarging T2 lesions.

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