Experimental Medications: New S1P Receptor Modulators
- Oral medication being studied at 20 mg per day
- Being studied in RRMS
Ponesimod is another selective S1P1 receptor modulator that completed a Phase II trial; results were reported in 2012. In this study, 462 people with RRMS were randomized to placebo or 10 mg, 20 mg, or 40 mg of ponesimod. Reductions in annualized relapse rate and reductions in new lesions were seen for all treatment groups versus placebo.
However, the 40-mg dose generated an increase in adverse events, which included swelling of the extremities and difficulty breathing. With an 83-percent decrease in gadolinium-enhancing lesions and a favorable adverse event profile, the 20-mg dose may have the best benefit-to-risk profile.
The company developing ponesimod, Actelion, further studied the efficacy and safety of the 10-mg and 20-mg doses in an extension of the Phase II trial. In October 2017, researchers presented an interim analysis of the extension trial’s findings at the ECTRIMS-ACTRIMS Meeting. They found that over the course of six years, the 20-mg dose reduced the risk of six-month confirmed disability accumulation (6 m-CDA) by about twice the extent seen with the 10-mg dose. Similarly, the annual relapse rate for the 20-mg dose was about one-half that of the 10-mg dose (0.153 vs. 0.227). The 20-mg dose also had more favorable findings on several MRI measures, including mean number of T1 gadolinium-enhancing lesions and new or enlarging T2 lesions per study subject. Meanwhile, the percentages of patients experiencing any adverse event, serious adverse events, and adverse events leading to treatment discontinuation, were largely similar between the two arms. For example, 15.1 percent of patients receiving 20 mg of ponesimod and 13.8 percent receiving the 10-mg dose had serious adverse events, while 12.2 percent of individuals in the 20-mg dose group and 10.3 percent of those receiving the 10-mg dose stopped treatment because of adverse events.53
These data suggest that the 20-mg dose may offer greater efficacy than the 10-mg dose with a comparable rate of adverse events, further refining the benefit-to-risk considerations for use of ponesimod.
The role of ponesimod in RRMS is being further evaluated in two ongoing trials, OPTIMUM and POINT. OPTIMUM is a multicenter, randomized, double-blind study comparing the efficacy and safety of ponesimod to Aubagio.54 The study aims to determine whether ponesimod is more effective than Aubagio in reducing relapses. The study seeks to enroll approximately 1,100 subjects, randomized in two groups in a 1:1 ratio to receive ponesimod at 20 mg per day or Aubagio at 14 mg per day.55
The POINT (POnesImod aNd Tecfidera) study employs a combination approach; 600 participants will be randomized either to Tecfidera alone or Tecfidera plus ponesimod to assess whether there is an added benefit in terms of disease control when the two medications are combined. The POINT study is the largest study in MS looking at a combination of oral medications.