Data were presented in 2012 on two new investigational oral agents now in Phase II trials that have a mechanism similar to that of Gilenya (fingolimod). Both drugs were well tolerated and reduced lesions related to RRMS. It is hoped that these agents, ONO-4641 and siponimod (BAF312), will maintain or improve on the efficacy and safety of Gilenya. However, both were still associated with cardiovascular effects, such as bradycardia (slowed heart rate).
Data from a Phase II dose-finding study of siponimod in patients with RRMS were also reported in 2012. Siponimod has a relatively short half-life compared to Gilenya, which means that the drug does not stay in the body as long. Researchers hope that this will minimize cardiac issues.
The trial had a complex design whose goal was to determine the most appropriate dosing regimen. One group of 188 patients received placebo or once-daily siponimod in doses of 10 mg, 2 mg, or 0.5 mg for six months. A second group of 109 patients were given one of two additional intermediate doses of 1.25 mg or 0.25 mg for three months.
At six months, the proportion of relapse-free patients as compared to placebo was 84 percent for the 10-mg group, 92 percent for the 2-mg group, and 77 percent for the 0.5-mg group. In the placebo group, 72 percent were relapse-free. After six months, the ARR (relapse rate) was lower with the three higher doses than the two lower doses and placebo. Additionally, MRI findings indicated that treatment with siponimod was associated with a reduction in active lesions on MRI. The 2-mg dose reached statistical significance versus placebo, with a reduction in active lesions of approximately 80 percent.
In the Phase II DreaMS trial, 407 patients with RRMS were randomly assigned to placebo or one of three different doses of ONO-4641 (0.05 mg, 0.10 mg, or 0.15 mg once daily for 26 weeks). The primary endpoint was the number of T1 gadolinium-enhancing lesions on MRI; secondary endpoints included new and enlarging T2 lesions.
All three treatment groups showed a substantial decrease in MRI disease activity as measured both by gadolinium-enhancing lesion numbers and new or enlarging T2 lesions. Compared to placebo, lesion counts were reduced by 82 percent in the 0.05 mg/day group; 92 percent in the 0.10 mg/day group, and 77 percent in the 0.15 mg/day group. The study was not designed to evaluate relapse rates or disability progression, but there was a statistically significant decrease in relapse rate with the 0.10-mg dose).
Adverse events were similar to those seen with Gilenya, including bradycardia and lymphopenia (a reduction in circulating lymphocytes) in some patients. These were dose-related and did not result in drug discontinuation. More safety data will be gathered and the drug is expected to advance to a Phase III study.
Ponesimod is another selective S1P receptor modulator that completed a Phase II trial, with results reported in 2012.31 In this study, 462 patients with RRMS were randomized to placebo or 10 mg, 20 mg, or 40 mg of ponesimod. Reductions in annualized relapse rate and new lesions were seen for all groups as compared with placebo, though the 40-mg dose generated an increase in adverse events including 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 of ponesimod may have the best benefit to risk profile in this trial.