Siponimod Reduced Progression in Secondary Progressive Multiple Sclerosis in a Phase 3 Trial

Results of a double-blind, randomized, phase 3 trial, published last week in The Lancet, show that siponimod—a selective sphingosine 1-phosphate (S1P) receptor modulator that may directly prevent degeneration of nerve fibers, suppress the autoimmune response that is causing damage, and promote recoating of nerves—slowed the progression of disability in secondary progressive multiple sclerosis (MS), a severe form of MS for which there is currently no treatment that prevents progression and disability.¹

The trial, conducted at 292 sites in 31 countries, ultimately included 1645 patients with secondary progressive MS and an Expanded Disability Status Scale score of 3.0 to 6.5. Patients received 2 mg per day of either the study drug or a placebo for up to 3 years or until their disability progressed after 6 months. Patients had their disability levels assessed every 3 months, as well as MRI scans at baseline, 12, 24, and 36 months.

In total, 1099 received siponimod and 546 received the placebo; 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study.

At baseline, the mean time since the first MS symptoms was 16.8 years (standard deviation [SD] 8.3) and the mean time since MS converted to a secondary progressive presentation was 3.8 years (SD 3.5). A majority (64%) of patients had not relapsed in the prior 2 years, and 56% needed walking assistance. The study’s primary endpoint was time to 3-month confirmed disability progression (CDP).

The study found the following:

• 288 (26%) of patients receiving siponimod and 173 (32%) patients receiving placebo had 3-month CDP (HR, 0.79; 95% CI, 0.65-0.95; relative risk reduction, 21%; P =.013).
• Adverse events (AEs) occurred in 89% of patients in the siponimod arm and 82% of patients in the placebo arm, and serious AEs were reported for 18% of patients in the siponimod arm versus 15% of patients in the placebo group.
• Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular edema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo.
• From the baseline to 24 months, the reduction in brain volume was less severe for patients in the siponimod arm.

The researchers concluded that siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators, and is likely to be a useful treatment for patients with secondary progressive MS.

“So far, no drug has consistently reduced disability progression in people with secondary progressive [MS]. These patients often have a high level of disability, and preventing further progression is important for their quality of life,” said lead author, Ludwig Kappos, MD, of the University of Basel, Switzerland, in a statement. “Although the effects of the drug on disability progression after [3] and [6] months are impressive, our study does not yet look at the long-term effects of siponimod, which we are investigating in the long-term follow-up of the study patients.”

In a linked article, however, Luanne Metz, MD, of the University of Calgary, Canada, expressed reservations about the study’s findings: “Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small. In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome are disappointing results and do not suggest that siponimod is an effective treatment for [secondary progressive MS]. Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial.”

References

1. Kappos L, Bar-Or A, Cree BA, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Published online March 22, 2018. Lancet. doi: 10.1016/S0140-6736(18)30475-6.

2. Metz LM, Liu WQ, Effective treatment of progressive MS remains elusive. Published online March 22, 2018. Lancet. doi: 10.1016/S0140-6736(18)30426-4.