Siponimod, a selective sphingosine 1-phosphate receptor modulator, appears to be generally safe and effective for the reduction of disability progression in secondary progressive multiple sclerosis (SPMS).1
Previous research demonstrated reduced brain lesion counts and annualized relapse rates in patients with relapsing-remitting MS treated with siponimod.2 The current phase 3 study examined the effects of siponimod in 1645 patients with SPMS. Patients were randomly assigned to receive either once-daily siponimod 2 mg (n=1099) or placebo (n=546) for up to 3 years or until confirmed disability progression. The primary end point was time to 3-month confirmed disability progression, and secondary end points included time to 3-month confirmed worsening of ≥20% from baseline in the timed 25-foot walk test and change from baseline in T2 lesion volume.
At baseline, mean time from MS symptom onset was 16.8 years, and mean time from conversion to SPMS was 3.8 years. Time since last relapse was >2 years in 64% of patients, and 56% required assistance with ambulation.
Ultimately, 82% of patients randomly assigned to siponimod and 78% assigned to placebo completed the study. Of patients in the siponimod group, 26% had 3-month confirmed disability progression compared with 32% of patients in the placebo group (hazard ratio [HR] 0.79; 95% CI, 0.65-0.95; relative risk reduction 21%; P =.013). The risk for 6-month confirmed disability progression was also reduced in the siponimod group (risk reduction 26%). Adjusted mean increase across all visits in the 12-item Multiple Sclerosis Walking Scale was 2.69 in the siponimod group vs 4.46 in placebo. In addition, annualized relapse rate (rate ratio 0.45; 95% CI, 0.34-0.59; risk reduction 55%; P <.0001) and time to confirmed first relapse were also reduced in the treatment group (HR 0.54; 95% CI, 0.41-0.70; risk reduction 46%; P <.0001), as well as increase in T2 lesion volume, decrease in brain volume, and gadolinium-enhancing lesions.
Overall, adverse events were more common in the treatment group (89% vs 82%), with 18% reporting serious adverse events in the siponimod group vs 15% in the placebo group. Common adverse events in the treatment group included lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at the time of treatment initiation, macular edema, hypertension, varicella zoster reactivation, and convulsion; frequency of infections, malignances, and deaths did not differ between groups. The investigators also noted that titration of the initial dose helped mitigate cardiac effects.
“Overall, the results of EXPAND suggest that siponimod might be a useful treatment for patients with SPMS,” the investigators concluded, noting that the drug has a similar safety profile as other drugs in the same class. Further research should focus on establishing whether siponimod exerts its effect on the pathogenic processes associated with disease progression or activity, or both, as this would help to better stratify patients for treatment.
- Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomized, phase 3 study [published online March 22, 2018]. Lancet. doi:10.1016/S0140-6736(18)30475-6
- Selmaj K, Li DK, Hartung HP, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013;12:756-767.