A double-blind, randomised, phase 3 study «Kappos L, Bar-Or A, Cree BAC, ym. Siponimod versus...»1 included a total of 1551 patients with secondary progressive multiple sclerosis (SPMS) and an Expanded Disability Status Scale (EDSS) score of 3.0–6.5. A total of 1005 patients were treated withsiponimod and 546 treated with placebo. The primary endpoint was time to 3-month confirmed disease progression (CDP). The two key secondary endpoints were time to 3-month confirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25FW) and change from baseline in T2 lesion volume. The study was of median 18 months' duration.

At baseline, the mean time since first MS symptoms was 16.8 years (SD 8.3), and the mean time since conversion to SPMS was 3.8 years (SD 3.5); 1055 (64%) patients had not relapsed in the previous 2 years. A gadolinium enhancing lesion was found in 21% of the patients in both groups. A total of 918 (56%) of 1651 patients needed walking assistance. A total of 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study.

A total of 288 (26%) of patients receiving siponimod and 173 (32%) of patients receiving placebo had 3-month CDP (HR 0.79, 95% CI 0.65–0.95; relative risk reduction 21%; p=0.013). No significant difference was observed in the time to 3-month confirmed worsening of at least 20% in T25FW for the overall population (HR 0·94, 95% CI 0·80–1·10; risk reduction 6%; p=0.44) or for patients with a baseline EDSS score of 5.5 or lower. Increase in T2 lesion volume from baseline was lower with siponimod than with placebo (adjusted mean over months 12 and 24 was 183.9 mm³ vs. 879.2 mm³; between-group difference −695.3 mm³, 95% CI −877.3 to −513.3, 0<0.0001).

Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod and 445 (82%) of 546 patients receiving placebo; SAEs were reported for 197 (18%) patients in the siponimod group and 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.

Clinical comments: The drop-out rate was of median 20%. The median time for the symptoms of MS was almost 17 years for the study group and the SD 8.3 was years, therefore the age distribution was wide, exposing the population to inconsistency. Twenty-one percent of the patients had a gadolinium enhancing lesion in their baseline MRI and 36% of them had relapsed within 2 years. Therefore it is plausible to suppose that more than 20% of the patients were still in relapsing-remitting or transition phase and not yet reached secondary progressive phase. This finding risks the study to indirectness, the results are not directly transferable to the target population of SPMS patients.