Safety and efficacy of amiselimod in relapsing multiple sclerosis (MOMENTUM): a randomised, double-blind, placebo-controlled phase 2 trial

BACKGROUND: Patients with multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system with autoimmune pathogenesis, have shown partial response to a number of immunomodulating treatments, but the search for more effective, safe, and convenient therapeutic options continues. Amiselimod is an oral selective modulator of sphingosine 1-phosphate 1 (S1P1) receptor, which is being developed for the treatment of various autoimmune-mediated diseases. We assessed the safety and efficacy of amiselimod in patients with relapsing- remitting multiple sclerosis. METHODS: In this double-blind phase 2 trial, patients aged 18-60 years with active relapsing-remitting multiple sclerosis from 84 centres in Europe and Canada were randomly assigned (1:1:1:1) with an interactive web-response system to receive once daily oral amiselimod 0.1 mg, 0.2 mg, 0.4 mg, or placebo for 24 weeks. All study personnel, site personnel, investigators, and patients were masked to the treatment assignment during the study. The primary endpoint was the total number of gadolinium-enhanced T1-weighted lesions on monthly brain MRI scans from weeks 8 to 24. Analysis was done on the predefined evaluable population (all randomised patients who did not have any major protocol deviations, completed 24 weeks of treatment as planned, and had at least three valid post-dose MRI scans). This trial is registered with ClinicalTrials.gov, number NCT01742052. FINDINGS: Between Jan 31, 2013, and Dec 24, 2013, 536 patients were screened and 415 patients randomly assigned to amiselimod 0.1 mg (n=105), 0.2 mg (n=103), 0.4 mg (n=104), or placebo (n=103). The median total number of gadolinium-enhanced T1-weighted lesions from weeks 8 to 24 did not differ between the amiselimod 0.1 mg and placebo groups (median 1.6 lesions [range 0-132] in the placebo group vs 2.0 [0-105] in the 0.1 mg group [median difference 0.0, 95% CI -1.0 to 0.0, p=0.7517]), but was significantly lower in the two higher amiselimod dose groups than in the placebo group (0.0 lesions [range 0-35] in the 0.2 mg group [median difference vs placebo -1.0, 95% CI -1.0 to 0.0, p=0.0021] and 0.0 [range 0-30] in the 0.4 mg group [-1.0, -1.2 to 0.0, p=0.0003]). The estimated incident rate ratio compared with placebo was dose-dependently decreased with amiselimod (0.1 mg 0.53 [95% CI 0.33-0.85; p=0.0079], 0.2 mg 0.39 [95% CI 0.24-0.63; p=0.0001], and 0.4 mg 0.23 [95% CI 0.14-0.38; p>0.0001]). The incidence of treatment-emergent adverse events, including infections and cardiac disorders, were similar in the amiselimod treatment groups (59 [56%] of 105 patients in the 0.1 mg group, 69 [67%] of 103 in the 0.2 mg group, and 58 [56%] of 104 in the 0.4 mg group) to the incidence in the placebo group (66 [64%] of 103 patients); the most common treatment-emergent adverse events were headache (ten [10%], ten [10%], and ten [10%] vs four [4%]) and nasopharyngitis (nine [9%], seven [7%], ten [10%] vs eight [8%]). No serious treatment-emergent adverse event was reported for more than one patient in any group and no clinically significant heart rate reduction was observed at any amiselimod dose. INTERPRETATION: Amiselimod 0.2 mg and 0.4 mg significantly reduced the total number of gadolinium-enhanced T1-weighted lesions. The safety and efficacy profiles of amiselimod suggest that this S1P1 receptor modulator is a new potential treatment in multiple sclerosis and potentially other immune-mediated inflammatory diseases and deserves further investigation. FUNDING: Mitsubishi Tanabe Pharma Corporation.