The Sphingosine 1-Phosphate Receptor Modulator Amiselimod is Efficacious for the Treatment of Active Ulcerative Colitis: Results from a Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial

Background:
There remains an unmet medical need for active ulcerative colitis (UC) treatments. Amiselimod is an investigational oral, sphingosine 1-phosphate (S1P) receptor modulator (highest affinity for S1P1, followed by S1P5) whose immunomodulatory mechanism of action includes decreasing circulating peripheral lymphocytes. The objective of this study was to evaluate the efficacy and safety of amiselimod for the treatment of mild to moderate UC.
Methods:
Individuals aged 18 to 75 years with mild to moderate UC (modified Mayo Score [MMS], 3-8) with an endoscopic subscore of ≥2 and active disease extending ≥15 cm from anal verge were enrolled in a phase 2, randomized, double-blind, placebo-controlled trial. Patients were randomly assigned (1:1:1) to (1) amiselimod 0.4 mg once daily (QD) for 2 weeks (loading dose), then 0.2 mg QD for 10 weeks (group A); (2) amiselimod 0.8 mg QD for 2 weeks (loading dose), then 0.4 mg QD for 10 weeks (group B); or (3) placebo QD. Concomitant stable doses (≥28 days prior to randomization) of oral/rectal 5-aminosalicylate or oral corticosteroids (≤20 mg/day prednisolone dose equivalent) were permitted. The primary endpoint was change in MMS from baseline at Week 12. Secondary endpoints included patients with endoscopic improvement (Mayo endoscopic subscore ≤1) and patients with clinical remission (rectal bleeding subscore 0; endoscopy subscore ≤1 [excluding friability]; and stool frequency subscore ≤1) at Day 85. Safety was monitored throughout the study.
Results:
The intention-to-treat population included 321 adults: group A (n=107); group B (n=107); and placebo (n=107). The mean (SD) age was 40.6 (14.5) years, 41.6 (12.4) years, and 40.5 (12.4) years, respectively; 41.1%, 40.2%, and 43.0% were female, respectively. Most patients had moderate UC (80.4%, 79.4%, and 79.4%, respectively) and baseline mean (SD) MMS scores were 5.8 (1.4), 5.7 (1.5), and 5.8 (1.4), respectively. The mean time since UC diagnosis was 7.1 years across treatment groups. The 2 amiselimod dosing groups were significantly more efficacious than placebo for improving MMS at Week 12 (mean change from baseline, -2.3 [group A], -2.3 [group B] vs -1.6 [placebo]; P< 0.01 for both vs placebo). A significantly larger percentage of patients in the 2 amiselimod treatment groups had endoscopic improvement versus placebo at Week 12 (42.1% [group A], 43.0% [group B] vs 23.4% [placebo]; P< 0.01 for both vs placebo). Significantly higher rates of clinical remission were achieved in patients in group A (33.6%) and group B (30.8%) compared with placebo (17.8%; P≤0.03 for both vs placebo). The most common treatment-emergent adverse events (AEs; excluding UC/leukopenia) with amiselimod (group A, group B) versus placebo were COVID-19 (3.7%, 4.7% vs 5.6%), anemia (5.6%, 3.7% vs 3.7%), and neutropenia (1.9%, 5.6% vs 0%). The rate of study discontinuation due to AEs was low (4.7%, 3.7% vs 2.8%) and were gastrointestinal related (UC/diarrhea), except for the following: ecchymosis (n=1 [placebo]), hypertension, (n=1 [group B]), lymphopenia (n=1 [group B]), and tachycardia (1 event each group B and placebo).
Conclusions:
Twelve weeks of treatment with amiselimod (both groups) was well tolerated and efficacious (statistically superior to placebo) as a potential treatment for induction of remission of UC.