SAFETY OF AMISELIMOD IN HEALTHY SUBJECTS: RESULTS FROM A PHASE 1 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY

Abstract

Objective To evaluate the safety profile of amiselimod, a selectivesphingosine 1‐phosphate receptor modulator which has beenshown to regulate lymphocyte trafficking and is in developmentfor the treatment of inflammatory bowel disease. Methods A randomized, double‐blind, multiple‐dose, placebo‐controlled, parallel study with a nested crossover designevaluated the safety and tolerability profile of amiselimod.Healthy adults were randomized in a 2:1:1 ratio during a 28‐daytreatment period accordingly: a single dose of placebo followedby oral amiselimod (upwardly titrated in doses ranging from 0.4to 1.6 mg to achieve 0.4 mg and 0.8 mg steady‐state exposure; asingle dose of oral moxifloxacin 400 mg followed by placebo; orplacebo followed by a single dose of moxifloxacin 400 mg. Thesafety population included all subjects who received at least onedose of treatment. Adverse events (AE) and serious AEs werecollected. Treatment‐emergent AEs were defined as an AE thatwas starting or worsening at the time of or after study drugadministration. Changes in clinical laboratory parameters(including lymphocyte counts), physical examinations, vitalsigns, and electrocardiogram parameters (including heart rate,PR, QRS, and QT intervals) were recorded. Subjects werepermitted to withdraw if lymphocyte counts were ≤ 0.2 x 109 /L. Results The safety population included 190 subjects of which 95 receivedamiselimod and 95 were in the combined moxifloxacin group.Subjects were 40% female, 83% white, and the mean (standarddeviation) age was 39.0 (8.8) years. The discontinuation ratewas 8% (n=8) in the amiselimod group and 4% (n=4) in themoxifloxacin group. Three subjects who received amiselimoddiscontinued because they met the stopping criteria for lowlymphocyte counts. One subject experienced an amiselimod‐related serious AE of atrial fibrillation on day 26 (after receivingamiselimod 1.6 mg for 3 of the preceding 4 days) that requiredhospitalization, cardioversion, and led to discontinuation. Nodeaths were reported. All other AEs were mild to moderate inseverity. Decreased white blood counts were the most commonlyreported TEAE, followed by headache and constipation (Table).Reductions in white blood counts returned to normal range afterstudy discontinuation without sequelae. Decreased neutrophils,lymphocytes and hemoglobin, and increased creatine kinase,alanine aminotransferase, and aspartate aminotransferase werereported, all of which resolved without sequelae. The meanabsolute lymphocyte count for amiselimod exhibited a gradualdecrease from predose (1.681 thou/uL) to a nadir of 0.424thou/uL on day 27 (Figure). Changes to vital signs, physicalexaminations, and ECG parameters were within normal limits. Conclusions Upwardly titrated doses of amiselimod ranging from 0.4 to 1.6mg were generally well tolerated in healthy subjects.