title: Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel-group, phase I study in healthy subjects.
abstract: Amiselimod (MT-1303) is a selective sphingosine 1-phosphate 1 (S1P1) receptor modulator which is currently being developed for the treatment of various autoimmune diseases. Unlike some other S1P receptor modulators, amiselimod seemed to show a favourable cardiac safety profile in preclinical, phase I and II studies. The aim of the current study was to characterize the cardiac effects of amiselimod by directly comparing it with fingolimod and placebo.
  
  
  
  A total of 81 healthy subjects aged 18-55 years were equally randomized to receive amiselimod 0.4 mg, amiselimod 0.8 mg, placebo or fingolimod 0.5 mg once daily for 28 days. The chronotropic/dromotropic and inotropic effects were evaluated using intensive Holter electrocardiogram and echocardiography.
  
  
  
  Unlike fingolimod, neither amiselimod dose exerted acute (1-6 h) negative chronotropic effects on Days 1 and 2. The lowest nadir mean hourly heart rate was observed on Day 14 in the amiselimod 0.4 mg group (least squares mean difference: -4.40 bpm, 95% confidence interval -7.15, -1.66) and Day 7 in the 0.8 mg group [-3.85 bpm (-6.58, -1.11)] compared with placebo, but these changes were smaller than those with fingolimod on Day 1 [-6.49 bpm (-8.95, -4.02)]. No clinically significant bradyarrhythmia or cardiac functional abnormalities were observed in either amiselimod group. Both amiselimod doses were well tolerated and no serious adverse events were reported. Fingolimod was also generally well tolerated, although one subject was withdrawn owing to highly frequent 2:1 atrioventricular blocks on Day 1.
  
  
  
  The study demonstrated a more favourable cardiac safety profile for amiselimod than fingolimod when administered over 28 days in healthy subjects.
authors.affiliation: Mitsubishi Tanabe Pharma Europe Ltd., Dashwood House, 69 Old Broad Street, London, EC2M 1QS, UK.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Harada
authors.affiliation: Mitsubishi Tanabe Pharma Europe Ltd., Dashwood House, 69 Old Broad Street, London, EC2M 1QS, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Wilbraham
authors.affiliation: Mitsubishi Tanabe Pharma Europe Ltd., Dashwood House, 69 Old Broad Street, London, EC2M 1QS, UK.
authors.forename: Guillemette
authors.initials: G
authors.lastname: de La Borderie
authors.affiliation: Mitsubishi Tanabe Pharma Corporation, 17-10, Nihonbashi-Koamicho, Chuo-ku, Tokyo, 103-8405, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Inoue
authors.affiliation: Principal Investigator, Covance CRU Ltd., Springfield House, Hyde Street, Leeds, LS2 9LH, UK.
authors.forename: Jim
authors.initials: J
authors.lastname: Bush
authors.affiliation: Cardiovascular and Cell Sciences Research Institute, St. George's University of London, London, SW17 0RE, UK.
authors.forename: A John
authors.initials: AJ
authors.lastname: Camm
mesh_terms: D000328:Adult; D054537:Atrioventricular Block / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D015716:Electrocardiography, Ambulatory; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011412:Propanolamines / Q000008:administration & dosage / Q000009:adverse effects*; D049349:Receptors, Lysosphingolipid / Q000187:drug effects* / Q000378:metabolism; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D011412:Propanolamines; D049349:Receptors, Lysosphingolipid; C000624397:amiselimod; D000068876:Fingolimod Hydrochloride
keywords: amiselimod (MT-1303); cardiac effects; fingolimod; healthy subject; sphingosine 1-phosphate