title: Amiselimod, a novel sphingosine 1-phosphate receptor-1 modulator, has potent therapeutic efficacy for autoimmune diseases, with low bradycardia risk.
abstract: We conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT-1303), a second-generation sphingosine 1-phosphate (S1P) receptor modulator, designed to reduce the bradycardia associated with fingolimod and other S1P receptor modulators.
  
  
  
  The selectivity of the active metabolite amiselimod phosphate (amiselimod-P) for human S1P receptors and activation of G-protein-coupled inwardly rectifying K+(GIRK) channels in human atrial myocytes were assessed. Its cardiac distribution was determined in rats, and cardiovascular telemetry was assessed in monkeys. We also examined the pharmacokinetics, pharmacodynamics and safety of amiselimod in healthy humans.
  
  
  
  Amiselimod-P showed potent selectivity for S1P1and high selectivity for S1P5receptors, with minimal agonist activity for S1P4and no distinct agonist activity for S1P2or S1P3receptors and approximately five-fold weaker GIRK activation than fingolimod-P. After oral administration of amiselimod or fingolimod at 1 mg·kg-1, the concentration of amiselimod-P in rat heart tissue was lower than that of fingolimod-P, potentially contributing to the minimal cardiac effects of amiselimod. A telemetry study in monkeys confirmed that amiselimod did not affect heart rate or ECG parameters. In healthy human subjects, peripheral blood lymphocyte counts gradually reduced over the 21 day dosing period, with similar lymphocyte count profiles with the highest doses by day 21, and no clinically significant bradycardia observed on day 1 or during the study.
  
  
  
  Amiselimod exhibited potent therapeutic efficacy with minimal cardiac effects at the anticipated clinical dose and is unlikely to require dose titration.
authors.affiliation: Research Unit/Frontier Therapeutic Sciences, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Sugahara
authors.affiliation: Research Unit/Frontier Therapeutic Sciences, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Research Unit/Frontier Therapeutic Sciences, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shimano
authors.affiliation: Research Unit/Frontier Therapeutic Sciences, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Mogami
authors.affiliation: Research Unit/Frontier Therapeutic Sciences, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kataoka
authors.affiliation: DMPK Research Laboratories, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: DMPK Research Laboratories, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hikida
authors.affiliation: DMPK Research Laboratories, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kumagai
authors.affiliation: Safety Research Laboratories, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
authors.forename: Mahoko
authors.initials: M
authors.lastname: Asayama
authors.affiliation: Safety Research Laboratories, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Mitsubishi Tanabe Pharma Europe, Dashwood House, London, UK.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Harada
authors.affiliation: Mitsubishi Tanabe Pharma Europe, Dashwood House, London, UK.
authors.forename: Pingping
authors.initials: P
authors.lastname: Ni
authors.affiliation: Data Science Department, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Inoue
authors.affiliation: Data Science Department, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Kawaguchi
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D001919:Bradycardia / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D015394:Molecular Structure; D010755:Organophosphates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011412:Propanolamines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D013329:Structure-Activity Relationship
chemical_list: D010755:Organophosphates; D011412:Propanolamines; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C000624397:amiselimod; C000624396:amiselimod phosphate