title: Effect of ceralifimod (ONO-4641) on lymphocytes and cardiac function: Randomized, double-blind, placebo-controlled trial with an open-label fingolimod arm.
abstract: This randomized, double-blind, placebo-controlled, 6-arm, parallel-design study investigated cardiac and hematological pharmacodynamic effects of ceralifimod (ONO-4641), a selective sphingosine-1-phosphate (S1P) receptor modulator, over a broad dose range in direct comparison with the nonselective S1P modulator fingolimod. Healthy subjects were assigned to ceralifimod (0.01, 0.025, 0.05, or 0.10 mg), fingolimod (0.5 mg), or placebo once daily for 14 days (n = 24 per group). After 14 days of treatment, mean absolute lymphocyte count percentage change from baseline was greatest in the fingolimod (-62%) and ceralifimod 0.10 mg (-56%) groups. On treatment cessation, lymphocyte recovery was faster in the ceralifimod versus the fingolimod group. Ceralifimod showed dose- and concentration-dependent chronotropic effect. Cardiac effects in the fingolimod group were dependent on fingolimod-P concentrations. Maximum mean heart rate (HR) effect on day 1 was larger with fingolimod (placebo-adjusted change from time-matched baseline HR [ΔΔHR], -14.9 beats per minute [bpm]) versus ceralifimod (ΔΔHR, -6.2 and -12.0 bpm for the 0.05- and 0.10-mg doses, respectively). Ceralifimod's effect on the PR interval was minor. Safety biomarker results suggest that potential therapeutic doses of ceralifimod, in particular the 0.05-mg dose, might result in reduced occurrence of bradycardia, atrioventricular block absolute lymphocyte count and grade 3/4 lymphopenia compared with fingolimod 0.5 mg.
authors: Merck KGaA, Darmstadt, Germany.
authors: Sonja
authors: S
authors: Krösser
authors: Merck KGaA, Darmstadt, Germany.
authors: Peter
authors: P
authors: Wolna
authors: EMD Serono, Inc., Billerica, MA, USA.
authors: Tanya Z
authors: TZ
authors: Fischer
authors: EMD Serono, Inc., Billerica, MA, USA.
authors: Ursula
authors: U
authors: Boschert
authors: Covance, Evansville, IN, USA.
authors: Randall
authors: R
authors: Stoltz
authors: iCardiac Technologies, Rochester, NY, USA.
authors: Meijian
authors: M
authors: Zhou
authors: iCardiac Technologies, Rochester, NY, USA.|Karolinska Institute, Department of Clinical Sciences, Danderyd's Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden.
authors: Borje
authors: B
authors: Darpo
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001384:Azetidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D001384:Azetidines; D007166:Immunosuppressive Agents; D009281:Naphthalenes; C000606993:ceralifimod; D000068876:Fingolimod Hydrochloride
keywords: heart rate; lymphocyte count; pharmacodynamics; sphingosine-1-phosphate