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Effect of ceralifimod (ONO‐4641) on lymphocytes and cardiac function: Randomized, double‐blind, placebo‐controlled trial with an open‐label fingolimod arm
Author(s) -
Krösser Sonja,
Wolna Peter,
Fischer Tanya Z.,
Boschert Ursula,
Stoltz Randall,
Zhou Meijian,
Darpo Borje
Publication year - 2015
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.513
Subject(s) - fingolimod , medicine , placebo , heart rate , chronotropic , bradycardia , pharmacodynamics , anesthesia , pr interval , cardiology , pharmacology , pharmacokinetics , blood pressure , multiple sclerosis , immunology , alternative medicine , pathology
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.