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.

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

“…In their publication, Krösser and colleagues [48] have investigated the PK of ceralifimod. They showed that at the highest dose tested (0.1 mg), which triggered a decrease in total lymphocyte count from baseline of 56 %, median t max of ceralifimod …”

“…This property is of particular relevance in case of (desired) pregnancy or opportunistic infections, e.g., progressive multifocal leukoencephalopathy (PML) [83]. In this respect, lymphopenia after discontinuation of S1P receptor modulators differs widely and the lymphocyte count reaches normal values (e.g., ≥80 % of baseline) between one week with ponesimod [37], ceralifimod [48], and siponimod [47], more than two weeks with ozanimod [84], and up to 3 months with fingolimod [80].…”

“…A similar effect was observed with once daily (o.d.) multiple-dose administration of selective S1P 1 receptor modulators such as ponesimod at doses >10 mg [37], siponimod at doses >2 mg [81], ceralifimod doses >0.1 mg [48], GSK2018682 doses >2 mg [77], and ozanimod at doses >1 mg [82]. A possibly clinically relevant aspect of the time course of PD effect is the time to recover a normal lymphocyte count after stopping therapy.…”

“…Natural killer (NK), NKT cell, granulocyte, and monocyte counts are not reduced by treatment with selective and non-selective S1P 1 receptor modulators [36,[45][46][47][48][49][50] maintaining the innate immune system against cancer and virally infected cells. T (CD3 + ) and B (CD20 + ) lymphocyte counts are decreased following the nonselective S1P receptor modulator fingolimod [45,[51][52][53], or the selective S1P 1 receptor modulators ponesimod [46], ceralifimod [48], or siponimod [47]. In addition, the effect on CD4 + T cells was more pronounced compared to cytotoxic CD8 + T cells [46][47][48]52].…”

“…T (CD3 + ) and B (CD20 + ) lymphocyte counts are decreased following the nonselective S1P receptor modulator fingolimod [45,[51][52][53], or the selective S1P 1 receptor modulators ponesimod [46], ceralifimod [48], or siponimod [47]. In addition, the effect on CD4 + T cells was more pronounced compared to cytotoxic CD8 + T cells [46][47][48]52]. Interestingly, non-pro-inflammatory T regulatory cells and pro-inflammatory CD4 + T cells such as Th1 and Th17 are involved in immunopathology [54,55] and pathogenesis [50] of MS.…”