Titration regimens mitigate mocravimod-induced negative chronotropic effect while preserving the pharmacokinetic and pharmacodynamic properties

Background: Sphingosine 1-phosphate receptor (S1PR) modulators can cause transient, dose-related negative chronotropic effects. Mocravimod is an oral S1PR modulator that is developed as a maintenance therapy in allogenic haematopoietic cell transplantation (allo-HCT). This phase I study evaluated whether two dose-titration regimens attenuate early bradycardia when initiating mocravimod while preserving pharmacokinetic (PK) and pharmacodynamic (PD) activity. Patients and methods: In this randomized, double-blind, placebo-controlled, parallel-group study, healthy adults received once-daily oral mocravimod using either dose titration (DT) regimen DT1 (0.3-2.0 mg with 4-day stepwise escalation) or regimen DT2 (0.5 mg to Day 14, 1.2 mg Days 15-18, then 2 mg), a fixed 2 mg regimen, or placebo for 21 days. The primary endpoint was the number of bradycardia episodes on treatment initiation and dose-escalation days derived from 24-hour Holter monitoring; PK of mocravimod and mocravimod-phosphate (whole blood) and PD effects (absolute lymphocyte count [ALC]) were assessed. Results: Fifty-six participants were randomized and 53 completed the study. Both titration regimens resulted in fewer bradycardia episodes than fixed initiation at 2 mg during the first week of treatment. Differences between titration and fixed dosing were no longer evident after Day 9, consistent with tolerance development. PK profiles were consistent with prior phase I data. By Day 21, DT1 achieved exposures close to the fixed 2 mg regimen, whereas DT2 yielded lower exposures, reflecting slower escalation. Peripheral lymphopenia developed in all active treatment groups and was comparable between regimens by Day 21, returning toward baseline by study end. Safety was similar between titration regimens and placebo, with similar distribution and incidence of adverse events. No serious adverse events occurred. Conclusion: Two practical titration regimens mitigated the early negative chronotropic effect observed with fixed-dose initiation of mocravimod at 2 mg once daily. Importantly, titration preserved the expected PK and PD profile, supporting dose escalation as an effective initiation strategy to improve early cardiac tolerability.