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Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study.

ABSTRACT: Ozanimod is a novel, selective, oral sphingosine-1-phosphate (1 and 5) receptor modulator in development for multiple sclerosis and inflammatory bowel disease. This randomized, double-blind, placebo-controlled, positive-controlled, parallel-group thorough QT study characterized the effects of ozanimod on cardiac repolarization in healthy subjects. Eligible subjects were randomized to 1 of 2 groups: ozanimod (escalated from 0.25 to 2 mg over 14 days) or placebo (for 14 days). A single dose of moxifloxacin 400 mg or placebo was administered on days 2 and 17. The primary end point was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (??QTcF). A total of 113/124 (91.1%) subjects completed the study. The upper limits of the 2-sided 90% confidence intervals for ??QTcF for both ozanimod 1 and 2 mg were below the 10-millisecond regulatory threshold. No QTcF >480 milliseconds or postdose change in QTcF of >60 milliseconds was observed. There was no evidence of a positive relationship between concentrations of ozanimod and its active metabolites and ??QTcF. Although ozanimod blunted the observed diurnal increase in heart rate, excursions below predose heart rates were no greater than with placebo. Results demonstrate that ozanimod does not prolong the QTc interval or cause clinically significant bradycardia, supporting ozanimod's evolving favorable cardiac safety profile.

SUBMITTER: Tran JQ

PROVIDER: S-EPMC5901414 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study.

Tran Jonathan Q JQ Hartung Jeffrey P JP Olson Allan D AD Mendzelevski Boaz B Timony Gregg A GA Boehm Marcus F MF Peach Robert J RJ Gujrathi Sheila S Frohna Paul A PA

Clinical pharmacology in drug development 20170807 3

Ozanimod is a novel, selective, oral sphingosine-1-phosphate (1 and 5) receptor modulator in development for multiple sclerosis and inflammatory bowel disease. This randomized, double-blind, placebo-controlled, positive-controlled, parallel-group thorough QT study characterized the effects of ozanimod on cardiac repolarization in healthy subjects. Eligible subjects were randomized to 1 of 2 groups: ozanimod (escalated from 0.25 to 2 mg over 14 days) or placebo (for 14 days). A single dose of mox ...[more]

PMID: 28783871

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Project description:BackgroundFabry disease is a rare inherited glycosphingolipid storage disorder caused by deleterious mutations in the GLA gene coding for the lysosomal enzyme ?-galactosidase A. The glucosylceramide synthase inhibitor lucerastat is an iminosugar with potential to provide oral substrate reduction therapy in Fabry disease, regardless of the patient´s underlying mutation. Since lucerastat exhibits systemic exposure and many patients with Fabry disease suffer from rhythm and conduction abnormalities its effects on cardiac repolarization were evaluated in a thorough QT study.MethodsIn Part A of this randomized, double-blind, placebo-controlled phase 1 study, single oral doses of 2000 and 4000 mg lucerastat were investigated to determine the supratherapeutic dose for Part B. The latter was a four-way crossover study to demonstrate that lucerastat at single oral therapeutic and supratherapeutic doses had no effect on the QTc interval?>?10 ms using concentration-QTc modeling as primary analysis. The primary ECG endpoint was placebo-corrected change-from-baseline (??) in Fridericia-corrected QTc (??QTcF). Open-label moxifloxacin served as positive control.ResultsThe effect of lucerastat on ??QTcF was predicted as 0.39 ms (90% confidence interval [CI]?-?0.13 to 0.90) and 1.69 ms (90% CI 0.33-3.05) at lucerastat peak plasma concentration after dosing with 1000 mg (5.2 µg/mL) and 4000 mg (24.3 µg/mL), respectively. A QTcF effect?>?10 ms was excluded up to lucerastat plasma concentrations of approximately 34.0 µg/mL. Lucerastat did not exert an effect on other ECG parameters. Across doses, absorption of lucerastat was rapid, its elimination half-life ranged from 8.0 to 10.0 h, and the pharmacokinetics (PK) of lucerastat were dose-proportional. Moxifloxacin PK were in line with published data and assay sensitivity was demonstrated by the moxifloxacin QTc response. Lucerastat was safe and well tolerated.ConclusionsLucerastat up to a dose of 4000 mg has no clinically relevant liability to prolong the QT interval or any clinically relevant effect on other ECG parameters. This will be an important factor in the overall benefit-risk assessment of lucerastat in the potential treatment of Fabry disease. Trial registration The study was registered with the ClinicalTrials.gov identifier NCT03832452 (February 6th, 2019, https://clinicaltrials.gov/ct2/show/NCT03832452 ) and the EudraCT number 2018-004546-42 (December 17th, 2018).

Dataset Information

Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study.

Publications

Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study.

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