Effect of Camlipixant on Cardiac Repolarization in Healthy Participants: A Thorough QT/QTc Study

Abstract RATIONALE: Camlipixant is being developed for the treatment of refractory chronic cough, including unexplained chronic cough, in adults. This thorough QT/corrected QT (QTc) study aimed to assess the effects of therapeutic and supratherapeutic doses of camlipixant on QTcF (Fridericia's formula correction) interval in healthy participants. METHODS: This Phase 1, single-center, partially double-blind, randomized study evaluated ascending single doses of camlipixant in healthy participants (aged 18-55 years). Eligible participants received camlipixant as a single oral therapeutic (50 mg) or supratherapeutic (200 and 400 mg) dose, moxifloxacin positive drug control (400 mg), or placebo. Treatment was administered according to a 5-period, fixed 20-sequence crossover design, with a 7-day washout period between treatments. In each period, plasma samples were collected to measure camlipixant and moxifloxacin concentrations. The primary endpoint was the placebo-corrected change from baseline QTcF interval (ΔΔQTcF). The relationship between camlipixant plasma concentration and ΔΔQTcF was quantified using linear mixed-effects modeling. Secondary endpoints included heart rate (HR), QTcF, PR, QRS, and QT intervals. Secondary objectives included assessment of camlipixant pharmacokinetics and safety. RESULTS: Overall, 38 participants were included (63.2% male; 84.2% White race; mean age 41.3 years); 34 participants completed all treatment periods. At the 50 and 200 mg camlipixant doses, the ΔΔQTcF 90% confidence interval upper limit was <10 milliseconds at all post-dose time points. At 0.5 hours post-dose, the peak LS mean ΔΔQTcF reached 1.8 and 6.9 milliseconds with 50 and 200 mg camlipixant, respectively, and 14 milliseconds with 400 mg camlipixant at 0.75 hours post-dose. As expected, the peak least-squared (LS) mean ΔΔQTcF reached 12.2 milliseconds at 0.75 hours post-moxifloxacin dose. Camlipixant did not have a clinically meaningful effect on HR or cardiac conduction (PR and QRS intervals) at the single 50, 200, and 400 mg doses tested; a dose-dependent QT prolongation was observed in by-time point analysis after dosing at 200 and 400 mg. Camlipixant plasma concentration versus ΔΔQTcF was linear over the dose range studied. The plasma concentration-ΔΔQTcF analysis demonstrated there was no ΔΔQTcF prolongation effect >10 milliseconds at camlipixant plasma concentrations up to ∼5,240 ng/mL. Pharmacokinetic parameters were consistent with results obtained in a previous first-in-human study. Thirty-four treatment-emergent adverse events (TEAEs) were reported by 19 participants. Overall, the most frequent TEAEs were headache and nausea (both 10.5%), with dysgeusia reported by two participants (5.3%). CONCLUSION: Single 50 or 200 mg doses of camlipixant had no clinically meaningful effect on cardiac repolarization.

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