Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval.

Objective: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc).
Methods: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling.
Results: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc.
Conclusion: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.
Competing Interests: Disclosure D.M.D. participated in an advisory board for Amryt and Corcept Therapeutics. R.P. received research support to Università Federico II di Napoli as a principal investigator for clinical trials from Camurus AB, Corcept Therapeutics, HRA Pharma, Neurocrine Biosciences, Novartis, Pfizer, Recordati, Shire, Strongbridge, and Takeda; research support to Università Federico II di Napoli from BioPharma, IBSA, Ipsen, Merck Serono, Novartis, Pfizer, and Strongbridge; and occasional consulting honoraria from BioPharma, BresMed, Corcept Therapeutics, HRA Pharma, Novartis, Pfizer, Recordati, and Strongbridge. T.K. received other financial or nonfinancial interests from Corcept Therapeutics. E.M. was an investigator for a clinical trial of relacorilant for Corcept Therapeutics and served as a speaker for IBSA, Ipsen, Merck, Novartis, Pfizer, and Recordati. C.N.M. received research support from Corcept Therapeutics. R.A.F. reports research grants from Corcept Therapeutics; has served as a speaker for HRA Pharma; and consulted and served as a speaker for Recordati. K.D. is a director and an employee of Jade Consultants, which was contracted by Corcept Therapeutics to work on this study. B.D. owns shares and is eligible for stock options in Clario, which was contracted by Corcept Therapeutics to perform this research. H.X. is an employee of Clario, which was contracted by Corcept Therapeutics to perform this research. J.M.C. is an employee of Corcept Therapeutics. A.L.H. is an employee of Corcept Therapeutics and has stock ownership/options in Corcept Therapeutics. A.G. M. is an employee of Corcept Therapeutics. The other authors have no multiplicity of interest to disclose.
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