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.</p

Selective serotonin re-uptake inhibitor treatment-emergent sexual dysfunction: randomized double-blind placebo-controlled parallel-group fixed-dose study of a potential adjuvant compound, VML-670

Sexual dysfunction is common during acute and continuation treatment of depressed patients with selective serotonin ( 5-hydroxytryptamine, 5-HT) re-uptake inhibitors ( SSRIs), but there is no consensus on clinical management. Compounds with 5-HT1A agonist properties have been proposed as adjuvant agents in patients continuing with SSRIs. Randomized double-blind placebo-controlled parallel-group fixed-dose 4-week treatment study. Previously depressed male or female patients in symptomatic remission receiving stable doses of fluoxetine or paroxetine but experiencing treatment-emergent sexual dysfunction were randomised to double-blind treatment with placebo or VML-670 ( a 5-HT1A and 5-HT1D agonist). Sexual dysfunction was assessed by the Arizona Sexual Experiences Scale ( ASEX). Two-hundred and eighty-eight patients ( 204 women, 84 men; mean age 44.2 years) received VML-670 ( n = 149; 107 women, 42 men) or placebo ( n = 139; 97 women, 42 men). In the intention-to-treat, last-observation carried forward analysis ( n = 282), proportionately more patients became free of sexual dysfunction with VML-670 ( 34.3% versus 27.9% with placebo) but this difference was not statistically significant. Male patients treated with VML-670 showed a significantly greater ( p = 0.01) improvement in ability to achieve and maintain penile erection ( a secondary outcome measure). A similar proportion of patients reported on-treatment, treatment-emergent adverse events with VML-670 ( 71.1%) and placebo ( 68.3%), and a similar proportion experienced at least one treatment-related adverse event ( 36.9% versus 35.3%). Double-blind treatment with VML-670 offered no significant advantage over placebo on the primary outcome measure in the overall sample. Further studies may be warranted in larger groups of male patients with sexual dysfunction