024: The Clinical Evaluation of QTc Interval Prolongation for the Dual Endothelin Receptor Antagonist Aprocitentan in a Thorough QT/QTc Study

Aprocitentan, is an orally active, once-daily (o.d.), dual endothelin receptor antagonist that has a novel mechanism of action for the treatment of hypertension. Doses of 12.5 and 25 mg aprocitentan are currently investigated in a Phase 3 study in subjects with difficult-to-control hypertension. As per guidance, adequate pre-marketing investigation of any potential QT liability is required for investigational products, which prompted the investigations in this thorough QT/QTc (TQT) study.

Description of Methods & Materials:

In this single-center, randomized, double-blind, placebo- and moxifloxacin-controlled (open-label), 4-way crossover study healthy male and female subjects had to undergo 4 periods of 28 days in which they received therapeutic doses of aprocitentan (10 days 25 mg aprocitentan o.d.), supratherapeutic doses of aprocitentan (10 days 100 mg aprocitentan o.d.), placebo (10 days placebo o.d.), and moxifloxacin to demonstrate assay sensitivity (9 days placebo o.d. and 400 mg moxifloxacin on Day 10) in a randomized sequence.

ECG variables were extracted in replicates at predefined time points from continuous 12-lead Holter ECG recordings on Day 1 and 10 for 24 hours. Pharmacokinetic (PK) plasma samples were obtained at corresponding time points. Data was analyzed using concentration-QT modeling. The primary endpoint was the placebo-corrected change from baseline in QTcF (∆∆QTcF). Other ECG study objectives were the investigation of the effect of aprocitentan on heart rate (HR), PR, and QRS interval as well as on ECG morphology. Standard safety, tolerability, and PK variables were collected during each of the periods.

Data & Results:

Of the 48 subjects enrolled in the study, 32 subjects completed study treatment. The main reasons for study treatment discontinuation were the occurrence of adverse events (AEs) (7 subjects) and withdrawal of consent (4 subjects). Assay sensitivity was demonstrated (P < 0.017). A linear mixed-effects model was applied. Results indicated that ∆∆QTcF increased with increasing aprocitentan concentrations. The predicted two‑sided 90% upper bound of the mean ∆∆QTcF confidence interval exceeded the 10 ms threshold of regulatory concern at 16.1 µg/mL, which was close to the geometric mean maximum concentration (i.e., 16.8 µg/mL) obtained with the 100 mg supratherapeutic dose (Figure 1). A small increase in Δ(Δ)HR was identified and there was no evidence of changes in PR and QRS intervals. There were no imbalances or relevant findings in categorical outlier analysis. No deaths or severe AEs were reported. Most treatment-emergent AEs were reported by subjects after treatment with 100 mg aprocitentan and included headache, nasal congestion, nausea, and peripheral edema. Following multiple-dose administration of 100 mg aprocitentan, asymptomatic decreases clinical laboratory variables, blood pressure, and body weight were observed. Except for a nontreatment-related decreases in hemoglobin, none of the changes were reported as AEs.

Interpretation, Conclusion or Significance:

At supratherapeutic doses of aprocitentan the threshold of regulatory concern was exceeded. Based on the available information, the risk of QT prolongation with therapeutic doses of aprocitentan is considered low. The therapeutic dose regimen of 25 mg aprocitentan o.d. was safe and well tolerated; the supratherapeutic dose regimen of 100 mg aprocitentan o.d. showed limited tolerability.