Modeling time-delayed concentration-QT effects with ACT-1014-6470, a novel oral complement factor 5a receptor 1 (C5a₁...

Area of Science:

• Pharmacology
• Clinical Trials
• Cardiovascular Safety

Background:

• ACT-1014-6470 is a novel oral antagonist targeting the complement factor 5a receptor 1.
• Understanding its cardiodynamic effects, particularly on the QT interval, is crucial for safe clinical development.

Purpose of the Study:

• To evaluate the cardiodynamic safety of ACT-1014-6470 in healthy subjects.
• To assess the effect of single and multiple ascending doses on electrocardiogram (ECG) parameters, specifically the QT interval.

Main Methods:

• Single- and multiple-ascending dose studies were conducted.
• 24-hour Holter ECG recordings were analyzed using categorical, morphological, and by-time point methods.
• Concentration-QT modeling and simulations were performed to predict effects at different doses and regimens.

Main Results:

• ACT-1014-6470 was well tolerated across tested doses.
• No significant effects on ECG parameters were found in categorical and morphological analyses.
• A delayed, dose-dependent increase in placebo-corrected QTcF was observed post-single dose and persisted with twice-daily dosing, suggesting non-concentration-dependent effects.

Conclusions:

• Concentration-QT modeling predicted that lower doses (e.g., 30 mg once daily, 10 mg twice daily) would not exceed the regulatory QTcF threshold.
• These doses may achieve adequate target engagement while potentially mitigating QT liability.
• The findings inform dose selection for future clinical trials to balance efficacy and safety.