Concentration-QTc Analysis Supporting Thorough QT Study Waiver for Forvisirvat: Electrocardiogram Assay Sensitivity...

Concentration-QTc analysis from Phase 1 studies is increasingly used to evaluate QTc prolongation risk as an alternative to thorough QT (TQT) studies. According to International Conference on Harmonization E14 documents, such analyses should include exposures at twice the highest clinically relevant exposure instead of a positive control to establish electrocardiogram (ECG) assay sensitivity; however, achieving this may be challenging when the highest dose in Phase 1 studies is restricted for various reasons. This study evaluated the QTc prolongation risk of forvisirvat via concentration-QTc analysis and demonstrated ECG assay sensitivity via the well-described meal effect. A double-blind, randomized, placebo-controlled, single ascending dose study evaluated the effect of forvisirvat on ECG parameters following single oral doses up to 80 mg in 32 healthy adults. Time-matched plasma forvisirvat concentrations and 12-lead ECG data were collected. The prespecified linear mixed-effects model assessed the impact of forvisirvat on baseline- and placebo-adjusted QT interval corrected by the Fridericia method (ΔΔQTcF). ECG assay sensitivity was established by prospectively evaluating the postprandial QTcF shortening. The two-sided 90% confidence interval (CI) for the model-predicted ΔΔQTcF was below 10 ms up to the maximum observed plasma concentration of 703 ng/mL. Meal-induced QTcF shortening was -6.38 ms (95% CI, -8.51 to -4.26) at 4 h after the standardized lunch, with the two-sided 95% CI below 0. Forvisirvat showed no QTcF prolongation, and ECG assay sensitivity was confirmed via meal-induced QTcF shortening. These results supported regulatory acceptance of a TQT study waiver by the Japanese Pharmaceuticals and Medical Devices Agency.