Key result
Forvisirvat administered in single oral doses up to 80 mg showed no QTcF prolongation (90% CI upper bound < 10 ms), with ECG assay sensitivity confirmed via meal-induced QTcF shortening.
Why the study?
Concentration-QTc analysis from Phase 1 studies is increasingly used to evaluate QTc prolongation risk as an alternative to thorough QT studies, but establishing ECG assay sensitivity without a positive control is challenging.
Does forvisirvat single oral doses up to 80 mg prolong the QTc interval in healthy adults compared to placebo?
RCT (n=32)
Double-blind
randomized
Does forvisirvat single oral doses up to 80 mg prolong the QTc interval in healthy adults compared to placebo?
Forvisirvat single oral doses up to 80 mg did not prolong the QTcF interval, supporting regulatory acceptance of a thorough QT study waiver via concentration-QTc analysis.
Supports forvisirvat QT waiver in development; leaves open translation to patients with cardiovascular disease.
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.
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Kashihara et al. (2026) conducted an RCT in Healthy adults (n=32). Forvisirvat vs. Placebo was evaluated on Baseline- and placebo-adjusted QT interval corrected by the Fridericia method (ΔΔQTcF). Forvisirvat administered in single oral doses up to 80 mg showed no QTcF prolongation (90% CI upper bound < 10 ms), with ECG assay sensitivity confirmed via meal-induced QTcF shortening.
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