102: Sisunatovir Inhibition of Multiple Ion Channel Subtypes Prevents the Risk for QT Prolongation Due to hERG Channel Inhibition

Statement of Purpose, Innovation or Hypothesis: Sisunatovir (PF-07923568) is a Respiratory Syncytial Virus F-protein inhibitor. The anticipated high clinical exposure of sisunatovir when co-administered with a CYP3A4 inhibitor is 288 ng/mL (128 µM). Sisunatovir inhibits the hERG channel in vitro (IC₅₀ 1.8 μM), potentially producing prolonged clinical QTc. Sisunatovir inhibits additional cardiac ion channel subtypes (Cav1.2 [IC₅₀ 19.8 μM] and Nav1.5 [IC₅₀ 12.1 μM]), potentially offsetting delayed repolarization of the cardiac action potential via hERG. The impact of sisunatovir on QTc prolongation, at high clinical exposures, was evaluated utilizing preclinical and clinical data.

Description of Methods & Materials: A human induced pluripotent stem cell (hiPSC) derived cardiomyocyte model used rate-corrected action potential duration (APDc) changes to predict the concentration associated with a clinical 10 ms QTc prolongation following acute (30-minute) or chronic (24-hour) exposure. An in silico model, trained on a library of clinical compounds with known proarrhythmic risk, was developed to define the potential for Torsade de Pointes (TdP). Sisunatovir’s effects on QTc prolongation at doses covering the high clinical exposure was assessed in a Phase 1 placebo- and positive-controlled study conducted in 43 adult healthy participants (NCT05878522). A pre-specified linear mixed effects (LME) model was used to characterize the relationship between sisunatovir concentration and QTc change. The LME model was used to derive predictions of placebo-corrected change from baseline in QTcF (ΔΔQTcF) and corresponding 2-sided 90% CIs for the concentration range of interest. Evaluation of the modeling results included linearity of the exposure-response relationship, hysteresis evaluation to test assumption that there is no time delay between drug concentrations and placebo-corrected changes in endpoints from baseline, and adequacy of the heart-rate correction factor to assess appropriateness of QTcF.

Data & Results: In the hiPSC model, acute sisunatovir exposure was predicted to cause a 10 ms increase in clinical QTc duration at 1.8 µM ( >14-fold above high clinical exposure). Chronic sisunatovir exposure was predicted to cause no prolongation in clinical QTc up to 76 µM ( >590-fold high clinical exposure). The silico model predicted ≥1.4 μM ( >10-fold high clinical exposure) would be associated with a TdP class probability risk of >0.5. These data predict there to be a low risk of significant clinical QTc prolongation with sisunatovir. The positive control, moxifloxacin, demonstrated the expected changes in QTcF, validating the adequate sensitivity of QT/QTc study (NCT05878522). Sisunatovir administration of 350 mg q12h under fed conditions exceeded the high clinical exposure by 1.2-fold with C_maxSS of 344 (CV: 87%) ng/mL. The mean ΔΔQTcF (90% CI) for the high clinical exposure was ‑0.37 (-2.45, 1.71) msec. Similarly, the mean ΔΔQTcF (90% CI) was estimated to be ‑0.93 (-3.44, 1.58) msec at the highest dose administered, 350 mg q12h. Based on these results, the upper bound of the two-sided 90% CIs for ΔΔQTcF at the concentrations of interest were lower than 10 msec, indicating the lack of a clinically relevant effect on QTc interval.

Interpretation, Conclusion or Significance: Preclinical models predicted that 200 mg sisunatovir q12h for 5 days is unlikely to result in QTc prolongation. The clinical concentration-response analyses did not identify a QTc signal of potential clinical concern.

Disclosures: No conflicts of interest.

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