022: Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy Participants

Statement of Purpose, Innovation or Hypothesis: Aficamten is a next-in-class small molecule, selective cardiac myosin inhibitor (CMI) in development for treatment of hypertrophic cardiomyopathy (HCM). This study was conducted to evaluate the effect of aficamten on QTc interval in healthy participants and thereby exclude a clinically concerning effect on QTc interval at therapeutic concentrations.

Description of Methods & Materials: This was a Phase 1, 2-part study in healthy participants. Part A (dose-finding; n=10) was open-label single-dose (SD) study to identify a dose for Part B (TQT study). Part B (n=34) was randomized, double-blind, positive- and placebo-controlled SD 3-way crossover study. Participants received 1 of 3 treatments on Day 1 in each period: SD of 50 mg aficamten, placebo, or 400 mg moxifloxacin under fasted conditions. ECG recordings and PK blood samples for aficamten and moxifloxacin were collected over 24 hours post-dose. The primary endpoint was placebo-corrected change from baseline in QTc using Fridericia’s correction (ddQTcF). Data were analyzed using Concentration-QT (C-QT) modeling (primary analysis) and by-timepoint analysis. Effect of aficamten on heart rate, PR, QRS and morphology was evaluated. Safety was assessed throughout study.

Data & Results: In Part A, aficamten 50 mg SD achieved C_max similar to that observed at 15 mg QD in patients with oHCM (Phase 3 intermediate dose) and was therefore selected for evaluation in Part B (TQT). The highest therapeutic dose of aficamten for oHCM (20 mg QD) would result in exposures exceeding those established as well tolerated in healthy participants, precluding evaluation of aficamten at doses above 50 mg in this study. Mean aficamten C_max in Part B (353 ng/mL; range:124‒1660 ng/mL) was comparable to mean C_max at 15 mg QD in oHCM patients at steady state (Phase 3, 358 ng/mL; range: 131‒1230 ng/mL). ddQTcF effect of aficamten was predicted to be ‒1.82 msec (90% CI: ‒3.43, ‒0.21 msec) at geometric mean C_max (298 ng/mL). The upper bound of 2‑sided 90% CI was < 10 msec using C-QT analysis and by-timepoint analysis at all time-points, suggesting lack of QTc prolongation up to aficamten concentrations of 1660 ng/mL. Predicted ddQTcF of moxifloxacin at geometric mean C_max was 15.3 msec. Lower bound of 90% CI for moxifloxacin exceeded 5 msec using C-QT and by-time point analyses at most timepoints, establishing assay sensitivity. Categorical and waveform analysis had no remarkable observations. One patient on aficamten had QTcF of >450 msec ( < 480 msec) and no patients had QTc change >30 msec or >60 msec. A small increase in HR ( < 10 bpm) was observed for moxifloxacin and aficamten (consistent with its mechanism of action) that was not clinically significant. There were no deaths, SAEs, or participants discontinued due to TEAEs in this study.

Interpretation, Conclusion or Significance: This is the first study to evaluate effect of a CMI in healthy participants to categorically ascertain the impact on QT interval. Aficamten 50 mg SD achieved comparable C_max to 15 mg QD dose in oHCM patients (Phase 3). Study treatments were safe and well tolerated. Based on C-QT and by-time point analyses, effect on ddQTcF by aficamten exceeding 10 msec can be excluded up to 1660 ng/mL.

Disclosures: Cytokinetics, Inc. sponsored this research; authors are employed by and/or hold stock in Cytokinetics.

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