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

Figures

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  FIGURE 1. Study design (Part B). aThere was a washout of ≥ 21 days between dosing in each period. bScreening of study participants occurred within 28 days prior to first dosing. cAll participants who received ≥ 1 dose of study drug (including participants who terminated the study early) returned to the CRU 30 (± 2) days after the last dose for follow‐up procedures and to determine if any AE occurred since the last study visit. AE, adverse event; CRU, clinical research unit; ECG, electrocardiogram; n, sample size; PK, pharmacokinetics.

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  FIGURE 2. Arithmetic mean (SD) plasma concentrations of aficamten following a single 50 mg dose in Parts A and Ba. aArithmetic mean (± SD) aficamten plasma concentrations following a single 50 mg dose in Part A (N = 10) and Part B (N = 33) are presented. The dotted line and green shaded portion depict the mean and range, respectively, of population PK‐estimated Cmax at steady state in participants treated with aficamten 20 mg QD as the last titrated dose (N = 65) in SEQUOIA‐HCM. Cmax, maximum plasma concentration; PK, pharmacokinetic; QD, once daily; SD, standard deviation.

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  FIGURE 3. Results of C‐QT analysis. Scatter plot of placebo‐corrected change from baseline QTcF and time‐matched plasma concentrations of (A) aficamtena, (B) CK‐3834282b, and (C) CK‐3834283c. aThe solid and dashed purple lines denote model predicted mean ΔΔQTcF and 90% CI, respectively, calculated as ΔΔQTcF = −1.1750—0.0039 × aficamten. The green and black circles denote time‐matched observed plasma concentrations and estimated ΔΔQTcF for aficamten and placebo, respectively. bThe solid and dashed purple lines denote model predicted mean ΔΔQTcF and 90% CI, respectively, calculated as ΔΔQTcF = −1.2124—0.0042 x CK‐3834282. The green and black circles denote time‐matched observed plasma concentrations and estimated ΔΔQTcF for CK‐3834282 and placebo, respectively. cThe solid and dashed purple lines denote model predicted mean ΔΔQTcF and 90% CI, respectively, calculated as ΔΔQTcF = −1.3423—0.0021 x CK‐3834283. The green and black circles denote time‐matched observed plasma concentrations and estimated ΔΔQTcF for CK‐3834283 and placebo, respectively. CI, confidence interval; Cmax, maximum plasma concentration; ΔΔQTcF, placebo‐corrected change from baseline QT interval using Fridericia's correction.

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  FIGURE 4. Mean (90% CI) placebo‐corrected change from baseline in QTcF versus time point for aficamten and moxifloxacina. aThe dotted lines denote the regulatory threshold of concern applicable to aficamten (10 msec) and moxifloxacin (5 msec). CI, confidence interval; ΔΔQTcF, placebo‐corrected change from baseline in QT interval using Fridericia's correction.