Towards a Quantitative Understanding of Aficamten Clinical Pharmacology: Pharmacokinetic‐Cardiodynamic Modeling to Support Safety and Efficacy

Figures

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  FIGURE 1. Visual predictive check for core laboratory (top) and site‐read (bottom) LVOT‐G (left) and LVEF (right) as a function of aficamten exposure (Cavg,24) in participants with oHCM in phase 2 and 3 studies (REDWOOD‐HCM and SEQUOIA‐HCM). Cavg,24, average concentration over 24 h; LVEF, left ventricular ejection fraction; LVOT‐G, left ventricular outflow tract gradient; oHCM, obstructive hypertrophic cardiomyopathy. Orange dashed lines are 50th, 5th and 95th percentiles of observed data, stratified into 10 bins, and connected across bin. Blue lines are corresponding median (solid) and 5th to 95th confidence intervals (dashed) of model predicted percentiles based on 1000 simulations.

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  FIGURE 2. Core laboratory (top) and site‐read (bottom) post‐Valsalva LVOT‐G (left) or LVEF (right) as a function of study week in participants with oHCM in the phase 3 trial (SEQUOIA‐HCM). LVEF, left ventricular ejection fraction; LVOT‐G, left ventricular outflow tract gradient; oHCM, obstructive hypertrophic cardiomyopathy. Solid line is the median value for 10,000 simulated participants, and the shaded region represents the 5th and 95th percentile range of predictions. The points are observed data, and the dashed lines represent the 5th, median, and 95th percentiles of the observed data.

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  FIGURE 3. Commercial dose regimen: Simulation of aficamten Cavg,24 and percent of participants with site‐read post‐Valsalva LVOT‐G < 30 mmHg and site‐read LVEF < 50% over 3 years of daily administration. Cavg,24, average concentration over 24 h; LVEF, left ventricular ejection fraction; LVOT‐G, left ventricular outflow tract gradient; QXW, frequency of dose titrations (i.e., dose titration every X weeks). Curves represent modeled probabilities in 10,000 simulated participants. Shaded bands represent 5th to 95th percentile prediction intervals based on 1000 simulated trials; each trial was composed of 142 participants resampled from the 10,000 simulated participants.

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  FIGURE 4. Commercial dose regimen: Simulation of the percent of participants on a given dose (5–20 mg) over 3 years of daily administration. QXW, frequency of dose titrations (i.e., dose titration every X weeks). Curves represent modeled probabilities in 10,000 simulated participants. Shaded bands represent 5th to 95th percentile prediction intervals based on 1000 simulated trials; each trial was composed of 142 participants resampled from the 10,000 simulated participants.