Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM

Abstract

Background: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM).

Methods and results: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation.

Conclusions: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM.

Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Keywords: aficamten; cardiac myosin inhibitor; hypertrophic cardiomyopathy.

Figure 1. Study design illustrating (A) visit schedule* and (B) dose titration scheme based on echocardiographic criteria.^†

*Focused echocardiogram. ^†Patients receiving aficamten start at a dose of 5 mg once daily (dose 1) and may receive up to 4 escalating doses (10, 15, or 20 mg once daily) over the initial 6 weeks of the trial if they continue to meet the escalation criteria or will stop at their current dose when the escalation criteria are not met. ^‡Dose escalation is not permitted in patients after an aficamten dose reduction. Patients taking aficamten 5 mg and with LVEF <50% will receive placebo. LVEF indicates left ventricular ejection fraction; LVOT‐G, left ventricular outflow tract gradient; PK, pharmacokinetic; SoC, standard of care; and W, week.

Figure 2. Effect of treatment on core laboratory‐ and site‐read measurements of LVEF over the study period* (A) and categorical changes in LVEF during the study phase (B).

LVEF indicates left ventricular ejection fraction. *Data were analyzed using core‐read echocardiograms performed at each study visit.

Figure 3. Predose and postdose plasma concentration of aficamten during the maintenance phase. (A) All available individual concentration measurements between weeks 8 and 24 independent of study week (median and IQR) and (B) mean (95% CI) by dose and study visit between weeks 8 and 24.

IQR indicates interquartile range.

Figure 4. Kernel density estimate plots illustrating the distribution of change in echocardiographic parameters, (A) LVEF, (B) resting LVOT‐G, and (C) Valsalva LVOT‐G, from baseline at every study visit in the aficamten (blue) and placebo (pink) groups.*

LVEF indicates left ventricular ejection fraction; and LVOT‐G, left ventricular outflow tract gradient. *Data were analyzed using all study visits between weeks 2 and 24 with core analysis of echocardiographic parameters. The mean (±SD) difference between the groups was −2.8% (±6.6) for LVEF (A), −13 (±33) mm Hg for resting LVOT‐G (B), and −18 (±40) mm Hg for Valsalva LVOT‐G (C). The gray vertical line denotes no change in echocardiographic parameter from baseline.