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Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From
Caroline J Coats1, Ahmad Masri2, Michael E Nassif3
1School of Cardiovascular and Metabolic Health University of Glasgow United Kingdom.
Insights
Aficamten effectively reduced left ventricular outflow tract gradients in obstructive hypertrophic cardiomyopathy patients. This cardiac myosin inhibitor demonstrated a favorable safety profile in the SEQUOIA-HCM trial.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by cardiac hypercontractility.
- Aficamten is a novel cardiac myosin inhibitor designed to treat oHCM.
Purpose of the Study:
- To analyze the pharmacokinetics, pharmacodynamics, and safety of aficamten in patients with oHCM.
- To evaluate the efficacy of a dosing algorithm targeting the lowest effective aficamten dose.
Main Methods:
- A randomized, placebo-controlled trial (SEQUOIA-HCM) involving 282 oHCM patients.
- Aficamten doses ranged from 5-20 mg daily, with titration to achieve specific gradient and ejection fraction targets.
- Safety endpoints included major adverse cardiac events, atrial fibrillation, and changes in left ventricular ejection fraction (LVEF).
Main Results:
- Aficamten exposure increased with dose and remained stable.
- A decrease in LVEF was observed, correlating with aficamten exposure; 4.9% of patients required dose reduction for LVEF <50%.
- No major adverse cardiovascular events were reported; treatment-emergent adverse events were similar between aficamten and placebo groups.
Conclusions:
- A site-based dosing strategy for aficamten successfully reduced left ventricular outflow tract gradients.
- Aficamten demonstrated a favorable safety profile in the treatment of obstructive hypertrophic cardiomyopathy.
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.
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