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Study of Aficamten for Obstructive Hypertrophic Cardiomyopathy
Quick Takes
- In a phase 2 trial with 28 symptomatic, obstructive HCM patients, aficamten use was associated with a large reduction in resting and Valsalva-induced LVOT gradient.
- Aficamten was associated with an improvement in NYHA symptoms compared to placebo.
- The EF reduction with aficamten was modest.
Study Questions:
What is the safety and tolerability of aficamten across different dose ranges in patients with symptomatic, obstructive hypertrophic cardiomyopathy (oHCM)?
Methods:
REDWOOD-HCM was a phase 2, multicenter, randomized, placebo-controlled, double-blind, dose-finding study in adults with symptomatic oHCM between January 2020 and May 2021 across 30 centers in Europe and North America. Eligible patients had symptomatic oHCM with New York Heart Association (NYHA) class II or III symptoms, and resting or Valsalva left ventricular outflow tract (LVOT) gradient ≥50 mm Hg and ejection fraction (EF) ≥60% on echocardiography. Medication dose was down-titrated if EF was <50% at any time and discontinued if EF was <40% at any time.
Results:
Overall, 28 patients were randomized to aficamten and 13 to placebo. In cohort 1 of aficamten (n = 14), the initial dose was 5 mg with an average final dose of 10 mg, and in cohort 2 (n = 14), initial dose was 10 mg with an average final dose of 14 mg. At 10 weeks of treatment, resting LVOT gradients were decreased in both aficamten cohorts (-40 ± 27 mm Hg in cohort 1 and -43 ± 37 mm Hg in cohort 2) and Valsalva LVOT gradients were also reduced (-36 ± 27 mm Hg in cohort 1 and -53 ± 44 mm Hg in cohort 2). EF showed mild reduction (-6 ± 7.5 in cohort 1 and -12 ± 6 in cohort 2). NYHA functional class improved in 43% in cohort 1, 64% in cohort 2, and 31% in the placebo group. Aficamten use was associated with reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) relative to placebo. Aficamten was well tolerated with no serious adverse events and no treatment interruptions or discontinuations. No arrhythmias were noted with aficamten with no impact on blood pressure, heart rate, or any laboratory variables.
Conclusions:
In a double-blinded, placebo-controlled trial, aficamten use in patients with symptomatic oHCM was associated with a decrease in resting and Valsalva LVOT gradient, improvement in NYHA class, and only modest EF reduction. The medication was well tolerated with no treatment interruptions or discontinuations.
Perspective:
oHCM is associated with a high symptom burden that is largely driven by hypercontractility leading to LVOT obstruction. Mavacamten, the first in class cardiac myosin inhibitor, has shown the ability to reduce dynamic LVOT gradient with an improvement in NYHA symptoms. Aficamten is a second in class cardiac myosin inhibitor that has more favorable pharmacokinetic features including shorter half-life, reversibility within 24 hours of discontinuation, and lack of drug–drug interactions. In this phase 2 trial, aficamten was associated with a significant reduction in resting and Valsalva-induced LVOT gradient with an improvement in symptoms. The medication was associated with only a modest reduction in EF. The medication was well tolerated with no associated treatment discontinuations. Limitations include small study size and short duration of follow-up.
Clinical Topics: Heart Failure and Cardiomyopathies, Noninvasive Imaging, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound
Keywords: Cardiac Myosins, Cardiomyopathies, Cardiomyopathy, Hypertrophic, Echocardiography, Drug Interactions, Heart Failure, Natriuretic Peptide, Brain, Sinus of Valsalva, Stroke Volume, Ventricular Outflow Obstruction
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