Aficamten Showcases oHCM Benefit in Phase 3 SEQUOIA-HCM Trial

Martin Maron, MD
Credit: HCM Academy

Results of the SEQUOIA-HCM trial suggest the cardiology community may soon witness the approval of a second cardiac myosin inhibitor for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM).

Presented at Heart Failure 2024 and simultaneously published in the New England Journal of Medicine, results of the 24-week, phase 3 trial suggest use of aficamten was associated with significantly greater improvement in peak oxygen uptake and for all 10 secondary end points included in the trial relative to placebo therapy. Published less than a week after the American College of Cardiology and American Heart Association recommended use of cardiac myosin inhibitors in their 2024 update to HCM guidelines, results of the trial provide the most substantial evidence to date of the benefits of aficamten for patients with obstructive HCM.

“The SEQUOIA-HCM trial demonstrated that aficamten can reliably and safely eliminate LVOT obstruction in patients with obstructive HCM using a simple and stepwise dosing regimen and was associated with substantial improvements in clinically relevant endpoints such as exercise capacity and symptoms,” said principal investigator Martin Maron, MD, of the Lahey Hospital and Medical Center. “HCM patients are often on multiple medications, which frequently provide suboptimal benefit, while aficamten was highly effective at providing clinical improvement as combination therapy, but also as monotherapy.”

Although mavacamten stands as the first and only cardiac myosin inhibitor boasting approval as of May 2024, excitement surrounding the potential of aficamten, a next-generation cardiac myosin inhibitor from Cytokinetics, has been building for several years and has grown stronger with each subsequent data release. A phase 3, international, double-blind, randomized, placebo-controlled trial, SEQUOIA-HCM enrolled and randomized patients with symptomatic obstructive HCM in a 1:1 ratio to receive aficamten, at a starting dose of 5 mg and a maximum dose of 20 mg, or placebo in addition to standard drug therapy for 24 weeks.

To be considered eligible for the trial patients needed to be 18 to 85 years of age, have a confirmed clinical diagnosis of HCM, a left ventricular wall thickness of at least 15 mm in the absence of pressure overload or other discernible concerns. Investigators noted patients were also required to have an LVEF of at least 60% at screening and have NYHA functional class II or III heart failure.

In total, the trial enrolled a randomized 282 patients, with 142 randomized to aficamten and 140 randomized to placebo. Investigators pointed out these groups had similar clinical characteristics and demographics. Overall, the study cohort had a mean age of 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. Assessments of baseline medication use revealed 61.3% of the patients were receiving beta-blockers and 12.8% were receiving disopyramideat screening.

The trial’s primary outcome of interest was change from baseline to week 24 in the peak oxygen uptake, which was assessed by cardiopulmonary exercise testing. The trial included 10 prespecified secondary endpoints, which were tested hierarchically and included change in KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy.

Upon analysis, results indicated the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, −0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P <.001). Results also indicated use of aficamten was associated with significant improvements in all 10 secondary endpoints, with select outcomes highlighted below:

• Change in KCCQ-CSS: 7 points (95% CI, 5 to 10)

• Improvement of 1 NYHA Class: 58.5% vs 24.3%
• Least-squares mean difference in LVOT gradient after Valsalva: –50 mm Hg (95% CI, −57 to −44)
• LVOT gradient of less than 30 mmHg after Valsalva: 49.3% vs 3.6%

Analysis of safety outcomes indicated serious adverse events occurred among 5.6% of the aficamten group and 9.3% of the placebo group. Additionally, 1 adverse event resulting in discontinuation of aficamten and 2 adverse events resulting in early discontinuation of placebo occurred during the trial. At week 24, investigators pointed out the LVEF among the aficamten group was reduced relative to the placebo group (least-squares mean difference, –4.8 percentage points; 95% CI, –6.3 to –3.2), but there was no marked difference between the groups in LVEF after the 4-week washout period.

“It was impressive to see that the beneficial effects of aficamten occurred rapidly and consistently over the treatment period and that the doses could be adjusted effectively and safely using only site read echocardiographic measures. It was also reassuring to see that in the very small number of patients found to have an ejection fraction below 50% on aficamten, there was no associated heart failure or the need for dose interruption, and that the effect on ejection fraction was reversible with treatment discontinuation.”

In an editorial published in the New England Journal of Medicine, Steve Ommen, MD, of the Mayo Clinic, detailed the progress made in the field of obstructive hypertrophic cardiomyopathy in the 60 years since it was first described as its own entity in 1964. Later in the editorial, Ommen, who was the chair of the writing committee for the aforementioned 2024 guideline update form the ACC and AHA, suggests the challenge now becomes outlining the appropriate role for these agents outside of the clinical trial environment.

“Undoubtedly, we now have more fixed ideas and preconceived notions than were carried into the 1964 symposium, so our challenge will be to keep our minds open enough to recognize when simple drugs are simply effective, when more complicated drugs may be required in selected patients, and when mechanical solutions are required. Matching the best option to each patient is the key to long-term success,” Ommen wrote.

References:

1. Maron MS, Masri A, Nassif ME. Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy. New England Journal of Medicine. Published online May 13, 2024. doi:10.1056/NEJMoa2401424
2. European Society of Cardiology. Sequoia-HCM Trial Meets Primary endpoint in obstructive hypertrophic cardiomyopathy. European Society of Cardiology. May 13, 2024. Accessed May 13, 2024. https://www.escardio.org/The-ESC/Press-Office/Press-releases/SEQUOIA-HCM-trial-meets-primary-endpoint-in-obstructive-hypertrophic-cardiomyopathy.
3. Ommen SR. Sixty Years of Hemodynamic Pharmacology in Obstructive Hypertrophic Cardiomyopathy. New England Journal of Medicine. Published online May 13, 2024. doi:10.1056/NEJMe2403937Sixty Years of Hemodynamic Pharmacology in Obstructive Hypertrophic Cardiomyopathy