Case Strengthens for Cardiac Myosin Inhibitor in SEQUOIA-HCM

Secondary efficacy analyses of the pivotal SEQUOIA-HCM trial continued to favor aficamten, supporting a potential role for another cardiac myosin inhibitor in obstructive hypertrophic cardiomyopathy (HCM).

In these randomized trial analyses, aficamten significantly improved the following outcomes compared with placebo:

• Relief from limiting symptoms (71% vs 42% ≥1 improvement in New York Heart Association functional class and/or ≥10 point increase in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score)
• Odds of complete hemodynamic response (68% vs 7% with rest and Valsalva gradients <30 mm Hg and <50 mm Hg, respectively)
• Enhanced exercise capacity (47% vs 24% with ≥1.5 mL/kg/min change in pVO2)
• Cardiac biomarker response (84% vs 8% with ≥50% decrease from baseline in NT-proBNP)

Additionally, 97% of the aficamten group achieved at least one of these above improvements by week 24 as compared with 59% in placebo-treated patients.

And the proportion of people deemed guideline-eligible for septal reduction therapy fell after treatment (88% vs 52%, P=0.002), Martin Maron, MD, of Lahey Hospital & Medical Center in Burlington, Massachusetts, told the audience during a late-breaking trial session held virtually by the Heart Failure Society of America (HFSA).

Past president of the HFSA Mark Drazner, MD, MSc, of UT Southwestern Medical Center in Dallas, said these were “impressive data” indicative of “dramatically favorable effects” of aficamten in obstructive HCM.

These results were the latest in a spate of SEQUOIA-HCM analyses — also covering echocardiography, cardiac MRI measures of cardiac remodeling, and patient-reported health status — all published in the Journal of the American College of Cardiology (JACC).

As reported previously, the SEQUOIA-HCM investigators had randomized 282 patients with symptomatic obstructive HCM to aficamten or placebo daily for 24 weeks atop standard drug therapy. The principal result was aficamten’s improvement of peak oxygen uptake. The patients averaged 59.1 years of age, with 59.2% men, mean baseline resting left ventricular outflow tract gradient 55.1 mm Hg, and mean baseline left ventricular ejection fraction (LVEF) of 74.8%.

Observers have previously noted that the aficamten data were also consistent with trial results for mavacamten (Camzyos), the first-in-class cardiac myosin inhibitor approved for obstructive HCM in 2022.

“We can expect a similarly favorable regulatory outcome for aficamten,” predicted Drazner, speaking as the HFSA session discussant.

National guidelines have recently begun endorsing cardiac myosin inhibitors with a class I recommendation for certain patients, as they actually treat the underlying cellular pathophysiological mechanism of actin-myosin bonding in HCM, unlike first-line beta-blockers or nondihydropyridine calcium-channel blockers.

“Myocardial hypercontractility in HCM occurs because of excessive availability of myosin heads ready to engage crossbridges with actin with a reduced proportion remaining in the energy-sparing super-relaxed state. By inhibiting the myosin ATPase, cardiac myosin inhibitors reduce the number of myosin heads available for engagement, thus addressing myocardial hypercontractility,” explained Michelle Kittleson, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, in an accompanying JACC editorial.

The downside to these cardiac myosin inhibitors is their reduction of LVEF. The FDA requires a risk evaluation and mitigation strategy so that mavacamten users don’t drop to ejection fractions under 50%.

In this regard, aficamten has the advantage over mavacamten due to its shorter half-life enabling faster dose titrations and drug washout.

Indeed, fewer than 5% of aficamten recipients in SEQUOIA-HCM had LVEF fall below 50%. This was supported by a separate substudy in which aficamten apparently improved multiple structural and physiologic parameters in obstructive HCM without significantly impairing LVEF.

Another difference between aficamten and mavacamten is that the former lacks drug interactions via the cytochrome P450 system.

Drazner suggested that the choice between the cardiac myosin inhibitors is not clear, however, and one would have to “wait to see” how the pharmacological differences translate into clinical differences.

Kittleson pointed out other remaining questions and cited ongoing trials addressing whether cardiac myosin inhibitors have a role to play in first-line therapy in obstructive HCM, as well as how they might fare in nonobstructive HCM.

One of those concerns about the trials is the substantial treatment effect of placebo, according to Morten Kvistholm Jensen, MD, PhD, and colleagues at Aarhus University Hospital, Denmark. “Ideally, modification of trial designs, screening procedures, and selection of endpoints could minimize the treatment effects in the placebo groups in future trials,” they suggested in another editorial in JACC.

This year’s in-person HFSA meeting, originally planned for Atlanta, had been cancelled due to Hurricane Helene.