‘Global Efficacy’ of Aficamten for Obstructive Disease Shown in SEQUOIA-HCM

Patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) may see gains across multiple measures of clinical response with the cardiac myosin inhibitor aficamten (Cytokinetics), according to data from a prespecified post hoc analyses of SEQUOIA-HCM.

Investigators say the findings demonstrate a “global efficacy” of the drug, with 97% of patients in the treatment arm having meaningful improvements in one or more of the four clinical efficacy measures they tested: LV outflow tract gradients, symptom improvement, exercise capacity, and cardiac biomarkers.

“For patients randomized to aficamten for 24 weeks, 68% of those patients achieved a complete hemodynamic response, 71% had a significant improvement in limiting symptoms, nearly half had an enhancement in exercise capacity, and 84% had a significant decrease in NT-proBNP levels,” said Martin S. Maron, MD (Lahey Hospital and Medical Center, Burlington, MA), who presented the results at a virtual late-breaking trial session of the Heart Failure Society of America (HFSA) 2024 annual meeting—moved online after the meeting was cancelled due to Hurricane Helene. They were simultaneously published in the Journal of the American College of Cardiology.

Importantly, the new data also show that among aficamten patients who were eligible for septal reduction therapy at baseline, most had converted to no longer meeting those criteria by week 24.

In the main SEQUOIA-HCM results, presented earlier this year at ESC Heart Failure 2024, aficamten increased peak oxygen uptake beyond thresholds considered clinically meaningful at 24 weeks compared with placebo. Prior to that study, the ability of aficamten to mitigate left ventricular contractility was demonstrated in the REDWOOD-HCM trial.

Maron and colleagues say understanding the totality of aficamten’s benefit by looking at its impact on more than one outcome, as this new analysis does, is helpful to both patients and physicians considering treatment initiation.

The findings likely put aficamten in line for “a similarly favorable regulatory outcome” as mavacamten (Camzyos; Bristol Myers Squibb), a myosin inhibitor approved by the US Food and Drug Administration in 2022 and by European regulators in 2023, noted discussant Mark Drazner, MD (UT Southwestern Medical Center, Dallas, TX).

Still, he said the impact of cardiac myosin inhibitors on long-term outcomes remains an open question.

“The favorable effects we've seen on the LV outflow tract gradients and the other physiological endpoints suggest there will be benefit, but we await those data,” Drazner said. So far, data from the EXPLORER-LTE trial do suggest maintenance of benefit over at least 3 years for mavacamten, he added.

Another open question is whether this class of drug is effective in nonobstructive hypertrophic cardiomyopathy, noted Drazner.

Guidelines from the American Heart Association and American College of Cardiology, released in 2024, “already give a class I indication for the use of [cardiac myosin inhibitors] for persistent symptoms from LV outflow tract obstruction when on beta-blockers, or diltiazem or verapamil if you can't tolerate a beta-blocker,” he added. “But should [cardiac myosin inhibitors] alter the natural history, that is, improve survival, they will move up to first-line therapy.”

Low Numbers Needed to Treat

For the analysis, which enrolled patients from 14 countries, Maron and colleagues assessed complete hemodynamic response (rest and Valsalva gradients of < 30 mm Hg and < 50 mm Hg, respectively), relief in limiting symptoms (an improvement of ≥ 1 in NYHA functional class and/or ≥ 10-point change in Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score), enhanced exercise capacity (≥ 1.5 mL/kg/min change in peak oxygen uptake), and ≥ 50% reduction in NT-proBNP.

The aficamten group consisted of 142 patients (mean age 59 years; 39% women) and the placebo group consisted of 140 patients (mean age 59 years; 42% women). All had a left ventricular ejection fraction of at least 60% and a LV outflow tract gradient of at least 30 mm Hg at rest and at least 50 mm Hg after the Valsalva maneuver.

A complete hemodynamic response was seen in 68.3% of the aficamten group at 24 weeks versus 7.1% of the placebo group, resulting in a number needed to treat (NNT) with aficamten to achieve benefit of 1.6. For reduction in NT-proBNP, the NNT was 1.3, for improvement in HF symptoms it was 3.5, and for enhanced exercise capacity it was 4.5.

Across the four outcomes categories, 23% of the aficamten group had improvement in all measures, 39% improved in three measures, 26% in two measures, and 9% in a single measure. None of the placebo patients achieved improvement in all four measures, while 4% saw improvement in three measures, 16% in two measures, and 39% in a single measure.

In an editorial accompanying the paper in JACC, Michelle M. Kittleson, MD, PhD (Smidt Heart Institute at Cedars-Sinai, Los Angeles, CA), notes that compared with mavacamten, aficamten has a shorter half-life, which enables more rapid dose titrations and drug washout. It also does not have drug interactions via the cytochrome P450 system.

In addition to questions about long-term benefits of aficamten and its use in nonobstructive HCM, Kittleson says other questions that are currently being addressed in ongoing trials include whether aficamten is a better first-line therapy than metoprolol and whether the cardiac myosin inhibitors influence survival.

“With ongoing clinical trial programs and the future substudies, we will move closer to our ultimate goal—a better understanding of therapeutic options to allow for individualized therapy focused on improving the quality of life and survival of our patients living with symptomatic obstructive HCM,” Kittleson writes.