Aficamten improves exercise capacity, quality of life in patients with obstructive HCM
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Key takeaways:
- Aficamten improved exercise capacity and quality of life in patients with obstructive hypertrophic cardiomyopathy.
- The degree of improved peak oxygen uptake could lead to lower death or transplantation risk.
In patients with obstructive hypertrophic cardiomyopathy, the cardiac myosin inhibitor aficamten improved exercise capacity and quality of life compared with placebo, according to the results of the SEQUOIA-HCM trial.
As Healio previously reported, topline results of the phase 3 SEQUOIA-HCM trial were announced in December showing that aficamten (Cytokinetics) improved peak oxygen uptake in patients with obstructive HCM on standard-of-care therapy compared with placebo. Martin S. Maron, MD, director of the Hypertrophic Cardiomyopathy Center at Lahey Hospital & Medical Center in Burlington, Massachusetts, and adjunct assistant professor of medicine at Tufts University School of Medicine, presented the full results, which were simultaneously published in The New England Journal of Medicine, at the European Society of Cardiology’s Heart Failure 2024 meeting.
‘Potentially advantageous’
“We were trying to learn whether aficamten could make an impact on improving the symptom burden and exercise capacity in a safe and effective way in patients with obstructive HCM,” Maron told Healio. “Aficamten has a relatively short half-life and a wide therapeutic window. Those aspects of its pharmacology are potentially advantageous. They provide the opportunity for rapid dose titration ... which translates to HCM patients experiencing relief of their symptoms quickly and sooner than any other drug therapy that’s currently available.”
The trial included 282 patients with obstructive HCM on standard-of-care therapy (mean age, 59 years; 41% women) who had left ventricular outflow tract obstruction gradient 30 mm Hg, Valsava 50 mm Hg, NYHA class II to IV HF and predicted peak oxygen uptake (peak VO2) 90 for age. Patients were randomly assigned to aficamten or placebo.
The primary endpoint was change in peak VO2 at 24 weeks. The first secondary endpoint in a hierarchy was change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score at 24 weeks.
The aficamten group had greater improvement in peak VO2 at 24 weeks compared with the placebo group (least squares mean difference, 1.74 mL/kg/min; standard error, 0.36; P = .000002), Maron said during the presentation, noting the risk for death or heart transplantation reduces 21% for each 1 mL/kg/min increase in peak VO2. There was no difference in treatment effect among prespecified subgroups, he said.
‘The effect was substantial’
“The effect was substantial,” Maron told Healio. “What we consider to be a clinically meaningful change in exercise capacity is a change in peak VO2 of 1 mL/kg/min, and therefore an improvement with aficamten of 1.74 far exceeds the clinically meaningful threshold for an improvement in functional capacity.”
Maron said all 10 secondary endpoints in the hierarchy favored the aficamten group (P < .0001 for all):
- change in KCCQ Clinical Summary Score at 24 weeks (least squares mean difference, 7 points);
- improvement in at least 1 NYHA class at 24 weeks;
- change in Valsava LV outflow tract gradient at 24 weeks;
- percentage of patients with Valsava LV outflow tract gradient < 30 mm Hg at 24 weeks;
- duration of eligibility for septal reduction therapy during 24 weeks of treatment;
- change in KCCQ Clinical Summary Score at 12 weeks;
- improvement in at least 1 NYHA class at 12 weeks;
- change in Valsava LV outflow tract gradient at 12 weeks;
- percentage of patients with Valsava LV outflow tract gradient < 30 mm Hg at 12 weeks; and
- total workload change from baseline to week 24.
Aficamten “is a treatment that improves substantially the quality of life of patients who would otherwise be very limited because of their heart disease,” Maron told Healio.
Compared with the placebo group, the aficamten group had 78 fewer days of eligibility for septal reduction therapy. In addition, the aficamten group had an 80% reduction in N-terminal pro-B type natriuretic peptide level at 24 weeks, Maron said.
Adverse event rates were similar between the groups, according to the researchers.
Aficamten is not yet approved for commercial use in the United States. Should it be approved by the FDA, it would be the second cardiac myosin inhibitor on the U.S. market after mavacamten (Camzyos, Bristol Myers Squibb).
“Risk of the major side effect of systolic dysfunction was very low,” Maron told Healio. “And when it did occur, it didn’t result in any treatment interruption or exacerbation of symptoms. That makes it different than other myosin inhibitors on the market right now, where that wasn’t quite the case.”
If approved, the drug could provide patients with obstructive HCM “a transformative therapy in terms of making their quality of life significantly better in a safe, reliable manner,” Maron said.
Researchers hope to evaluate aficamten in patients with symptomatic nonobstructive HCM, who have even fewer treatment options than those with obstructive HCM, Maron told Healio.
Reference:
For more information:
Martin S. Maron, MD, can be reached at martin.maron@lahey.org; X (Twitter): @martinmaronmd.
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Maron MS, et al. Late-breaking clinical trials: LVAD, HFpEF and hypertrophic cardiomyopathy. Presented at: Heart Failure 2024; May 11-14, 2024; Lisbon, Portugal.
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