Topline data show aficamten improves outcomes for adults with obstructive HCM
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Key takeaways:
- Aficamten was shown to improve exercise capacity and symptoms for adults with obstructive HCM.
- Aficamten is the second cardiac myosin inhibitor demonstrated to improve outcomes in this patient population.
Compared with placebo, aficamten was associated with increased exercise capacity and improvements in symptoms of obstructive hypertrophic cardiomyopathy, according to topline results of the phase 3 SEQUOIA-HCM trial.
Aficamten (Cytokinetics), a selective, small molecule cardiac myosin inhibitor, was associated with improved peak oxygen uptake (least square mean difference, 1.74 mL/kg/min; 95% CI, 1.04-2.44; P = .000002), and the treatment effect was consistent across all prespecified subgroups, according to a company press release.
“SEQUOIA-HCM is a pivotal trial that we hope will demonstrate what the clinical benefit of the drug is to patients in terms of how it improves their exercise capacity, how it addresses their symptoms and their function,” Fady I. Malik, MD, PhD, executive vice president of research and development at Cytokinetics, told Healio. “The prior studies showed us that the drug worked as we designed it. It reduced the contractility of the heart. ... We are talking about obstructive HCM, so these patients have an obstruction that leads to a pressure gradient where the blood is trying to exit the heart. We showed that it reduced that.”
Improvement in all key secondary endpoints
The company reported statistically significant improvement in all 10 prespecified secondary endpoints at 12 and 24 weeks (P for all < .0001), including:
- Kansas City Cardiomyopathy Questionnaire Clinical Summary Score;
- NYHA functional class;
- provoked left ventricular outflow tract gradient;
- proportion less than 30 mm Hg;
- exercise workload; and
- guideline-eligibility for septal reduction therapy.
Aficamten was well-tolerated, with similar rates of treatment emergent serious adverse events compared with placebo (5.6% with aficamten vs. 9.3% with placebo), according to the release.
The researchers reported no instances of worsening HF or treatment interruptions attributable to low LVEF.
In addition, core echocardiographic left ventricular ejection fraction was less than 50% in 3.5% of the aficamten group compared with 0.7% of the placebo group.
“The longstanding standard of care in HCM tried to address what the primary problem was indirectly. [Those therapies] either worked by slowing the heart down so that it could fill more ... or by trying indirectly to reduce the contractility of the heart, which is fundamentally the driving pathology,” Malik told Healio. “What cardiac myosin inhibitors do is target that contractile machinery directly and reduce the contractility at the source by inhibiting the motor — myosin.
“Nothing else really addresses that fundamental basic problem,” he said.
Aficamten and mavacamten for obstructive HCM
The only other disease-specific non-surgical treatment for obstructive HCM is mavacamten (Camzyos, Bristol Myers Squibb), also a cardiac myosin inhibitor, which was approved by the FDA in 2022 based on the results of the phase 3 EXPLORER-HCM trial.
As Healio previously reported, mavacamten improved symptoms, quality of life and functional status in patients with obstructive HCM with a left ventricular outflow tract gradient of 50 mm Hg or greater and NYHA class II to III symptoms.
“Mavacamten emerged from our research as well. ... As became evident in terms of its clinical development, it seemed there were some potential areas where another drug could be developed that could be designed as a next-in-class molecule,” Malik told Healio. “The issues we wanted to focus on were reversibility of the effect. ... We hope that 5 years from now, the therapies [patients] have been taking, which are decades old and never based on addressing the disease directly, are going to be replaced by therapies that are designed to address the disease head on,” Malik told Healio.
The full results of the pivotal SEQUOIA-HCM trial will be presented at a medical conference in 2024, the company stated in the release.
Results of a second trial, MAPLE-HCM, randomizing patients to aficamten as first-line therapy vs. beta-blockers, the current first-line therapy, may be available in 2025. And results of a third trial, ACACIA-HCM, evaluating aficamten in patients with nonobstructive HCM may be available in 2026, according to Malik.
“In the course of a couple of years, we will have evidence across the whole spectrum of the disease,” Malik said.
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