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LISBON, Portugal — A novel oral drug offers clinically meaningful improvements in exercise capacity in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) and reduces the burden of limiting symptoms, new data from the SEQUOIA-HCM trial reveal.
Aficamten is an investigational next-generation selective cardiac myosin inhibitor that reduces left ventricular contractility. Findings from the previous phase 2 REDWOOD-HCM trial suggested that the drug leads to ” clinically relevant” decreases in pressure gradients.
Now, findings from SEQUOIA-HCM show that aficamten confers benefits across a range of measures, said Martin S. Maron, MD, director of the Hypertrophic Cardiomyopathy Center at Lahey Hospital and Medical Center in Burlington, Massachusetts, who presented the findings at the Heart Failure Association of the European Society of Cardiology 2024
The study, simultaneously published in The New England Journal of Medicine, suggests that aficamten led to clinically meaningful improvements in exercise capacity. It also “decreased the burden of limiting symptoms, based on improvements in both physician- and patient-derived metrics,” Maron said at the conference to rapturous applause.
“Robust functional and symptomatic improvements and relief of obstruction was observed early and remained durable throughout the treatment period,” he explained. “In totality, SEQUOIA-HCM underscores the clinical efficacy of aficamten in the treatment of patients with symptomatic obstructive HCM.”
SEQUOIA-HCM meets the criteria for a trial to be deemed “important,” said Perry M. Elliott, MD, PhD, professor of cardiovascular medicine and director of the Institute of Cardiovascular Science at University College London, United Kingdom.
The results show that aficamten is “effective in improving symptoms, exercise capacity, quality of life, and drug-refractory outflow tract obstruction,” he continued.
“Of course, we need long-term data to tell whether this is truly sustainable,” Elliott added. “But I think we now have two pivotal trials that, to my mind at least, mean that myosin inhibitors should now be regarded as standard of care in drug-refractory hypertrophic cardiomyopathy.”
Myosin Inhibitors for HCM
Steve R. Ommen, MD, from the Department of Medicine at the Mayo Clinic in Rochester, Minnesota, wrote in an accompanying editorial with the published study: “The availability of cardiac myosin inhibitors as a tool for symptomatic patients with HCM is a benefit.”
“Refining the appropriate role for these drugs should soon follow with more clinical experience outside the clinical trial environment,” he added, noting that “it seems prudent to continue to use widely available, easy-to-use, cost-effective agents, including beta-blockers and calcium-channel blockers, as first-line therapy in most patients.”
“If patients remain symptomatic or have side effects from these drugs, then all options should be discussed, including treatment with disopyramide or cardiac myosin inhibitors and invasive septal reduction therapy,” Ommen added.
Maron began his presentation by explaining that obstructive HCM is associated with limiting symptoms “particularly exertional dyspnea and decreased exercise capacity, which of course substantially impact a patient’s quality of life.”
Cardiac hypercontractility “is an important disease-related mechanism that’s responsible for driving LVOT [left ventricular outflow tract obstruction],” which is a primary determinant of the limiting symptoms, he said.
Because a current first-line medical therapy for obstructive HCM has “limited efficacy and important side effects,” Maron said, there is “currently an unmet treatment need.”
The pharmacologic features of aficamten offer a wide therapeutic window, with no need for serum plasma drug concentration monitoring, and allow for rapid dose adjustments, all with “minimal drug-drug interactions,” he explained.
Building on the REDWOOD-HCM trial, SEQUOIA-HCM enrolled patients with obstructive HCM who were already receiving standard-of-care therapy and randomly assigned them to standard of care plus aficamten or placebo.
Aficamten was initiated at a dose of aficamten 5 mg that could be escalated to a maximum dose of 20 mg. “Those dose escalations occurred at weeks 2, 4, and 6 and were based on echocardiographic assessment,” Maron explained.
The primary endpoint was change in peak oxygen uptake (pVO2) from baseline to week 24; among the 10 secondary endpoints was change in the self-reported Kansas City Cardiomyopathy Questionnaire (KCCQ)–Clinical Summary Score (CSS) from baseline, assessed in a hierarchical manner.
Of the 282 study participants, approximately 40% were women, and the mean age was 59.0 years. The aficamten and placebo groups were “really well balanced,” Maron explained.
“Patients were on typical background therapy for obstructive HCM,” he reported, which included beta-blockers for slightly more than 60% of participants, calcium-channel blockers for around 30%, and disopyramide for slightly more than 10%.
The study met its primary endpoint. There was no change in pVO2 from baseline to week 24 in the placebo group, whereas there was a significant increase of 1.8 mL/kg/min in the aficamten group (P=.000002). This resulted in a least square mean between-group difference at week 24 of 1.7 mL/kg/min.
For context, previous data have “demonstrated that the risk of death or transplant is reduced by about 18% for each increase in pVO2 of 1 mL/kg/min,” so the increase seen with aficamten “far exceeds the clinically meaningful threshold for an enhancement in exercise capacity,” Maron said.
This effect was seen across “every single one of the prespecified subgroups,” including the subgroup in which patients were stratified by baseline beta-blocker use, he reported.
At week 24, aficamten was significantly better than placebo was for all 10 secondary endpoints (P <.0001 the least square mean difference in left ventricular outflow tract gradient after valsalva maneuver was mm hg least-squares kccq-css score points and of patients experienced an improvement from baseline at one new york heart association functional class.>
On exploratory analysis, patients in the aficamten group spent 78 fewer days eligible for invasive septal reduction than did patients in the placebo group (P <.0001 and experienced an reduction in n-terminal pro-b-type natriuretic peptide levels from baseline to week>
In a separate presentation of SEQUOIA-HCM data, 73.9% of patients in the aficamten group experienced at least one adverse event after starting treatment compared with 70.7% in the placebo group.
In addition, atrial fibrillation was experienced by 2.8% of patients in the aficamten group and 2.9% of patients in the placebo group, reported Caroline J. Coats, MD, PhD, School of Cardiovascular and Metabolic Health, University of Glasgow, United Kingdom.
Palpitations were more common in the aficamten group than in the placebo group (7.0% vs 2.9%), as was hypertension (7.7% vs 2.1).
At week 24, the left ventricular ejection fraction was modestly lower in the aficamten group than in the placebo group, with a least-squares mean difference of -4.8%.
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