Myosin Inhibitor Boosts QoL, Eases Symptoms in Obstructive HCM

Patients with obstructive hypertrophic cardiomyopathy (HCM) who took the myosin inhibitor aficamten (Cytokinetics) showed major improvements in heart failure (HF) symptoms, functional capacity, hemodynamics, and quality of life in an observational cohort study.

The findings, from the REDWOOD-HCM OLE open-label extension study, are in line with those of its progenitor placebo-controlled, phase-2 study, REDWOOD-HCM. They are also consistent with the longer experience of the first-in-class myosin inhibitor mavacamten (Camzyos, Bristol Myers Squibb), which the US Food and Drug Administration approved for symptomatic obstructive HCM earlier this year.

In the open-label extension study of aficamten, patients reported “substantial and significant” gains in Kansas City Cardiomyopathy Questionnaire (KCCQ) scores for up to 6 months, “benefits that were observed very early in the treatment course,” said Sara Saberi, MD, University of Michigan, Ann Arbor.

Patients taking the drug also showed reductions in echocardiographic left ventricular outflow tract (LVOT) gradient, a gauge of LVOT obstruction, a hallmark of obstructive HCM. The LVOT improvements were observed both at rest and during Valsalva maneuver.

“Aficamten obliterated resting obstruction” after 4 weeks of treatment and significantly improved “dynamic” obstruction within 6 weeks, said Saberi, who reported the study October 2 at the Heart Failure Society of America (HFSA) 2022 Annual Scientific Meeting, held in National Harbor, Maryland.

Myosin inhibitors target the underlying disease process of obstructive HCM, characterized by left ventricular (LV) hypertrophy, myocardial fibrosis, hypercontractility, and abnormal myocardial relaxation.

In the main REDWOOD-HCM study, as previously reported, aficamten conferred similar hemodynamic benefits and was associated with a significant decline in natriuretic peptide levels. But symptom relief for patients on the drug compared with placebo fell short of significance.

The myosin-inhibitor line of research in obstructive HCM “is an exciting area because we have at least two members of this class showing very similar results, in terms of improvement in cardiac function. The declines in natriuretic peptides are really quite striking,” John G.F. Cleland, MD, PhD, University of Glasgow Institute of Health and Wellbeing, Scotland, who is not connected with the study, said during the question-and-answer period following Saberi’s presentation.

Meanwhile, the REDWOOD-HCM OLE cohort’s mean LV ejection fraction (LVEF), which had started at 69%, declined slightly but significantly across the 24 weeks but didn’t descend below 65%.

“Presumably,” speculated Cleland, patients with HCM account for many who have the recently proposed phenotype of HF with supranormal ejection fraction (HFsnEF), characterized by an LVEF greater than 65%. Cleland is a coauthor on a 2020 paper that makes one of the earliest references to a HFsnEF phenotype.

“I’m really encouraged by the results that I’m seeing” based on the myosin-inhibitor studies in obstructive HCM, Cleland told | Medscape Cardiology. “I think the key question is whether they are effective just in people with left ventricular outflow tract obstruction, or also the nonobstructive patients — do they work equally well in them?”

Were the drugs to show similar results in nonobstructive HCM, Cleland said, “that would be a real game-changer.”

The open-label extension study followed 42 patients who had participated in the REDWOOD-HCM randomized trial, 25 of them women. About half of the cohort was in New York Heart Association (NYHA) class 2 at baseline with the remainder in NYHA class 3.

About 70% and 62% of patients had improved 1 step in NYHA class at week 12 and 24, respectively. About 8% and 14%, respectively, had improved by 2 NYHA-class steps, Saberi reported.

Prevalence of NYHA Functional Classes at Baseline and Follow-up in REDWOOD-HCM OLE
NYHA Class Baseline Week 12 Week 24
NYHA 1 0% 41% 45%
NYHA 2 52% 51% 48%
NYHA 3 48% 8% 7%

Slightly less than one-fourth of patients (P < .0001) showed no change in NYHA class at either time. No one in the study worsened in NYHA functional class, Saberi reported.

Patient-reported outcomes by KCCQ scores improved consistently. The mean KCCQ Overall Summary Score (OSS) improved by 16.5 (P < .0001) and 17.6 (P = .0015) points at 12 and 24 weeks, respectively, compared to baseline.

About 73% and 72% of patients, respectively, improved by at least 5 KCCQ-OSS points at weeks 12 and 24 in parallel with other KCCQ domains. That level of improvement at 24 weeks was achieved for the KCCQ clinical summary score by 69% of patients, for the KCCQ total symptom score by 62%, and for the KCCQ quality of life score by 69%.

A change in KCCQ-OSS score by at least 20 points was achieved by 36% of patients at week 12 and by 40% at week 24.

Biomarker improvements paralleled the gains in clinical and patient-reported outcomes. Natriuretic peptide levels went down by 70% by week 12 compared to baseline, a reduction that persisted at week 24 (P < .0001). And levels of cardiac troponin I by high-sensitivity assay fell by 30% at both weeks 14 and 24 (P < .005).

The randomized SEQUOIA-HCM trial, recently underway and looking primarily at functional capacity, is assigning a planned 270 patients with obstructive HCM to aficamten or placebo at 1 of 4 echo-guided dosages.

Saberi disclosed consulting for or receiving honoraria from Bristol Myers Squibb (BMS) and Cytokinetics; serving on steering committees for trials supported by BMS and Cytokinetics; and serving as a site principal investigator for studies supported by BMS, Cytokinetics, and Novartis. Cleland disclosed no relevant financial relationships.

Heart Failure Society of America (HFSA) 2022 Annual Scientific Meeting: Improvement in KCCQ Scores in Patients with Obstructive Hypertrophic Cardiomyopathy Treated with Aficamten in the REDWOOD-HCM OLE Study. Presented October 2, 2022.

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