Cytokinetics’ Aficamten Hits Dual Phase III Endpoints in Non-Obstructive HCM

Key Points

• Aficamten met both Phase III ACACIA-HCM primary endpoints in 517 patients with symptomatic non-obstructive hypertrophic cardiomyopathy, improving patient-reported health status and peak oxygen consumption versus placebo.
• The drug was generally well tolerated, but heart-failure events and treatment interruptions for reduced ejection fraction were more common with aficamten, particularly during dose titration. Longer-term extension data suggested benefits were maintained beyond 96 weeks.
• Cytokinetics plans to submit a supplemental FDA application for aficamten in non-obstructive HCM in the fourth quarter, expanding the drug’s potential beyond its obstructive HCM indication.

Cytokinetics NASDAQ: CYTK presented primary results from its Phase III ACACIA-HCM trial evaluating aficamten in patients with symptomatic non-obstructive hypertrophic cardiomyopathy, or nHCM, reporting that the study met its dual primary endpoints for patient-reported health status and exercise capacity.

The results were presented at a cardiology congress in Munich and were accompanied by publications in the New England Journal of Medicine and Circulation, according to Fady Malik, Cytokinetics’ executive vice president of research and development. Malik said the company plans to submit a supplemental new drug application to the FDA for aficamten in nHCM later this year.

Trial Results

ACACIA-HCM enrolled 517 patients with symptomatic nHCM and randomized them equally to aficamten or placebo. Patients received aficamten doses ranging from 5 milligrams to 20 milligrams and were followed in a blinded manner for up to 72 weeks, including a four-week withdrawal period. The primary analysis was conducted at week 36.

Ahmad Masri, director of the Hypertrophic Cardiomyopathy Center at Oregon, said the trial’s dual primary endpoints were changes from baseline in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, or KCCQ-CSS, and peak oxygen consumption, or peak VO2.

• KCCQ-CSS improved by a placebo-adjusted 3 points at week 36 in favor of aficamten, with a P value of 0.021.
• Peak VO2 improved by a placebo-adjusted 0.67 milliliters per kilogram per minute, with a P value of 0.003.
• New York Heart Association class improvement of at least one class showed a 14% difference favoring aficamten at week 36, with a P value of less than 0.001.
• The study also reported favorable results for a composite exercise Z-score and for NT-proBNP, a cardiac biomarker.

Masri said treatment effects across prespecified subgroup analyses, including patients using beta blockers, those with intracavitary obstruction and those with differing genotype status, were generally consistent in favor of aficamten.

Among other secondary endpoints, aficamten showed an effect on left atrial volume index, though it did not reach statistical significance, with a P value of 0.058. Time to first composite cardiovascular event did not differ between the aficamten and placebo groups.

Responder Analysis and Clinical Context

Martin Maron, director of the Hypertrophic Cardiomyopathy Center at Tufts Medical Center, discussed an additional analysis intended to assess clinically meaningful changes for individual patients rather than mean changes across treatment groups.

According to Maron, more than 70% of aficamten-treated patients achieved a prespecified threshold for clinically meaningful symptom improvement, based on improvement in NYHA class and the Patient Global Impression of Change questionnaire. About half achieved a defined improvement in exercise capacity, while more than half showed improvement in left ventricular relaxation and more than 63% had a substantial reduction in BNP.

Maron said more than half of aficamten-treated patients achieved improvement across three or more of the five clinical, functional and biological measures evaluated, compared with 13% of placebo-treated patients. He characterized the findings as evidence of a broad treatment effect in a population with limited treatment options.

Christina Paitazoglou, a cardiologist at University Heart Center in Germany who was not involved in the trial, said nHCM patients remain symptomatic despite current heart-failure-guideline-based care and have lacked a targeted therapy. She noted that the trial’s improvement in peak VO2 was notable because such exercise parameters can be difficult to improve in heart-failure populations.

Safety Findings and Extension Study

Masri said aficamten was generally well tolerated, with no new safety signals reported. The least-squares mean difference in left ventricular ejection fraction, or LVEF, was 4.4%. Treatment interruption due to reduced LVEF occurred in 3% of aficamten-treated patients.

Heart failure events occurred in 4.7% of patients receiving aficamten and 1.2% of placebo recipients. Masri said these events occurred during the drug initiation and titration phase and were managed with diuretics and outpatient care. There was no difference between groups in new-onset atrial fibrillation, he said.

Maron said 12 serious heart failure events occurred in the aficamten arm, compared with three in the placebo arm, and stated that all aficamten events occurred during the titration period. He said patients responded to limited heart-failure therapy and that the events appeared unrelated to ejection fraction.

More than 80% of ACACIA-HCM participants elected to enroll in the FOREST-HCM open-label extension study. Maron said longer-term data from FOREST, using a titration approach incorporating echocardiographic assessment and physician judgment, showed a lower incidence of serious heart failure events than in ACACIA-HCM. He also said clinical benefits appeared to be maintained beyond 96 weeks in the extension study.

Regulatory Plans

Robert Blum, Cytokinetics’ president and chief executive officer, said the company intends to file its supplemental FDA application for nHCM in the fourth quarter. He said Cytokinetics would provide updates on plans for other geographies during its next earnings call.

Blum also said the company has launched MYKORZA for obstructive HCM in the U.S., Germany and China, and has received approval from the U.K.’s MHRA alongside positive guidance from NICE in the U.K. and Wales.

About Cytokinetics (NASDAQ:CYTK)

Cytokinetics, Inc is a late‐stage biopharmaceutical company focused on the discovery and development of novel small‐molecule therapeutics that modulate muscle function. Founded in 1998 and headquartered in South San Francisco, California, the company applies its proprietary insights in muscle biology to address diseases characterized by impaired muscle performance. Its research spans both cardiac and skeletal muscle targets, aiming to deliver innovative medicines for conditions with significant unmet medical need.

The company's most advanced program, omecamtiv mecarbil, is being evaluated for the treatment of heart failure by enhancing cardiac muscle contractility.

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