Cytokinetics Shares Phase 3 ACACIA-HCM Win: Aficamten Hits Dual Endpoints in nHCM Trial

Key Points

• ACACIA-HCM met both primary endpoints, showing statistically significant improvements at week 36 in KCCQ (least-squares mean difference +3.0 points, P=0.021) and peak VO2 (+0.67 mL/kg/min, P=0.003) for aficamten versus placebo.
• No new safety signals were identified, although LVEF <50% occurred in 10% of aficamten patients versus 1% on placebo (two aficamten patients had serious heart-failure events); most ejection-fraction declines were reversible after treatment interruption and typically recovered within about one week.
• Cytokinetics plans to discuss results with the FDA and other regulators and present detailed data at upcoming medical meetings, positioning aficamten as a potential first-in-class therapy to address hypercontractility in non-obstructive HCM.

Cytokinetics NASDAQ: CYTK reported positive top-line results from ACACIA-HCM, a pivotal Phase 3 trial evaluating aficamten in patients with symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM). On a conference call, President and CEO Robert Blum said the study showed “statistically significant improvements in both KCCQ clinical summary score as well as peak VO2,” with effects favoring aficamten versus placebo “throughout the treatment period.”

Blum described the readout as an “exciting step” toward the potential for aficamten to address the “full spectrum of HCM,” adding that patients with nHCM currently have “no approved therapies to address the underlying hypercontractility associated with this disease.”

Trial design and endpoints

Fady Malik, Cytokinetics’ executive vice president of R&D, said ACACIA-HCM was a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial that compared aficamten to placebo in symptomatic nHCM. Participants were randomized 1:1 and underwent echo-guided dose escalation from 5 mg to 20 mg every two weeks as long as left ventricular ejection fraction (LVEF) remained above 60%. Patients could remain on the same dose or be down-titrated if LVEF fell below 50%.

The trial included a 36-week primary treatment period and continued treatment up to 72 weeks to evaluate additional secondary and exploratory endpoints, including time to first cardiovascular event, Malik said. The study randomized 516 participants outside Japan; a Japan cohort remains blinded for a potential approval effort there and was excluded from the primary analysis, according to Malik.

The dual primary endpoint was change from baseline to week 36 in:

• Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score
• Peak oxygen consumption (peak VO2)

Secondary endpoints included New York Heart Association (NYHA) functional class improvement, a composite Z-score tied to exercise testing parameters, and biomarkers and structural measures including NT-proBNP and left atrial volume index, Malik said.

Primary endpoint results: KCCQ and peak VO2

Malik said the trial met both primary endpoints with “statistically significant and clinically meaningful improvements” at week 36 versus placebo. For KCCQ, patients receiving aficamten improved by 11.4 points versus 8.4 points on placebo, yielding a least-squares mean difference of 3.0 points (P=0.021). For peak VO2, aficamten patients improved by 0.64 mL/kg/min versus 0.03 mL/kg/min on placebo, for a least-squares mean difference of 0.67 mL/kg/min (P=0.003).

Malik noted the statistical significance threshold for each dual primary endpoint was set at 0.025, and both achieved that bar “with no recycling of alpha spend necessary.”

He also highlighted the trajectory of KCCQ over time: “At the end of titration at week eight, the curves begin to separate and clearly remain divergent throughout the duration of the trial.” During washout, he said, aficamten patients saw a rapid reduction in KCCQ scores that brought them down to match placebo.

Malik contextualized the magnitude of KCCQ improvements by comparing them to prior aficamten studies, citing KCCQ increases of 12 points in SEQUOIA-HCM, 10.6 points in Cohort 4 of REDWOOD-HCM, and 11 points after 96 weeks in FOREST-HCM in nHCM. He acknowledged a higher-than-expected placebo KCCQ increase in ACACIA-HCM and suggested it could reflect “improvement in clinical care, greater compliance with background medical therapy, or other aspects of standard of care patients receive in a clinical trial.”

Secondary endpoints and clinical meaningfulness

Malik said statistically significant improvements were observed in key secondary endpoints, including the proportion of patients improving by at least one NYHA functional class, the composite Z-score, and NT-proBNP.

On the call, Malik and Stephen Heitner, senior vice president and head of clinical research and development, discussed how they view clinical meaningfulness of changes in peak VO2 and KCCQ. Malik noted that in heart failure trials with therapies that affect major outcomes, KCCQ deltas “rarely” exceed one or two points; he said ACACIA-HCM showed a three-point delta at week 36 and larger deltas at other time points that were not detailed.

Heitner described prior work in obstructive HCM linking patient-perceived minimal improvement to peak VO2, suggesting a minimal important difference “anywhere between 0.35 and 0.5.” He added he would be “surprised” if non-obstructive HCM yielded a different threshold once similar analyses are performed in ACACIA-HCM.

Safety findings and next steps

On safety, Malik said “no new safety signals” were identified. LVEF less than 50% occurred in 10% of participants on aficamten versus 1% on placebo, and two participants on aficamten had serious adverse events of heart failure associated with LVEF below 50%. Treatment interruptions due to LVEF below 40% occurred in 3% of aficamten patients.

Stuart Kupfer, senior vice president and chief medical officer, said most ejection fraction declines did not lead to clinical consequences and generally did not require interruption, and he described the company’s experience that after interruption, ejection fraction typically recovers “within approximately one week,” after which patients may resume at a lower dose.

Blum said Cytokinetics plans to discuss ACACIA-HCM results with the U.S. Food and Drug Administration and other regulators. He said the company will not comment on filing timelines yet, but intends to “move as swiftly as possible” following regulatory discussions.

Malik said the company aims to present more detailed results at a medical meeting, pointing to the European Society of Cardiology (ESC) meeting at the end of August as the next major venue, though he said the company did not yet have insight into whether it would be on the program.

In closing remarks, Blum said steering committee members used descriptors including “transformational” and called the results a “home run” and “best case scenario,” while emphasizing the company will provide further detail when the full dataset is presented.

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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