ACACIA-HCM Seeks to Prove Aficamten's Benefit in Nonobstructive Hypertrophic Cardiomyopathy

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Ahmad Masri, MD, MS, offers perspective om the study design of the ACACIA-HCM trial and the unmet need within nonobstructive hypertrophic cardiomyopathy.

At the Heart Failure Society of America (HFSA) 2023 Annual Scientific Meeting, the cardiology community was given new insight into the design of a trial that could provide evidence of benefit with use of a cardiac myosin inhibitor for the treatment of nonobstructive hypertrophic cardiomyopathy.

The phase 3 ACACIA-HCM trial, which opened enrollment in September 2023, is expected to enroll 420 patients with nonobstructive hypertrophic cardiomyopathy and build on the findings from cohort 4 of the REDWOOD-HCM trial.

“As the first Phase 3 clinical trial of aficamten in non-obstructive hypertrophic cardiomyopathy, ACACIA-HCM represents an important advancement in the development program for aficamten alongside our two ongoing Phase 3 clinical trials in obstructive HCM,” said Fady I. Malik, MD, PhD, Cytokinetics’ Executive Vice President of Research & Development.


A phase 2, multicenter, randomized, placebo-controlled, double-blind, dose finding clinical trial of aficamten, the REDWOOD-HCM trial included 4 cohorts, with cohorts 1, 2, and 3 enrolling patients with obstructive HCM and cohort 4 enrolling patients with non-obstructive HCM. A total of 41 patients were enrolled in cohort 4, with all these patients being classified as New York Heart Association (NYHA) Class II or III with left ventricular ejection fraction (LVEF) of 60% or greater without a resting or provoked left ventricle outflow tract (LVOT) gradient. Further inclusion criteria required patients to have an NT-proBNP equal to or greater than 300 pg/mL and no history of an LVEF of less than 45%.

Per trial protocol, all patients received aficamten at a beginning dose of 5 mg once daily, which was increased to 10 and 15 mg based on LVEF. Trial participants participated in visits at baseline and weeks 2, 4, 6, 10, and 12, with the total treatment duration lasting 10 weeks and the final 2 weeks serving as a washout period.

Upon analysis, results from cohort 4 indicated use of aficamten was associated with significant improvements in NT-proBNP, which decreased by a mean of 66% (P <.0001) and hs-cTnI levels, which decreased significantly at each study visit (P <.05). Investigators pointed out both NT-proBNP and hs-cTnI levels returned to baseline levels following the 2-week washout period. Additionally, an improvement of at least 1 NYHA functional class was observed among 54% of patients in the cohort, with 2 patients improving from NYHA class III to NYHA class I.


A multicenter, randomized, double-blind, placebo-controlled clinical trial designed to assess the safety and efficacy of aficamten relative to placebo therapy in patients with symptomatic nonobstructive hypertrophic cardiomyopathy, the phase 3 ACACIA-HCM trial is expected to enroll 420 patients and randomize them in a 1:1 ratio to receive aficamten or placebo therapy. Aimed at assessing the effect of the agent on health-related quality of life, the trial’s primary outcome of interest is the change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score from baseline to Week 36.

According to a release from Cytokinetics, the trial will consist of 2 parts, with part 1 lasting from day 1 to week 36 and part 2 lasting from week 6 to week 72. As per trial protocol, all patients will be included in part 1 and, at the conclusion of part 1, will continue into part 2 until the last randomized patient has completed part 1.

Each patient included in the trial will receive up to 4 escalating doses of aficamten or placebo based on echocardiographic guidance. Those randomized to aficamten will begin with a once-daily 5 mg and, at weeks 2, 4, and 6, patients will receive an echocardiogram to determine if they will be uptitrated to escalating doses of 10, 15, or 20 mg, with dose escalation occurring only if a patient has an LVEF equal to or greater than 60%. Of note, patients who do not meet escalation criteria will continue to receive their current dose or may be down-titrated if their LVEF is less than 50%. The trial will also include a cardiac MRI and PK subsidy, which will enroll up to 100 and 30 participants, respectively.

With an interest in learning more about the trial design and the unmet need in nonobstructive hypertrophic cardiomyopathy, the editorial team of HCPLive Cardiology sat down with Ahmad Masri, MD, MS, director of the Cardiomyopathy Center at Oregon Health and Science University and ACACIA-HCM investigator, during their on-site coverage of HFSA 2023.

Masri reports having received funding for consulting or research grants from Cytokinetics, Lexicon, Pfizer, Ionis, Bristol Myers Squibb, and more.


  1. Masri A, Abraham PT, Arad M, et al. A Phase 3, Multicenter, Randomized, Double-blind Trial To Evaluate The Efficacy And Safety Of Aficamten Compared To Placebo In Adults With Symptomatic Non-obstructive Hypertrophic Cardiomyopathy. Paper presented at: Heart Failure Society of America 2023 Annual Scientific Meeting; October 6 - 9; Cleveland, OH. Accessed October 9, 2023.
  2. Cytokinetics announces start of acacia-HCM, a pivotal phase 3 clinical trial of Aficamten in patients with symptomatic non-obstructive hypertrophic cardiomyopathy. Cytokinetics, Inc. September 6, 2023. Accessed October 10, 2023.
  3. Campbell P. AFICAMTEN shows promise in difficult to treat non-obstructive hypertrophic cardiomyopathy. HCP Live. March 6, 2023. Accessed October 10, 2023.