Cytokinetics Announces Positive Topline Data for Aficamten in SEQUOIA-HCM

Martin Maron, MD
Credit: HCM Academy

Cytokinetics Inc. has announced positive topline results from the phase 3 SEQUOIA-HCM trial examining aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM).

Announced on December 27, 2023, topline results indicate use of aficamten, a next-generation selective cardiac myosin inhibitor, was associated with significantly improved exercise capacity compared to placebo as well as statistically significant and clinically meaningful improvements were also observed in all 10 prespecified secondary endpoints.

“Cardiac myosin inhibition represents an exciting new therapy option for patients with symptomatic obstructive HCM and I am pleased to see these impressive results from SEQUOIA-HCM,” said principal investigator Martin Maron, MD, director of the Hypertrophic Cardiomyopathy Center at Lahey Hospital and Medical Center. “A therapy like aficamten that improves exercise capacity in a clinically meaningful manner, absent low LVEF events that interrupt treatment, should be a welcome addition for HCM patients as well as the clinicians who treat them.”

Cytokinetics announced the launch of the SEQUOIA-HCM trial in February 2022 after positive data from the phase 2 REDWOOD-HCM trial of aficamten. In REDWOOD-HCM, which was presented by Maron at the Heart Failure Society of America 2021 Annual Scientific Meeting, patients were randomized to receive 1 of 2 aficamten dosing regimens, which included echocardiography assessments to guide dose levels, or placebo therapy for 10 weeks.

In REDWOOD-HCM, use of aficamten for 10 weeks was associated statistically significant reductions from baseline compared to placebo in the average resting left ventricular (LV) outflow tract pressure gradient (LVOT-G) (p=0.0003, p=0.0004, Cohort 1 and Cohort 2, respectively) and the average post-Valsalva LVOT-G (P for Cohort 1=.001; P for Cohort 2<.0001). Results also indicated the majority of patients treated with aficamten (78.6% in Cohort 1 and 92.9% in Cohort 2) achieved a resting gradient less than 30 mmHg and post-Valsalva gradient less than 50 mmHg at week 10 compared to placebo (7.7%).

A randomized, placebo-controlled, double-blind, multicenter, international trial, SEQUOIA-HCM was designed to assess the safety and efficacy of aficamten in patients with symptomatic obstructive HCM on background medical therapy relative to placebo for 24 weeks. The trial’s primary endpoint was change in peak oxygen uptake, which was measured by CPET, from baseline to week 24.

The trial enrolled 282 patients. This cohort had a mean age of 59.1 (Standard Deviation [SD], 12.9) years, 40.4% were women, and 78.7% were non-Hispanic White. As it relates to HCM history, The mean KCCQ-CSS at baseline was 74.7 (SD, 18.0), 24.1% were considered SRT eligible, and the majority of patients were considered NYHA functional class II (75.9%) or III (23.8%).

Topline results announced by Cytokinetics indicate use of aficamten was associated with statistically significant improvements in peak exercise capacity, with a least square mean difference in peak oxygen uptake of 1.74 (95% confidence interval [CI], 1.04 - 2.44; (P=.000002) mL/kg/min relative to placebo. The company’s release points out the treatment effect observed in the trial were constant across all prespecified subgroups reflective of patient baseline characteristics and treatment strategies.

Secondary endpoint results of interest spotlighted by Cytokinetics included statistically significant improvements in KCCQ-CSS at weeks 12 and 24, the proportion of patients with an improvement of 1 or more NYHA functional class at weeks 12 and 24, and guideline-eligibility for septal reduction therapy.

Safety results highlighted by Cytokinetics suggested aficamten was well-tolerated in SEQUOIA-HCM, with treatment-emergent serious adverse events occurring among 5.6% and 9.3% of patients in the aficamten and placebo groups, respectively. Additionally, there were no reports of worsening heart failure or treatment interruptions due to low LVEF observed in the trial.

According to the December 27, 2023, release from Cytokinetics announcing SEQUOIA-HCM topline results, the company plans to present full results at an upcoming medical conference. Aficamten is also the subject of 2 ongoing phase 3 trials in MAPLE-HCM and ACACIA-HCM, which are examining the agent in as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM and in patients with symptomatic non-obstructive HCM, respectively.

“We believe these results are consistent with those observed in REDWOOD-HCM, the Phase 2 clinical trial of aficamten, and FOREST-HCM, the ongoing open label extension clinical trial, and may reflect a profile enabling of aficamten to become the cardiac myosin inhibitor of choice among physicians and patients,” said Fady I. Malik, MD, PhD, executive vice president of Research and Development at Cytokinetics. “We thank the patients, investigators and site personnel who participated in SEQUOIA-HCM and continue to support our ongoing clinical research and look forward to sharing the full results from this trial at a medical meeting in 2024.”

References:

1. Cytokinetics, Inc. Cytokinetics announces positive results from Sequoia-HCM, the pivotal phase 3 clinical trial of Aficamten in patients with obstructive hypertrophic cardiomyopathy. Cytokinetics, Inc. December 27, 2023. Accessed December 27, 2023. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-positive-results-sequoia-hcm-pivotal.
2. Cytokinetics, Inc. Cytokinetics announces start of Sequoia-HCM, a phase 3 clinical trial of Aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy. Cytokinetics, Inc. February 23, 2022. Accessed December 27, 2023. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-start-sequoia-hcm-phase-3-clinical-trial.
3. Campbell P. AFICAMTEN shows potential for hypertrophic cardiomyopathy in Redwood-HCM. HCP Live. September 15, 2021. Accessed December 27, 2023. https://www.hcplive.com/view/aficamten-shows-potential-for-hypertrophic-cardiomyopathy-in-redwood-hcm.
4. Cytokinetics, Inc. Cytokinetics presents baseline characteristics from Sequoia-HCM at the HCM Society Scientific Sessions. Cytokinetics, Inc. October 6, 2023. Accessed December 27, 2023. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-presents-baseline-characteristics-sequoia-hcm-hcm.