Aficamten in the Spotlight at ESC Congress, with Ahmad Masri, MD, MS

Obstructive hypertrophic cardiomyopathy (HCM) is a disease state that has experienced a boom in progress during recent years. Chief among these advances, in terms of improving patient outcomes, has been the cardiac myosin inhibitor class, which recently received endorsement from the American College of Cardiology and American Heart Association in their 2024 update to HCM guidelines.¹

Although mavacamten holds the title as the first cardiac myosin inhibitor to receive approval for this condition, excitement and anticipation surrounding the potential of aficamten, a next-generation cardiac myosin inhibitor from Cytokinetics, if it were to receive approval from the US Food and Drug Administration. According to the company, a regulatory submission is expected before the close of Q3 2024.^1,2

At the European Society of Cardiology (ESC) Congress 2024, the agent was the subject of at least a half dozen presentations examining data from the clinical trial program, which includes the SEQUOIA-HCM and FOREST-HCM trials. As part of our on-site coverage of the meetings, the editorial team of HCPLive Cardiology sat down with leading subject matter expert Ahmad Masri, MD, MS, director of the Hypertrophic Cardiomyopathy Center at Oregon Health & Science University, about the data he was involved in. In this interview segment, Masri highlights a trio of studies shedding further light on the potential benefits and role of aficamten in the management of obstructive HCM. For more on aficamten, check out our interviews with Masri on a CMR substudy of SEQUOIA-HCM and an integrated safety analysis of the REDWOOD-HCM, SEQUOIA-HCM, and FOREST-HCM trials.^3,4,5

Aficamten and Quality of Life

The first study highlighted by Masri focused on the effects of aficamten on symptom burden and quality of life among patients with obstructive HCM and was presented by John A. Spertus, MD, MPH, clinical director of Outcomes Research at Saint Luke's Mid America Heart Institute. The study sought o evaluate the effects leveraging Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) and the Seattle Angina Questionnaire Summary Score (SAQ-SS) from all 282 SEQUOIA-HCM participants.³

Results of the analysis indicated use ofaficamten was associated significant improvement in KCCQ-OSS (7.9 points; 95% Confidence Interval [CI], 4.8 to 11; P <.001) At 24 weeks. Further analysis demonstrated improvements of 20 points or more in KCCQ-OSS were observed among 30% of patients treated with aficamten compared to 12% of patients treated with placebo, which translated to a number needed to treat (NNT) of 5.8.³

When assessing effect on SAQ-SS, investigators found aficamten significantly improved SAQ-SS scores (7.8 points; 95% CI, 4.7 to 11; P <.001), with 31% of patients treated with aficamten experiencing an improvement of 20 points or greater compared to 14% of patients on placebo (NNT, 5.8). Investigators pointed out SAQ-SS score improvements were also observed among patients with minimal angina within the trial. ³

Investigators highlighted no significant heterogeneity observed in improvements for KCCQ-OSS and SAQ-SS according to patient baseline characteristics, including the severity of disease or level of symptom burden.³

Aficamten and Echocardiography Data

The next study highlighted by Masri examined the effect of aficamten through the lens of echocardiography data and was presented by Sheila Hegde MD, MPH, a cardiovascular medicine specialist in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital. The study leveraged data from SEQUOIA-HCM to assess the effects of aficamten on Valsalva left ventricular outflow (LVOT) gradients and left ventricular ejection fraction (LVEF).⁴

Results of the study demonstrated use of aficamten significantly reduced resting and Valsalva LVOT gradients as well as improved left atrial volume index, lateral and septal e' velocities, and lateral and septal E/e' (all P ≤.001). Further analysis showed use of aficamten increased LV end-systolic volume and decreased wall thickness decreased (all P ≤.003). Additionally, use was associated with a mild reversible decrease in LVEF (-4.8%; 95% CI, -6.4 to -3.3; P <.001), a decrease in absolute LV global circumferential strain (-3.7%; 95% CI, 1.8 to 5.6; P < .001), and no change in LV global longitudinal strain. Investigators pointed out several measures, including LVEF, LVOT gradients, and E/e' returned to baseline following the washout period.⁴

Additional analysis provided evidence suggesting use of aficamten improved pVO2 and reduction in NT-proBNP were associated with improvement in lateral e' velocity and septal and lateral E/e' (all P < .03) while improvement in KCCQ-CSS was associated with a decrease in both LVOT gradients (all P <.001).⁴

Aficamten and Withdrawal of Standard of Care

Next, Masri highlighted findings from an analysis he presented from within the FOREST-HCM trial focused on the withdrawal of standard of care medications in patients with obstructive HCM treated with aficamten. In the analysis, 145 patients from FOREST-HCM who had completed at least 24 weeks of treatment. At baseline, 136 (93.8%) were on standard of care medications, which included beta blockers, calcium channel blockers, and disopyramide.⁵

Attempted standard of care withdrawal occurred among 64 patients (47%), with a comparator group of 72 patients (53%) who continued standard of care medications. The primary outcome of interest was achievement of successful withdrawal, which was defined as a 50% dose reduction in at least 1 medication.⁵

Among those who attempted withdrawal, 59 patients (92%) succeeded, with 38 (64%) discontinuing at least one SoC medication and 27 (71%) maintaining monotherapy with aficamten. Additional analysis revealed there were no significant differences in aficamten’s treatment effect on various clinical parameters, including LVOT gradient, LVEF, and NYHA Functional Class, during the post-withdrawal period compared to pre-withdrawal.⁵

References:

1. Campbell P. Aficamten showcases OHCM benefit in phase 3 Sequoia-HCM trial. HCP Live. May 13, 2024. Accessed September 4, 2024. https://www.hcplive.com/view/aficamten-showcases-ohcm-benefit-in-phase-3-sequoia-hcm-trial.
2. Cytokinetics, Inc. Cytokinetics announces initiation of phase 1 study of Aficamten in healthy Japanese participants. Cytokinetics, Inc. June 17, 2024. Accessed September 3, 2024. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-initiation-phase-1-study-aficamten.
3. Sherrod CF 4th, Saberi S, Nassif ME, et al. Effect of Aficamten on Health Status Outcomes in Obstructive Hypertrophic Cardiomyopathy: Results from SEQUOIA-HCM. J Am Coll Cardiol. Published online August 29, 2024. doi:10.1016/j.jacc.2024.08.014
4. Hegde SM, Claggett BL, Wang X, et al. Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. Published online August 24, 2024. doi:10.1016/j.jacc.2024.08.002
5. Masri A. Effect of Aficamten on Cardiac Structure and Function in Patients with Obstructive Hypertrophic Cardiomyopathy: The SEQUOIA-HCM CMR Trial. Presented at: European Society of Cardiology Congress 2024. August 30 - September 2, 2024. London, UK.