Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy.

Background: Aficamten, a next-in-class cardiac myosin inhibitor, improved peak oxygen uptake (pVO ₂ ) and lowered resting and Valsalva left ventricular outflow (LVOT) gradients in adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM), a phase 3, multicenter, randomized, double-blinded, placebo-controlled study.
Objectives: The authors sought to evaluate the effect of aficamten on echocardiographic measures of cardiac structure and function in SEQUOIA-HCM.
Methods: Serial echocardiograms were performed over 28 weeks in patients randomized to receive placebo or aficamten in up to 4 individually titrated escalating doses (5-20 mg daily) over 24 weeks based on Valsalva LVOT gradients and left ventricular ejection fraction (LVEF).
Results: Among 282 patients (mean age 59 ± 13 years; 41% female, 79% White, 19% Asian), mean LVEF was 75% ± 6% with resting and Valsalva LVOT gradients of 55 ± 30 mm Hg and 83 ± 32 mm Hg, respectively. Over 24 weeks, aficamten significantly lowered resting and Valsalva LVOT gradients, and improved left atrial volume index, lateral and septal e' velocities, and lateral and septal E/e' (all P ≤ 0.001). LV end-systolic volume increased and wall thickness decreased (all P ≤ 0.003). Aficamten resulted in a mild reversible decrease in LVEF (-4.8% [95% CI: -6.4% to -3.3%]; P < 0.001) and absolute LV global circumferential strain (-3.7% [95% CI: 1.8%-5.6%]; P < 0.0010), whereas LV global longitudinal strain was unchanged. Several measures, including LVEF, LVOT gradients, and E/e' returned to baseline following washout. Among those treated with aficamten, improved pVO ₂ and reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) were associated with improvement in lateral e' velocity and septal and lateral E/e' (all P < 0.03), whereas improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (KCCQ-CSS) was associated with a decrease in both LVOT gradients (all P < 0.001).
Conclusions: Compared with placebo, patients receiving aficamten demonstrated significant improvement in LVOT gradients and measures of LV diastolic function, and several of these measures were associated with improvements in pVO ₂ , KCCQ-CSS, and NT-proBNP. A modest decrease in LVEF occurred yet remained within normal range. These findings suggest aficamten improved multiple structural and physiological parameters in oHCM without significant adverse changes in LV systolic function. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).
Competing Interests: Funding Support and Author Disclosures The SEQUOIA-HCM trial is funded by Cytokinetics, Incorporated. Representatives of Cytokinetics have been involved in the design and conduct of the study reported in this paper. Study design and data analysis was supported by the funder and aided by coauthors. Manuscript drafting was completed independently but reviewed by the funder. Dr Wang is supported by a ACC/Merck Research Fellowship. Dr Hegde’s and Dr Wang’s institutions have received fees for core lab services from Cytokinetics and Bristol Myers Squibb. Dr Masri has received research grants from Pfizer, Ionis, Attralus, and Cytokinetics; and has received fees from Cytokinetics, BMS, Eidos/BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Prothena, BioMarin, AstraZeneca, and Tenaya. Dr Nassif has received research and grant support from AstraZeneca and Cytokinetics; and has received consulting/advisory fees from Vifor and Cytokinetics. Dr Barriales-Villa has received consultant/advisor fees from MyoKardia/Bristol Myers Squibb. Dr Cardim has received speaker fees from Cytokinetics and Bristol Myers Squibb. Dr Coats has received speaker fees from Alnylam and Pfizer; and has received advisory fees from Cytokinetics and Roche Diagnostics. Dr Kramer has received research grants from Cytokinetics, BMS, and Eli Lilly; and is a consultant for Eli Lilly. Dr Maron has received consultant/advisor fees from Imbria and Takeda; and has received steering committee fees for SEQUOIA-HCM from Cytokinetics, Incorporated. Dr Michels’ institution has received a research grant from Bristol Myers Squibb; has received consultant/ advisor fees from Cytokinetics and Bristol Myers Squibb/Myokardia and Alnylam; and has received speaker fees from Bristol Myers Squibb and Pfizer. Dr Olivotto has received research grants from Bristol Myers Squibb, Cytotinetics, Sanofi, Benzyme, Amicus, Bayer, Menarini International, Chiesi, and Boston Scientific; has received consulting fees from Bristol Myers Squibb, Amicus, Sanofi, and Genzyme; and has served as an Advisory Board member for Cytokinetics, Bristol Myers Squibb, Chiesi, and Rocket Pharma. Dr Saberi has received consultant/advisor fees from Bristol Myers Squibb; and has received research grants from Cytokinetics, Bristol Myers Squibb, Cytokinetics, Novartis, and Actelion Pharmaceuticals. Drs Jacoby, Heitner, Kupfer, Meng, and Malik, and Ms Wohltman are employees of and hold stock in Cytokinetics, Incorporated. Dr Solomon has received research grants from Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos/Bridgebio, Gossamer, GSK, Ionis, Lilly, NIH/NHLBI, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, BMS, Cardior, Cardurion, Corvia, Cytokinetics, GSK, Lilly, Novartis, Roche, Theracos, Quantum Genomics, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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