TY - JOUR

T1 - Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy

AU - Maron, Martin S.

AU - Masri, Ahmad

AU - Nassif, Michael E

AU - Barriales-Villa, Roberto

AU - Arad, Michael

AU - Cardim, Nuno

AU - Choudhury, Lubna

AU - Claggett, Brian

AU - Coats, Caroline J

AU - Düngen, Hans-Dirk

AU - Garcia-Pavia, Pablo

AU - Hagège, Albert A

AU - Januzzi, James L

AU - Lee, Matthew M.Y.

AU - Lewis, Gregory D

AU - Ma, Chang-Sheng

AU - Michels, Michelle

AU - Olivotto, Iacopo

AU - Oreziak, Artur

AU - Owens, Anjali T

AU - Spertus, John A

AU - Solomon, Scott D

AU - Tfelt-Hansen, Jacob

AU - van Sinttruije, Marion

AU - Veselka, Josef

AU - Watkins, Hugh

AU - Jacoby, Daniel L

AU - Heitner, Stephen B

AU - Kupfer, Stuart

AU - Malik, Fady I

AU - Meng, Lisa

AU - Wohltman, Amy

AU - Abraham, Theodore P

AU - SEQUOIA-HCM Investigators

N1 - Copyright © 2024 Massachusetts Medical Society.

PY - 2024

Y1 - 2024

N2 - BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility.METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24.RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups.CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

AB - BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility.METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24.RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups.CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

KW - Humans

KW - Double-Blind Method

KW - Male

KW - Middle Aged

KW - Female

KW - Cardiomyopathy, Hypertrophic/drug therapy

KW - Aged

KW - Exercise Test

KW - Oxygen Consumption/drug effects

KW - Ventricular Outflow Obstruction/drug therapy

KW - Adult

KW - Cardiac Myosins/antagonists & inhibitors

KW - Exercise Tolerance/drug effects

KW - Valsalva Maneuver

KW - Benzylamines

KW - Uracil/analogs & derivatives

U2 - 10.1056/NEJMoa2401424

DO - 10.1056/NEJMoa2401424

M3 - Journal article

C2 - 38739079

VL - 390

SP - 1849

EP - 1861

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 20

ER -