Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM

Caroline J Coats; Ahmad Masri; Michael E Nassif; Roberto Barriales-Villa; Michael Arad; Nuno Cardim; Lubna Choudhury; Brian Claggett; Hans-Dirk Düngen; Pablo Garcia-Pavia; Albert A Hagège; James L Januzzi; Matthew M Y Lee; Gregory D Lewis; Chang-Sheng Ma; Martin S Maron; Zi Michael Miao; Michelle Michels; Iacopo Olivotto; Artur Oreziak; Anjali T Owens; John A Spertus; Scott D Solomon; Jacob Tfelt-Hansen; Marion van Sinttruije; Josef Veselka; Hugh Watkins; Daniel L Jacoby; Polina German; Stephen B Heitner; Stuart Kupfer; Justin D Lutz; Fady I Malik; Lisa Meng; Amy Wohltman; Theodore P Abraham; SEQUOIA‐HCM Investigators *

doi:10.1161/JAHA.124.035993

Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM

Caroline J Coats^*, Ahmad Masri, Michael E Nassif, Roberto Barriales-Villa, Michael Arad, Nuno Cardim, Lubna Choudhury, Brian Claggett, Hans-Dirk Düngen, Pablo Garcia-Pavia, Albert A Hagège, James L Januzzi, Matthew M Y Lee, Gregory D Lewis, Chang-Sheng Ma, Martin S Maron, Zi Michael Miao, Michelle Michels, Iacopo Olivotto, Artur OreziakAnjali T Owens, John A Spertus, Scott D Solomon, Jacob Tfelt-Hansen, Marion van Sinttruije, Josef Veselka, Hugh Watkins, Daniel L Jacoby, Polina German, Stephen B Heitner, Stuart Kupfer, Justin D Lutz, Fady I Malik, Lisa Meng, Amy Wohltman, Theodore P Abraham, SEQUOIA‐HCM Investigators *

^*Corresponding author for this work

Department of Cardiology

16 Citations (Scopus)

Abstract

BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM).

METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation.

CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM.

REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Original language	English
Article number	e035993
Journal	Journal of the American Heart Association
Volume	13
Issue number	15
ISSN	2047-9980
DOIs	https://doi.org/10.1161/JAHA.124.035993
Publication status	Published - 6 Aug 2024

Keywords

Adult
Aged
Atrial Fibrillation/drug therapy
Benzylamines
Cardiomyopathy, Hypertrophic/physiopathology
Dose-Response Relationship, Drug
Double-Blind Method
Female
Humans
Male
Middle Aged
Stroke Volume/drug effects
Treatment Outcome
Uracil/analogs & derivatives
Ventricular Function, Left/drug effects
cardiac myosin inhibitor
hypertrophic cardiomyopathy
aficamten

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10.1161/JAHA.124.035993

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Coats, C. J., Masri, A., Nassif, M. E., Barriales-Villa, R., Arad, M., Cardim, N., Choudhury, L., Claggett, B., Düngen, H.-D., Garcia-Pavia, P., Hagège, A. A., Januzzi, J. L., Lee, M. M. Y., Lewis, G. D., Ma, C.-S., Maron, M. S., Miao, Z. M., Michels, M., Olivotto, I., ... SEQUOIA‐HCM Investigators * (2024). Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM. Journal of the American Heart Association, 13(15), Article e035993. https://doi.org/10.1161/JAHA.124.035993

Coats, CJ, Masri, A, Nassif, ME, Barriales-Villa, R, Arad, M, Cardim, N, Choudhury, L, Claggett, B, Düngen, H-D, Garcia-Pavia, P, Hagège, AA, Januzzi, JL, Lee, MMY, Lewis, GD, Ma, C-S, Maron, MS, Miao, ZM, Michels, M, Olivotto, I, Oreziak, A, Owens, AT, Spertus, JA, Solomon, SD, Tfelt-Hansen, J, van Sinttruije, M, Veselka, J, Watkins, H, Jacoby, DL, German, P, Heitner, SB, Kupfer, S, Lutz, JD, Malik, FI, Meng, L, Wohltman, A, Abraham, TP & SEQUOIA‐HCM Investigators * 2024, 'Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM', Journal of the American Heart Association, vol. 13, no. 15, e035993. https://doi.org/10.1161/JAHA.124.035993

@article{03c03285ecdb478f9754e1abcba40c2b,

title = "Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM",

abstract = "BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM).METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50\%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50\%, and treatment-emergent adverse events. At week 8, 3.6\%, 12.9\%, 35\%, and 48.6\% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9\% (95\% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9\%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50\%. There were no treatment interruptions or heart failure worsening for LVEF <50\%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation.CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.",

keywords = "Adult, Aged, Atrial Fibrillation/drug therapy, Benzylamines, Cardiomyopathy, Hypertrophic/physiopathology, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Stroke Volume/drug effects, Treatment Outcome, Uracil/analogs \& derivatives, Ventricular Function, Left/drug effects, cardiac myosin inhibitor, hypertrophic cardiomyopathy, aficamten",

author = "Coats, \{Caroline J\} and Ahmad Masri and Nassif, \{Michael E\} and Roberto Barriales-Villa and Michael Arad and Nuno Cardim and Lubna Choudhury and Brian Claggett and Hans-Dirk D{\"u}ngen and Pablo Garcia-Pavia and Hag{\`e}ge, \{Albert A\} and Januzzi, \{James L\} and Lee, \{Matthew M Y\} and Lewis, \{Gregory D\} and Chang-Sheng Ma and Maron, \{Martin S\} and Miao, \{Zi Michael\} and Michelle Michels and Iacopo Olivotto and Artur Oreziak and Owens, \{Anjali T\} and Spertus, \{John A\} and Solomon, \{Scott D\} and Jacob Tfelt-Hansen and \{van Sinttruije\}, Marion and Josef Veselka and Hugh Watkins and Jacoby, \{Daniel L\} and Polina German and Heitner, \{Stephen B\} and Stuart Kupfer and Lutz, \{Justin D\} and Malik, \{Fady I\} and Lisa Meng and Amy Wohltman and Abraham, \{Theodore P\} and \{SEQUOIA‐HCM Investigators *\}",

year = "2024",

month = aug,

day = "6",

doi = "10.1161/JAHA.124.035993",

language = "English",

volume = "13",

journal = "Journal of the American Heart Association",

issn = "2047-9980",

publisher = "American Heart Association Inc.",

number = "15",

}

TY - JOUR

T1 - Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy

T2 - Results From SEQUOIA-HCM

AU - Coats, Caroline J

AU - Masri, Ahmad

AU - Nassif, Michael E

AU - Barriales-Villa, Roberto

AU - Arad, Michael

AU - Cardim, Nuno

AU - Choudhury, Lubna

AU - Claggett, Brian

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 - Maron, Martin S

AU - Miao, Zi Michael

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 - German, Polina

AU - Heitner, Stephen B

AU - Kupfer, Stuart

AU - Lutz, Justin D

AU - Malik, Fady I

AU - Meng, Lisa

AU - Wohltman, Amy

AU - Abraham, Theodore P

AU - SEQUOIA‐HCM Investigators

PY - 2024/8/6

Y1 - 2024/8/6

N2 - BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM).METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation.CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

AB - BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM).METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation.CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

KW - Adult

KW - Aged

KW - Atrial Fibrillation/drug therapy

KW - Benzylamines

KW - Cardiomyopathy, Hypertrophic/physiopathology

KW - Dose-Response Relationship, Drug

KW - Double-Blind Method

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Stroke Volume/drug effects

KW - Treatment Outcome

KW - Uracil/analogs & derivatives

KW - Ventricular Function, Left/drug effects

KW - cardiac myosin inhibitor

KW - hypertrophic cardiomyopathy

KW - aficamten

UR - https://www.scopus.com/pages/publications/85200827341

U2 - 10.1161/JAHA.124.035993

DO - 10.1161/JAHA.124.035993

M3 - Journal article

C2 - 39056349

SN - 2047-9980

VL - 13

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

IS - 15

M1 - e035993

ER -

Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM

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