Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA‐HCM
Authors: Coats Caroline J. , Masri Ahmad , Nassif Michael E. , Barriales‐Villa Roberto , Arad Michael , Cardim Nuno , Choudhury Lubna , Claggett Brian , Düngen Hans‐Dirk , Garcia‐Pavia Pablo , Hagège Albert A. , Januzzi James L. , Lee Matthew M. Y. , Lewis Gregory D. , Ma Chang‐Sheng , Maron Martin S. , Miao Zi Michael , Michels Michelle , Olivotto Iacopo , Oreziak Artur , Owens Anjali T. , Spertus John A. , Solomon Scott D. , Tfelt‐Hansen Jacob , van Sinttruije Marion , Veselka Josef , Watkins Hugh , Jacoby Daniel L. , German Polina , Heitner Stephen B. , Kupfer Stuart , Lutz Justin D. , Malik Fady I. , Meng Lisa , Wohltman Amy , Abraham Theodore P. , Zhang Yuhui , Yang Haibo , Shao Chunli , Yuan Zuyi , Zeng Qingchun , Li Xiaodong , Wang Yushi , Shu Yan , Chen Mulei , Tao Ling , Li Xinli , Wang Jingfeng , Yu Zaixin , Cheng Xiang , Hong Kui , Zemanek David , Bundgaard Henning , Thune Jens , Jensen Morten , Mogensen Jens , Habib Gilbert , Charron Philippe , Lhermusier Thibault , Trochu Jean‐Noël , Reant Patricia , Logeart Damien , Mitrovic Veselin , Bekfani Tarek , Edelmann Frank , Seidler Tim , Meder Benjamin , Schulze Paul Christian , Stoerk Stephan , Rassaf Tienush , Merkely Bela , Zfat‐Zwas Donna , Halabi Majdi , Paz Offir , Piltz Xavier , Metra Marco , Canepa Marco , Musumeci Beatrice , Emdin Michele , Amin Ahmad , Knackstedt Christian , Wojakowski Wojciech , Dudek Dariusz , Toste Alexandra , Bastos José Mesquita , Blanes Juan Ramón Gimeno , Urbano Rafael Jesus Hidalgo , Alvarez Ana Garcia , Diaz Luis Miguel Rincón , Vera Tomas Vicente Ripoll , Elliott Perry , Glasgow NHS Greater , Cooper Rob , Heart Liverpool , Mahmod Masliza , Pantazis Antonis , Esteban Maria Teresa Tome , Health Oregon , Marian Ali , Owens David , McGrew Frank , Bach Richard , Wever‐Pinzon Omar , Collado Elias , Turer Aslan , Hannawi Bashar , Geske Jeffrey , Heart Penn , Symanski John , Heart Sanger , Kramer Christopher , Sarswat Nitasha , Ahmad Ferhaan , Markowitz Jeremy , Lakdawala Neal , Jani Sandeep , Brinkley Marshall , Bilen Ozlem , Asher Craig , Emani Sitaramesh , Sharma Abhinav , Fermin David , Lyle Melissa , Raymer David , Darlington Andrew , Nielsen Christopher , Wang Andrew , Nagueh Sherif , Martinez Matthew , Desai Milind , Tower‐Rader Albree , Kelly Jacob , Heart Alaska , Rader Florian , Sen Sounok , Bering Patrick , Maurer Mathew , Mitter Sumeet , Sherrid Mark , Wong Timothy , Hussain Zainal , Saberi Sara , Naidu Srihari , Enciso Jorge Silva 
Published: July 2024

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.