Efficacy and Safety of Aficamten in Obstructive Hypertrophic Cardiomyopathy Patients Eligible for Septal Reduction Therapy: A FOREST-HCM Analysis

B. Meder (Heidelberg)¹, L. Choudhury (Chicago, IL)², P. Garcia-Pavia (Madrid)³, T. P. Abraham (San Francisco, CA)⁴, R. Barriales-Villa (A Coruna)⁵, O. Bilen (Atlanta, GA)⁶, P. Elliott (London)⁷, A. Hagege (Paris)⁸, S. F. Nagueh (Houston, TX)⁹, S. S. Naidu (Valhalla, NY)¹⁰, M. E. Nassif (Kansas City, MO)¹¹, I. Olivotto (Florenz)¹², A. Oreziak (Warsaw)¹³, A. T. Owens (Philadelphia, PA)¹⁴, O. Wever Pinzon (Salt Lake City)¹⁵, F. Rader (Los Angeles, CA)¹⁶, A. Tower-Rader (Boston, MA)¹⁷, J. Godown (South San Francisco, CA)¹⁸, S. B. Heitner (South San Francisco, CA)¹⁸, D. L. Jacoby (South San Francisco, CA)¹⁸, S. Kupfer (South San Francisco, CA)¹⁸, F. I. Malik (South San Francisco, CA)¹⁸, T. J. Simkins (South San Francisco, CA)¹⁸, J. Wei (South San Francisco, CA)¹⁸, S. Saberi (Ann Arbor, MI)¹⁹, A. Masri (Portland, OR)^20
1Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; ²Northwestern University Feinberg School of Medicine Chicago, IL, USA; ³Hospital Universitario Puerta de Hierro de Majadahonda, IDIPHISA, CIBERCV, and Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid, Spanien; ⁴University of California San Francisco San Francisco, CA, USA; ⁵Complexo Hospitalario Universitario A Coruña, INIBIC, CIBERCV-ISCIII A Coruna, Spanien; ⁶Emory University School of Medicine Division of Cardiology Atlanta, GA, USA; ⁷The Heart Hospital Department of Cardiology London, Großbritannien; ⁸Hôpital Européen Georges-Pompidou, Departement de Cardiologie Assistance Publique Hôpitaux de Paris Paris, Frankreich; ⁹Houston Methodist DeBakey Heart and Vascular Center Section of Cardiology Houston, TX, USA; ¹⁰New York Medical College Westchester Medical Center Valhalla, NY, USA; ¹¹Saint Luke’s Mid America Heart Institute Kansas City, MO, USA; ¹²Azienda Ospedaliero-Universitaria Careggi Cardiomyopathy Unit Florenz, Italien; ¹³National Institute of Cardiology Warsaw, Polen; ¹⁴University of Pennsylvania Philadelphia, PA, USA; ¹⁵University of Utah Health Sciences Center Salt Lake City, USA; ¹⁶Cedars-Sinai Smidt Heart Institute Los Angeles, CA, USA; ¹⁷Massachusetts General Hospital Boston, MA, USA; ¹⁸Cytokinetics, Incorporated South San Francisco, CA, USA; ¹⁹University of Michigan Medical Center Ann Arbor, MI, USA; ²⁰Oregon Health & Science University Portland, OR, USA

Background
Septal reduction therapy (SRT) is offered to patients with obstructive hypertrophic cardiomyopathy (HCM) who remain severely symptomatic despite standard of care medical therapy. We report the efficacy and safety of aficamten in SRT-eligible patients and assess the impact on SRT eligibility in the phase 2 open-label FOREST-HCM trial (NCT04848506).  

Methods
Patients completing an aficamten parent study were offered participation in FOREST-HCM. Aficamten was initiated in all participants at 5mg and escalated (10, 15, and 20 mg) at investigators’ discretion with protocol guidance according to left ventricular ejection fraction (LVEF) and left ventricular outflow tract gradient (LVOT-G) criteria. SRT eligibility was defined based on current guidelines as New York Heart Association (NYHA) class III or IV and any peak LVOT-G ≥50 mmHg. Baseline SRT-eligible patients were compared to those who were not eligible for SRT. Changes from baseline to maintenance dosing of aficamten (Week 12 for protocol amendment 4 or Week 24 for protocol amendment 6) were assessed. Durability of response was assessed to 96 weeks (mean follow up duration 92.4+42.4 weeks).

Results
A total of 317 obstructive HCM patients reached maintenance dosing of aficamten during FOREST-HCM (cutoff date May 9th, 2025) and were included in the analysis (mean age 60.6 ± 1.4 years, 44.5% female). 104 (33%) patients were SRT-eligible at baseline and only 3 (2.9%) remained SRT-eligible after titration was completed. Between baseline and reaching maintenance dosing of aficamten, SRT-eligible patients demonstrated significant improvements in Valsalva LVOT-G (109.1 mmHg ± 8.1 mmHg vs 39.5 mmHg ± 5.4 mmHg; p<0.001), NYHA classification (100% class III at baseline vs 32.7% class I, 62.5% class II, and 4.8% class III at follow-up; p<0.001), NTpro-BNP (geometric mean [95% CI]) (725 pg/mL [579, 907] vs 165 pg/mL [136, 201]; p<0.001), and KCCQ-CSS (58.0 ± 3.7 vs 78.2 ± 3.5; p<0.001) with modest reduction in LVEF (69.5% ± 1.1% vs 66.2% ± 1.1%; p<0.001) (Figure). These improvements in SRT-eligible patients were similar to those observed in non-SRT eligible patients. There were no occurrences of LVEF <40% and 2 baseline SRT-eligible patients with transient occurrences of LVEF <50% with an exposure-adjusted incidence rate of 1.0 per 100 patient-years. The benefits of aficamten in baseline SRT-eligible patients were sustained through 96-weeks follow-up (Figure) and only 1 patient (0.9%) in the cohort remained SRT-eligible at week 96.


Conclusions
Aficamten therapy, with dosing determined by echocardiographic guidance and clinical judgment of the treating physician, led to rapid resolution of SRT eligibility in nearly all patients in this large cohort of obstructive HCM patients. This was achieved in the setting of only rare transient LVEF excursions to <50%. These data suggest that chronic aficamten treatment may provide a safe and effective alternative to SRT in patients with obstructive HCM.