Aficamten – One More Cardiac Myosin Inhibitor for HOCM

Mavacamten is now approved for treatment of symptomatic hypertrophic obstructive cardiomyopathy and endorsed by mult-society guidelines. Now we have Aficamten, next in class cardiac myosin inhibitor for HOCM. Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy was published in 2023, with 28 patients on  aficamten 13 on placebo. There was substanital reduction in LVOT gradients and most patients experienced improvement in biomarkers and symptoms [1]. Now a phase 3 trial (SEQUOIA-HCM) of aficamten has been published online in NEJM ahead of print [2]. The study had 142 patients in aficamten group and 140 in the placebo group. There was significantly greater improvement in peak oxygen uptake with aficamten compared to placebo.

Aficamtem was designed to have smaller reductions in left ventricular ejection fraction with increasing dose compared to mavacamten in order to have a wider therapeutic window. Similarly, it has a shorter plasma half-life allowing more personalized dose adjustments as often as every two weeks [2]. A drug review has mentioned that aficamten has fewer drug-drug interactions, which could make it a preferable option [3]. Unlike mavacamten which had attenuation of benefit among patients on beta-blockers in the EXPLORER-HCM trial, effect of aficamten was similar with or without beta-blockers. It was also independent of the presence of a pathogenic sarcomere gene variant. Aficamten is associated with greater reduction in the serum NT-proBNP level than placebo [2]. BNP had been shown to be an independent predictor of morbidity and mortality in hypertrophic cardiomyopathy in an earlier study involving 772 patients [4]. Patients in the aficamten group with LVEF less than 50% did not need interruption of treatment or have exacerbation of heart failure, indicating the shallow dose-response relationship [2].

References

1. Maron MS, Masri A, Choudhury L, Olivotto I, Saberi S, Wang A, Garcia-Pavia P, Lakdawala NK, Nagueh SF, Rader F, Tower-Rader A, Turer AT, Coats C, Fifer MA, Owens A, Solomon SD, Watkins H, Barriales-Villa R, Kramer CM, Wong TC, Paige SL, Heitner SB, Kupfer S, Malik FI, Meng L, Wohltman A, Abraham T; REDWOOD-HCM Steering Committee and Investigators. Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2023 Jan 3;81(1):34-45. doi: 10.1016/j.jacc.2022.10.020. PMID: 36599608.
2. Maron MS, Masri A, Nassif ME, Barriales-Villa R, Arad M, Cardim N, Choudhury L, Claggett B, Coats CJ, Düngen HD, Garcia-Pavia P, Hagège AA, Januzzi JL, Lee MMY, Lewis GD, Ma CS, Michels M, Olivotto I, Oreziak A, Owens AT, Spertus JA, Solomon SD, Tfelt-Hansen J, van Sinttruije M, Veselka J, Watkins H, Jacoby DL, Heitner SB, Kupfer S, Malik FI, Meng L, Wohltman A, Abraham TP; SEQUOIA-HCM Investigators. Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy. N Engl J Med. 2024 May 13. doi: 10.1056/NEJMoa2401424. Epub ahead of print. PMID: 38739079.
3. Sebastian SA, Padda I, Lehr EJ, Johal G. Aficamten: A Breakthrough Therapy for Symptomatic Obstructive Hypertrophic Cardiomyopathy. Am J Cardiovasc Drugs. 2023 Sep;23(5):519-532. doi: 10.1007/s40256-023-00599-0. Epub 2023 Aug 1. PMID: 37526885.
4. Geske JB, McKie PM, Ommen SR, Sorajja P. B-type natriuretic peptide and survival in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2013 Jun 18;61(24):2456-2460. doi: 10.1016/j.jacc.2013.04.004. Epub 2013 Apr 16. PMID: 23602778.