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American Journal of Cardiovascular Drugs

Erschienen in:

01.08.2023 | Review Article

Aficamten: A Breakthrough Therapy for Symptomatic Obstructive Hypertrophic Cardiomyopathy

verfasst von: Sneha Annie Sebastian, Inderbir Padda, Eric J. Lehr, Gurpreet Johal

Erschienen in: American Journal of Cardiovascular Drugs | Ausgabe 5/2023

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Abstract

Aficamten is a novel cardiac myosin inhibitor that has demonstrated its ability to safely lower left ventricular outflow tract (LVOT) gradients and improve heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM). Based on the REDWOOD-HCM open label extension (OLE) study, participants receiving aficamten had significantly reduced resting and Valsalva LVOT gradient within 2 weeks after initiating treatment, with ongoing improvements over 24 weeks, and recent evidence suggests effects can sustain up to 48 weeks. While beta-blockers, calcium channel blockers, and disopyramide have shown some benefits in managing HCM, they have limited direct impact on the underlying disease process in patients with obstructive HCM. Aficamten achieves its therapeutic effect by reducing hypercontractility and improving diastolic function in obstructive HCM. Mavacamten was the first cardiac myosin inhibitor approved for symptomatic obstructive HCM. However, aficamten has a shorter human half-life (t_1/2) and fewer drug–drug interactions, making it a preferable treatment option. This review evaluates the long-term clinical value and safety of aficamten in patients with obstructive HCM based on available data from completed and ongoing clinical trials. Additionally, the molecular basis of sarcomere-targeted therapy in reducing LVOT gradients is explored, and its potential in managing obstructive HCM is discussed.

Graphical Abstract

Chuang C, Collibee S, Ashcraft L, et al. Discovery of aficamten (CK-274), a next-generation cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathy. J Med Chem. 2021;64(19):14142–52. https://doi.org/10.1021/acs.jmedchem.1c01290.CrossRefPubMed

Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2015;65(12):1249–54. https://doi.org/10.1016/j.jacc.2015.01.019.CrossRefPubMed

Geisterfer-Lowrance AA, Kass S, Tanigawa G, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62(5):999–1006. https://doi.org/10.1016/0092-8674(90)90274-i.CrossRefPubMed

Harris SP, Lyons RG, Bezold KL. In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament. Circ Res. 2011;108(6):751–64. https://doi.org/10.1161/CIRCRESAHA.110.231670.CrossRefPubMedPubMedCentral

Spudich JA. Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations. Pflugers Arch. 2019;471(5):701–17. https://doi.org/10.1007/s00424-019-02259-2.CrossRefPubMedPubMedCentral

Sebastian SA, Panthangi V, Singh K, et al. Hypertrophic cardiomyopathy: current treatment and future options. Curr Probl Cardiol. 2022;48(4): 101552. https://doi.org/10.1016/j.cpcardiol.2022.101552.CrossRefPubMed

Ho CY, Carlsen C, Thune JJ, et al. Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2009;2(4):314–21. https://doi.org/10.1161/CIRCGENETICS.109.862128.CrossRefPubMedPubMedCentral

Ho CY, Olivotto I, Jacoby D, et al. Study design and rationale of EXPLORER-HCM: evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy. Circ Heart Fail. 2020;13(6): e006853. https://doi.org/10.1161/CIRCHEARTFAILURE.120.006853.CrossRefPubMed

Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020;142(25):e533–57. https://doi.org/10.1161/CIR.0000000000000938.CrossRefPubMed

10.

Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396(10253):759–69. https://doi.org/10.1016/S0140-6736(20)31792-X.CrossRefPubMed

11.

Maron MS, Masri A, Choudhury L, et al. Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2023;81(1):34–45. https://doi.org/10.1016/j.jacc.2022.10.020.CrossRefPubMed

12.

Nag S, Trivedi DV, Sarkar SS, et al. The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations. Nat Struct Mol Biol. 2017;24(6):525–33. https://doi.org/10.1038/nsmb.3408.CrossRefPubMedPubMedCentral

13.

Spudich JA. The myosin mesa and a possible unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy. Biochem Soc Trans. 2015;43(1):64–72. https://doi.org/10.1042/BST20140324.CrossRefPubMedPubMedCentral

14.

Trivedi DV, Adhikari AS, Sarkar SS, Ruppel KM, Spudich JA. Hypertrophic cardiomyopathy and the myosin mesa: viewing an old disease in a new light. Biophys Rev. 2018;10(1):27–48. https://doi.org/10.1007/s12551-017-0274-6.CrossRefPubMed

15.

Brunello E, Fusi L, Ghisleni A, et al. Myosin filament-based regulation of the dynamics of contraction in heart muscle. Proc Natl Acad Sci USA. 2020;117(14):8177–86. https://doi.org/10.1073/pnas.1920632117.CrossRefPubMedPubMedCentral

16.

Daniels MJ, Fusi L, Semsarian C, Naidu SS. Myosin modulation in hypertrophic cardiomyopathy and systolic heart failure: getting inside the engine. Circulation. 2021;144(10):759–62. https://doi.org/10.1161/CIRCULATIONAHA.121.056324.CrossRefPubMedPubMedCentral

17.

Day SM, Tardiff JC, Ostap EM. Myosin modulators: emerging approaches for the treatment of cardiomyopathies and heart failure. J Clin Investig. 2022;132(5): e148557. https://doi.org/10.1172/JCI148557.CrossRefPubMedPubMedCentral

18.

Kawana M, Spudich JA, Ruppel KM. Hypertrophic cardiomyopathy: mutations to mechanisms to therapies. Front Physiol. 2022;13: 975076. https://doi.org/10.3389/fphys.2022.975076.CrossRefPubMedPubMedCentral

19.

Robert-Paganin J, Pylypenko O, Kikuti C, Sweeney HL, Houdusse A. Force generation by myosin motors: a structural perspective. Chem Rev. 2020;120(1):5–35. https://doi.org/10.1021/acs.chemrev.9b00264.CrossRefPubMed

20.

Lee KH, Sulbarán G, Yang S, et al. Interacting-heads motif has been conserved as a mechanism of myosin II inhibition since before the origin of animals. Proc Natl Acad Sci USA. 2018;115(9):E1991–2000. https://doi.org/10.1073/pnas.1715247115.CrossRefPubMedPubMedCentral

21.

Teerlink JR, Felker GM, McMurray JJ, et al. Chronic oral study of myosin activation to increase contractility in heart failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet. 2016;388(10062):2895–903. https://doi.org/10.1016/S0140-6736(16)32049-9.CrossRefPubMed

22.

Fang JC, Filippatos G, Fonseca C, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med. 2021;384(2):105–16. https://doi.org/10.1056/NEJMoa2025797.CrossRefPubMed

23.

Lewis GD, Voors AA, Cohen-Solal A, et al. Effect of omecamtiv mecarbil on exercise capacity in chronic heart failure with reduced ejection fraction: the METEORIC-HF randomized clinical trial. JAMA. 2022;328(3):259–69. https://doi.org/10.1001/jama.2022.11016.CrossRefPubMedPubMedCentral

24.

Voors AA, Tamby JF, Cleland JG, et al. Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial. Eur J Heart Fail. 2020;22(9):1649–58. https://doi.org/10.1002/ejhf.1933.CrossRefPubMed

25.

Heitner SB, Jacoby D, Lester SJ, et al. Mavacamten treatment for obstructive hypertrophic cardiomyopathy: a clinical trial. Ann Intern Med. 2019;170(11):741–8. https://doi.org/10.7326/M18-3016.CrossRefPubMed

26.

Ho CY, Mealiffe ME, Bach RG, et al. Evaluation of mavacamten in symptomatic patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2020;75(21):2649–60. https://doi.org/10.1016/j.jacc.2020.03.064.CrossRefPubMed

27.

Desai MY, Owens A, Geske JB, et al. Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy. J Am Coll Cardiol. 2022;80(2):95–108. https://doi.org/10.1016/j.jacc.2022.04.048.CrossRefPubMed

28.

Cytokinetics. Cytokinetics Presents New Data From REDWOOD-HCM OLE in Late Breaking Clinical Trial Session at the HFSA Annual Scientific Meeting. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-presents-new-data-redwood-hcm-ole-late-breaking-0. Accessed 3 Mar 2023.

29.

ClinicalTrials.gov. CY 6031 study will evaluate the effects of treatment with aficamten (CK-3773274) over a 24-week period on cardiopulmonary exercise capacity and health status in patients with symptomatic oHCM (SEQUOIA-HCM) SEQUOIA-HCM. https://www.clinicaltrials.gov/ct2/show/NCT05186818. Accessed 1 Mar 2023.

30.

Malik FI, Robertson LA, Armas DR, et al. A phase 1 dose-escalation study of the cardiac myosin inhibitor aficamten in healthy participants. JACC Basic Transl Sci. 2022;7(8):763–75. https://doi.org/10.1016/j.jacbts.2022.04.008.CrossRefPubMedPubMedCentral

31.

Masri A, Olivotto I. Cardiac myosin inhibitors as a novel treatment option for obstructive hypertrophic cardiomyopathy: addressing the core of the matter. J Am Heart Assoc. 2022;11(9): e024656. https://doi.org/10.1161/JAHA.121.024656.CrossRefPubMedPubMedCentral

32.

Owens A, Masri A, Abraham T, et al. Efficacy and safety of aficamten and disopyramide coadministration in obstructive hypertrophic cardiomyopathy: results from REDWOOD-HCM cohort 3. J Am Coll Cardiol. 2022;79(9_Supplement):244. https://doi.org/10.1016/S0735-1097(22)01235-9.CrossRef

33.

Cytokinetics. Cytokinetics Announces Results from Cohort 3 of REDWOOD-HCM Presented at American College of Cardiology 71st Annual Scientific Session. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-results-cohort-3-redwood-hcm-presented. Accessed 8 May 2023.

34.

Masri A, Sherrid M, Choudhury L, et al. Aficamten in patients with symptomatic non-obstructive hypertrophic cardiomyopathy (REDWOOD-HCM cohort 4). J Am Coll Cardiol. 2023;81(8_Supplement):609. https://doi.org/10.1016/S0735-1097(23)01053-7.CrossRef

35.

Cytokinetics. Cytokinetics presents positive results from cohort 4 of REDWOOD-HCM and long-term results from FOREST-HCM at the American College of Cardiology 72nd Annual Scientific Session. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-presents-positive-results-cohort-4-redwood-hcm-and. Accessed 8 May 2023.

36.

Saberi S, Abraham T, Choudhury L, et al. Long-term efficacy and safety of aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2023;81(8):324. https://doi.org/10.1016/S0735-1097(23)00768-4.CrossRef

37.

Saberi S., Abraham T, Choudhury L, et al. FOREST-HCM investigators. Long-term efficacy and safety of aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy. https://cytokinetics.com/wp-content/uploads/2023/03/ACC23-FOREST-HCM-Poster-FINAL-V2.pdf. Accessed 9 May 2023.

38.

ClinicalTrials.gov. CY 6022 is an Open Label Study to Collect Long-term Safety and Tolerability Data for Aficamten (CK-3773274) (FOREST-HCM). https://clinicaltrials.gov/ct2/show/NCT04848506. Accessed 4 Mar 2023.

39.

Cytokinetics. Cytokinetics Announces Start of SEQUOIA-HCM, a Phase 3 Clinical Trial of Aficamten in Patients with Symptomatic Obstructive Hypertrophic Cardiomyopathy. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-start-sequoia-hcm-phase-3-clinical-trial. Accessed 3 Mar 2023.

40.

Cytokinetics. Cytokinetics Announces Receipt of Breakthrough Therapy Designation from FDA for Aficamten. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-receipt-breakthrough-therapy-designation. Accessed 4 Mar 2023.

41.

Tsukamoto O. Direct sarcomere modulators are promising new treatments for cardiomyopathies. Int J Mol Sci. 2019;21(1):226. https://doi.org/10.3390/ijms21010226.CrossRefPubMedPubMedCentral

42.

Keam SJ. Mavacamten: first approval. Drugs. 2022;82(10):1127–35. https://doi.org/10.1007/s40265-022-01739-7.CrossRefPubMedPubMedCentral

43.

Grillo MP, Erve JCL, Dick R, et al. In vitro and in vivo pharmacokinetic characterization of mavacamten, a first-in-class small molecule allosteric modulator of beta cardiac myosin. Xenobiotica. 2019;49(6):718–33. https://doi.org/10.1080/00498254.2018.1495856.CrossRefPubMed

44.

MyoKardia, Inc., a wholly owned subsidiary of Bristol Myers Squibb. CAMZYOS^TM (mavacamten): US prescribing information. 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf. Accessed 4 Mar 2023.

45.

Suman N, Darshan VT. To lie or not to lie: super-relaxing with myosins. Elife. 2021;10: e63703. https://doi.org/10.7554/eLife.63703.CrossRef

46.

Packard E, de Feria A, Peshin S, Reza N, Owens AT. Contemporary therapies and future directions in the management of hypertrophic cardiomyopathy. Cardiol Ther. 2022;11(4):491–507. https://doi.org/10.1007/s40119-022-00283-5.CrossRefPubMedPubMedCentral

47.

ClinicalTrials.gov. A Study to Evaluate the Efficacy, Safety, and Tolerability of MYK-224 in Participants with Symptomatic Obstructive Hypertrophic Cardiomyopathy. NCT05556343. https://clinicaltrials.gov/ct2/show/NCT05556343. Accessed 3 Mar 2023.

48.

BioSpace. MyoKardia Begins Dosing in Phase 1 Clinical Study of MYK-224 for Hypertrophic Cardiomyopathy. Aug 21, 2019. https://www.biospace.com/article/myokardia-begins-dosing-in-phase-1-clinical-study-of-myk-224-for-hypertrophic-cardiomyopathy/. Accessed 3 Mar 2023.

49.

Ferguson BS, Stern JA, Oldach MS, et al. Acute effects of a mavacamten-like myosin-inhibitor (MYK-581 in a feline model of obstructed hypertrophic cardiomyopathy: evidence of improved ventricular filling (beyond obstruction reprieve). Eur Heart J. 2020;41(2_Supplement):ehaa946.3713. https://doi.org/10.1093/ehjci/ehaa946.3713.CrossRef

50.

ClinicalTrials.gov. Efficacy and Safety of Aficamten (CK-3773274) Compared with metoprolol succinate in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction (MAPLE-HCM). Available at: https://www.clinicaltrials.gov/ct2/show/NCT05767346. Accessed 9 May 2023.

Titel: Aficamten: A Breakthrough Therapy for Symptomatic Obstructive Hypertrophic Cardiomyopathy
verfasst von: Sneha Annie Sebastian
Inderbir Padda
Eric J. Lehr
Gurpreet Johal
Publikationsdatum: 01.08.2023
Verlag: Springer International Publishing
Erschienen in: American Journal of Cardiovascular Drugs / Ausgabe 5/2023
Print ISSN: 1175-3277
Elektronische ISSN: 1179-187X
DOI: https://doi.org/10.1007/s40256-023-00599-0

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Aficamten: A Breakthrough Therapy for Symptomatic Obstructive Hypertrophic Cardiomyopathy

Abstract

Graphical Abstract

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