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Recent trend in the therapy of hypertrophic cardiomyopathy: Cardiac myosin inhibitors

Year 2023, Volume: 1 Issue: 2, 110 - 122, 29.08.2023

Abstract

Cardiac myosin inhibitors are a new class of drugs that have recently been approved in obstructive hypertrophic cardiomyopathy. The main mechanism of action is to reduce the pathologically increased cardiac hypercontractility. Current drug therapies have not been demonstrated to modify the natural progress of the disease. Mavacamten is the first approved oral drug to reduce the generation of actin-myosin cross-bridges, thus inhibiting the probability of systolic and diastolic cross-bridge occurence. In clinical studies, it has been shown that mavacamte increases exercise capacity, reduces the left ventricle outflow tract pressure and improves health status by regressing symptoms. However, mavacamten therapy requires continuous monitoring due to the risk of exacerbation of heart failure symptoms. Altertative cardiac myosin inhibitors, aficamten, MYK-224, and MYK-581 are currently under investigation. These drugs have provided a novel treatment approach for obstructive hypertrophic cardiomyopathy. Further studies will lead to the development of targeted therapies that have the ability to reduce the natural course of this disease.

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Project Number

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References

  • Altibi, A., et al. (2023). Baseline and longitudinal ımaging of hypertrophic cardiomyopathy in the era of emerging therapeutics. Current cardiology reports, 25(6), 583–595. https://doi.org/10.1007/s11886-023-01883-w
  • Anderson, R. L., et al. (2018). Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. Proceedings of the National Academy of Sciences of the United States of America, 115(35), E8143–E8152. https://doi.org/10.1073/pnas.1809540115.
  • Awinda, P. O., et al. (2021). Mavacamten decreases maximal force and Ca2+ sensitivity in the N47K-myosin regulatory light chain mouse model of hypertrophic cardiomyopathy. American journal of physiology. Heart and circulatory physiology, 320(2), H881–H890. https://doi.org/10.1152/ajpheart.00345.2020
  • Basit, H., Brito, D., & Sharma, S. (2023). Hypertrophic Cardiomyopathy. In StatPearls. StatPearls Publishing.
  • Bello, J., & Pellegrini, M. V. (2023). Mavacamten. In StatPearls. StatPearls Publishing.
  • Chuang, C., et al. (2021). Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy. Journal of medicinal chemistry, 64(19), 14142–14152. https://doi.org/10.1021/acs.jmedchem.1c01290
  • Cremer, P. C., et al. (2022). Myosin Inhibition and Left Ventricular Diastolic Function in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Insights From the VALOR-HCM Study. Circulation. Cardiovascular imaging, 15(12), e014986. https://doi.org/10.1161/CIRCIMAGING.122.014986
  • Desai, M. Y., et al. (2022). Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy. Journal of the American College of Cardiology, 80(2), 95–108. https://doi.org/10.1016/j.jacc.2022.04.048
  • Desai, M. Y., et al. (2023). Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks. Circulation, 147(11), 850–863. https://doi.org/10.1161/CIRCULATIONAHA.122.062534
  • Edelberg, J. M., et al. (2022). The impact of mavacamten on the pathophysiology of hypertrophic cardiomyopathy: A narrative review. American journal of cardiovascular drugs : drugs, devices, and other interventions, 22(5), 497–510. https://doi.org/10.1007/s40256-022-00532-x
  • Green, E. M., et al. (2016). A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science (New York, N.Y.), 351(6273), 617–621. https://doi.org/10.1126/science.aad3456
  • Grillo, M. P., et al. (2019). In vitro and in vivo pharmacokinetic characterization of mavacamten, a first-in-class small molecule allosteric modulator of beta cardiac myosin. Xenobiotica; the fate of foreign compounds in biological systems, 49(6), 718–733. https://doi.org/10.1080/00498254.2018.1495856
  • Heitner, S. B., et al. (2019). Mavacamten Treatment for Obstructive Hypertrophic Cardiomyopathy: A Clinical Trial. Annals of internal medicine, 170(11), 741–748. https://doi.org/10.7326/M18-3016.
  • Ho, C. Y., et al. (2020a). Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology, 75(21), 2649–2660. https://doi.org/10.1016/j.jacc.2020.03.064.
  • Ho, C. Y., et al. (2020b). Study Design and Rationale of EXPLORER-HCM: Evaluation of Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy. Circulation. Heart failure, 13(6), e006853. https://doi.org/10.1161/CIRCHEARTFAILURE.120.006853
  • Iavarone, M., et al. (2022). Medical treatment of patients with hypertrophic cardiomyopathy: An overview of current and emerging therapy. Archives of cardiovascular diseases, 115(10), 529–537. https://doi.org/10.1016/j.acvd.2022.06.003
  • Kawas, R. F., et al. (2017). A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle. The Journal of biological chemistry, 292(40), 16571–16577. https://doi.org/10.1074/jbc.M117.776815.
  • Keam S. J. (2022). Mavacamten: First Approval. Drugs, 82(10), 1127–1135. https://doi.org/10.1007/s40265-022-01739-7
  • Kogut, J., & Popjes, E. D. (2020). Hypertrophic Cardiomyopathy 2020. Current cardiology reports, 22(11), 154. https://doi.org/10.1007/s11886-020-01381-3
  • Krendel, M., & Mooseker, M. S. (2005). Myosins: tails (and heads) of functional diversity. Physiology (Bethesda, Md.), 20, 239–251. https://doi.org/10.1152/physiol.00014.2005.
  • Lehman, S. J., Crocini, C., & Leinwand, L. A. (2022). Targeting the sarcomere in inherited cardiomyopathies. Nature reviews. Cardiology, 19(6), 353–363. https://doi.org/10.1038/s41569-022-00682-0.
  • Malik, F. I., et al. (2022). A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants. JACC. Basic to translational science, 7(8), 763–775. https://doi.org/10.1016/j.jacbts.2022.04.008
  • Maron, B. J., et al. (2022). Diagnosis and Evaluation of Hypertrophic Cardiomyopathy: JACC State-of-the-Art Review. Journal of the American College of Cardiology, 79(4), 372–389. https://doi.org/10.1016/j.jacc.2021.12.002
  • Maron, M. S., et al. (2023). Phase 2 Study of Aficamten in Patients with Obstructive Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology, 81(1), 34–45. https://doi.org/10.1016/j.jacc.2022.10.020.
  • Mavacamten FDA label, 2023, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214998s001lbl.pdf, Accessed on 23 June 2023.
  • Olivotto, I., et al. (2020). Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England), 396(10253), 759–769. https://doi.org/10.1016/S0140-6736(20)31792-X
  • Packard, E., et al. (2022). Contemporary Therapies and Future Directions in the Management of Hypertrophic Cardiomyopathy. Cardiology and therapy, 11(4), 491–507. https://doi.org/10.1007/s40119-022-00283-5
  • Rader, F., et al. (2021). Long-term safety of mavacamten in patients with obstructive hypertrophic cardiomyopathy: interim results of the MAVA-long term extension (LTE) study. Journal of the American College of Cardiology, 77(18_Supplement_1), 532. https:// doi.org/ 10. 1016/ S0735- 1097(21) 01891-X.
  • Raj, M. A., Ranka, S., & Goyal, A. (2022). Hypertrophic Obstructive Cardiomyopathy. In StatPearls. StatPearls Publishing.
  • Robert-Paganin, J., et al. (2020). Force Generation by Myosin Motors: A Structural Perspective. Chemical reviews, 120(1), 5–35. https://doi.org/10.1021/acs.chemrev.9b00264.
  • Rohde, J. A., et al. (2018). Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin. Proceedings of the National Academy of Sciences of the United States of America, 115(32), E7486–E7494. https://doi.org/10.1073/pnas.1720342115
  • Rosenzveig, A., et al. (2023). Current and emerging pharmacotherapy for the management of hypertrophic cardiomyopathy. Expert opinion on pharmacotherapy, 1–12. Advance online publication. https://doi.org/10.1080/14656566.2023.2219840.
  • Saberi, S., et al. (2021). Mavacamten Favorably Impacts Cardiac Structure in Obstructive Hypertrophic Cardiomyopathy: EXPLORER-HCM Cardiac Magnetic Resonance Substudy Analysis. Circulation, 143(6), 606–608. https://doi.org/10.1161/CIRCULATIONAHA.120.052359
  • Sarkar, S. S., et al. (2023). Preclinical characterization of CK-4021586, a new class of cardiac myosin inhibitors for the treatment of hypertrophic cardiomyopathy. Biophysical Journal, 122(3), 122a. https://doi.org/10.1016/j.bpj.2022.11.828
  • Scellini, B., et al. (2021). Mavacamten has a differential impact on force generation in myofibrils from rabbit psoas and human cardiac muscle. The Journal of general physiology, 153(7), e202012789. https://doi.org/10.1085/jgp.202012789.
  • Spertus, J. A., et al. (2021). Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England), 397(10293), 2467–2475. https://doi.org/10.1016/S0140-6736(21)00763-7
  • Spudich J. A. (2019). Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations. Pflugers Archiv: European journal of physiology, 471(5), 701–717. https://doi.org/10.1007/s00424-019-02259-2.
  • Wheeler, M. T., et al. (2023). Effects of Mavacamten on Measures of Cardiopulmonary Exercise Testing Beyond Peak Oxygen Consumption: A Secondary Analysis of the EXPLORER-HCM Randomized Trial. JAMA cardiology, 8(3), 240–247. https://doi.org/10.1001/jamacardio.2022.5099
  • Zampieri, M., et al. (2021). Pathophysiology and Treatment of Hypertrophic Cardiomyopathy: New Perspectives. Current heart failure reports, 18(4), 169–179. https://doi.org/10.1007/s11897-021-00523-0.
Year 2023, Volume: 1 Issue: 2, 110 - 122, 29.08.2023

Abstract

Project Number

None

References

  • Altibi, A., et al. (2023). Baseline and longitudinal ımaging of hypertrophic cardiomyopathy in the era of emerging therapeutics. Current cardiology reports, 25(6), 583–595. https://doi.org/10.1007/s11886-023-01883-w
  • Anderson, R. L., et al. (2018). Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. Proceedings of the National Academy of Sciences of the United States of America, 115(35), E8143–E8152. https://doi.org/10.1073/pnas.1809540115.
  • Awinda, P. O., et al. (2021). Mavacamten decreases maximal force and Ca2+ sensitivity in the N47K-myosin regulatory light chain mouse model of hypertrophic cardiomyopathy. American journal of physiology. Heart and circulatory physiology, 320(2), H881–H890. https://doi.org/10.1152/ajpheart.00345.2020
  • Basit, H., Brito, D., & Sharma, S. (2023). Hypertrophic Cardiomyopathy. In StatPearls. StatPearls Publishing.
  • Bello, J., & Pellegrini, M. V. (2023). Mavacamten. In StatPearls. StatPearls Publishing.
  • Chuang, C., et al. (2021). Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy. Journal of medicinal chemistry, 64(19), 14142–14152. https://doi.org/10.1021/acs.jmedchem.1c01290
  • Cremer, P. C., et al. (2022). Myosin Inhibition and Left Ventricular Diastolic Function in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Insights From the VALOR-HCM Study. Circulation. Cardiovascular imaging, 15(12), e014986. https://doi.org/10.1161/CIRCIMAGING.122.014986
  • Desai, M. Y., et al. (2022). Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy. Journal of the American College of Cardiology, 80(2), 95–108. https://doi.org/10.1016/j.jacc.2022.04.048
  • Desai, M. Y., et al. (2023). Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks. Circulation, 147(11), 850–863. https://doi.org/10.1161/CIRCULATIONAHA.122.062534
  • Edelberg, J. M., et al. (2022). The impact of mavacamten on the pathophysiology of hypertrophic cardiomyopathy: A narrative review. American journal of cardiovascular drugs : drugs, devices, and other interventions, 22(5), 497–510. https://doi.org/10.1007/s40256-022-00532-x
  • Green, E. M., et al. (2016). A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science (New York, N.Y.), 351(6273), 617–621. https://doi.org/10.1126/science.aad3456
  • Grillo, M. P., et al. (2019). In vitro and in vivo pharmacokinetic characterization of mavacamten, a first-in-class small molecule allosteric modulator of beta cardiac myosin. Xenobiotica; the fate of foreign compounds in biological systems, 49(6), 718–733. https://doi.org/10.1080/00498254.2018.1495856
  • Heitner, S. B., et al. (2019). Mavacamten Treatment for Obstructive Hypertrophic Cardiomyopathy: A Clinical Trial. Annals of internal medicine, 170(11), 741–748. https://doi.org/10.7326/M18-3016.
  • Ho, C. Y., et al. (2020a). Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology, 75(21), 2649–2660. https://doi.org/10.1016/j.jacc.2020.03.064.
  • Ho, C. Y., et al. (2020b). Study Design and Rationale of EXPLORER-HCM: Evaluation of Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy. Circulation. Heart failure, 13(6), e006853. https://doi.org/10.1161/CIRCHEARTFAILURE.120.006853
  • Iavarone, M., et al. (2022). Medical treatment of patients with hypertrophic cardiomyopathy: An overview of current and emerging therapy. Archives of cardiovascular diseases, 115(10), 529–537. https://doi.org/10.1016/j.acvd.2022.06.003
  • Kawas, R. F., et al. (2017). A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle. The Journal of biological chemistry, 292(40), 16571–16577. https://doi.org/10.1074/jbc.M117.776815.
  • Keam S. J. (2022). Mavacamten: First Approval. Drugs, 82(10), 1127–1135. https://doi.org/10.1007/s40265-022-01739-7
  • Kogut, J., & Popjes, E. D. (2020). Hypertrophic Cardiomyopathy 2020. Current cardiology reports, 22(11), 154. https://doi.org/10.1007/s11886-020-01381-3
  • Krendel, M., & Mooseker, M. S. (2005). Myosins: tails (and heads) of functional diversity. Physiology (Bethesda, Md.), 20, 239–251. https://doi.org/10.1152/physiol.00014.2005.
  • Lehman, S. J., Crocini, C., & Leinwand, L. A. (2022). Targeting the sarcomere in inherited cardiomyopathies. Nature reviews. Cardiology, 19(6), 353–363. https://doi.org/10.1038/s41569-022-00682-0.
  • Malik, F. I., et al. (2022). A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants. JACC. Basic to translational science, 7(8), 763–775. https://doi.org/10.1016/j.jacbts.2022.04.008
  • Maron, B. J., et al. (2022). Diagnosis and Evaluation of Hypertrophic Cardiomyopathy: JACC State-of-the-Art Review. Journal of the American College of Cardiology, 79(4), 372–389. https://doi.org/10.1016/j.jacc.2021.12.002
  • Maron, M. S., et al. (2023). Phase 2 Study of Aficamten in Patients with Obstructive Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology, 81(1), 34–45. https://doi.org/10.1016/j.jacc.2022.10.020.
  • Mavacamten FDA label, 2023, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214998s001lbl.pdf, Accessed on 23 June 2023.
  • Olivotto, I., et al. (2020). Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England), 396(10253), 759–769. https://doi.org/10.1016/S0140-6736(20)31792-X
  • Packard, E., et al. (2022). Contemporary Therapies and Future Directions in the Management of Hypertrophic Cardiomyopathy. Cardiology and therapy, 11(4), 491–507. https://doi.org/10.1007/s40119-022-00283-5
  • Rader, F., et al. (2021). Long-term safety of mavacamten in patients with obstructive hypertrophic cardiomyopathy: interim results of the MAVA-long term extension (LTE) study. Journal of the American College of Cardiology, 77(18_Supplement_1), 532. https:// doi.org/ 10. 1016/ S0735- 1097(21) 01891-X.
  • Raj, M. A., Ranka, S., & Goyal, A. (2022). Hypertrophic Obstructive Cardiomyopathy. In StatPearls. StatPearls Publishing.
  • Robert-Paganin, J., et al. (2020). Force Generation by Myosin Motors: A Structural Perspective. Chemical reviews, 120(1), 5–35. https://doi.org/10.1021/acs.chemrev.9b00264.
  • Rohde, J. A., et al. (2018). Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin. Proceedings of the National Academy of Sciences of the United States of America, 115(32), E7486–E7494. https://doi.org/10.1073/pnas.1720342115
  • Rosenzveig, A., et al. (2023). Current and emerging pharmacotherapy for the management of hypertrophic cardiomyopathy. Expert opinion on pharmacotherapy, 1–12. Advance online publication. https://doi.org/10.1080/14656566.2023.2219840.
  • Saberi, S., et al. (2021). Mavacamten Favorably Impacts Cardiac Structure in Obstructive Hypertrophic Cardiomyopathy: EXPLORER-HCM Cardiac Magnetic Resonance Substudy Analysis. Circulation, 143(6), 606–608. https://doi.org/10.1161/CIRCULATIONAHA.120.052359
  • Sarkar, S. S., et al. (2023). Preclinical characterization of CK-4021586, a new class of cardiac myosin inhibitors for the treatment of hypertrophic cardiomyopathy. Biophysical Journal, 122(3), 122a. https://doi.org/10.1016/j.bpj.2022.11.828
  • Scellini, B., et al. (2021). Mavacamten has a differential impact on force generation in myofibrils from rabbit psoas and human cardiac muscle. The Journal of general physiology, 153(7), e202012789. https://doi.org/10.1085/jgp.202012789.
  • Spertus, J. A., et al. (2021). Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England), 397(10293), 2467–2475. https://doi.org/10.1016/S0140-6736(21)00763-7
  • Spudich J. A. (2019). Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations. Pflugers Archiv: European journal of physiology, 471(5), 701–717. https://doi.org/10.1007/s00424-019-02259-2.
  • Wheeler, M. T., et al. (2023). Effects of Mavacamten on Measures of Cardiopulmonary Exercise Testing Beyond Peak Oxygen Consumption: A Secondary Analysis of the EXPLORER-HCM Randomized Trial. JAMA cardiology, 8(3), 240–247. https://doi.org/10.1001/jamacardio.2022.5099
  • Zampieri, M., et al. (2021). Pathophysiology and Treatment of Hypertrophic Cardiomyopathy: New Perspectives. Current heart failure reports, 18(4), 169–179. https://doi.org/10.1007/s11897-021-00523-0.
There are 39 citations in total.

Details

Primary Language English
Subjects Medical Pharmacology
Journal Section Reviews
Authors

Cahit Demirkıran 0000-0003-3240-1549

Şeniz Demiryürek This is me 0000-0003-4762-4745

Abdullah Tuncay Demiryürek 0000-0002-9994-8541

Project Number None
Publication Date August 29, 2023
Published in Issue Year 2023 Volume: 1 Issue: 2

Cite

APA Demirkıran, C., Demiryürek, Ş., & Demiryürek, A. T. (2023). Recent trend in the therapy of hypertrophic cardiomyopathy: Cardiac myosin inhibitors. Recent Trends in Pharmacology, 1(2), 110-122.