Ahmad Masri, MD, MS: 2024 Update on Development and Future of Cardiac Myosin Inhibitor Class

Although it does not receive the same level of fanfare as other classes of pharmacotherapies in the cardiometabolic health space, the development of the cardiac myosin inhibitor class represents a significant advancement in the management of hypertrophic cardiomyopathy and, potentially, cardiovascular medicine as a whole in recent years.

In April 2022, the FDA made history with the approval of mavacamten (Camzyos) for treatment of adults with symptomatic New York Heart Association class II-III obstructive HCM to improve functional capacity and symptoms based on data from the phase 3 EXPLORER-HCM trial. Results from the trial, which included 251 adult patients, suggested treatment with mavacamten was associated with improvements in exercise capacity, LVOT obstruction, NYHA functional class, and health status relative to placebo therapy.¹

Although mavacamten boasts the title of being the first FDA-approved cardiac myosin inhibitor, excitement around the development of aficamten, a next-generation cardiac myosin inhibitor, has continued to grow as the agent has progressed through its phase 2 and phase 3 clinical programs, with the excitement reaching a fever pitch in late 2023 when Cytokinetics announced in December. According to the announcement from Cytokinetics, use of aficamten was associated with significantly improved exercise capacity compared to placebo therapy as well as statistically significant and clinically meaningful improvements in all 10 prespecified secondary endpoints.²

Beyond the mavacamten and aficamten, development of additional cardiac myosin inhibitors is underway in the form of clinical programs for MYK-224 from Bristol Myers Squibb and EDG-7500 from Edgewise Therapeutics.^3,4

In late January 2024, a trio of clinicians from the Hypertrophic Cardiomyopathy Center in the Knight Cardiovascular Institute at Oregon Health and Science University penned an editorial in the Canadian Journal of Cardiology highlighting recent advancements in the class. With Ahmad Masri, MD, MS, director of the Hypertrophic Cardiomyopathy Center at Oregon Health and Science University, serving as the senior author, the review provides a timely update on the development of the cardiac myosin inhibitor class in hypertrophic cardiomyopathy and offers clinicians with a roadmap for implementation of cardiac myosin inhibitors in practice as well as spotlighting gaps in current understanding.⁵

Relevant disclosures for Masri include Cytokinetics, Bristol Myers Squibb, Eidos, Pfizer, Ionis, Lexicon, AstraZeneca, Tenaya, and others.

HCPLive: Building on your recent publication, how exciting is the development of CMIs for cardiomyopathy and is there potential for utility in other cardiovascular diseases?

Masri: I think you're referring to a review article that we wrote for the Canadian Journal of Cardiology, where it was a pretty long review article discussing CMIs—their history, development, and what we know about them so far.

As you know, this field is just moving at such a rapid pace really, that in one year from now, we probably could write another similar length paper on this. We are looking at about 4 cardiac in total. So, we know of mavacamten and aficamten, there is also MYK-224 from Bristol Myers Squibb and then there is also a cardiac myosin inhibitor or modulator that EdgeWise Therapeutics is working on.

We would expect the usual transition through phases of evaluation sometime soon. At this stage, since the class early in its evaluation there is still a lot of room there to consider what to assess and evaluate, we still don't know enough about aficamten from the trials. Right now, we only have the press release and, although we have the REDWOOD data and the FOREST-HCM data, we really need to see SEQUOIA data.We also need to see ACACIA-HCM, which would be the nonobstructive trial

For mavacamten, we haven't seen its performance in ODYSSEY-HCM—if, through the reduction of LVF in obstructive, does this shadow what's going to come out from the non-obstructive population. So, what we're looking at is a trade-off of efficacy, negative inotrope, and relaxation. This this is kind of almost a formula; you change one parameter, one other might work or not work and, as such, I think this is what's being changed in behavior right now is development of cardiac myosin inhibitors that are maybe more or less specific, a shorter half-life, no drug-drug interaction, which is a major, major issue for ultimately freely using a medication because when you have tremendous amount of drug to drug interaction that complicates things for anyone. Then another point is negative inotrope. The less you are affecting the systolic function, LVEF and whatnot, the more favorable a profile would be obviously for a myosin inhibitor.

We only talk about obstructive HCM or no obstructive HCM in isolation, but the reality is, you want to expand this concept you want to go for hypertrophic cardiomyopathy as a disease entity. a reminder that we classify these because we traditionally had different treatment for obstruction, and we had no treatments for nonobstructive HCM. Additionally, because of the gradient can create a more rapid and more progressive disease than that having no obstruction, but if you end up having a drug that works for everything, it just becomes a drug for hypertrophic cardiomyopathy period. If you could confirm that behavior in different clinical trials—that is our ultimate goal in the HCM space.

But think beyond HCM, you know, we have a humongous population of heart failure with preserved ejection fraction where patients have also left ventricular hypertrophy. Patients also have hyper contractility, where their ejection fraction is very high for sometimes with explained reasons, sometimes unexplained reasons, and I see this as our next population to think about. there is already actually a study of mavacamten in HFpEF, for example. We don't know the results of that study yet or what it's going to entail, but this is what people are thinking about and opening up more disease indications for these myosin inhibitors. That's why I think development of more therapeutics is certainly encouraged and allowing us to understand how each therapy behaves in each population is going to be really of tremendous importance to our community.

HCPLive: Are we approaching an age of precision medicine in cardiomyopathy?

Masri: That's an excellent question. In my view, cardiology as a field has often been overshadowed by early interventions targeting the myocardium, which, unfortunately, yielded mixed results due to their lack of specificity or potential harm in certain contexts. Consequently, the focus shifted away from neurohormonal modulation, despite the fact that many of these drugs primarily affect systems and organs outside the heart, rather than directly targeting the myocardium.

However, in recent years, we've witnessed a paradigm shift towards the development of therapies that precisely target the underlying pathophysiology of cardiovascular diseases, rather than employing a one-size-fits-all approach to different challenges or manifestations. A prime example of this is the advent of myosin inhibitors. Prior to their introduction, we lacked the ability to target the sarcomere, despite decades of research indicating its central role in conditions like hypertrophic cardiomyopathy.

This represents a significant advancement towards precision medicine in cardiology. With these new therapies, dosages are tailored to individual patients based on factors such as their symptoms, clinical status, and echocardiographic findings. Unlike the approach with neurohormonal modulation, where dosages are increased until tolerability limits are reached, here we have specific metrics guiding dose adjustments, allowing for truly personalized treatment.

Looking ahead, the potential for gene therapy in hypertrophic cardiomyopathy, particularly targeting genes like myosin-binding protein C3, holds promise. While these programs are still in their early stages, they offer a glimpse into a future where therapies can be finely tuned to address the specific genetic mutations underlying various phenotypes of cardiomyopathy.

In essence, the shift towards therapies that target the root cause of cardiomyopathies represents a revolutionary departure from the traditional blanket approach of treating heart failure with preserved or reduced ejection fraction. By embracing this personalized approach, we are poised to usher in a new era of precision medicine in cardiology.

Relevant disclosures for Masri include Cytokinetics, Bristol Myers Squibb, Eidos, Pfizer, and others.

References:

1. _{^{U.S. Food and Drug Administration Approves CamzyosTM (mavacamten) for the Treatment of Adults With Symptomatic New York Heart Association Class II-III Obstructive Hypertrophic Cardiomyopathy (HCM) to Improve Functional Capacity and Symptoms. Bristol Myers Squibb. April 28, 2022. Accessed February 19, 2024. https://news.bms.com/news/details/2022/U.S.-Food-and-Drug-Administration-Approves-Camzyos-mavacamten-for-the-Treatment-of-Adults-With-Symptomatic-New-York-Heart-Association-Class-II-III-ObstructiveHypertrophic-Cardiomyopathy-HCM-to-Improve-Functional-Capacity-and-Symptoms/default.aspx.}}
2. _{^{Campbell P. Cytokinetics announces positive topline data for Aficamten in Sequoia-HCM. HCP Live. December 27, 2023. Accessed February 19, 2024. https://www.hcplive.com/view/cytokinetics-announces-positive-topline-data-for-aficamten-in-sequoia-hcm.}}
3. _{^{A Study to Evaluate the Efficacy, Safety, and Tolerability of MYK-224 in Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy (MERCUTIO). Clinicaltrials.gov. Accessed February 19, 2024. https://clinicaltrials.gov/study/NCT05556343.}}
4. _{^{BioSpace. Edgewise therapeutics begins dosing first-in-human phase 1 trial of EDG-7500, its lead clinical candidate for hypertrophic cardiomyopathy (HCM) and other serious diseases of cardiac diastolic dysfunction. BioSpace. September 14, 2023. Accessed February 19, 2024. https://www.biospace.com/article/releases/edgewise-therapeutics-begins-dosing-first-in-human-phase-1-trial-of-edg-7500-its-lead-clinical-candidate-for-hypertrophic-cardiomyopathy-hcm-and-other-serious-diseases-of-cardiac-diastolic-dysfunction/.}}
5. _{^{Haraf R, Habib H, Masri A. The Revolution of Cardiac Myosin Inhibitors in Hypertrophic Cardiomyopathy. Can J Cardiol. Published online January 25, 2024. doi:10.1016/j.cjca.2024.01.022}}