Impact of Cardiac Myosin Inhibitor Class on oHCM, with Anjali Owens, MD, and Andrew Wang, MD

(L to R) Anjali Owens, MD, and Andrew Wang, MD
Credit: University of Pennsylvania and Duke University School of Medicine

Among specialties, cardiology is often regarded as one of the most competitive fields in medicine. The competitive nature that has found a home in the field has been put to good use as clinicians and researchers find themselves tasked with addressing the leading cause of death, with the World Health Organization reporting more than 1 in 4 deaths worldwide was attributable to ischemic heart disease or stroke.

In recent years, this inherent competitiveness and push for innovation has manifested in an explosion in new medication classes for a slew of for a multitude of cardiovascular conditions, including some lacking effective treatment options such as obstructive hypertrophic cardiomyopathy (HCM).

For decades, management of the condition was limited, but results of the phase 2 PIONEER-HCM trial and subsequent phase 3 EXPLORER-HCM trial provided evidence of a potential treatment option for obstructive HCM.^1,2 Treatment algorithms were transformed in April 2022 with the US Food and Drug Administration approval of mavacamten (Camzyos), a cardiac myosin inhibitor from Bristol Myers Squibb, for treatment of symptomatic obstructive HCM.³ Looking at the pipeline, a next generation cardiac myosin inhibitor from Cytokinetics, called aficamten, has shown promise in phase 1 and phase 2 trials, with the company announcing the launch of the phase 3 MAPLE-HCM trial in June 2023.⁴

During a visit to the MJH Life Sciences studio for a panel discussion on obstructive HCM management, HCPLive Cardiology sat down with a pair of experts in HCM to learn more about recent advancements. A portion of the conversation with these experts, Anjali Owens, MD, director of the Center for Inherited Cardiovascular Disease and associate professor of medicine at the University of Pennsylvania, and Andrew Wang, MD, director of the Duke Hypertrophic Cardiomyopathy Clinic and professor of medicine at Duke University School of Medicine, is the subject of the Q&A found below.

HCPLive Cardiology: There has been an explosion in knowledge and management practices surrounding HCM. Can you describe how it has been to take part in and witness this revolution on the front lines of both research and care?

Owens: Well, the journey has been truly remarkable. It's held immense significance for us as medical practitioners and has equally proven transformative for our patients who, until now, lacked specific therapies for their ailments. What we've witnessed over the past decade is a shift from merely describing the heart's physical attributes—its thickness, its strength, the ejection fraction's variations—towards delving into a profound comprehension of the molecular and genetic foundations underpinning these diseases.

This enhanced grasp of the origins of cardiomyopathy has paved the way for us to now possess targeted treatments tailored to each distinct disease type, whether rare, prevalent, or falling in between. Observing this evolution has truly been awe-inspiring, and the ability to engage with our patients and explain their condition while outlining potential treatments has been deeply fulfilling.

Wang: In the broader realm of heart failure, there has been a consistent advancement in comprehending guideline-directed medical therapy. Each identified beneficial class within this context has fostered the belief in the ongoing potential to enhance outcomes for patients facing various types of heart failure. Notably, the most substantial progress has occurred in systolic heart failure, featuring numerous established classes with several others yet to be investigated. While many attempts have fallen short in demonstrating advantages in significant clinical endpoints like rehospitalization or mortality, there have also been notable successes. The latest triumph comes from the introduction of SGLT2 inhibitors, a breakthrough that has also extended its influence on heart failure with preserved ejection fraction.

When considering the rarer cardiomyopathies, both amyloid and hypertrophic cardiomyopathy serve as prime illustrations of conditions that previously lacked targeted treatments aligned with their pathology. Over the past five to six years, groundbreaking therapies have emerged for both conditions, marking a turning point in improving outcomes for affected patients. This progress underscores the power of optimism. While there were several unsuccessful attempts, even including the enhancement of exercise capacity in hypertrophic cardiomyopathy, the existence of one successful therapy generates heightened enthusiasm for the potential of others in the pipeline. Thus, the infusion of positive energy proves to be a driving force within the realm of heart failure.

HCPLive Cardiology: Can you reflect on the impact of the cardiac myosin inhibitor class on management of hypertrophic cardiomyopathy?

Owens: I believe the category of medications known as cardiac myosin inhibitors has truly revolutionized the field. Particularly for individuals with obstructive HCM, mavacamten stands out, having gained FDA approval for treating symptomatic cases of this condition. As you mentioned, aficamten is also part of this class but is still undergoing clinical trials, awaiting FDA endorsement. It is another promising agent that demonstrates efficacy in patients dealing with symptomatic obstructive HCM.

These drugs exhibit significant benefits that complement our existing standard-of-care therapies, which predominantly involve beta blocker medications, calcium channel blockers, and, for severely symptomatic and obstructed cases, disopyramide or even invasive septal reduction procedures.

To possess a medication that, firstly, addresses the root issue underlying the disease and, secondly, offers an alternative pharmacological choice for patients who prefer not to pursue invasive interventions, has undeniably transformed the landscape of available treatments and options. What remains to be seen is how we will address patients with non-obstructive HCM. Will there be medications like cardiac myosin inhibitors or another solution tailored to their condition?

Wang: The impact has been immense. I've overseen our hypertrophic cardiomyopathy program for the past two decades, and prior to the commercial availability of cardiac myosin inhibitors, the treatment options remained relatively stagnant. While patients still derived benefits, a significant portion of them ultimately required septal reduction therapies and invasive interventions. This was due to our limited capacity to achieve substantial improvement through medical means alone.

Consequently, there existed a substantial gap between effective medical therapy and the more definitive invasive treatments like alcohol septal ablation and surgical myectomy. This void has now been effectively filled by cardiac myosin inhibitors. These inhibitors present an entirely fresh and highly effective avenue for addressing patients dealing with obstructive hypertrophic cardiomyopathy. This shift not only alters the landscape but also extends the spectrum in both directions—perhaps a bit earlier into medical therapy.

Rather than progressing from beta blockers to drugs like disopyramide, the approach now could involve directly initiating cardiac myosin inhibitors. Similarly, instead of reaching a point where standard treatments have proven ineffective and contemplating septal reduction therapy, the VALOR-HCM trial has demonstrated that even severely symptomatic patients who would typically be candidates for invasive procedures can significantly reduce their clinical need for such interventions by using cardiac myosin inhibitors.

This change marks a significant advancement in our treatment offerings. It provides patients with more options. Some patients might choose to explore cardiac myosin inhibitors, either for a short or extended duration. Others might still prefer the definitive route, seeking fewer medications and fewer follow-up visits. This flexibility empowers patients to make choices aligned with their preferences and needs.

Editor’s note: these transcripts have been edited for grammar and clarity using artificial intelligence.

References:

1. Heitner SB, Jacoby D, Lester SJ, et al. Mavacamten Treatment for Obstructive Hypertrophic Cardiomyopathy: A Clinical Trial. Ann Intern Med. 2019;170(11):741-748. doi:10.7326/M18-3016
2. 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 [published correction appears in Lancet. 2020 Sep 12;396(10253):758]. Lancet. 2020;396(10253):759-769. doi:10.1016/S0140-6736(20)31792-X
3. Campbell P. FDA approves Mavacamten (Camzyos) for obstructive hypertrophic cardiomyopathy. HCP Live. April 28, 2022. Accessed August 23, 2023. https://www.hcplive.com/view/fda-approves-mavacamten-for-obstructive-hypertrophic-cardiomyopathy.
4. Cytokinetics announces start of Maple-HCM, a phase 3 clinical trial of Aficamten compared to metoprolol in patients with symptomatic obstructive hypertrophic cardiomyopathy. Cytokinetics, Inc. June 20, 2023. Accessed August 23, 2023. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-start-maple-hcm-phase-3-clinical-trial.