Milind Desai, MD, MBA

Milind Desai, MD: Real-World Data Supports Mavacamten’s Safety for oHCM

Real-world results from the Risk Evaluation and Mitigation Strategy (REMS) program confirmed mavacamten, a cardiac myosin inhibitor for 

obstructive hypertrophic cardiomyopathy (oHCM)

, maintained a favorable safety profile in more than 6,000 real-world patients.

American Heart Association (AHA) Scientific Sessions 2024

, data collected between April 2022 and February 2024 revealed that temporary treatment interruption due to reduced left ventricular ejection fraction (LVEF <50%) was rare, occurring in only 4.6% of patients, while HF requiring hospitalization (HFH) was even less frequent (1.3%).

“Overall, all the REMS objectives with regards to the mavacamten program were achieved based on the current report,” presenting investigator Milind Y. Desai, MD, MBA, a professor of medicine at the Cleveland Clinic Lerner College of Medicine, told 

. “Of course, REMS is not a clinical trial, we don’t have extensive data, but that is not what this program was designed [to do]. Every patient in the United States is represented here."

Among the 1,929 patients treated with mavacamten for at least 1 year, 4.04% experienced LVEF reductions to <50% and 0.21% had concurrent HFH, often linked to confounders like atrial fibrillation. Across 29,111 health status forms submitted during the study, LVEF <50% was reported in 0.9% of cases, and HFH occurred in only 0.3%. Additionally, drug interaction monitoring—part of the REMS protocol—led to dose adjustments in 0.25% of cases and discontinuation of interacting medications in 0.32%.

Overall, these findings reinforce mavacamten’s safety and tolerability for patients with symptomatic NYHA class II-III oHCM, even with prolonged use. Clinicians can be reassured by these real-world outcomes, demonstrating effective risk management under the REMS program. Further dosing analyses are expected to provide additional insights into optimizing long-term treatment strategies.

“The next programs will inevitably require a REMS program and they have a playbook they can adapt off of the mavacamten experience,” Desai told HCPLive. “I would imagine the future set of cardiologists or practicing clinicians who may have to deal with the REMS program, we have a huge contemporary lesson to learn from."

Disclosures: Desai reports relevant disclosures with Bristol Myers Squibb, Cytokinetics, Edgewise, and others.

Desai MY, Seto D, Cheung M, Coiro M, et al. Mavacamten: Real-World Experience from 22 Months of the Risk Evaluation and Mitigation Strategy (REMS) Program. Presented at the American Heart Association (AHA) Scientific Sessions 2024. Chicago, Illinois. November 16-18, 2024.

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Mavacamten, a cardiac myosin inhibitor for obstructive hypertrophic cardiomyopathy, demonstrated a favorable safety profile in over 6,000 patients under the REMS program. Data from April 2022 to February 2024 showed low incidences of reduced left ventricular ejection fraction and heart failure requiring hospitalization. Among patients treated for at least a year, LVEF reductions and HFH were rare. Drug interaction monitoring led to minimal dose adjustments and medication discontinuations. These findings support mavacamten's safety and tolerability, providing a model for future REMS programs in cardiology.

Milind Desai, MD describes favorable real-world safety outcomes from mavacamten use over 22 months of the Risk Evaluation and Mitigation Strategy (REMS) program.

Milind Desai, MD: Real-World Safety Data Supports Mavacamten for oHCM

 So in the last few minutes, I'm going to ask each of you as you look into the future caring for our patients with obstructive HCM [hypertrophic cardiomyopathy] and non-obstructive HCM, what other things are you excited about? We talked a little bit about the myosin inhibitors, but clearly there are other things that Milind alluded to that are coming down the pike for us. It's an exciting time to be in HCM position. What are the things that you're most looking forward to and Jim, I'll start with you.

 Yeah, thanks very much. I'll put my clinical trial hat on. We've fully enrolled a clinical trial looking at metabolic manipulation of myocardial function using a partial fatty acid oxidase inhibitor in patients with HCM. So approaching the question from a completely different angle that would be additive together with cardiac myosin inhibition, so thinking about newer pathways to address in patients with HCM to improve their symptoms. That's really exciting to me.

 So speaking as a heart failure, transplant cardiologist is what I spend most of my time doing. I think we still have so many unanswered questions in patients with non-obstructive HCM with advanced symptoms. What's the role of guideline directed medical therapy—was just traditional garden variety heart failure with preserved ejection fraction therapy like mineralocorticoid antagonists, angiotensin receptor neprilysin inhibitors, SGLT2 inhibitors. Do they work? Will they be effective in non-obstructive HCM? I think that is an unmet need in a huge space that I'm hopeful in the future we'll have more answers.

 I agree with you completely. That group of patients are perhaps the most difficult and challenging to treat in the clinic and hopefully will make some headway there. Milind, what are you looking forward to?

 I will start with what Michelle alluded to the next frontier is the non-obstructive HCM. So I am not a heart failure transplant doctor, but can mavacamten or CMIs [cardiac myosin inhibitors] work in this space because it's not all about the LVOT [left ventricular outflow tract] obstruction. There are structural changes that are happening, and we are answering this question in an ongoing randomized clinical trial, RCHCM, and there is another one with aficamten, that is being planned coming down the pike. That will help us clear some of that air. Of course, we need to understand the other drugs like SGLT. Could that work? But the bigger picture I think is the genetic space, the gene therapies, the adenovirus-based therapies that can help modulate the deficient protein in the heart of MYBPC3 so that space is active and brewing the business of gene editing CRISPR, etcetera. All these things obviously, I often joke as long as it does not create mutant Ninja Turtles down the road, meaning the uncertain offshoot effects, I think the future is bright. Honestly, I just told this to one of my patients a couple of days ago is that I can excitedly look forward to having a potential cure for this disease before I hang my boots into retirement. So I'm looking forward to all and plus the PROs [patient reported outcomes] and the shared-decision making. The other thing is the HCMR trial, hypertrophic cardiomyopathy registry from NIH which I am also part of, so I have to plug it in. That is going to start reading out in the next year or so that will help understand the risk stratification space a lot more.

 What's left? They've taken all the low hanging fruit And even the high hanging fruit from the tree. No fruit left on the tree.

 You're climbing all the way up the tree to the top.

 No fruit left on the tree. So I would echo what Jim said. I think that the potential for positive remodeling of the left ventricle not only pathologically with hypertrophy, but maybe reducing the progression of fibrosis would be a major advancement. If we can show that a therapy reduces progressive fibrosis that we can see on late gadolinium enhancement, we know its association with worsening progressive heart failure as well as ventricular arrhythmias, that would be a huge benefit. As Milind said that fibrosis is also shown with severe diastolic dysfunction as well, and many of our patients have some symptoms with outflow tract relief from diastolic dysfunction. So I think that is another unmet need. The last thing I would say is you know how normal can we make patients feel? With obstructive hypertrophic cardiomyopathy, will they be safe to be highly competitive, vigorous athletes, even with this condition? Can we really get close to normalizing what they really can do and feel like they can do and want to do?

 Yeah, that's what's a wonderful goal. It is a lofty goal, but one that we may meet. So with that, I'd like to thank you all for joining our panel today. This has been a very rich, informative and lively discussion and thank you audience for watching our HCPLive Peer Exchange®. You can subscribe to the enewsletter and receive other great content right in your inbox. Thanks again everyone.

Transcript is AI-generated and edited for clarity and readability.

Andrew Wang, MD; James Januzzi, MD; Michelle M. Kittleson, MD, PhD; and Milind Desai, MD, MBA, share a look into the future of oHCM treatment.

The Future of oHCM Treatment

 Let me take that point over to Michelle. So, Michelle, you said I gave you a softball earlier, but this is the hard one. What is left in terms of unanswered questions, and to build on Milind’s point, what does disease modification mean? You’re a heart failure doctor, like myself . Are we affecting the natural history of disease? What do we need to know to get that answer?

 I think Milind started off the conversation. He punted the volleyball to me. I'm going to spike it over the net with what are the unanswered questions regarding cardiac myosin inhibitors. Like we said, beta blockers are traditionally first-line therapy. But, are they the best first-line therapy? So MAPLE-HCM [hypertrophic cardiomyopathy] is a phase 3 multicenter randomized active comparator clinical trial that's going to pit beta blockers against aficamten in patients with symptomatic obstructive HCM. Looking at a peak VO2 [peak oxygen consumption] change, and I'm very interested to see how that study pans out. I think other things we need to know which everyone's mentioned, I'll just sum up a long-term safety and efficacy cost effectiveness. I think we need to know response based on those important individualized patient traits of sex, race, ethnicity, gene mutation, and then the potential for prevention. So I'm so excited that we have the potential to answer all of these questions.

Michelle M. Kittleson, MD, PhD, comments on remaining unanswered questions regarding CMIs in treatment of oHCM, highlighting disease modification.

Unanswered Questions About CMIs in oHCM

 So Jim, let me ask you in the last few minutes that we have, what's your approach in the real world to really implementing these agents? What kind of infrastructure is there? How do you select the patient? How do you go about doing this in the real world?

 Yeah, great question. This illustrates the importance of a team sport here. You really do need an infrastructure because when you use cardiac myosin inhibitors, it's done under what's called a Risk Evaluation and Mitigation Strategies, or REMS approach, which includes following patients with echocardiogram to evaluate the ejection fraction [EF] in particular. Dr Owens, you made that point very, very clearly. Often our patients don't feel that their EF is low of course. So understanding where their ejection fraction is settled is critically important because temporary cessation and dose reduction in the case of mavacamten may be necessary. So it's important to coordinate this with your team. We use natriuretic peptides as well—you mentioned that right in the very beginning. One of the things that we're examining both clinically at the Massachusetts General Heart Center but also in the DISCOVER-HCM study is trying to understand if trajectories of NT-proBNP [pro-brain natriuretic peptide] helped to inform what the echocardiogram is going to show you, right? So you'll see a reduction in NT-proBNP from the reduction in the LV [left ventricular] outflow tract gradient. But then if you have excessive left ventricular ejection fraction lowering, who knows? It's possible you might see a rise in NT-proBNP overtime, so close follow up is critically important it's necessary to educate patients about the fact that, for example, mavacamten is metabolized by cytochrome P450 enzymes, so they need to know that can accommodate use of inhibitors or inducers of the P450 system could be associated with risk for progressive systolic dysfunction or loss of effectiveness of the drug. These are just important aspects that we engage with our patients on to make sure they understand—it's not a free lunch—but they really do find a substantial improvement in their symptoms and association with its use.

 If I could add one thing also to what Jim was saying, I think we've all noted that patients who develop atrial fibrillation are much more likely to have a reduction in their ejection fraction. So in addition to counseling them, regarding if you start any new medicines, please let us check for drug-drug interactions. In mavacamten at least. I think for cardiac myosin inhibitors in general, the occurrence of atrial fibrillation [Afib], which is common in patients with hypertrophic cardiomyopathy, can be the provocation for reduced ejection fraction. I tell my patients, if we're starting you on this and you have recurrence or develop atrial fibrillation, I would like to see you sooner than the scheduled echocardiogram to be sure we're not missing something.

 Yeah, it's such an important point. We've seen that in the trials and also in the long-term extension that any kind of intercurrent illness that could be non-cardiac in nature, severe pneumonia, urinary tract infection—which makes sense that it may be a time where you need more contractility, that you may have a drop in ejection fraction if you're on a myosin inhibitor, and of course the paroxysms of A-fib particularly rapid A-fib. Jim, did you have something to add to that?

 The other thing that I think is going to be really interesting is the long-term consequences of use of the drug in terms of potential effects on reverse cardiac remodeling. We just simply don't know, but it's being examined now, cardiac myosin inhibitors in other forms of heart failure for this exact reason.

 An important thing, brief comment. I'm going to make is as follows. This is why taking the conversation of therapy a little bit more upstream would be important because we know the biggest risk factor for Afib is a big left atrium. So can we reduce the protoplasm that results in these downstream arrhythmias, etcetera, to a point where, you know, we are breaking the cycle here. So we have to start thinking in a broader, more upstream manner.

Expert cardiologists share approaches to implementing mavacamten and aficamten in the clinical treatment of oHCM.

Milind Desai, MD, MBA

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