James Januzzi, MD

 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.

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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.

Implementing Novel Agents in the Treatment of oHCM

 And speaking of options which we all like to have, Andrew, can you tell us about the next in class cardiac myosin inhibitor aficamten, which is currently still in clinical trials, not yet FDA approved, but walk us through the data we have for that agent?

 Aficamten is a cardiac myosin inhibitor that works at a different site on the myosin head, but also reduces the actin-myosin interaction by inhibiting myosin ATPase. So it has a very similar effect to mavacamten at the chemical or biochemical level in that it reduces the power stroke and the hyper-contractility in patients with hypertrophic cardiomyopathy [HCM] and reduces the ejection fraction a few percentage points, just like mavacamten does. It has been studied and in a published phase 2 trial called the REDWOOD-HCM trial in which there were 41 patients, it was a randomization 2 to 1 aficamten to placebo and among the patients treated with aficamten, often there was a lower dose arm and then a subsequent higher dose arm. The study showed that there was a dose-dependent reduction in left ventricular outflow tract gradient [LVOT] to greater than 50% of baseline. So the higher doses were more effective, and this was associated with really the same benefits that we saw in the PIONEER=HCM trial as well as the EXPLORER--trial. That that degree of reduction in left ventricular outflow tract gradient was associated with that just as a grade of 50% greater reduction in. NT-BNP [N-terminal natriuretic peptide] level, improvement of their New York Heart Association [NYHA] class and their quality of life. So really, I think this confirms that cardiac myosin inhibitors are very effective for treating outflow tract obstruction, and by doing that, improving all of the hemodynamic abnormalities that we see in in patients with obstructive hypertrophic cardiomyopathy. Aficamten has completed its phase 3 clinical trial enrollment and we are waiting for the readout of that study, which will probably be later this year or early 2024. So in that study, it was a 1 to 1 randomization in patients with obstructive symptomatic hypertrophic cardiomyopathy randomized to aficamten versus placebo and the primary endpoint was a little bit different. It did not include a composite with NYHA class. It was just peak VO2 [peak oxygen consumption] but NYHA class, LVOT gradient, BNP, quality of life—all of those are included as secondary endpoints. So I think we're all very excited to see those results. It does have a much shorter half-life which allows it to be titrated more rapidly in in 2-week intervals to see the effect on the outflow track gradient. The washout as a result is much quicker if a patient does have side effects from it, discontinuation of it will lead to a quicker washout.

 Right. I think we've sort of touched us on this on the edges, but you know it, we really need to address up front that these agents modulate contractility. The safety concern is that if you get too much of the drug that you can have a drop in ejection fraction. Many of the patients in the trials and now we've seen in real life are asymptomatic with that drop in ejection fraction and because of that, you really need to monitor them with serial echocardiograms. If the objection fraction drops below 50, then, as we've said several times in the panel, you either reduce the dose if you're dealing with the drug like aficamten that has a relatively short or half-life, or you temporarily discontinue the drug, in the situation of mavacamten that has a long half-life. Then you repeat the echocardiogram, await the ejection fraction to return above 50, which again these agents are reversible and cardiac specific. So once you do that, repeat the echocardiogram, the ejection fraction is above 50, then you can restart at a lower dose.

Andrew Wang, MD, and Anjali Owens, MD, review the clinical trials of aficamten, a CMI used for treating patients with oHCM.

James Januzzi, MD

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