Clinical Trials of Mavacamten in oHCM

Anjali Owens, MD: So, Milind, let's go back to you and give us some of the data on mavacamten specifically, which we know is the only FDA approved cardiac myosin inhibitor approved in April of 2022. Give us some of the background data, top line results. You don't have to give too much of the weeds, although I know you know them all, on the trials we've had. I'll ask you to really focus maybe on the early earlier trials, PIONEER-HCM and of course the pivotal phase 3 EXPLORER-HCM trial.

Milind Desai, MD, MBA: So yes, thank you again in the obstructive HCM [hypertrophic cardiomyopathy] population, the PIONEER-HCM which basically was the pioneer of trials in this space. It was a phase 2 trial, small population. But it was divided into 2 cohorts with a lower dose, 2 mg and 5 mg and then the other one is 10 mg and 20 mg and open label. So obviously everybody knew that they were getting the goods, and there were 21 patients. Fundamentally the thought process was can it do what it's touted to do? This means reduce LV [left ventricular] outflow tract gradient, can it help improve the oxygen consumption on cardiopulmonary excise testing, and more importantly, what does it do to the behavior of the LV ejection fraction [EF]? Is the benefit to risk ratio ultra favorable? The answer was yes to those in the phase 2 trials and meaning it was excellent enough to proceed to the pivotal phase 3 trial, the EXPLORER-HCM trial, which is multicenter randomized double blinded placebo-controlled in many countries in across the pond and here. There were 251 patients placebo versus mavacamten, and they were followed up for a period of basically 30 weeks. It included adult patients with obstructive HCM with the primary endpoint as all of us know as what was the improvement in NYHA [New York Heart Association] class and what was the improvement in peak VO2 [peak oxygen consumption] So the endpoints were how many people improve their NYHA class by at least one or peak VO2 by 1.5, the combination of the 2, or peak VO2 by 3 mils per kilo if there was no improvement in NYHA class. This was obviously the primary endpoints, secondary endpoints where what happens to the gradients—Quality of life Kansas City Cardiomyopathy Questionnaire (KCCQ).

 Basically, there were some biomarkers on echocardiography, LA [left atrial] size, wall thickness, and a small MRI sub study looking at mass regression, fibrosis stabilization, etcetera. So what were the results across every category? Mavacamten performed significantly better than placebo improvement in NYHA class improvement KCCQ, improvement in peak VO2, gradients, biomarkers, troponin, BNP [brain natriuretic peptide], LA, LV mass, and fibrosis so across the board it was significantly positive. That as you alluded to was the primary reason why it got approved by the FDA last April to treat patients with class 2-3 obstructive HCM. The background therapy was only 1 background therapy was allowed, so it was not your maximally tolerated background therapy.

Anjali Owens, MD: So vast majority of patients were Class 2 either on a beta blocker or calcium channel blocker, some somatic obstructive HCM. As you mentioned, we saw the 3 things that we want to see when we’re treating these patients. They felt better, they exercise longer, and their gradients came down. So that's exactly what you'd like to see in your patient. Michelle, take us through recently the FDA approved to expand the label of mavacamten based on the data for the VALOR-HCM trial. So can you walk us through the top line results, the design of valor, and keep in mind that the first author is sitting next to you there?

Michelle M. Kittleson, MD, PhD: Listen, I am so excited that I got to answer this question even though Milind is the wizard of the VALOR-HCM trial, because I love this trial. I have no skin in the game, so I'm totally unbiased telling you I love this trial. I think it is so incredibly important for clinicians who care for patients with HCM because we got 112 patients with obstruct symptomatic obstructive HCM, but not just symptomatic obstructive HCM—symptoms that are so bad they're willing to move forward with septal reduction therapy. They're saying, “I feel so horrible you can crack open my chest or give me a controlled myocardial infarction to help me feel better,” as Andrew said, these therapies are only for quality of life. So these patients felt so bad they were all gung-ho and ready to do something invasive just to improve their quality of life. They go ahead and get mavacamten and lo and behold, after 16 weeks of mavacamten, all of a sudden, the vast majority of people who get mavacamten and say, "Actually, I feel great, I don’t need you to crack open my chest anymore”. As opposed to placebo, There is still a high percentage, 14% versus essentially 70% end up not proceeding. That's an enormous effect size. So anyway, long story short, I'm really excited that this is crucial information for clinicians, but not just as your gradient get better, because listen, if you follow me on the platform formerly known as Twitter or you've read my book, you know that I believe that the road to bad outcome starts with class plausible pathophysiology, surrogate endpoints, and wishful thinking. However, both EXPLORER-HCM and VALOR-HCM give us really nice data to hang our hats on, saying it doesn't just look good in theory, patients feel so much dramatically better that they're going to not go through an invasive therapy. So that's my take on VALOR-HCM.

Anjali Owens, MD: As Andrew told us, you know we feel that. The data with mavacamten is edging on both sides and this is the side toward that more severe sick patient. 93% of patients were class 3, 30% were on combination therapies with beta blocker, calcium blocker, and 20% were on disopyramide. So these were really maximally medically treated patients.

Milind Desai, MD, MBA: One comment I'm going to make. People can argue, “Oh I can deal with any therapy for 16 weeks” for the primary endpoint. As you very well know, you were right behind me actually in the manuscript. At 16 weeks every patient was offered SRT [septal reduction therapy]. Every patient was. Ninety-five percent chose to be on medical therapy, so there is a strong demonstrated preference to lesser invasive, noninvasive options. I think that was another important take from the study.

Anjali Owens, MD: To further that point, all of the patients had already been evaluated by a surgeon or an interventional cardiologist and deemed to be candidates. So they were really actively considering these therapies and voted with their feet for the medical therapy in this trial. Jim, back to you about how you think we can translate this to the clinic.

James Januzzi, MD: Yeah, thanks very much. So look, you know, I was going to jump in with respect to the praise for the VALOR-HCM trial because you know other studies were important, but this one really informs some very important clinical decisions. In addition, although you heard Dr Kittleson cast some shade at surrogate endpoints. Everything in this study lines up in a way that makes sense, right? You know, improvements in LV outflow track gradient, 3% drop in ejection fraction in parallel, but not too much. There were some patients that dropped their EF a bit too far but with dose reduction, their ejection fraction was in an acceptable range. The natriuretic peptide and troponin reductions about 50% reduction in both of the markers in parallel with improvement in obstruction.

For me as a trialist, one of the best parts of VALOR-HCM was the long-term extension where patients in the placebo arm were then crossed over to receive mavacamten, and guess what? They had almost identical improvements in LV outflow tract obstruction, Kansas City Cardiomyopathy Questionnaire, and biomarker reductions comparable to those folks who started on the drug at the beginning. So it really illustrates that, as I said earlier, we have another tool in the toolbox and the question really now is where in the hierarchy of decision-making does that tool…? Many of us now look at mavacamten as something to put ahead of septal reduction therapy for many of our patients, particularly those who are resistant to the idea of an invasive management strategy and so it really is an open question in 2023. How we will continue to expand use of mavacamten as an alternative as a leader ahead of SRT, as a way to assess the impact on symptoms, for example, before planned SRT. There are a number of different things that I've seen my colleagues approach this question with, but the bottom line is we have I think when applied carefully, a really effective therapy for HCM that we had been lacking for so long.

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