The VALOR-HCM Trial: Encouraging Findings for Patients with Obstructive HCM

In this insightful interview, Rawan Amir, MBBS, and CardioNerds Academy Fellow, spoke with Milind Desai, MD, MBA, director of the Center for Hypertrophic Cardiomyopathy and medical director of the Center of Aortic Diseases, Cleveland Clinic, about the Phase III VALOR-HCM trial, which assessed mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy.

Rawan Amir: Hello everyone. My name is Rawan Amir, Internal Medicine, PGY-3 at the University of Maryland Medical Center, soon to be cardiology fellow at John’s Hopkins and I’m a Cardionerds Academy Fellow at House Taussig. It is my pleasure to be here with Dr. Milind Desai, Professor of Medicine and Director of the Center for Hypertrophic Cardiomyopathy at the Cleveland Clinic.

Rawan Amir: Dr. Desai, I was there at the ACC 22′, when you first presented the results of VALOR-ACM, the energy in the room was electrifying. How did you feel while presenting the extraordinary results of this trial?

Dr. Milind Desai: First and foremost, thank you so much for the invitation and the kind words. I think the important thing was we were in a face to face meeting after two years, and so the hall was full. So just that was very, very, awe inspiring, for the lack of a better term. Yes. I mean, the burden of the moment was not lost on me. Let me be frank. But once I got into the groove, I think at the end of the day, the results spoke for themselves and I was glad to be able to present in person to such a large audience. In retrospect, it was a fun experience.

Rawan Amir: It was amazing. We do have a few questions about the trial and the trial process itself. So, we do know that in 2020, the EXPLORER-HCM trial studied the effect of mavacamten on exercise capacity, New York Heart Association Functional Class, and LVOT obstruction in patients with obstructive HCM, with remarkable improvement in pretty much all parameters. So, what was your goal with VALOR-HCM and how does it add to the mavacamten story?

Dr. Milind Desai: Thank you so much. So, if you recall, in the EXPLORER-HCM, the patients were predominantly NYHA Class II and III, so about 72, 73% patients with NYHA Class II and the remainder in Class III. They were not at a point where septal reduction therapy was a recommended at the time. The other important difference is the patients were not on combination therapy. They were only on one monotherapy. They were certainly excluded if they were on disopyramide and the follow up, the titration, up and down titration, of the drug was based on pharmacokinetic levels in the blood. Contract distinct that with VALOR, 93% patients were in NYHA Class III, every patient was referred to an experienced HCM center for consideration of SRT and every patient met criteria for SRT before being considered for the trial.

Dr. Milind Desai: Combination therapy was allowed and in fact, 36% patients were on combination therapy. 20% patients were on disopyramide and basically we chose a real life way of monitoring these patients. And what I mean by that is, the assessment and dose titration was done based on echo measurements of ejection traction and LV outflow tract radius. So, this was a lot more real life type trial and of a much more sicker population. So, it extends the findings of the EXPLORER study into a much sicker population.

Rawan Amir: And how did you arrive at the 16 week mark for follow up and planning the outcomes of the trial?

Dr. Milind Desai: That’s a very important point. And as you know… And this is a crucial question because most HCM management, we don’t think about 16 week… I mean, we talk about it in months, certainly if not years. But, remember the first thing I said, these were all sick patients referred for SRT, meaning if they were not participating in the trial, they would have been undergoing SRT in that timeframe. So, given this was a placebo control arm, we did not think it was ethical for us to deprive patients and give them only placebo, especially because these patients were interactively symptomatic on maximally tolerated medical therapy.

Dr. Milind Desai: So, we know the amount of time it takes for the drug to reach steady state and basically see major effect, is about four weeks. We did not want it to be a four week trial. We certainly did not want to deprive people for anything longer. So, that’s how we came up after back and forth discussion with 16 weeks. Important to realize all also, is as a secondary, not a secondary, but as a downstream trial, there is a long term extension where patients were given at 16 weeks an opportunity to choose SRT or continuing the mavacamten like a blinded dose arm for the next few weeks, and then long term extension for almost 128 weeks. 95% patients chose to continue in the study.

Rawan Amir: That’s incredible. And that brings me to my next question, which I think is a very, very important one. So, what does this mean for our patients? I know that we’re currently waiting for a final decision by the FDA, but if mavacamten is approved, what will its role be in the treatment of this patient population and how will it modify the role for septal reduction therapies?

Dr. Milind Desai: So, that’s a very important question. So, look, to me, the way I look at it is it’s never this or that. It is always this plus minus that. Take the example of statins and PCI, or statins and cabbage. It is never this or that. It is always… you are expanding the tent under which the patient has a lot more to choose from in terms of medical therapy.

Dr. Milind Desai:  So, how do I look at SRT or mavacamten in the context of SRT? So, I like to divide the patients into four buckets. One bucket of patients could be who feel so much better after starting mavacamten than they don’t need SRT. The second group is somebody who says, “I just don’t want to have an SRT right now. I want to wait childbearing.” Or whatever. There are various reasons in life people may choose to delay a procedure. They say, “Can I get this effective therapy for a few years?” The third group is somebody who’s high risk for surgery, or does not have appropriate anatomy for alcohol ablation. This could serve in that purpose. And the fourth, I suspect the biggest group, is patients who do not have access to high volume SRT centers.

Dr. Milind Desai: Now, remember the guidelines say in order to have good SRT outcome, you should go to a center that offers less than 1% mortality. Unfortunately in the world, even in USA, there is not enough such centers. So, the big problem is getting access to these high volume centers. The other important thing to point out is if you go to a low volume SRT center, your mortality could be as high as 16%, forget less than 1%. So, my suspicion is, access to a high volume SRT program might drive the utilization of it and time will… So, where does it fit in with a other medical therapy? Do you do it in addition to beta blocker or calcium [inaudible 00:08:25] blocker? Do you do this in addition to other maximally tolerated medical therapy? We will have to see, and we have to balance the side effect profile of other drugs also.

Rawan Amir: Yeah. Well, its going to be…

Dr. Milind Desai:  In the VALOR study, it was used in combination with other therapies and found to be safe.

Rawan Amir: Yes. We are all very excited to see what the FDA decides and what the next steps are going to be when trying to see which patients would benefit most and how we’re going to incorporate this into our standard of therapy.

Rawan Amir: One final question for you, Dr. Desai, as a lucitropic drug designed for myocardial relaxation, would you anticipate studying mavacamten beyond symptomatic obstructive HCM? Either in different HCM phenotypes, or maybe even beyond HCM for patients with, for instance, heart failure with [Audio glitch 00:09:20].

Dr. Milind Desai: Yeah. That’s a million dollar question that is going to be answered hopefully in the next few years. You’re absolutely right. It is a lucitropic drug and to me, right now… So, let’s just step back for a second. Obstructive symptomatic hypertrophic cardiomyopathy patient. Obstructive patients, at least today we have SRT. If you get access to a high volume center, you have a treatment option. For nonobstructive HCM, there’s not much treatment options. Right? So, if this drug works, there is a huge market or huge unmet need in that population for an effective precision drug that was specifically developed to work on the sarcomere. So, absolutely, that is an important subgroup that needs to be tested and we are in the planning stages of a non-obstructive HCM trial that should go online in the next few months. Now, expanding it to [inaudible 00:10:26], many have come, many have tried, not too many have been able to conquer that. So, again, studies are being planned in that context and time will tell if these drugs, specifically, pan out in the context of relaxation. So, we got to wait for the right science.

Rawan Amir: Well, it looks like the next few years are going to be extremely exciting for the world of HCM and heart failure with [inaudible 00:10:55], hopefully.

Dr. Milind Desai: Let’s hope so.

Rawan Amir: Thank you so much Dr. Desai, for taking the time to be here and congratulations once again on such a phenomenal trial.

Dr. Milind Desai: Thank you so much for having me here. It’s been my pleasure. Thank you.