Advances in Treatment of Obstructive Hypertrophic Cardiomyopathy - Episode 9

Emerging Therapies for oHCM

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Steve R. Ommen, MD, discusses the use of novel agents in the pipeline for the treatment of obstructive hypertrophic cardiomyopathy (oHCM).

James Januzzi, MD: There’s been interest about newer therapies, including for nonobstructive HCM [hypertrophic cardiomyopathy], focusing on the heart muscle, trying to reverse remodel the heart muscle. But that’s not so much focused on HCM per se, negative inotrope, but more about remodeling. Sacubitril-valsartan is being examined, for example.

But I’d like to focus on the drugs that reduce inotropy, either mavacamten or aficamten, to get a better sense of what these drugs are. Because we hear a lot about them, and for us as general cardiologists, heart failure specialists, it can be challenging to really understand what they are. The class of drugs that affects heart muscles the way these drugs do is fascinating. Let me start off with Dr Ommen. Since you’ve described the interaction between actin and myosin, can you tell us, how do these drugs work?

Steve R. Ommen, MD: The quick and dirty is they decrease the number of actin-myosin cross-bridges. It loosens up that interaction, so it decreases contractility by a straightforward sarcomeric approach. It’s straightforward from my standpoint, as I wasn’t the drug company or the basic scientist who figured it out, but that’s in a nutshell what they do.

James Januzzi, MD: That’s really helpful. So they reduce inotropy very directly then.

Steve R. Ommen, MD: Yes.

James Januzzi, MD: Understood.

Steve R. Ommen, MD: With minimal impact on other loading conditions. They don’t change outflow or preload and they’re not dropping blood pressure. It’s a pure negative inotropic play.

James Januzzi, MD: That’s very helpful. Is the response to these drugs predictable? In other words, is it something that needs to be monitored?

Steve R. Ommen, MD: It’s definitely something that will need to be monitored, and we can get into some of the trials that are there.

James Januzzi, MD: We’ll do that now, in fact.

Steve R. Ommen, MD: Almost all of the markers that you look at—gradient, 6-minute walk time—are pointed or trended in the right direction. The EXPLORER-HCM trial was a 30-week randomized trial that looked at this. There was a prespecified endpoint that was both subjective and objective combined, improvement in NYHA [New York Heart Association] class, which we’ve talked about, coupled with an improvement in VO2 [maximal oxygen consumption] of at least 1.5 mL/kg/min.

In the trial, 37% of the active drug-treated patients achieved that endpoint vs 17% in the placebo group. That’s balanced against about a 10% rate of the negative inotrope being too aggressive or an EF [ejection fraction] drop to less than 50%. That’s just the basic shell of the EXPLORER-HCM study, but then John did some work with the KCCQ [Kansas City Cardiomyopathy Questionnaire] on the broader measures of how patients felt about it, and it would be good to turn to him and get his take on that.

James Januzzi, MD: Yes, I’d love to hear about this, John, because this gets right to the heart of the matter—no pun intended—about addressing symptoms.

Transcript Edited for Clarity