Use of Cardiac Myosin Inhibitors (CMI) in oHCM

Anjali Owens, MD: With this novel mechanism of action modulating contractility where do you think that these agents could fill a gap in the care of our obstructive HCM [hypertrophic cardiomyopathy] patients?

Andrew Wang, MD: So as Milind said, these drugs cardiac myosin inhibitors are very potent, but titratable drugs to help reduce hypercontractility, we think of the normal person's ejection fraction is greater than 55%. Many patients with hypertrophic cardiomyopathy have ejection fractions above 70%. In the EXPLORER-HCM trial, I think the baseline ejection fraction was 72%. So again much higher than normal and mavacamten, in that trial reduced the on average the ejection fraction just by about 4%. Now there were there was a wide range, but the average reduction was 4%. Yet with only a 4% reduction, there was a really a greater than 50% reduction in the outflow tract gradient or reduction in BNP [B-type natriuretic peptide], so really a big gain for a little bit of reduction in contractility. I think this really has been somewhat of a revolutionary change with regard to our management options for hypertrophic cardiomyopathy. I think all of us here have been doing this a long time. Up until last year when we had an FDA-approved cardiac myosin inhibitor, we would get a patient on background medical therapy, but a high percentage them still were symptomatic. Maybe they were better, but still symptomatic, yet not so symptomatic that they were willing to cross the line to an invasive therapy. So we would say “Well, you're doing okay. You're NYHA [New York Heart Association] class 2. You're better than you were before. And you don't want to go on a septal reduction therapy. Let's just keep an eye on it. You let me know if things get worse”. That might trigger us to say let's move ahead with something else. There was a big gap, a high percentage of patients were still symptomatic, still NYHA, class 2, maybe even class 3. On background, medical therapy yet reluctant to go to for an invasive therapy, they were also somewhat used to living this way. You know that they've lived this way a long time, and so they don't necessarily understand how they could feel without the outflow tractive production having a cardiac myosin inhibitor, actually I think really fills not only that gap, but edges into both sides of that gap. This means I think we think about it earlier for patients that are on background medical therapy, but still have NYHA class 2 symptoms before adding or changing to a different medicine. Listen, and I also think that we are now using it as a way to say, well, you are NYHA class 3, but based on the VALOR-HCM data, we think that you can be very well managed and have a significant improvement of your symptoms on a cardiac myosin inhibitor. So it not only filled the gap of what was missing, but I think offers options for patient who want to feel better but want to do it under their own terms.

Anjali Owens, MD: This is such an important point that we no longer have to settle for patients feeling better, but not great and still remaining limited in things that they want to do physically. I think that's such an important point. As you sit with the patient, they just make their world a little bit smaller so that they don’t have to go up the stairs. They no longer have to go to the basement, and they don't take the dog for the 2–mile walk. They just do less because they feel limited, and now we don't have to settle for that because the cardiac myosin inhibitors give us another option for treating the symptoms of obstruction.

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