Mavacamten Fills Treatment Needs for Symptomatic Obstructive Hypertrophic Cardiomyopathy

Milind Desai, MD, national principal investigator of the VALOR-HCM trial, discussed new results presented at the American College of Cardiology 2022 Scientific Sessions.

Pharmacy Times spoke with Milind Desai, MD, national principal investigator of the VALOR-HCM trial investigating mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). Results of the trial were presented at the American College of Cardiology 2022 Scientific Sessions in Washington, DC.

Q: Can you give an overview of mavacamten?

Milind Desai, MD: Mavacamten is a novel direct cardiac myosin inhibitor, which was developed specifically to counter what is wrong in hypertrophic cardiomyopathy. So, essentially it works on the actin myosin cross bridges within the myocardium within the sarcomere. In hypertrophic cardiomyopathy, the biggest issue is that of hyper contractility and mavacamten helps to reduce the hyper contractility. What that essentially does is it makes the heart function more efficiently, it makes it more compliant and more energy efficient.

So, in prior phase 1, 2 and 3 studies, it has been shown to improve your symptoms significantly and to improve your left ventricular outflow tract gradient, which is very common in obstructive HCM patients. [It also] improves quality of life and shows improvement in functional capacity as well as some key biomarkers like BMP and troponin I.

Q: How is severely symptomatic HCM typically managed, and how have treatment options evolved in recent years?

So, yes, thank you so much. So obstructive HCM. So, what is the fundamental problem there is there's thickening of the heart muscle at the base of the ventricle, and when there is a resulting combination of this thickening heart muscle and systolic anterior motion of the mitral valve, they result in left ventricular outflow tract obstruction. So, in the past, a hierarchical approach to management has been to use drugs—therapies that reduce contractility or reduce heart rate, or both. Unfortunately, none of the drugs were specifically developed for countering hypertrophic obstructive cardiomyopathy. So, the commonly used drugs are beta blockers, or non-dihydropyridine calcium channel blockers like Verapamil. And since the 1980s, it was recognized that disopyramide, which is a class Ia antiarrhythmic, in addition to the antiarrhythmic effects, it also can result in reduced contractility and reduced gradients. So, these are the typical hierarchical drugs that are used, and mind you, none of them were developed for the specific reason of countering HCM. It's just serendipitous use in this disease.

Now, once patients get to a point where they remain symptomatic despite maximally tolerated medical therapy, then they move to the next phase, which is typically called septal reduction therapy. The 2 common ways of doing it is (1) surgical myectomy, where, through open heart surgery, we shave the thick part of the muscle. In some patients, we may have to do a mitral valve repair. And the goal is to relieve outflow tract obstruction. The other way is to do it through the percutaneous intervention approach where you identify a suitable set of perforated branch, a branch that supplies that part of the thick muscle of the heart, and then squirt some alcohol in it. And that results in shrinkage—a controlled scar formation and shrinkage of the heart muscle, thus, opening up the outflow tract. So, the fundamental thing is [option 1] removes the obstruction. The other one shrinks the thick muscle, indirectly removing obstruction. So, these are the standard ways how people relieve outflow tract obstruction. There's a couple of newer techniques that are being developed, but they are still experimental.

Q: Why is there a need for alternatives to alcohol ablation and surgical septal myectomy?

So, that's a very important and interesting question. Let's do some math here. The expected prevalence of HCM is 1 in 200 to 1 in 500, and the prevalence is across the world. So, there's about 15 to 20 million people in the world with HCM, number one, and about 60% to 70% of them have obstructive HCM. Let's say hypothetically, a little more than 10 million people. The gold standard treatment is septal reduction therapy, so far, that we know of. We know that this is the gold standard treatment, but it is not widely available. Even in the United States, even in North America, and certainly across the world, it is not widely available [because] there are not enough experienced centers to be doing that. That’s number 1.

Number 2, even within centers that do it, there's wide heterogeneity in outcomes survival. So, the guidelines recommend that you should have a myectomy or alcohol ablation at a center that that has excellent outcomes, meaning less than 1% mortality. Fine, great, there aren’t too many such centers around in the world.

The other part is there are United States national inpatient sample data that has shown that if this procedure works great, in the right hands at the right center, okay, but the US National inpatient sample has shown that the average 30-day post-operative mortality after myectomy across the variety of US hospitals is about 5.9%. That’s not less than 1%, it’s almost 6%. And it can range from up to 16% in low volume centers to 3.8% in not-so-low-volume centers, or that do enough, but not enough to reach less than 1% mortality.

Hence, while these work great in the right hands, there are not enough centers and in the centers that do it, the outcomes are heterogeneous and so clear. That plus the fact that we may be dealing with almost 10 million people out there, I can assure you we are not doing 10 million septal reduction therapy procedures. This world does not yet have that bandwidth to do so. So, clearly there's an unmet need. And the drug therapy as I told you has never been developed to counter a specifically target HCM.