Advances in oHCM Therapy

Anjali Owens, MD: So Milind, let's start with you. How is the advancement in the knowledge about pathophysiology? You talked to us about mice and heavy chain myosin binding protein C [MYBPC3] sarcomere variance at the very beginning. How is further understanding of that pathophysiology led to the development of new therapies?

Milind Desai, MD, MBA: You take a genetic abnormality, recognize it, dissect it, and then understand enough about it to then go and develop a precision tool to work on it. So what are we talking about? We know we briefly talked about in HCM [hypertrophic cardiomyopathy], what is happening is there's excessive actin myosin cross-bridging that happens at a myocyte level which results in the hypercontractility. This is a good lesson in life—not everything that is vigorous is good. So bottom line is we know there's a lot of hypercontractility; there is a fair bit of inefficient use of energy and stiffness, excessive fibrosis. All those things lead to the pathophysiology of hypertrophic cardiomyopathy. To top it off, this excessive hypertrophy and hypercontractility results in the outflow tract obstruction that you see so. I think we need to take the microscopic and the macroscopic perspective together and working on a precision drug like the cardiac myosin family of inhibitors. What do they do? These types of drugs reduce the actin myosin cross-bridging, so they don't shut them all off. Otherwise, you know we won't have a heart that is beating. So they shut enough of them to reduce the edge of hypercontractility so from hypercontractile you become appropriately contracted. It makes the heart utilize energy more efficiently. In doing so the most important part at this point of time is that it reduces the outflow tract obstruction, which then has a lot of downstream positive impact, including improvement in symptoms, quality of life reduction in MR [mitral regurgitation], improvement in diastolic function, LA [left atrial] volume reduction, and mass regression. Most importantly, we are in the business for making patients feel better and perhaps avoid invasive therapies that may have heterogeneous outcomes, so it helps reduce the rate of septal reduction therapy. We are just getting started here as you very well know, we are getting started here.

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