Dr Stephen Heitner Details the Significance of the PIONEER-OLE Study in Treating Obstructive HCM

For patients with obstructive hypertrophic cardiomyopathy (HCM) in the PIONEER-OLE study, mavacamten was shown to improve patients' symptoms, reduce LVOT obstruction, and essentially improve myocardial efficiency, said Stephen Heitner, MD, director of Clinical Trials and director of the Hypertrophic Cardiomyopathy Center at the Oregon Health and Science University.

Transcript

Can you discuss the significance of the PIONEER-OLE results and what they tell us about the clinical benefits of mavacamten in obstructive HCM?

PIONEER-HCM showed us that mavacamten improved patients’ symptoms, reduced LVOT [left ventricular outflow tract] obstruction, improved patients’ ability to exercise—essentially improving myocardial efficiency in these patients with obstructive HCM. PIONEER-OLE, a portion of those patients who were able, we targeted the specific plasma dose for the individual patients and that kind of dose range was what we thought would be effective based on the PIONEER-HCM study. So, number 1, it was a targeted dose–targeted plasma concentration in fact in these individuals. We showed that mavacamten is obviously safe and well tolerated in individuals for up to a year–in some patients we’ve got on study now for more than a year and a half. So, number 1, it’s safe and well tolerated, and number 2, is that it is highly effective at achieving what we want, which is to reduce the LVOT obstruction to what we consider below the surgical threshold.

Secondly, it actually seems to impact cardiac remodeling advantageously. So, what we start to see after 12, 24, 36, and now 48 weeks, is that the heart is starting to reshape itself into a more normal looking heart. That’s manifest by a reduced left atrial volume—so the atrium is actually getting smaller, which is a good thing. Secondly, we see that the measurements that we use in order to kind of gauge the left ventricular filling pressures, are returning towards normal. So, that’s your e’ velocity and your E/e’, which is a well-known marker of left ventricular filling pressures using echo [echocardiography], and your NT-proBNP, which is a plasma marker for a similar concept, actually is tremendously reduced. The last thing that we see in the PIONEER-OLE is a reduction in left ventricular wall thickness in the septum. Now, it’s important to understand that there are only 13 patients that have been on this therapy for the period of time that I’m talking about, and echocardiography is not the most precise tool for measuring wall thickness. The third caveat is that echocardiography that we did in this study, which was read by a core lab in Boston, they just used the standard American Society of Echocardiography measurements, but it seems like the wall thickness in the septum, which is where the majority of hypotrophy is in these patients, is starting to become reduced by about a millimeter or so.