More answers on mavacamten

New research on drug elucidates successful HCM treatment mechanism

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SOUTH SAN FRANCISCO, Calif.—Biopharmaceutical company MyoKardia Inc., which specializes in developing precision cardiovascular medicine, recently shared data that further clarify the mechanism of action of its lead drug candidate, mavacamten. A presentation detailing these results, “In Vivo Cardiac Effects of Mavacamten (MYK-461): Evidence for Negative Inotropy and Improved Compliance (#405),” was part of the Drug Discovery for Heart Failure session of the American Heart Association Scientific Sessions.
Mavacamten is an investigational compound that has demonstrated the ability to modulate cardiac myosin to reduce the excess contractility characteristic of hypertrophic cardiomyopathy (HCM). This severe, progressive genetic condition causes the walls of the heart to thicken, which can lead to obstructed blood flow from the left ventricle. In addition, this thickened heart muscle is less compliant  and fills with less blood, thereby reducing cardiac output. The most recently released data from the in-vivo study demonstrated that mavacamten successfully improved myocardial compliance while preserving systemic pressures.
“The observation that mavacamten may improve distensibility while reducing contractility increases our understanding of mavacamten’s mechanism of action and hemodynamic effects,” said Dr. Robert McDowell, chief scientific officer of MyoKardia, in a press release. “We look forward to potentially verifying the clinical implications of this early evidence of improved myocardial relaxation and of a rightward shift in the diastolic pressure-volume relationship, as it could greatly inform MyoKardia’s ongoing research to address diseases of impaired diastolic function.”
MyoKardia had previously reported positive top-line results from its first patient cohort in late summer, which indicated that Mavacamten treatment led to a meaningful reduction, in the first few weeks of treatment, in resting left ventricle outflow tract (LVOT) gradient, with a less pronounced reduction in resting left ventricle ejection fraction (LVEF). The reduction in LVOT gradient seen in nine out of 10 patients by week 2 led to the addition of a second, low-dose cohort in the PIONEER-HCM trial. The trial demonstrated a clinically and statistically significant reduction in left ventricular outflow tract gradient. Additional data indicated meaningful improvements in patients’ exercise capacity as measured by peak VO2, as well as a reversal of positive outcomes after the therapy was discontinued.
“These data strengthen the case, initially seen with the release of the topline results, that Mavacamten, by targeting the underlying biomechanical defect of the disease, can affect multiple clinically meaningful metrics that characterize the oHCM disease burden,” commented Dr. Stephen Heitner, director of the HCM Clinic at Oregon Health and Science University’s Knight Cardiovascular Institute, and lead investigator for the PIONEER-HCM study. “On behalf of the investigators, I am pleased to present these additional data showing the concordant and positive effects of mavacamten, with patients feeling better and displaying improvements in exercise capacity.”
A second, low dose cohort from the PIONEER-HCM trial is now being completed, and data from this group of patients are expected in the first quarter of 2018. The low-dose cohort will provide researchers a detailed understanding of the relationship between mavacamten’s dose and responses as measured by reductions in gradient, ejection fraction and peak VO2. In the second quarter of 2018, a pivotal Phase 3 trial of mavacamten will begin.
In healthy animals, the pharmacological effect of mavacamten was compared to that of metoprolol, a beta blocker commonly prescribed in the management of HCM, in an acute setting. Mavacamten reduced systolic performance and increased end diastolic volume (EDV) while preserving end diastolic pressures (EDP) and systemic blood pressure. By contrast, metoprolol, at matched levels of negative systolic performance, caused increased EDP with significantly less increase in EDV. Chronic treatment with mavacamten over a nine-month period showed a comparable profile, characterized by preserved echocardiographic indices of diastole and filling pressure. Taken together, these data indicate a distinct and unique mode of action for mavacamten, providing evidence of improved left ventricular compliance that accompanies reduced myocardial contractility.
“We are excited by the preclinical findings that mavacamten can improve diastolic compliance in healthy animals, and we will shortly be sharing data from our PIONEER-HCM study looking at diastolic impact of the drug in obstructive HCM patients,” adds McDowell. “In addition, our upcoming Phase 2 trial in non-obstructive patients is designed to test whether, in the absence of an outflow tract obstruction, treatment with mavacamten can still yield the same improvement in feel and function reported in the obstructive population, and whether those improvements can be attributed to improving diastolic compliance. Non-obstructive HCM is largely a disease of impaired relaxation. If mavacamten or another of our research candidates can be shown to increase relaxation of the heart, this could allow us to look at new indications in which diastolic dysfunction is the primary cause. We are actively exploring the potential lusitropic effects of our preclinical, discovery-stage leads.”
According to McDowell, approximately 40 percent of heart failure patients suffer from impaired relaxation during diastole. Those patients whose relaxation defects can be attributed to the heart muscle itself might benefit from a therapeutic agent that improves relaxation, particularly if it does not impair systolic contraction. Positive findings with mavacamten in non-obstructive HCM could offer promise that this or similar mechanisms could provide benefit for these other patient populations.
“We are actively looking for second-generation mechanisms that increase diastolic compliance with reduced impact on systolic performance. We know HCM is characterized by increased contractility and a thickening of the heart walls. With mavacamten, we tried to target the biomechanical defects underlying the condition by modulating cardiac myosin activation to bring down that excessive contractility. If mavacamten is also acting by addressing the impaired distensibility of the heart that is part of HCM, it opens the door to a new understanding of mavacamten’s hemodynamic effects on disease,” says McDowell.

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