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48-Week Results for Mavacamten Draw Crowd at AHA Session

Mary Caffrey
Mavacamten is a first-in-class small-molecule therapy that reduces the contractility of cardiac muscles by binding with myosin, a protein involved in muscle contraction that is often affected by a gene mutation in hypertrophic cardiomyopathy.
One of the last events of the 2019 American Heart Association Scientific Sessions had no empty seats and dozens left standing to hear about mavacamten after recent news that a treatment might be near for patients who suffer from dangerous thickening of the heart muscle.

A week prior, MyoKardia had released encouraging results from PIONEER-OLE, an open-label extension of its original phase 2 study. As lead investigator Stephen B. Heitner, MD, explained Monday during the AHA’s final “rapid fire” abstract session, the 13 patients who continued to the 48-week mark are seeing a reduction in symptoms of obstructive hypertrophic cardiomyopathy (HCM), and the treatment is measurably undoing damage. Echocardiography shows interventricular septal thickness reduced by an average of 3.2 mm, and 1.3 mm of that reduction came after the 36-week mark.

Heitner, director of the Hypertrophic Cardiomyopathy Clinic at the Oregon Health and Sciences University Knight Cardiovascular Institute, explained that mavacamten is a first-in-class small-molecule therapy that reduces the contractility of cardiac muscles by binding with myosin, a protein involved in muscle contraction that is often affected by a gene mutation in HCM.

In HCM, the heart muscle thickens or becomes “hypertrophied” without any apparent cause, although there’s been extensive work in recent years to understand the genetic causes of many cases. HCM may not show symptoms for years, and when they emerge as tiredness or shortness of breath, cardiomyopathy might not be an obvious culprit. But if undetected, HCM can cause sudden cardiac death.

In most cases of HCM, as blood exits the heart through the left ventricle, the left ventricular outflow tract (LVOT) becomes blocked by the enlarged heart muscle, which restricts blood flow to the body; this is known as obstructive HCM. In remaining cases, called non-obstructive HCM, the disease is marked by diastolic impairment and can still limit daily activities.

The 13 patients (9 male, mean age 57.8 years) in PIONEER-OLE were among the 21 who took part in the earlier phase 2 PIONEER study, Heitner said; those results were reported earlier this year in Annals of Internal Medicine.

“We employed a [pharmacokinetic]-directed dosing strategy individual to each patient,” he said, with doses starting at 5 mg and titrated up to maximum of 15 mg per day. The only major change from the early phase 2 study was that patients were permitted to be on beta blockers.

Results at 48 weeks were as follows:
  • The LVOT gradient, which measures obstruction of the left ventricle, decreased from an average of 89.9 mmHg at baseline to 21.4 mmHg, with statistical significance among 12 patients. Heitner noted that the study had statistical significance at 36 weeks; the fact that the data missed at 48 weeks “needs to be viewed with a pinch of salt, because there are only 13 patients in the study.”
  • Resting LVOT fell from 67.3 mmHg at baseline to 15.3 mmHg at week 48; every patient achieved a level below 55 mmHg, which is the threshold for surgical intervention. Thus, mavacamten has the potential to eliminate the need for costly and risky surgeries in patients whose disease has progressed.
  • NT-proBNP, a marker of cardiac wall stress, decreased from 1836 pg/mL to 206 pg/mL at week 48.
  • New York Heart Association classifications were remeasured at weeks 24 and 48, and 9 of the 12 patients evaluated achieved Class I status.
Best of all, Heitner said, “Patients felt better.” This was confirmed with a Kansas City Cardiomyopathy Questionnaire, which showed an improvement of 14 points on a scale of 0 to 100; an improvement of 6 points is considered clinically significant.

Some patients have been on mavacamten for almost 18 months, and thus far, the drug is very well tolerated. At 48 weeks, there were 64 adverse events (AEs) of which 4 were serious, but Heitner said it was not felt that any were related to the study drug.

The effects are “persistent and durable,” he said, and echocardiography shows that the improvements in the heart muscle are occurring over time without damage to the heart wall. “The data suggest that mavacamten has a favorable impact on the cardiac structure,” Heitner said.

Enrollment of 251 patients in EXPLORER, a phase 3 trial, was complete in July 2019, and topline results are expected in the second quarter of 2020, according to MyoKardia’s recent third-quarter financial results.


Heitner SB, Lester S, Wang A, et al. Precision pharmacological treatment for obstructive hypertrophic cardiomyopathy with mavacamten: one-year results from PIONEER-OLE. Presented at the 2019 American Heart Association Scientific Sessions, Philadelphia, Pennsylvania; November 18, 2019. Abstract RF295.

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