American Heart Association

American Heart Association

December 05, 2019
3 min read

PIONEER-OLE: Mavacamten may improve symptoms, obstruction in hypertrophic cardiomyopathy

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Stephen B. Heitner

PHILADELPHIA — Patients with obstructive hypertrophic cardiomyopathy who were treated with mavacamten for 1 year had improvements in left ventricular outflow tract gradients, symptoms and N-terminal pro-B-type natriuretic peptide, according to data presented at the American Heart Association Scientific Sessions.

“The PIONEER open-label extension study shows that the initial results observed in the phase 2 PIONEER-HCM study are sustained and durable, and, importantly, that mavacamten can reduce or eliminate the obstruction of the left ventricle without depressing ejection fraction,” Stephen B. Heitner, MD, director of the Hypertrophic Cardiomyopathy Clinic at Knight Cardiovascular Institute and assistant professor of medicine in the division of cardiovascular medicine at Oregon Health and Science University in Portland, told Healio.

This current open-label extension study included 13 patients (mean age, 58 years; nine men) with obstructive hypertrophic cardiomyopathy who completed the PIONEER-HCM trial.

“With the PIONEER open-label extension [study], there was about a 6- to 18-month gap where we had some attrition of our patients ... but of the 21 patients, 13 did go on for this study,” Heitner said during the presentation.

Data from the PIONEER-HCM trial were used to employ a dosing strategy for mavacamten that was specific to each patient. The starting dose was 5 mg per day, which was titrated at 6 weeks to an individualized dose of 5 mg, 10 mg or 15 mg.

“Mavacamten is the first treatment specifically intended for hypertrophic cardiomyopathy,” Heitner said in an interview. “Its mechanism is to target the underlying biomechanical basis of the disease, ie, hypercontractility. Mavacamten acts by restoring the proportion of myosin heads that are overly engaged with actin to levels seen in normal individuals. The high degree of actin-myosin crosslinking seen in patients with hypertrophic cardiomyopathy is responsible for the hypercontractility we see clinically. By restoring this proportion to normal, LV outflow tract obstruction is relieved, patients feel better and can exert themselves to a greater degree.”

Patients were assessed at 4, 6, 8 and 12 weeks, and every 12 weeks thereafter to monitor the efficacy, safety and drug concentration of mavacamten.

At 48 weeks, treatment with mavacamten resulted in improvements in LV outflow tract rest gradient (–73.6 mm Hg; P = .0313) and LV outflow tract post-exercise gradient (–93.2 mm Hg; P = .0313). Improvements were also seen in left atrial volume index (–17.1 mL/m2) and lateral E/e’ (–4.1; P for both = .0313), in addition to NT-proBNP (–3,638 pg/mL; P = .0625).


There was a significant reduction in interventricular septal thickness without changes in LV ejection fraction or posterior wall thickness.

At 24 weeks, 10 patients had an improvement in NYHA class of at least one class and three patients remained at class II. At 48 weeks, three patients were considered class I and three patients were class II.

Improvements in Kansas City Cardiomyopathy Questionnaire Overall Symptom Scores were also seen at 24 weeks (mean score, 89.4; change = 15.3; P = .0059), which remained consistent throughout 48 weeks (mean score, 89.3; change = 16.3; P = .3125).

Mavacamten was well tolerated up to 55 weeks, during which 11 patients reported 64 adverse events. The majority of reported events were mild, moderate and reversible. There were also four drug-unrelated serious adverse events.

“As remarkable as the results of the PIONEER-OLE study have been and continue to be, it is imperative to see results from a randomized and placebo-controlled study, and for a longer period of time,” Heitner told Healio. “The ongoing studies of mavacamten in the phase 3 EXPLORER study and in a long-term extension study available to EXPLORER participants will provide important confirmations of the data observed with mavacamten to date.” – by Darlene Dobkowski


Heitner SB, et al. Session HF.RF037. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Disclosures: The study is sponsored by MyoKardia. Heitner reports he received research grants from Cytokinetics, Eidos, MyoKardia and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.