MyoKardia Presents 36-week Data from PIONEER-OLE Study of Mavacamten at the European Society of Cardiology Congress 2019
Durability of Mavacamten's Safety and Efficacy Profile Demonstrated through Nine Months in this Study of Patients with Symptomatic, Obstructive HCM
Statistically Significant Changes in Key Biomarkers Maintained, Indicative of Potential Improvements in Cardiac Function and Favorable Impact on Long-Term Disease Burden
The PIONEER-OLE study enrolled thirteen patients from the Phase 2 PIONEER-HCM study of mavacamten, and twelve patients were evaluable at 36 weeks. Patients received once-daily oral doses of mavacamten individually adjusted to target concentrations to eliminate the obstruction of the left ventricular outflow tract (LVOT). Mavacamten treatment resulted in reductions in patients’ resting and provoked LVOT gradient while maintaining a left ventricular ejection fraction (LVEF) above 55% at all times of assessment during the study through week 36.
“The data from our PIONEER-OLE study continue to demonstrate mavacamten’s potential to make a substantial difference in the lives of patients. As mavacamten acts to reduce the excessive contractility and improve ventricular filling of the HCM heart, patients are reporting feeling better, and the obstruction of the left ventricle has been consistently reduced or eliminated,” said
PIONEER-OLE 36-week Results
The PIONEER-OLE study was initiated in
Patients received once-daily oral doses of 5 mg mavacamten at study start with an individualized dose adjustment at Week 6 to a dose of 5 mg, 10 mg, or 15 mg aimed at eliminating the obstruction of the left ventricular outflow tract, while maintaining LVEF above normal range. Eleven patients remained on background beta blocker medications.
Patients entered the PIONEER-OLE study with a mean baseline resting LVOT gradient, a measure of obstruction, of 67.3 mmHg and a mean provoked LVOT gradient of 89.9 mmHg. Mavacamten reduced or eliminated resting LVOT gradient to a mean of 21.1 mmHg and provoked LVOT gradient to a mean of 31.5 mmHg at Week 36 without reducing left ventricular ejection fraction (LVEF) below normal (50%).
PIONEER-OLE: Observed Mean Values (SD)
|Resting LVOT gradient (mmHg)||67.3 (42.80)||21.1 (20.89)|
|Provoked LVOT gradient (mmHg)||89.9 (30.72)||31.5 (23.25)|
|Resting LVEF (%)||72.0 (4.90)||69.4 (6.04)|
Reductions or elimination of LVOT obstruction has been demonstrated to be a good predictor for improvements in patient symptoms and exercise capacity. Per protocol, an assessment of
A number of key biomarkers of cardiac stress and filling pressure continue to show significant improvements with mavacamten treatment.
- NT-proBNP, an established circulating blood marker of cardiac wall stress, decreased approximately 10-fold to ranges closer to normal (considered less than 125 pg/mL). At baseline, the mean NT-proBNP for the 13 patients enrolled in PIONEER-OLE was 1836 pg/mL, and at Week 36 the mean value for 12 evaluable patients was 186 pg/mL.
- E/e’, a non-invasive marker of left ventricular filling pressure, decreased from 12.8 to 8.5 at Week 36 among the 12 patients evaluable for response. A normal range of E/e’ is less than 8. E/e’ is considered a key measure of diastolic compliance and is an indicator of the left ventricle’s ability to relax and fill.
- Investigators also observed that left atrial (LA) volume index decreased with mavacamten treatment from 40.9 mL/m2 to 30.4 mL/m2 at week 36. The LA volume index increases when pressure is elevated and decreases when filling pressure in the left ventricle returns to normal levels, typically in the range of 16-34 mL/m2. Elevated left atrial volume may be associated with increased risk of atrial fibrillation in HCM patients.
PIONEER-OLE: Biomarker Measurements, Mean (SD)
|NT-proBNP (pg/mL)||<125||1836 (2886)||186 (125)||-1722 (2956)*|
|E/e’||<8||12.8 (2.9)||8.5 (2.3)||-4.1 (3.0)*|
|LA volume index (mL/m2)||16-34||40.9 (16.4)||30.4 (8.7)||-10.9 (12.8)*|
These data were presented today in an oral presentation titled “Long-term safety and effectiveness of mavacamten in symptomatic obstructive hypertrophic cardiomyopathy patients: update from the PIONEER open-label extension (PIONEER-OLE) study” (abstract #228) by
In addition to the 36-week PIONEER-OLE data,
Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease in which excessive contraction of the heart muscle and reduced ability of the left ventricle to fill can lead to the development of debilitating symptoms and cardiac dysfunction. HCM is estimated to affect one in every 500 people. The most frequent cause of HCM is mutations in the heart muscle proteins of the sarcomere. In approximately two-thirds of HCM patients, the path followed by blood exiting the heart, known as the left ventricular outflow tract (LVOT), becomes obstructed by the enlarged and diseased muscle, restricting the flow of blood from the heart to the rest of the body (obstructive HCM). In other patients, the thickened heart muscle does not block the LVOT, and their disease is driven by diastolic impairment due to the enlarged and stiffened heart muscle (non-obstructive HCM). In either obstructive or non-obstructive HCM patients, exertion can result in fatigue or shortness of breath, interfering with a patient’s ability to participate in activities of daily living. HCM has also been associated with increased risks of atrial fibrillation, stroke, heart failure and sudden cardiac death.
About Mavacamten (MYK-461)
Mavacamten is a novel, oral, allosteric modulator of cardiac myosin being developed for the treatment of hypertrophic cardiomyopathy (HCM). Mavacamten is intended to reduce cardiac muscle contractility by inhibiting the excessive myosin-actin cross-bridge formation that underlies the excessive contractility, left ventricular hypertrophy and reduced compliance characteristic of HCM.
MyoKardia’s mission is to change the world for people with serious cardiovascular disease through bold and innovative science.
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Source: MyoKardia, Inc.