BMS has published data showing treatment with mavacamten showed sustained improvement in left ventricular outflow tract (LVOT) gradients, New York Heart Association (NYHA) Class and N-terminal pro brain natriuretic peptide (NT-proBNP) levels.
Bristol Myers Squibb today announced new, interim results from the EXPLORER-LTE cohort of the MAVA-LTE study (NCT03723655), the largest and longest evaluation of mavacamten, an investigational, first-in-class cardiac myosin inhibitor, in patients with symptomatic obstructive hypertrophic cardiomyopathy (obstructive HCM). These data, which showed sustained improvements in cardiovascular outcomes at 48 and 84 weeks, were presented today as a late-breaking clinical trial at the American College of Cardiology’s 71st Annual Scientific Session.
EXPLORER-LTE enrolled 231 of the 244 patients who were eligible for the long-term extension study at the end of the Phase 3 parent trial, EXPLORER-HCM (NCT03470545). Over 200 patients remained on study for more than 48 weeks, and 67 patients had reached 84 weeks. Clinically meaningful improvements were sustained in left ventricular outflow tract (LVOT) gradients, New York Heart Association (NYHA) Class and N-terminal pro brain natriuretic peptide (NT-proBNP) levels at 48 weeks and up to 84 weeks. The safety profile remained consistent with EXPLORER-HCM. No new safety signals were observed during longer term follow-up and the exposure adjusted event rates were stable or lower in this cohort.
“These data underscore the potential of mavacamten to offer rapid and sustained improvement in key cardiac measures in patients living with this chronic, and sometimes progressive, disease,” said Florian Rader, M.D., M.Sc. co-director of the Clinic for Hypertrophic Cardiomyopathy, Cedars-Sinai Medical Center.
EXPLORER-LTE is a cohort of the MAVA-LTE study, an ongoing, dose-blinded, 5-year study of mavacamten in patients with symptomatic obstructive HCM who completed the EXPLORER-HCM trial. EXPLORER-HCM enrolled a total of 251 adult patients with NYHA Class II or III obstructive HCM. All participants had measurable left ventricular ejection fraction (LVEF) ≥55% and LVOT gradient (resting and/or provoked) ≥50 mmHg at baseline. Patients were randomized in a 1:1 ratio to receive either a starting dose of 5 mg of mavacamten or placebo once daily for 30 weeks.
All participants in the EXPLORER-LTE cohort started on 5 mg of mavacamten daily and dose adjustments were made at Weeks 4, 8 and 12 based on site-read echocardiography measures of Valsalva LVOT gradient and LVEF only. Dose adjustment was also possible at Week 24 following site-read echocardiography assessment of post-exercise LVOT gradient. Temporary discontinuation criteria included LVEF <50%, mavacamten plasma trough concentration ≥1000 ng/mL or increase in corrected QT interval by Fredericia (QTcF) >15%. Current efficacy and safety data are representations of interim data from April 2019 through August 2021 in the ongoing MAVA-LTE study. As of the August 2021 interim analysis cutoff date, 94% of patients remained on mavacamten.
Findings included:
- Resting LVOT gradient decreased from baseline by an average of -35.6 mmHg ± 32.6 mmHg at Week 48. Similar reductions persisted throughout this extension period (up to 84 weeks).
- Similarly, Valsalva LVOT gradient decreased from baseline by an average of -45.3 mmHg ± 35.9 mmHg at Week 48. Sustained efficacy persisted throughout this extension period (up to 84 weeks).
- Serum NT-proBNP levels decreased from baseline by a median of -480 ng/L (IQR: −1104 ng/L, −179 ng/L) at Week 48. Similar reductions persisted throughout this extension period (up to 84 weeks).
- At Week 48, 67.5% (139/206) of patients improved by ≥1 NYHA Class from baseline, with 60.2% (124/206) improving by 1 NYHA Class and 7.3% (15/206) improving by 2 NYHA Classes. Improvements in NYHA Class were first observed at Week 12 and showed sustained improvement through Week 48.
- Resting LVEF decreased from baseline by -7.0% ± 8.3% at Week 48. Similar level of reduction persisted throughout this extension period (up to 84 weeks).
- Safety data showed 10 (4.3%) study participants permanently discontinuing due to treatment-emergent adverse events (TEAEs) and 26 (11%) discontinuing temporarily for any reason and resuming treatment thereafter. Of these, 12 (5.2%) patients had LVEF <50%, 2 of which were considered TEAEs, and all recovered LVEF >50% without further side effects.
“Interim results from this EXPLORER-LTE cohort build upon the clinical evidence supporting the potential for longer-term use of mavacamten in patients with symptomatic obstructive HCM,” said Marie-Laure Papi, vice president and mavacamten development program lead, Bristol Myers Squibb. “We look forward to the opportunity to bring this medicine to patients and eagerly await the U.S. Food and Drug Administration’s decision on our New Drug Application later this month.”