Mavacamten is a first-in-class, oral, allosteric modulator of cardiac myosin being evaluated for the treatment of symptomatic obstructive hypertrophic cardiomyopathy.
The EXPLORER-LTE study found that treatment with mavacamten provides sustained improvement in left ventricular outflow tract (LVOT) gradients, as well as New York Heart Association (NYHA) Class and N-terminal pro brain natriuretic peptide (NT-proBNP) levels, according to data presented at the American College of Cardiology 2022 Scientific Sessions.
Mavacamten is a first-in-class, oral, allosteric modulator of cardiac myosin currently under investigation for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM). Obstructive HCM thickens the heart walls and makes it more difficult for the heart to expand normally and fill with blood. Mavacamten aims to target the underlying pathophysiology of the condition.
Mavacamten has previously been found to reduce cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation that results in hypercontractility, left ventricular hypertrophy, and reduced compliance. Based on data from the EXPLORER-HCM study, a prescription drug user fee act (PDUFA) date has been set for April 28, 2022.
The EXPLORER-LTE trial involves a cohort of the MAVA-LTE study, the largest and longest evaluation of mavacamten in patients with symptomatic obstructive HCM. 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.
More than 200 patients remained on study for more than 48 weeks and 67 patients reached 84 weeks. Clinically meaningful improvements were sustained in LVOT gradients, NYHA Class, and NT-proBNP levels at 48 weeks and up to 84 weeks. The safety profile remained consistent with EXPLORER-HCM and no new safety signals were observed during longer term follow-up. The exposure-adjusted event rates were also 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, MD, MSc, co-director of the Clinic for Hypertrophic Cardiomyopathy at Cedars-Sinai Medical Center, in a statement.
All participants in the EXPLORER-LTE cohort started therapy on 5 mg of mavacamten daily and dose adjustments were made at weeks 4, 8, and 12 based on echocardiography measures of Valsalva LVOT gradient and left ventricular ejection fraction (LVEF). Dose adjustment was also possible at week 24 following site-read echocardiography assessment of LVOT gradient after exercise.
As of the August 2021 interim analysis cutoff date, 94% of patients remained on mavacamten. Furthermore, resting LVOT gradient decreased from baseline by an average of -35.6 mmHg plus or minus 32.6 mmHg at week 48. Similar reductions persisted throughout the extension period and up to 84 weeks.
Similarly, the Valsalva LVOT gradient decreased from baseline by an average of -45.3 mmHg plus or minus 35.9 mmHg at week 48, with sustained efficacy persisting throughout the extension period. Serum NT-proBNP levels decreased from baseline by a median of -480 ng/L at week 48.
Furthermore, at week 48, 67.5% of patients improved by 1 or greater NYHA Class from baseline, with 60.2% improving by 1 NYHA Class and 7.3% improving by 2 classes. Improvements in NYHA Class were first observed at week 12 and showed sustained improvement through week 48, according to the study. Resting LVEF also decreased from baseline by -7% plus or minus 8.3% at week 48.
Safety data showed that 10 participants (4.3%) permanently discontinued due to treatment-emergent adverse events (TEAEs) and 26 (11%) discontinued temporarily for any reason and resumed treatment thereafter. Of these, 12 (5.2%) had LVEF 50% or higher, 2 of which were considered TEAEs, and all recovered an LVEG of 50% or less without further AEs.
“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 at Bristol Myers Squibb, in a statement.
Bristol Myers Squibb Announces Data From EXPLORER-LTE Demonstrating Sustained Improvements in Clinically Meaningful Cardiovascular Outcomes at Week 48 and 84 in Patients with Symptomatic Obstructive Hypertrophic Cardiomyopathy Receiving Mavacamten. News release. Bristol Myers Squibb; April 3, 2022. Accessed April 3, 2022. https://news.bms.com/news/details/2022/Bristol-Myers-Squibb-Announces-Data-from-EXPLORER-LTE-Demonstrating-Sustained-Improvements-in-Clinically-Meaningful-Cardiovascular-Outcomes-at-Weeks-48-and-84-in-Patients-with-Symptomatic-Obstructive-Hypertrophic-Cardiomyopathy-Receiving-Mavacamten/default.aspx