Long-term effect of mavacamten in obstructive hypertrophic cardiomyopathy

Abstract

Background and aims: Long-term safety and efficacy of mavacamten in patients with obstructive hypertrophic cardiomyopathy (HCM) are unknown. MAVA-LTE (NCT03723655) is an ongoing, 5-year, open-label extension study designed to evaluate the long-term effects of mavacamten.

Methods: Participants from EXPLORER-HCM (NCT03470545) could enrol in MAVA-LTE upon study completion.

Results: At the latest data cut-off, 211 (91.3%) of the 231 patients originally enrolled in MAVA-LTE still received mavacamten. Median (range) time on study was 166.1 (6.0-228.1) weeks; 185 (80.1%) and 99 (42.9%) patients had completed the Week 156 and 180 visits, respectively. Sustained reductions from baseline to Week 180 occurred in left ventricular outflow tract gradients [mean (standard deviation): resting, -40.3 (32.7) mmHg; Valsalva, -55.3 (33.7) mmHg], N-terminal pro B-type natriuretic peptide [median (interquartile range): -562 (-1162.5, -209) ng/L], and EQ-5D-5L score [mean (standard deviation): 0.09 (0.17)]. Mean left ventricular ejection fraction (LVEF) decreased from 73.9% (baseline) to 66.6% (Week 24) and 63.9% (Week 180). At Week 180, 74 (77.9%) of the 95 patients improved by at least one New York Heart Association class from baseline. Over 739 patient-years exposure, 20 patients (8.7%; exposure-adjusted incidence: 2.77/100 patient-years) experienced 22 transient reductions in LVEF to <50% resulting in temporary treatment interruption (all recovered LVEF of ≥50%). Five (2.2%) patients died (all considered unrelated to mavacamten).

Conclusions: Long-term mavacamten treatment resulted in sustained improvements in cardiac function and symptoms in patients with obstructive HCM, with no new safety concerns identified. Transient, reversible reductions in LVEF were observed in a small proportion of patients during long-term follow-up.

Keywords: Efficacy; Long-term outcomes; MAVA-LTE (EXPLORER cohort); Mavacamten; Obstructive hypertrophic cardiomyopathy; Safety.

Structured Graphical Abstract

Figure 1

Mean (standard deviation) resting left ventricular outflow tract (A) and Valsalva left ventricular outflow tract (B) gradients over time. Baseline values represent those from the beginning of MAVA-LTE, not the beginning of EXPLORER-HCM. For re-enrolled patients, the baseline value is considered the first measurement following re-enrolment. The number of patients at each time point reflects the number of evaluable results from those who had reached the stated week by the interim cut-off date. BL, baseline; HCM, hypertrophic cardiomyopathy; LTE, Long-Term Extension; LVOT, left ventricular outflow tract

Figure 2

Proportion of patients who achieved a Valsalva left ventricular outflow tract gradient of ≤30 mmHg by visit. The values above the bars indicate the n (%) of patients who achieved a Valsalva left ventricular outflow tract gradient of ≤30 mmHg at each time point

Figure 3

Median (interquartile range) N-terminal pro B-type natriuretic peptide over time. Baseline values represent those from the beginning of MAVA-LTE, not the beginning of EXPLORER-HCM. For re-enrolled patients, the baseline value is considered the first measurement following re-enrolment. The number of patients at each time point reflects the number of evaluable results from those who had reached the stated week by the interim cut-off date. BL, baseline; HCM, hypertrophic cardiomyopathy; LTE, Long-Term Extension; NT-proBNP, N-terminal pro B-type natriuretic peptide

Figure 4

New York Heart Association class distribution over time (A) and change in New York Heart Association class from baseline (B). The number of patients at each time point refers to the number of patients who had a visit scheduled at each week and for whom data are available. NYHA, New York Heart Association

Figure 5

Mean (standard deviation) Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath domain score over time. The number of patients at each time point refers to the number of patients who had a visit scheduled at each week and for whom data are available. Lower scores indicate less shortness of breath. When the mean value minus the standard deviation value was <0, the lower error bar was set to 0. BL, baseline; HCMSQ SoB, Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath

Figure 6

Mean (standard deviation) left ventricular ejection fraction over time. Baseline values represent those from the beginning of MAVA-LTE, not the beginning of EXPLORER-HCM. For re-enrolled patients, the baseline value is considered the first measurement following re-enrolment. The number of patients at each time point reflects the number of evaluable quantitative results from those who had reached the stated week by the interim cut-off date. Some central-read LVEF measurements were qualitative and, therefore, did not contribute to the overall mean LVEF value for the study visit. BL, baseline; HCM, hypertrophic cardiomyopathy; LTE, Long-Term Extension; LVEF, left ventricular ejection fraction

Figure 7

Change in mavacamten dose by study visit. The number of patients at each time point refers to the number of patients who had a study visit scheduled at each week and for whom data are available. Categories relate to the change in mavacamten dose from the previous visit. For Week 24, the previous visit was Week 16

Figure 8

Event-free rate of occurrences of left ventricular ejection fraction <50%, left ventricular ejection fraction <40%, and treatment-emergent adverse events of cardiac failure over time. For patients with <56 days between enrolment periods, events contribute based on initial dosing (left ventricular ejection fraction <50% and left ventricular ejection fraction <40% analyses). LVEF, left ventricular ejection fraction