Abstract Introduction Mavacamten was efficacious and well tolerated in patients (pts) with obstructive HCM over a median follow-up of 62 weeks in a previous interim analysis of the ongoing MAVA-LTE study (NCT03723655) (data cut-off; August 31, 2021). Here, we report an updated cumulative analysis of the EXPLORER cohort of MAVA-LTE up to 120 weeks. Methods Pts who completed EXPLORER-HCM (NCT03470545) could enroll in MAVA-LTE. All pts initiated the study with mavacamten 5 mg/day per protocol; dose adjustments to 2.5, 10, or 15 mg were based on site-read Valsalva left ventricular outflow tract (LVOT) gradient and LV ejection fraction (LVEF). Results In total, 231 pts (median age, 61 years; 39% female) enrolled in the EXPLORER cohort of MAVA-LTE. Median time on study was 101 weeks at data cut-off (May 31, 2022) with variations due to differences in enrollment timing. At data cut-off, 215 pts remained on treatment (total adjusted exposure: 475 pt-years). Mavacamten dosing of pts who reached week 120 (n=80) was: 2.5 mg (27.5%); 5 mg (31.3%); 10 mg (26.3%); 15 mg (12.5%). Between weeks 48–120, 34 of 231 (14.7%) pts underwent dose adjustments. Mavacamten treatment showed sustained improvements in mean [SD] change from baseline to week 120 in LVOT gradients (resting, −35.3 [33.0] mmHg; Valsalva, −47.0 [37.3] mmHg), left atrial volume index (−8.5 [10.3] mL/m2) and E/e’ average (−3.9 [5.0]) (Table). At week 120, 83.5% of pts had a Valsalva LVOT gradient ≤30 mmHg. Mavacamten was associated with sustained reduction from baseline to week 120 in N-terminal pro B-type natriuretic peptide (NT-proBNP) level (Table); 75.9% of pts improved by ≥1 class New York Heart Association class (Figure). Mean (SD) LVEF decreased by 9.1% (7.1) from baseline to week 120 but remained in the normal range. Since the previous interim analysis (data cut-off: August 31, 2021), 1 additional transient reduction in LVEF <50% occurred resulting in temporary treatment interruption (a total of 13 pts [5.6%] experienced LVEF <50% from study initiation). The pt resumed treatment at a lower dose 4 weeks after the event. In total, 74 serious adverse events (SAE) were reported in 47 pts (20.3%), with 18 new SAEs and 13 additional pts (5.6%) with SAEs since the previous interim analysis, including 1 new SAE (atrial fibrillation) considered drug related. No new safety signals were identified. One additional death (leading to a total of 4) occurred, due to intracranial hemorrhage. Like the previous 3 deaths (due to acute myocardial infarction, cardiac arrest, and bacterial endocarditis) the event was considered unrelated to the study drug. Conclusions Long-term mavacamten treatment up to 120 weeks showed sustained improvements in LVOT obstruction, symptoms, and NT-proBNP levels in pts with symptomatic obstructive HCM consistent with the findings of the parent study. Mavacamten treatment continues to be well tolerated with no new safety signals observed.