Abstract Body (Do not enter title and authors here): Introduction: In patients with obstructive hypertrophic cardiomyopathy (oHCM), the SEQUOIA-HCM trial demonstrated that aficamten, a next-in-class cardiac myosin inhibitor, improved exercise capacity, heart failure symptoms and hemodynamics compared with placebo. Aficamten’s impact on overall quality-of-life (QoL) in oHCM has not been reported.

Hypothesis: Aficamten, compared with placebo, improves QoL as assessed by the EQ-5D-5L.

Aims: To describe EQ-5D-5L changes in patients enrolled in SEQUOIA-HCM.

Methods: SEQUOIA-HCM (NCT05186818) is a phase III, placebo-controlled trial of adults with symptomatic oHCM randomized to aficamten (n=142) or placebo (n=140) on top of standard-of-care medical therapy. Participants underwent blinded dose escalation over 6 weeks and were treated for 24 weeks followed by a 4-week washout. EQ-5D-5L (ranges from 0 to 1) and overall QoL using the Visual Analogue Scale (VAS; from 0 to 100) was measured at baseline through week 28 with higher scores indicating better QoL. Aficamten treatment effect on EQ-5D-5L was estimated using linear regression (study visits) and mixed effects regression (overall treatment effect) using all follow-up data with model adjustments for baseline EQ-5D-5L score and randomization stratification variables.

Results: Mean age (n=282) was 59.1±12.9 years (40.8% women; 79.1% white). Aficamten baseline EQ-5D-5L index and VAS scores were 0.8±0.19 and 71.2±17.9 (placebo: 0.78±0.2; 68.9±18.6), respectively. Aficamten improved the EQ-5D-5L by 0.026 (95% CI: -0.001, 0.052; p=0.056) and the VAS by 2.8 points (95% CI: 0.8, 4.8; p=0.006) versus placebo with significant differences as early as 8 weeks after treatment initiation (p=0.005). After treatment withdrawal at 24 weeks, QoL benefits in aficamten-treated patients decreased compared with placebo (Figure: Index, p<0.001; VAS, p=0.003), with hemodynamic parameters returning to baseline.

Conclusions: Aficamten yielded early, sustained and significant improvement in overall QoL compared with placebo. Withdrawal of aficamten was associated with the loss of treatment benefits and perhaps an increased perception of pre-treatment symptoms. These data support a role of aficamten in improving QoL among patients with oHCM.