Cytokinetics (CYTK) Study result summary

Study design and methodology

• ACACIA-HCM was a phase III, multi-center, randomized, double-blind, placebo-controlled trial evaluating aficamten in symptomatic non-obstructive HCM patients, with dose escalation based on echocardiography from 5 to 20 mg every 2 weeks.

• 516 participants outside Japan were randomized 1:1 to aficamten or placebo, stratified by atrial fibrillation and intracavitary obstruction; Japanese cohort continues in a blinded extension for local approval.

• Dosing was titrated based on echocardiographic guidance, with up to four escalating doses.

• Key inclusion criteria included LVOT-G <30 mmHg at rest, LVEF ≥60%, RER ≥1.00, peak VO2 ≤90% predicted, NT-proBNP ≥300 pg/mL (or ≥900 pg/mL with atrial fibrillation), NYHA class II/III, KCCQ CSS ≤85.

• Treatment lasted 36 weeks for primary endpoints, with up to 72 weeks for secondary and exploratory endpoints, including time to first cardiovascular event.

Efficacy results

• Statistically significant improvements were observed in both dual primary endpoints: KCCQ clinical summary score and peak VO2 at week 36 versus placebo.

• KCCQ increased by 11.4 points for aficamten vs. 8.4 for placebo (LS mean difference 3.0, P=0.021); peak VO2 increased by 0.64 vs. 0.03 (LS mean difference 0.67, P=0.003).

• Statistically significant improvements were also observed in key secondary endpoints, including NYHA functional class, composite Z-score, and NT-proBNP reduction.

• Treatment effects were robust and consistent throughout the trial, with rapid loss of benefit upon discontinuation.

• At Week 36, pVO2 increased for aficamten recipients but remained unchanged for placebo, aligning with prior obstructive HCM trials.

Clinical significance and context

• Improvements in KCCQ and peak VO2 are considered clinically meaningful, with KCCQ changes of 5-10 points seen as relevant and 10-20 as highly meaningful.

• The magnitude of benefit aligns with prior aficamten studies (SEQUOIA-HCM, REDWOOD-HCM, FOREST-HCM), reinforcing the consistency of effect.

• This is the first trial to show significant and meaningful effects on both exercise capacity and symptoms in non-obstructive HCM.

• No approved therapies currently exist for non-obstructive HCM.

• HCM is the most common monogenic inherited cardiovascular disorder, with up to 800,000 undiagnosed cases in the US.