Aficamten
Details
Aficamten (CK-3773274) is a next-in-class, selective cardiac myosin inhibitor (allosteric) developed by Cytokinetics for symptomatic obstructive hypertrophic cardiomyopathy. It reduces myocardial hypercontractility by decreasing the number of active actin–myosin cross-bridges, stabilising myosin in its folded-back OFF state. Unlike mavacamten, aficamten has a shallow dose-response relationship facilitating individualized dose adjustment and no clinically important drug-drug interactions. It has been studied in the REDWOOD-HCM (phase 2) and SEQUOIA-HCM (phase 3, vs placebo) trials, and most recently in MAPLE-HCM (phase 3, vs metoprolol as monotherapy).
Key Facts
- Mechanism: Allosteric cardiac myosin ATPase inhibitor → reduces actin-myosin cross-bridge number → decreases sarcomere hypercontractility → reduces dynamic LVOTO → improves energetics and hemodynamics. (sources/aficamten-maplehcm-nejm-2025)
- Shallow dose-response curve: Pharmacologically designed for individualized titration; fewer abrupt LVEF changes vs agents with steeper dose-response; no clinically important drug-drug interactions (contrast with mavacamten which requires REMS and has CYP2C19 interactions). (sources/aficamten-maplehcm-nejm-2025)
- SEQUOIA-HCM (NEJM 2024) — Phase 3 RCT vs placebo on background therapy: Phase 3, double-blind, placebo-controlled RCT (N=282; 101 sites; 14 countries; 24 weeks). Aficamten added to background standard therapy (beta-blockers 61%; disopyramide 13%) produced a placebo-corrected peak VO2 improvement of +1.7 ml/kg/min (P<0.001), exceeding the minimal clinically important difference of 1.0 ml/kg/min. All 10 prespecified secondary endpoints were significant: NYHA improvement ≥1 class (58.5% vs 24.3%), KCCQ-CSS +7 points, Valsalva LVOTO gradient −50 mmHg, post-Valsalva LVOTO <30 mmHg in 49.3% vs 3.6%, and SRT eligibility reduced by 78 fewer days. NT-proBNP (exploratory) decreased by ~80%. LVEF <50% occurred transiently in 3.5%; no HF exacerbations. Gradient reduction was evident by week 2 (−20 mmHg difference). All benefits reversed after 4-week washout. Benefit was consistent regardless of background beta-blocker use — contrasting with EXPLORER-HCM for mavacamten. (sources/aficamten-sequoiahcm-nejm-2024, rating: very high)
- MAPLE-HCM (NEJM 2025) — Head-to-head vs metoprolol as monotherapy: Phase 3, double-blind, double-dummy RCT (N=175; 71 sites; 24 weeks). Aficamten monotherapy was superior to metoprolol monotherapy on peak VO2 (difference +2.3 ml/kg/min; P<0.001) and all prespecified secondary endpoints except LV mass index: NYHA improvement 51% vs 26%, KCCQ-CSS difference +6.9 points (P=0.002), Valsalva LVOTO gradient −40.7 vs −3.8 mmHg, NT-proBNP 81% relative difference favoring aficamten, LAVi −3.8 vs +2.8 ml/m². This is the first RCT to demonstrate that a cardiac myosin inhibitor as monotherapy is superior to beta-blockers as monotherapy in obstructive HCM. (sources/aficamten-maplehcm-nejm-2025, rating: very high)
- Beta-blocker failure on objective endpoints: In MAPLE-HCM, metoprolol — despite reducing peak HR by 23.4 bpm — did NOT improve LVOTO gradient, NT-proBNP (actually increased), LAVi (actually increased), or peak VO2 (decreased by 1.2 ml/kg/min). Metoprolol only improved subjective endpoints (NYHA class 26%, KCCQ-CSS +8.7 points). This confirms that beta-blocker benefit in obstructive HCM is largely chronotropic, not hemodynamic. (sources/aficamten-maplehcm-nejm-2025)
- Washout reversibility: All hemodynamic and clinical benefits of aficamten reversed after 4-week washout — consistent with reversible pharmacodynamic mechanism (no structural/permanent effects on sarcomere). (sources/aficamten-maplehcm-nejm-2025)
- Safety: LVEF <50% in only 1% with aficamten in MAPLE-HCM (transient, asymptomatic); dose reduction required in only 5% vs 30% with metoprolol. Serious adverse events 8% vs 7%. Favorable safety profile relative to mavacamten (which had 5.7–21.5% LVEF <50% depending on indication). (sources/aficamten-maplehcm-nejm-2025)
- Dosing in MAPLE-HCM: Starting 5 mg; maximum 20 mg; 76% of patients achieved 15–20 mg by week 24 with most on maximum dose.
- Guideline status (as of 2026): Not yet independently recommended as first-line; current AHA 2024 and ESC 2023 guidelines recommend as step-2/step-3 add-on to beta-blockers; MAPLE-HCM results may prompt future guideline updates supporting monotherapy or first-line use.
Contradictions / Open Questions
- Aficamten monotherapy superior to metoprolol — but guidelines have not been updated: MAPLE-HCM (2025) demonstrates that aficamten as monotherapy outperforms metoprolol as monotherapy on objective endpoints. Current AHA 2024 and ESC 2023 guidelines still position cardiac myosin inhibitors as step 2–4 therapy after beta-blockers. No guideline update has been issued. The data support reconsideration of beta-blocker-first step-care paradigm, especially for patients intolerant of beta-blockers or with predominantly hemodynamic symptoms. (sources/aficamten-maplehcm-nejm-2025)
- Long-term outcomes unknown: MAPLE-HCM was 24 weeks — provides no data on SCD reduction, HF hospitalisation, mortality, or long-term remodeling relative to metoprolol. Long-term comparative safety and efficacy data are needed before positioning aficamten as preferred first-line monotherapy.
- Class specificity — aficamten vs mavacamten: Both are cardiac myosin inhibitors but with different pharmacokinetic/pharmacodynamic properties (mavacamten: CYP2C19 interactions, steeper dose-response, REMS required, 5–21% LVEF <50%; aficamten: no major drug interactions, shallow dose-response, lower LVEF reduction rate). No head-to-head comparison between the two drugs exists.
Connections
- Related to entities/HCM
- Related to entities/Mavacamten
- Related to concepts/LVOTO
- Related to concepts/Sarcomere-Biology
- Related to concepts/Septal-Reduction-Therapy