Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM)

Authors, Journal, Affiliations, Type, DOI

• Iacopo Olivotto et al. (on behalf of EXPLORER-HCM study investigators)
• The Lancet 2020; 396: 759–69. Published online August 29, 2020
• Multicentre: 68 clinical cardiovascular centres in 13 countries (USA, Spain, Poland, and others)
• Phase 3 randomised, double-blind, placebo-controlled, parallel-group trial
• Funded by MyoKardia; multiple authors had financial ties to MyoKardia
• DOI: https://doi.org/10.1016/S0140-6736(20)31792-X

Overview

EXPLORER-HCM is the pivotal phase 3 RCT that established mavacamten — a first-in-class allosteric cardiac myosin ATPase inhibitor — as the first disease-specific pharmacological therapy for obstructive HCM. 251 adults with symptomatic obstructive HCM (LVOT gradient ≥50 mmHg, NYHA II–III) were randomised 1:1 to mavacamten (starting 5 mg, titrated to 2.5–15 mg) or placebo for 30 weeks, on background beta-blocker or calcium channel blocker therapy. Mavacamten met its primary functional composite endpoint (37% vs 17%; p=0.0005) and all secondary endpoints, with marked reductions in LVOT gradient, biomarkers, and patient-reported symptoms. Safety was broadly similar to placebo; transient LVEF reductions occurred in 7 mavacamten patients and resolved after temporary discontinuation.

Keywords

Hypertrophic cardiomyopathy, mavacamten, cardiac myosin inhibitor, LVOT gradient, peak oxygen consumption, NYHA class, EXPLORER-HCM, phase 3

Key Takeaways

Study Design and Population

• Phase 3, double-blind, placebo-controlled RCT; N=251 (mavacamten n=123, placebo n=128); 97% completed treatment
• Eligibility: age ≥18 years, unexplained LV hypertrophy (max wall thickness ≥15 mm or ≥13 mm if familial), LVOT gradient ≥50 mmHg (rest, Valsalva, or exercise), LVEF ≥55%, NYHA class II–III
• Key exclusions: disopyramide use (safety reasons), paroxysmal/persistent AF on screening ECG, QTc >500 ms, recent syncope or sustained VT, NYHA class IV
• Most patients (92%) on background beta-blocker or calcium channel blocker; disopyramide excluded
• Dose titration at weeks 8 and 14 targeting LVOT gradient <30 mmHg and plasma concentration 350–700 ng/mL; doses of 2.5, 5, 10, or 15 mg used

Primary Endpoint

• Composite at 30 weeks: ≥1.5 mL/kg/min pVO2 increase + ≥1 NYHA class reduction, OR ≥3.0 mL/kg/min pVO2 increase with no NYHA worsening
• Mavacamten 37% vs placebo 17% (+19.4%; 95% CI 8.7–30.1; p=0.0005)

Secondary Endpoints (all significant)

• Post-exercise LVOT gradient: −47 mmHg (mavacamten) vs −10 mmHg (placebo) → between-group difference −35.6 mmHg (95% CI −43.2 to −28.1; p<0.0001)
• Peak VO2: +1.4 mL/kg/min greater improvement with mavacamten (95% CI 0.6–2.1; p=0.0006)
• NYHA ≥1 class improvement: 65% vs 31% (34% absolute difference; 95% CI 22–45; p<0.0001)
• KCCQ-CSS: +9.1 points (95% CI 5.5–12.7; p<0.0001)
• HCMSQ-SoB: −1.8 (95% CI −2.4 to −1.2; p<0.0001)

Exploratory Endpoints

• Complete response (all LVOT gradients <30 mmHg + NYHA class I): 27% vs 1% (+26.6%; 95% CI 18.3–34.8)
• Post-exercise LVOT gradient <30 mmHg: 57% vs 7% (49.6 pp difference)
• Post-exercise LVOT gradient <50 mmHg: 74% vs 21% (53.5 pp difference)
• NT-proBNP: 80% greater reduction vs placebo (geometric mean ratio 0.202; 95% CI 0.169–0.241)
• hs-cTnI: 41% greater reduction vs placebo (geometric mean ratio 0.589; 95% CI 0.500–0.693)
• Mean LVEF reduction: −3.9% (mavacamten) vs −0.01% (placebo); clinically modest

Subgroup Analysis — Beta-Blocker Use

• Patients NOT on beta-blockers showed substantially greater primary endpoint benefit: +52.6% (95% CI 32.9–72.2)
• Patients ON beta-blockers: +8.7% (95% CI −3.6 to 21.1) — attenuated but directionally consistent
• LVOT gradient reduction, NYHA improvement, VE/VCO2 slope improvement, and biomarker reductions were consistent regardless of beta-blocker use
• Attenuation in beta-blocker group attributed to HR limitation on CPET (pVO2 is heart-rate dependent), not true attenuation of mavacamten's hemodynamic effect

Safety

• Serious adverse events: 8% (mavacamten) vs 9% (placebo) — comparable
• Transient LVEF <50% in 7 mavacamten patients (5 during treatment, 4 at end of treatment [3 overlap]); LVEF normalised in all after temporary discontinuation
• 1 sudden death (placebo group); no sudden deaths in mavacamten group
• No significant changes in heart rate, blood pressure, QT interval, or NSIVT rates
• No heart failure events in mavacamten group
• Stress cardiomyopathy in 2 mavacamten patients; atrial fibrillation in 2 (vs 4 placebo)

Limitations of the Document

• Excluded disopyramide users — an important real-world HCM drug (disopyramide exclusion was for safety reasons, not efficacy)
• Excluded NYHA class IV patients — most symptomatic real-world patients unrepresented
• Underrepresentation of younger patients (<50 years) and non-white patients (93–89% white)
• Industry-funded (MyoKardia); multiple co-authors employed by or consulting for MyoKardia
• 30-week treatment period — long-term safety and efficacy require ongoing extension study (MAVA-LTE)
• Primary endpoint pVO2 component is confounded by beta-blocker use (chronotropic limitation), potentially underestimating mavacamten benefit in beta-blocker subgroup
• No placebo patients on disopyramide — cannot assess mavacamten vs disopyramide directly

Key Concepts Mentioned

• concepts/LVOTO — primary therapeutic target; post-exercise LVOT gradient reduced by 35.6 mmHg
• concepts/Sarcomere-Biology — mavacamten acts via allosteric myosin ATPase inhibition, reducing crossbridge cycling
• concepts/Septal-Reduction-Therapy — mavacamten achieved LVOT <50 mmHg in 74% (threshold for SRT); complete response in 27%
• concepts/Cardiopulmonary-Exercise-Testing — pVO2 and VE/VCO2 slope used as endpoints

Key Entities Mentioned

• entities/Mavacamten — pivotal phase 3 efficacy and safety data
• entities/HCM — disease under study

Wiki Pages Updated

• wiki/sources/mavacamten-explorer-hcm-lancet-2020.md — created
• wiki/entities/Mavacamten.md — updated with EXPLORER-HCM trial numbers
• wiki/concepts/LVOTO.md — added EXPLORER-HCM trial section
• wiki/concepts/Sarcomere-Biology.md — added EXPLORER-HCM source
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated