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Points to Consider for the Development of Drugs for Hypertrophic Cardiomyopathy (Early Consideration)

2026.02.17

• Early Consideration Papers
• Hypertrophic Cardiomyopathy
• Study Design

Introduction

Hypertrophic cardiomyopathy (HCM) is a condition marked by abnormal thickening of the ventricular myocardium and impaired diastolic function. Diagnostic criteria include a left ventricular wall thickness ≥15 mm (or ≥13 mm with family history), excluding other causes of hypertrophy. HCM is designated as an intractable disease in Japan, with 4,388 patients recorded in FY2023 through the Intractable Disease Medical Treatment Recipient Certificate system. Current pharmacotherapy focuses on symptom relief, though disease-modifying agents, such as the myosin inhibitor mavacamten, are available only for obstructive HCM (oHCM). This document outlines considerations for clinical development strategies of HCM therapeutics in Japan and may evolve as new evidence emerges.

Considerations for Overall Development Strategy

Given the heterogeneity of HCM and differences between oHCM and non-obstructive HCM (nHCM), confirmatory studies should be planned separately for each phenotype when evaluating therapeutic agents intended for both. Due to limited patient populations, active consideration should be given to participation in multi-regional clinical trials from early development stages. In scenarios where overseas confirmatory data are available or ongoing, Japanese development strategies may incorporate domestic or multi-regional trials that assess the similarity of Japanese and non-Japanese patients while referencing overseas trial results for efficacy and safety evaluation. Plans should also consider pediatric indications, with recommended inclusion of trials to determine appropriate pediatric dosages, administration, and formulations.

Considerations for Confirmatory Trials

• Study Design: Confirmatory trials are generally expected to be randomized, double-blind, parallel-group comparative studies with suitable control groups. Standard therapies should be maintained in the trial arms, and placebo controls should be used where appropriate. When a therapy with a similar mechanism exists, trials may compare superiority or non-inferiority with active comparators, provided the choice is justified by anticipated clinical positioning.
• Efficacy Endpoints: Long-term prognosis improvement is the ultimate goal, but due to rarity of disease, mortality endpoints may be impractical. Peak oxygen uptake (pVO₂) is recommended as a primary endpoint when survival endpoints are not feasible. Secondary endpoints should include survival-related measures and symptom assessments (e.g., Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, NYHA functional classification). For oHCM, left ventricular outflow tract (LVOT) pressure gradients may serve as useful biomarkers.
• Evaluation Period: The duration of trials should reflect the expected time to therapeutic effect and include adequate evaluation of long-term safety and efficacy where chronic use is anticipated.
• Study Population: Trials should enroll patients receiving standard therapy while minimizing effects of therapy changes during the study. Special safety considerations apply for agents that reduce hypercontractility, such as the risk of heart failure with reduced left ventricular ejection fraction (LVEF).
• Dosage and Administration: Dosage regimens for confirmatory trials should be informed by dose-response data specific to each phenotype. When dosage determination is cross-referenced to other phenotypes, sufficient justification must be provided.

Conclusion
The PMDA’s early considerations for hypertrophic cardiomyopathy drug development clarify key expectations for Japan, including early engagement in multi-regional trials, phenotype-specific development for oHCM and nHCM, and the use of appropriate functional and patient-reported endpoints. By addressing both scientific and practical challenges of this rare disease, the guidance is expected to support more efficient, globally aligned development and improve patient access to innovative HCM therapies in Japan.

Reference

https://www.pmda.go.jp/files/000278942.pdf