Points to Consider in the Clinical Development of Drugs for Transthyretin Amyloid Cardiomyopathy (Early Consideration) in Japan

1. Introduction

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a type of systemic amyloidosis that leads to amyloid fibril deposition in the myocardium and progressive cardiac dysfunction. It is designated as an intractable disease in Japan. While transthyretin tetramer stabilizers such as tafamidis are currently the only approved therapies for ATTR-CM in Japan, several other therapeutic agents are under development to address unmet medical needs. The Early Consideration document by the Pharmaceuticals and Medical Devices Agency (PMDA) outlines clinical development considerations based on current scientific knowledge.

2. Overall Development Strategy

Because ATTR-CM is a rare disease with a limited patient population in Japan, conducting confirmatory trials based solely in Japan with mortality/morbidity (M/M) events as primary endpoints is challenging. The PMDA therefore encourages multi-regional clinical trials (MRCTs) from early stages to gather sufficient efficacy and safety data. Inclusion criteria and enrollment feasibility should account for the latest diagnostic practices and epidemiological data.

It is recommended that if the target population comprises both wild-type and variant transthyretin ATTR-CM patients, both subpopulations be included in confirmatory studies. Data from non-Japanese patients may be integrated to strengthen evaluations given the scarcity of variant type patients in Japan.

3. Confirmatory Trial Considerations

3.1 Trial Design

Confirmatory trials should generally be randomized, double-blind, controlled studies. Selection of comparator treatments should reflect the investigational drug’s anticipated clinical positioning; placebo may be used with background therapy, or approved ATTR-CM therapies may serve as active comparators to demonstrate superiority or non-inferiority.

3.2 Primary Endpoints

The improvement of morbidity/mortality is considered the true measure of clinical benefit. It is recommended that primary endpoints of confirmatory trials be all-cause or cardiovascular death or a composite of death with other clinically important events related to survival outcomes (e.g., cardiovascular hospitalization).

3.3 Secondary and Exploratory Endpoints

Endpoints such as exercise tolerance (e.g., 6-minute walk test), quality of life measures, and biomarkers such as N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin may be useful as secondary or exploratory endpoints to demonstrate efficacy and clinical relevance, but should not replace survival outcomes as primary endpoints.

3.4 Evaluation Period and Statistical Considerations

The evaluation period for confirmatory studies should be appropriate for the expected time required to observe therapeutic effects. Statistical analyses should include time-to-event or incidence comparisons, and analysis methods that account for varying clinical importance of composite components may be appropriate. In MRCTs, ensuring consistency between overall and Japanese populations is critical.

4. Regulatory and Scientific Engagement

Given the complexities in ATTR-CM drug development, consulting with PMDA early is strongly recommended to align on trial design, endpoints, and overall strategy to avoid delays during review.

5. Summary

The Early Consideration guidance provides a framework for the clinical development of ATTR-CM drugs in Japan, emphasizing the use of multi-regional approaches, rigorous confirmatory trial design with clinically meaningful endpoints, and early dialogue with regulators to facilitate efficient and scientifically sound drug development.