Pathway for Development and Validation of Multi-domain Endpoints for Amyloid Light Chain (AL) Amyloidosis
Abstract
Immunoglobin light chain (AL) amyloidosis is a rare disease in which a plasma cell dyscrasia leads to deposition of insoluble amyloid fibrils in multiple organs. To facilitate development of new therapies for this heterogenous disease, a public–private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify clinical trial endpoints and analytic strategies across affected organ systems and life impacts via specialized working groups. This review summarizes the proceedings of the Statistical Group and proposes a pathway for development and validation of multi-domain endpoints (MDEs) for potential use in AL amyloidosis clinical trials. Specifically, drawing on candidate domain-specific endpoints recommended by each organ-specific working group, different approaches to constructing MDEs were considered. Future studies were identified to assess the validity, meaningfulness and performance of MDEs through use of natural history and clinical trial data. Ultimately, for drug development, the context of use in a regulatory evaluation, the specific patient population, and the investigational therapeutic mechanism should drive selection of appropriate endpoints. MDEs for AL amyloidosis, once developed and validated, will provide important options for advancing patient-focused drug development in this multi-system disease.
My Take
Rare diseases present a fundamental challenge for drug development: how do you measure treatment benefit when the disease affects multiple organ systems differently in different patients? AL amyloidosis exemplifies this challenge. It’s a condition where misfolded proteins deposit throughout the body—heart, kidneys, nerves, liver—with each patient presenting a unique constellation of organ involvement. A therapy that helps one patient’s cardiac function might benefit another’s renal function. Traditional single-endpoint trial designs struggle to capture this heterogeneity.
This paper emerged from the Amyloidosis Forum, a public-private partnership I was fortunate to contribute to alongside FDA statisticians, clinical experts, patient advocates, and industry researchers. Our goal was to chart a rigorous pathway for developing multi-domain endpoints that could detect treatment effects across the diverse ways AL amyloidosis manifests. We evaluated several composite endpoint approaches—response criteria similar to those used in rheumatology, progression-free survival composites, hierarchical endpoints like the Finkelstein-Schoenfeld method, and multi-domain responder indices—each with distinct strengths depending on whether a therapy is expected to improve function or slow decline.
What I find most valuable about this work is that it provides a generalizable framework. The principles we articulated—ensuring each component is clinically meaningful, evaluating natural history to understand endpoint behavior, assessing overlap between domains, and matching the endpoint structure to the expected treatment effect—apply far beyond AL amyloidosis. For anyone working in rare disease drug development where patient heterogeneity is the norm rather than the exception, this paper offers a roadmap for thinking through endpoint selection in a way that’s both scientifically defensible and aligned with what regulators need to see.