Peripheral Nervous, Hepatic, and Gastrointestinal Endpoints for AL Amyloidosis Clinical Trials: Report from the Amyloidosis Forum Multi-organ System Working Group

Abstract

Systemic immunoglobulin light chain (AL) amyloidosis is a heterogeneous rare disease driven by a destructive monoclonal gammopathy and typified by misfolded immunoglobulin light and/or heavy chains which aggregate and deposit in organs as insoluble amyloid fibrils. Disease heterogeneity is driven by the degree of multi-systemic involvement; cardiac, renal, neurological, and gastrointestinal (GI) systems are affected to varying degrees in different patients. While prognosis is primarily driven by hematologic response to treatment and outcomes associated with cardiac events and overall survival, the involvement of the peripheral nervous, hepatic, and GI systems can also have a significant impact on patients. The Amyloidosis Forum ( https://amyloidosisforum.org ) is a public-private partnership between the nonprofit Amyloidosis Research Consortium ( www.arci.org ) and the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research formed to advance drug development for the treatment of systemic amyloid disorders. A series of virtual workshops focused on the development of novel, patient-relevant endpoint components and analytical strategies for clinical trials in AL amyloidosis. This review summarizes the proceedings and recommendations of the Multi-Systemic Working Group which identified, reviewed, and prioritized endpoints relevant to the impacts of AL amyloidosis on the peripheral nervous, hepatic, and GI systems. The Working Group comprised amyloidosis experts, patient representatives, statisticians, and representatives from the FDA, Medicines and Healthcare products Regulatory Agency (MHRA), and pharmaceutical companies. Prioritized neuropathy/autonomic endpoints included a modified form of the Neuropathy Impairment Score (NIS + 7) and the Composite Autonomic Symptom Score (COMPASS-31), respectively. Alkaline phosphatase was identified as the most relevant indicator of liver involvement and disease progression. Following extensive review of potential GI endpoints, the Working Group identified multiple exploratory endpoints. These recommended components will be further explored through evaluation of clinical trial datasets and possible integration into composite endpoint analysis.

Keywords: AL amyloidosis; Clinical trial endpoint; Light-chain amyloidosis; Multi-systemic; Peripheral nervous, hepatic, gastrointestinal.

Fig. 1

Prevalence of presenting symptoms and organ involvement. Most common presenting symptoms in patients with AL amyloidosis based on global patient survey results (A); adapted with permission [50]. Organ involvement distribution (B) in patients with mass spectrometry (MS)-verified typing of AL amyloidosis (N = 592); reproduced with permission [3]

Fig. 2

The Amyloidosis Forum set out to develop a novel multidomain composite endpoint and/or analyses methods for use in clinical trials for immunoglobulin light chain (AL) amyloidosis. Specialized working groups identified and prioritized organ specific and health-related quality of life (HRQOL) endpoints; an additional working group focused on statistical approaches to analysis of clinical trial data. From these recommendations and post hoc analysis of available clinical trial data, the Amyloidosis Forum will develop and evaluate candidate composite endpoints and potential surrogate endpoints to facilitate drug development in AL amyloidosis