The Amyloidosis Forum: a public private partnership to advance drug development in AL amyloidosis

Abstract

Background: Immunoglobulin light chain (AL) amyloidosis is a rare, multi-systemic disorder characterized by two disease processes: an underlying plasma cell dyscrasia that provides the source of pathologic light chains, and the resulting organ dysfunction caused by deposition of amyloid light chain fibrils. There are no FDA approved treatments for AL amyloidosis; regimens developed for multiple myeloma are used off-label to treat the plasma cell disorder and no therapies are directed at organ deposition. Thus, an unmet medical need persists despite advances in disease management. A public-private partnership was recently formed between the Amyloidosis Research Consortium (ARC) and the US Food and Drug Administration (FDA) to bridge scientific gaps in drug development for the treatment of AL amyloidosis.

Main body: The inaugural Amyloidosis Forum was convened at FDA on 12 November 2019 and led by a multidisciplinary panel of physicians, health outcomes professionals, and representatives from the FDA, ARC, and pharmaceutical companies. Patients provided important perspectives on the pathway to diagnosis, challenges of rigorous treatment, and the burden of disease. The panel reviewed the epidemiology, pathobiology, and clinical features of AL amyloidosis. Hematologic characteristics, staging systems, and response criteria were examined with clear consensus that a "deep response" to plasma cell-directed treatments was critical to overall survival. Emphasis was placed on the heterogeneous clinical phenotypes of AL amyloidosis, including cardiovascular, renal, neurological, and gastrointestinal system manifestations that contribute to morbidity and/or mortality, but render challenges to clinical trial endpoint selection. FDA representatives discussed regulatory perspectives regarding demonstration of clinical benefits of investigational therapies in the context of a rare disease with multi-systemic manifestations. The panel also highlighted the potential importance of well-designed health-related quality of life instruments, quantification of system organ effects, the potential of advanced imaging technologies, and survival prediction models.

Conclusions: The Amyloidosis Forum identified a clear need for novel trial designs that are scientifically rigorous, feasible, and incorporate clinically meaningful endpoints based on an understanding of the natural history of the disease in an evolving therapeutic landscape. Future forums will delve into these issues and seek to include participation from additional stakeholders.

Keywords: AL amyloidosis; Drug development; Light-chain amyloidosis; Primary amyloidosis.

Fig. 1

The Amyloidosis Forum Structure and Goals. The Amyloidosis Forum is a public-private partnership established to identify and bridge the scientific gaps in drug discovery and development for the treatment of AL Amyloidosis. The PPP seeks to leverage expertise and resources of all stakeholders (academia, industry, patients, and regulatory agencies) for the conduct of mutually beneficial scientific activities in the precompetitive domain to support bringing new, safe and efficacious therapies to patients with AL Amyloidosis

Fig. 2

Prevalence of Presenting Symptoms and Organ Involvement. Most common presenting symptoms in AL amyloidosis patients based on global patient survey results (Panel a); adapted with permission from ARC. Organ involvement distribution (Panel b) in patients with mass-spectrometry-verified typing of AL amyloidosis (N = 592); reproduced with permission (Muchtar et al. Mayo Clin Proc. 2019;94 (3):472–483)

Fig. 3

Kinetics of Organ Response. Time to achievement of maximal organ response stratified by increased order of depth of organ response in patients with cardiac (Panel a; NT-proBNP response), renal (Panel b; proteinuria response), or hepatic (Panel c; alkaline phosphate response) involvement. Patients (N = 414) were included if they achieved either a hematologic or organ response. Reproduced with permission (Muchtar et al. Leukemia. 2018;32 (10):2240–2249)

Fig. 4

Overall Survival by Composite Organ and Hematologic Response. The composite hematologic and organ response (CHOR) model (Panel a). Group 1 defined by summary score of 0–3; Group 2 defined by summary score of 4–5. Overall survival in the composite model was similar in the Mayo Clinic (Panel b; p < 0.001) and Pavia (Panel c; p < 0.001) cohorts. Reproduced with permission (Sidana et al. 2017. Am Soc Hematol. 130:abstract #3046)

Fig. 5

SF-36 Benchmark Scores. SF-35 physical component summary (PCS) score of AL amyloidosis patients relative to other chronic conditions in the US population. Reproduced with permission (Sanchorawala et al. Oral presentation at: Amyloidosis Research Consortium Key Opinion Leader Meeting; September 16, 2015; Boston MA)

Fig. 6

Clinical Trial Endpoints. Overview of established hematologic response criteria and target organs to measure responses to treatment in relation to established objective endpoints and the identified need for novel endpoints to enable early and robust trial readouts