Proposed Cardiac End Points for Clinical Trials in Immunoglobulin Light Chain Amyloidosis: Report From the Amyloidosis Forum Cardiac Working Group

Abstract

Immunoglobulin light chain amyloidosis is a rare, multisystemic, phenotypically heterogenous disease affecting cardiovascular, renal, neurological, and gastrointestinal systems to varying degrees. Its underlying cause is a plasma cell dyscrasia characterized by misfolding of monoclonal immunoglobulin light chains which leads to aggregation and deposition of insoluble amyloid fibrils in target organs. Prognosis is primarily dependent on extent of cardiac involvement and depth of hematologic response to treatment. To facilitate development of new therapies, 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 novel/composite end points and analytic strategies to expedite clinical trials for development of new therapies for the primary hematologic disorder and organ system manifestations. Specialized working groups identified organ-specific end points; additional working groups reviewed health-related quality of life measures and statistical approaches to data analysis. Each working group comprised amyloidosis experts, patient representatives, statisticians, and representatives from the Food and Drug Administration, the UK Medicines and Healthcare Products Regulatory Agency, and pharmaceutical companies. This review summarizes the proceedings and recommendations of the Cardiac Working Group. Using a modified Delphi method, the group identified, reviewed, and prioritized cardiac end points relevant to immunoglobulin light chain amyloidosis in the context of an antiplasma cell therapy. Prioritized cardiovascular end points included overall survival, hospitalization, N-terminal pro-B-type natriuretic peptide level, 6-minute walk test, Kansas City Cardiac Questionnaire, and cardiac deterioration progression-free survival. These recommended components will be further explored through evaluation of clinical trial datasets and formal guidance from regulatory authorities.

Keywords: amyloidosis; clinical trial; immunoglobulin light chains; prognosis; progression-free survival.

Figure 1.

A community approach to development of a novel multidomain end point in immunoglobulin light chain (AL) amyloidosis. The Amyloidosis Forum set out to develop a novel multidomain composite end point and analyses methods for use in clinical trials for AL amyloidosis. Specialized working groups identified and prioritized organ-specific and health-related quality of life (HRQoL) end points; 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 end points and potential surrogate end points to facilitate drug development in AL amyloidosis. Auto indicates autonomic; and GI, gastrointestinal.

Figure 2.

Pathophysiology and biologic plausibility of N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a relevant biomarker in immunoglobulin light chain (AL) amyloidosis. In non-AL amyloidosis heart failure, multiple pathways influence biochemical response to cardiac stress; NT-proBNP release is primarily related to myocardial stress (left). In AL amyloidosis, elevations of NT-proBNP levels directly reflect cardiomyocyte insult by toxic light chains (right) in addition to stress induced by extracellular amyloid fibrils. BNP indicates B-type natriuretic peptide; ERK, extracellular-signal regulated kinase; JNK, c-Jun N-terminal kinases; and P38 MAPK, 38-kDa mitogen-activated protein kinase.

Figure 3.

Proposed components of progression in cardiac immunoglobulin light chain (AL) amyloidosis. Proposed components of a composite heart failure outcome for use in AL amyloidosis clinical trials. N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been demonstrated to be a surrogate for cardiac death. Meaningful thresholds are established for both response (decline of >30% and >300 ng/L if baseline >650 ng/L) and for progression (increase of >30% and >300 ng/L if baseline >650 ng/L). CV indicates cardiovascular; and HF, heart failure.