Emerging Therapeutics for the Treatment of Light Chain and Transthyretin Amyloidosis

Abstract

Cardiac amyloidosis is a restrictive cardiomyopathy that results from the deposition of misfolded light chain or transthyretin proteins, most commonly, in cardiac tissue. Traditionally, treatment options for light chain (AL) and transthyretin (ATTR) amyloidosis have been limited. However, there are now multiple novel therapeutics in development and several therapeutics recently approved that promise to revolutionize clinical management of AL and ATTR. Most of these agents disrupt specific stages of amyloidogenesis such as light chain or transthyretin protein production, formation of amyloidogenic intermediates, or amyloid fibril aggregation. Others aim to remove existing amyloid tissue deposits using monoclonal antibody technology. Although these advances represent an important step forward in the care of cardiac amyloidosis patients, additional studies are needed to define the optimal treatment paradigms for AL and ATTR and to validate clinical, imaging, or serum biomarker strategies that may confirm a cardiac response to therapy.

Keywords: AL, light chain amyloidosis; ASCT, autologous stem cell transplantation; ATTR, transthyretin amyloidosis; CA, cardiac amyloidosis; GLS, global longitudinal strain; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MMP, matrix metalloproteinase; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; SAP, serum amyloid P; cardiac amyloidosis; clinical trials; therapeutics.

Graphical abstract

Central Illustration

Pathophysiology of Light Chain and Transthyretin Amyloidosis and Mechanism of Action of Novel Therapeutics (A) Abnormal plasma cells overproduce κ or λ light chains, which misfold and aggregate into amyloid fibrils. The light chain amyloid fibrils deposit in multiple end-organs causing organ dysfunction. Carfilzomib, daratumumab, elotuzumab, isatuximab, ixazomib, pomalidomide, and venetoclax reduce light chain production; doxycycline inhibits formation of light chain amyloid fibrils; 11-1F4, GSK2398852, and NEOD001 remove light chain amyloid deposits from tissue. (B) Transthyretin is synthesized in hepatocytes as a homotetramer, which dissociates into alternatively folded monomers that self-assemble to form insoluble amyloid fibrils. The transthyretin amyloid fibrils deposit in multiple end-organs causing organ dysfunction. Patisiran and inotersen inhibit transthyretin synthesis by targeting transthyretin mRNA; AG10, diflunisal, tafamidis, and tolcapone stabilize the transthyretin tetramer; PRX004 targets misfolded transthyretin and removes tissue amyloid deposits; GSK2398852 removes amyloid deposits from tissue. *Drug development has been suspended or terminated.