Novel pharmacotherapies for cardiac amyloidosis

Abstract

Amyloidosis refers to a range of protein misfolding disorders that can cause organ dysfunction through progressive fibril deposition. Cardiac involvement often leads to significant morbidity and mortality and increasingly has been recognized as an important cause of heart failure. The two main forms of cardiac amyloidosis, light chain (AL) and transthyretin (ATTR) amyloidosis, have distinct mechanisms of pathogenesis. Recent insights have led to the development of novel pharmacotherapies with the potential to significantly impact each disease. This review will summarize the preclinical and clinical data for these emerging treatments for AL and ATTR amyloidosis.

Cardiac amyloidosis: An update on diagnosis and treatment

“…The development of the proteasome inhibitor bortezomib has improved effi cacy and survival in AL causing a faster and more complete hematologic response than prior regimens. 43,67,68 The most commonly used fi rst-line treatment consists of a 3-drug combination with the alkylating agent cyclophosphamide, the proteasome inhibitor bortezomib, and the steroid dexamethasone, which is given weekly. 43 A retrospective study by Sperry et al 8 showed that patients receiving an alkylating agent, bortezomib, and a steroid had the best outcomes compared with other regimens.…”

“…For patients with refractory or relapsed disease, the CD38 monoclonal antibody daratumumab can be used if patients meet myeloma criteria and has been found to be effective thus far. 68,69 Newer proteasome inhibitors such as ixazomib, which is taken orally, are being studied in alternative combination regimens. 70 High-dose chemotherapy with autologous stem cell transplant can be considered in patients with an acceptable cardiac risk profi le and may offer more complete and durable remission than chemotherapy, although this is controversial.…”

“…Given its target of a conserved 3' untranslated region of TTR mRNA, patisiran should theoretically yield benefi ts not just in FAP but to both ATTRm-CA and ATTRwt-CA. 68,77 ASOs are single-stranded oligonucleotides, typically 20 nucleotides in length, that bind to mRNA and elicit enzymatic mRNA degradation and reduced protein expression. Inotersen (IONIS-TTR Rx ) is an ASO drug that targets a conserved region of TTR mRNA.…”

“…More studies are needed in the ATTR cardiac population. 68,77 Stabilize the TTR tetramer. The TTR tetramer has 2 thyroxine binding pockets that stabilize the structure when bound preventing dissociation.…”

“…Both new and repurposed agents have been found to stabilize the TTR tetramer, including difl unisal, tafamidis, tolcapone, and AG10. 68,77 Difl unisal (Dolobid) is a nonacetylated salicylate nonsteroidal anti-infl ammatory drug used for over 3 decades to treat arthritis and musculoskeletal pain. Unrelated to its anti-infl ammatory properties, it interacts with TTR's thyroxine binding pocket to increase the stability of the tetramer.…”