Current and emerging treatment options for transthyretin amyloid cardiomyopathy.

Abstract

Transthyretin amyloidosis (ATTR) is a condition caused by TTR protein misfolding and amyloid deposition, particularly in the heart and nervous system, leading to organ dysfunction. Advances in therapeutic strategies have revolutionised the management of ATTR amyloidosis. Treatments available in clinical practice include TTR stabilisers (tafamidis and acoramidis), which prevent the dissociation of TTR tetramer into monomers and oligomers that subsequently form amyloid fibrils, and gene-silencing therapies (patisiran, inotersen and vutrisiran), which suppress the hepatic synthesis of TTR, which is the amyloid precursor protein. Novel treatment strategies that are at various stages of development include Clustered Regularly Interspaced Short Palindromic Repeats-Cas9 gene-editing technology (nexiguran ziclumeran), which, if successful, offers the prospect of a single-dose treatment, and monoclonal (cormitug and ALXN220) and pan-amyloid antibodies (AT-02) that seek to target and remove amyloid fibrils that have deposited in the myocardium. Amyloid removal remains a significant unmet clinical need, and hence, the ability to promote amyloid degradation and clearance through the use of antiamyloid therapies would represent a groundbreaking advancement in the treatment of ATTR amyloidosis. The success of ATTR-specific disease-modifying therapies has already altered the treatment landscape and changed the perception of ATTR amyloidosis from a progressive and fatal disease to one that is treatable through the availability of highly effective disease-modifying therapies. However, important questions remain, including the long-term safety of these drugs, whether combining therapies with different mechanisms of action has an additive prognostic benefit and how best to monitor the treatment response.