Pathogenic variants of the transtiretin gene (TTRv) result in the production of amyloidogenic fibrils that deposit in the extracellular space of many tissues, resulting in amyloidogenic multisystemic disease (ATTRv). Several tissues may be affected in different combinations, including the peripheral nerves and the cardiac system, which are usually the main targets, but also the kidneys, eyes, gastrointestinal system, central nervous system and musculoskeletal structures.

ATTRv is a progressive disease that results in death around 8 to 15 years after the onset of the disease, even more rapidly when the cardiac system is involved early. However, the natural history of the disease has changed with the introduction of treatments that, by different mechanisms, decrease the production of amyloid fibrils.

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Transthyretin (TTR) is a tetrameric protein synthesized essentially by the liver. TTR molecules may misfold and store as amyloid fibrils in the heart and other organs, leading to TTR-related amyloidosis (ATTR) . ATTR can follow the deposition of either variant ATTR (ATTRv), which was previously known as mutant ATTR, or wild-type ATTR (ATTRwt). ATTR is an underdiagnosed disease, as well as a crucial determinant of morbidity and mortality. Cardiac involvement is common in ATTR, leading to transthyretin cardiomyopathy (ATTR-CA). ATTR-CA is a progressive disorder, and patients ultimately develop heart failure, arrhythmias, and cardiac conduction disturbances, resulting in decreased functional capacity, diminished quality of life, and death. Until recently, treatment of ATTR-CA was limited to treating symptoms and complications; however, the development of new specific therapies that delay or stop the progress of the cardiomyopathy has positively modified the outcomes . These specific treatments work by targeting the inhibition of TTR synthesis (inotersen or patisiran); tetramer stabilization (diflunisal, tafamidis, or acoramidis [AG10]); inhibition of oligomer aggregation and disruption (epigallocatechin-3-gallate); and degradation and reabsorption of amyloid fibers (doxycycline-tauroursodeoxycholic acid [TUDCA] or doxycycline-ursodeoxycholic acid [UDCA]).4

In patients with ATTR-CA, either ATTRv or ATTRwt, tafamidis is considered the agent of choice due to the proven clinical benefit in cardiovascular outcomes. Tafamidis is a kinetic TTR stabilizer that binds to the unoccupied thyroxine binding sites of tetrameric TTR and blocks the amyloidogenic cascade. It was first adopted for treatment of symptomatic ATTRv polyneuropathy, and it is the only therapy approved with effectiveness to treat ATTR-CA. This recommendation is essentially based on the results of a large, well-designed phase III randomized clinical trial (RCT), ATTR-ACT. In this study, tafamidis (20 and 80 mg, pooled) showed a decline in all-cause mortality and cardiovascular-related hospitalization, decreased decline in 6-minute walk test, slower deterioration in quality of life, and a minor increase of NT-proBNP in patients with biopsy-proven ATTRwt or ATTRv CA with heart failure and NYHA class I to III at 30 months. The safety profile was similar to placebo, and individuals with NYHA classes I and II reached the most meaningful benefit. ATTR-ACT was not designed to assess a specific dose; therefore, further analysis from ATTR-ACT and its long-term extension study support tafamidis 80 mg as the optimal dose to be used in clinical practice.

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