Tafamidis stabilizes transthyretin, preventing misfolding and the formation of amyloid. Transthyretin is formed in the liver and is involved in the transport of the thyroid hormone, thyroxine. Mutations in the TTR gene can lead to transthyretin amyloidosis in which there is a build-up of an abnormally modified protein in various organs. These insoluble deposits result in a chronic disease that is associated with the progressive degeneration of the nervous system (polyneuropathy). Treatment with this therapy delays neurologic progression in transthyretin familial amyloid polyneuropathy, a similar condition in which amyloid is deposited in the nerves after transthyretin misfolding.
Transthyretin amyloid cardiomyopathy is a rare, progressive, fatal disease. The hereditary form is caused by mutations in the TTR gene and typically presents in 50-70 year-olds, while the acquired (wild-type) form presents in 60-80 year-olds. The disease is caused when the transport protein, transthyretin, becomes unstable and misfolds, leading to the formation of amyloid, which is deposited in the heart. This causes the heart muscle to become stiff and results in heart failure. The medicine has not yet been approved for the treatment of transthyretin amyloid cardiomyopathy, but has orphan drug designation from the European Medicines Agency (EMA) and Fast Track designation from the US Food and Drug Administration (FDA).
The ATTR-ACT trial2 assessed the efficacy and safety of tafamidis in patients with hereditary and acquired transthyretin amyloid cardiomyopathy. The trial enrolled 441 patients aged 18-90 years from 48 centres in 13 countries. Patients were randomised in a 2:1:2 ratio to tafamidis 80 mg, tafamidis 20 mg, or placebo - all taken orally, once a day, for 30 months.
The primary endpoint was the hierarchical combination of all-cause death and cardiovascular-related hospitalisations from baseline to 30 months. The two tafamidis groups were combined and compared with the placebo group. Secondary outcomes included the change from baseline to 30 months in exercise capacity (assessed with the six-minute walk test) and in health-related quality of life (assessed using the Kansas City Cardiomyopathy Questionnaire).
A total of 264 patients received the drug and 177 received placebo. Tafamidis significantly reduced death and cardiovascular-related hospitalisation compared to placebo (p=0.0006). During the 30-month follow-up, 78 (29.5%) patients receiving the medicine died compared to 76 (42.9%) receiving placebo - this included patients who underwent heart transplant or received a cardiac mechanical assist device as these were classified as death in the analysis.3 Rates of cardiovascular-related hospitalisations were 52.3% and 60.5% in the tafamidis and placebo groups, respectively.
The therapy also reduced the decline in six-minute walk distance and quality of life compared with placebo. The incidence of individual adverse events were similar or fewer with drug treatment. Discontinuations of study drug due to treatment-related adverse events were less common with tafamidis than placebo.