|Trade names||Vyndaqel, Vyndamax, others|
|Other names||Tafamidis meglumine|
|Main uses||Familial amyloid polyneuropathy (transthyretin amyloidosis)|
|Side effects||Abdominal pain, diarrhea, infection|
|Typical dose||20 to 80 mg OD|
|Chemical and physical data|
|Molar mass||308.11 g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Tafamidis, sold under the brand names Vyndaqel among others, is a medication used to treat familial amyloid polyneuropathy (FAP), also known as transthyretin amyloidosis. It is taken by mouth. It can be stopped after liver transplantation.
Common side effects include abdominal pain, diarrhea, and infection. Use during pregnancy is believed to harm the baby. It works by stabilizing the protein transthyretin, thus decreasing the formulation amyloids.
Tafamidis was approved for medical use in Europe in 2011 and the United States in 2019. In the United Kingdom a month of 20 mg per day costs the NHS about £10,700 as of 2021. This amount in the United States costs about 4,900 USD.
Tafamidis is used to delay disease progression in adults with transthyretin amyloidosis (ATTR) whose disease leads to loss of nerve function (ATTR with polyneuropathy, ATTR-PN) or to heart disease (ATTR with cardiomyopathy, ATTR-CM). It is taken by mouth.
Women should not get pregnant while taking it and should not breast feed while taking it. People with FAP who have received a liver transplant should not take it.
More than 10% of people in trials had one or more of urinary tract infections, vaginal infections, upper abdominal pain, or diarrhea.
Tafamidis does not appear to interact with cytochrome P450 but does inhibit BCRP, so is likely to affect availability of drugs including methotrexate, rosuvastatin, and imatinib, and inhibits OAT1 and OAT3 so is likely to interact with NSAIDs and other drugs that rely on those transporters.
Tafamidis is a pharmacological chaperone that stabilizes the correctly folded tetrameric form of the transthyretin (TTR) protein by binding in one of the two thyroxine-binding sites of the tetramer. In people with FAP, the individual monomers fall away from the tetramer, misfold, and aggregate; the aggregates harm nerves.
The maximum plasma concentration is achieved around two hours after dosing; in plasma it is almost completely bound to proteins. Based on preclinical data, it appears to be metabolized by glucuronidation and excreted via bile; in humans, around 59% of a dose is recovered in feces, and approximately 22% in urine.
The chemical name of tafamidis is 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. The molecule has two crystalline forms and one amorphous form; it is manufactured in one of the possible crystalline forms. It is marketed as a meglumine salt. It is slightly soluble in water.
The laboratory of Jeffery W. Kelly at The Scripps Research Institute began looking for ways to inhibit TTR fibril formation in the 1990s.: 210  Tafamidis was eventually discovered by Kelly's team using a structure-based drug design strategy; the chemical structure was first published in 2003. In 2003, Kelly co-founded a company called FoldRx with Susan Lindquist of MIT and the Whitehead Institute and FoldRx developed tafamidis up through submitting an application for marketing approval in Europe in early 2010. FoldRx was acquired by Pfizer later that year.
Tafamidis was approved by the European Medicines Agency (EMA) in November 2011, to delay peripheral nerve impairment in adults with transthyretin-related hereditary amyloidosis. The U.S. Food and Drug Administration (FDA) rejected the application for marketing approval in 2012, on the basis that the clinical trial did not show efficacy based on a functional endpoint, and the FDA requested further clinical trials. In May 2019, the FDA approved two tafamidis preparations, Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis), for the treatment of transthyretin-mediated cardiomyopathy (ATTR-CM). The drug was approved in Japan in 2013; regulators there made the approval dependent on further clinical trials showing better evidence of efficacy.
The FDA approved tafamidis meglumine based primarily on evidence from a clinical trial (NCT01994889) of 441 adults. The trial was conducted at 60 sites in Belgium, Brazil, Canada, Czech Republic, Spain, France, Greece, Italy, Japan, Netherlands, Sweden, Great Britain, and the United States.
There was one trial that evaluated the benefits and side effects of tafamidis for the treatment of ATTR-CM. In the trial, people with ATTR‑CM were randomly assigned to receive either tafamidis (either 20 or 80 mg) or placebo for 30 months. About 90% of people in the trial were taking other drugs for heart failure (consistent with the standard of care).
The EMA designated tafamidis an orphan medicine and the FDA designated tafamidis meglumine an orphan drug. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
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Tafamidis was approved for the treatment of ATTR with loss of nerve function (ATTR-PN) in the European Union in 2011, and in Japan in 2013. In the United States, it was rejected for the treatment of ATTR-PN. The reason for this is that the FDA saw insufficient evidence for its efficacy in this form of ATTR.
Tafamidis can also be used to treat a different form of ATTR that leads to heart disease (ATTR with cardiomyopathy, ATTR-CM). It was approved for the treatment of this form of the disease in the United States in 2019 and in the European Union in 2020. In the United States, there are two approved preparations for the treatment of ATTR-CM: tafamidis meglumine (Vyndaqel) and tafamidis (Vyndamax). The two preparations have the same active moiety, tafamidis, but they are not substitutable on a milligram to milligram basis.
Tafamidis (Vyndamax) and tafamidis meglumine (Vyndaqel) were approved for medical use in Australia in March 2020.
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