Tafamidis

Tafamidis is used to delay nerve damage in adults who have transthyretin amyloidosis with polyneuropathy, or heart disease in adults who have transthyretin amyloidosis with cardiomyopathy.{{cite web|title=Vyndaqel 20 mg soft capsules - Summary of Product Characteristics|url=https://www.medicines.org.uk/emc/product/2837|publisher=Electronic Medicines Compendium|access-date=2 April 2018}}{{cite web | title=Vyndaqel- tafamidis meglumine capsule, liquid filled Vyndamax- tafamidis capsule, liquid filled | website=DailyMed | date=30 August 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1b4121ee-a733-4456-a917-be2603477839 | access-date=24 November 2019}} It is taken by mouth.

Women should not get pregnant while taking it and should not breastfeed while taking it. People with familial amyloid polyneuropathy who have received a liver transplant should not take it.

An alternative treatment is acoramidis.

More than 10% of people in clinical 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 it inhibits ATP-binding cassette super-family G member 2, so is likely to affect the levels of certain drugs including methotrexate, rosuvastatin, and imatinib. It also inhibits organic anion transporter 1 and organic anion transporter 3/solute carrier family 22 member 8 so is likely to interact with non-steroidal anti-inflammatory agents and other drugs that rely on those transporters.

Tafamidis is a pharmacological chaperone that stabilizes the correctly folded tetrameric form of the transthyretin protein by binding in one of the two thyroxine-binding sites of the tetramer. In people with familial amyloid polyneuropathy, 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 {{chem name|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.{{cite web|title=Assessment report: Vyndaqel tafamidis meglumine Procedure No.: EMEA/H/C/002294|url=https://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002294/WC500117838.pdf|publisher=EMA|date=2011|access-date=1 April 2020|archive-date=17 June 2018|archive-url=https://web.archive.org/web/20180617223158/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002294/WC500117838.pdf|url-status=dead}} See EMA [http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002294/human_med_001498.jsp&mid=WC0b01ac058001d124 index page] {{Webarchive|url=https://web.archive.org/web/20180620171154/http://www.ema.europa.eu/ema//index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F002294%2Fhuman_med_001498.jsp&mid=WC0b01ac058001d124 |date=20 June 2018 }} for updates.

The laboratory of Jeffery W. Kelly at The Scripps Research Institute began looking for ways to inhibit transthyretin fibril formation in the 1990s.{{cite book| vauthors = Labaudiniere R | veditors = Pryde DC, Palmer MJ |title=Orphan Drugs and Rare Diseases.|date=2014|publisher=Royal Society of Chemistry|series=RSC Drug Discovery Series No. 38|isbn=978-1-84973-806-4|chapter=Chapter 9: Discovery and Development of Tafamidis for the Treatment of TTR Familial Amyloid Polyneuropathy}}{{rp|210}} Tafamidis was eventually discovered by Kelly's team using a structure-based drug design strategy; the chemical structure was first published in 2003.{{cite journal | vauthors = Razavi H, Palaninathan SK, Powers ET, Wiseman RL, Purkey HE, Mohamedmohaideen NN, Deechongkit S, Chiang KP, Dendle MT, Sacchettini JC, Kelly JW | title = Benzoxazoles as transthyretin amyloid fibril inhibitors: synthesis, evaluation, and mechanism of action | journal = Angewandte Chemie | volume = 42 | issue = 24 | pages = 2758–2761 | date = June 2003 | pmid = 12820260 | doi = 10.1002/anie.200351179 }} In 2003, Kelly co-founded a company called FoldRx with Susan Lindquist of the Massachusetts Institute of Technology and the Whitehead Institute,{{cite journal| vauthors = Borman S |title=Attacking Amyloids|journal=Chemical & Engineering News|date=25 January 2010|volume=88|issue=4|pages=30–32|doi=10.1021/cen-v088n004.p030}}{{cite journal| vauthors = Breznitz SM, O'Shea RP, Allen TJ |title=University Commercialization Strategies in the Development of Regional Bioclusters|journal=Journal of Product Innovation Management|date=March 2008|volume=25|issue=2|pages=129–142|doi=10.1111/j.1540-5885.2008.00290.x}} and FoldRx developed tafamidis up through submitting an application for marketing approval in Europe in early 2010.{{cite journal | vauthors = Jones D | title = Modifying protein misfolding | journal = Nature Reviews. Drug Discovery | volume = 9 | issue = 11 | pages = 825–827 | date = November 2010 | pmid = 21030987 | doi = 10.1038/nrd3316 | s2cid = 30702908 }} FoldRx was acquired by Pfizer later that year.

Tafamidis was approved by the European Medicines Agency in November 2011, to delay peripheral nerve impairment in adults with transthyretin-related hereditary amyloidosis.{{cite journal | vauthors = Said G, Grippon S, Kirkpatrick P | title = Tafamidis | journal = Nature Reviews. Drug Discovery | volume = 11 | issue = 3 | pages = 185–186 | date = March 2012 | pmid = 22378262 | doi = 10.1038/nrd3675 | s2cid = 256746210 }} The U.S. Food and Drug Administration 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 requested further clinical trials.{{cite news| vauthors = Grogan K |title=FDA rejects Pfizer rare disease drug tafamidis|url=http://www.pharmatimes.com/news/fda_rejects_pfizer_rare_disease_drug_tafamidis_977149|work=Pharma Times|date=19 June 2012}} In May 2019, the FDA approved two tafamidis preparations, Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis), for the treatment of transthyretin-mediated cardiomyopathy. The drug was approved in Japan in 2013; regulators there made the approval dependent on further clinical trials showing better evidence of efficacy.{{cite web|title=Report on the Deliberation Results|url=https://www.pmda.go.jp/files/000153750.pdf|publisher=Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare|date=2 September 2013}}

The FDA approved tafamidis meglumine based primarily on evidence from a clinical trial of 441 adult patients 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 transthyretin amyloidosis with cardiomyopathy, in which patients were randomly assigned to receive either tafamidis (either 20 or 80 mg) or placebo for 30 months. About 90% of patients in the trial were taking other drugs for heart failure (consistent with the standard of care).

The European Medicines Agency designated tafamidis an orphan medicine and the Food and Drug Administration also designated tafamidis meglumine as an orphan drug.{{cite web | title=Tafamidis meglumine Orphan Drug Designation and Approval | website=U.S. Food and Drug Administration | date=3 May 2019 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=363312 | archive-url=https://web.archive.org/web/20191219071105/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=363312 | archive-date=19 December 2019 | url-status=live | access-date=18 December 2019}} {{PD-notice}}

Tafamidis was approved in the European Union in 2011 for the treatment of transthyretin amyloidosis with polyneuropathy, and in Japan in 2013.{{cite web | title=Vyndaqel EPAR | website=European Medicines Agency | date=16 October 2019 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/vyndaqel | access-date=24 November 2019}} In the United States, it was rejected for the treatment of transthyretin amyloidosis with polyneuropathy because the Food and Drug Administration saw insufficient evidence for its efficacy.{{cite web | title=FDA rejects Pfizer rare disease drug tafamidis | website=PharmaTimes online | date=19 June 2012 | url=http://www.pharmatimes.com/news/fda_rejects_pfizer_rare_disease_drug_tafamidis_977149 | access-date=2 June 2021}}

Tafamidis can also be used to treat transthyretin amyloidosis with cardiomyopathy. 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: tafamidis meglumine (Vyndaqel) and tafamidis (Vyndamax).{{cite web | title=Drug Approval Package: Vyndaquel & Vyndamax | website=U.S. Food and Drug Administration | date=13 June 2019 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211996Orig1s000,%20212161Orig1s000TOC.cfm | access-date=24 November 2019}} {{PD-notice}}{{cite web | title=Drug Trial Snapshots: Vyndaqel/Vyndamax | website=U.S. Food and Drug Administration (FDA) | date=28 May 2019 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/drug-trial-snapshots-vyndaqelvyndamax | archive-url=https://web.archive.org/web/20191219070125/https://www.fda.gov/drugs/resources-information-approved-drugs/drug-trial-snapshots-vyndaqelvyndamax | archive-date=19 December 2019 | url-status=live | access-date=18 December 2019}} {{PD-notice}} The two preparations have the same active moiety, tafamidis, but they are not substitutable on a milligram to milligram basis.{{cite web | title=FDA approves new treatments for heart disease caused by a serious rare disease, transthyretin mediated amyloidosis | website=U.S. Food and Drug Administration | date=14 September 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatments-heart-disease-caused-serious-rare-disease-transthyretin-mediated | archive-url=https://web.archive.org/web/20190914151619/https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatments-heart-disease-caused-serious-rare-disease-transthyretin-mediated | archive-date=14 September 2019 | url-status=live | access-date=24 November 2019}} {{PD-notice}}

Tafamidis (Vyndamax) and tafamidis meglumine (Vyndaqel) were approved for medical use in Australia in March 2020.{{cite web | title=AusPAR: Tafamidis and Tafamidis meglumine | website=Therapeutic Goods Administration | date=10 September 2020 | url=https://www.tga.gov.au/auspar/auspar-tafamidis-and-tafamidis-meglumine | access-date=23 September 2020}}

Tafamidis is available in a total of 64 countries.{{cite journal | vauthors = Brito D, Albrecht FC, de Arenaza DP, Bart N, Better N, Carvajal-Juarez I, Conceição I, Damy T, Dorbala S, Fidalgo JC, Garcia-Pavia P, Ge J, Gillmore JD, Grzybowski J, Obici L, Piñero D, Rapezzi C, Ueda M, Pinto FJ | title = World Heart Federation Consensus on Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM) | language = en-US | journal = Global Heart | volume = 18 | issue = 1 | pages = 59 | date = 2023-10-26 | pmid = 37901600 | doi = 10.5334/gh.1262 | doi-access = free | pmc = 10607607 }}

Pfizer reported revenue of {{US$|3.321 billion}} for Vyndaqel in 2023.{{cite web | title=Pfizer's year in review | website=Pfizer 2023 Annual Report | date=31 December 2023 | url=https://www.pfizer.com/sites/default/files/investors/financial_reports/annual_reports/2023/ | access-date=30 December 2024}}

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• {{cite journal | vauthors = Adams D | title = Recent advances in the treatment of familial amyloid polyneuropathy | journal = Therapeutic Advances in Neurological Disorders | volume = 6 | issue = 2 | pages = 129–139 | date = March 2013 | pmid = 23483184 | pmc = 3582309 | doi = 10.1177/1756285612470192 }}
• {{cite journal | vauthors = Coelho T, Maia LF, Martins da Silva A, Waddington Cruz M, Planté-Bordeneuve V, Lozeron P, Suhr OB, Campistol JM, Conceição IM, Schmidt HH, Trigo P, Kelly JW, Labaudinière R, Chan J, Packman J, Wilson A, Grogan DR | title = Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial | journal = Neurology | volume = 79 | issue = 8 | pages = 785–792 | date = August 2012 | pmid = 22843282 | pmc = 4098875 | doi = 10.1212/WNL.0b013e3182661eb1 }}

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