Tafamidis

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Tafamidis
Tafamidis.svg
Clinical data
Trade names Vyndaqel, Vyndamax, others
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administration 		By mouth
ATC code
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Identifiers
  • 2-(3,5-Dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
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ECHA InfoCard 100.246.079 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H7Cl2NO3
Molar mass 308.11 g·mol−1
3D model (JSmol)
  • O=C(O)c3ccc1nc(oc1c3)-c2cc(Cl)cc(Cl)c2
  • InChI=1S/C14H7Cl2NO3/c15-9-3-8(4-10(16)6-9)13-17-11-2-1-7(14(18)19)5-12(11)20-13/h1-6H,(H,18,19) X mark.svgN
  • Key:TXEIIPDJKFWEEC-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Tafamidis, sold under the brand names Vyndaqel and Vyndamax, [5] is a medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis. It can be used to treat both hereditary forms, familial amyloid cardiomyopathy and familial amyloid polyneuropathy, as well as wild-type transthyretin amyloidosis, which formerly was called senile systemic amyloidosis. It works by stabilizing the quaternary structure of the protein transthyretin. In people with transthyretin amyloidosis, transthyretin falls apart and forms clumps called (amyloid) that harm tissues including nerves and the heart. [6] [7]

Contents

The US Food and Drug Administration considers tafamidis to be a first-in-class medication. [8]

Medical use

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. [4] [5] [7] [9] It is taken by mouth. [4] [5]

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. [4]

Adverse effects

More than 10% of people in clinical trials had one or more of urinary tract infections, vaginal infections, upper abdominal pain, or diarrhea. [4]

Interactions

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. [4]

Pharmacology

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. [9] In people with familial amyloid polyneuropathy, the individual monomers fall away from the tetramer, misfold, and aggregate; the aggregates harm nerves. [9]

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. [4]

Chemistry

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. [10]

History

The laboratory of Jeffery W. Kelly at The Scripps Research Institute began looking for ways to inhibit transthyretin fibril formation in the 1990s. [11] : 210  Tafamidis was eventually discovered by Kelly's team using a structure-based drug design strategy; the chemical structure was first published in 2003. [12] [13] [14] In 2003, Kelly co-founded a company called FoldRx with Susan Lindquist of the Massachusetts Institute of Technology and the Whitehead Institute, [14] [15] and FoldRx developed tafamidis up through submitting an application for marketing approval in Europe in early 2010. [13] FoldRx was acquired by Pfizer later that year. [13]

Tafamidis was approved by the European Medicines Agency in November 2011, to delay peripheral nerve impairment in adults with transthyretin-related hereditary amyloidosis. [9] 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. [16] In May 2019, the FDA approved two tafamidis preparations, Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis), for the treatment of transthyretin-mediated cardiomyopathy. [7] The drug was approved in Japan in 2013; regulators there made the approval dependent on further clinical trials showing better evidence of efficacy. [17]

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. [18]

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. [18] About 90% of patients in the trial were taking other drugs for heart failure (consistent with the standard of care). [18]

The European Medicines Agency designated tafamidis an orphan medicine [6] and the Food and Drug Administration also designated tafamidis meglumine as an orphan drug. [19]

Society and culture

Tafamidis was approved in the European Union in 2011 for the treatment of transthyretin amyloidosis with polyneuropathy, and in Japan in 2013. [6] [17] 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. [20] [7]

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). [7] [21] [18] The two preparations have the same active moiety, tafamidis, but they are not substitutable on a milligram to milligram basis. [7]

Tafamidis (Vyndamax) and tafamidis meglumine (Vyndaqel) were approved for medical use in Australia in March 2020. [22]

Tafamidis is available in a total of 64 countries. [23]

Related Research Articles

An orphan drug is a pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by the conditions. The conditions that orphan drugs are used to treat are referred to as orphan diseases. The assignment of orphan status to a disease and to drugs developed to treat it is a matter of public policy that depends on the legislation of the country.

<span class="mw-page-title-main">Amyloidosis</span> Metabolic disease involving abnormal deposited amyloid proteins

Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight loss, shortness of breath, palpitations, and feeling faint with standing. In AL amyloidosis, specific indicators can include enlargement of the tongue and periorbital purpura. In wild-type ATTR amyloidosis, non-cardiac symptoms include: bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, small fiber neuropathy, and autonomic dysfunction.

<span class="mw-page-title-main">Transthyretin</span> Serum protein related to amyloid diseases

Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: transports thyroxine and retinol. The liver secretes TTR into the blood, and the choroid plexus secretes TTR into the cerebrospinal fluid.

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<span class="mw-page-title-main">Familial amyloid polyneuropathy</span> Medical condition

Familial amyloid polyneuropathy, also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis abbreviated also as ATTR, or Corino de Andrade's disease, is an autosomal dominant neurodegenerative disease. It is a form of amyloidosis, and was first identified and described by Portuguese neurologist Mário Corino da Costa Andrade, in 1952. FAP is distinct from senile systemic amyloidosis (SSA), which is not inherited, and which was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied. FAP can be ameliorated by liver transplantation.

<span class="mw-page-title-main">Cardiac amyloidosis</span> Medical condition

Cardiac amyloidosis is a subcategory of amyloidosis where there is depositing of the protein amyloid in the cardiac muscle and surrounding tissues. Amyloid, a misfolded and insoluble protein, can become a deposit in the heart's atria, valves, or ventricles. These deposits can cause thickening of different sections of the heart, leading to decreased cardiac function. The overall decrease in cardiac function leads to a plethora of symptoms. This multisystem disease was often misdiagnosed, with a corrected analysis only during autopsy. Advancements of technologies have increased earlier accuracy of diagnosis. Cardiac amyloidosis has multiple sub-types including light chain, familial, and senile. One of the most studied types is light chain cardiac amyloidosis. Prognosis depends on the extent of the deposits in the body and the type of amyloidosis. New treatment methods are actively being researched in regards to the treatment of heart failure and specific cardiac amyloidosis problems.

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Familial amyloid cardiomyopathy (FAC), or transthyretin amyloid cardiomyopathy (ATTR-CM) results from the aggregation and deposition of mutant and wild-type transthyretin (TTR) protein in the heart. TTR is usually circulated as a homo-tetramer—a protein made up of four identical subunits—however, in FAC populations, TTR dissociates from this typical form and misassembles into amyloid fibrils which are insoluble and resistant to degradation. Due to this resistance to degradation, when amyloid fibrils accumulate in the heart's walls, specifically the left ventricle, rigidity prevents the heart from properly relaxing and refilling with blood: this is called diastolic dysfunction which can ultimately lead to heart failure.

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Wild-type transthyretin amyloid (WTTA), also known as senile systemic amyloidosis (SSA), is a disease that typically affects the heart and tendons of elderly people. It is caused by the accumulation of a wild-type protein called transthyretin. This is in contrast to a related condition called transthyretin-related hereditary amyloidosis where a genetically mutated transthyretin protein tends to deposit much earlier than in WTTA due to abnormal conformation and bioprocessing. It belongs to a group of diseases called amyloidosis, chronic progressive conditions linked to abnormal deposition of normal or abnormal proteins, because these proteins are misshapen and cannot be properly degraded and eliminated by the cell metabolism.

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<span class="mw-page-title-main">Patisiran</span> Pharmaceutical drug

Patisiran, sold under the brand name Onpattro, is a medication used for the treatment of polyneuropathy in people with hereditary transthyretin-mediated amyloidosis, a fatal rare disease that is estimated to affect 50,000 people worldwide.

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Vutrisiran, sold under the brand name Amvuttra, is a medication used for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. It is a double stranded small interfering RNA (siRNA) that interferes with the expression of the transthyretin (TTR) gene. Transthyretin is a serum protein made in the liver whose major function is transport of vitamin A and thyroxine. Rare mutations in the transthyretin gene result in accumulation of large amyloid deposits of misfolded transthyretin molecules most prominently in peripheral nerves and the heart. Patients with hATTR typically present with polyneuropathy or autonomic dysfunction followed by cardiomyopathy which, if untreated, is fatal within 5 to 10 years.

Eplontersen, sold under the brand name Wainua, is a medication used for the treatment of transthyretin-mediated amyloidosis. It is a transthyretin-directed antisense oligonucleotide. It was developed to treat hereditary transthyretin amyloidosis by Ionis Pharmaceuticals and AstraZeneca.

References

  1. 1 2 "Vyndamax and Vyndaqel Australian prescription medicine decision summary". Therapeutic Goods Administration (TGA). 17 July 2020. Retrieved 16 August 2020.
  2. ↑ "Summary Basis of Decision (SBD) for Vyndaqel". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  3. ↑ "Health product highlights 2021: Annexes of products approved in 2021". Health Canada . 3 August 2022. Retrieved 25 March 2024.
  4. 1 2 3 4 5 6 7 "Vyndaqel 20 mg soft capsules - Summary of Product Characteristics". Electronic Medicines Compendium. Retrieved 2 April 2018.
  5. 1 2 3 4 "Vyndaqel- tafamidis meglumine capsule, liquid filled Vyndamax- tafamidis capsule, liquid filled". DailyMed . 30 August 2019. Retrieved 24 November 2019.
  6. 1 2 3 4 "Vyndaqel EPAR". European Medicines Agency . 16 October 2019. Retrieved 24 November 2019.
  7. 1 2 3 4 5 6 "FDA approves new treatments for heart disease caused by a serious rare disease, transthyretin mediated amyloidosis". U.S. Food and Drug Administration . 14 September 2019. Archived from the original on 14 September 2019. Retrieved 24 November 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  8. ↑ "New Drug Therapy Approvals 2019". U.S. Food and Drug Administration. 31 December 2019. Retrieved 15 September 2020.
  9. 1 2 3 4 Said G, Grippon S, Kirkpatrick P (March 2012). "Tafamidis". Nature Reviews. Drug Discovery. 11 (3): 185–186. doi:10.1038/nrd3675. PMID   22378262. S2CID   256746210.
  10. ↑ "Assessment report: Vyndaqel tafamidis meglumine Procedure No.: EMEA/H/C/002294" (PDF). EMA. 2011. Archived from the original (PDF) on 17 June 2018. Retrieved 1 April 2020. See EMA index page Archived 20 June 2018 at the Wayback Machine for updates.
  11. ↑ Labaudiniere R (2014). "Chapter 9: Discovery and Development of Tafamidis for the Treatment of TTR Familial Amyloid Polyneuropathy". In Pryde DC, Palmer MJ (eds.). Orphan Drugs and Rare Diseases. RSC Drug Discovery Series No. 38. Royal Society of Chemistry. ISBN   978-1-84973-806-4.
  12. ↑ Razavi H, Palaninathan SK, Powers ET, Wiseman RL, Purkey HE, Mohamedmohaideen NN, et al. (June 2003). "Benzoxazoles as transthyretin amyloid fibril inhibitors: synthesis, evaluation, and mechanism of action". Angewandte Chemie. 42 (24): 2758–2761. doi:10.1002/anie.200351179. PMID   12820260.
  13. 1 2 3 Jones D (November 2010). "Modifying protein misfolding". Nature Reviews. Drug Discovery. 9 (11): 825–827. doi:10.1038/nrd3316. PMID   21030987. S2CID   30702908.
  14. 1 2 Borman S (25 January 2010). "Attacking Amyloids". Chemical & Engineering News. 88 (4): 30–32. doi:10.1021/cen-v088n004.p030.
  15. ↑ Breznitz SM, O'Shea RP, Allen TJ (March 2008). "University Commercialization Strategies in the Development of Regional Bioclusters". Journal of Product Innovation Management. 25 (2): 129–142. doi:10.1111/j.1540-5885.2008.00290.x.
  16. ↑ Grogan K (19 June 2012). "FDA rejects Pfizer rare disease drug tafamidis". Pharma Times.
  17. 1 2 "Report on the Deliberation Results" (PDF). Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare. 2 September 2013.
  18. 1 2 3 4 "Drug Trial Snapshots: Vyndaqel/Vyndamax". U.S. Food and Drug Administration (FDA). 28 May 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  19. ↑ "Tafamidis meglumine Orphan Drug Designation and Approval". U.S. Food and Drug Administration . 3 May 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  20. ↑ "FDA rejects Pfizer rare disease drug tafamidis". PharmaTimes online. 19 June 2012. Retrieved 2 June 2021.
  21. ↑ "Drug Approval Package: Vyndaquel & Vyndamax". U.S. Food and Drug Administration . 13 June 2019. Retrieved 24 November 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  22. ↑ "AusPAR: Tafamidis and Tafamidis meglumine". Therapeutic Goods Administration . 10 September 2020. Retrieved 23 September 2020.
  23. ↑ Brito D, Albrecht FC, de Arenaza DP, Bart N, Better N, Carvajal-Juarez I, et al. (26 October 2023). "World Heart Federation Consensus on Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM)". Global Heart. 18 (1): 59. doi: 10.5334/gh.1262 . PMC   10607607 . PMID   37901600.

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