- Accession Number
- Small Molecule
- Approved, Investigational
Tafamidis is a novel specific transthyretin (TTR) stabilizer or dissociation inhibitor. TTR ordinarily assumes a tetramer configuration that primarily serves to transport retinol-binding protein-vitamin A complex as well as thyroxine (to a small degree) in the blood. In TTR-related disorders such as TTR familial amyloid polyneuropathy (TTR-FAP), tetramer dissociation is accelerated and results in unregulated amyloidogenesis and amyloid fibril formation. The unwanted deposition of such formations in various tissues eventually contributes to the failure of autonomic and peripheral nervous system functions.
Tafamidis was approved by the European Medicines Agency (EMA) in 2011 under the market name Vyndaqel for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adult patients with early-stage symptomatic polyneuropathy to delay peripheral neurologic impairment. Tafamidis is an investigational drug under the FDA and - despite prior approval rejections in 2012 - in June 2017, Pfizer received FDA Fast Track Designation for tafamidis.
Tafamidis was developed by Jeffery W. Kelly in the company FoldRx that he had co-founded with Susan Lindquist of MIT and the Whitehead Institute. FoldRx was eventually acquired by Pfizer, who - despite the approval of tafamidis for use by the European Medicines Agency as well as in Japan - continues to run clinical trials to obtain formal FDA approval in the United States.
- External IDs
- FX-006 / FX-1005 / FX-1006 / FX006 / FX1006
- Product Ingredients
Ingredient UNII CAS InChI Key Tafamidis meglumine ZU7CF08A1A 951395-08-7 DQJDBUPLRMRBAB-WZTVWXICSA-N
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Vyndaqel Capsule 20 mg Oral Pfizer 2011-11-16 Not applicable Vyndaqel Capsule 20 mg Oral Pfizer 2011-11-16 Not applicable
- CAS number
- Average: 308.116
- Chemical Formula
- InChI Key
- IUPAC Name
- 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
Tafamidis is indicated for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment [Label].
Transthyretin (TTR), also referred to as prealbumin, is an endogenous, soluble, beta-sheet rich, 127-amino acid, non-glycosylated protein that is largely synthesized and secreted into the blood flow by the liver . This TTR circulates in the blood flow primarily in a tetramer configuration with only a very small amount of dissociated monomer . In the blood, TTR tetramer main functions generally revolve around binding retinol-binding protein bound to retinol (holo-retinol-binding protein) and a small amount of thyroxine, followed by transporting these substances to tissues . TTR tetramer consequently possesses two distinct dimer-dimer interfaces, the less stable of which comprises two highly conserved thyroxine binding sites . Despite possessing the ability to bind and transport thyroxine, less than 10% of the thyroxine in blood is bound to TTR, leaving more than 99% of the thyroxine binding sites in TTR unbound .
Tafamidis is consequently a rationally designed, non-NSAID benzoxazole derivative that specifically binds with high affinity and selectivity to the two typically vacant thyroxine binding sites on the native tetrameric form of TTR and functions to kinetically stabilize the tetramer, slowing monomer formation, misfolding, and amyloidogenesis . Given this rational design, tafamidis demonstrates effective target specificity, resulting in a low-toxicity profile and good patient tolerance .
Nevertheless, TTR dissociation into monomers in TTR familial amyloid polyneuropathy (TTR-FAP) is a progressive illness, a condition whose worsening can only be slowed - and not cured - by tafamidis therapy. The only formal treatment that can halt the progress of TTR-FAP is a liver transplant. General complications associated with transplant surgery including the inherent possibility for complications arising either during or as a result of the transplant procedure as well as the subsequent need for successful transplant patients to take various immune system suppressants to prevent long-term transplant organ rejection contribute to the natural risk associated with a liver transplant.
- Mechanism of action
Transthyretin (TTR) amyloid polyneuropathy (also known as TTR familial amyloid polyneuropathy, TTR-FAP) results from genetic mutations in the TTR gene that cause destabilization of ordinary TTR tetramers and/or speed up TTR tetramer dissociation into monomers . TTR-FAP itself is a multi-faceted, progressive, axonal degenerative neuropathy characterized by sensory, motor, and autonomic impairment [Label].
The dissociation of TTR tetramers to monomers is, in fact, the rate-limiting step in the pathogenesis of TTR-FAP [Label]. The folded monomers that comprise ordinary TTR tetramers undergo partial denaturation to produce alternatively folded monomeric amyloidogenic intermediates [Label]. These intermediates then misassemble into a variety of soluble oligomers, profilaments, filaments, and amyloid fibrils [Label]. These various undesired, soluble aggregates subsequently deposit upon tissues where they ultimately are not expected to be present or needed . In particular, studies demonstrating TTR's ability to influence nerve physiology by enhancing nerve regeneration in mouse models  emphasizes a potential function of TTR for nerve biology and repair that may assist in explaining why mutant TTR aggregrates preferentially deposit in the peripheral nervous system of patients with TTR-FAP .
Tafamidis is subsequently a rationally designed pharmaceutical that specifically binds non-cooperatively to the two thyroxine binding sites on the native tetrameric form of TTR to prevent its dissociation into monomers [Label]. Tafamidis is consequently formally considered to be a specific stabilizer of TTR, and its inhibition of TTR tetramer dissociation forms the rationale for its use as a treatment to slow - but not cure - the disease progression of TTR-FAP [Label].
Target Actions Organism ATransthyretinchaperone Humans
After oral administration of tafamidis soft capsule, the maximum plasma concentration (Cmax) is achieved at a median time (tmax) of 2 hours after dosing in the fasted state [Label]. Concomitant administration of food decreased the rate of absorption, but not the extent of absorption [Label]. These results support the administration of tafamidis with or without food [Label].
- Volume of distribution
The apparent steady-state volume of distribution is reported to be 25.7 liters [Label].
- Protein binding
Tafamidis is highly protein bound at 99.9% in plasma [Label].
Based on preclinical data, it is believed that tafamidis is primarily metabolized by glucuronidation and then excreted by way of the bile [Label].
- Route of elimination
In humans, about 59% of a total administered dose of tafamidis is recovered in the feces, and approximately 22% of the dose is recovered in the urine [Label].
- Half life
After daily administration of a 20mg tafamidis dose for fourteen days in healthy subjects, the mean steady-state half-life observed was 59 hours [Label].
After daily administration of a 20mg tafamidis dose for fourteen days in healthy subjects, the mean total clearance observed was 0.42 L/h [Label].
The most common adverse effects associated with taking tafamidis include urinary tract infection, vaginal infection, diarrhea, and upper abdominal pain [Label].
No cases of acute overdose have yet been reported [Label]. In clinical trials of healthy volunteers, the highest dose of tafamidis administrated was 480 mg in a single dose and 60 mg once daily for two weeks [Label]. The reported treatment-related adverse events were mild to moderate and included headache, somnolence, myalgia, insomnia, hordeolum, photosensitivity reaction, and presyncope [Label].
- Affected organisms
- Humans and other mammals
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
- General References
- Scott LJ: Tafamidis: a review of its use in familial amyloid polyneuropathy. Drugs. 2014 Aug;74(12):1371-8. doi: 10.1007/s40265-014-0260-2. [PubMed:25022953]
- Coelho T, Merlini G, Bulawa CE, Fleming JA, Judge DP, Kelly JW, Maurer MS, Plante-Bordeneuve V, Labaudiniere R, Mundayat R, Riley S, Lombardo I, Huertas P: Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis. Neurol Ther. 2016 Jun;5(1):1-25. doi: 10.1007/s40120-016-0040-x. Epub 2016 Feb 19. [PubMed:26894299]
- Fleming CE, Saraiva MJ, Sousa MM: Transthyretin enhances nerve regeneration. J Neurochem. 2007 Oct;103(2):831-9. doi: 10.1111/j.1471-4159.2007.04828.x. [PubMed:17897357]
- PFIZER RECEIVES FDA FAST TRACK DESIGNATION FOR TAFAMIDIS FOR TRANSTHYRETIN CARDIOMYOPATHY [Link]
- External Links
- ATC Codes
- N07XX08 — Tafamidis
- PDB Entries
- 3tct / 4his / 6fft
- FDA label
- Download (184 KB)
- Download (24.8 KB)
- Clinical Trials
Phase Status Purpose Conditions Count 1 Completed Basic Science Healthy Volunteers 8 1 Completed Basic Science TTR Cardiomyopathy 2 1 Recruiting Basic Science Healthy Volunteers 1 2 Active Not Recruiting Treatment Bilateral Knee Osteoarthritis 1 2 Completed Treatment Knee Osteoarthritis (Knee OA) 5 2 Completed Treatment Knee Osteoarthritis (Knee OA) / Type 2 Diabetes Mellitus 1 2 Completed Treatment Osteoarthritis of the Hip / Osteoarthritis of the Shoulder 1 2 Terminated Treatment Post-traumatic Osteoarthritis of the Knee 1 3 Active Not Recruiting Treatment ATTR-PN 1 3 Active Not Recruiting Treatment TTR-CM 1 3 Completed Treatment Knee Osteoarthritis (Knee OA) 2 3 Completed Treatment Transthyretin (TTR) Amyloid Cardiomyopathy 1 3 Completed Treatment Transthyretin Familial Amyloid Polyneuropathy 1 3 Recruiting Treatment Knee Osteoarthritis (Knee OA) 1 3 Recruiting Treatment Osteoarthritis, Hip 1 3 Recruiting Treatment Transthyretin (TTR) Amyloid Cardiomyopathy 1 Not Available Active Not Recruiting Not Available Transthyretin Familial Amyloid Poluneuropathy 1
- Not Available
- Not Available
- Dosage forms
Form Route Strength Capsule Oral 20 mg
- Not Available
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0323 mg/mL ALOGPS logP 3.91 ALOGPS logP 4.21 ChemAxon logS -4 ALOGPS pKa (Strongest Acidic) 3.73 ChemAxon pKa (Strongest Basic) -0.41 ChemAxon Physiological Charge -1 ChemAxon Hydrogen Acceptor Count 3 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 63.33 Å2 ChemAxon Rotatable Bond Count 2 ChemAxon Refractivity 84.69 m3·mol-1 ChemAxon Polarizability 29.74 Å3 ChemAxon Number of Rings 3 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon
- Predicted ADMET features
- Not Available
- Mass Spec (NIST)
- Not Available
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
- This compound belongs to the class of organic compounds known as phenyl-1,3-oxazoles. These are aromatic heterocyclic compounds containing a 1,3-oxazole substituted at one or more positions by a phenyl group.
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Sub Class
- Direct Parent
- Alternative Parents
- Benzoxazoles / Dichlorobenzenes / Aryl chlorides / Heteroaromatic compounds / Oxacyclic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds / Organooxygen compoundsOrganonitrogen compounds / Organochlorides / Organic oxides / Hydrocarbon derivatives show 4 more
- Phenyl-1,3-oxazole / Benzoxazole / 1,3-dichlorobenzene / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Heteroaromatic compoundCarboxylic acid derivative / Carboxylic acid / Oxacycle / Azacycle / Monocarboxylic acid or derivatives / Organopnictogen compound / Organic oxygen compound / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide / Organohalogen compound / Organochloride / Organonitrogen compound / Organooxygen compound / Aromatic heteropolycyclic compound show 15 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- 1,3-benzoxazoles, monocarboxylic acid, dichlorobenzene (CHEBI:78538)
- Pharmacological action
- General Function
- Identical protein binding
- Specific Function
- Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.
- Gene Name
- Uniprot ID
- Uniprot Name
- Molecular Weight
- 15886.88 Da
Drug created on October 17, 2016 15:30 / Updated on December 14, 2018 17:14