Tafamidis

Identification

Name
Tafamidis
Accession Number
DB11644
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
Synonyms
  • Tafamidis
  • Tafamidisum
External IDs
FX-006 / FX-1005 / FX-1006 / FX006 / FX1006
Product Ingredients
IngredientUNIICASInChI Key
Tafamidis meglumineZU7CF08A1A951395-08-7DQJDBUPLRMRBAB-WZTVWXICSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VyndaqelCapsule20 mgOralPfizer2011-11-16Not applicableEu
VyndaqelCapsule20 mgOralPfizer2011-11-16Not applicableEu
Categories
UNII
8FG9H9D31J
CAS number
594839-88-0
Weight
Average: 308.116
Monoisotopic: 306.980298509
Chemical Formula
C14H7Cl2NO3
InChI Key
TXEIIPDJKFWEEC-UHFFFAOYSA-N
InChI
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)
IUPAC Name
2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
SMILES
OC(=O)C1=CC2=C(C=C1)N=C(O2)C1=CC(Cl)=CC(Cl)=C1

Pharmacology

Indication

Tafamidis is indicated for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment [Label].

Pharmacodynamics

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 [2]. This TTR circulates in the blood flow primarily in a tetramer configuration with only a very small amount of dissociated monomer [2]. 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 [2]. TTR tetramer consequently possesses two distinct dimer-dimer interfaces, the less stable of which comprises two highly conserved thyroxine binding sites [2]. 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 [2].

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 [2]. Given this rational design, tafamidis demonstrates effective target specificity, resulting in a low-toxicity profile and good patient tolerance [2].

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 [2]. 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 [2]. In particular, studies demonstrating TTR's ability to influence nerve physiology by enhancing nerve regeneration in mouse models [3] 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 [2].

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].

TargetActionsOrganism
ATransthyretin
chaperone
Humans
Absorption

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].

Metabolism

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].

Clearance

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].

Toxicity

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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. 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]
  2. 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]
  3. 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]
  4. PFIZER RECEIVES FDA FAST TRACK DESIGNATION FOR TAFAMIDIS FOR TRANSTHYRETIN CARDIOMYOPATHY [Link]
External Links
KEGG Drug
D09673
PubChem Compound
11001318
PubChem Substance
347828016
ChemSpider
9176510
BindingDB
50197883
ChEBI
78538
ChEMBL
CHEMBL2103837
HET
3MI
Wikipedia
Tafamidis
ATC Codes
N07XX08 — Tafamidis
PDB Entries
3tct / 4his / 6fft
FDA label
Download (184 KB)
MSDS
Download (24.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers8
1CompletedBasic ScienceTTR Cardiomyopathy2
1RecruitingBasic ScienceHealthy Volunteers1
2Active Not RecruitingTreatmentBilateral Knee Osteoarthritis1
2CompletedTreatmentKnee Osteoarthritis (Knee OA)5
2CompletedTreatmentKnee Osteoarthritis (Knee OA) / Type 2 Diabetes Mellitus1
2CompletedTreatmentOsteoarthritis of the Hip / Osteoarthritis of the Shoulder1
2TerminatedTreatmentPost-traumatic Osteoarthritis of the Knee1
3Active Not RecruitingTreatmentATTR-PN1
3Active Not RecruitingTreatmentTTR-CM1
3CompletedTreatmentKnee Osteoarthritis (Knee OA)2
3CompletedTreatmentTransthyretin (TTR) Amyloid Cardiomyopathy1
3CompletedTreatmentTransthyretin Familial Amyloid Polyneuropathy1
3RecruitingTreatmentKnee Osteoarthritis (Knee OA)1
3RecruitingTreatmentOsteoarthritis, Hip1
3RecruitingTreatmentTransthyretin (TTR) Amyloid Cardiomyopathy1
Not AvailableActive Not RecruitingNot AvailableTransthyretin Familial Amyloid Poluneuropathy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral20 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0323 mg/mLALOGPS
logP3.91ALOGPS
logP4.21ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)3.73ChemAxon
pKa (Strongest Basic)-0.41ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area63.33 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity84.69 m3·mol-1ChemAxon
Polarizability29.74 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Oxazoles
Direct Parent
Phenyl-1,3-oxazoles
Alternative Parents
Benzoxazoles / Dichlorobenzenes / Aryl chlorides / Heteroaromatic compounds / Oxacyclic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds
show 4 more
Substituents
Phenyl-1,3-oxazole / Benzoxazole / 1,3-dichlorobenzene / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Heteroaromatic compound
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
1,3-benzoxazoles, monocarboxylic acid, dichlorobenzene (CHEBI:78538)

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Chaperone
General Function
Identical protein binding
Specific Function
Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.
Gene Name
TTR
Uniprot ID
P02766
Uniprot Name
Transthyretin
Molecular Weight
15886.88 Da

Drug created on October 17, 2016 15:30 / Updated on December 14, 2018 17:14