title: Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis.
abstract: Transthyretin (TTR) transports the retinol-binding protein-vitamin A complex and is a minor transporter of thyroxine in blood. Its tetrameric structure undergoes rate-limiting dissociation and monomer misfolding, enabling TTR to aggregate or to become amyloidogenic. Mutations in the TTR gene generally destabilize the tetramer and/or accelerate tetramer dissociation, promoting amyloidogenesis. TTR-related amyloidoses are rare, fatal, protein-misfolding disorders, characterized by formation of soluble aggregates of variable structure and tissue deposition of amyloid. The TTR amyloidoses present with a spectrum of manifestations, encompassing progressive neuropathy and/or cardiomyopathy. Until recently, the only accepted treatment to halt progression of hereditary TTR amyloidosis was liver transplantation, which replaces the hepatic source of mutant TTR with the less amyloidogenic wild-type TTR. Tafamidis meglumine is a rationally designed, non-NSAID benzoxazole derivative that binds with high affinity and selectivity to TTR and kinetically stabilizes the tetramer, slowing monomer formation, misfolding, and amyloidogenesis. Tafamidis is the first pharmacotherapy approved to slow the progression of peripheral neurologic impairment in TTR familial amyloid polyneuropathy. Here we describe the mechanism of action of tafamidis and review the clinical data, demonstrating that tafamidis treatment slows neurologic deterioration and preserves nutritional status, as well as quality of life in patients with early-stage Val30Met amyloidosis.
authors.affiliation: Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal. tcoelho@netcabo.pt.
authors.forename: Teresa
authors.initials: T
authors.lastname: Coelho
authors.affiliation: Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.affiliation: Pfizer Rare Disease Research Unit, Cambridge, MA, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Bulawa
authors.affiliation: Pfizer Rare Disease Research Unit, Cambridge, MA, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Fleming
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.affiliation: The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.affiliation: Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Mathew S
authors.initials: MS
authors.lastname: Maurer
authors.affiliation: CHU Henri Mondor, Créteil, France.
authors.forename: Violaine
authors.initials: V
authors.lastname: Planté-Bordeneuve
authors.affiliation: Labaudiniere Consulting LLC, Lewes, DE, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Labaudinière
authors.affiliation: Pfizer Inc., New York, NY, USA.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Mundayat
authors.affiliation: Pfizer Inc., New York, NY, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Riley
authors.affiliation: FORUM Pharmaceuticals, Watertown, MA, USA.
authors.forename: Ilise
authors.initials: I
authors.lastname: Lombardo
authors.affiliation: Massachusetts General and McLean Hospitals, Harvard Medical School, Boston, MA, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Huertas
keywords: Familial amyloid cardiomyopathy; Familial amyloid polyneuropathy; Hereditary TTR amyloid cardiomyopathy; Pharmacology; Senile systemic amyloidosis; Therapeutic use; Wild-type TTR amyloidosis