Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis
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Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Coelho, T., G. Merlini, C. E. Bulawa, J. A. Fleming, D. P. Judge, J. W. Kelly, M. S. Maurer, et al. 2016. “Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis.” Neurology and Therapy 5 (1): 1-25. doi:10.1007/s40120-016-0040-x. http://dx.doi.org/10.1007/s40120-016-0040-x. Published Version doi:10.1007/s40120-016-0040-x Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:27822117 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Neurol Ther (2016) 5:1–25 DOI 10.1007/s40120-016-0040-x REVIEW Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis Teresa Coelho • Giampaolo Merlini • Christine E. Bulawa • James A. Fleming • Daniel P. Judge • Jeffery W. Kelly • Mathew S. Maurer • Violaine Plante´-Bordeneuve • Richard Labaudinie`re • Rajiv Mundayat • Steve Riley • Ilise Lombardo • Pedro Huertas To view enhanced content go to www.neurologytherapy-open.com Received: August 25, 2015 / Published online: February 19, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com ABSTRACT accelerate tetramer dissociation, promoting amyloidogenesis. TTR-related amyloidoses are Transthyretin (TTR) transports the rare, fatal, protein-misfolding disorders, retinol-binding protein–vitamin A complex characterized by formation of soluble and is a minor transporter of thyroxine in aggregates of variable structure and tissue blood. Its tetrameric structure undergoes deposition of amyloid. The TTR amyloidoses rate-limiting dissociation and monomer present with a spectrum of manifestations, misfolding, enabling TTR to aggregate or to encompassing progressive neuropathy and/or become amyloidogenic. Mutations in the TTR cardiomyopathy. Until recently, the only gene generally destabilize the tetramer and/or accepted treatment to halt progression of hereditary TTR amyloidosis was liver Electronic supplementary material The online transplantation, which replaces the hepatic version of this article (doi:10.1007/s40120-016-0040-x) source of mutant TTR with the less contains supplementary material, which is available to authorized users. amyloidogenic wild-type TTR. Tafamidis T. Coelho (&) M. S. Maurer Hospital de Santo Anto´nio, Centro Hospitalar do Columbia University College of Physicians and Porto, Porto, Portugal Surgeons, New York, NY, USA e-mail: [email protected] V. Plante´-Bordeneuve G. Merlini CHU Henri Mondor, Cre´teil, France Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy R. Labaudinie`re Labaudiniere Consulting LLC, Lewes, DE, USA C. E. Bulawa Á J. A. Fleming Pfizer Rare Disease Research Unit, Cambridge, MA, R. Mundayat Á S. Riley USA Pfizer Inc., New York, NY, USA D. P. Judge I. Lombardo Johns Hopkins University School of Medicine, FORUM Pharmaceuticals, Watertown, MA, USA Baltimore, MD, USA P. Huertas J. W. Kelly Massachusetts General and McLean Hospitals, The Scripps Research Institute, La Jolla, CA, USA Harvard Medical School, Boston, MA, USA 2 Neurol Ther (2016) 5:1–25 meglumine is a rationally designed, non-NSAID background, and extent of progression. benzoxazole derivative that binds with high Non-fibrillar aggregates and amyloid composed affinity and selectivity to TTR and kinetically of mutant and/or WT TTR of hepatic origin stabilizes the tetramer, slowing monomer accumulate in various tissues and organs, formation, misfolding, and amyloidogenesis. particularly the peripheral and autonomic Tafamidis is the first pharmacotherapy nerves and heart, leading to tissue damage and approved to slow the progression of peripheral end-organ failure [1–3]. TTR gene expression by neurologic impairment in TTR familial amyloid the choroid plexus and retinal pigmented polyneuropathy. Here we describe the epithelium leads to leptomeningeal and ocular mechanism of action of tafamidis and review degeneration linked to TTR amyloidogenesis, the clinical data, demonstrating that tafamidis respectively [4]. treatment slows neurologic deterioration and Tafamidis (2-(3,5-dichloro-phenyl)-benzoxazole- preserves nutritional status, as well as quality of 6-carboxylic acid) is a once-daily, orally life in patients with early-stage Val30Met bioavailable, non-NSAID small molecule, and amyloidosis. specific kinetic stabilizer of TTR [5]. In clinical studies, tafamidis slowed peripheral neurologic impairment and additional clinical Keywords: Familial amyloid cardiomyopathy; manifestations in patients with Val30Met Familial amyloid polyneuropathy; Hereditary amyloidosis and was associated with an TTR amyloid cardiomyopathy; Pharmacology; excellent safety profile [6–8]. Tafamidis is the Senile systemic amyloidosis; Therapeutic use; first pharmacotherapy approved to treat Wild-type TTR amyloidosis TTR-FAP in the European Union and several countries in Latin America and the Asia-Pacific INTRODUCTION including Argentina and Japan. The aim of this article is to focus on TTR as a The transthyretin (TTR)-related amyloidoses are drug target, to provide the rationale used in the rare, fatal protein misfolding and aggregation development of tafamidis, and review disorders. Historically, the TTR amyloidoses comprehensively the pharmacology of this were grouped into three categories: (1) disease-modifying therapy for TTR wild-type TTR amyloidosis (TTRwt), formerly amyloidoses. This article is based on known as senile systemic amyloidosis, previously conducted studies and does not presenting as a cardiomyopathy and involving involve any new studies of human or animal the aggregation of wild-type (WT) TTR; (2) subjects performed by any of the authors. familial amyloid polyneuropathy (FAP); and (3) hereditary TTR amyloid cardiomyopathy, formerly known as familial amyloid STRUCTURE AND FUNCTIONS cardiomyopathy (FAC). Both hereditary forms OF TTR involve aggregation of primarily mutant TTR. Current knowledge suggests that the TTR Transthyretin, also known as prealbumin, is a amyloidoses do not fit neatly into these soluble, b-sheet rich, 127-amino acid, categories, as patients often exhibit a spectrum non-glycosylated protein primarily synthesized of phenotypes depending on mutation, genetic and secreted into the blood by the liver. TTR Neurol Ther (2016) 5:1–25 3 circulates in the blood predominantly as a globulin has the highest affinity for T4 [28, 29]. 55 kDa tetramer, along with a very small Thus, given the low level of circulating T4,less amount of dissociated monomer [6]. than 10% of T4 in blood is bound to TTR and more The monomeric subunits of TTR fold into a than 99% of the T4 binding sites in circulating b-sandwich tertiary structure that TTR are vacant [21]. Thus, TTR is thought to play spontaneously assembles into a tetramer only a minor role in the physiological transport of within the cellular endoplasmic reticulum. The T4. In contrast, TTR is the primary T4 carrier in tetramer exhibits two distinct dimer–dimer cerebrospinal fluid [10]. interfaces, the less stable of which makes up In addition, transthyretin may be a natural two highly conserved thyroxine (T4) binding detoxifier, as its T4 binding sites bind small sites [9–13]. The three-dimensional structures of molecules with substituted aromatic rings the TTR tetramer bound to T4 and its other connected by linkers of variable chemical known ligand, the vitamin A–retinol-binding composition [30]. These structures include protein complex, have been solved [14–16]. stilbenes, flavones, benzoxazoles, Transthyretin is expressed from embryonic tetrahydroquinolines, dihydropyridines, development through adult life and its blood benzodiazepines, and phenoxazines [31, 32]. concentration over this time reflects those of Emerging evidence suggests that WT TTR may total body nitrogen and total body potassium also have a protective effect in Alzheimer’s levels [17]. Serum TTR concentration so closely disease through an interaction with the mimics the body’s nitrogen balance that it has amyloidogenic Ab-amyloid peptide [30]. TTR been widely used as a marker of malnutrition has also been shown to influence nerve and inflammation in several conditions [17–19]. physiology and to enhance nerve regeneration In fact, TTR is a negative acute phase reactant in the mouse [33]. A role for TTR in nerve [20]. In adult humans, plasma TTR biology and repair may explain the preferential concentrations range from 3 to 6 lM; the TTR deposition of mutant TTR aggregates in the concentration in cerebrospinal fluid is an order peripheral nervous system of patients with of magnitude lower (approximately 0.36 lM) TTR-FAP [33]. [21–23]. The half-life of TTR in vivo blood is 24–48 h [22, 24, 25]. MOLECULAR MECHANISM OF TTR In blood, the TTR tetramer binds AMYLOIDOGENESIS retinol-binding protein bound to retinol (holo-retinol-binding protein) and a small Experiments with cell lines and Drosophila amount of T4, and transports them to tissues on melanogaster model systems demonstrate the the minute-to-hour timescale [9, 26, 27]. proteotoxicity associated with various TTR Although TTR is the only known transporter of sequences linked to pathology [3, 34–39]. circulating holo-retinol-binding