We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Tafamidis for the treatment of transthyretin amyloidosis

    Massimiliano Lorenzini

    University College London Institute for Cardiovascular Science & Barts Heart Centre, St Bartholomew's Hospital, London, UK

    Cardiology, Department of Experimental, Diagnostic & Specialty Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy

    &
    Perry M Elliott

    *Author for correspondence:

    E-mail Address: perry.elliott@ucl.ac.uk

    University College London Institute for Cardiovascular Science & Barts Heart Centre, St Bartholomew's Hospital, London, UK

    Published Online:https://doi.org/10.2217/fca-2018-0078

    Transthyretin (TTR) related cardiomyopathy is an underdiagnosed cause of heart failure but is increasingly recognized in various settings – from patients admitted with heart failure to symptomatic aortic stenosis – and is rapidly becoming the most frequent form of systemic amyloidosis. Following the recent publication of the landmark ATTR-ACT trial that showed tafamidis to be the first treatment to improve survival in patients with TTR-related cardiac amyloidosis and heart failure, we reviewed the drug's rationale, characteristics and evidence supporting its use in TTR amyloidosis.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet 387(10038), 2641–2654 (2016).
    • 2 Ando Y, Coelho T, Berk JL et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J. Rare Dis. 8(1), 1–18 (2013).
    • 3 Maurer MS, Schwartz JH, Gundapaneni B et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N. Engl. J. Med. 379(11), 1007–1016 (2018). •• Landmark randomized controlled trial investigating the effect of tafamidis on survival and CV hospitalizations in transthyretin (TTR) related cardiomyopathy.
    • 4 Dickson PW, Aldred AR, Marley PD, Tu GF, Howlett GJ, Schreiber G. High prealbumin and transferrin mRNA levels in the choroid plexus of rat brain. Biochem. Biophys. Res. Commun. 127(3), 890–895 (1985).
    • 5 Foss TR, Wiseman RL, Kelly JW. The pathway by which the tetrameric protein transthyretin dissociates. Biochemistry 44(47), 15525–15533 (2005).
    • 6 Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve 36(4), 411–423 (2007).
    • 7 Bartalena L, Robbins J. Thyroid hormone transport proteins. Clin. Lab. Med. 13(3), 583–598 (1993).
    • 8 Schreiber G, Southwell BR, Richardson SJ. Hormone delivery systems to the brain – transthyretin. Exp. Clin. Endocrinol. Diabetes 103(2), 75–80 (1995).
    • 9 Johnson SM, Wiseman RL, Sekijima Y, Green NS, Adamski-Werner SL, Kelly JW. Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses. Acc. Chem. Res. 38(12), 911–921 (2005).
    • 10 Hurshman AR, White JT, Powers ET, Kelly JW. Transthyretin aggregation under partially denaturing conditions is a downhill polymerization. Biochemistry 43(23), 7365–7381 (2004).
    • 11 Reixach N, Deechongkit S, Jiang X, Kelly JW, Buxbaum JN. Tissue damage in the amyloidoses: transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc. Natl Acad. Sci. USA 101(9), 2817–2822 (2004).
    • 12 Coelho T, Maia LF, Martins da Silva A et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 79(8), 785–792 (2012). • Randomized controlled trial of tafamidis for the treatment of TTR-related neuropathy in patients with V30M mutation.
    • 13 Hou X, Aguilar M-I, Small DH. Transthyretin and familial amyloidotic polyneuropathy. FEBS J. 274(7), 1637–1650 (2007).
    • 14 Hammarstrom P, Jiang X, Hurshman AR, Powers ET, Kelly JW. Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity. Proc. Natl Acad. Sci. USA 99(Suppl. 4), 16427–16432 (2002).
    • 15 Zhao L, Buxbaum JN, Reixach N. Age-related oxidative modifications of transthyretin modulate its amyloidogenicity. Biochemistry 52(11), 1913–1926 (2013).
    • 16 Mutations in hereditary amyloidosis. Mutations in transthyretin gene (TTR). http://amyloidosismutations.com/mut-attr.php
    • 17 Conceição I, De Carvalho M. Clinical variability in type I familial amyloid polyneuropathy (Val30Met): comparison between late- and early-onset cases in Portugal. Muscle Nerve 35(1), 116–118 (2007).
    • 18 Ikeda S, Nakazato M, Ando Y, Sobue G. Familial transthyretin-type amyloid polyneuropathy in Japan: clinical and genetic heterogeneity. Neurology 58(7), 1001–1007 (2002).
    • 19 Suhr OB, Svendsen IH, Andersson R, Danielsson A, Holmgren G, Ranløv PJ. Hereditary transthyretin amyloidosis from a Scandinavian perspective. J. Intern. Med. 254(3), 225–235 (2003).
    • 20 Rapezzi C, Quarta CC, Obici L et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur. Heart J. 34(7), 520–528 (2013).
    • 21 Quarta CC, Buxbaum JN, Shah AM et al. The amyloidogenic V122I transthyretin variant in elderly Black Americans. N. Engl. J. Med. 372(1), 21–29 (2015).
    • 22 Ando Y, Nakamura M, Araki S. Transthyretin-related familial amyloidotic polyneuropathy. Arch. Neurol. 62(7), 1057 (2005).
    • 23 Sattianayagam PT, Hahn AF, Whelan CJ et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur. Heart J. 33(9), 1120–1127 (2012).
    • 24 Koike H, Misu K, Ikeda S et al. Type I (transthyretin Met30) familial amyloid polyneuropathy in Japan: early- vs late-onset form. Arch. Neurol. 59(11), 1771–1776 (2002).
    • 25 Koike H, Tanaka F, Hashimoto R et al. Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from nonendemic areas. J. Neurol. Neurosurg. Psychiatry 83(2), 152–158 (2012).
    • 26 Rapezzi C, Riva L, Quarta CC et al. Gender-related risk of myocardial involvement in systemic amyloidosis. Amyloid 15(1), 40–48 (2008).
    • 27 Suhr OB, Lundgren E, Westermark P. One mutation two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition. J. Intern. Med. 281(4), 337–347 (2017).
    • 28 González-López E, Gagliardi C, Dominguez F et al. Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths. Eur. Heart J. 38(24), 1895–1904 (2017).
    • 29 Connors LH, Sam F, Skinner M et al. Heart failure resulting from age-related cardiac amyloid disease associated with wild-type transthyretin: a prospective, observational cohort study. Circulation 133(3), 282–290 (2016).
    • 30 Martinez-Naharro A, Treibel T, Abdel-Gadir A et al. Magnetic resonance in transthyretin cardiac amyloidosis. J. Am. Coll. Cardiol. 70(4), 466–477 (2017).
    • 31 Quarta CC, Solomon SD, Uraizee I et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation 129(18), 1840–1849 (2014).
    • 32 Rapezzi C, Quarta CC, Riva L et al. Transthyretin-related amyloidoses and the heart: a clinical overview. Nat. Rev. Cardiol. 7(7), 398–408 (2010).
    • 33 de Carvalho M, Conceição I, Bentes C, Luís MLS. Long-term quantitative evaluation of liver transplantation in familial amyloid polyneuropathy (Portuguese V30M). Amyloid 9(2), 126–133 (2002).
    • 34 Okamoto S, Wixner J, Obayashi K et al. Liver transplantation for familial amyloidotic polyneuropathy: impact on Swedish patients' survival. Liver Transplant. 15(10), 1229–1235 (2009).
    • 35 Saelices L, Chung K, Lee JH et al. Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition. Proc. Natl Acad. Sci. USA 115(29), E6741–E6750 (2018).
    • 36 Stangou AJ, Hawkins PN, Heaton ND et al. Progressive cardiac amyloidosis following liver transplantation for familial amyloid polyneuropathy: implications for amyloid fibrillogenesis. Transplantation 66(2), 229–233 (1998).
    • 37 Coelho T, Chorão R, Sousa A, Alves I, Torres MF, Saraiva MJM. Compound heterozygotes of transthyretin Met30 and transthyretin Met119 are protected from the devastating effects of familial amyloid polyneuropathy. Neuromuscul. Disord. 6, S20 (1996).
    • 38 Longo Alves I, Hays MT, Saraiva MJM. Comparative stability and clearance of [Met30]transthyretin and [Met119]transthyretin. Eur. J. Biochem. 249(3), 662–668 (1997).
    • 39 Hammarström P, Wiseman RL, Powers ET, Kelly JW. Prevention of transthyretin arnyloid disease by changing protein misfolding energetics. Science 299(5607), 713–716 (2003).
    • 40 White JT, Kelly JW. Support for the multigenic hypothesis of amyloidosis: the binding stoichiometry of retinol-binding protein, vitamin A, and thyroid hormone influences transthyretin amyloidogenicity in vitro. Proc. Natl Acad. Sci. USA 98(23), 13019–13024 (2001).
    • 41 Sekijima Y, Dendle MA, Kelly JW. Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid 13(4), 236–249 (2006).
    • 42 Bulawa CE, Connelly S, Devit M et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc. Natl Acad. Sci. USA 109(24), 9629–9634 (2012). • In vitro and ex vivo evidence of the effect of tafamidis on TTR.
    • 43 European Medicines Agency summary of the European public assessment report (EPAR) for Vyndaqel. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002294/human_med_001498.jsp&mid=WC0b01ac058001d124
    • 44 Suhr O, Danielsson A, Holmgren G, Steen L. Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy. J. Intern. Med. 235(5), 479–485 (1994).
    • 45 Coelho T, Maia LF, Da Silva AM et al. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J. Neurol. 260(11), 2802–2814 (2013).
    • 46 Merlini G, Planté-Bordeneuve V, Judge DP et al. Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis. J. Cardiovasc. Transl. Res. 6(6), 1011–1020 (2013).
    • 47 Barroso FA, Judge DP, Ebede B et al. Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years. Amyloid 24(3), 194–204 (2017).
    • 48 Yukio A, Yoshiki S, Konen O et al. Effects of tafamidis treatment on transthyretin (TTR) stabilization, efficacy, and safety in Japanese patients with familial amyloid polyneuropathy (TTR-FAP) with Val30Met and non-Varl30Met: a Phase III, open-label study. J. Neurol. Sci. 362, 266–271 (2016).
    • 49 Conceição I, Miranda B, Castro J, de Carvalho M. Hereditary amyloidosis related to transthyretin V30M: disease progression in treated and untreated patients. Eur. J. Neurol. 25(11), 1320-e115 (2018).
    • 50 Mundayat R, Stewart M, Alvir J et al. Positive effectiveness of tafamidis in delaying disease progression in transthyretin familial amyloid polyneuropathy up to 2 years: an analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS). Neurol. Ther. 7, 87–101 (2018).
    • 51 Maurer MS, Grogan DR, Judge DP et al. Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes. Circ. Heart Fail. 8(3), 519–526 (2015).
    • 52 Ruberg FL, Maurer MS, Judge DP et al. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am. Heart J. 164(2), 222.e1–228.e1 (2012).
    • 53 Sultan MB, Gundapaneni B, Schumacher J, Schwartz JH. Treatment with tafamidis slows disease progression in early-stage transthyretin cardiomyopathy. Clin. Med. Insights Cardiol. 11, 1–4 (2017).
    • 54 Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the analysis of composite end points in clinical trials based on clinical priorities. Eur. Heart J. 33(2), 176–182 (2012). • Clear explanation of a novel method to optimize the analysis of composite end points in clinical trials.
    • 55 Gillmore JD, Maurer MS, Falk RH et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 133(24), 2404–2412 (2016). •• Multicenter study that provided the evidence basis for reaching a definitive diagnosis of TTR-related cardiac amyloidosis noninvasively.
    • 56 Longhi S, Lorenzini M, Gagliardi C et al. Coexistence of degenerative aortic stenosis and wild-type transthyretin-related cardiac amyloidosis. JACC Cardiovasc. Imaging 9(3), 325–327 (2016).
    • 57 Castano A, Narotsky DL, Hamid N et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur. Heart J. 38(38), 2879–2887 (2017).
    • 58 Cavalcante JL, Rijal S, Abdelkarim I et al. Cardiac amyloidosis is prevalent in older patients with aortic stenosis and carries worse prognosis. J. Cardiovasc. Magn. Reson. 19(1), 98 (2017).
    • 59 Adams D, Gonzalez-Duarte A, O'Riordan WD et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379(1), 11–21 (2018).
    • 60 Benson MD, Waddington-Cruz M, Berk JL et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N. Engl. J. Med. 379(1), 22–31 (2018).
    • 61 Solomon SD, Adams D, Kristen A et al. Effects of patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis: an analysis of the APOLLO Study. Circulation 139(4), 431–443 (2018).