Skip to main content

Long-term treatment of transthyretin familial amyloid polyneuropathy with tafamidis: a clinical and neurophysiological study

Abstract

Tafamidis is a transthyretin (TTR) stabilizer recently approved to slow the neurologic impairment in TTR familial amyloid polyneuropathy (TTR-FAP). The pivotal studies on Tafamidis reported encouraging results on the short term, in the early onset Val30Met-TTR-FAP patients at an early stage of the neuropathy. However, the effect of the drug in the non-Val30Met patients, at a more advanced stage of the disease and on the long term, is less known. In this study, we report the effect of Tafamidis in 43 TTR-FAP patients with a variety of pathogenic mutations, including 53% of non-Val30Met variants, at different stages of neuropathy followed on the long term. General and neurological assessment was performed in a standardized protocol every 6–12 months along with neurophysiological variables, including testing of small nerve fibres. The mean follow-up under treatment was 2 years with a subset of 26 patients treated for 3 years. Overall, Tafamidis was well tolerated. A significant clinical deterioration of the neuropathy and the patient’s general condition was observed across the 3 years follow-up, although neurophysiological parameters remained stable for the first 2 years. In contrast, patients had a significant increase of BMI under treatment. Deterioration of the neuropathy correlated to an older age at disease onset or treatment initiation and to poor clinical status at baseline. A higher BMI at baseline was associated with a lower progression of the neuropathy. About one-third of the patients who received 3 years of tafamidis had still preserved walking capacity or good clinical condition, suggesting that tafamidis slowed the disease progression in some patients. Overall, our work shows that tafamidis is well tolerated in TTR-FAP but does not prevent the steady progression of the neuropathy on the long term. Age, neurologic status, and general condition at baseline appear to be best predictors of tafamidis efficacy on the neurological function.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. 1.

    Gertz MA, Benson MD, Dyck PJ, Grogan M, Coelho T, Cruz M et al (2015) Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol 66:2451–2466

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Planté-Bordeneuve V, Said G (2011) Familial amyloid polyneuropathy. Lancet Neurol 10:1086–1097

    Article  PubMed  Google Scholar 

  3. 3.

    Lefaucheur JP, Ng Wing Tin S, Kerschen P, Damy T, Planté-Bordeneuve V (2013) Neurophysiological markers of small fibre neuropathy in TTR-FAP mutation carriers. J Neurol 260:1497–1503

    Article  PubMed  Google Scholar 

  4. 4.

    Holmgren G, Steen L, Ekstedt J, Groth CG, Ericzon BG, Eriksson S et al (1991) Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet 40:242–246

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Holmgren G, Ericzon BG, Groth CG, Steen L, Suhr O, Andersen O et al (1993) Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 341:1113–1116

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Benson MD (2013) Liver transplantation and transthyretin amyloidosis. Muscle Nerve 47:157–162

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Ericzon BG, Wilczek HE, Larsson M, Wijayatunga P, Stangou A, Pena JR et al (2015) Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative? Transplantation 99:1847–1854

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Tasaki M, Ueda M, Obayashi K, Koike H, Kitagawa K, Ogi Y et al (2013) Effect of age and sex differences on wild-type transthyretin amyloid formation in familial amyloidotic polyneuropathy: a proteomic approach. Int J Cardiol 170:69–74

    Article  PubMed  Google Scholar 

  9. 9.

    Johnson SM, Connelly S, Fearns C, Powers ET, Kelly JW (2012) The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. J Mol Biol 421:185–203

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Coelho T, Maia LF, Martins da Silva A, Waddington Cruz M, Planté-Bordeneuve V, Lozeron P et al (2012) Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 79:785–792

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Coelho T, Maia LF, da Silva AM, Cruz MW, Planté-Bordeneuve V, Suhr OB et al (2013) Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol 260:2802–2814

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Lozeron P, Théaudin M, Mincheva Z, Ducot B, Lacroix C, Adams D et al (2013) Effect on disability and safety of Tafamidis in late onset of Met30 transthyretin familial amyloid polyneuropathy. Eur J Neurol 20:1539–1545

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Merlini G, Planté-Bordeneuve V, Judge DP, Schmidt H, Obici L, Perlini S et al (2013) Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis. J Cardiovasc Transl Res 6:1011–1020

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Dyck PJ, Davies JL, Litchy WJ, O’Brien PC (1997) Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort. Neurology 49:229–239

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Steen L, Ek B (1983) Familial amyloidosis with polyneuropathy. A long-term follow-up of 21 patients with special reference to gastrointestinal symptoms. Acta Med Scand 214:387–397

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Yates JW, Chalmer B, McKegney FP (1980) Evaluation of patients with advanced cancer using the Karnofsky performance status. Cancer 45:2220–2224

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Lefaucheur JP, Wahab A, Planté-Bordeneuve V, Sène D, Ménard-Lefaucheur I, Rouie D et al (2015) Diagnosis of small fiber neuropathy: a comparative study of five neurophysiological tests. Neurophysiol Clin 45:445–455

    Article  PubMed  Google Scholar 

  18. 18.

    Ng Wing Tin S, Planté-Bordeneuve V, Salhi H, Goujon C, Damy T, Lefaucheur JP (2015) Characterization of pain in familial amyloid polyneuropathy. J Pain 16:1106–1114

    Article  PubMed  Google Scholar 

  19. 19.

    Mariani LL, Lozeron P, Théaudin M, Mincheva Z, Signate A, Ducot B et al (2015) French familial amyloid polyneuropathies network (CORNAMYL) study group. Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France. Ann Neurol 78:901–916

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Ando Y, Sekijima Y, Obayashi K, Yamashita T, Ueda M, Misumi Y et al (2016) 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

    Article  PubMed  Google Scholar 

  21. 21.

    Cortese A, Vita G, Luigetti M, Russo M, Bisogni G, Sabatelli M et al (2016) Monitoring effectiveness and safety of Tafamidis in transthyretin amyloidosis in Italy: a longitudinal multicenter study in a non-endemic area. J Neurol 263:916–924

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T et al (2013) Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 310:2658–2667

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Adams D, Coelho T, Obici L, Merlini G, Mincheva Z, Suanprasert N et al (2015) Rapid progression of familial amyloidotic polyneuropathy: a multinational natural history study. Neurology 85:675–682

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Suanprasert N, Berk JL, Benson MD, Dyck PJ, Klein CJ, Gollob JA et al (2014) Retrospective study of a TTR FAP cohort to modify NIS + 7 for therapeutic trials. J Neurol Sci 344:121–128

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Violaine Planté-Bordeneuve.

Ethics declarations

Conflicts of interest

Daniel Azoulay, Philippe Le Corvoisier, Cyrille Feray, Tarik Nordine, Jean Pascal Lefaucheur: None. Samar S. Ayache: travel grants or compensation from Genzyme, Biogen, Novartis, and Roche. Hayet Salhi: travel expenses from Pfizer, LFB. Farida Gorram: grants from Pfizer. Thibaud Damy: travel expense Pfizer; consultancy Alnylam, Ionis, Pfizer. Violaine Planté-Bordeneuve: travel expenses from Pfizer, Alnylam; Consultancy, Ionis, Pfizer; speaking fees from Pfizer, Prothena.

Ethical standards

The study was approved by our local Ethic commitee.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Planté-Bordeneuve, V., Gorram, F., Salhi, H. et al. Long-term treatment of transthyretin familial amyloid polyneuropathy with tafamidis: a clinical and neurophysiological study. J Neurol 264, 268–276 (2017). https://doi.org/10.1007/s00415-016-8337-3

Download citation

Keywords

  • Amyloidosis
  • Longitudinal study
  • Neurophysiology
  • Peripheral neuropathy
  • Response
  • Small nerve fibres
  • Transthyretin
  • Genetics
  • Treatment