Tafamidis polyneuropathy amelioration requires modest increases in transthyretin stability even though increases in plasma native TTR and decreases in non-native TTR do not predict response

Abstract

Background

TTR aggregation causes hereditary transthyretin (TTR) polyneuropathy (ATTRv-PN) in individuals with destabilised TTR variants. ATTRv-PN can be treated with ligands that bind TTR and prevent aggregation. One such ligand, tafamidis, is widely approved to treat ATTRv-PN. We explore how TTR stabilisation markers relate to clinical efficacy in 210 ATTRv-PN patients taking tafamidis.

Methods

TTR concentration in patient plasma was measured before and after tafamidis treatment using assays for native or combined native + non-native TTR. TTR tetramer dissociation kinetics, which are slowed by tafamidis binding, were also measured.

Results

Native TTR levels increased by 56.8% while combined native + non-native TTR levels increased by 3.1% after 24 months of tafamidis treatment, implying that non-native TTR decreased. Accordingly, the fraction of native TTR increased from 0.54 to 0.71 with tafamidis administration. Changes in native and non-native TTR levels were uncorrelated with clinical response to tafamidis. TTR tetramer dissociation generally slowed to an extent consistent with ∼40% of TTR being tafamidis-bound. Male non-responders had a lower extent of binding.

Conclusions

Native and non-native TTR concentration changes cannot be used as surrogate measures for therapeutic efficacy. Also, successful tafamidis therapy requires only moderate TTR stabilisation. Male patients may benefit from higher tafamidis doses.

Keywords:

• Amyloid
• hereditary TTR amyloid polyneurophathy (ATTRv-PN)
• kinetic stabilisation
• tafamidis
• transthyretin (TTR)

Acknowledgments

We thank the team of doctors that have followed the patients at the Unidade Corino de Andrade, especially Ana Martins da Silva, Maria Cristina Alves, Marcio Cardoso, and Luis Maia. We thank the nurses who collected the patient blood samples, especially Susana Ferrerira and the study coordinators Katia Valdrez, Inês Cardoso, and Alexandra Sousa. We are particularly grateful to the patients and their families for participating in the study.

Disclosure statement

JWK and ETP discovered tafamidis and receive royalty payments for its sales. JWK was a founder and shareholder in FoldRx, which first developed tafamidis as a therapeutic. JWK is a paid consultant for and has received support for travel and accommodations from Pfizer, which sells tafamidis. TC has participated as an investigator in clinical trials for FoldRx, Pfizer, Alnylam, Ionis, and Prothena that were paid per protocol to Centro Hospitilar do Porto. TC is a consultant for Pfizer, Alnylam, Ionis, and Prothena. TC has been supported for travel, accommodation, and registration for scientific meetings by Pfizer, Alnylam, Ionis and Biogen.

Additional information

Funding

This work was supported by an American Heart Association Predoctoral fellowship and an Ellen Browning Scripps Foundation fellowship to C. M. and by an NIH grant to J. W. K. and T. C. (DK 046335).