Tafamidis concentration required for transthyretin stabilisation in cerebrospinal fluid

Abstract

Background

Hereditary transthyretin (TTR) amyloidosis (ATTRv) initially presents as a polyneuropathy and/or a cardiomyopathy. Central nervous system (CNS) pathology in ATTRv amyloidosis, including focal neurological episodes, dementia, cerebrovascular bleeding, and seizures, appears around a decade later. Wild-type (WT) TTR amyloidosis (ATTRwt) causes a cardiomyopathy. CNS pathology risk likely also increases in these patients as cardiomyopathy progresses. Herein, we study tafamidis-mediated TTR kinetic stabilisation in cerebrospinal fluid (CSF).

Methods

Varying tafamidis concentrations (50–1000 nM) were added to CSF from healthy donors or ATTRv patients, and TTR stabilisation was measured via the decrease in dissociation rate.

Results

Tafamidis meglumine (Vyndaqel) can be dosed at 20 or 80 mg QD. The latter dose is bioequivalent to a 61 mg QD dose of tafamidis free acid (Vyndamax). The tafamidis CSF concentration in ATTRv patients on 20 mg Vyndaqel is ∼125 nM. By linear extrapolation, we expect a CSF concentration of ∼500 nM at the higher dose. When tafamidis is added to healthy donor CSF at 125 or 500 nM, the WT TTR dissociation rate decreases by 42% or 87%, respectively.

Conclusions

Tafamidis stabilises TTR in CSF to what is likely a clinically meaningful extent at CSF concentrations achieved by the normal tafamidis dosing regimen.

Keywords:

• Amyloid
• CNS amyloidosis
• kinetic stabilisation
• transthyretin
• tafamidis

Acknowledgments

We would like to acknowledge the team of neurologists, cardiologists, nephrologists and ophthalmologists who have carefully observed and followed the patients at the Unidade Corino de Andrade. In particular, we thank the physicians and nurses at Unidade Corino de Andrade who collected the CSF samples. Finally, we thank all the patients and their families for their willingness to participate and support this study.

Disclosure statement

J.W.K. and E.T.P. discovered tafamdis and receive sales royalties from Pfizer. J.W.K. was a paid consultant for and has received support for travel and accommodations from Pfizer, which sells tafamidis. T. C. 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. T. C. is a consultant for Pfizer, Alnylam, Ionis, and Prothena. T. C. 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 the National Institutes of Health grant DK046335 (J.W.K. and T.C.). Writing and editing support was provided by Emily P. Bentley.