Cerebrospinal fluid and vitreous body exposure to orally administered tafamidis in hereditary ATTRV30M (p.TTRV50M) amyloidosis patients

Abstract

Hereditary transthyretin (TTR) amyloidosis associated with the TTRV30M (p.TTRV50M) mutation presents predominantly as an axonal polyneuropathy, with variable involvement of other organs. Serious central nervous system (CNS) and eye manifestations, including stroke, dementia, vitreous opacities and glaucoma, have been reported in untreated V30M TTR amyloidosis patients, and in these patients after treatment with liver transplantation (LT). Distinct therapies for V30M TTR amyloidosis developed during the last decade exhibit promising results in slowing the peripheral and autonomic nervous system pathology. However, the effect of these therapies on the CNS and eye manifestations of V30M TTR amyloidosis is not known. Herein, we show that in a small cohort of patients taking tafamidis orally (20 mg tafamidis meglumine daily) we could detect this small molecule in the cerebrospinal fluid (CSF) and the vitreous body. In the CSF, the ratio of TTR tetramer to tafamidis was ≈2:1, leading to a moderate kinetic stabilization of TTR in the CSF of these patients. Our data suggest that tafamidis can cross the CSF–blood and eye–blood barriers. Future studies comparing CNS and eye manifestations in patients treated with LT, kinetic stabilizers or TTR lowering drugs are essential to understand the clinical effect of our observations.

Keywords:

• ATTRV30M amyloidosis
• familial amyloid polyneuropathy
• CNS amyloid angiopathy
• eye amyloidosis

Disclosure statement

J.W.K. receives royalties related to tafamidis sales and sales milestones. T.C. has received funding from Pfizer Inc., Alnylam Pharmaceuticals and Ionis Pharmaceuticals for scientific meeting expenses (travel, accommodation and registration), and received honoraria from Pfizer Inc. and Alnylam Pharmaceuticals for training. C.M., A.M.S., N.F., J.M. and M.N. declare that they have no competing conflict of interest.

Additional information

Funding

This work was supported by an American Heart Association Pre-doctoral Fellowship awarded to C.M. [16PRE31130009] and critical National Institutes of Health support to J.W.K. [DK 46335].