CSF/plasma levels, transthyretin stabilisation and safety of multiple doses of tolcapone in subjects with hereditary ATTR amyloidosis

Abstract

Purpose

To investigate the effect of tolcapone on cerebrospinal fluid (CSF) transthyretin (TTR) tetramer stability in patients with hereditary transthyretin (ATTRv) amyloidosis.

Methods

A total of 9 patients were enrolled in the study (3 men, 50.3 ± 14.4 years old). Three patients had central nervous system (CNS) involvement. Patients were assigned to receive tolcapone 300 mg/day or 600 mg/day for 7 days. Plasma and CSF were collected at baseline and 2 h after the final tolcapone dose.

Results

The mean CSF tolcapone and 3-O-Methyltolcapone (3-OMT) concentration were 39.4 ± 36.3 ng/mL and 26.0 ± 4.9 ng/mL, respectively, after 7 days of tolcapone dosing. Tolcapone and 3-OMT were detected in the CSF of patients with or without CNS symptoms. The mean total study drug (tolcapone + 3-OMT) to TTR molar ratio in CSF was 1.15 ± 0.59. Orally administered tolcapone significantly increased CSF TTR concentration and decreased monomer content under semi-denaturing conditions. Eight adverse events (AEs) were reported in 6 patients. All AEs were mild in severity and resolved.

Conclusions

Tolcapone was able to cross the blood brain-barrier, highlighting its potential to decrease CNS manifestations of ATTRv amyloidosis. Tolcapone was well tolerated by patients with ATTRv amyloidosis.

Keywords:

• Hereditary ATTR amyloidosis
• transthyretin
• tolcapone
• cerebrospinal fluid
• cerebral amyloid angiopathy

Acknowledgments

The authors thank Gorica Malisanovic, MD, PhD and Yolaine Jeune-Smith, PhD for medical writing support of this manuscript.

Disclosure statement

Dr. Michael Roberts and Dr. Paul F. Glidden are consultants for and have equity ownership in Corino Therapeutics, Inc. Dr. Yoshiki Sekijima has received advisory fees from Corino Therapeutics, Inc.

Additional information

Funding

The study was supported by Corino Therapeutics, Inc.