Transthyretin stabilization activity of the catechol-O-methyltransferase inhibitor tolcapone (SOM0226) in hereditary ATTR amyloidosis patients and asymptomatic carriers: proof-of-concept study

• Published in: Amyloid Vol. 26; no. 2; pp. 74 - 84
• Main Authors: Gamez, Josep, Salvadó, María, Reig, Núria, Suñé, Pilar, Casasnovas, Carles, Rojas-Garcia, Ricard, Insa, Raúl
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 03.04.2019
• Subjects: Adult; Aged; Amyloid Neuropathies, Familial - drug therapy; Amyloid Neuropathies, Familial - metabolism; Amyloidogenesis inhibitor; catechol O-methyltransferase inhibitors; Catechol O-Methyltransferase Inhibitors - therapeutic use; drug repositioning; drug repurposing; Female; hereditary ATTR amyloidosis; Humans; Male; Middle Aged; Mutation, Missense; Prealbumin - genetics; Prealbumin - metabolism; Proof of Concept Study; proof-of-concept; Protein Aggregation, Pathological - prevention & control; tolcapone; Tolcapone - pharmacology; Tolcapone - therapeutic use; transthyretin; TTR aggregation; TTR stabilization; drug repurposing; Amyloidogenesis inhibitor; tolcapone; transthyretin; TTR stabilization; proof-of-concept; catechol O-methyltransferase inhibitors; hereditary ATTR amyloidosis; drug repositioning; TTR aggregation
• ISSN: 1350-6129; 1744-2818; 1744-2818
• DOI: 10.1080/13506129.2019.1597702

Objective: To assess the transthyretin (TTR) stabilization activity of tolcapone (SOM0226) in patients with hereditary ATTR amyloidosis, asymptomatic carriers and healthy volunteers. Methods: A phase IIa proof-of-concept trial included two phases separated by a 6-week washout period. Phase A: single 200 mg dose of tolcapone; phase B: three 100 mg doses taken at 4 h intervals. The primary efficacy variable was TTR stabilization. Results: Seventeen subjects were included (wild type, n = 6; mutation TTR Val30Met, n = 11). TTR stabilization was observed in all participants. Two hours after dosing, 82% of participants in phase A and 93% of those in phase B reached a TTR stabilization value of at least 20%. In phase A, there was an increase of 52% in TTR stabilization vs baseline values 2 h after dosing, which decreased to 22.9% at 8 h. In phase B, there was a significant increase of 38.8% in TTR stabilization 2 h after the first 100 mg dose. This difference was maintained after 10 h and decreased after 24 h. No serious adverse events were observed. Conclusions: The ability of tolcapone for stabilizing TTR supports further development and repositioning of the drug for the treatment of ATTR amyloidosis. Trial registration: EudraCT identifier: 2014-001586-27 Trial registration: ClinicalTrials.gov identifier: NCT02191826.