Transthyretin stabilization activity of the catechol-O-methyltransferase inhibitor tolcapone (SOM0226) in hereditary ATTR amyloidosis patients and asymptomatic carriers: proof-of-concept study#. (3rd April 2019)

• Record Type: Journal Article
• Authors: Gamez, Josep; Salvadó, María; Reig, Núria; Suñé, Pilar; Casasnovas, Carles; Rojas-Garcia, Ricard; Insa, Raúl
• Is Part Of: Amyloid. Volume 26:Number 2(2019)
• Page Start: 74
• Page End: 84
• Publication Date: 2019-04-03
• Subjects: Amyloidogenesis inhibitor -- tolcapone -- catechol O-methyltransferase inhibitors -- drug repositioning -- drug repurposing -- hereditary ATTR amyloidosis -- proof-of-concept -- transthyretin -- TTR aggregation -- TTR stabilization; Amyloidosis -- Periodicals; 616.3995
• DOI: 10.1080/13506129.2019.1597702
• Languages: English
• ISSNs: 1350-6129

Abstract

Abstract: 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. EudraCT trial number : 2014-001586-27 ClinicalTrials.gov Identifier : NCT02191826