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Transthyretin stabilization activity of the catechol-O-methyltransferase inhibitor tolcapone (SOM0226) in hereditary ATTR amyloidosis patients and asymptomatic carriers: proof-of-concept study# |
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| Authors: | Josep Gamez María Salvadó Núria Reig Pilar Suñé Carles Casasnovas Ricard Rojas-Garcia |
| Affiliation: | 1. Neuromuscular Disorders Clinic, Department of Neurology, Vall d’Hebron University Hospital, VHIR, European Reference Network on Rare, Neuromuscular Disorders (ERN EURO-NMD), UAB, Barcelona, Spain;2. Research and Development Department, SOM Biotech, S.L, Barcelona, Spain;3. Pharmacy Department, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Barcelona, Spain;4. Neuromuscular Disorders Unit, Neurology Department, Bellvitge University Hospital – IDIBELL, Barcelona, Spain;5. Department of Neurology, Neuromuscular Diseases Unit Hospital de la Santa Creu i Sant Pau, Center for Networked Biomedical Research into Rare Diseases (CIBERER), UAB, Barcelona, Spain |
| 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 |
| Keywords: | Amyloidogenesis inhibitor tolcapone catechol O-methyltransferase inhibitors drug repositioning drug repurposing hereditary ATTR amyloidosis proof-of-concept transthyretin TTR aggregation TTR stabilization |