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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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          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.

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          Journal
          Amyloid
          Amyloid
          Informa UK Limited
          1350-6129
          1744-2818
          April 03 2019
          May 23 2019
          April 03 2019
          : 26
          : 2
          : 74-84
          Affiliations
          [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
          Article
          10.1080/13506129.2019.1597702
          31119947
          4d45d74f-7668-4347-a9f8-a9075b13029a
          © 2019
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