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Amyloid. 2019 Jun;26(2):74-84. doi: 10.1080/13506129.2019.1597702. Epub 2019 May 23.

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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a 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.
b Research and Development Department , SOM Biotech, S.L , Barcelona , Spain.
c Pharmacy Department, Vall d'Hebron Research Institute (VHIR) , Hospital Universitari Vall d'Hebron , Barcelona , Spain.
d Neuromuscular Disorders Unit, Neurology Department , Bellvitge University Hospital - IDIBELL , Barcelona , Spain.
e 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.


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 Identifier: NCT02191826.


Amyloidogenesis inhibitor; TTR aggregation; TTR stabilization; catechol O-methyltransferase inhibitors; drug repositioning; drug repurposing; hereditary ATTR amyloidosis; proof-of-concept; tolcapone; transthyretin

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