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

<b>Objective:</b> To assess the transthyretin (TTR) stabilization activity of tolcapone (SOM0226) in patients with hereditary ATTR amyloidosis, asymptomatic carriers and healthy volunteers. <b>Methods:</b> 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. <b>Results:</b> Seventeen subjects were included (wild type, <i>n</i> = 6; mutation TTR Val30Met, <i>n</i> = 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. <b>Conclusions:</b> The ability of tolcapone for stabilizing TTR supports further development and repositioning of the drug for the treatment of ATTR amyloidosis. <b>Trial registration:</b> EudraCT identifier: 2014-001586-27 <b>Trial registration:</b>ClinicalTrials.gov identifier: NCT02191826.