Study of ARO-AAT in Patients with Alpha-1 Antitrypsin Deficiency Associated Liver Dieseae (AATD)

Severe alpha1-antitrypsin (AAT) deficiency (PiZZ genotype) causes liver disease due to accumulation of the mutant Z protein (Z-AAT), which presents histologically as Z-AAT globules. An open-label, Phase 2 study (NCT03946449) that was presented as a later breaker talk at EASL by Pavel Strnad, analyzed the efficacy of AROAAT, an RNAi therapeutic aiming to suppress ZAAT synthesis. Serum Z-AAT was reduced after the first dose and sustained through 1 year (78-97% reductions). There was a substantial decrease in liver total Z-AAT protein at Week 24 (72-95%) and Week 48 (77-97%). All 9 patients had a decrease in the Z-AAT globules and sustained reductions in ALT and GGT. 6 of 9 patients had a ≥1-stage improvement in fibrosis at either Week 24 or 48. AROAAT was generally well tolerated. These data demonstrate that removal of the causative factor, ZAAT, in AATD liver disease allows clearance of accumulated Z-AAT and can result in fibrosis regression.