Safety and efficacy of zetomipzomib in relapsed or insufficiently responding autoimmune hepatitis: Results from the randomized, double-blind, placebo-controlled, phase 2a PORTOLA study and open-label extension.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disease with limited treatments and a need for glucocorticoid-sparing therapies. Zetomipzomib is a selective immunoproteasome inhibitor in development for AIH. APPROACH AND RESULTS: PORTOLA was a randomized, double-blind, placebo-controlled, phase 2a trial at 24 US centers evaluating weekly subcutaneous zetomipzomib (60 mg) versus placebo in adults with AIH and active disease despite ≥3 months of standard-of-care therapy or flare after remission. Participants completing the 24-week period could enter a 24-week open-label extension (OLE). The primary endpoint was complete biochemical remission [CR: normalized liver enzymes and immunoglobulin G (if elevated), glucocorticoid dose ≤baseline] by week 24, assessed in the full analysis set (FAS) and steroid-based subgroup [intention-to-treat (ITT)]; safety was evaluated in all treated participants (NCT05569759). Between April 20, 2023, and July 2, 2024, 24 participants were randomized; 23 (zetomipzomib n=16, placebo n=7) comprised the FAS. By week 24, CR occurred in 50% zetomipzomib and 42.9% placebo participants (difference: 7.1% [95% CI: -38.5, 48.3]); 37.5% of zetomipzomib participants achieved CR with a steroid taper to ≤5 mg/day versus 14.3% with placebo. In the ITT steroid-based subgroup (n=21), CR occurred in 57.1% zetomipzomib versus 28.6% placebo participants (28.6%; -20.2, 65.4); only zetomipzomib participants achieved CR with taper to ≤5 mg/day (42.9%). Common adverse events (AEs) were injection site reactions (93.8% vs. 57.1%) and systemic injection reactions (75% vs. 14.3%). Three zetomipzomib participants (18.8%) discontinued due to AEs; serious AEs occurred in 2 zetomipzomib and 1 placebo participant, not drug-related. OLE safety was consistent, with no serious AEs. CONCLUSION: Zetomipzomib resulted in numerically higher CR rates than placebo, with evidence of steroid-sparing activity in a difficult-to-treat population, and warrants evaluation in larger randomized studies.