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
Craig S. Lammert, Ethan M. Weinberg, Seth N. Sclair, Robert J. Fontana, Neel K. Anand, Janet L. Anderl, David Bade, Shraddha Desai, Christopher J. Kirk, Diana Lam, Eric Lowe, Tony Muchamuel, Kiruthi Palaniswamy, Rachel Peterson, Kathryn Ray, Zung To, Brian B. Tuch, Jennifer A. Whang, Aparna Goel,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.