Safety and Efficacy of Zetomipzomib in Relapsed or Insufficiently Responding Autoimmune Hepatitis: Results from the Randomised, Double-Blind, Placebo-Controlled, Phase 2a PORTOLA Study and Open-Label Extension

Background:&nbsp;Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disease with limited treatments and the need for glucocorticoid-sparing therapies. Zetomipzomib is a tripeptide ketoepoxide-based selective inhibitor of the immunoproteasome in development for AIH.&nbsp;<br><br>Methods:&nbsp;PORTOLA was a randomised, double-blind, placebo-controlled, phase 2a study conducted at 24 US academic centres 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 complete response. Participants completing the 24-week double-blind treatment period (DBTP) could enter a 24-week open-label extension (OLE). The primary endpoint was complete biochemical response (CR: normalisation of liver enzymes and immunoglobulin G [if elevated], with glucocorticoid dose ≤baseline) by week 24. Efficacy was assessed in the full analysis set (FAS) and steroid-based therapy subgroup (intention-to-treat [ITT] set); safety was evaluated in treated participants (NCT05569759).&nbsp;<br><br>Findings:&nbsp;Between April 20, 2023, and July 2, 2024, 24 participants were randomised; 23 received zetomipzomib (n=16) or placebo (n=7) and were in the FAS. By week 24, CR occurred in 8/16 (50%) zetomipzomib and 3/7 (42·9%) placebo participants (difference vs placebo: 7·1% [95% CI; -38·5, 48·3]). In the steroid-based therapy subgroup (ITT, n=21), 8/14 (57·1%) zetomipzomib and 2/7 (28·6%) placebo participants achieved CR (28·6%; -20·2, 65·4); only zetomipzomib participants achieved CR with steroid taper to ≤5 mg/day (6 [42·9%]; 42·9%&nbsp;&nbsp;[-5·7, 71·1]) and 0 mg/day (4 [28·6%]; 28·6% [-15·7, 58·1]). Common adverse events (AEs) in the DBTP were injection site reactions (ISRs; 15/16 [93·8%] zetomipzomib; 4/7 [57·1%] placebo) and systemic injection reactions (SIRs; 12/16 [75%]; 1/7 [14·3%]). Serious AEs occurred in two zetomipzomib and one placebo participant, all unrelated to study drug. During the OLE, ISRs and SIRs remained most frequent, with no serious AEs reported.&nbsp;<br><br>Interpretation:&nbsp;Zetomipzomib demonstrated higher CR rates than placebo, with evidence of steroid-sparing activity, warranting evaluation in larger randomised studies.&nbsp;Funding&nbsp;Kezar Life Sciences