Zetomipzomib Shows Promise for Autoimmune Hepatitis in Phase 2a PORTOLA Trial

Kezar Life Sciences has announced positive topline results from the PORTOLA phase 2a clinical trial of zetomipzomib in patients with autoimmune hepatitis (AIH).1

According to a March 25, 2025, press release from the company, treatment with zetomipzomib resulted in steroid-sparing biochemical remissions in accordance with AASLD treatment guidelines in a difficult-to-treat, refractory AIH patient population.1

“I am impressed by the totality of efficacy and safety data from the PORTOLA study,” said Gideon Hirschfield, Chair of Autoimmune Liver Disease Research and Director of the Francis Family Liver Clinic, at the Toronto General Hospital.1 “Zetomipzomib represents a potent and targeted therapy for patients, and I believe these results will positively contribute to the design of a registrational trial of zetomipzomib in AIH, where patients are in need of better treatment options.”

A novel, first-in-class selective immunoproteasome inhibitor, zetomipzomib is thought to have broad therapeutic potential across multiple autoimmune diseases, with preclinical research demonstrating that selective immunoproteasome inhibition results in a broad anti-inflammatory response in animal models of several autoimmune diseases while avoiding immunosuppression. Additionally, data generated from completed clinical trials suggest zetomipzomib exhibits a favorable safety and tolerability profile for development in severe, chronic autoimmune diseases.1

Zetomipzomib was previously being explored in lupus nephritis in the phase 2b PALIZADE clinical, which was placed on clinical hold and later terminated following the recommendation of the IDMC after its assessment of 4 Grade 5 serious adverse events (SAEs) that occurred in patients enrolled in the Philippines and Argentina.2

PORTOLA is a placebo-controlled, randomized, double-blind phase 2a clinical trial evaluating the efficacy and safety of zetomipzomib in patients with AIH who are insufficiently responding to standard of care or have relapsed from a previous complete biochemical response (CR). The trial enrolled 24 patients who were randomly assigned in a 2:1 ratio to receive 60 mg of zetomipzomib or placebo in addition to background therapy for 24 weeks, with a protocol-suggested steroid taper.1

All patients were required to receive a starting daily steroid dose of 20-40 mg/day of prednisone (or budesonide equivalent), and physicians were encouraged to taper daily steroid usage to 5 mg/day, consistent with AIH treatment guidelines established by the AASLD.1

The primary efficacy endpoint of PORTOLA, which was not powered for efficacy, evaluated the proportion of patients who achieved CR by week 24, measured as normalization of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and Immunoglobulin G (IgG) values if elevated at baseline, with steroid dose levels not exceeding baseline.1

Results showed that, consistent with the AASLD treatment goals, zetomipzomib treatment resulted in greater rates of CR combined with reduction of steroid dosage to 5 mg/day or less, compared with placebo.1

In the ITT population, without regard to steroid taper, 50.0% of zetomipzomib patients achieved a CR compared with 37.5% of placebo patients. Additionally, 31.3% of zetomipzomib patients achieved both a CR and steroid taper to 5 mg/day or less compared with 12.5% of placebo patients. While 18.8% of zetomipzomib patients achieved both a CR and complete steroid withdrawal to zero mg/day, this was not achieved in any (0%) placebo patients.1

Investigators noted the median duration of response in zetomipzomib patients achieving a CR was 27.6 weeks, including the ongoing open-label extension, and no disease flares were reported in any zetomipzomib-treated patient achieving CR.1

In a prespecified subgroup analysis of patients who entered the study on a steroid-based therapy at the time of screening, without regard to a steroid taper, 57.1% of zetomipzomib patients achieved a CR compared with 28.6% of placebo patients. Additionally, 35.7% of patients in the zetomipzomib arm achieved a CR and steroid taper to ≤ 5 mg/day compared with 0% of placebo patients, and 21.4% of patients on zetomipzomib achieved a CR and complete steroid withdrawal to zero mg/day compared with 0% of placebo patients.1

According to the press release from Kezar, treatment-emergent adverse events (TEAEs) were seen in all patients, with injection site reactions being the most commonly reported TEAE in both arms. Systemic injection reactions, with onset occurring 8-24 hours post-dose and usually resolving within 48 hours, were all Grade 1 and Grade 2.1

Of note, 3 patients experienced treatment-emergent SAEs: 1 in the placebo arm, a Grade 3 variceal bleeding with hematemesis and atrial fibrillation; and 2 in the zetomipzomib arm, a Grade 3 fever occurring after the week 24 liver biopsy, and a Grade 3 influenza infection that fully resolved during the study. All SAEs were considered unrelated to study treatment, and all 3 patients completed the double-blind treatment period.1

“We are pleased to announce these exciting results from the PORTOLA trial, the first successful randomized study in treatment-refractory AIH,” said Chris Kirk, CEO and co-founder of Kezar.1 “We are encouraged by the safety and efficacy data in this difficult-to-treat patient population, specifically durable and steroid-sparing remissions experienced by patients treated with zetomipzomib. We are eager to work with the FDA Division of Hepatology and Nutrition to remove the partial clinical hold and align on an appropriate trial design to demonstrate the clinical benefit of zetomipzomib in AIH.”

References

1. Kezar Life Sciences. Kezar Life Sciences Announces Positive Topline Results from the PORTOLA Phase 2a Trial Evaluating Zetomipzomib for the Treatment of Patients with Autoimmune Hepatitis (AIH) and Reports Fourth Quarter and Year End 2024 Financial Results. March 25, 2025. Accessed March 25, 2025. https://ir.kezarlifesciences.com/news-releases/news-release-details/kezar-life-sciences-announces-positive-topline-results-portola

2. Kezar Life Sciences. Kezar Life Sciences Announces Positive IDMC Safety Review of PORTOLA Trial of Zetomipzomib in Patients with Autoimmune Hepatitis and Provides PALIZADE Update. October 17, 2024. Accessed March 25, 2025. https://ir.kezarlifesciences.com/news-releases/news-release-details/kezar-life-sciences-announces-positive-idmc-safety-review