A Study of Zetomipzomib (KZR-616) in Patients With Autoimmune Hepatitis (PORTOLA)

A Randomized, Double-blind, Placebo-controlled, Phase 2a Study With Open-label Extension to Evaluate the Safety and Efficacy of Zetomipzomib (KZR-616) in Patients With Autoimmune Hepatitis

This was a Phase 2a, multi-center, placebo-controlled study in which patients with autoimmune hepatitis received zetomipzomib or placebo in addition to standard-of-care for 24 weeks; an optional open-label extension period allowed participants to receive zetomipzomib (KZR-616) for an additional 24 weeks of treatment.

Study Overview

• Status: Completed
• Conditions: Autoimmune Hepatitis
• Intervention / Treatment: Drug: placebo; Drug: zetomipzomib; Drug: zetomipzomib in open-label extension

Detailed Description

This was a Phase 2a, multi-center, randomized, double-blind, placebo-controlled study with an open-label extension to evaluate safety, tolerability, and efficacy of zetomipzomib in patients with autoimmune hepatitis (AIH) who have not benefited from standard-of-care treatment, had an incomplete response to ≥3 months of standard-of-care treatment, or had a disease flare after standard of care.

Zetomipzomib or placebo were administered weekly for a 24-week treatment period in addition to standard-of-care (glucocorticoids), followed by a 4-week off-treatment safety follow-up period. Zetomipzomib and placebo was administered subcutaneously (SC) once weekly.

At the end of the 24-week treatment period, eligible participants from both the zetomipzomib- and placebo-treated arms who completed the double-blind treatment period could enroll in the open-label extension period to receive up to an additional 24 weeks of treatment with zetomipzomib.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • Los Angeles, California, United States, 90033
      • Keck School of Medicine of USC
    • Redwood City, California, United States, 94063
      • Stanford Medicine
    • San Francisco, California, United States, 94109
      • California Pacific Medical Center
    • San Francisco, California, United States, 94132
      • University of California, San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612
      • Rush University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Manhasset, New York, United States, 11030
      • Northwell Health Center for Liver Disease and Transplantation
    • New York, New York, United States, 10016
      • New York University Langone Health/Grossman School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria for the Double-blind Treatment Period:

• Must be aged ≥18 years.

  • Must have a clinical diagnosis of AIH and signs of active disease despite standard-of-care therapy for ≥3 months or disease flare after experiencing complete remission induced by standard-of-care treatment, including:

    • Screening ALT values that are 1.25 to 10 times the upper limit of the normal range (ULN)
    • Liver biopsy results with Ishak score (modified HAI) ≥5/18 indicating active AIH, from a biopsy performed at Screening, or within 6 months prior to Screening
    • Mild or no hepatic impairment (Child Pugh category A)
  • Must be willing to use and taper glucocorticoid therapy.
  • Must be willing to use effective contraception.

Key Exclusion Criteria for the Double-blind Treatment Period:

• Have a concomitant diagnosis of primary biliary sclerosis, primary sclerosing cholangitis, IgG 4 related cholangitis, drug related AIH (at Screening) or a history of drug-related AIH.
• Have clinical evidence of significant unstable or uncontrolled diseases other than the disease under study.
• Are receiving oral or injectable immunomodulating treatment for any other autoimmune disease prior to enrollment in the study. Patients who have been using such treatments must follow the specified washout periods.
• Have an active infection (eg, acute hepatitis E, cytomegalovirus, or Epstein-Barr virus) requiring systemic therapy with antibiotic, antiviral, or antifungal treatment, or has had any febrile illness within 7 days prior to Day -1.
• Have a history of thyroiditis, celiac disease, or other autoimmune disorder known to be associated with transaminitis.
• Have liver cirrhosis with significant impairment of liver function (Child Pugh category B or C) or have decompensated cirrhosis.
• Patients with histology confirmed coincident non-alcoholic steatohepatitis.

Key Inclusion Criteria for the Open-label Extension Period:

• Same as Double-blind Treatment Period inclusion criteria, except the following modifications:

  • ALT value can be normal or, if elevated, in the range of 1.25 to 10 times the upper limit of normal
• Must have completed the Double-blind Period study visits through Week 24, including all Week 24 Visit assessments.
• Must be willing to maintain glucocorticoid therapy or continue to taper glucocorticoid therapy.

Key Exclusion Criteria for the Open-label Extension Period:

• Same as Double-blind Treatment Period except no need to re-test for HIV, HBV, HCV, and TB.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo + standard-of-care (glucocorticoids); Initial 30 mg dose of placebo (sterile water for injection), followed by weekly 60 mg doses of placebo, for the remaining 23 weeks of the treatment period.	Drug: placebo; Subcutaneous injection of placebo; Other Names: sterile water for injection
Experimental: zetomipzomib + standard-of-care (glucocorticoids); Initial 30 mg dose of zetomipzomib, followed by weekly 60 mg doses of zetomipzomib, for the remaining 23 weeks of the treatment period.	Drug: zetomipzomib; Subcutaneous injection of zetomipzomib with a target dose of 60 mg weekly; Other Names: KZR-616
Experimental: zetomipzomib + standard-of care (glucocorticoids) open-label extension period; Initial 30 mg dose of zetomipzomib at the open-label extension (OLE) Week 1 visit, followed by weekly doses of 60 mg of zetomipzomib, for up to a total of 24 additional weeks of treatment.	Drug: zetomipzomib in open-label extension; Subcutaneous injection of zetomipzomib with a target dose of 60 mg weekly; Other Names: KZR-616

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients Who Achieved Complete Biochemical Response	The number of patients who achieve complete biochemical response (CR), defined as normal ALT, AST, and IgG values (if IgG level is elevated at Baseline) with glucocorticoid dose not higher than starting dose (at Baseline), by Week 24 of the Double-Blind Treatment Period. Analyses were also conducted at Week 12, Week 16, and Week 20.	Week 12, Week 16, Week 20, and Week 24
The Safety and Tolerability of Zetomipzomib	Proportion of participants who experience AEs (adverse events) and SAEs (serious adverse events) during the double-blind treatment period (DBTP) and the open-label extension (OLE).	Baseline through end of study visit (DBTP, Week 28 and OLE, Up to Week 24)
Proportion of Participants Experiencing a Disease Flare Among the Participants Who Achieved a CR During the Double-blind Treatment Period	Proportion of participants experiencing a disease flare among the participants who achieved a complete biochemical response (CR) during the double-blind treatment period.	Start of open-label extension (OLE) period through End of Study (EOS) up to OLE Week 25

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alanine Aminotransferase (ALT)	Changes from baseline in alanine aminotransferase (ALT) during the double-blind treatment period.	Weeks 12, 16, 20, and 24
Partial Response	Proportion of participants who achieved a partial response (PR) during the double-blind treatment period of the study.	Weeks 12, 16, 20, and 24
Time to Complete Response	Time to complete response (CR), defined as the duration from first dose of study drug (zetomipzomib or placebo) to first CR, during the double-blind treatment period was measured using the Kaplan-Meier method. Due to the small sample size, not enough events of participants achieving CR were observed to provide Kaplan-Meier estimates for the 25th percentile, median, and 75th percentile time to CR.	Baseline through Week 24
Disease Flare After CR	Proportion of participants who experienced a disease flare after complete response (CR) during the double-blind treatment period.	Week 24
Treatment Failures	Proportion of participants who were considered treatment failures, defined as ALT or AST level worsened ≥2 times that of the Baseline value that is sustained for ≥1 week as verified via repeat laboratory assessments, despite compliance with standard of care (ie, with regard to inclusion criteria) or protocol-defined therapy or a glucocorticoid dose is increased above the Baseline dose, it may be considered a treatment failure unless attributed to an adverse event not relating to AIH, during the double-blind treatment period.	Week 24
Complete Response With Glucocorticoid Taper to ≤10 mg	Percentage of participants who achieved complete response with successful glucocorticoid taper to ≤10 mg by Week 24 of the double-blind treatment period.	Weeks 12, 16, 20, and 24
Complete Response With Glucocorticoid Taper to ≤5 mg	Percentage of participants who achieved complete response and glucocorticoid taper to ≤5 mg by Week 24 of the double-blind treatment period.	Weeks 12, 16, 20, and 24
Complete Response With Glucocorticoid Taper to 0 mg	Percentage of participants who achieved complete response with glucocorticoid taper to 0 mg by Week 24 of the double-blind treatment period.	Weeks 12, 16, 20, and 24
Partial Response With Glucocorticoid Taper to ≤10 mg	Percentage of participants who achieved partial response with successful glucocorticoid taper to ≤10 mg by Week 24 of the double-blind treatment period.	Week 24
Partial Response With Glucocorticoid Taper to ≤5 mg	Percentage of participants who achieved partial response and glucocorticoid taper to ≤5 mg by Week 24 of the double-blind treatment period.	Week 24
Partial Response With Glucocorticoid Taper to 0 mg	Percentage of participants who achieved partial response with glucocorticoid taper to 0 mg by Week 24 of the double-blind treatment period.	Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Glucocorticoid Dose	Mean change from Baseline in glucocorticoid dose for participants during the double-blind treatment period at Weeks 12, 16, 20 and 24	Weeks 12, 16, 20, and 24

Collaborators and Investigators

• Sponsor: Kezar Life Sciences, Inc.
• Investigators: Principal Investigator: Craig Lammert, MD, Indiana University; Principal Investigator: Ethan Weinberg, MD, University of Pennsylvania

Publications and helpful links

Helpful Links

• Corporate website

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2023
• Primary Completion (Actual): April 30, 2025
• Study Completion (Actual): April 30, 2025

Study Registration Dates

• First Submitted: September 29, 2022
• First Submitted That Met QC Criteria: October 3, 2022
• First Posted (Actual): October 6, 2022

Study Record Updates

• Last Update Posted (Estimated): January 13, 2026
• Last Update Submitted That Met QC Criteria: December 19, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: steroids; glucocorticoids; liver enzymes; disease flare; immunoproteasome inhibition; selective proteasome inhibition; ALT (alanine aminotransferase); AST (aspartate aminotransferase)
• Additional Relevant MeSH Terms: Autoimmune Diseases; Immune System Diseases; Digestive System Diseases; Liver Diseases; Hepatitis, Chronic; Hepatitis; Hepatitis, Autoimmune; Therapeutics; Drug Administration Routes; Drug Therapy; Injections; KZR-616
• Other Study ID Numbers: KZR-616-208

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No