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

Study Overview

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

Detailed Description

This is 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 will be 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 will be administered subcutaneously (SC) once weekly.

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

Primary completion date represents the anticipated completion date of the double-blind portion of the study. Study completion date represents the anticipated completion date of the open-label extension portion of the study.

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

Contacts and Locations

• Study Contact: Name: Kezar Life Sciences, Inc.; Phone Number: (650) 822-5600; Email: PORTOLA@kezarbio.com

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Recruiting
      • Mayo Clinic Arizona
      • Contact: Hugo Vargas, MD
      • Principal Investigator: Hugo Vargas, MD
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California, Los Angeles
      • Contact: Sammy Saab, MD
      • Principal Investigator: Sammy Saab, MD
    • Los Angeles, California, United States, 90033
      • Recruiting
      • Keck School of Medicine of USC
      • Contact: Lily Dara, MD
      • Principal Investigator: Lily Dara, MD
    • Redwood City, California, United States, 94063
      • Recruiting
      • Stanford Medicine
      • Contact: Aparna Goel, MD
      • Principal Investigator: Aparna Goel, MD
    • San Francisco, California, United States, 94109
      • Recruiting
      • California Pacific Medical Center
      • Principal Investigator: Kidist Yimam, MD
      • Contact: Kidist Yimam, MD
    • San Francisco, California, United States, 94132
      • Recruiting
      • University of California, San Francisco
      • Contact: Michele Tana, MD
      • Principal Investigator: Michele Tana, MD
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado
      • Principal Investigator: Lisa Forman, MD
      • Contact: Lisa Forman, MD
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale University
      • Principal Investigator: Marina Silveira, MD
      • Contact: Marina Silveira, MD
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Mayo Clinic Florida
      • Contact: Surakit Pungpapong, MD
      • Principal Investigator: Surakit Pungpapong, MD
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami
      • Contact: Paul Martin, MD
      • Principal Investigator: Paul Martin, MD
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University
      • Contact: Josh Levitsky, MD
      • Principal Investigator: Josh Levitksy, MD
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • Rush University
      • Contact: Steven Flamm, MD
      • Principal Investigator: Steven Flamm, MD
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Indiana University
      • Contact: Craig Lammert, MD
      • Principal Investigator: Craig Lammert, MD
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Recruiting
      • Ochsner Clinic Foundation
      • Principal Investigator: George Therapondos, MD
      • Contact: George Therapondos, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Principal Investigator: Daniel Pratt, MD
      • Contact: Daniel Pratt, MD
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Beth Israel Deaconess Medical Center
      • Contact: Vilas Patwardhan, MD
      • Principal Investigator: Vilas Patwardhan, MD
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan Medical Center
      • Contact: Robert Fontana, MD
      • Principal Investigator: Robert Fontana, MD
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Kevin Korenblat, MD
      • Principal Investigator: Kevin Korenblat, MD
  • New York
    • Manhasset, New York, United States, 11030
      • Recruiting
      • Northwell Health Center for Liver Disease and Transplantation
      • Contact: Harmit Kalia, DO
      • Principal Investigator: Harmit Kalia, DO
    • New York, New York, United States, 10016
      • Recruiting
      • New York University Langone Health/Grossman School of Medicine
      • Contact: Raiya Sarwar, MD
      • Principal Investigator: Raiya Sarwar, MD
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke University Medical Center
      • Contact: Matthew Kappus, MD
      • Principal Investigator: Matthew Kappus, MD
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • University Hospitals Cleveland Medical Center
      • Principal Investigator: Seth Sclair, MD
      • Contact: Seth Sclair, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
      • Principal Investigator: Ethan Weinberg, MD
      • Contact: Ethan Weinberg, MD
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Recruiting
      • Virginia Commonwealth University
      • Contact: Sayed Aseem, MD
      • Principal Investigator: Sayed Aseem, MD

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 at 5 mg/day 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
Experimental: zetomibzomib + 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
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) 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 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
To evaluate the efficacy of zetomipzomib	Proportion of patients who achieve complete biochemical remission (CR) with successful glucocorticoid taper by Week 24.	Week 24
To evaluate the safety and tolerability of zetomipzomib	Proportion of patients who experience AEs (adverse events) and SAEs (serious adverse events), including incidence and severity of AEs and SAEs, incidence of AEs leading to drug discontinuation, and changes in laboratory parameters and vital signs.	Baseline through 28 weeks.
To evaluate the efficacy of zetomipzomib during the open-label extension period	Proportion of patients experiencing a disease flare among the patients who achieved a complete biochemical remission (CR) during the double-blind treatment period.	Start of open-label extension (OLE) period through End of Study (EOS) at OLE Week 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alanine aminotransferase (ALT)	Mean changes from baseline in alanine aminotransferase (ALT)	Week 24
Partial Remission	Proportion of patients who achieve a partial remission (PR)	Week 24
Time to complete remission	Time to complete remission (CR)	Baseline through Week 24
Time to partial remission	Time to partial remission (PR)	Baseline through Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentrations of zetomipzomib and its metabolites	Maximum plasma concentration [Cmax]	Baseline through Week 16
Plasma concentrations of zetomipzomib and its metabolites	Time of maximum plasma concentration [Tmax]	Baseline through Week 16
Plasma concentrations of zetomipzomib and its metabolites	Area under the concentration-time curve [AUC]	Baseline through Week 16

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 (Estimated): September 1, 2024
• Study Completion (Estimated): March 1, 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): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Liver enzymes; steroids; glucocorticoids; disease flare; immunoproteasome inhibition; selective proteasome inhibition; ALT (alanine aminotransferase); AST (aspartate aminotransferase)
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Immune System Diseases; Autoimmune Diseases; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis, Autoimmune
• 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