Clinical trial NCT05569759: A Study of Zetomipzomib (KZR-616) in Patients With Autoimmune Hepatitis (PORTOLA)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Autoimmune Hepatitis
Keywords: immunoproteasome inhibition
selective proteasome inhibition
disease flare
Liver enzymes
ALT (alanine aminotransferase)
AST (aspartate aminotransferase)
glucocorticoids
steroids
Lead sponsor: Kezar Life Sciences, Inc.
Sponsor class: INDUSTRY
First posted: 2022-10-06
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: To evaluate the efficacy of zetomipzomib
timeFrame: Week 24
measure: To evaluate the safety and tolerability of zetomipzomib
timeFrame: Baseline through 28 weeks.
measure: To evaluate the efficacy of zetomipzomib during the open-label extension period
timeFrame: Start of open-label extension (OLE) period through End of Study (EOS) at OLE Week 29
Secondary outcomes:
measure: Alanine aminotransferase (ALT)
timeFrame: Weeks 12, 16, 20, and 24
measure: Partial Remission
timeFrame: Weeks 12, 16, 20, and 24
measure: Time to complete remission
timeFrame: Baseline through Week 24
measure: Time to partial remission
timeFrame: Baseline through Week 24
measure: Disease flare after CR
timeFrame: Week 24
measure: Treatment failures
timeFrame: Week 24
measure: Successful glucocorticoid taper
timeFrame: Week 24
Other outcomes:
measure: Plasma concentrations of zetomipzomib and its metabolites
timeFrame: Baseline through Week 16
measure: Plasma concentrations of zetomipzomib and its metabolites
timeFrame: Baseline through Week 16
measure: Plasma concentrations of zetomipzomib and its metabolites
timeFrame: Baseline through Week 16
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Los Angeles
country: United States
facility: Keck School of Medicine of USC
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Redwood City
country: United States
facility: Stanford Medicine
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Manhasset
country: United States
facility: Northwell Health Center for Liver Disease and Transplantation
state: New York
city: New York
country: United States
facility: New York University Langone Health/Grossman School of Medicine
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Indiana University
name: Craig Lammert, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Ethan Weinberg, MD
role: PRINCIPAL_INVESTIGATOR
References: