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

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.

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.