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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Autoimmune Hepatitis

Intervention / Treatment
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* Drug: zetomipzomib
* Drug: placebo
* Drug: zetomipzomib in open-label extension


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: zetomibzomib + standard-of-care (glucocorticoids)<br>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<br>* Subcutaneous injection of zetomipzomib with a target dose of 60 mg weekly<br>* Other names: KZR-616;|
| Placebo Comparator: placebo + standard-of-care (glucocorticoids)<br>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<br>* Subcutaneous injection of placebo<br>* Other names: sterile water for injection;|
| Experimental: zetomipzomib + standard-of care (glucocorticoids) open-label extension period<br>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<br>* Subcutaneous injection of zetomipzomib with a target dose of 60 mg weekly<br>* Other names: KZR-616;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunoproteasome inhibition, selective proteasome inhibition, disease flare, Liver enzymes, ALT (alanine aminotransferase), AST (aspartate aminotransferase), glucocorticoids, steroids