Autoimmune Hepatitis
Conditions
Keywords
immunoproteasome inhibition, selective proteasome inhibition, disease flare, liver enzymes, ALT (alanine aminotransferase), AST (aspartate aminotransferase), glucocorticoids, steroids
Brief summary
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.
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.
Interventions
DRUGzetomipzomib
Subcutaneous injection of zetomipzomib with a target dose of 60 mg weekly
DRUGplacebo
Subcutaneous injection of placebo
DRUGzetomipzomib in open-label extension
Subcutaneous injection of zetomipzomib with a target dose of 60 mg weekly
Sponsors
Kezar Life Sciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Experiencing a Disease Flare Among the Participants Who Achieved a CR During the Double-blind Treatment Period | Start of open-label extension (OLE) period through End of Study (EOS) up to OLE Week 25 | Proportion of participants experiencing a disease flare among the participants who achieved a complete biochemical response (CR) during the double-blind treatment period. |
| Patients Who Achieved Complete Biochemical Response | Week 12, Week 16, Week 20, and Week 24 | 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. |
| The Safety and Tolerability of Zetomipzomib | Baseline through end of study visit (DBTP, Week 28 and OLE, Up to Week 24) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Complete Response | Baseline through Week 24 | 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. |
| Disease Flare After CR | Week 24 | Proportion of participants who experienced a disease flare after complete response (CR) during the double-blind treatment period. |
| Treatment Failures | Week 24 | 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. |
| Complete Response With Glucocorticoid Taper to ≤10 mg | Weeks 12, 16, 20, and 24 | Percentage of participants who achieved complete response with successful glucocorticoid taper to ≤10 mg by Week 24 of the double-blind treatment period. |
| Complete Response With Glucocorticoid Taper to 0 mg | Weeks 12, 16, 20, and 24 | Percentage of participants who achieved complete response with glucocorticoid taper to 0 mg by Week 24 of the double-blind treatment period. |
| Partial Response With Glucocorticoid Taper to ≤10 mg | Week 24 | Percentage of participants who achieved partial response with successful glucocorticoid taper to ≤10 mg by Week 24 of the double-blind treatment period. |
| Partial Response With Glucocorticoid Taper to ≤5 mg | Week 24 | Percentage of participants who achieved partial response and glucocorticoid taper to ≤5 mg by Week 24 of the double-blind treatment period. |
| Partial Response With Glucocorticoid Taper to 0 mg | Week 24 | Percentage of participants who achieved partial response with glucocorticoid taper to 0 mg by Week 24 of the double-blind treatment period. |
| Complete Response With Glucocorticoid Taper to ≤5 mg | Weeks 12, 16, 20, and 24 | Percentage of participants who achieved complete response and glucocorticoid taper to ≤5 mg by Week 24 of the double-blind treatment period. |
| Alanine Aminotransferase (ALT) | Weeks 12, 16, 20, and 24 | Changes from baseline in alanine aminotransferase (ALT) during the double-blind treatment period. |
| Partial Response | Weeks 12, 16, 20, and 24 | Proportion of participants who achieved a partial response (PR) during the double-blind treatment period of the study. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glucocorticoid Dose | Weeks 12, 16, 20, and 24 | Mean change from Baseline in glucocorticoid dose for participants during the double-blind treatment period at Weeks 12, 16, 20 and 24 |
Countries
United States
Participant flow
Pre-assignment details
The randomization stratification factor for the study was use of glucocorticoids at Screening (ie, glucocorticoid use, no glucocorticoid use at Screening).
Participants by arm
| Arm | Count |
|---|---|
| Zetomipzomib + Standard-of-care (Glucocorticoids) Participants received an initial 30 mg dose of zetomipzomib, followed by weekly 60 mg doses of zetomipzomib, for the remaining 23 weeks of the double-blind treatment period in addition to standard of care.
Participants who completed the double-blind treatment period could elect to continue in the open-label extension (OLE) period of the study. Participants who enrolled in the OLE period received an initial 30 mg dose of zetomipzomib at the OLE Week 1 visit, followed by weekly doses of 60 mg of zetomipzomib in addition to standard of care, for up to a total of 24 additional weeks of treatment.
zetomipzomib: Subcutaneous injection of zetomipzomib with a target dose of 60 mg weekly | 16 |
| Placebo + Standard-of-care (Glucocorticoids) Participants received an 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 double-blind treatment period in addition to standard of care.
placebo: Subcutaneous injection of placebo
Participants who completed the double-blind treatment period could elect to continue in the open-label extension (OLE) period of the study. Participants who enrolled in the OLE period received an initial 30 mg dose of zetomipzomib at the OLE Week 1 visit, followed by weekly doses of 60 mg of zetomipzomib in addition to standard of care, for up to a total of 24 additional weeks of treatment. | 7 |
| Total | 23 |
Baseline characteristics
| Characteristic | Zetomipzomib + Standard-of-care (Glucocorticoids) | Placebo + Standard-of-care (Glucocorticoids) | Total |
|---|---|---|---|
| Age, Continuous | 54.4 years STANDARD_DEVIATION 15.6 | 48.9 years STANDARD_DEVIATION 19.7 | 52.7 years STANDARD_DEVIATION 16.7 |
| Baseline ALT | 106.7 U/L STANDARD_DEVIATION 49 | 143.4 U/L STANDARD_DEVIATION 75.2 | 117.9 U/L STANDARD_DEVIATION 59 |
| Baseline AST | 79.5 U/L STANDARD_DEVIATION 50.4 | 107.0 U/L STANDARD_DEVIATION 40.6 | 87.8 U/L STANDARD_DEVIATION 48.4 |
| Baseline IgG | 1865.3 mg/dL STANDARD_DEVIATION 842.5 | 1985.1 mg/dL STANDARD_DEVIATION 579.2 | 1901.7 mg/dL STANDARD_DEVIATION 760.7 |
| Baseline IgG (Abnormal at Baseline) | 2396.7 mg/dL STANDARD_DEVIATION 751.8 | 2213.0 mg/dL STANDARD_DEVIATION 514.5 | 2331.1 mg/dL STANDARD_DEVIATION 661.5 |
| Duration of AIH | 5.5 years STANDARD_DEVIATION 5.9 | 8.3 years STANDARD_DEVIATION 7.6 | 6.3 years STANDARD_DEVIATION 6.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 6 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Glucocorticoid Dose at Baseline | 21.3 mg/day STANDARD_DEVIATION 3.4 | 20.0 mg/day STANDARD_DEVIATION 0 | 20.9 mg/day STANDARD_DEVIATION 2.9 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian Indian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Chinese | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Filipino | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Guamanian or Chamorro | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Japanese | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Korean | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Multi-Racial | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Samoan | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Vietnamese | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 13 Participants | 6 Participants | 19 Participants |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 13 Participants |
| Sex: Female, Male Male | 8 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 7 | 0 / 9 | 0 / 5 |
| other Total, other adverse events | 16 / 16 | 7 / 7 | 9 / 9 | 5 / 5 |
| serious Total, serious adverse events | 2 / 16 | 1 / 7 | 0 / 9 | 0 / 5 |
Outcome results
Primary
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.
Time frame: Week 12, Week 16, Week 20, and Week 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Patients Who Achieved Complete Biochemical Response | Week 12 | 6 Participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Patients Who Achieved Complete Biochemical Response | Week 16 | 7 Participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Patients Who Achieved Complete Biochemical Response | Week 20 | 8 Participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Patients Who Achieved Complete Biochemical Response | Week 24 | 8 Participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Patients Who Achieved Complete Biochemical Response | Week 24 | 3 Participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Patients Who Achieved Complete Biochemical Response | Week 12 | 3 Participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Patients Who Achieved Complete Biochemical Response | Week 20 | 3 Participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Patients Who Achieved Complete Biochemical Response | Week 16 | 3 Participants |
Primary
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.
Time frame: Start of open-label extension (OLE) period through End of Study (EOS) up to OLE Week 25
Population: Participants who enrolled in the optional open-label extension following their completion of the double-blind treatment period of the study and achieved a complete response during the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Proportion of Participants Experiencing a Disease Flare Among the Participants Who Achieved a CR During the Double-blind Treatment Period | 0 participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Proportion of Participants Experiencing a Disease Flare Among the Participants Who Achieved a CR During the Double-blind Treatment Period | 0 participants |
Primary
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).
Time frame: Baseline through end of study visit (DBTP, Week 28 and OLE, Up to Week 24)
Population: The Safety Set (N=23) includes all participants who received at least one dose of IMP and were analyzed as randomized to treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | The Safety and Tolerability of Zetomipzomib | Serious adverse events | 2 participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | The Safety and Tolerability of Zetomipzomib | Adverse events | 16 participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | The Safety and Tolerability of Zetomipzomib | Adverse events | 7 participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | The Safety and Tolerability of Zetomipzomib | Serious adverse events | 1 participants |
| Open-label Extension: Zetomipzomib + standard-of Care (Glucocorticoids) (Zetomipzomib in DBTP) | The Safety and Tolerability of Zetomipzomib | Serious adverse events | 0 participants |
| Open-label Extension: Zetomipzomib + standard-of Care (Glucocorticoids) (Zetomipzomib in DBTP) | The Safety and Tolerability of Zetomipzomib | Adverse events | 9 participants |
| Open-label Extension: Zetomipzomib + standard-of Care (Glucocorticoids) (Placebo in DBTP) | The Safety and Tolerability of Zetomipzomib | Serious adverse events | 0 participants |
| Open-label Extension: Zetomipzomib + standard-of Care (Glucocorticoids) (Placebo in DBTP) | The Safety and Tolerability of Zetomipzomib | Adverse events | 5 participants |
Secondary
Alanine Aminotransferase (ALT)
Changes from baseline in alanine aminotransferase (ALT) during the double-blind treatment period.
Time frame: Weeks 12, 16, 20, and 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Alanine Aminotransferase (ALT) | Week 12 | -49.8 U/L | Standard Deviation 67.1 |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Alanine Aminotransferase (ALT) | Week 16 | -46.4 U/L | Standard Deviation 70.4 |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Alanine Aminotransferase (ALT) | Week 20 | -29.4 U/L | Standard Deviation 100.8 |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Alanine Aminotransferase (ALT) | Week 24 | -22.8 U/L | Standard Deviation 103.5 |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Alanine Aminotransferase (ALT) | Week 24 | -80.6 U/L | Standard Deviation 58 |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Alanine Aminotransferase (ALT) | Week 12 | -47.3 U/L | Standard Deviation 116.5 |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Alanine Aminotransferase (ALT) | Week 20 | -33.3 U/L | Standard Deviation 113.4 |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Alanine Aminotransferase (ALT) | Week 16 | -65.8 U/L | Standard Deviation 81.7 |
Secondary
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.
Time frame: Weeks 12, 16, 20, and 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg | By Week 12 | 6.3 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg | By Week 16 | 6.3 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg | By Week 20 | 12.5 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg | By Week 24 | 25.0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg | By Week 24 | 0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg | By Week 12 | 0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg | By Week 20 | 0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg | By Week 16 | 0 percent of participants |
Secondary
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.
Time frame: Weeks 12, 16, 20, and 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg | By Week 12 | 18.8 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg | By Week 16 | 37.5 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg | By Week 20 | 43.8 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg | By Week 24 | 43.8 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg | By Week 24 | 25.0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg | By Week 12 | 25.0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg | By Week 20 | 25.0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg | By Week 16 | 25.0 percent of participants |
Secondary
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.
Time frame: Weeks 12, 16, 20, and 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg | By Week 12 | 12.5 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg | Be Week 16 | 25.0 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg | By Week 20 | 37.5 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg | By Week 24 | 37.5 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg | By Week 24 | 12.5 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg | By Week 12 | 0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg | By Week 20 | 12.5 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg | Be Week 16 | 12.5 percent of participants |
Secondary
Disease Flare After CR
Proportion of participants who experienced a disease flare after complete response (CR) during the double-blind treatment period.
Time frame: Week 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Disease Flare After CR | 0 Participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Disease Flare After CR | 0 Participants |
Secondary
Partial Response
Proportion of participants who achieved a partial response (PR) during the double-blind treatment period of the study.
Time frame: Weeks 12, 16, 20, and 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Partial Response | Week 12 | 4 Participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Partial Response | Week 16 | 1 Participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Partial Response | Week 20 | 1 Participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Partial Response | Week 24 | 2 Participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Partial Response | Week 24 | 1 Participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Partial Response | Week 12 | 2 Participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Partial Response | Week 20 | 0 Participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Partial Response | Week 16 | 0 Participants |
Secondary
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.
Time frame: Week 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Partial Response With Glucocorticoid Taper to 0 mg | 12.5 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Partial Response With Glucocorticoid Taper to 0 mg | 0 percent of participants |
Secondary
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.
Time frame: Week 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Partial Response With Glucocorticoid Taper to ≤10 mg | 31.3 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Partial Response With Glucocorticoid Taper to ≤10 mg | 25.0 percent of participants |
Secondary
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.
Time frame: Week 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Partial Response With Glucocorticoid Taper to ≤5 mg | 12.5 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Partial Response With Glucocorticoid Taper to ≤5 mg | 12.5 percent of participants |
Secondary
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.
Time frame: Baseline through Week 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Time to Complete Response | NA weeks |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Time to Complete Response | NA weeks |
Secondary
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.
Time frame: Week 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Treatment Failures | 2 Participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Treatment Failures | 1 Participants |
Other Pre-specified
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
Time frame: Weeks 12, 16, 20, and 24
Population: The Intent to Treat (ITT) Set included all randomized participants (N=24).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Change From Baseline in Glucocorticoid Dose | Week 20 | -10.0 mg/day | Standard Deviation 11.35 |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Change From Baseline in Glucocorticoid Dose | Week 12 | -6.2 mg/day | Standard Deviation 9.44 |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Change From Baseline in Glucocorticoid Dose | Week 16 | -8.3 mg/day | Standard Deviation 10.59 |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Change From Baseline in Glucocorticoid Dose | Week 24 | -12.5 mg/day | Standard Deviation 9.79 |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Change From Baseline in Glucocorticoid Dose | Week 24 | -4.7 mg/day | Standard Deviation 11.43 |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Change From Baseline in Glucocorticoid Dose | Week 20 | -7.2 mg/day | Standard Deviation 10.3 |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Change From Baseline in Glucocorticoid Dose | Week 16 | -3.0 mg/day | Standard Deviation 13.83 |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Change From Baseline in Glucocorticoid Dose | Week 12 | -3.2 mg/day | Standard Deviation 11.7 |
Post Hoc
Complete Response (Subset of Participants on Steroids at Screening)
For the subset of the intent to treat population who were on glucocorticoid steroids at Screening, the percentage of participants who achieved complete response by Week 24 of the double-blind treatment period is presented.
Time frame: Weeks 12, 16, 20, and 24
Population: The subset of participants in the intent to treat population who were on glucocorticoids at Screening.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response (Subset of Participants on Steroids at Screening) | Week 12 | 42.9 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response (Subset of Participants on Steroids at Screening) | Week 20 | 57.1 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response (Subset of Participants on Steroids at Screening) | Week 24 | 57.1 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response (Subset of Participants on Steroids at Screening) | Week 16 | 50.0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response (Subset of Participants on Steroids at Screening) | Week 24 | 28.6 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response (Subset of Participants on Steroids at Screening) | Week 12 | 28.6 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response (Subset of Participants on Steroids at Screening) | Week 16 | 28.6 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response (Subset of Participants on Steroids at Screening) | Week 20 | 28.6 percent of participants |
Post Hoc
Complete Response With Glucocorticoid Taper to 0 mg (Subset of Participants on Steroids at Screening)
For the subset of the intent to treat population who were on glucocorticoid steroids at Screening, the percentage of participants who achieved complete response with successful glucocorticoid taper to 0 mg by Week 24 of the double-blind treatment period is presented.
Time frame: Weeks 12, 16, 20, and 24
Population: The subset of participants in the intent to treat population who were on glucocorticoids at Screening. Of note, one participant met the SAP definition of CR with glucocorticoid taper to 0 mg at Week 4 with normalized ALT, AST, and IgG while taking no glucocorticoid steroids and is included in this dataset. After further review of the data, notes in the database stated the reason for the participant taking no glucocorticoids for 7 days was due to the glucocorticoid medication unavailability.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg (Subset of Participants on Steroids at Screening) | By Week 12 | 7.1 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg (Subset of Participants on Steroids at Screening) | By Week 16 | 7.1 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg (Subset of Participants on Steroids at Screening) | By Week 20 | 14.3 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg (Subset of Participants on Steroids at Screening) | By Week 24 | 28.6 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg (Subset of Participants on Steroids at Screening) | By Week 24 | 0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg (Subset of Participants on Steroids at Screening) | By Week 12 | 0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg (Subset of Participants on Steroids at Screening) | By Week 20 | 0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to 0 mg (Subset of Participants on Steroids at Screening) | By Week 16 | 0 percent of participants |
Post Hoc
Complete Response With Glucocorticoid Taper to ≤10 mg (Subset of Participants on Steroids at Screening)
For the subset of the intent to treat population who were on glucocorticoid steroids at Screening, the percentage of participants who achieved complete response with successful glucocorticoid taper to ≤10 mg by Week 24 of the double-blind treatment period is presented.
Time frame: Weeks 12, 16, 20, and 24
Population: The subset of participants in the intent to treat population who were on glucocorticoids at Screening.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg (Subset of Participants on Steroids at Screening) | By Week 12 | 21.4 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg (Subset of Participants on Steroids at Screening) | By Week 16 | 42.9 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg (Subset of Participants on Steroids at Screening) | By Week 20 | 50.0 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg (Subset of Participants on Steroids at Screening) | By Week 24 | 50.0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg (Subset of Participants on Steroids at Screening) | By Week 24 | 14.3 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg (Subset of Participants on Steroids at Screening) | By Week 12 | 14.3 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg (Subset of Participants on Steroids at Screening) | By Week 20 | 14.3 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤10 mg (Subset of Participants on Steroids at Screening) | By Week 16 | 14.3 percent of participants |
Post Hoc
Complete Response With Glucocorticoid Taper to ≤5 mg (Subset of Participants on Steroids at Screening)
For the subset of the intent to treat population who were on glucocorticoid steroids at Screening, the percentage of participants who achieved complete response with successful glucocorticoid taper to ≤5 mg by Week 24 of the double-blind treatment period is presented.
Time frame: Weeks 12, 16, 20, and 24
Population: The subset of participants in the intent to treat population who were on glucocorticoids at Screening. Of note, one participant met the SAP definition of CR with glucocorticoid taper to 0 mg at Week 4 with normalized ALT, AST, and IgG while taking no glucocorticoid steroids and is included in this dataset. After further review of the data, notes in the database stated the reason for the participant taking no glucocorticoids for 7 days was due to the glucocorticoid medication unavailability.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg (Subset of Participants on Steroids at Screening) | By Week 12 | 14.3 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg (Subset of Participants on Steroids at Screening) | By Week 16 | 28.6 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg (Subset of Participants on Steroids at Screening) | By Week 20 | 42.9 percent of participants |
| Double-blind Treatment Period: Zetomipzomib + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg (Subset of Participants on Steroids at Screening) | By Week 24 | 42.9 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg (Subset of Participants on Steroids at Screening) | By Week 24 | 0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg (Subset of Participants on Steroids at Screening) | By Week 12 | 0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg (Subset of Participants on Steroids at Screening) | By Week 20 | 0 percent of participants |
| Double-blind Treatment Period: Placebo + Standard-of-care (Glucocorticoids) | Complete Response With Glucocorticoid Taper to ≤5 mg (Subset of Participants on Steroids at Screening) | By Week 16 | 0 percent of participants |