A Trial of Inebilizumab in Participants With Autoimmune Hepatitis

A Phase 2/3, Randomized, Double-blind, Multicenter, Placebo-controlled Study of Inebilizumab in Participants With Autoimmune Hepatitis

The main objectives of this trial are to evaluate the safety and tolerability of inebilizumab in participants with autoimmune hepatitis (AIH) (Part 1) and to evaluate the efficacy of inebilizumab on AIH disease activity and glucocorticoid (GC) use in the management of AIH (Part 2).

This study will consist of a screening period (up to 56 days), a randomized controlled treatment period (78 weeks), an optional open label period (OLP) up to 78 weeks (or until potential availability of the marketed drug) for eligible participants who complete the treatment period, and a safety follow-up (SFU) period up to 78 weeks.

The randomized controlled treatment period will be divided in 2 parts, a phase 2 dose confirmation and safety part (Part 1) and an efficacy evaluating phase 3 (Part 2). Part 1 will conclude when the last Part 1 participant has had the opportunity to complete the Week 26 visit. Part 2 will begin without pausing enrollment; the same randomization ratio and study procedures are maintained.

Inclusion Criteria:

• Signed informed consent.
• Age ≥ 18 years or legal adult age within the country, whichever is older and < 75 years at the time of signing the informed consent.
• Participants must have either inadequate response to at least 9 months of SOC or are intolerant to SOC within 6 months of screening. Inadequate response to SOC treatment is defined as ALT ≥ 2 upper limit of normal (ULN) at screening after at least 9 months of SOC, including prednisone (or equivalent) > 5 mg/day and at least one conventional steroid sparing agent at guideline-concordant target or highest appropriate dose, that is azathioprine (AZA) or 6-mercaptopurine (6-MP) at appropriate weight-based dosing (typically up to 2 mg/kg/day AZA or 1 mg/kg/day 6-MP) or mycophenolate (MMF) up to 2 g/day, as judged appropriate by the investigator and documented in the medical record.

Intolerance to SOC treatment is defined as any clinically significant adverse event related to treatment that results in discontinuation of the medication or prevents dose optimization necessary to achieve or maintain biochemical response, as determined by the Principal Investigator (PI). Intolerance applies to GCs, AZA, 6-MP, or MMF. Presence of one or more clinically significant adverse effects attributed to SOC include but not limited to side effects that, in the opinion of the investigator, compromise participant's safety or quality of life, exacerbate comorbid conditions, or render continued use medically inappropriate.

• Participants with disease activity at screening as follows: ALT ≥ 2 x ULN to ≤ 7 x ULN. ALT ULN values will be gender specific.

• Participant must have a biopsy proven definitive diagnosis of AIH according to simplified diagnostic criteria (score ≥ 7). Liver biopsy should be obtained within 90 days prior to randomization. Participants must have a mHAI score ≥ 5 in the biopsy.

• Participant should be on:

  • No increase in GC dose during the 28 days immediately preceding whichever biopsy is designated as the baseline sample-historical or screening-and the dose post biopsy must remain unchanged through the day of randomization AND
  • Stable maximum tolerated doses of AZA or 6-MP for at least 12 weeks prior to screening (baseline) liver biopsy until randomization and during the entire treatment period unless dose reduction is deemed necessary for safety or tolerance reasons OR
  • Stable maximum tolerated doses of MMF/mycophenolic acid (MPA) for at least 12 weeks prior to screening (baseline) liver biopsy until randomization and during the entire treatment period unless dose reduction is deemed necessary for safety or tolerance reasons.

• Participants must use protocol-specified contraception during treatment and for an additional 6 months after the last dose of trial intervention.

Exclusion Criteria:

• Diagnosis of definitive overlap autoimmune liver or rheumatologic syndrome with autoimmune hepatitis (eg, AIH + primary biliary cholangitis [PBC], AIH + primary sclerosing cholangitis [PSC], AIH related to Systemic Lupus Erythematosus, etc) where established overlap criteria are met.

• Acute liver failure (ALF) at screening (e.g., acute hepatic dysfunction with coagulopathy and any degree of encephalopathy) in the investigator's judgment.

• Participant has known history of:

  • Allergy or reaction to any component of inebilizumab formulation or history of anaphylaxis to any human gamma globulin therapy.
  • Allergy to or intolerance of protocol-required treatment, including medications for prophylaxis of infusion reactions (antipyretic such as paracetamol/acetaminophen or equivalent, diphenhydramine or equivalent, and methylprednisolone or equivalent).

• Active malignancy or history of malignancy that was active within the last 10 years, except as follows:

  • In situ carcinoma of the cervix treated with apparent success with curative therapy for > 12 months prior to screening
  • Curatively treated breast ductal carcinoma in situ
  • Cutaneous basal cell or squamous cell carcinoma treated with apparent success with curative therapy for > 12 months prior to screening
  • Prostate cancer treated with radical prostatectomy or radiation therapy with curative intent > 3 years prior to screening and without known recurrence or current treatment
  • Thyroid cancer for which complete surgical resection has been performed within 5 years with well-differentiated histology (papillary thyroid carcinoma or follicular thyroid carcinoma) and there is no evidence of active disease.

• Known positive test for human immunodeficiency virus (HIV) infection. Evidence of HIV infection or positive for HIV antibodies at initial screening or current acquired, common variable or inherited, primary or secondary immunodeficiency.

• Presence or history of viral hepatitis infection:

  • Positive test for, or prior treatment for, hepatitis B. A positive test for hepatitis B is detection of either:

    • Positive for hepatitis B surface antigen (HBsAg) OR
    • anti-HBc

  • Participants with a history of or current hepatitis C virus (HCV) infection, even those considered to be cured.

• Active tuberculosis (TB) or latent TB with no documented history of adequate treatment per local SOC.

• Positive test for TB during screening is defined as positive QuantiFERON® test. At screening, all participants must be tested with an interferon-γ release assay (IGRA) (QuantiFERON®).

• History of > 1 episode of herpes zoster (any grade) and/or any other definite or probable opportunistic infection in the 12 months prior to screening.

• Estimated glomerular filtration rate < 45 mL/min/1.73 m^2 using chronic kidney disease epidemiology (CKD-EPI) 2021 formula.

• Blood tests at screening that meet any of the following criteria:

  • Hemoglobin < 7.5 g/dL
  • Neutrophils < 1200/mm^3
  • Platelets < 150 x 10^9/L
  • international normalized ratio (INR) > 1.3
  • cluster of differentiation 19 (CD19)+ B cells at screen < 40 cells/µL; an exclusionary value may be repeated.
  • Serum albumin level < 35 g/L
  • Direct bilirubin (BIL) in serum >ULN
  • Total BIL ≥ 2.0 mg/dL
  • ALP > 1.5 x ULN
  • AST > 7 x ULN Note: Participants with baseline cytopenia (where permitted) may be enrolled if, in the Investigator's judgment, the cytopenia derives from an alternative to AIH condition (eg, medication effect, nutritional deficiency, anemia of chronic disease etc).

• Active, clinically significant infection at the time of randomization (investigational product administration may be delayed until recovery, if within screening window, otherwise participant may be rescreened).

• History or evidence of uncontrolled alcohol use disorder (AUD), defined as participants who have a history of significant alcohol consumption, ie, consumption of >2 units/day for males and >1 unit/day for females, sustained for ≥ 3 consecutive months.

• History of recurrent significant infections (eg, requiring hospitalization or IV antibiotics) within the past 12 months.

• Major surgery within 8 weeks before screening.

• Severe cardiovascular, respiratory, endocrine, gastrointestinal, hematological, neurological, psychiatric, or systemic disorder, or any other condition that, in the opinion of the Investigator, would place the participant at unacceptable risk of complications, interfere with evaluation of the Investigational product or confound the interpretation of participant safety or trial results.

• Known immunodeficiency disorder.

• Participants with moderate-to-severe metabolic dysfunction-associated steatohepatitis (MASH) on screening/baseline liver biopsy, defined by central pathology review as steatosis grade ≥ 2 with lobular inflammation ≥ 1, and hepatocellular ballooning ≥ 1.

• Participants with decompensated cirrhosis, either historical or present at screening defined by:

  • Histologic cirrhosis on screening or prior liver biopsy (fibrosis stage F4 / Ishak 5-6), and
  • Prior hepatic decompensation or Child-Pugh B-C.
  • Child-Pugh category A at screening, without a history of prior hepatic decompensation (ascites, encephalopathy, variceal bleeding, spontaneous bacterial peritonitis [SBP], hepatorenal syndrome [HRS], acute-on-chronic liver failure, or progression to decompensated cirrhosis), is eligible.

• Participant with a history of drug-induced liver injury (DILI), regardless of offending agent.

• Receipt of any biologic B cell-depleting therapy (eg, rituximab, ocrelizumab, obinutuzumab, ofatumumab, inebilizumab, ianalumab) in the 6 months prior to screening.

• Receipt of non-depleting B cell-directed therapy (eg, belimumab), abatacept, or other biologic immunomodulatory agent within 6 months prior screening.

• Receipt of tumor necrosis factor (TNF) inhibitors (eg, infliximab, adalimumab) within 6 months prior screening.

• Receipt of immunosuppressive agents such as calcineurin inhibitors (tacrolimus, cyclosporin except eye drops), methotrexate, mammalian target of rapamycin inhibitors (eg, everolimus) within 6 weeks prior screening.

• Receipt of any investigational agent < 12 weeks or < 5 half-lives of the drug (whichever is longer) prior to screening.

• History of inability to be tapered off of GC therapy due to adrenal insufficiency or due to recurrent or prolonged systemic glucocorticoid therapy for any medical condition other than AIH (eg, severe steroid-dependent asthma) according to PI.

• All vaccines are prohibited within 4 weeks before the first dose of trial treatment.

  • Participants are recommended to be administered vaccines at least 4 weeks prior to dosing in accordance with local recommendations prior to enrollment to allow for adequate immune response.

• Required regular use of medications with known hepatotoxicity.

• Current use of:

  • GCs (prednisone > 20 mg/day, or equivalent dose of other GCs)
  • AZA > 2 mg/kg/day
  • 6-MP > 1 mg/kg/day
  • MMF > 2 g/day or MPA > 1440 mg/day.

• Any concomitant immunosuppressive treatment, alone or in combination with GCs, except for AZA, 6-MP, MMF, and MPA.

• Undetectable levels of 6-thioguanine nucleotides (6-TGN) or MPA during screening unless participants are not on AZA or MMF/MPA due to intolerance per protocol.

• No new Herbal and Dietary Supplements (HDS) products for 4 weeks prior to first dose of inebilizumab.

• Currently receiving a trial intervention, or less than 30 days or 5 half-lives if known (whichever is later) since ending a trial intervention in another investigational device or drug trial.

• Unable to safely undergo a liver biopsy.

• Participant unlikely to be able to complete all protocol-required procedures, restrictions and requirements, in the judgment of the individual and investigator.

• History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator, would pose a risk to participant safety.

• Currently pregnant (confirmed with positive pregnancy test) or breastfeeding or planning to become pregnant, donate eggs, or breastfeed while on trial until an additional 6 months after the last dose of inebilizumab (if applicable) with highest teratogenic risk.

• Participants of childbearing potential with a positive pregnancy test assessed by serum pregnancy test at screening and a urine pregnancy test at Day 1 visit.

• Participant unwilling to abstain from donating blood or plasma during the trial.

In order for participants to continue to OLP, they must:

• Have completed the randomized controlled treatment period Week 78 visit and received all doses or not discontinued investigational product for any of the following reasons:

  • Anaphylaxis or a serious hypersensitivity reaction that occurred within 7 days after IV dosing and cannot be attributed to another known allergen exposure.
  • Any adverse events or significant laboratory abnormality that, in the opinion of the investigator, Amgen, or Data Monitoring Committee (DMC), warrants discontinuation of dosing.
  • Any life-threatening (grade 4) infection.
  • Any event of sepsis or febrile neutropenia.
  • Any infection listed as either a definite or probable opportunistic infection.
  • Any grade 3 infusion related reactions (IRR).
  • Any grade 4 serious adverse events.
  • Pregnancy or a decision to become pregnant.
  • Malignancy.
  • Absolute neutrophil count < 800 cells/µL confirmed by repeat testing.
  • Determination that the participant was ineligible for trial participation and continuation of investigational product could pose a safety risk to the participant in the judgment of the investigator or the sponsor.
  • Significant noncompliance with the trial protocol, as judged by the investigator or Amgen.

• Receive dose 1 in the OLP within the window of 7 days after the randomized controlled treatment period Week 78 visit and only after the Week 78 biopsy has been completed.

• Participants who meet protocol-defined early escape criteria and discontinue the RCP may enter the OLP, provided they have not discontinued investigational product for safety-related reasons that preclude further dosing.