Study of IMC-I109V in Non-cirrhotic HBeAg-negative Chronic HBV Infection

Study Overview
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Brief Summary
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IMC-I109V is an immune-mobilizing monoclonal T cell receptor (TCR) against viruses (ImmTAV®), a new class of bispecific protein therapeutics designed for the treatment of chronic hepatitis B virus (HBV) infection (CHB). This is the first in-human study of IMC-I109V in persons with CHB.

Detailed Description
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IMC-I109V-101 is a first-in-human (FIH) study designed to assess the safety, tolerability, and pharmacokinetic (PK) profile of IMC-I109V in single and multiple dose regimens and to provide a preliminary assessment of antiviral activity, when administered to virally suppressed hepatitis B e-antigen (HBeAg)-negative participants receiving long-term NA therapy. The aim of this study is to identify safe, tolerable, and clinically active dose (CAD) regimens of IMC-I109V for further clinical development. The IMC-I109V study is divided into 2 main parts: Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD).

Official Title
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An Open-label Study Evaluating the Safety, Antiviral Activity, and Pharmacokinetics of IMC-I109V in HLA-A*02:01 Positive Participants With Chronic HBV Infection Who Are Non-Cirrhotic, Hepatitis B e Antigen-negative, and Virally Suppressed

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: IMC-I109V-101 Single Ascending Dose
* Drug: IMC-I109V-101 Multiple Ascending Doses


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years old at time of informed consent HLA-A*02:01 positive Documented evidence of CHB based on one of the following: a. Positive HBsAg and HBV DNA at least 6 months prior to the Screening visit; OR b. Historical liver biopsy consistent with CHB infection. Have been receiving entecavir and/or tenofovir (including tenofovir alafenamide) for ≥12months prior to screening and are willing to continue. HBV DNA negative at screening No history of liver cirrhosis AND prior assessment of fibrosis demonstrating non-cirrhotic status at screening Participants of childbearing potential who are sexually active with a non-sterilized partner must agree to use highly effective methods of birth control from the trial screening date until 3 months after the final dose of the study intervention or longer if required by local regulations Exclusion Criteria: Pregnant or lactating persons Known co-infection with any of the following: HIV, Hepatitis C virus, OR Hepatitis D virus Changes in HBeAg status within 3 months prior to the screening visit Known HBV genotype A Gilbert's syndrome Any known pre-existing medical or psychiatric condition that could interfere with the participant's ability to provide informed consent or participate in study conduct, or that may confound study findings including, but not limited to: Immunologically-mediated disease, e.g. inflammatory bowel disease (Crohn's disease, ulcerative colitis), rheumatoid arthritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, scleroderma, or sarcoidosis within 5 years of the screening visit. Current or history of any clinically significant cardiac abnormalities/dysfunction, e.g. congestive heart failure, myocardial infarction ≤6 months prior to the screening visit, pulmonary hypertension, complex congenital heart disease, significant arrhythmia, or active cardiac ischemia. Evidence of decompensated liver disease including, but not limited to, a history or presence of clinical ascites, bleeding esophageal varices, hepatorenal syndrome, or hepatic encephalopathy. Significant immunosuppression from, but not limited to immunodeficiency conditions such as common variable hypogammaglobulinemia Evidence of active or suspected malignancy, or a history of malignancy ≤3 years prior to the screening visit (except adequately treated carcinoma in situ, basal cell carcinoma of the skin, or stage 0 HCC that has been treated). NOTE: Participants under evaluation for malignancy are not eligible Receiving or planning to receive systemic immunosuppressive medications during the study or ≤ 2 months prior to Day1, including but not limited to prednisone >10 mg/day (or equivalent), methotrexate, cyclosporine, or interferon. NOTE: Local steroid therapy is allowed (eg, inhaled, otic, ophthalmic, or intra-articular medications) Use of any live vaccines against infectious diseases within 4 weeks of the first planned administration of study intervention or use of any non-live vaccines against infectious diseases within 2 weeks of the first planned administration of study intervention. Treatment with any investigational drug or enrollment in any other clinical study ≤ 3 months prior to Day1, or at any time during participation in the study. Clinical diagnosis of substance abuse with alcohol, narcotics, or cocaine ≤12 months prior to the screening visit, except for those participants monitored in an opioid substitution maintenance program.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Participants will receive a single dose of IMC-I109V-101 in Part 1 (SAD) and 24 weekly doses in Part 2 (MAD).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Single Ascending Dose (SAD)<br>SAD will be approximately 10 weeks for each participant, comprising a maximum 42-day screening period, a 1-day treatment period involving a single administration of IMC-I109V and a 28-day follow-up period, for a total of 8 visits. Visits will take place on Day -1 and Days 1, 2, 3, 8, 15, 22, and 29. Follow-up may be extended in participants who achieve a decrease in HBsAg of > 0.5 log10 IU/mL at Day 29. | Drug: IMC-I109V-101 Single Ascending Dose<br>* Single dose administration of IMC-I109V-101<br>* Other names: SAD;|
| Experimental: Part 2: Multiple Ascending Doses (MAD)<br>MAD will be approximately 54 weeks for each participant, comprising a maximum 42-day screening period, a 24-week treatment period involving weekly administration of IMC-I109V, and a 24-week follow-up period, with a total of 29 visits. Visits will take place on Day -1 and Days 1, 3 and 8, Weeks 3 (Day 15) through 24, Weeks 28, 36, 48 and 49. Participants who have achieved HBsAg <100 IU/mL at end of Week 24 may be considered for further study treatments of up to Week 48 and follow-up visits every 12 weeks to Week 72. Treatment will be discontinued at Week 16 in participants who have not shown evidence of a response to IMC-I109V, in order to minimize unnecessary drug exposure in participants who are unlikely to achieve reductions in viral biomarkers with further doses. | Drug: IMC-I109V-101 Multiple Ascending Doses<br>* Multidose administration of IMC-I109V-101<br>* Other names: MAD;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment-emergent adverse events (TEAEs) |  | Up to 280 days post-dose | 
| Incidence of serious adverse events (SAEs) |  | Up to 280 days post-dose | 
| Incidence of adverse events (AEs) leading to treatment discontinuation |  | Up to 280 days post-dose | 
| Incidence of dose-limiting toxicities (DLTs) |  | Up to 280 days post-dose | 
| Changes in Vital Signs | Number of participants with, and rate of, Grade 1, Grade 2, Grade 3, and Grade 4 (as applicable per NCI CTCAE v5.0) vital sign abnormalities. | Up to 280 days post-dose | 
| Changes in electrocardiogram | QTcF interval absolute values and changes from baseline. | Up to 280 days post-dose | 
| Change in safety laboratory parameters | Number of participants with, and rate of, Grade 1, Grade 2, Grade 3, and Grade 4 (as applicable per NCI CTCAE v5.0) laboratory abnormalities. | Up to 280 days post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum drug concentration (Cmax) |  | Up to 162 days post-dose | 
| Area under the plasma concentration versus time curve (AUC) |  | Up to 280 days post-dose | 
| The time to reach maximum drug concentration (Tmax) |  | Up to 280 days post-dose | 
| The elimination half-life (t1/2) |  | Up to 280 days post-dose | 
| Incidence of anti-IMC-109V antibody formations |  | Up to 280 days post-dose | 
| Antiviral Effects: HBsAg change from baseline |  | Up to 280 days post-dose | 
| Antiviral Effects: HBcrAg change from baseline |  | Up to 280 days post-dose | 
| Antiviral Effects: HBV RNA change from baseline |  | Up to 280 days post-dose | 
| Antiviral Effects: HBsAb change from baseline |  | Up to 280 days post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HBeAg negative, HLA-A*02;01 Positive, T Cell Receptor (TCR)