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

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

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.

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 3 main parts: Part 1 - Single Ascending Dose (SAD); Part 2 - Multiple Ascending Dose (MAD), in HBeAg-negative CHB; Part 3 will evaluate safety, tolerability, antiviral activity, PK and anti-tumor efficacy of Multiple Ascending Doses of IMC-I109V in participants with HBV-associated hepatocellular carcinoma (HBV HCC) who are virally suppressed on NA therapy.

Inclusion Criteria

Parts 1 and 2:

• ≥18 to 65 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

Part 3:

• ≥18 years old at time of informed consent
• HLA-A*02:01 positive
• ECOG ≤1
• Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology / cytology, or clinically by American Association for the Study of Liver Diseases criteria
• Failed or intolerant of ≥1 systemic therapy
• At least one measurable lesion (per RECIST 1.1) which is either not previously treated or, if treated, has clearly progressed prior to enrollment
• 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
• Life expectancy >3 months from time of enrolment
• Have compensated cirrhosis with a Child-Pugh score ≤ 7 (A or B7)
• On entecavir and/or tenofovir (disoproxil fumarate or alafenamide) with HBV DNA <100IU/ml at screening; willingness to continue for at least 6 months after the last dose of study drug
• Quantitative HBV surface antigen ≤ 5,000 IU/mL 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:

Parts 1 and 2:

• 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.

Part 3:

• Pregnant or lactating persons
• Untreated or symptomatic CNS metastases
• Significant ongoing toxicity from prior anticancer treatment -
• Ascites requiring recurrent paracentesis
• Inadequate washout from prior anticancer therapy
• Prior cellular therapy for HBV-associated HCC
• Known HBV genotype A
• Decompensated liver disease
• Surgical intervention or local / loco-regional therapy for HBV HCC within 28 days of planned first dose of study treatment
• Active hepatitis C virus (HCV) infection
• Untreated HIV infection
• Significant secondary malignancy
• Clinically significant lung, heart, or autoimmune disease
• Ongoing requirement for immunosuppressive treatment
• Prior solid organ or bone marrow transplant
• Hypersensitivity to study drug or excipients, or pre-medications
• Systemic antibiotics, vaccines or major surgery within 2-4 weeks prior to the first dose of study intervention
• Out-of-range laboratory values, including ALT or AST > 3x upper limit of normal (ULN), total bilirubin and direct bilirubin > 1.5x ULN, Albumin ≤ 28 g/L, International normalized ratio (INR) > 1.3