Evaluation of Safety, Pharmacokinetics, and Antiviral Activity of IMC-M113V in HLA-A*2:01 Positive Patients with Virologically Suppressed Chronic HIV Infection

Trial ID: 2024-513938-38-00
Protocol: IMC-M113V-103
Sponsor: Immunocore Limited

Trial statistics

science

test molecule

location_city

research sites

public

countries

medical_information

disease

person_search

investigators

handshake

vendors

Diseases & Conditions

HIV infection

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of IMC-M113V in subjects with chronic HIV infection who are virologically suppressed. This evaluation is conducted in two parts: Part 1 involves a Single Ascending Dose (SAD) study to assess the safety and tolerability of a single dose of IMC-M113V during antiretroviral therapy (ART). Part 2 involves a Multiple Ascending Dose (MAD) study to assess the safety and tolerability of IMC-M113V when administered in a multiple dose schedule, up to at least week 12, in participants receiving ART. The clinical relevance of this objective lies in ensuring that IMC-M113V can be safely administered to patients, which is crucial for its potential use as a therapeutic agent in managing chronic HIV infection.

The secondary objectives of the study are as follows:

To characterize the pharmacokinetic (PK) profile of IMC-M113V in single dose and multiple dose schedules.
To evaluate the incidence of anti-IMC-M113V antibody formation following single and multiple infusions.
To determine pharmacodynamic (PD) changes in the systemic immune response in relation to treatment with IMC-M113V, including changes in peripheral cytokines and lymphocyte counts.
To determine the incidence and duration of post-treatment control during analytical therapy interruption in participants completing multiple dose schedules.
To determine the recommended Phase 2 dosing regimen.

Participants

The clinical trial involves a total of **10 participants** diagnosed with **chronic HIV infection**. The study population includes both male and female subjects, aged between **18 to 65 years**, who are **HLA-A*02:01-positive** and weigh at least **50 kg**. Participants have been on continuous antiretroviral therapy (ART) for a minimum of 12 months and a maximum of 15 years, with consistently undetectable plasma HIV RNA levels (< 50 copies/mL) throughout the 12-month period prior to screening. Additionally, participants have a current CD4+ T cell count greater than 450 cells/μL and CD4+ cells constituting more than 15% of total lymphocytes, with a CD4+ T cell nadir above 200 cells/μL. The trial population was selected based on these criteria, ensuring a focus on individuals with stable health status under ART. The study also considers lifestyle factors such as contraception use. The trial includes a vulnerable population, highlighting the importance of informed consent in the study process.

Plans and Procedures

The clinical trial is designed to evaluate the safety, pharmacokinetics, and antiviral activity of **IMC-M113V** in subjects with **chronic HIV infection** who are virologically suppressed. This is a Phase 1/2 study, structured as an open-label, dose-escalation trial. The trial is divided into two parts: a Single Ascending Dose (SAD) study and a Multiple Ascending Dose (MAD) study. The primary objective of Part 1 is to assess the safety and tolerability of a single dose of IMC-M113V administered during antiretroviral therapy (ART). Part 2 aims to evaluate the safety and tolerability of multiple doses over a period extending to at least 12 weeks in participants receiving ART. The trial is expected to conclude by August 2026, with recruitment having commenced in March 2022.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age (18-65 years), HLA-A*02:01 positivity, and a history of consistent ART with undetectable plasma HIV RNA levels. Following successful screening, participants will receive the investigational product, **IMC-M113V**, administered as a **solution for infusion**. Subsequent visits will include regular follow-ups to monitor safety, pharmacokinetics, and immune response, with assessments of treatment-emergent adverse events, dose-limiting toxicities, and changes in laboratory parameters. The end-of-study visit will occur 28 days after the last infusion, marking the completion of the participant's involvement.

The expected duration of participant involvement varies depending on the dosing schedule, with the MAD study extending up to 12 weeks. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, dose-limiting toxicities, or any adverse events necessitating treatment interruption or discontinuation. The trial will also assess secondary endpoints such as pharmacokinetic parameters, incidence of anti-IMC-M113V antibody formation, and changes in serum cytokines and peripheral blood lymphocyte counts. The study aims to identify at least one tolerable dosing regimen for further evaluation in subsequent development phases.

Treatment

The clinical trial involves the administration of **IMC-M113V**, an experimental medication developed by Immunocore Limited. IMC-M113V is a **bispecific protein** with a high-affinity T-cell receptor domain fused to an antibody single-chain variable fragment against CD3. This biologic is formulated as a **solution for infusion** and is intended for intravenous administration. The trial is structured in two parts: a Single Ascending Dose (SAD) study and a Multiple Ascending Dose (MAD) study. In the SAD study, IMC-M113V is administered as a single dose, while in the MAD study, it is administered in multiple doses up to at least week 12. The dosing schedule is designed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the drug in HLA-A*2:01 positive subjects with chronic HIV infection who are virologically suppressed.

Participants in the trial will continue to receive their standard antiretroviral therapy (ART) as a non-experimental treatment. This standard-of-care therapy is maintained throughout the study to ensure that participants remain virologically suppressed. The combination of IMC-M113V with ART aims to assess the potential synergistic effects on the participants' immune response and viral load. Compliance with the dosing schedule and ART will be monitored closely to ensure adherence and to evaluate the safety and efficacy of the investigational treatment.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on safety-related parameters, including the incidence and severity of treatment-emergent adverse events (TEAEs), dose-limiting toxicities (DLTs), changes in safety laboratory parameters, vital signs, and electrocardiogram (QTcF) readings. Additionally, the incidence of serious adverse events (SAEs) and adverse events leading to treatment interruption, dose reduction, or discontinuation will be monitored through 28 days after the last infusion of the study treatment.

Secondary endpoints will evaluate the pharmacokinetics (PK) of IMC-M113V, including parameters such as area under the curve (AUC), maximum concentration (Cmax), time to reach maximum concentration (Tmax), and half-life (t1/2) at multiple time points from baseline up to 72 hours post-dose in both Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) studies. The incidence of anti-IMC-M113V antibody formation will also be assessed following administration of one or more doses of the study drug. Changes in serum cytokines/chemokines and peripheral blood lymphocyte counts will be measured from baseline through 72 hours post-dosing with IMC-M113V in both SAD and MAD schedules and during follow-up.

Additional secondary endpoints include the proportion of participants with plasma viral load (pVL) less than 200 copies/mL 12 weeks after interruption of antiretroviral therapy (ART), the proportion of participants resuming ART before week 24, and the duration of post-treatment control (pVL < 200 copies/mL) after ART interruption. The duration of virological suppression (pVL < 1000 copies/mL) after ART interruption will also be evaluated. The identification of at least one tolerable dosing regimen for further evaluation in subsequent development is a key objective of the study.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

18-65 years
HLA-A*02:01-positive
≥ 50 kg
Evidence of HIV-1 infection • On continuous ART for a minimum of 12 months and maximum of 15 years • Consistently undetectable plasma HIV RNA (< 50 copies/mL) throughout the 12-month period prior to screening • Current CD4+ T cell count > 450 cells/μL and CD4+ cells >15% total lymphocytes • CD4+ T cell nadir > 200 cells/μL
Contraception
Informed Consent

cancel

Exclusion Criteria

Confirmed HIV controller with HIV RNA consistently below 2000 copies/mL for at least 12 months and on ≥ 2 determinations.
Initiated ART within 12 weeks of a diagnosis of primary HIV infection (PHI) Diagnosis of PHI is confirmed by any of: a. positive HIV-1 serology preceded by a recent negative HIV-1 antibody (Ab) test, b. Negative HIV Ab test plus positive viral antigen or RNA test c. HIV-1 Ab avidity test consistent with recent infection, or d. Weakly reactive or equivocal 4th generation HIV Ab/Ag test.
Recent diagnosis of an AIDS-defining condition within 90 days prior to screening excludes participation in Part 1. Any history of AIDS-defining condition excludes participation in Part 2.
Individuals receiving an ART regimen containing a non-nucleoside reverse transcriptase inhibitor may not enrol in Part 2 unless willing and able to switch to a short-acting alternative prior to receiving their first dose of study drug.
Medical Conditions Co-infection with HBV Current active Mycobacterium tuberculosis infection or known untreated latent infection. Significant cardiovascular disease or impaired cardiac function Active autoimmune disease requiring immunosuppressive treatment Prior solid organ or bone marrow transplant. History of malignant disease Pregnant or lactating women.
Recent immunotherapy medication Systemic treatment with steroids or any other immunosuppressive drug use
Prior treatment with investigational HIV-targeted therapy
Recent use of live vaccine
Prior treatment with ImmTAC molecule
Participation in other interventional studies
If any of the following laboratory exclusion criteria are met, then the site may have the participant retested. If a single value is within ±10% of the listed laboratory exclusion criterion value upon retest, and the value is considered not clinically significant by the physician Investigator, the participant may be considered for enrolment: a. Hemoglobin < 120 g/L for participants assigned male at birth; < 110 g/L for participants assigned female at birth b. Platelet count < 150 × 109/L c. Alanine aminotransferase (ALT) > 3 × ULN (upper limit of normal) d. eGFR(Foundation, 2009) < 60 mL/min/1.73 m2 (calculated using CKD-EPI equation, 2009; or measured)
Inability or unwillingness to adhere to safer sex practices during ART interruption.
Hypersensitivity to study treatment or excipient Any medical condition that would interfere with the participation in the study