10E8.4/iMab Bispecific Antibody and VRC07-523LS Monoclonal Antibody in HIV-infected Adults

Study Overview
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Brief Summary
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This is an open-label phase 1b clinical trial enrolling people living with HIV (PLWH) who are antiretroviral therapy (ART)-naïve or have not been on ART for > 24 weeks. This study will enroll PLWH to assess the safety, tolerability, and antiviral effect of bispecific and long-acting bNAbs, alone and in combination. The study will be conducted as a single center study at National Institute for Medical Research-Mbeya Medical Research Center (NIMR-MMRC) in Mbeya, Tanzania. 20 PLWH will be sequentially enrolled into one of 5 arms, each arm comprised of 4 participants. Sequential enrollment will occur in the following order: Arm 1 will receive standard daily oral ART. Arm 2 will receive a single dose of 10E8.4/iMab 600mg intravenous injection (IV). Arm 3 will receive a single dose of 10E8.4/iMab 600mg intramuscular injection (IM). Arm 4 will receive a single dose of 10E8.4/iMab 1800mg IV. Arm 5 will receive a single dose of combination therapy with both 10E8.4/iMab 1800mg IV and VRC07-523LS 1200mg IV.

Detailed Description
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Although global initiatives have made great strides in controlling the human immunodeficiency virus (HIV) pandemic, HIV and acquired immune deficiency syndrome (AIDS) continue to impact the lives and livelihoods of a significant portion of the population. In 2019, 38 million individuals were living with HIV and 690,000 died of AIDS-related causes. Despite extensive global efforts for disease control over the last 20 years, 1.7 million individuals contract HIV annually. Antiretroviral therapy (ART) reduces morbidity and mortality associated with HIV by suppressing viral replication but does not eradicate infection. There are barriers to universal ART use that include toxicities, costs, drug resistance, and the need for lifelong adherence. To overcome these barriers, HIV broadly neutralizing antibodies (bNAbs) represent a novel approach to HIV prevention and treatment. The primary endpoint of change in viral load will be assessed at day 14. Participants will then transition to Step 2, during which all participants will take standard daily oral ART and have viral load monitored through Step 2 week 48.

Official Title
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Phase 1b Single Dose Clinical Trial of a Novel Long-Acting Bispecific Antibody in People With HIV to Inform Development for HIV Pre- and Post-Exposure Prophylaxis

Conditions
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HIV-1-infection

Intervention / Treatment
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* Drug: ART
* Drug: 10E8.4/iMab
* Drug: VRC07-523LS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to read and write in Kiswahili and/or English Able and willing to provide written informed consent Passes Test of Understanding (TOU) Aged 18-50 years, inclusive Antiretroviral Therapy (ART)-naïve or no ART for > 24 weeks at the time of screening HIV RNA 1,000-100,000 copies/mL CD4 ≥ 500 cells/mm3 Laboratory criteria at screening within protocol-specified limits for blood, chemistry and urinalysis Willing and able to participate in study visits and procedures for up to 50 weeks Willing and able to begin ART as directed during the study Willing and able to use barrier protection during sex with partners without HIV or partners with unknown HIV status throughout Step 1 and until viral suppression <200 copies/mL is confirmed in Step 2 Willing and able to adhere to the following contraception requirements: Participants who are able to become pregnant must agree to use at least one method of highly effective contraception if participating in sexual activity that could lead to pregnancy. This must begin at least 14 days prior to study enrollment. Participants who engage in sexual activity that could lead to their partner becoming pregnant and who are of reproductive potential must agree to use a barrier method of contraception to avoid pregnancy in a sexual partner of reproductive potential. The barrier method must be used for the duration of the study. Exclusion Criteria: Weight >100 kg Previous receipt of humanized or human monoclonal antibody whether licensed or investigational (other than for the prevention and/or treatment of SARS-CoV2/COVID-19) History of viral failure on two or more ART regimens Planned or anticipated need for enfuvirtide, maraviroc, fostemsavir, or ibalizumab for antiretroviral therapy. AIDS-defining illness, as enumerated by the WHO Stage 3 or 4, within the six months prior to enrollment Ongoing oral thrush Active injection or other recreational drug use within the previous 12 months that, in the opinion of the investigator, would impede the participant's ability to safely and consistently adhere to the study protocol History of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis in the 2 years prior to enrollment. History of chronic urticaria requiring daily treatment Known active hepatitis B virus infection or positive hepatitis B surface antigen at any time in the past Known active hepatitis C virus infection or positive hepatitis C antibody at any time in the past Untreated syphilis Estimated GFR < 50 mL/min within the past 90 days Pregnant or breast-feeding Receipt of licensed vaccine or other investigational study agent within 28 days prior to enrollment or any past participation in an investigational HIV vaccine study with receipt of active product Current or planned participation in another interventional clinical trial during the study period, including clinical trials of investigational new drugs or investigating a new application for an approved medication Chronic or recurrent use of medications that modify host immune response, such as oral steroids, parenteral steroids, or cancer chemotherapy (note: locally-acting medications-such as inhaled, topical, or intra-articular steroids-are allowed) Any other chronic or clinically significant medical condition that in the opinion of the investigator would jeopardize the safety or rights of the participant including, but not limited to: diabetes mellitus type I, chronic hepatitis, renal failure; OR clinically significant forms of: drug or alcohol abuse, mental illness, severe asthma, autoimmune disease, decompensated psychiatric disorders, hypertension, heart disease, or cancer Any medications that, in the opinion of the investigator, would preclude intramuscular injections Study site employee

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Sequential Assignment
Interventional Model Description: Participants are assigned to 1 to 5 arm sequentially.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1: Oral ART<br>Participants will receive standard daily oral ART. | Drug: ART<br>* ART is a combination of three or more drugs from different classes of antiretroviral medication.<br>* Other names: antiretroviral therapy;|
| Experimental: Arm 2: 10E8.4/iMab 600mg IV.<br>Participants will receive a single dose of 10E8.4/iMab 600mg IV. | Drug: 10E8.4/iMab<br>* 10E8.4/iMab is an engineered bispecific antibody with two arms combined into a single molecule that exhibits synergistic enhancement of antiviral activity. 10E8.4/iMab will be administered IV at the 600mg or 1800mg dose or IM at 600mg dose to participants in Step 1 per the Schedule of Events (SOE) based on the arm the participant is assigned.<br>* Other names: ibalizumab;|
| Experimental: Arm 3: 10E8.4/iMab 600mg IM.<br>Participants will receive a single dose of 10E8.4/iMab 600mg IM. | Drug: 10E8.4/iMab<br>* 10E8.4/iMab is an engineered bispecific antibody with two arms combined into a single molecule that exhibits synergistic enhancement of antiviral activity. 10E8.4/iMab will be administered IV at the 600mg or 1800mg dose or IM at 600mg dose to participants in Step 1 per the Schedule of Events (SOE) based on the arm the participant is assigned.<br>* Other names: ibalizumab;|
| Experimental: Arm 4:10E8.4/iMab 1800mg IV.<br>Participants will receive a single dose of 10E8.4/iMab 1800mg IV. | Drug: 10E8.4/iMab<br>* 10E8.4/iMab is an engineered bispecific antibody with two arms combined into a single molecule that exhibits synergistic enhancement of antiviral activity. 10E8.4/iMab will be administered IV at the 600mg or 1800mg dose or IM at 600mg dose to participants in Step 1 per the Schedule of Events (SOE) based on the arm the participant is assigned.<br>* Other names: ibalizumab;|
| Experimental: Arm 5: Combination 10E8.4/iMab and VRC07-523LS therapy<br>Participants will receive a single dose of combination therapy with both 10E8.4/iMab 1800mg IV. and VRC07-523LS 1200mg IV. | Drug: 10E8.4/iMab<br>* 10E8.4/iMab is an engineered bispecific antibody with two arms combined into a single molecule that exhibits synergistic enhancement of antiviral activity. 10E8.4/iMab will be administered IV at the 600mg or 1800mg dose or IM at 600mg dose to participants in Step 1 per the Schedule of Events (SOE) based on the arm the participant is assigned.<br>* Other names: ibalizumab;Drug: VRC07-523LS<br>* VRC07-523LS is an engineered variant of VRC01, a bNAb that targets the CD4 binding site of the HIV-1 envelope. VRC07-523LS will be administered IV at the 1200mg dose to participants in Step 1 per the SOE.<br>* Other names: VRC01 variant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Grade 3 or higher antibody-related reactogenicity and adverse events | Includes potentially life-threatening, or fatal events. | Up to Week 48 in Step 2 | 
| Change in plasma HIV RNA from day 0 to day 14 | Viral RNA copies/mL will be measured. | Day 0 and Day 14 in Step 1 | 
| Proportion of participants with HIV RNA < 50 copies/mL at day 14 | Percentage of participants will be calculated. | Up to Day 14 in Step 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportions of participants with HIV RNA <50 copies/mL | Percentage of participants will be calculated. | Up to Week 48 in Step 2 | 
| Proportions of participants with HIV RNA < 200 copies/mL | Percentage of participants will be calculated. | Up to Week 48 in Step 2 | 
| Proportions of participants with HIV RNA <1000 copies/mL | Percentage of participants will be calculated. | Up to Week 48 in Step 2 | 
| Peripheral HIV RNA | Serum level of viral RNA (copies/mL) will be measured. | Up to Week 48 in Step 2 | 
| Plasma level of 10E8.4/iMab | Serum level of 10E8.4/iMab (ug/mL) will be measured. | Up to Week 48 in Step 2 | 
| Plasma level of VRC07-523LS | Serum level of VRC07-523LS (ug/mL) will be measured. | Up to Week 48 in Step 2 | 
| CD4 receptor occupancy | The percentage of CD4 cells that bind to 10E8.4/iMab will be measured. | Up to Week 48 in Step 2 | 
| HIV reservoir size | Will measure HIV DNA in copies/million cells. | Up to Week 48 in Step 2 | 
| Neutralization sensitivity of 10E8.4/iMab | Half-maximal inhibitory concentration (IC50) will be measured. | Up to Week 48 in Step 2 | 
| Neutralization sensitivity of VRC07-523LS | Half-maximal inhibitory concentration (IC50) will be measured. | Up to Week 48 in Step 2 | 
| Presence of anti-bNAb antibodies | The anti-drug antibody titer in serum will be measured. | Up to Week 48 in Step 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antiretroviral therapy (ART), VRC07-523LS, 10E8.4/iMab, Monoclonal antibody, Bispecific antibody, Broadly neutralizing antibodies, Viral suppression, Ibalizumab, 10E8