Safety and Tolerability of AAV8 Delivery of a Broadly Neutralizing Antibody in Adults Living With HIV: a Phase 1, Dose-escalation Trial

Study Overview
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Brief Summary
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Background: The Human Immunodeficiency Virus (HIV) attacks the immune system. Scientists have created a gene that could be transferred to the cells of people with HIV. The gene should tell the cells to make an antibody called VRC07. This antibody fights HIV. The VRC07 gene is packaged into a man-made version of a virus called AAV8. Objectives: To see if AAV8-VRC07 is safe. To study if it causes cells to produce the VRC07 antibody. Eligibility: Adults ages 18-65 who are HIV infected but in general good health and have been taking the same HIV medicine for at least 3 months Design: Participants were screened in a different protocol. Participants received the study product on day 1. It was injected one or more times in the upper arm or thigh using a needle. Participants weight was measured to calculate the dose. Women may have had a pregnancy test. For 7 days after getting the study product, participants checked their temperature with a thermometer. They noted any symptoms in an electronic or paper diary. Participants will have study visits. At each one, they will have a physical exam and medical history. They will have blood drawn and may have saliva collected. The study visit schedule is as follows: For 12 weeks: 1 visit a week For the next 12 weeks: 1 visit every other week Then about 1 visit a month After 1 year in the study: a visit every 6 months for the next 4 years. Total study participation is 5 years.

Detailed Description
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Design: This is a Phase I study of the safety and tolerability of AAV8-VRC07 (VRC-HIVAAV070-00-GT) expressing VRC07 human monoclonal antibody with broad HIV-1 neutralizing activity in HIV-1 infected adults. It is a dose-escalation study to examine pharmacokinetics of VRC07 expression following intramuscular (IM) administration of AAV8-VRC07 in participants on anti-retroviral therapy (ARV). The hypotheses are: 1) AAV8-VRC07 will be safe for human administration and will not elicit hypersensitivity or anti-drug antibody (ADA) to VRC07; and 2) intramuscular delivery of AAV8-VRC07 will result in production of biologically active VRC07 antibody at a concentration in serum that is measurable and safe. Description: AAV8-VRC07 was developed by VRC, NIAID, NIH, and manufactured by the Clinical Vector Core, Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania (PA). It is composed of an AAV8 recombinant vector expressing genes encoding the heavy and light chains of the VRC07 monoclonal antibody. AAV8-VRC07 was supplied at 2.84 x 10^13 vector genomes (vg)/mL. Participants: HIV-1 infected adult volunteers (18 to 65 years old) on a stable antiretroviral regimen for more than or equal to 3 months, with controlled viremia, under the care of a physician, and without additional clinically significant medical conditions. Study Plan: There are 3 dose escalation groups. Sequentially enrolled participants were assigned to the dosage level being evaluated at the time of enrollment. All injections were administered intramuscularly (IM) by needle and syringe. Cumulative safety data were reviewed weekly by a Protocol Safety Review Team (PSRT) that included an Independent Safety Monitor (ISM) while injections were being administered. Safety, including reactogenicity and unsolicited adverse events (AEs), laboratory findings, pharmacokinetics, and VRC07 antibody levels in blood were assessed after the injection and summarized for an interim analysis at 4 weeks post injection. The second participant in each dose group was injected after the 4 weeks safety assessment for the first participant. Decisions regarding dose escalation and participant enrollments were based on safety data and the VRC07 concentration in blood at 4 weeks after product administration. The pharmacokinetics of VRC07 at each dose level was evaluated to determine the dose that would result in antibody production that achieves at least 50 mcg/mL VRC07 concentration in serum at 4 weeks post injection with a target set point of more than or equal to 5 mcg/mL at 12 weeks post injection.

Official Title
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VRC 603: A Phase I Dose-Escalation Study of the Safety of AAV8-VRC07 (VRC-HIVAAV070-00-GT) Recombinant AAV Vector Expressing VRC07 HIV-1 Neutralizing Antibody in Antiretroviral-Treated, HIV-1 Infected Adults With Controlled Viremia

Conditions
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HIV-1 Infected Adults With Controlled Viremia

Intervention / Treatment
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* Genetic: VRC-HIVAAV070-00-GT (AAV8-VRC07)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: A volunteer must have met all of the following criteria: Able and willing to complete the informed consent process. 18 to 65 years of age. HIV-1 infected. On a stable antiretroviral regimen for greater than or equal to 3 months. Available for clinical follow-up through the last study visit. Based on history and examination, must be in general good health with no evidence of clinically significant lab abnormalities and without additional clinically significant medical conditions as per exclusion criteria. Willing to maintain or establish a relationship with a primary health care provider for medical management of HIV infection while participating in the study. Willing to have blood samples collected, stored indefinitely, and used for research purposes. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process. Laboratory tests assessing individual's health will be conducted within 84 days prior to enrollment and values must meet the following criteria: White blood cell count (WBC) 2,500-12,000/mm^3; WBC differential either within institutional normal range or accompanied by approval of the Principal Investigator (PI) or designee; Platelets = 125,000-400,000/mm^3; Hemoglobin greater than or equal to 10.0 gm/dL; Creatinine less than or equal to 1.25 x upper limit of normal (ULN); Alanine aminotransferase (ALT) less than or equal to 1.1 x ULN; Aspartate aminotransferase (AST) less than or equal to 1.1 x ULN; and, Viral Load (VL) less than or equal to 50 copies/mL and a CD4 count greater than or equal to 300/mcL (microliter). Male-Specific Criteria: Males must agree to use condoms for all sexual activity of any reproductive potential for 52 weeks after receiving the study product. Female-Specific Criteria: If a woman is sexually active with a male partner and has no history of hysterectomy, tubal ligation or menopause, she must agree to use either a prescription birth control method or a barrier birth control method from the time of study enrollment through study Week 52, or to be monogamous with a partner who has had a vasectomy. Negative beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment for women presumed to be of reproductive potential. EXCLUSION CRITERIA: A volunteer would have been excluded if one or more of the following conditions applied: Previous receipt of monoclonal antibody whether licensed or investigational. Previous receipt of gene therapy product. Ongoing AIDS-related opportunistic infection (including oral thrush). Active injection drug use or active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. A titer of pre-existing antibodies to AAV8 capsid is greater than 1:90. Weight > 115 kg for Group 3 participants only. History of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis within the 2 years prior to enrollment that has a reasonable risk of recurrence. Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM injections or blood draws. Active liver disease such as chronic hepatitis. Hypertension that is not well controlled by medication. Woman who is breast-feeding or planning to become pregnant during the study participation. Receipt of any investigational study agent within 28 days prior to enrollment. Current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Any other chronic or clinically significant medical condition that in the opinion of investigator would jeopardize the safety or rights of the volunteer, including, but not limited to: diabetes mellitus type I; OR clinically significant forms of asthma, autoimmune disease, psychiatric disorders, heart disease, or cancer.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: AAV8-VRC07 (5 x 10^10 vg/kg IM)<br>AAV8-VRC07 (5 x 10^10 vg/kg) administered by intramuscular (IM) injection (Day 0) | Genetic: VRC-HIVAAV070-00-GT (AAV8-VRC07)<br>* AAV8-VRC07 is a recombinant AAV vector expressing a HIV-1 CD4 binding site-specific neutralizing antibody, VRC07<br>|
| Experimental: Group 2: AAV8-VRC07 (5 x 10^11 vg/kg IM)<br>AAV8-VRC07 (5 x 10^11 vg/kg) administered by IM injection (Day 0) | Genetic: VRC-HIVAAV070-00-GT (AAV8-VRC07)<br>* AAV8-VRC07 is a recombinant AAV vector expressing a HIV-1 CD4 binding site-specific neutralizing antibody, VRC07<br>|
| Experimental: Group 3: AAV8-VRC07 (2.5 x 10^12 vg/kg IM)<br>AAV8-VRC07 (2.5 x 10^12 vg/kg) administered by IM injection (Day 0) | Genetic: VRC-HIVAAV070-00-GT (AAV8-VRC07)<br>* AAV8-VRC07 is a recombinant AAV vector expressing a HIV-1 CD4 binding site-specific neutralizing antibody, VRC07<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of AAV8-VRC07 Product Administration | Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for Any Local Symptom is the number of participants reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. | 7 days after AAV8-VRC07 product administration, at approximately Week 1 | 
| Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of AAV8-VRC07 Product Administration | Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for Any Systemic Symptom is the number of participants reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. | 7 days after AAV8-VRC07 product administration, at approximately Week 1 | 
| Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following AAV8-VRC07 Product Administration | Unsolicited adverse event (AE) data collection included AEs of all severities from the date of product administration through the Day 56 (8 weeks) post-product administration visit. After the Day 56 (8 weeks) post-product administration visit, only serious AEs (SAEs reported as a separate outcome and in the AE module) and new chronic medical conditions that require ongoing medical management (reported as a separate outcome) will be recorded through the last study visit. The relationship between a non-serious AE and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity. | Day 0 through 8 weeks after AAV8-VRC07 product administration | 
| Number of Participants With Abnormal Laboratory Measures of Safety Following AAV8-VRC07 Product Administration | Abnormal laboratory results recorded as unsolicited adverse events (AEs) are summarized. Safety lab parameters included hematology (hemoglobin, hematocrit, mean corpuscular volume (MCV), platelets, and neutrophil, lymphocyte, monocyte, eosinophil and basophil counts) and chemistry (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine). Complete Blood Count (CBC) with differential and chemistry (ALT, AST and creatinine) results were collected at different timepoints throughout the study per the protocol's schedule of evaluations. Institutional laboratory normal ranges as well as the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 were used. | Day 0 through 8 weeks after AAV8-VRC07 product administration | 
| Geometric Mean Endpoint Titer of Anti-AAV8 Antibodies | Anti-AAV8 antibodies were analyzed by enzyme-linked immunosorbent assay (ELISA) using a vector-matched AAV8 capsid as the capture agent. Group geometric means and 95% confidence intervals (CIs) for the endpoint titers for the AAV8 ELISA assay are reported at baseline, week 12 for the peak response, and week 44 for durability. Values below the lower limit of detection (LOD) were imputed to the lower LOD (30) and values above the assay upper LOD were imputed to the upper LOD (21870). | Day 0 through 44 Weeks after AAV8-VRC07 product administration | 
| Number of Participants Who Attained A 50 mcg/mL VRC07 Serum Concentration | In order to determine the optimal AAV8-VRC07 dose, participants must have attained a 50 mcg/mL VRC07 Serum Concentration. If no participants attained at least 50 mcg/mL VRC07 serum concentration, then the optimal AAV8-VRC07 dose cannot be determined. | Day 0 through 52 Weeks after AAV8-VRC07 product administration | 
| Geometric Mean Concentration of VRC07 Serum Antibodies (PK ELISA) | For the pharmacokinetic (PK) primary outcome analysis, PK ELISA detected VRC07 serum antibodies in mcg/mL, using the VRC01 anti-idiotype Fab specific 5C9 monoclonal antibody (mAb). Only visits that had detectable PK ELISA concentrations for any participant are reported. Results are reported in group geometric mean mcg/mL concentrations with 95% CIs. The protocol specifies that a more sensitive assay can also be used; the more sensitive Singulex assay results are reported later in the secondary outcome measure. Values below the lower limit of detection (LOD) were imputed to the lower LOD (1 mcg/mL) with no 95% CI. | Day 0 through 52 Weeks after AAV8-VRC07 product administration | 
| Number of Participants With Serious Adverse Events (SAEs) Following AAV8-VRC07 Product Administration | SAEs are recorded from receipt of study product through the last expected study visit at Year 5 (260 weeks). The relationship between a SAE and the study product is assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity. | Day 0 through 5 Years (260 weeks) after AAV8-VRC07 product administration | 
| Number of Participants With New Chronic Medical Conditions Following AAV8-VRC07 Product Administration | New chronic medical conditions are recorded from receipt of study product through the last expected study visit at Year 5 (260 weeks). The relationship between a new chronic medical condition and the study product is assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity. | Day 0 through 5 Years (260 weeks) after AAV8-VRC07 product administration | 
| Number of Participants Who Produced VRC07 Anti-drug Antibodies (ADA) | A three-tiered assay was used for ADA evaluation. The tier 1 screening assay measures specific and non-specific binding of serum proteins to VRC07 and the assay membrane. The tier 2 assay is a qualitative competition assay in which exogenously added VRC07 removes any VRC07-binding proteins from the serum prior to the binding assay. If the addition of the exogenous VRC07 results in a reduction of signal, the specificity of VRC07 binding is confirmed. The tier 3 assay is a qualitative assay that assesses the ability of VRC07-binding serum protein to prevent VRC07-mediated neutralization of an HIV pseudovirus in vitro. Only samples positive for a tier will be analyzed in subsequent tiers. | Day 0 through 5 Years (260 weeks) after AAV8-VRC07 product administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Value of CD4 Cell Counts | The clinical effects of pAAV8-VRC07 on cluster of differentiation 4 (CD4) cell count were assessed. CD4 Cell Count (cells/mL) shown as reported by the Clinical Center serology lab. Values are reported as group geometric means and 95% CIs. | Day 0 through 44 Weeks after AAV8-VRC07 product administration | 
| Viral Load | The clinical effects of pAAV8-VRC07 on viral load were assessed. Viral Load is expressed in polymerase chain reaction (PCR) copies/mL, as reported by the Clinical Center serology lab. Values below the limit of quantification (<20 copies/mL) or none detected were imputed to 10 copies/mL. Results are displayed as median(range). | Day 0 through 44 Weeks after AAV8-VRC07 product administration | 
| Concentration of VRC07 Serum Antibodies (Singulex Assay) | The serum concentration of VRC07 at specified time intervals for 1 year after injection was determined, and if persistent, then every 6 months as long as there is detectable antibody in serum. The PK Singulex assay utilizes a microparticle-based immunoassay coupled with a fluorescent detection system to detect serum antibodies in the ng/mL range. Values below the limit of detection or none detected were set to 0.10 ng/mL; therefore, a value of 0.10 ng/mL means that the VRC07 concentration for that assay was below the limit of detection. Results are displayed as median(range). | Day 0 through 52 weeks after AAV8-VRC07 product administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARV Therapy, Broadly Neutralizing, Gene Transfer, Monoclonal Antibody, AAV8