A Clinical Trial of PGDM1400 and PGT121 and VRC07-523LS Monoclonal Antibodies in HIV-infected and HIV-uninfected Adults

Study Overview
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Brief Summary
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This is a Phase 1 study to evaluate the safety, tolerability, pharmacokinetics and anti-viral efficacy of the PGDM1400 and PGT121 and VRC07-523LS mAbs for HIV prevention and therapy.

Detailed Description
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This is a Phase 1 study to evaluate the safety, tolerability, pharmacokinetics and anti-viral efficacy of the PGDM1400, PGT121 and VRC07-523LS mAbs for HIV prevention and therapy. PGDM1400, PGT121 and VRC07-523LS mAbs are recombinant human IgG1 monoclonal antibodies that target V1V2 (PGDM1400), a V3 glycan-dependent epitope (PGT121) and the CD4 binding site (VRC07-523LS) epitope region of the HIV envelope protein. PGT121, PGDM1400 and VRC07-523LS mAb were chosen for this study because of their potency, their ability to neutralize a wide array of cross-clade HIV viruses in a complementary pattern and their proven antiviral activity in animal studies e.g., their capacity to robustly prevent and treat simian-human immunodeficiency virus (SHIV) in rhesus monkeys.

Official Title
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A Phase 1 Randomized Placebo-controlled Clinical Trial of the Safety, Pharmacokinetics and Antiviral Activity of PGDM1400 and PGT121 and VRC07-523LS Monoclonal Antibodies in HIV-uninfected and HIV-infected Adults

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: PGDM1400/Placebo (3mg/kg IV)
* Biological: PGDM1400/Placebo (10mg/kg IV)
* Biological: PGDM1400/Placebo (30mg/kg IV)
* Biological: PGDM1400 + PGT121/Placebo (3mg/kg + 3mg/kg IV)
* Biological: PGDM1400 + PGT121/Placebo (10mg/kg + 10mg/kg IV)
* Biological: PGDM1400 + PGT121/Placebo (30mg/kg + 30mg/kg IV)
* Biological: PGDM1400 + PGT121 + VRC07-523LS (20mg/kg + 20mg/kg + 20 mg/kg IV)
* Biological: PGDM1400 + PGT121 (MTD IV)


Participation Criteria
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Eligibility Criteria
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Groups 1 and 2 Inclusion Criteria: HIV-uninfected males or females age 18-50 years old Willing to maintain low risk behavior for HIV infection Groups 1 and 2 Exclusion Criteria: • Confirmed HIV-infection, pregnancy or lactation, significant acute or chronic disease and clinically significant laboratory abnormalities Group 3 Inclusion Criteria: HIV-infected males or females age 18-65 years old Not on antiretroviral therapy with HIV-1 RNA plasma level between 1,000 and 100,000 copies/ml, CD4 cell count ≥ 300 cells/uL Group 3 Exclusion Criteria: • Significant acute or chronic medical condition other than HIV infection, and clinically significant laboratory abnormalities

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1A HIV-Uninfected<br>PGDM1400 low dose | Biological: PGDM1400/Placebo (3mg/kg IV)<br>* 3/1 (6/2 if DLT)<br>|
| Experimental: Group 1B HIV-Uninfected<br>PGDM1400 mid dose | Biological: PGDM1400/Placebo (10mg/kg IV)<br>* 3/1 (6/2 if DLT)<br>|
| Experimental: Group 1C HIV-Uninfected<br>PGDM1400 high dose | Biological: PGDM1400/Placebo (30mg/kg IV)<br>* 3/1 (6/2 if DLT)<br>|
| Experimental: Group 2A HIV-Uninfected<br>PGDM1400 + PGT121 low dose | Biological: PGDM1400 + PGT121/Placebo (3mg/kg + 3mg/kg IV)<br>* 3/1 (6/2 if DLT)<br>|
| Experimental: Group 2B HIV-Uninfected<br>PGDM1400 + PGT121 mid dose | Biological: PGDM1400 + PGT121/Placebo (10mg/kg + 10mg/kg IV)<br>* 3/1 (6/2 if DLT);<br>|
| Experimental: Group 2C HIV-Uninfected<br>PGDM1400 + PGT121 high dose | Biological: PGDM1400 + PGT121/Placebo (30mg/kg + 30mg/kg IV)<br>* 3/1 (6/2 if DLT)<br>|
| Experimental: Group 3A HIV-infected off ART<br>PGDM1400 + PGT121 + VRC07-523LS at 20mg/kg; HIV+ without ART | Biological: PGDM1400 + PGT121 + VRC07-523LS (20mg/kg + 20mg/kg + 20 mg/kg IV)<br>* 3 (max 9)<br>|
| Experimental: Group 3B HIV-infected off ART<br>PGDM1400 + PGT121 at high dose; HIV + without ART | Biological: PGDM1400 + PGT121 (MTD IV)<br>* 3 (max 9)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Proportion of participants with moderate or greater reactogenicity (e.g., solicited adverse events) for 3 days following IV infusion of PGDM1400 mAb alone, and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb Proportion of participants with adverse events (AEs), including safety laboratory (biochemical, hematological) parameters, during the first 56 days following IV infusion of PGDM1400 mAb alone and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb, that are moderate or greater, and/or related to PGDM1400 mAb or PGT121 mAb or VRC07-523LS mAb Proportion of participants with SAEs throughout the study period following IV infusion of PGDM1400 mAb alone and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb, that are related to PGDM1400 mAb or PGT121 mAb or VRC07-523LS mAb | 6 Months post infusion | 
| Elimination half-life (t1/2) | Elimination half-life following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults | 6 Months post infusion | 
| Clearance (CL/F) | Clearance following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults. | 6 months post infusion | 
| Volume of distribution (Vz/F) | Volume of distribution following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults | 6 months post infusion | 
| Area under the concentration decay curve (AUC) | AUC following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults | 6 months post infusion | 
| Impact of viral load and/or ART | Impact of viral load and/or ART on PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb disposition | 6 months post infusion | 
| Antiviral activity of PGDM1400 in combination with PGT121 or PGDM1400 in combination with PGT121 and VRC07-523LS mAbs | Antiviral activity following IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb, in viremic HIV-infected adults not on ART: Change in plasma HIV-1 RNA levels from baseline (mean of pre-entry and entry values) | 6 Months post infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum antibody titers against bNAbs | Serum anti-PGDM1400 antibody titers, Serum anti-PGT121 antibody titers and Serum anti-VRC07-523LS antibody titers | 6 Months post infusion | 
| CD4+ T cell count | Determine if IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb, has any impact on CD4+ T cell counts in HIV-infected adults. Change in CD4+ T cell count compared to baseline as measured by single platform flow cytometry | 6 Months post infusion | 
| HIV genotyping of circulating virus | Compare plasma virus genotype activity before and after IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb to determine if PGDM1400 mAb and PGT121 mAb and/or PGT121VRC07-523LS mAb induced viral escape mutations have developed in viremic HIV-infected adults not on ART Genotypic analysis: Development of sequence variations in epitopes known to result in reduced PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization susceptibility or known to cause resistance to antiretroviral drugs | 6 Months post infusion | 
| HIV phenotyping of circulating virus | Compare plasma virus phenotypic activity before and after IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb to determine if PGDM1400 mAb and PGT121 mAb and/or PGT121VRC07-523LS mAb induced viral escape mutations have developed in viremic HIV-infected adults not on ART. Phenotypic analysis: Changes in viral susceptibility to PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization Phenotypic analysis: Changes in viral susceptibility to PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization. | 6 months post infusion |