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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: 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)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

8

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: International AIDS Vaccine Initiative
• Collaborators: Beth Israel Deaconess Medical Center; Ragon Institute of MGH, MIT and Harvard; University of Texas Health, Houston AIDS Research Team (HART); Orlando Immunology Clinic
• Investigators: Principal Investigator: Boris Juelg, MD, PhD, Beth Israel Deaconess Medical Center, Center for Virology and Vaccine Research, Ragon Institute of MGH, MIT and Harvard; Study Chair: Kathryn Stephenson, MD, MPH, Beth Israel Deaconess Medical Center, Center for Virology and Vaccine Research

Publications and helpful links

General Publications

• Julg B, Stephenson KE, Wagh K, Tan SC, Zash R, Walsh S, Ansel J, Kanjilal D, Nkolola J, Walker-Sperling VEK, Ophel J, Yanosick K, Borducchi EN, Maxfield L, Abbink P, Peter L, Yates NL, Wesley MS, Hassell T, Gelderblom HC, deCamp A, Mayer BT, Sato A, Gerber MW, Giorgi EE, Gama L, Koup RA, Mascola JR, Monczor A, Lupo S, Rolle CP, Arduino R, DeJesus E, Tomaras GD, Seaman MS, Korber B, Barouch DH. Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial. Nat Med. 2022 Jun;28(6):1288-1296. doi: 10.1038/s41591-022-01815-1. Epub 2022 May 12.

Helpful Links

• IAVI Website

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2017
• Primary Completion (Actual): April 20, 2020
• Study Completion (Actual): April 20, 2020

Study Registration Dates

• First Submitted: May 12, 2017
• First Submitted That Met QC Criteria: June 28, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): September 14, 2020
• Last Update Submitted That Met QC Criteria: September 11, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: IAVI T002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No