Drug Database: PGDM1400

Mechanism of Action

Broadly neutralizing antibody (bNAb). PGDM1400 is a recombinant human IgG1 monoclonal antibody. It is a second-generation bNAb that targets the V2 apex region on the HIV-1 envelope glycoprotein trimer and has broad and potent neutralizing activity against 83% of a large panel of cross-clade pseudoviruses.^4–6 The long-acting engineered variant of PGDM1400, known as PGDM100LS, was designed with an LS mutation to improve in vivo half-life.²

Second-generation HIV bNAbs are naturally occurring antibodies with potent neutralizing activity against a broad array of HIV strains. The utility of bNAbs is being researched for both HIV prevention and treatment/cure. By binding to sites on HIV envelope and through Fc receptor interactions, bNAbs can potentially 1) inhibit cell-free and cell-to-cell viral entry, 2) induce cellular phagocytosis and destruction by macrophages or antibody dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells, and 3) promote the maturation and activity of dendritic cells.^7–10 Because it is difficult to induce in vivo generation of bNAbs using conventional vaccination techniques, bNAbs may need to be given by passive transfer, whereby a bNAb is directly administered to an individual.^7,11

PGDM1400 and PGDM1400LS, are being studied for HIV prevention and/or as a possible component to HIV treatment or cure.^1,3

Half-life (T_½)

In the Phase 1/2a IAVI T003 study (NCT03721510) evaluating triple bNAb therapy with PGT121, PGDM1400, and VRC07-523LS administered via IV infusion in adults with and without HIV, the median elimination half-life of PGDM1400 was approximately 24 days.^12,13

PGDM1400LS is expected to have an extended plasma half-life compared to PGDM1400.²

Resistance

The IAVI T003 study (NCT03721510) evaluated monthly infusions of triple bNAb therapy (PGT121, PGDM1400, and VRC07-523LS) in 12 participants with viral suppression. Two participants who had viral rebound early in the study were found to have pre-existing baseline virus that was resistant to PGT121 and PGDM1400. In one of the two participants, the rebound virus selected for new PGT121 and VRCC07-523LS mutations, which were not present at baseline. Five participants experienced late viral rebound with low plasma levels of PGT121 and PGDM1400 but high levels of VRC07-523LS. One of the five participants received only three doses of triple bNAb infusions, and late rebound occurred despite having virus that was susceptible to the three bNAbs. In a second participant, the virus at rebound was found to be fully resistant to PGT121 and PGDM1400. In a third participant, rebound occurred with virus that had intermediate resistance to PGT121 and PGDM1400.^12,13

Select Clinical Trials

Select Clinical Trials

Study Identifiers: IAVI T003; NCT03721510

Sponsor: International AIDS Vaccine Initiative
Phase: 1/2a
Status: This study has been completed. 
Study Purpose: The purpose of this open-label study was to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the bNAbs PGT121, VRC07-523LS, and PGDM1400 in adults with and without HIV.
Study Population: 

• Participants were adults without and with HIV.
• Participants with HIV had been on ART for at least 24 months, had HIV RNA <50 copies/mL for at least 12 months and at screening, and had CD4 counts ≥400 cells/mm³.¹²

Selected Study Results: Results presented at CROI 2024 showed that triple bNAb therapy with PGT121, VRC07-523LS, and PGDM1400 was generally safe and well tolerated. Most participants (83%) who received bNAb therapy while undergoing an analytical treatment interruption of ART maintained viral suppression for at least 28 weeks (duration of the dosing period). Although bNAb concentrations declined to low or undetectable levels during the follow-up period, 36% of the participants who completed follow-up had viral suppression through the end of the study (Week 44).¹³ 

Study Identifier: NCT04983030

Sponsor: Boris Juelg, MD PhD
Phase: 1/2a
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety, immunogenicity, and efficacy of therapeutic HIV vaccines (Ad26.Mos4.HIV prime and MVA-BN-HIV boost) in combination with bNAbs (PGT121, PGDM1400, and VRC07-523LS) in adults on suppressive ART. Researchers will assess whether this combination strategy can control participants’ viral load levels during an ATI of ART.
Study Population: 

• Participants are adults with HIV who have been on a suppressive ART regimen for at least 48 weeks prior to screening.
• Participants have HIV RNA <50 copies/mL at screening and at least one documented result of HIV RNA <50 copies/mL after the last ART change.
• Participants have CD4 counts >450 cells/mm3 at screening and at least one documented result >300 cells/mm³ within the past 48 weeks prior to randomization.¹⁴

Additional studies evaluating PGDM1400 for HIV treatment have been completed or are being conducted, including the following Phase 1 trials:

• IAVI T002 (NCT03205917): A study that evaluated the safety, tolerability, pharmacokinetics, and antiviral activity of the bNAbs PGDM1400, PGT121, and VRC07-523LS in adults without HIV and adults with HIV who were not on ART. This study has been completed, and results are available from CROI 2022 and Nature Medicine (2022).¹⁵
• RV 582 (NCT05769569): A study evaluating the safety and efficacy of VRC07-523LS, PGDM1400LS, and N-803 (an IL-15 superagonist) in combination with the therapeutic HIV vaccines Ad26.Mos4.HIV, MVA-BN-HIV, and A244d11 gp120/ALFQ for the induction of HIV remission. See the ClinicalTrials.gov record for this study’s status.¹⁶