Drug information

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PGDM1400
Other Names
PGDM1400LS (long-acting form of PGDM1400)
Drug Class
Broadly Neutralizing Antibodies
Organization:
PGDM1400LS is being developed by the National Institute of Allergy and Infectious Diseases (NIAID)
Phase of Development

PGDM1400LS is in Phase 1/2a development as a broadly neutralizing antibody for HIV treatment. (PGDM1400LS is also being studied for HIV prevention.)

(Compound details obtained from Treatment Action Group website,1 Protocol HVTN 143/HPTN 109,2 and ClinicalTrials.gov3)

Pharmacology

Pharmacology

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 PGDM1400LS, 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 as a possible component to HIV treatment or cure. Additionally, PGDM1400LS is currently under clinical development for HIV prevention.1,3

Half-life (T½)

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 VRC07-523LS 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 published in Nature Medicine (2024) and 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, 42% of the participants had viral suppression for at least 38 to 44 weeks.13,14

Study Identifier: NCT04983030

Sponsor: Boris Juelg, MD PhD
Phase: 1/2a
Status: This study is ongoing, but not 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.15

Study Identifiers: IMPAACT 2042; Tatelo Plus Study; NCT06508749

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 1/2
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the impact of three bNAbs (PGDM1400LS, VRC07-523LS, and PGT121.414.LS) or ATI on viral reservoir, immune function, and maintenance of HIV suppression in early ART-treated children in Botswana.
Study Population:

  • Participants are children and young adults (24 weeks to 25 years of age) with HIV who were previously enrolled in the EIT/Tatelo or Moso Cohort Study.
  • Participants have been receiving ART and have HIV RNA <40 copies/mL.16

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).17
  • RV 630/ACHIEV (NCT06484335): A trial evaluating the safety and efficacy of the bNAbs VRC07-523LS and PGDM1400LS in combination with therapeutic HIV vaccines for the induction of HIV remission in adults with HIV who initiated ART during the acute stage of infection. See the ClinicalTrials.gov record for this study’s status.18

Adverse Events

Adverse Events

IAVI T003; NCT03721510

In this Phase 1/2a trial, three participants without HIV received a single infusion of PGT121 and VRC07-523LS and three other participants without HIV received a single infusion of PGT121, VRC07-523LS, and PGDM1400. Thereafter, 12 participants with HIV received up to six monthly infusions of PGT121, VRC07-523LS, and PGDM1400. All three bNAbs studied were reported to be generally safe and well tolerated. There were four serious adverse events (SAEs) and/or a Grade 3 or higher adverse event (AE), all of which were considered unrelated to the study bNAbs.12,13

Drug Interactions

Drug Interactions

Drug-drug interactions associated with PGDM1400 are currently unknown.

References

References

  1. Treatment Action Group website. Research toward a cure trials. Accessed May 7, 2025
  2. HIV Vaccine Trials Network and HIV Prevention Trials Network. Protocol HVTN 143/HPTN 109: a phase 1 clinical trial to evaluate the safety, tolerability, and pharmacokinetics of monoclonal antibodies VRC01.23LS, PGT121.414.LS and PGDM1400LS administered via intravenous infusion in adults without HIV [Version 1.0]; June 7, 2023. Accessed May 7, 2025
  3. National Institute of Allergy and Infectious Diseases (NIAID). A randomized, double blind, controlled, Phase 2 clinical trial to evaluate the safety, tolerability, pharmacokinetics, and neutralization of VRC07-523LS, PGT121.414.LS, and PGDM1400LS broadly neutralizing monoclonal antibodies given intravenously in adult participants without HIV. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 31, 2025. NLM Identifier: NCT06812494. Accessed May 7, 2025
  4. Julg B, Stephenson KE, Wagh K, et al. Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a Phase 1 clinical trial. Nat Med. 2022;28(6):1288-1296. doi:10.1038/s41591-022-01815-1. Accessed May 7, 2025
  5. Griffith SA, McCoy LE. To bnAb or not to bnAb: defining broadly neutralising antibodies against HIV-1. Front Immunol. 2021;12:708227. doi:10.3389/fimmu.2021.708227. Accessed May 7, 2025
  6. Julg B, Tartaglia LJ, Keele BF, et al. Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge. Sci Transl Med. 2017;9(406):eaal1321. doi:10.1126/scitranslmed.aal1321. Accessed May 7, 2025
  7. Halper-Stromberg A, Nussenzweig MC. Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest. 126(2):415-423. doi:10.1172/JCI80561. Accessed May 7, 2025
  8. Bruel T, Guivel-Benhassine F, Amraoui S, et al. Elimination of HIV-1-infected cells by broadly neutralizing antibodies. Nat Commun. 2016;7. doi:10.1038/ncomms10844. Accessed May 7, 2025
  9. Stephenson KE, Barouch DH. Broadly Neutralizing Antibodies for HIV Eradication. Curr HIV/AIDS Rep. 2016;13(1):31-37. doi:10.1007/s11904-016-0299-7. Accessed May 7, 2025
  10. Liu Y, Cao W, Sun M, Li T. Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities. Emerg Microbes Infect. 9(1):194-206. doi:10.1080/22221751.2020.1713707. Accessed May 7, 2025
  11. Caskey M, Klein F, Lorenzi JCC, et al. 3BNC117 a broadly neutralizing antibody suppresses viremia in HIV-1-infected humans. Nature. 2015;522(7557):487-491. doi:10.1038/nature14411. Accessed May 7, 2025
  12. International AIDS Vaccine Initiative. A Phase 1/2a open label study of the safety, tolerability, pharmacokinetics and antiviral activity of PGT121, VRC07-523LS and PGDM1400 monoclonal antibodies in HIV-uninfected and HIV-infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 16, 2018. NLM Identifier: NCT03721510. Accessed May 7, 2025
  13. Juelg BD, Walker-Sperling VE, Wagh K, et al. Therapeutic efficacy of a triple combination of HIV-1 broadly neutralizing antibodies. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2024; Denver, CO. Accessed May 7, 2025
  14. Julg B, Walker-Sperling VEK, Wagh K, et al. Safety and antiviral effect of a triple combination of HIV-1 broadly neutralizing antibodies: a phase 1/2a trial. Nat Med. 2024;30(12):3534-3543. doi:10.1038/s41591-024-03247-5. Accessed May 7, 2025
  15. Boris Juelg, MD PhD. A safety, immunogenicity and efficacy Phase 1/2a study of a heterologous Ad26.Mos4.HIV, MVA-BN-HIV vaccine regimen plus broadly neutralizing antibodies PGT121, PGDM1400, and VRC07-523LS in HIV-1-infected adults on suppressive ART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 5, 2021. NLM Identifier: NCT04983030. Accessed May 7, 2025
  16. National Institute of Allergy and Infectious Diseases (NIAID). Phase I/II trial to evaluate the impact of three broadly neutralizing antibodies or analytic treatment interruption on viral reservoir, immune function, and maintenance of HIV suppression in early treated children in Botswana. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 26, 2024. NLM Identifier: NCT06508749. Accessed May 7, 2025
  17. International AIDS Vaccine Initiative. 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. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 12, 2017. NLM Identifier: NCT03205917. Accessed May 7, 2025
  18. Henry M. Jackson Foundation for the Advancement of Military Medicine. Approach to control HIV with immune enhancement and vaccination (ACHIEV): safety and efficacy of broadly neutralizing antibodies combined with therapeutic vaccination for the induction of HIV remission. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 31, 2024. NLM Identifier: NCT06484335. Accessed May 7, 2025

Last Reviewed: May 7, 2025