Drug Database: VH3810109

Pharmacology Pharmacology

Pharmacology

Mechanism of Action

Broadly neutralizing antibody (bNAb). VH3810109 (also known as GSK3810109A and N6LS) is a human IgG1 monoclonal antibody belonging to the VRC01 antibody class. It is a modified version of the parent bNAb (N6), optimized with an LS mutation to extend its plasma half-life. VH3810109 is a next-generation bNAb that targets the CD4 binding site on HIV envelope gp120 and has broad and potent neutralizing activity against 98% of a comprehensive panel of HIV isolates, including isolates that are resistant to VRC01.^4-6

Next-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.^6–9 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.^7,10

VH3810109 has been studied for HIV prevention and is also being developed as a possible component to HIV treatment or cure.^1,3,11

Half-life (T_½)

A Phase 1 dose-escalation trial (NCT03538626) investigated the safety and pharmacokinetics of VH3810109 administered by intravenous (IV) and subcutaneous (SC) infusion in healthy adults. The estimated serum half-life of VH3810109 ranged from 33 to 52 days with IV dosing (5, 20, or 40 mg/kg) and was 36 to 46 days with SC dosing (5 mg/kg). The addition of recombinant human hyaluronidase PH20 (rHuPH20) to SC administration of VH3810109 (5 or 20 mg/kg) yielded a VH3810109 half-life of 42 to 57 days.¹²

Resistance

In a Phase 2b trial (EMBRACE; NCT05996471), participants received either IV VH3810109 (n = 50) or SC VH3810109 plus rHuPH20 (n = 49) administered every 4 months, each in combination with long-acting cabotegravir administered monthly. Through Month 6, four participants (two in each VH3810109 dosing group) had confirmed virologic failure (CVF). None of the participants in the active comparator arm receiving standard-of-care ART experienced CVF. Both participants who met CVF in the IV VH3810109 group had virus with phenotypic resistance to VH3810109 (IC₉₀ >2 µg/mL) but no evidence of INSTI resistance-associated mutations (RAMs). One participant with CVF who received SC VH3810109 had an INSTI RAM.^13,14

Select Clinical Trials Select Clinical Trials

Select Clinical Trials

Study Identifiers: BANNER; NCT04871113

Sponsor: ViiV Healthcare
Phase: 2a
Status: This study has been completed.
Study Purpose: The purpose of this open-label trial was to evaluate the antiviral activity, safety, and tolerability of a single IV or SC infusion of VH3810109 administered at various dose levels in treatment-naive adults.
Study Population:

• Participants were treatment-naive adults with HIV.
• Participants had HIV RNA ≥5,000 copies/mL and CD4 counts ≥250 cells/mm3.^15,16

Selected Study Results: Results presented at EACS 2023 and CROI 2024 showed that monotherapy with a single IV or SC infusion of VH3810109 was capable of producing a substantial reduction in viral load levels from baseline in treatment-naive participants. The antiviral response was dose-dependent and correlated with drug exposure. SC dosing led to lower drug exposure and lower antiviral response compared to IV dosing. IV and SC infusions of VH3810109 were safe and well tolerated.^17,18
Additional Published Material:

• CROI, 2023: Impact of baseline factors on virologic response to bNAb VH3810109 (N6LS) in BANNER
• EACS, 2023: Safety and tolerability of VH3810109 (N6LS) among antiretroviral therapy–naive adults living with HIV-1: results from the monotherapy phase of the Phase 2a BANNER study

Study Identifiers: EMBRACE; NCT05996471

Sponsor: ViiV Healthcare
Phase: 2b
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the safety and efficacy of IV VH3810109 and SC VH3810109 with rHuPH20, each in combination with intramuscular (IM) long-acting cabotegravir. Experimental interventions will be compared to standard-of-care ART.
Study Population:

• Participants are adults with HIV who have been on an uninterrupted ART regimen for at least 6 months prior to screening. Any prior changes to ART must not have been done due to treatment failure.
• Participants are not currently on cabotegravir or fostemsavir and have no previous exposure to cabotegravir.
• Participants have HIV RNA <50 copies/mL at screening and have had HIV RNA <50 copies/mL in the 12 months prior to screening. Participants have CD4 counts ≥350 cells/mm³.
• Participants have virus with phenotypic sensitivity to VH3810109.¹³

Selected Study Results: Results presented at CROI 2025 indicated that VH3810109 administered either IV or SC with rHuPH20 every 4 months, in combination with monthly long-acting cabotegravir, was effective in maintaining viral suppression in most of the participants. The proportion of participants maintaining viral suppression through Month 6 was 96% in the IV VH3810109 group and 88% in the SC VH3810109 plus rHuPH20 group. In comparison, 96% of participants in the oral standard-of-care group maintained suppression through Month 6. Study investigators noted that based on results, IV VH3810109 administered every 6 months, in combination with long-acting cabotegravir, was selected for further evaluation in the second part of the EMBRACE study.¹⁴

Additional studies of VH3810109 have also been conducted, including the following Phase 1 trials:

• SPAN (NCT05291520): A single-dose study that evaluated the safety and pharmacokinetics of VH3810109 plus rHuPH20 in healthy participants without HIV. This study has been completed, and results are available from CROI 2024.^19,20
• VRC 609 (NCT03538626): A dose-escalation study that evaluated the safety and pharmacokinetics of VH3810109 administered with or without rHuPH20 in healthy adults without HIV. This study has been completed, and results are available from CROI 2023 and Lancet HIV (2025).^12,21,22

Adverse Events Adverse Events

Adverse Events

BANNER (NCT04871113)

In this Phase 2a trial, 62 participants received a single IV or SC infusion of VH3810109 monotherapy administered at different dose levels. Thirteen (21%) participants had a Grade 1 or 2 drug-related adverse event (AE). The most common drug-related AEs included headache (n = 3), injection site pain (n = 3), injection site bruising (n = 2), and abdominal pain (n = 2). No Grade 3 or 4 drug-related AEs and no serious adverse events (SAEs) were reported. A total of seven (11%) participants experienced nine injection site reactions (ISRs), all of which were mild and lasted a maximum of 10 days. No injection site nodules occurred.^15,23

EMBRACE (NCT05996471)

In this Phase 2b study, participants were randomized to receive either IV VH3810109 given every 4 months, in combination with monthly IM cabotegravir (n = 50); SC VH3810109 plus rHuPH20 given every 4 months, in combination with monthly IM cabotegravir (n = 49); or oral standard-of-care ART (n = 26). VH3810109- or cabotegravir-related AEs occurred in 64% of participants in the IV VH3810109 group and 65% of participants in the SC VH3810109 group. Eight participants in the SC VH3810109 group and none of the participants in the IV VH3810109 group experienced Grade 3 AEs related to VH3810109 or cabotegravir. Participants receiving SC VH3810109 had three serious AEs, and three participants withdrew from the study due to AEs. AEs leading to study withdrawal included cabotegravir-associated injection site pain, hepatitis B reactivation, and anxiety/depression. In the IV VH3810109 arm, there were no AEs resulting in study withdrawal and no serious AEs related to the study drugs.^13,14

Four participants in the IV VH3810109 group reported four ISRs related to VH3810109, all of which were Grade 1 and resolved within 3 days. Twenty-five participants in the SC VH3810109 group reported 70 ISRs related to VH3810109 (39 Grade 1; 20 Grade 2; and 11 Grade 3). In both groups, there were no serious ISRs related to VH3810109 and no ISRs resulting in study discontinuation.¹⁴

Drug Interactions Drug Interactions

Drug Interactions

Drug-drug interactions associated with VH3810109 are currently unknown.

References References

References

1. Jefferys R. Antiretroviral therapy. Treatment Action Group Pipeline Report 2024. Accessed June 16, 2025
2. ViiV Healthcare: Press release, dated November 21, 2019. ViiV Healthcare announces exclusive licensing agreement with the National Institutes of Health for investigational “bNAb” with potential for long-acting HIV treatment and prevention. Accessed June 16, 2025
3. Jefferys R. HIV vaccines & passive immunization. Treatment Action Group Pipeline Report 2022. Accessed June 16, 2025
4. Widge AT, Houser KV, Gaudinski MR, et al. Phase I dose-escalation study of human monoclonal antibody N6LS in healthy adults. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Boston, MA. Poster 508. Accessed June 16, 2025
5. Huang J, Kang BH, Ishida E, et al. Identification of a CD4-binding-site antibody to HIV that evolved near-pan neutralization breadth. Immunity. 2016;45(5):1108-1121. doi:10.1016/j.immuni.2016.10.027. Accessed June 16, 2025
6. 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 June 16, 2025
7. Halper-Stromberg A, Nussenzweig MC. Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest. 2016;126(2):415-423. doi:10.1172/JCI80561. Accessed June 16, 2025
8. Bruel T, Guivel-Benhassine F, Amraoui S, et al. Elimination of HIV-1-infected cells by broadly neutralizing antibodies. Nat Commun. 2016;7:10844. Accessed June 16, 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 June 16, 2025
10. Caskey M Klein F, Lorenzi JC, et al. 3BNC117 a broadly neutralizing antibody suppresses viremia in HIV-1-infected humans. Nature. 2015;522(7557):487-491. Accessed June 16, 2025
11. Treatment Action Group website. Research toward a cure trials. Accessed June 16, 2025
12. Wu RL, Houser KV, Happe M, et al. N6LS with rHuPH20 enables safe high-dose monoclonal antibody subcutaneous delivery. Poster presented at: Conference on Retroviruses and Opportunistic Infections; February 19-22, 2023; Seattle, WA. Poster 499. Accessed June 16, 2025
13. ViiV Healthcare. A Phase 2a multicentre, randomized, open-label, two-part adaptive design study to evaluate the antiviral effect, safety and tolerability of GSK3810109A, an HIV-1 specific broadly neutralizing human monoclonal antibody in antiretroviral-naïve HIV-1-infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 28, 2021. NLM Identifier: NCT04871113. Accessed June 16, 2025
14. Taiwo B, Leone P, Gartland M, et al. VH3810109 (N6LS) efficacy and safety in adults who are virologically suppressed: the EMBRACE study. Conference on Retroviruses and Opportunistic Infections (CROI); March 9-12, 2025; San Francisco, CA. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2025. Accessed June 16, 2025
15. ViiV Healthcare. A Phase 2a multicentre, randomized, open-label, two-part adaptive design study to evaluate the antiviral effect, safety and tolerability of GSK3810109A, an HIV-1 specific broadly neutralizing human monoclonal antibody in antiretroviral-naïve HIV-1-infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 28, 2021. NLM Identifier: NCT04871113. Accessed June 16, 2025
16. Leone P, Ferro A, Rolle C-P, et al. VH3810109 (N6LS) reduces viremia across a range of doses in ART-naive adults living with HIV: proof of concept achieved in the Phase IIa BANNER (207959, NCT04871113) Study. Slides presented at: HIV Drug Therapy Glasgow; October 23-26, 2022; Virtual and Glasgow, United Kingdom. Accessed June 16, 2025
17. Edwards AY, Ashraf W, Zweers T, et al. Pharmacokinetics/pharmacodynamics and virological activity of VH3810109 (N6LS) in antiretroviral-naive viremic adults from the Phase 2a BANNER study. European AIDS Conference; October 18-21, 2023; Warsaw, Poland. Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2023. Accessed June 16, 2025
18. Leone P, Ferro A, Lupo S, et al. VH3810109 (N6LS) in antiretroviral therapy-naive adults with HIV-1: Phase 2a BANNER efficacy data. Conference on Retroviruses and Opportunistic Infections; March 3-6, 2024; Denver, CO. Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2024. Accessed June 16, 2025
19. ViiV Healthcare. A Phase 1, open-label, single-dose study of the safety and pharmacokinetics of a human monoclonal antibody, GSK3810109, administered either subcutaneously or intravenously with recombinant human hyaluronidase PH20 (rHuPH20) to healthy adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 16, 2022. NLM Identifier: NCT05291520. Accessed June 16, 2025
20. Win B, Leone P, Losos J, et al. High-dose VH3810109 (N6LS) ± recombinant human hyaluronidase PH20: Phase I SPAN study safety results. Abstract presented at: Conference on Retroviruses and Opportunistic Infections; March 3-6, 2024; Denver, CO. Abstract 639. Accessed June 16, 2025
21. National Institute of Allergy and Infectious Diseases (NIAID). VRC 609: A Phase I, open-label, dose-escalation study of the safety and pharmacokinetics of a human monoclonal antibody, VRC-HIVMAB091-00-AB (N6LS), administered intravenously or subcutaneously with or without recombinant human hyaluronidase PH20 (rHuPH20) to healthy adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 24, 2018. NLM Identifier: NCT03538626. Accessed June 16, 2025
22. Wu RL, Houser KV, Gaudinski MR, et al. Safety and pharmacokinetics of N6LS, a broadly neutralising monoclonal antibody for HIV: a phase 1, open-label, dose-escalation study in healthy adults. Lancet HIV. Published online May 20, 2025:S2352-3018(25)00041-4. doi:10.1016/S2352-3018(25)00041-4. Accessed June 16, 2025

23. Leone P, Cahn P, Rolle CP, et al. Safety and tolerability of VH3810109 (N6LS) among antiretroviral therapy–naive adults living with HIV-1: results from the monotherapy phase of the Phase 2a BANNER study. European AIDS Conference; October 18-21, 2023; Warsaw, Poland. Accessed June 16, 2025