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

Select Clinical Trials Select Clinical Trials

Select Clinical Trials

Study Identifiers: BANNER Study; 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 intravenous (IV) or subcutaneous (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.^13,14

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.^15,16
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 recombinant human hyaluronidase PH20 (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/mm³.¹⁷

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

• SPAN (NCT05291520): A Phase 1 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.^18,19
• VRC 609 (NCT03538626): A Phase 1 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.^12,20

Adverse Events Adverse Events

Adverse Events

BANNER Study (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, all of which were mild and lasted a maximum of 10 days. No injection site nodules occurred.^13,21

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 July 24, 2024
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 July 24, 2024
3. Jefferys R. HIV vaccines & passive immunization. Treatment Action Group Pipeline Report 2022. Accessed July 24, 2024
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 July 24, 2024
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 July 24, 2024
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 July 24, 2024
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 July 24, 2024
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 July 24, 2024
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 July 24, 2024
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 July 24, 2024
11. Treatment Action Group website. Research toward a cure trials. Accessed July 24, 2024
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 July 24, 2024
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 July 24, 2024
14. 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 July 24, 2024
15. 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 July 24, 2024
16. 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 July 24, 2024
17. ViiV Healthcare. A Phase 2b multicenter, randomized, open-label study comparing the efficacy, safety, PK, and tolerability of VH3810109, administered either intravenously or as a subcutaneous infusion with rHuPH20, in combination with CAB LA to standard of care in virologically suppressed adults living with HIV. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 9, 2023. NLM Identifier: NCT05996471. Accessed July 24, 2024
18. 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 July 24, 2024
19. 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 July 24, 2024
20. 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 July 24, 2024

21. 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 July 24, 2024