Drug Database: Lotivibart

Pharmacology Pharmacology

Pharmacology

Mechanism of Action

Broadly neutralizing antibody (bNAb). Lotivibart (also known as VH3810109 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. Lotivibart is a second-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

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.^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

Lotivibart is being developed as a possible component to HIV treatment or cure.^2,11

Half-life (T_½)

A Phase 1 study (SPAN; NCT05291520) evaluated the safety and pharmacokinetics of single lotivibart doses administered intravenously (IV) and subcutaneously (SC) in combination with recombinant human hyaluronidase PH20 (rHuPH20) in adults without HIV. The median terminal half-life of lotivibart ranged from 43 to 73 days—46.1 days with SC dosing (20 mg/kg) in combination with rHuPH20, 47.3 days with IV dosing (60 mg/kg), and 43.3 days with SC dosing (approximately 40 mg/kg) in combination with rHuPH20.¹²

Resistance

In a Phase 2b trial (EMBRACE; NCT05996471), participants received either IV lotivibart (n = 50) or SC lotivibart plus rHuPH20 (n = 49) administered every 4 months, each in combination with long-acting cabotegravir administered monthly. Through Month 6, four participants receiving lotivibart (two in each lotivibart dosing group) had confirmed virologic failure (CVF). By Month 12, there was one additional participant in the SC lotivibart group who met CVF. Three out of five participants with CVF from the lotivibart groups had baseline phenotypic sensitivity to lotivibart (IC₉₀ ≤1 µg/mL). Two participants receiving IV lotivibart and one participant receiving SC lotivibart developed reduced sensitivity to lotivibart at the time of CVF. Two participants receiving SC lotivibart and no participants receiving IV lotivibart had cabotegravir resistance-associated mutations (RAMs) at CVF.^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 lotivibart 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 and published in J Infect Dis (2025) showed that monotherapy with a single IV or SC infusion of lotivibart 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 lotivibart were safe and well tolerated.^17-19
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 lotivibart and SC lotivibart 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 lotivibart.¹³

Selected Study Results: Results presented at CROI 2025 indicated that lotivibart 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 lotivibart group and 88% in the SC lotivibart plus rHuPH20 group. In comparison, 96% of participants in the oral standard-of-care group maintained suppression through Month 6. IV lotivibart was more tolerable than SC lotivibart. Study investigators noted that based on results, IV lotivibart administered every 6 months, in combination with long-acting cabotegravir, was selected for further evaluation in the second part of the EMBRACE study.²⁰
Additional Published Material:

• CROI, 2026: Maintenance of HIV suppression at 12 months with VH3810109 (N6LS) Q4M + CAB LA QM: the EMBRACE study

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

• SPAN (NCT05291520) was a single-dose study that evaluated the safety and pharmacokinetics of IV lotivibart and SC lotivibart coadministered with rHuPH20 in healthy adults without HIV. This study has been completed, and results are available from CROI 2024 and Antimicrob Agents Chemother (2025).²¹
• VRC 609 (NCT03538626) was a dose-escalation study that evaluated the safety and pharmacokinetics of IV lotivibart and SC lotivibart coadministered with rHuPH20 in healthy adults without HIV. This study has been completed, and results are available from CROI 2023 and Lancet HIV (2025).²²
• ENTRANCE (NCT07053384) is a study evaluating the impact of IV lotivibart administered with or without fostemsavir and in combination with an INSTI-based ART regimen on the viral reservoir in adults with HIV. This study is ongoing, but not recruiting participants.²³

Adverse Events Adverse Events

Adverse Events

BANNER (NCT04871113)

In this Phase 2a trial, 62 participants received a single IV or SC infusion of lotivibart monotherapy administered at different dose levels. Drug-related adverse events (AEs), all of which were Grade 1 or 2, occurred in 13 (21%) participants. The most common drug-related AEs included headache (n = 3), abdominal pain (n = 2), and infusion site pain (n = 2). There were no Grade 3 or 4 drug-related AEs, serious adverse events (SAEs), or study discontinuations due to an AE. A total of seven (11%) participants had nine infusion site reactions (ISRs), all of which were mild and lasted a maximum of 10 days.¹⁹

EMBRACE (NCT05996471)

In this Phase 2b study, participants received either IV lotivibart given every 4 months, in combination with monthly IM cabotegravir (n = 50); SC lotivibart plus rHuPH20 given every 4 months, in combination with monthly IM cabotegravir (n = 49); or oral standard-of-care ART (n = 26). Through Month 12 of the study, 12 (24%) participants in the IV lotivibart group and 26 (53%) participants in the SC lotivibart group experienced a lotivibart-related AE, most of which were Grade 1 or 2 in severity. Eight (16%) participants in the SC lotivibart group had Grade 3 lotivibart-related AEs, all of which were associated with ISRs. In the IV lotivibart group, there were no study withdrawals due to drug-related AEs. In the SC lotivibart group, three participants withdrew from the study due to a drug-related AE— lotivibart/cabotegravir-related anxiety and depression (n = 1), cabotegravir-related injection site pain (n=1), and cabotegravir-related injection site abscess and cellulitis (n=1). No drug-related SAEs occurred in either of the lotivibart groups.^13,14,24

In the IV lotivibart group, four (8%) participants experienced lotivibart-related ISRs, all of which were Grade 1 and lasted a median duration of 2 days. In the SC lotivibart group, 25 (51%) participants had lotivibart-related ISRs, of which 58% were Grade 1 and lasted a median of 7 days. There were no serious or severe immune reactions related to lotivibart infusions.¹⁴

Drug Interactions Drug Interactions

Drug Interactions

Drug-drug interactions associated with lotivibart are currently unknown.

References References

References

1. National Center for Biotechnology Information. PubChem substance record for SID 507427715, lotivibart, Source: FDA Global Substance Registration System (GSRS). Accessed July 27, 2026
2. Jefferys R. The antiretroviral therapy pipeline 2025. Treatment Action Group Pipeline Report 2025. Accessed July 27, 2026
3. ViiV Healthcare website. HIV medicines in development. Accessed July 27, 2026
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 27, 2026
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 27, 2026
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 27, 2026
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 27, 2026
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 27, 2026
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 27, 2026
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 27, 2026
11. Treatment Action Group website. Research toward a cure trials. Accessed July 27, 2026
12. Leone PA, Losos J, Wannamaker P, et al. VH3810109 (N6LS) broadly neutralizing antibody safety, pharmacokinetics, and anti-drug antibody incidence in adults without HIV: phase 1 SPAN study results. Antimicrob Agents Chemother. 69(9):e00258-25. doi:10.1128/aac.00258-25. Accessed July 27, 2026
13. 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 27, 2026
14. Rolle C-P, Luetkemeyer AF, Bettacchi C, et al. Maintenance of HIV suppression at 12 months with VH3810109 (N6LS) Q4M + CAB LA QM: the EMBRACE study. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2026; Denver, CO. Accessed July 27, 2026
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 July 27, 2026
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 July 27, 2026
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 July 27, 2026
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 July 27, 2026
19. Leone PA, Ferro A, Rolle CP, et al. VH3810109 efficacy, safety, pharmacokinetics, and incidence of antidrug antibodies in adults with HIV-1 naive to antiretroviral therapy: BANNER study results. J Infect Dis. 2025;232(6):e1022-e1032. doi:10.1093/infdis/jiaf450. Accessed July 27, 2026
20. 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 July 27, 2026
21. 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 27, 2026
22. 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 27, 2026
23. ViiV Healthcare. An exploratory Phase 1b, multicenter, randomized, open-label study to investigate the impact of the administration of intravenous VH3810109 with or without oral fostemsavir in combination with integrase inhibitor-based antiretroviral therapy on the viral reservoir in adults living with HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 26, 2025. NLM Identifier: NCT07053384. Accessed July 27, 2026

24. Rolle C-P, Luetkemeyer AF, Bettacchi C, et al. Maintenance of HIV suppression at 12 months with VH3810109 (N6LS) Q4M + CAB LA QM: the EMBRACE study. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2026; Denver, CO. Abstract 178. Accessed July 27, 2026