Pharmacology

Pharmacology

Mechanism of Action

Broadly neutralizing antibody (bNAb). VRC01 is a human IgG1 monoclonal antibody that has demonstrated in vitro neutralizing activity against approximately 90% of a diverse panel of HIV strains. It is a next-generation bNAb that targets a conserved region of the CD4 binding site on the HIV envelope gp120.^2,6–8

Next-generation 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 the 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 by natural killer cells, and (3) promote the maturation and activity of dendritic cells.^9–12 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.^10,13

VRC01 has been studied for HIV prevention and is currently being studied as a possible component to HIV treatment or cure. A long-acting version of VRC01, called VRC01LS, is also in clinical development.^3-5,14

Half-life (T_1/2)

In a Phase 1 dose-escalation study (NCT01950325), short-term administration of intravenous (IV) infusions of VRC01 (doses from 1 mg/kg to 40 mg/kg) and subcutaneous (SC) infusions of VRC01 (5 mg/kg) in adults with HIV yielded a terminal half-life of 12 days for IV VRC01 and 11 days for SC VRC01.² In a Phase 1 study of VRC01LS (NCT02599896) administered to healthy adults without HIV, the elimination half-life of IV VRC01LS (doses from 5 mg/kg to 40 mg/kg) was 71 ± 18 days.¹⁵

Resistance

In two Phase 1 studies (NCT02463227 and NCT02471326), a total of 24 participants with chronic HIV infection received multiple IV infusions of VRC01 (40 mg/kg) monotherapy to determine whether VRC01 could prevent or delay viral rebound after analytical treatment interruption (ATI) of ART. Results showed that the efficacy of VRC01 monotherapy was limited, partly due to the presence of preexisting baseline resistance to VRC01 in a high number of participants and the emergence/development of VRC01-resistant HIV, including virus with high-level resistance, following VRC01 administration and discontinuation of ART.¹⁶

In a Phase 2 study (RV 397; NCT02664415), VRC01 use was evaluated in individuals who had initiated ART during acute HIV infection and who had durable virological suppression. Researchers found that VRC01 did not select for Env mutations and did not increase neutralization in this homogenous viral population.^17,18

The emergence of VRC01-resistant virus has also been reported in two parallel Phase 2b prevention trails (HVTN 704/HPTN 085; NCT02716675 and HVTN 703/HPTN 081; NCT02568215) evaluating VRC01 infusions (10 mg/kg or 30 mg/kg) administered every 8 weeks in at-risk individuals without HIV. In some of the participants who acquired HIV during the study, infection occurred with virus that had innate resistance to VRC01; however, investigators also found evidence of VRC01 resistance mutations that emerged after infection.^19,20

 

Select Clinical Trials

Select Clinical Trials

VRC01 for HIV treatment

Study Identifiers: IMPAACT 2008; NCT03208231

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 1/2
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate the safety and efficacy of VRC01 plus ART in clearing the latent HIV reservoir in infants who were initiating ART.
Study Population:

• Participants were infants (aged 0–12 weeks) with HIV who were initiating ART.
• Participants had a CD4 percentage of greater than 15% at screening.²¹ 

Selected Study Results: Results presented at AIDS 2022 showed that there were no safety concerns with VRC01 administered subcutaneously in infants. The addition of VRC01 to ART was not more effective than ART alone in reducing viral reservoir size (as measured by HIV-1 DNA in PBMCs). Researchers noted that baseline resistance to ART and VRC01, as well as low VRC01 trough concentrations in some infants, may have contributed to the diminished efficacy of VRC01.²²

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Study Identifiers: Tatelo Study; NCT03707977

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 1/2
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate the safety and efficacy of the investigational bNAbs VRC01LS and 10-1074 in maintaining HIV suppression in a cohort of children who had received early ART treatment.
Study Population:

• Participants were children who had initiated ART from less than 7 days of age and who continued ART for at least 96 weeks.
• Participants had HIV RNA <40 copies/mL for at least 24 weeks before study entry.^23,24

Selected Study Results: Results published in Sci Transl Med (2023) and presented at CROI 2022 showed that dual bNAb treatment with VRC01LS and 10-1074 was safe and effective. Among study participants who stopped ART, 44% maintained viral load levels less than 40 copies/mL through 24 weeks of bNAb-only treatment. Participants with a longer time on ART and bNAb overlap were more likely to succeed along with those who enrolled earlier in the study and had favorable pre-intervention clinical and reservoir characteristics.^24,25

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Study Identifiers: RV 397; NCT02664415

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety of VRC01 and efficacy of VRC01 in preventing viral rebound in participants undergoing ATI.
Study Population:

• Participants were adults with HIV (from the RV 254 study) who had initiated ART during acute HIV infection and who had been on ART for at least 24 months prior to enrollment.
• Participants had HIV RNA <50 copies/mL within the past 12 months of study entry and CD4 counts >400 cells/mm³ within 3 months of enrollment.
• Participants had undetectable integrated HIV DNA in PBMCs within 6 months of enrollment.¹⁷

Selected Study Results: Results published in Lancet HIV (2019) showed that infusions of VRC01 were safe, with no serious adverse events (SAEs) reported during the study.  However, VRC01 had no significant impact on the proportion of participants maintaining viral suppression at 24 weeks after ART interruption.²⁶

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Study Identifiers: (1) HVTN 804/HPTN 095; NCT04801758 and (2) HVTN 805/HPTN 093; NCT04860323

Sponsor: HIV Vaccine Trials Network
Phase: Not available
Status: HVTN 804/HPTN 095 is ongoing, but not recruiting participants. HVTN 805/HPTN 093 is currently recruiting participants.
Study Purpose: The purpose of these open-label studies is to evaluate the ability of the immune system to control viral load levels during an analytical treatment interruption of ART in participants who received VRC01 or placebo and acquired HIV while enrolled in the antibody-mediated prevention (AMP) studies, HVTN 704/HPTN 085 or the HVTN 703/HPTN 081.
Study Population:

• Participants acquired HIV-1 infection within 8 weeks of their last infusion during the HVTN 704/HPTN 085 or the HVTN 703/HPTN 081 trials and initiated ART within 28 weeks of their HIV-1 diagnosis date.
• Participants have been receiving ART for at least 1 year. Participants who are on an NNRTI are willing to switch to a PI- or INSTI-containing regimen for at least 4 weeks prior to initiating a treatment interruption of ART.
• Participants had HIV RNA ≥1,000 copies/mL prior to initiating ART and have one undetectable HIV RNA measurement at screening and more than 9 months prior to screening.
• Participants have CD4 counts ≥450 cells/mm³ within 90 days prior to enrollment.^27,28

Selected Study Results: Early observations from the HVTN 805/HPTN 093 trial were presented at AIDS 2022. Thus far, 11 African women who had acquired HIV during the HVTN 703/HPTN 081 AMP study enrolled to undergo ATI. Eight of the 11 women met ART re-initiation criteria and resuppressed after restarting ART. The median time from the start of ATI to meeting ART re-initiation criteria was 17.1 weeks. Four participants had at least one viral load decline of at least 0.5 log₁₀ copies/mL while off ART, indicating possible immune-mediated temporary viral control. There were no SAEs or Grade 2 or higher ATI-related adverse events (AEs).²⁹

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Additional early-phase studies investigating HIV treatment with VRC01 or VRC01LS have been or are being conducted. Some of these studies include:

• RV 398 (NCT02591420): A Phase 1 study that evaluated the safety and antiviral effects of a single VRC01 infusion in adults with early acute HIV infection who received ART simultaneously or one week later. This study has been completed, and results are available from CROI 2023.³⁰
• VRC 607/ACTG A5378 (NCT02840474): A Phase 1 trial that evaluated the safety and antiviral effects of the bNAbs VRC01LS and VRC07-523LS in treatment-naive adults with HIV. This study has been completed and results are available from IAS 2019.³¹
• IMPAACT P1115 (NCT02140255): A Phase 1/2 trial evaluating the use of early intensive ART regimens to achieve HIV remission in infants. One of the regimens studied will include the use of VRC01 added to ART. This study is currently recruiting participants. Results thus far are available from CROI 2022.³²

VRC01 for HIV prevention

Study Identifiers: (1) HVTN 704/HPTN 085 AMP Study; NCT02716675 and (2) HVTN 703/HPTN 081 AMP Study; NCT02568215

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 2b
Status: These studies have been completed.
Study Purpose: The purpose of these studies was to evaluate the safety and efficacy of VRC01 administered every 8 weeks in preventing HIV-1 infection among adults who were at risk of acquiring HIV.
Study Population:

• Participants in HVTN 704/HPTN 085 were men and transgender persons who have sex with men who did not have HIV but who were at risk of acquiring HIV.
• Participants in HVTN 703/HPTN 081 were heterosexual women in sub-Saharan Africa who did not have HIV but who were at risk of acquiring HIV.^4,5,20

Selected Study Results: Results published in The New England Journal of Medicine (2021) showed that overall, VRC01 did not significantly protect participants from acquiring HIV in either trial. The overall lack of efficacy was due to a low percentage of VRC01-sensitive virus circulating in the regions where the trials were conducted. When looking at the effectiveness of VRC01 infusions in preventing the acquisition of VRC01-sensitive HIV strains in participants from both trials, VRC01 was 75% effective. The number and severity of AEs were similar across treatment groups.²⁰
Additional Published Material:

• J Acquir Immune Defic Syndr, 2022: Infusion reactions after receiving the broadly neutralizing antibody VRC01 or placebo to reduce HIV-1 acquisition: results from the Phase 2b antibody-mediated prevention randomized trials

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Additional studies evaluating VRC01 or VRC01LS for HIV prevention have been completed, including the IMPAACT P1112 trial (NCT02256631) that looked at the safety and pharmacokinetics of three bNAbs (VRC01, VRC01LS, and VRC07-523LS) in HIV-exposed infants who were at increased risk of mother-to-child HIV transmission.¹⁴ Results to this trial are available from J Infect Dis (2020) and J Infect Dis (2021).

 

Adverse Events

Adverse Events 

IMPAACT 2008 (NCT03208231)

In the Phase 1/2 IMPAACT 2008 trial, 61 infants initiating ART enrolled to receive either four SC doses of VRC01 plus ART (n = 30) or ART only (n = 31). Ninety percent of infants had local injection-site reactions (ISRs), all of which were Grade 2 or lower. Grade 3 or higher AEs, none of which were related to VRC01, occurred in 40% of infants receiving VRC01 and 47% of infants receiving ART only.^21,22

Tatelo Study (NCT03707977)

In this Phase 1/2 trial, 28 children received daily ART in combination with the bNAbs VRC01LS and 10-1074 administered every 4 weeks for at least 8 weeks (ART/bNAb overlap step). Twenty-five children completed the ART/bNAb overlap step and entered the bNAb-only step of the study, where ART was discontinued for up to 24 weeks. No infusion reactions were reported throughout the study. Five Grade 3 AEs occurred in three participants. One of the Grade 3 events (neutropenia) was considered possibly related to bNAb treatment. No Grade 4 AEs occurred, and there were no study drug discontinuations due to Grade 3 or 4 AEs.^23,24

RV 397 (NCT02664415)

In this Phase 2 study, 14 participants received VRC01 monotherapy and five participants received placebo. Infusion-related AEs occurred with 30.3% of VRC01 infusions and with 37.5% of placebo infusions. The majority of the infusion-related AEs were mild, except for one case of moderate infusion-site bruising and one case of severe generalized urticaria, both of which occurred in a participant receiving VRC01. The case of severe generalized urticaria occurred during the participant’s first VRC01 infusion and led to study withdrawal. No SAEs were reported. No anti-VRC01 antibodies were detected among participants.^17,26

HVTN 704/HPTN 085 (NCT02716675) and HVTN 703/HPTN 081 (NCT02568215)

In both Phase 2b prevention studies, participants received infusions of either VRC01 (10 or 30 mg/kg) or placebo every 8 weeks for a total of 10 infusions. The number and severity of AEs was similar across treatment groups. Additionally, the percentage of participants experiencing reactogenic events was similar across groups. In the HVTN 703/HPTN 081 trial, VRC01-related AEs were more common than placebo-related AEs. Moderate to severe AEs that were related to VRC01 occurred in 1.2% of participants in HVTN 704/HPTN 085 and in 3.0% of participants in HVTN 703/HPTN 081.²⁰ 

 

Drug Interactions

Drug Interactions

Drug-drug interactions associated with VRC01 are currently unknown.

 

References

References

1. National Center for Biotechnology Information. PubChem Substance Record for SID 472419986, VRC-01, Source: FDA Global Substance Registration System (GSRS). Accessed October 24, 2023
2. Lynch RM, Boritz E, Coates EE, et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Trans Med. 2015;7(319):319ra206. doi:10.1126/scitranslmed.aad5752. Accessed October 24, 2023
3. Treatment Action Group website. Research toward a cure trials. Accessed October 24, 2023
4. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection among men and transgender persons who have sex with men. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 17, 2016. NLM Identifier: NCT02716675. Accessed October 24, 2023
5. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection in women in Sub-Saharan Africa. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 1, 2015. NLM Identifier: NCT02568215. Accessed October 24, 2023
6. Li Y, O’Dell S, Walker LM, et al. Mechanism of neutralization by the broadly neutralizing HIV-1 monoclonal antibody VRC01. J Virol. 2011;85(17):8954-8967. doi:10.1128/JVI.00754-11. Accessed October 24, 2023
7. Wu X, Yang Z-Y, Li Y, et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science. 2010;329(5993):856-861. doi:10.1126/science.1187659. Accessed October 24, 2023
8. Nishimura Y, Martin MA. Of mice, macaques and men: broadly neutralizing antibody immunotherapy for HIV-1. Cell Host Microbe. 2017;22(2):207-216. doi:10.1016/j.chom.2017.07.010. Accessed October 24, 2023
9. Jefferys R and Jacobson J. HIV/AIDS and Cure Basics – Module 12. Therapeutic vaccines and immune-based therapies. HIV Cure Research Training Curriculum. May 2015. Accessed October 24, 2023
10. 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 October 24, 2023
11. 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 October 24, 2023
12. Stephenson KE, Barouch DH. Broadly neutralizing antibodies for HIV eradication. Curr HIV/AIDS Rep. 2016;13:31-37. Accessed October 24, 2023
13. Caskey M, Klein F, Lorenzi JCC, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015;522(7557):487-491. doi:10.1038/nature14411. Accessed October 24, 2023
14. National Institute of Allergy and Infectious Diseases (NIAID). Open-label, dose-escalating, Phase I study to determine safety and pharmacokinetic parameters of subcutaneous (SC) VRC01, VRC01LS, and VRC07-523LS, potent anti-HIV neutralizing monoclonal antibodies, in HIV-1-exposed infants. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 1, 2014. NLM Identifier: NCT02256631. Accessed October 24, 2023 
15. Gaudinski MR, Coates EE, Houser KV, et al. Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: a phase 1 open-label clinical trial in healthy adults. PLoS Med. 2018;15(1):e1002493. doi:10.1371/journal.pmed.1002493. Accessed October 24, 2023
16. Bar KJ, Sneller MC, Harrison LJ, et al. Effect of HIV antibody VRC01 on viral rebound after treatment interruption. N Engl J Med. 2016;375(21):2037-2050. doi:10.1056/NEJMoa1608243. Accessed October 24, 2023
17. National Institute of Allergy and Infectious Diseases (NIAID). Safety and therapeutic efficacy of the broadly neutralizing HIV-1 specific monoclonal antibody VRC01 during analytic treatment interruption in patients who initiated antiretroviral therapy during early acute HIV infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 20, 2016. NLM Identifier: NCT02664415. Accessed October 24, 2023
18. Cale EM, Bai H, Bose M, et al. Neutralizing antibody VRC01 failed to select for HIV-1 mutations upon viral rebound. J Clin Invest. 2020;130(6):3299-3304. doi:10.1172/JCI134395. Accessed October 24, 2023
19. Williamson C, Westfall D, Den W, et al. Analysis of genetic diversity and VRC01 pressure on HIV-1 breakthrough viruses from the AMP trial (HVTN 703/HPTN 081 and HVTN 704/085). Abstract presented at: HIV Research for Prevention (HIVR4P); January 27-28 and February 3-4, 2021; Chicago, IL. Abstract OA03.04LB. Accessed October 24, 2023
20. Corey L, Gilbert PB, Juraska M, et al. Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition. N Engl J Med. 2021;384(11):1003-1014. doi:10.1056/NEJMoa2031738. Accessed October 24, 2023
21. National Institute of Allergy and Infectious Diseases (NIAID). Phase I/II multisite, randomized, controlled study of monoclonal antibody VRC01 with combination antiretroviral therapy to promote clearance of HIV-1-infected cells in infants. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered June 30, 2017. NLM Identifier: NCT03208231. Accessed October 24, 2023
22. Khaitan A, Lindsey J, Capparelli E, et al. Phase I/II study of monoclonal antibody VRC01 with early antiretroviral therapy to promote clearance of HIV-1 infected cells in infants (IMPAACT 2008). Abstract presented at: International AIDS Conference; Montreal, Canada and Virtual; July 29–August 2, 2022. Abstract OALBB0102. Accessed October 24, 2023
23. National Institute of Allergy and Infectious Diseases (NIAID). A clinical trial to evaluate the impact of broadly neutralizing antibodies VRC01LS and 10-1074 on maintenance of HIV suppression in a cohort of early-treated children in Botswana (dual bNAb treatment in children). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). October 12, 2018. NLM Identifier: NCT03707977. Accessed October 24, 2023
24. Shapiro RL, Ajibola G, Maswabi K, et al. Broadly neutralizing antibody treatment maintained HIV suppression in children with favorable reservoir characteristics in Botswana. Science Translational Medicine. 2023;15(703):eadh0004. doi:10.1126/scitranslmed.adh0004. Accessed October 24, 2023
25. Shapiro RL, Maswabi K, Ajibola G, et al. Treatment with broadly neutralizing antibodies in children with HIV in Botswana (The Tatelo Study). Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 12-16, 2022; Virtual. Accessed October 24, 2023
26. Crowell TA, Colby DJ, Pinyakorn S, et al. VRC01 in acutely treated HIV-infected adults: a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2019;6(5):e297-e306. doi:10.1016/S2352-3018(19)30053-0. Accessed October 24, 2023
27. HIV Vaccine Trials Network. Antiretroviral analytical treatment interruption (ATI) to assess immunologic and virologic responses in participants who received VRC01 or placebo and became HIV-infected during HVTN 704/HPTN 085. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 1, 2021. NLM Identifier: NCT04801758. Accessed October 24, 2023
28. HIV Vaccine Trials Network. Antiretroviral analytical treatment interruption (ATI) to assess immunologic and virologic responses in participants who initiated ART in early HIV infection after having received VRC01 or placebo in HVTN 703/HPTN 081. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 14, 2021. NLM Identifier: NCT04860323. Accessed October 24, 2023
29. Karuna S, Bar K, DeCamp A, et al. Analytical treatment interruption (ATI) among African women with early ART initiation with or without VRC01 circulating at HIV acquisition: study design and early observations of viral rebound and control. Poster presented at: International AIDS Conference; July 29-August 2, 2022; Montreal, Canada and Virtual. Poster EPLBB08. Accessed October 24, 2023
30. National Institute of Allergy and Infectious Diseases (NIAID). Safety and virologic effect of a human monoclonal antibody (VRC01) administered intravenously to adults during early acute HIV infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 28, 2015. NLM Identifier: NCT02591420. Accessed October 24, 2023
31. National Institute of Allergy and Infectious Diseases (NIAID). VRC 607-ACTG A5378: a Phase 1, single dose study of the safety and virologic effect of an HIV-1 specific broadly neutralizing human monoclonal antibody, VRC-HIVMAB080-00-AB (VRC01LS) or VRC-HIVMAB075-00-AB (VRC07-523LS), administered intravenously to HIV-infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered July 19, 2016. NLM Identifier: NCT02840474. Accessed October 24, 2023
32. National Institute of Allergy and Infectious Diseases (NIAID). Very early intensive treatment of HIV-infected infants to achieve hiv remission: a Phase I/II proof of concept study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 13, 2014. NLM Identifier: NCT02140255. Accessed October 24, 2023