Drug information

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Other Names
VRC-HIVMAB060-00-AB, VRC-HIVMAB080-00-AB, VRC01LS (long-acting form of VRC01)
Drug Class
Broadly Neutralizing Antibodies
Registry Number
1412901-55-3 (CAS)
Organization
NIAID Vaccine Research Center (VRC)
Phase of Development

VRC01 is in Phase 2 development as a broadly neutralizing antibody for HIV treatment. VRC01 has also been studied for HIV prevention.

(Compound details obtained from ChemIDplus Advanced,1Science Translational Medicine article,2 Treatment Action Group website,3 and ClinicalTrials.gov4,5)

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

Half-life (T1/2): 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.14

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.15

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.16,17

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.18,19

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.20

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 VRC01.21


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 VRC01LS and the investigational bNAb 10-1074 in maintaining HIV suppression in a cohort of children who had received early ART treatment.
Study Population:

  • Participants were children (at least 96 weeks of age) who had received ART from less than 7 days through at least 96 weeks of life.
  • Participants had HIV RNA <40 copies/mL for at least 24 weeks before study entry.22

Selected Study Results: Findings presented at CROI 2022 showed that dual bNAb treatment with VRC01LS and 10-1074 given by IV infusion was well tolerated. No infusion reactions occurred and there was one case of Grade 3 neutropenia that was possibly treatment-related. Among 28 children who entered the study and received ART plus dual bNAbs (Step 1), 25 children underwent an analytical treatment interruption (ATI) of ART while continuing on dual bNAbs (Step 2). Eleven children (44%) were able to maintain viral load levels of less than 40 copies/mL for 24 weeks off ART. Fourteen children (56%) had viral rebound to greater than 400 copies/mL during the treatment interruption period, and all resuppressed after restarting ART.23


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.16
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.24


Study Identifiers: (1) HVTN 804/HPTN 095; NCT04801758 and (2) HVTN 805/HPTN 093; NCT04860323
Sponsor: HIV Vaccine Trials Network
Phase: Not available
Status: These studies are 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.25,26

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).27


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 evaluating the safety and antiviral effects of VRC01 when given alone and when given with ART in adults with early acute HIV infection. This study has been completed.28
  • VRC 607/ACTG A5378 (NCT02840474): A Phase 1 trial that evaluated the safety and antiviral effects of VRC01LS and another long-acting bNAb called VRC07-523LS in adults with HIV who had never received ART. This study has been completed and results are available from IAS 2019.29
  • 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 2022.30


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.4,5,19

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.19
Additional Published Material:


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.31 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.20,21


Tatelo Study (NCT03707977):

In this Phase 1/2 trial, 28 children received ART plus monthly infusions of both VRC01LS and 10-1074 for 8–32 weeks (Step 1). Thereafter, 25 children continued with monthly dual bNAb treatment while off ART for up to 24 weeks (Step 2). Both VRC01LS and 10-1074 were well tolerated, and no infusion reactions occurred in any children. There were five Grade 3 AEs reported, including one case of neutropenia which was possibly related to bNAb treatment. No Grade 4 AEs occurred.22,23


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.16,24


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 081.19

Drug Interactions

Drug Interactions

Drug-drug interactions associated with VRC01 are currently unknown.

References

References

  1. United States National Library of Medicine. ChemIDplus Advanced: VRC01. https://chem.nlm.nih.gov/chemidplus/rn/1412901-55-3. Accessed August 22, 2022
  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
  3. Treatment Action Group website. Research toward a cure trials. https://www.treatmentactiongroup.org/cure/trials. Accessed August 22, 2022
  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. https://clinicaltrials.gov/ct2/show/NCT02716675. Accessed August 22, 2022
  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. https://clinicaltrials.gov/ct2/show/NCT02568215. Accessed August 22, 2022
  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
  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
  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
  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. https://www.avac.org/sites/default/files/u16/Theraeutic_Vaccine_Module_June.pptx. Accessed August 22, 2022
  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
  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.
  12. Stephenson KE, Barouch DH. Broadly neutralizing antibodies for HIV eradication. Curr HIV/AIDS Rep. 2016;13:31-37
  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
  14. 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
  15. 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
  16. 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. https://clinicaltrials.gov/ct2/show/NCT02664415. Accessed August 22, 2022
  17. 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
  18. 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. https://programme.hivr4p.org/Abstract/Abstract/1409. Accessed August 22, 2022
  19. 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
  20. 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. https://clinicaltrials.gov/ct2/show/NCT03208231. Accessed August 22, 2022
  21. 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. https://programme.aids2022.org/Abstract/Abstract/?abstractid=12869. Accessed August 22, 2022
  22. 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. https://clinicaltrials.gov/ct2/show/NCT03707977. Accessed August 22, 2022
  23. 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. http://www.croiwebcasts.org/console/player/50298?mediaType=slideVideo&. Accessed August 22, 2022
  24. 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
  25. 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. https://www.clinicaltrials.gov/ct2/show/NCT04801758. Accessed August 22, 2022
  26. 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. https://clinicaltrials.gov/ct2/show/NCT04860323. Accessed August 22, 2022
  27. 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. https://www.hptn.org/sites/default/files/inline-files/Africa AMP ATI_805-093-5390_IAS ePoster_Final.pdf. Accessed August 22, 2022
  28. 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. https://clinicaltrials.gov/ct2/show/NCT02591420. Accessed August 22, 2022
  29. National Institute of Allergy and Infectious Diseases (NIAID). 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. https://clinicaltrials.gov/ct2/show/NCT02840474. Accessed August 22, 2022
  30. 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. https://clinicaltrials.gov/ct2/show/NCT02140255. Accessed August 22, 2022
  31. 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. https://clinicaltrials.gov/ct2/show/NCT02256631. Accessed August 22, 2022

Last Reviewed: August 22, 2022