Drug Database: Vedolizumab

Pharmacology

Pharmacology

Mechanism of Action

α₄β₇ integrin antagonist. Vedolizumab is a humanized IgG1 monoclonal antibody (mAb) that is currently FDA-approved for the treatment of ulcerative colitis and Crohn’s disease. As such, it functions by binding to the α₄β₇ integrin receptor, located on the surface of certain T lymphocytes. Vedolizumab inhibits the homing of T-lymphocytes to inflamed gut-associated lymphoid tissue by blocking the interaction between α₄β₇ integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), a protein found on gut endothelial cells.³

The α₄β₇ integrin gut-homing receptor plays a critical role in the pathogenesis of HIV, a disease that targets gut tissues. Early during HIV infection, gastrointestinal tissues are a primary site of viral replication and reservoir formation. Viral destruction of CD4 cells in gastrointestinal tissues contributes to the development of immune deficiencies.^4–8 Research has shown that HIV not only preferentially infects CD4 cells expressing high levels of α₄β₇ integrin, but also incorporates α₄β₇ integrin into its own viral envelope. Consequently, viral replication and transmission in gut tissues is rapidly established.^4,6,9,10

Blockade of α₄β₇ integrin by vedolizumab is currently being explored as a possible strategy to help individuals with HIV control viral load levels, even in the absence of ART.^11–13

Half-life (T_½)

At a dose level of 300 mg, vedolizumab has a half-life of about 25 days.³

Metabolism/Elimination

Vedolizumab is degraded to small peptides and amino acids.¹⁴

Select Clinical Trials

Select Clinical Trials

Study Identifier: NCT03577782

Sponsor: Hospitales Universitarios Virgen del Rocío
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate the safety of vedolizumab and whether vedolizumab plus ART administration could help treatment-naive individuals control viral load levels during an analytical treatment interruption of ART.
Study Population:

• Participants were treatment-naive adults with HIV.
• Participants had HIV RNA >10,000 copies/mL and CD4 counts >350 cells/mm³.^2,11,15

Selected Study Results: Results presented at CROI 2022 showed that although vedolizumab was safe and well-tolerated, it had no substantial impact on viral remission after participants underwent an analytical treatment interruption of ART.¹⁶
Additional Published Material:

• GeSIDA, 2019 (abstract PO-48): Safety and efficacy of vedolizumab combined with antiretroviral therapy to achieve permanent virological remission in HIV-infected subjects without previous antiretroviral therapy

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Study Identifiers: HAVARTI; NCT03147859

Sponsor: Ottawa Hospital Research Institute
Phase: 2
Status: The status of this study is unknown.
Study Purpose: The purpose of this open-label trial is to evaluate vedolizumab’s safety and ability to control viral load levels in individuals with chronic HIV infection undergoing an analytical treatment interruption of ART.
Study Population:

• Participants are adults with HIV who have been on ART for 2 to 10 years with HIV RNA <50 copies/mL.
• Participants have CD4 counts >500 cells/mm3 and have had nadir CD4 counts >200 cells/mm³.^12,17

Selected Study Results: Results presented at CROI 2019, showed that vedolizumab given at two different doses and administered both before and after a treatment interruption of ART was generally safe. No drug-related severe adverse events were reported. No participants had sustained viral suppression after treatment interruption of ART. Notably, the higher dose of vedolizumab appeared to have a significantly greater effect on reducing viral rebound compared with the lower dose of vedolizumab.¹⁷

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Study Identifiers: (1) EHVA T02/ANRS VRI07; NCT04120415 and (2) AMEP-EHVA T02; NCT05280392

Sponsor: ANRS, Emerging Infectious Diseases
Phase: The EHVA T02/ANRS VRI07 study is a Phase 2 trial. The AMEP-EHVA T02 study is an observational trial.
Status: These studies are currently recruiting participants.
Study Purpose: The purpose of the EHVA T02/ANRS VRI07 study is to evaluate the ability of vedolizumab administered with and without the therapeutic HIV vaccine MVA HIV-B in controlling viral load levels in individuals undergoing an analytical treatment interruption of ART. The AMEP-EHVA T02 study is a follow-on trial evaluating the experience of people who were offered to participate in the EHVA T02/ANRS VRI07 trial.
Study Population:

• Participants are adults with HIV who started ART after 2009 and have been on ART for at least 1 year prior to screening.
• Participants have HIV RNA <50 copies/mL and CD4 counts >500 cells/mm3 at screening. Participants have had nadir CD4 counts >300 cells/mm³.^13,18

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A Phase 1 study (NCT02788175) evaluating the efficacy of vedolizumab on controlling viral rebound in individuals undergoing an analytical treatment interruption of ART has also been completed and results are available from Science Translational Medicine (2019).¹⁹

Adverse Events

Adverse Events

NCT03577782

In this Phase 2 study, ten participants were enrolled, and six participants completed 24 weeks of treatment with vedolizumab plus ART, followed by interruption of treatment. Vedolizumab was reported as being well tolerated. No serious adverse events (SAEs) occurred throughout the study period.^11,15,16

HAVARTI (NCT03147859)

In this Phase 2 trial, eight adults with HIV received intravenous infusions of vedolizumab (four participants each in the 300 and 150 mg dose groups). Vedolizumab was administered both before and after ART treatment interruption. No drug-related severe adverse events (AEs) were reported. Influenza and severe Grade 3 transient hepatitis each occurred in one participant. There were no other Grade 2 or higher AEs reported.^12,17

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Additional AEs known to be associated with vedolizumab use are described in the FDA-approved Full Prescribing Information for Entyvio.³

Drug Interactions

Drug Interactions

Typical drug-drug interactions are not expected with monoclonal antibody therapies. Vedolizumab does not modulate cytokine production; therefore, the possibility of vedolizumab causing CYP-mediated drug interactions is lower than that with drugs that do affect cytokines.²⁰

Additional drug-drug interactions between vedolizumab and coadministered drugs are described in the FDA-approved Full Prescribing Information for Entyvio.³

References

References

1. National Center for Biotechnology Information. PubChem substance record for SID 472387049, vedolizumab, Source: FDA Global Substance Registration System (GSRS). Accessed February 3, 2023
2. Treatment Action Group website. Research toward a cure trials. Accessed February 3, 2023
3. Takeda Pharmaceuticals America, Inc. Entyvio: full prescribing information, October 24, 2022. DailyMed. Accessed February 3, 2023
4. Arthos J, Cicala C, Nawaz F, et al. The role of integrin α4β7 in HIV pathogenesis and treatment. Curr HIV/AIDS Rep. 2018;15(2):127-135. doi:10.1007/s11904-018-0382-3. Accessed February 3, 2023
5. Brenchley J, Douek D. HIV infection and the gastrointestinal immune system. Mucosal Immunol. 2008;1(1):23-30. doi:10.1038/mi.2007.1. Accessed February 3, 2023
6. National Institutes of Health (NIH) news release, dated October 13, 2016. Scientists at NIH and Emory achieve sustained SIV remission in monkeys. Accessed February 3, 2023
7. Sivro A, Schuetz A, Sheward D, et al. Integrin α4β7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes. Sci Transl Med. 2018;10(425):eaam6354. doi:10.1126/scitranslmed.aam6354. Accessed February 3, 2023
8. Pham HT, Mesplède T. The latest evidence for possible HIV-1 curative strategies. Drugs Context. 2018;7. doi:10.7573/dic.212522. Accessed February 3, 2023
9. Uzzan M, Tokuyama M, Rosenstein AK, et al. Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1–infected individuals. Sci Transl Med. 2018;10(461). doi:10.1126/scitranslmed.aau4711. Accessed February 3, 2023
10. Guzzo C, Ichikawa D, Park C, et al. Virion incorporation of integrin α4β7: implications for HIV-1 pathogenesis. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 13-16, 2017; Seattle, WA. Abstract 64LB. Accessed February 3, 2023
11. Hospitales Universitarios Virgen del Rocío. Phase II clinical trial to analyze the safety and efficacy of vedolizumab combined with antiretroviral therapy to achieve permanent virological remission in HIV-infected subjects without previous antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 12, 2018. NLM Identifier: NCT03577782. Accessed February 3, 2023
12. Ottawa Hospital Research Institute. Vedolizumab treatment in antiretroviral drug treated chronic HIV infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 3, 2017. NLM Identifier: NCT03147859. Accessed February 3, 2023
13. ANRS, Emerging Infectious Diseases. EHVA T02 (European HIV Vaccine Alliance Therapeutic Trial 02)/ANRS VRI07: a Phase II randomised, placebo-controlled trial of vedolizumab with or without therapeutic HIV MVA vaccine in individuals who started antiretrovirals during primary or chronic Infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 30, 2019. NLM Identifier: NCT04120415. Accessed February 3, 2023
14. European Medicines Agency. Entyvio: EPAR – public assessment report, March 20, 2014. Accessed February 3, 2023
15. Jimenez-Leon MR, Gasca Capote C, Espinosa N, et al. Safety and efficacy of vedolizumab combined with antiretroviral therapy to achieve permanent virological remission in HIV-infected subjects without previous antiretroviral therapy. Presented at: XI Congreso Nacional GeSIDA; December 10-13, 2019; Toledo, Spain. Abstract PO-48. Accessed February 3, 2023
16. Jiménez-León MR, Gasca-Capote C, Roca-Oporto C, et al. Phase 2 clinical trial of vedolizumab and ART in subjects with no previous ART. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 12-16, 2022; Virtual. Poster 359. Accessed February 3, 2023
17. McGuinty M, Angel J, Kumar A, et al. Seeking suppression in HAVARTI: viremia & T cells after vedolizumab & ATI in HIV/ART. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7, 2019; Seattle, WA. Poster 393. Accessed February 3, 2023
18. ANRS, Emerging Infectious Diseases. Expectation, motivation and experience of HIV-patients regarding participation to the EHVA T02/ANRS VRI 07 HIV cure-related clinical trial (AMEP-EHVA T02). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 11, 2022. NLM Identifier: NCT05280392. Accessed February 3, 2023
19. National Institute of Allergy and Infectious Diseases (NIAID). An exploratory, open-label study of vedolizumab (anti-alpha4beta7 antibody) in subjects with HIV infection undergoing analytical treatment interruption. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 28, 2016. NLM Identifier: NCT02788175. Accessed February 3, 2023
20. Rosario M, Dirks NL, Milch C, et al. A review of the clinical pharmacokinetics, pharmacodynamics, and immunogenicity of vedolizumab. Clin Pharmacokinet. 2017;56(11):1287-1301. doi:10.1007/s40262-017-0546-0. Accessed February 3, 2023

Last Reviewed: February 3, 2023