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 being explored as a possible strategy to help individuals with HIV control viral load levels, even in the absence of ART.^11,12

Half-life (T_½)

At a dose level of 300 mg, vedolizumab has a half-life of about 24 days.³

Metabolism/Elimination

Vedolizumab is degraded to small peptides and amino acids.¹³

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.^2,11,14

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.¹⁵
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

Study Identifiers: HAVARTI; NCT03147859

Sponsor: Ottawa Hospital Research Institute
Phase: 2
Status: This study is currently recruiting participants.
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.^12,16

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.¹⁶

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).¹⁷

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.^11,14,15

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.^12,16

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.¹⁸

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 January 16, 2024
2. Treatment Action Group website. Research toward a cure trials. Accessed January 16, 2024
3. Takeda Pharmaceuticals America, Inc. Entyvio: full prescribing information, September 21, 2023. DailyMed. Accessed January 16, 2024
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 January 16, 2024
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 January 16, 2024
6. National Institutes of Health (NIH) news release, dated October 13, 2016. Scientists at NIH and Emory achieve sustained SIV remission in monkeys. Accessed January 16, 2024
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 January 16, 2024
8. Pham HT, Mesplède T. The latest evidence for possible HIV-1 curative strategies. Drugs Context. 2018;7. doi:10.7573/dic.212522. Accessed January 16, 2024
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 January 16, 2024
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 January 16, 2024
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 January 16, 2024
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 January 16, 2024
13. European Medicines Agency. Entyvio: EPAR – public assessment report, March 20, 2014. Accessed January 16, 2024
14. 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 January 16, 2024
15. 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 January 16, 2024
16. 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 January 16, 2024
17. 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 January 16, 2024
18. 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 January 16, 2024

Last Reviewed: January 16, 2024