Drugs

Vedolizumab

Other Names: Entyvio, VDZ Drug Class: a4ß7 Integrin Antagonist
Molecular Formula: C6528 H10072 N1732 O2042 S42
Registry Number: 943609-66-3 (CAS) Chemical Name: Immunoglobulin G1, anti-(human integrin LPAM-1 (lymphocyte Peyer's patch adhesion molecule 1)) (human-Mus musculus heavy chain), disulfide with human-Mus musculus kappa-chain, dimer Organization: Takeda Pharmaceuticals America, Inc. Phase of Development: Vedolizumab is in Phase 2 development for HIV treatment.

(Compound details obtained from ChemIDplus Advanced,1 Treatment Action Group website,2 and Entyvio Full Prescribing Information3)

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.11,12

Half-life (T½): 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.13


Clinical Trials


Study Identifiers: NCT03577782
Sponsor: Hospitales Universitarios Virgen del Rocío
Phase: 1/2
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate whether vedolizumab plus ART administration can help treatment-naive individuals control viral load levels during a treatment interruption of ART.
Study Population:
  • Participants are treatment-naive adults with HIV.
  • Participants have HIV RNA >10,000 copies/mL and CD4 counts >350 cells/mm3.11

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 a treatment interruption of ART.
Study Population:
  • Participants are adults with HIV who have been on ART for 2 to 10 years and who have had HIV RNA ≤50 copies/mL.
  • Participants have HIV RNA <50 copies/mL and CD4 counts >500 cells/mm3. Participants have had nadir CD4 counts >200 cells/mm3.12,14
Selected Study Results:

A Phase I study (NCT02788175) evaluating the efficacy of vedolizumab on controlling viral rebound in individuals undergoing a treatment interruption of ART has also been completed.15


Adverse Events


In the Phase 2 HAVARTI trial (NCT03147859), 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.12,14

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


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.16

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


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Vedolizumab. https://chem.nlm.nih.gov/chemidplus/rn/943609-66-3. Accessed September 16, 2019
  2. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed September 16, 2019
  3. Takeda Pharmaceuticals America, Inc. Entyvio: full prescribing information, June 2019. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6e94621c-1a95-4af9-98d1-52b9e6f1949c. Accessed September 16, 2019
  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
  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
  6. National Institutes of Health (NIH) news release, dated October 13, 2016. Scientists at NIH and Emory achieve sustained SIV remission in monkeys. https://www.nih.gov/news-events/news-releases/scientists-nih-emory-achieve-sustained-siv-remission-monkeys. Accessed September 16, 2019
  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. Science Translational Medicine. 2018;10(425):eaam6354. doi:10.1126/scitranslmed.aam6354
  8. Pham HT, Mesplède T. The latest evidence for possible HIV-1 curative strategies. Drugs Context. 2018;7. doi:10.7573/dic.212522
  9. Uzzan M, Tokuyama M, Rosenstein AK, et al. Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals. bioRxiv. June 2018:346684. doi:10.1101/346684
  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. https://www.croiconference.org/sessions/virion-incorporation-integrin-%CE%B14%CE%B27-implications-hiv-1-pathogenesis. Accessed September 16, 2019
  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. https://clinicaltrials.gov/ct2/show/NCT03577782. Accessed September 16, 2019
  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. https://clinicaltrials.gov/ct2/show/NCT03147859. Accessed September 16, 2019
  13. European Medicines Agency. Entyvio: EPAR – public assessment report, March 20, 2014. https://www.ema.europa.eu/en/documents/assessment-report/entyvio-epar-public-assessment-report_en.pdf. Accessed September 16, 2019
  14. 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. http://www.croiconference.org/sites/default/files/posters-2019/1430_McGuinty_0393.pdf. Accessed September 16, 2019
  15. 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. https://clinicaltrials.gov/ct2/show/NCT02788175. Accessed September 16, 2019
  16. 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


Last Reviewed: September 16, 2019