Vedolizumab

Medical use

Ulcerative colitis and Crohn's disease

Vedolizumab has been approved for use in adults with moderate to severe ulcerative colitis or Crohn's disease having a poor response to tumor necrosis factor (TNF) blockers or corticosteroids, or for those who are steroid-dependent.

Checkpoint inhibitor colitis

Main article: Checkpoint inhibitor induced colitis

Vedolizumab may be used to treat steroid refractory checkpoint inhibitor induced colitis, if infliximab is ineffective or contraindicated.

Clinical trials

Ulcerative colitis

Vedolizumab has been investigated in several studies in adult patients. Patients with moderate to severe active disease in whom conventional therapy or TNF-alpha antagonists were ineffective or could not be tolerated received either vedolizumab or placebo. The main measure of effectiveness was the proportion of patients whose symptoms improved after six weeks of treatment. Vedolizumab was shown to be more effective than placebo: 47% (106 out of 225) of patients who received vedolizumab showed an improvement in symptoms, compared with 26% (38 out of 149) of patients who received placebo. The study also showed that vedolizumab maintained the effect up to 52 weeks more effectively than placebo. Moreover, vedolizumab treatment was shown to achieve higher percentage of clinical remissions (31.3% vs. 22.5%) in patients with ulcerative colitis in comparison to adalimumab treatment.

Crohn's disease

In one main study in adult patients with moderate to severe active Crohn's disease in whom conventional therapy or TNF-alpha antagonists were ineffective or could not be tolerated, vedolizumab was shown to be more effective than placebo: 15% (32 out of 220) of patients receiving vedolizumab showed improved symptoms after 6 weeks of treatment, compared with 7% (10 out of 148) of patients on placebo. The maintenance of the effect up to 52 weeks was more effective with vedolizumab than with placebo.

History

The cell line used to develop vedolizumab was created by physician scientists at the Massachusetts General Hospital in Boston as a result of work executed in Dr. Robert Colvin's lab. This was part of a program to analyze the molecular basis of lymphocyte activation. An antibody was isolated that reacted with long term activated antigen-specific (tetanus toxoid) T-lymphocytes originally isolated from blood lymphocytes. The cell lines were created in Dr. Jim T. Kurnick's lab. Although the antibody did not block primary activation of T-lymphocytes, it appeared late after activation with a number of lymphocytic stimuli, and was named "Act-1" because it was the first activation marker identified by this group of investigators. Dr. Andrew Lazarovits, a postdoctoral fellow in the laboratory, discovered the murine homologue of MLN0002, chiefly published the original key papers, and up until the late 1990s, coordinated and led the studies for its development and application for Crohn's disease and ulcerative colitis. Dr. Lynn Baird's group showed the antibody reacted with a single protein band of 63Kd, and Dr. Atul Bhan's group showed that it stained tissue lymphocytes but did not react with non-lymphoid tissues. Although Act-1 had limited efficacy in its ability to prevent kidney rejection in a sub-human primate transplantation model, Dr. Lazarovits continued to investigate the activities of Act-1 when he returned to Canada to become the Director of Transplantation at the University of Western Ontario.

It was later determined that the Act-1 monoclonal antibody reacted with an α4β7 integrin that was subsequently shown to interact with a gut-associated addressin, MadCAM. Early work with Dr. Bruce Yacyshyn showed differential expression in inflammatory bowel disease. Dr. Lazarovits isolated the antibody to produce the murine homologue MLN0002 which he licensed with the Massachusetts General Hospital to Millennium Pharmaceuticals of Boston for further development. Scientists at LeukoSite realized the potential of this antibody to treat inflammatory bowel disease, and this company was eventually acquired by Millennium which took an exclusive license to the cell line from Massachusetts General Hospital. In vivo proof of concept ultimately led to the decision to humanize the antibody and move it into clinical trials as "Vedolizumab". In addition to its reactivity to gut-associated lymphoid tissues, Act-1 antibody also stains large numbers of lymphocytes in rheumatoid synovium, and has been shown by Dr. A. A. Ansari of Emory University to prevent or delay onset of AIDS in a monkey-model of Simian Immunodeficiency Virus-induced AIDS. Thus, reactivity with this antibody may show widespread applicability in inflammatory processes of diverse etiologies.

Society and culture

Legal status

Takeda filed a Marketing Authorization Application (MAA) in the European Union on 7 March 2013 and a biologic license application (BLA) with the U.S. Food and Drug Administration on 21 June 2013 for both Crohn's disease and ulcerative colitis. On 4 September 2013, vedolizumab was given a Priority Review Status, which functions to expedite potential acceptance to market.

In March 2014, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for vedolizumab (brand name Entyvio).

In May 2014, vedolizumab (Entyvio) was approved by the FDA for treatment of both moderate-to-severe ulcerative colitis and moderate-to-severe Crohn's disease. In May 2014, Entyvio was approved for medical use in the European Union. In April 2015, Health Canada approved Entyvio.

Research

Vedolizumab eventually completed a number of phase III clinical trials for Crohn's Disease and Ulcerative Colitis (GEMINI I, GEMINI II, and GEMINI III) that demonstrate that vedolizumab is an effective and well tolerated drug. The results of the GEMINI 1 and GEMINI 2 randomized, placebo controlled multicenter trials of induction and maintenance therapy in Crohn's disease and ulcerative colitis have been published. An additional clinical trial, GEMINI LTS (Long-term Safety), is still being run.

;HIV infection In October 2016, scientists from Emory University and National Institute of Allergy and Infectious Diseases (NIAID) published a paper which claimed that they applied daily ART (antiretroviral therapy) of 90 days followed by simianized (rhesus macaques) anti α4β7 antibody on SIV+ rhesus macaques for 23 weeks. Twenty three months after stopping both ART and anti-α4β7 antibody treatment, the in vivo SIV level still remained undetectable. Therefore, treating HIV+ people with ART and anti-α4β7 simultaneously may be a new therapy that could potentially lead to an HIV infection cure. In mice, vedolizumab was not able to prevent or control HIV-infections. Phase 1 clinical trial of that therapy has been initialized by NIAID since May 2016. For each of the participants, they will get vedolizumab infusions every four weeks for 30 weeks. Before the 23rd week of vedolizumab infusions, cART (combination ART) is kept. During the 30 weeks, blood draws are repeated for baseline tests. After the 22-week-cART is stopped, both viral load and CD4 count will be monitored biweekly. If HIV viral load goes high or their CD4 cell counts decrease by too much when vedolizumab is used alone, cART will be brought back on the participants. The published results from this clinical trial suggest "that blockade of α4β7 may not be an effective strategy for inducing virological remission in HIV-infected individuals after ART interruption" because only one patient showed prolonged virus suppression.

References

References

1. (21 June 2022). "Prescription medicines: registration of new chemical entities in Australia, 2014".
2. (4 May 2016). "Health Canada New Drug Authorizations: 2015 Highlights".
3. (3 April 2020). "Entyvio- vedolizumab injection, powder, lyophilized, for solution".
4. (17 September 2018). "Entyvio EPAR".
5. "Statement on a Nonproprietary Name Adopted by the USAN Council - Vedolizumab". United States Adopted Names Council. American Medical Association. ama-assn.org.
6. (September 2009). "The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases". The Journal of Pharmacology and Experimental Therapeutics.
7. (November 2012). "Exclusive antagonism of the α4 β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates". Inflammatory Bowel Diseases.
8. (19 May 2020). "Recommendation: Vedolizumab (Entyvio - Takeda Canada Inc.)". Canadian Agency for Drugs and Technologies in Health (CADTH).
9. (June 2018). "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline". Journal of Clinical Oncology.
10. (February 2020). "Checkpoint Inhibitor-Induced Colitis". The American Journal of Gastroenterology.
11. "12 Studies found for: Vedolizumab: Ulcerative Colitis: Phase 3, 4". ClinicalTrailsGov.
12. "Summary of the risk management plan (RMP) for Entyvio". European Medicines Agency.
13. (September 2019). "Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis". The New England Journal of Medicine.
14. (October 1984). "Lymphocyte activation antigens. I. A monoclonal antibody, anti-Act I, defines a new late lymphocyte activation antigen". Journal of Immunology.
15. (December 2008). "Treatment of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin". Clinical Gastroenterology and Hepatology.
16. (October 1984). "Lymphocyte activation antigens. I. A monoclonal antibody, anti-Act I, defines a new late lymphocyte activation antigen". Journal of Immunology.
17. (November 1994). "Crohn's disease, ulcerative colitis, and normal intestinal lymphocytes express integrins in dissimilar patterns". Gastroenterology.
18. (8 March 2013). "Takeda Submits Marketing Authorisation Application for Vedolizumab in Moderately to Severely Active Ulcerative Colitis and Crohn's Disease in the European Union". Takeda Pharmaceutical Company Limited.
19. (21 June 2013). "Takeda Submits Vedolizumab BLA". Drug Discovery and Development.
20. (4 September 2013). "Takeda's New Investigational Drug Vedolizumab is Granted Priority Review Status by U.S. Food and Drug Administration for Ulcerative Colitis". Takeda Pharmaceutical Company Limited.
21. (21 March 2014). "Entyvio Opinion". European Medicines Agency.
22. (20 May 2014). "FDA approves Entyvio to treat ulcerative colitis and Crohn's diseas". U.S Food and Drug Administration.
23. (9 June 2015). "Entyvio Summary Basis of Decision". Health Canada.
24. "Vedolizumab". ClinicalTrials.gov.
25. (23 August 2013). "Data Published in the New England Journal of Medicine for Vedolizumab, an Investigational New Drug from Takeda for Moderately to Severely Active Ulcerative Colitis and Crohn's Disease". Takeda Pharmaceutical Company Limited.
26. {{ClinicalTrialsGov. NCT00783718
27. {{ClinicalTrialsGov. NCT00783692
28. {{ClinicalTrialsGov. NCT01224171
29. (September 2012). "Vedolizumab for the treatment of ulcerative colitis and Crohn's disease". Immunotherapy.
30. (March 2013). "Vedolizumab for Crohn's disease". Expert Opinion on Biological Therapy.
31. (August 2013). "Vedolizumab as induction and maintenance therapy for ulcerative colitis". The New England Journal of Medicine.
32. (August 2013). "Vedolizumab as induction and maintenance therapy for Crohn's disease". The New England Journal of Medicine.
33. {{ClinicalTrialsGov. NCT00790933
34. (October 2016). "Sustained virologic control in SIV+ macaques after antiretroviral and α4β7 antibody therapy". Science.
35. (March 2019). "Vedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice". AIDS.
36. "Vedolizumab (Anti-α4β7) in Subjects With HIV Infection Undergoing Analytical Treatment Interruption".
37. (September 2019). "An open-label phase 1 clinical trial of the anti-α₄β₇ monoclonal antibody vedolizumab in HIV-infected individuals". Science Translational Medicine.