Vedolizumab

Vedolizumab (trade name Entyvio) is a monoclonal antibody developed by Millennium Pharmaceuticals, Inc (a subsidiary of Takeda Pharmaceuticals) for the treatment of ulcerative colitis and Crohn's disease.[1] It binds to integrin α4β7 (LPAM-1, lymphocyte Peyer's patch adhesion molecule 1, a dimer of Integrin alpha-4 and Integrin beta-7).[1][2] Blocking the α4β7 integrin results in gut-selective anti-inflammatory activity.[3] It is marketed under the trade name Entyvio.

Vedolizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetIntegrin α4β7
Clinical data
Trade namesEntyvio
AHFS/Drugs.comMultum Consumer Information
License data
Pregnancy
category
  • US: B (No risk in non-human studies)
    ATC code
    Legal status
    Legal status
    Identifiers
    CAS Number
    DrugBank
    ChemSpider
    • none
    UNII
    Chemical and physical data
    FormulaC6528H10072N1732O2042S42
    Molar mass146836.99 g·mol−1
     NY (what is this?)  (verify)

    Medical uses

    Ulcerative colitis

    Vedolizumab has been investigated in one main study 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 6 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.[5] 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.[6]

    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.[5]

    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.[7][8][8]

    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. 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,[9][10] 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.[10]

    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.[11] Dr. Lazarovits isolated the antibody to produce the murine homologue MLN002 which he licensed with the Massachusetts General Hospital to Millennium Pharmaceuticals of Boston for further development.[9] 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.

    Approval status

    Takeda filed a Marketing Authorization Application (MAA) in the European Union on March 7, 2013[12] and a Biologic License Application (BLA) with the U.S. Food and Drug Administration on June 21, 2013 for both Crohn's disease and ulcerative colitis.[13] On September 4, 2013, vedolizumab was given a Priority Review Status, which functions to expedite potential acceptance to market.[14]

    On December 9, 2013, the Gastrointestinal Drugs Advisory Committee (GIDAC) and Drug Safety and Risk Management Advisory Committee (DSaRM) discussed the vedolizumab application for approval for both ulcerative colitis and Crohn's disease under the trade name Entyvio.[15] The voting went as follows:

    1. Safety and efficacy data outweigh potential risks 21–0
    2. In favour of UC treatment 21–0
    3. In favour for CD treatment 20–1.[16][17]

    Although GIDAC/DSaRM were a non-binding advisory committee, their opinions as field experts represent one of the last steps towards drug acceptance.

    On 20 March 2014, the Committee for Medicinal Products for Human Use (CHMP, the committee advising the European Commission) adopted a positive opinion, recommending the granting of a marketing authorization for vedolizumab (brand name Entyvio).[18]

    On 20 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.[19] On May 27, 2014, Entyvio was approved for the treatment of both ulcerative colitis and Crohn's disease in the 28 European Union states as well as Norway, Iceland and Liechtenstein. On April 28, 2015 Health Canada approved Entyvio.[20]

    Research

    Vedolizumab eventually completed a number of phase 3 clinical trials[21][22] for Crohn's Disease and Ulcerative Colitis (GEMINI I,[23] GEMINI II,[24] and GEMINI III[25]) that demonstrate that vedolizumab is an effective and well tolerated drug.[26][27] 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.[28][29] An additional clinical trial, GEMINI LTS (Long-term Safety), is still being run.[30]

    HIV infection

    On October 13, 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.[31] In mice vedolizumab was not able to prevent or control HIV-infections.[32] 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 during when vedolizumab is used alone, cART will be brought back on the participants.[33] 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 patient showed prolonged virus suppression.[34]

    gollark: I don't know if they will when they're off the releasy ratios, but whatever.
    gollark: They're just piling up in alpine.
    gollark: Stupid caveblocking new releases...
    gollark: The good code on a slightly messy?
    gollark: It's probably terrafied.

    References
    1. "Statement on a Nonproprietary Name Adopted by the USAN Council - Vedolizumab" (PDF). United States Adopted Names Council. American Medical Association. ama-assn.org. Archived from the original (PDF) on February 20, 2012.
    2. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER (September 2009). "The binding specificity and selective antagonism of vedolizumab, an anti-α4β7 integrin therapeutic antibody in development for inflammatory bowel diseases". J. Pharmacol. Exp. Ther. 330 (3): 864–75. doi:10.1124/jpet.109.153973. PMID 19509315.
    3. Fedyk ER, Wyant T, Yang LL, Csizmadia V, Burke K, Yang H, Kadambi VJ (November 2012). "Exclusive antagonism of the α4β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates". Inflamm. Bowel Dis. 18 (11): 2107–19. doi:10.1002/ibd.22940. PMID 22419649.
    4. https://clinicaltrials.gov/ct2/results?term=Vedolizumab&cond=Ulcerative+Colitis&recrs=g&recrs=h&recrs=e&recrs=m&age_v=&gndr=&type=&rslt=&phase=2&phase=3&phase=5&Search=Apply
    5. Summary of the risk management plan (RMP) for Entyvio, EMA.
    6. Sands, Bruce E.; Peyrin-Biroulet, Laurent; Loftus, Edward V.; Danese, Silvio; Colombel, Jean-Frédéric; Törüner, Murat; Jonaitis, Laimas; Abhyankar, Brihad; Chen, Jingjing; Rogers, Raquel; Lirio, Richard A.; Bornstein, Jeffrey D.; Schreiber, Stefan (26 September 2019). "Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis". New England Journal of Medicine. 381 (13): 1215–1226. doi:10.1056/NEJMoa1905725. PMID 31553834.
    7. Brahmer, Julie R.; Lacchetti, Christina; Schneider, Bryan J.; Atkins, Michael B.; Brassil, Kelly J.; Caterino, Jeffrey M.; Chau, Ian; Ernstoff, Marc S.; Gardner, Jennifer M.; Ginex, Pamela; Hallmeyer, Sigrun; Holter Chakrabarty, Jennifer; Leighl, Natasha B.; Mammen, Jennifer S.; McDermott, David F.; Naing, Aung; Nastoupil, Loretta J.; Phillips, Tanyanika; Porter, Laura D.; Puzanov, Igor; Reichner, Cristina A.; Santomasso, Bianca D.; Seigel, Carole; Spira, Alexander; Suarez-Almazor, Maria E.; Wang, Yinghong; Weber, Jeffrey S.; Wolchok, Jedd D.; Thompson, John A. (10 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. 36 (17): 1714–1768. doi:10.1200/JCO.2017.77.6385. PMC 6481621. PMID 29442540.
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    12. "Takeda Submits Marketing Authorisation Application for Vedolizumab in Moderately to Severely Active Ulcerative Colitis and Crohn's Disease in the European Union". Press Release. Takeda Pharmaceutical Company Limited. 2013-03-08.
    13. "Takeda Submits Vedolizumab BLA". Drug Discovery and Development. 2013-06-21.
    14. "Takeda's New Investigational Drug Vedolizumab is Granted Priority Review Status by U.S. Food and Drug Administration for Ulcerative Colitis". Press Release. Takeda Pharmaceutical Company Limited. 2013-09-04.
    15. http://www.fdalive.com/results.cfm
    16. http://www.takeda.com/news/files/20131210_04_en.pdf
    17. https://research.tdwaterhouse.ca/research/public/Markets/NewsArticle/100-343p7866-1
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    19. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm398065.htm
    20. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2015_entyvio_169414-eng.php
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    29. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, Lukas M, Fedorak RN, Lee S, Bressler B, Fox I, Rosario M, Sankoh S, Xu J, Stephens K, Milch C, Parikh A (August 2013). "Vedolizumab as induction and maintenance therapy for Crohn's disease" (PDF). N. Engl. J. Med. 369 (8): 711–21. doi:10.1056/NEJMoa1215739. PMID 23964933.
    30. Clinical trial number NCT00790933 at ClinicalTrials.gov
    31. Byrareddy SN, Arthos J, Cicala C, Villinger F, Ortiz KT, Little D, et al. (October 2016). "Sustained virologic control in SIV+ macaques after antiretroviral and α4β7 antibody therapy". Science. 354 (6309): 197–202. doi:10.1126/science.aag1276. PMC 5405455. PMID 27738167.
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