Vedolizumab, A New Treatment for Ulcerative Colitis & Crohn's Disease Looks Promising - Info & Clinical Trial Included

Vedolizumab, a potentially new treatment for UC and Crohn's disease is being fast tracked for review by the FDA.  The BLA (biologics license application) will give priority review to the ulcerative colitis application and standard review to the Crohn's disease application.
The part of the clinical trial that is most important to me is the said adverse effects that were found in the patients who participated in the study.  Based on the concluding trial results, the adverse effects of the drug is said to be the same as the placebo.  That's great news.  I'm going to continue to watch this drug for new updates and news pertaining to safety. So far, this new treatment by Takeda Pharmaceuticals looks promising.
I have also included the clinical trial abstract below.  

Gastroenterology & Endoscopy News - New IBD Drug, Vedolizumab, Receives Priority Review Status for Ulcerative Colitis: 

On Sept. 4, Takeda Pharmaceutical Company Ltd., announced that it received priority review status from the FDA for its drug vedolizumab, an investigational antibody for the treatment of adults with moderately to severely active Crohn’s disease (CD) and ulcerative colitis (UC). Takeda submitted a biologics license application (BLA) to the FDA in June for the treatment of CD and UC; the UC application will receive priority review, and the application for CD will be reviewed under the standard timeline.

The FDA grants priority review status for drugs that are designed to treat a serious condition, and that if approved, would provide a significant improvement in safety or effectiveness. Priority review designation allows for an eight-month review period compared with the standard 12-month review.

“The need to seek new treatment options is well recognized,” said William J. Sandborn, MD, chief, Division of Gastroenterology, and professor of medicine, University of California, San Diego School of Medicine, in a press statement. “Vedolizumab has demonstrated the potential to be another possible treatment option for people with moderately to severely active CD and UC.”

Vedolizumab is a humanized monoclonal antibody that specifically antagonizes α4β7 integrin and inhibits it from binding to its target receptor, mucosal addressin cell adhesion molecule-1 (MAdCAM-1). MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract. It interacts with α4β7 integrin, which is expressed on a subset of circulating white blood cells, to mediate the inflammatory process in patients with CD and UC.

Takeda’s BLA submission is supported by four Phase III clinical studies—GEMINI I, II and III, and GEMINI LTS (Long-Term Safety)—which comprise the GEMINI Studies^TM, a clinical program designed to investigate the efficacy and safety of vedolizumab in clinical response and remission in patients with moderate to severe CD and UC. Patients enrolled in the studies failed at least one conventional therapy for inflammatory bowel disease, including corticosteroids, immunomodulators and/or a tumor necrosis factor–alpha antagonist. The results of the Phase III studies of vedolizumab in patients with CD and UC were published recently in the New England Journal of Medicine (Sandborn WJ et al. N Engl J Med2013;369:711-721 and Feagan BG et al. N Engl J Med 2013;369:699-710, respectively).

According to Takeda, vedolizumab has been studied in 2,700 patients in nearly 40 countries, making it the largest Phase III clinical trial program to date to simultaneously evaluate CD and UC. GEMINI LTS is an ongoing, open-label, long-term safety study of vedolizumab and is designed to collect data on the occurrence of important clinical safety events resulting from the administration of vedolizumab.

—Based on a press release from Takeda Pharmaceutical Company Ltd.

Clinical Trial - PUBMED.gov

 N Engl J Med. 2013 Aug 22;369(8):699-710. doi: 10.1056/NEJMoa1215734.

Vedolizumab as induction and maintenance therapy for ulcerative colitis.

Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, Van Assche G, Axler J, Kim HJ, Danese S, Fox I, Milch C, Sankoh S, Wyant T, Xu J, Parikh A; GEMINI 1 Study Group.

Collaborators (225)

Source

Robarts Clinical Trials, Robarts Research Institute, and Department of Medicine, University of Western Ontario, London, Canada. bfeagan@robarts.ca

Abstract

BACKGROUND:

Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis.

METHODS:

We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.

RESULTS:

Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0 .001="" 41.8="" 44.8="" 4="" 52="" 8="" and="" at="" ayo="" clinic="" clinical="" continued="" every="" in="" no="" of="" patients="" receive="" remission="" score="" subscore="" to="" vedolizumab="" week="" weeks="" were="" who="">1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0 .001="" 17.9="" 29.1="" 40.4="" 4="" adverse="" and="" ci="" events="" every="" for="" frequency="" groups.="" in="" of="" p="" percentage="" placebo="" points="" similar="" the="" to="" vedolizumab="" vs.="" was="" weeks="">

CONCLUSIONS:

Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).

Comment in

• Inhibition of leukocyte trafficking in inflammatory bowel disease. [N Engl J Med. 2013]

PMID:

 

23964932

 

[PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/?term=23964932

MMP Vaccination That Blocks Inflammatory Response, Has Potential To Treat Crohn's Disease

Crohn's Disease, Lupus, rheumatoid arthritis are only a few autoimmune diseases that create an inflammatory response in the body when it is not necessary, which leads the immune system to attack the body's healthy tissue. This as we know, can result in terrible symptoms and damage to the tissue being attacked.
A group of researchers created a vaccination that would produce antibodies only against the MMP2 & MMP9 enzymes, the enzymes responsible for unnecessary inflammatory as seen in Crohn's patients. Could being immunized with this antibody be the answer to treat Crohn's Disease and other autoimmune conditions? Is this a safe solution?
Read below to read the article.

Vaccination Creates Antibody that Blocks Autoimmune Activity in Mice
ProHealth.com
December 28, 2011


The team is excited both by this ‘vaccination’ method's potential for treating Crohn’s disease in humans, but by its potential application in treatment of many other diseases as well.

After years of work on the problem, researchers at Israel’s Weizmann Institute believe they’ve found a way to “turn the tables” on autoimmune disorders such as rheumatoid arthritis and Crohn’s disease. These disorders turn the immune system against the body's own tissues.

In an animal model of Crohn’s disease, Prof. Irit Sagi, PhD, and her research group have tricked the immune systems of mice into targeting a key villain in the autoimmune process - an enzyme known as MMP9 (a member of the matrix metalloproteinase family).

As outlined in their report, published Dec 25 by Nature Medicine, MMPs can cut through collagen and other support materials in the body. And, when working normally they are crucial for cellular mobilization, proliferation, wound healing, and other jobs. But when some members of the family – especially MMP9 – get out of control, they can "aid and abet" autoimmune disease and cancer metastasis.

The team therefore focused on finding ways to block these proteins in hopes of finding effective treatments for a number of diseases.

Originally, Dr. Sagi and others had designed synthetic drug molecules to directly target MMPs. But these drugs proved to be fairly crude tools that had extremely severe side effects.

• The body normally produces its own MMP inhibitors, known as TIMPs, as part of its tight regulation program for keeping these enzymes in line.

• But as opposed to the synthetic drugs, these natural inhibitors work in a highly selective manner.

• An arm on each TIMP is precisely constructed to reach into a cleft in the enzyme that shelters the active bit – a metal zinc ion surrounded by three histidine peptides – closing it off like a snug cork.

• “Unfortunately,” says Dr. Sagi, “it is quite difficult to reproduce this precision synthetically.”

Getting the Immune System to Create MMP-9 Antibodies

Then co-author Dr. Netta Sela-Passwell began working on an alternative approach as a student and later a PhD researcher in Dr. Sagi’s lab. She and Dr. Sagi decided that, rather than attempting to design a synthetic molecule to directly attack MMPs, they would try coaxing the immune system into targeting MMP-9 through immunization.

Just as immunization with a killed virus induces the immune system to create antibodies that then attack live viruses, an MMP immunization would trick the body into creating antibodies that block the enzyme at its active site.

Together with Prof. Abraham Shanzer of the Organic Chemistry Department, they created an artificial version of the metal zinc-histidine complex at the heart of the MMP9 active site. They then injected these small, synthetic molecules into mice and afterward checked the mice’s blood for signs of immune activity against the MMPs.

The antibodies they found, which they dubbed “metallobodies,” were similar but not identical to TIMPS, and a detailed analysis of their atomic structure suggested they work in a similar way – reaching into the enzyme’s cleft and blocking the active site.

The metallobodies were selective for just two members of the MMP family – MMP2 and 9 – and they bound tightly to both the mouse versions of these enzymes and the human ones.

As the team hoped, when they had induced an inflammatory condition that mimics Crohn's disease in mice, the symptoms were prevented when mice were treated with metallobodies. “We are excited not only by the potential of this method to treat Crohn’s,” says Dr. Sagi, but by the potential of using this approach to explore novel treatments for many other diseases.”

Yeda, the technology transfer arm of the Weizmann Institute, has applied for a patent for the synthetic immunization molecules as well as the generated metallobodies. Millions of autoimmune disease sufferers can only hope that human trials of this promising 'vaccination' concept will proceed soon.

Source: Based on Weizmann Institute News Release, Dec 26, 2011