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Vedolizumab Brings Endoscopic Remission in Some Patients With Crohn's Disease

my little penguin

Staff member
Vedolizumab Brings Endoscopic Remission in Some Patients With Crohn's Disease
By Will Boggs MD
July 24, 2019

NEW YORK (Reuters Health) - About 1 patient in 8 experiences endoscopic remission of Crohn's disease after completing 26 weeks of treatment with the gut-selective monoclonal antibody vedolizumab, according to results from a phase 3b single-group study.
"(These) data are in line with other biologics," Dr. Silvio Danese from Humanitas University, Rozzano, Milan, Italy told Reuters Health via email.
Rather than targeting clinical symptoms alone, the new Crohn's disease management paradigm aims for both endoscopic healing and symptomatic remission.
Dr. Danese and colleagues in the VERSIFY study tested vedolizumab in 101 patients with moderately-to-severely active Crohn's disease. Everyone received vedolizumab infusions on day 1 and at weeks 2, 6, 14, and 22, and a subset of 56 patients received infusions at weeks 30, 38, and 46. The primary endpoint was endoscopic remission (defined as a Simple Endoscopic Score for CD of 4 or less) at week 26.

Twelve patients (11.9%) achieved the primary endpoint, according to the July 4th Gastroenterology online report.
Among the 56 patients followed for 52 weeks, 9 (16.1%) were in endoscopic remission at week 26 and 1 additional patient was in endoscopic remission at week 52 (for a total of 17.9%).
Endoscopic remission rates at week 26 were higher in TNF-antagonist-naïve patients than in patients who had failed TNF-antagonist treatment (19.6 versus 5.5%).
Endoscopic remission rates were also higher in patients with moderate rather than severe endoscopic disease activity at baseline and in patients with shorter disease duration.
In the 26-week study, 24.4% of patients achieved histologic responses and 41.6% achieved clinical remission. Among patients followed through week 52, 20.5% had histologic responses and 50.0% achieved clinical remission.
Health-related quality of life showed clinically meaningful improvements over the course of the study, and treatment-related adverse events affected 11.9% of patients during the first 26 weeks and 5.4% of patients during the second 26 weeks of the study.
Fifteen patients in the first 26 weeks and 7 patients in the second 26 weeks discontinued treatment prematurely for perceived lack of efficacy, and 2 and 3 patients, respectively, discontinued because of adverse events.
These findings "support vedolizumab as a first-line biologic therapeutic option," the researchers conclude.

Dr. David T. Rubin from University of Chicago Medicine and Biological Sciences, Chicago, Illinois, who has also investigated the use of vedolizumab for treating inflammatory bowel disease, told Reuters Health that the low endoscopic remission rates are "a reality of such deeper endpoints in Crohn's disease. They are hard to get, and harder to get in patients who have been resistant to prior therapies, which is the case for clinical trials, and further demonstrated that the patients in this phase 3b study who had previously exposure or failure of anti-TNF therapies did worse than those who were naïve to these treatments."

"It is of interest that the histological endpoints were better than endoscopic, but this has been reported with ulcerative colitis, too, and may be a result of a differential response between endoscopy and histology, but may simply be differences in the sampling or scoring systems and doesn't necessarily mean that patients really achieve improvement in histological endpoints while maintaining endoscopic activity," he said in an email.

"While it is known that vedolizumab achieved its clinical endpoints in 6-10 weeks, this assessment shows the time to 'deeper' endpoints is longer," he added. "This has implications for clinicians managing patients in several important ways: first, to not give up on the therapy too soon or else you may be underestimating the benefit that can be achieved with vedolizumab; and second, when to reassess for objective evidence of improvement."

Takeda Development Center Americas, Inc. sponsored the study, employed 2 of the 10 authors, and had various relationships with the other 8 authors. Dr. Rubin has also received funding from Takeda.

SOURCE: http://bit.ly/2y31Tne
Gastroenterology 2019.

Reuters Health Information © 2019
Cite this: Vedolizumab Brings Endoscopic Remission in Some Patients With Crohn's Disease - Medscape - Jul 22, 2019.




Well-known member
Just wanted to add an opinion if I can, and maybe elaboraty shortly on why I am so convinced that Vedoluzimab does not work for crohn's disease. Trials show it doesn't work, but why.

Vedoluzimab is so called ''gut specific'' (this isn't completely correct which I will detail later).

Why is it ''gut specific'', all those other biologics for crohn's disease are not gut specific.

Vedoluzimab is a ''gut specific'' evolution of Natalizumab (Tysabri). Natalizumab trials resulted in deaths in trials, and was then withdrawn. Natalizumab is no longer on the market.

So, Vedoluzimab was invented, it is an evolution of Natalizumab that is more ''gut specific'' and therefore, so the manufacturer claims, has less side effects.

Vedoluzimab blocks integrin α4β7. It isn't properly explained anywhere what it does, and the manufacturer probably likes it that way. You don't want pesky patients asking too many questions. You need to know what α4β7 does before you understand what Vedoluzimab does, which also isn't easy.

Integrin are proteins that mediate adhesion, what α4β7 actually does is help lymphocyte enter mucosal lymphoid tissue. The idea behind Vedoluzimab is that if you block α4β7, you're going to block lymphocytes from entering mucosal lymphoid tissue and decrease inflammation.

You can already see that the name ''gut specific'' doesn't make a whole lot of sense, it's ''mucosal lymphoid tissue'' specific.

This can work for UC, because in UC, inflammation is at the gut mucosa in UC. And Vedoluzimab does work for UC.

But inflammation in crohn's disease is very very different. Inflammation in crohn's disease is in the lamina propria, it in deeper transmural tissue. It causes wall thickening, it can cause strictures, it can cause fistula in some patients. Secondly, it is macrophages deep into tissue where the problems are in crohn's disease, these macrophages can't clear invasive bacteria due to a lack of cytokine release and autophagy problems, which leads to a cascade of inflammation of the adpative immune system trying to compensate.

Crohn's disease is -nothing- like UC. You're not going to help crohn's disease patients with deep transmural inflammation by blocking α4β7 at the mucosa level. You'll help UC patients, but it's not going to work for crohn's disease, α4β7 is not an important player in the inflammatory process in crohn's disease.

But Kiny, what about that 3% of crohn's disease patients who claim they do get better on vedoluzimab. Well, at the very least, one should consider the possibilty that these people might not have CD but a disease that is mimmicking CD.
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Well-known member
To just elabore a bit. I don't like the term ''IBD'', I find it extremely unhelpful to put two very different diseases under the same umbrella.

Vedoluzimab is a good example. The manufacturer can claim it works for IBD. Which is helpful for their bottom line, but not for patients. If they couldn't use ''IBD'' they would have to say it works for UC, and it doesn't work for CD, which would be much more helpful for patients.

But more importantly, when you talk about what is driving the inflammation, you need to know if the inflammation is caused by immune cells migrating to the mucosa, or is it caused by bacteria entering into tissue.

Behr has a nice study about this https://www.ncbi.nlm.nih.gov/pubmed/19924803 He calls it the outside-in paradigm. He believes, as I do, that the inflammation is being directed at pathogens within tissue, not at commensals in the lumen. I for example do not believe our bodies simply one day decided to attack our microbiome, just for the heck of it. I believe bacteria are entering tissue through peyer's patches.

I do not believe that is the case in UC, it might, but it highly unlikely. UC does not feature deep inflammation, the inflammation in UC is either directed at the tissue itself (which would indicate that UC is caused by a response to a self-antigen, making it an autoimmune disease), or it is directed at the microbiome (but then why are antibiotics so ineffective in UC).

Anyway. As you can see, the theory that the inflammation in crohn's disease is happening in tissue in response to penetrating bacteria explains why Vedoluzimab does not work. Vedoluzimab blocks lymphocytes from entering mucosal lymphoid tissue, but in crohn's disease, it is the bacteria who are entering the tissue and the inflammatory cascade is likely caused by intracellular pathogens deep into tissue.


Well-known member
All the data on treatment supports the (well established by now) theory that inflammation in crohn's disease is directed at pathogens (with a possibly minor role for fungi) within intestinal tissue.

TNF-α blockers like infliximab and certain antibiotics that are macrophage penetrating like cipro are incredibly good at lowering acute inflammation in crohn's disease. Not only does CRP and calprotectin drop, but other markers show these two treatments are very effective in treating acute inflammation in CD. OmpC (E coli) and certain antibodies that are relevant to CD.

Medication that interacts with tissue macrophages, either by blocking TNF-α or by being macrophage penetrating like certain antibiotics, can lower inflammation spectacularly.

(I am not saying antibiotics should be used long term to treat CD, you will simply run into resistance and give a fitness advantage to tissue penetrating bacteria in the lumen).

But medication that does not interact with tissue macrophages, like vedoluzimab, does not work.
Ok I finally read the whole paper, and I really don't think it's that bad. First, consider the population of patients they're using:

"We performed a phase 3b, open-label, single-group study of 101 patients with at least 3 months of active CD (a CD Activity Index [CDAI] score of 220–450, a simple endoscopic score for CD [SES-CD] of 7 or more, 1 or more mucosal ulcerations [identified by endoscopy], and failure of conventional therapy) from March 2015 through December 2017. Among the patients enrolled, 54.5% had previous failure of 1 or more tumor necrosis factor (TNF) antagonists and 44.6% had severe endoscopic disease activity (SES-CD scores above 15) at baseline."​
So, most have already failed one or more TNF agents, all have failed some other therapies, and almost half have severe endoscopic disease activity. This is a challenging population!

18% achieved endoscopic remission at 52 weeks, which isn't that exciting, but endoscopic remission is not an easy target. "Clinical remission", measured using the CDAI, is a much easier target that most studies use, but it's also a less meaningful target.

What you really want is endoscopic remission/mucosal healing plus bowel wall thickness normalization. Clinical remission is nice and all, but those are what we should really be going for.

Is Entyvio moving people in that direction? Well, the MRI results are actually pretty good:

Remission was detected by magnetic resonance enterography in 21.9% of patients at week 26 (95% CI 9.3–40.0) and in 38.1% at week 52 (95% CI 18.1–61.6).​
From my recent research, I've concluded that bowel wall thickness normalization is both the toughest and the most meaningful of the remission criteria, and "remission detected by MRE" includes that, so I'd say that 38% is really a solid result.

My conclusion is that it works for some people and isn't necessarily worse than other biologics.