Gastroenterology Thought Leader Panel #13 2011-12

I haven’t been blogging very much lately.  I don’t personally have inflammatory bowel disease (I know, TMI), but with the way I’ve been eating this Christmas, I’m able to mimic at least temporarily many of the symptoms (I know, REALLY TMI).  I have about 7 hours left in 2011, and then an early hangover in 2012 before I get back to training.  Goodbye edible food.  Hello stupid protein shakes.  Anyway, with today’s obsession being Crohn’s-like symptomatology, I figures I would post some comments from BOLT’s most recent Gastroenterology Thought Leader Panel.


So first read through the following commercial interruption… As always, if you’re a patient and we can help you out, we will.  And if you work for one of those Dark Side pharma companies, time to tap that 2012 budget before the person down the hall does.


In Gastroenterology Thought Leader Panel #10, conducted in April 2010, we asked six internationally recognized experts in the treatment of inflammatory bowel disease to engage with us in a thought exercise with the aim of ranking the most medically valuable initiatives in the developmental pipeline.  Each was asked to “buy” five agents that they were most looking forward to having available in the next few years – their “Fantasy Formulary”.  In Gastroenterology TLP #13 2011-12, we rerun and expand this thought experiment.


The Panel was most interested in opining on recent clinical data related to three groups of therapeutics:  integrin/adhesion/MAdCAM, IL-23/IL-23 and (new to the survey in late 2011 vs early 2010) JAK.  These three classes accounted for 53% of the Panel’s value allocation.  They predict the likelihood of approvals and use in the treatment of inflammatory bowel disease.  A second tier of mechanisms, accounting for 24% of the value to the Panel included a variety of probiotics/fetal transplants (helminthes, bacterial IL10 delivery), stem cell transplants, and IL6 inhibitors.


Other mechanisms discussed in this report include TNF, steroids, CCR9, PI3k, folate, IL-17, GMCSF, S1P, and IP10.




Drugs mentioned in this report include:

Company Generic Brand
Abbott (Eisai) adalimumab Humira (with Eisai)
AblynxAblynx / Pfizer ALX-0061ATN-103
Anterogen ANTG-ASC-203
Ardeypharm E. coli nissle 1917
Avaxia AVX-470; polyclonal bovine anti-TNF
Bayer-Schering sargramostin; GMCSF Leukine
Bristol-Myers Squibb  MDX-1100
Celgene PDA001
ChemoCentryx / GlaxoSmithKline CCX-282 B Traficet-EN
Elan / Biogen natalizumab Tysabri
Emergent / Pfizer X1 TNFR x Anti-IL6
FalkSalix / Dr. Falk LT-02 + Mutaflorbudesonide Budenofalk
Ferring FE-301
Genentech / Roche rhuMAb-b7; RG7413
J&J / Janssen / Merck / Essex infliximabustekinumab; CNTO-1275




Lilly INCB-28050 / LY3009104
Merck (Schering-Plough) SCH-900222
Millennium / Takeda vedolizumab (MLN-02)
Neovacs TNF Kinoid
Novartis secukinumab; AIN-457fingolimod Gilenia
Osiris Therapeutics mesenchymal stem cell Prochymal


tofacitinib; CP-690550PF-00547659





Santaris budesonide Entocort MMX
Toray TRK-170
UCB certolizumab Cimzia
Vertex VX-509

Whenever i put the word “tofacitinib” into a blog i get 2,000 hits the first day.  It’s like throwing chum into the water.  So I’m putting my feet back on the boat now…  “tofacitinib, tofacitinib TOFACITINIB” (or is it “beetlejuice, beetlejuice BEETLEJUICE”?)


  • Mechanistically there is no good rationale for why tofacitinib should be more effective in ulcerative colitis than in Crohn’s, yet Pfizer is moving forward with tofacitinib first for ulcerative colitis in patients who fail conventional therapy.  The oral agent looks very similar to an anti-TNF in terms of speed and depth of response, and mucosal healing.  The first patients should go on study in 2011, so a registration for UC will be late 2013; roughly two years after the drug is first available for rheumatoid arthritis, and one year after psoriasis.  “Failing conventional therapy” means that they are going to try and position as an alternative to Remicade in UC patients who are 5-ASA failures.  So this is the typical filing package for an anti-TNF for ulcerative colitis.  Pfizer is also going to try for milder disease, as an alternative to prednisone.  And, they will ultimately redo the Crohn’s study and seek approval for both diseases.  The initial Crohn’s data wasn’t very good.  There was a decrease in C-reactive protein, but the clinical endpoint was not met.  It appears that the problem in the Crohn’s study was a dose related issue, and there will be a Ph-III Crohn’s trial in the future.  The other point on the failed Crohn’s trial is it highlights just how much harder it is to get consistent interpretation of a Crohn’s endpoint, than it is for all to agree on an ulcerative colitis responder.  Pfizer told one panelist that they are afraid to study tofacitinib at a higher dose due to concerns over lipid effects.  Another Panelist heard from Pfizer that they are being cautious over a liver enzyme signal.  More to the point, the pivotal RA trial had four deaths and four opportunistic infections.  While it was easy to explain away three of the deaths, it is clear that two sides of the sword for tofacitinib, a strength and a weakness, are that it is a very potent oral immunosuppressive.



“Did they just run the wrong Crohn’s trial or the wrong dose?  That is why I would like to see the full paper.  The abstract doesn’t help much.  The thing is that in Crohn’s disease we see more cases where you include patients with high CDAI but they don’t really have intestinal inflammation.  It doesn’t work as well on them of course because they don’t have inflammation.  As you know the CDAI is based mainly on subjective measures.  So a patient with IBS can have a very high CDAI, but doesn’t have Crohn’s disease.  We saw this in the SONIC trial where 30% had a negative colonoscopy in inclusion and they didn’t have a profit of combination therapy of azathioprine and Remicade or Remicade alone.  I am not sure if every patient had a colonoscopy in the Crohn’s disease trial of Pfizer.  Were these really all inflammatory patients or were their results watered down by non-inflammatory patients.  I think for UC with regard to toxicity it seems to be that there was a not a big issue in UC.  However, the exact data were not mentioned in the discussion as well as in the abstract how many people you actually needed to put on a lipid lowering agent.  That could be a problem.  I perhaps agree with the other boards – if you have equal choice of effective drugs, for example anti-TNF and this drug, but you end up having to put almost every patient on a lipid lowering agent to tolerate this drug then everyone will chose first an anti-TNF.  Given what you know what dose seems to be the best compromise for efficacy and safety for the UC patients?  I think the higher dose was better.  There was clearly a dose dependent effect.  The next trial I think they are just testing two doses and we just have to wait and see how this comes out.  I can’t predict.  I’m not ever sure if the lipid story is a dose dependent story, or is it individually based and it doesn’t matter how much you give someone”.


“The issue is that UC is very easy in that it is a homogenous population to study.  They present the same way.  Generally you can follow symptoms because they correlate very well with UC findings endoscopically.  Crohn’s is a completely different animal.  You have got people with complications and fibrostenosis that have symptoms that drive up scores but are not going to respond to therapy.  You have people with small bowel overgrowth, diarrhea related to surgeries or mildly shortened bowel, superimposed irritable bowel.  It is a much more complicated disease to assess and study.  I think what is going to happen is that you are going to see much more emphasis on objective measures of inflammation, inflammatory markers, calprotectins, mucosal healing at least to get people into studies to eliminate patients who have other things causing their Crohn’s disease activity index to go up.  Maybe that was the point about the JAK inhibitors is that is what happened.  We included some of these people that have other problems that get better just with getting medical care as part of trial as opposed to real bona fide Crohn’s inflammation.  I wasn’t part of the studies so I can’t answer that, but that is feeling as I sit on that advisory board.  It is brought up over and over and over again.  This is not like rheumatology where we can count someone’s joints and if they are hot and swollen it is easy.  It is right in front of you.  So we don’t have that in Crohn’s”.


“First you have the JAK inhibitors.  Tofacitinib of course is furthest along.  A lot of people have said to me that they really are looking forward to the Vertex drug because it is a more pure JAK-3 inhibitor.  The reason is that they feel it will get around the cholesterol issue associated with JAK-1 and the anemia associated with JAK-2.  Do you have a point of view on that?  I agree with the notion, but the question is are we going to be trading off efficacy in terms of having a more specific target.  We won’t know until we try it in people.  But I think about again the 3-year plan, the tofacitinib data in UC is spectacular.  I mean maybe the best signal we’ve seen in the modern era with anything, including the biologics, and this was a relatively refractory moderate-to-severe population.  So that is going to be moving forward rapidly.  Whether the Vertex or any of the other JAK inhibitors that are out there are going to make a dent, I think it is intriguing to try and get more specificity, the question is whether it is going to work.  I am not going to even bet on it.  In the initial Crohn’s trial Pfizer ran my recollection is that they had a decrease in c-reactive protein, but they sure didn’t hit the clinical endpoint.  Most people have said it was a poor trial design, but there is no real reason that a JAK approach should work better in UC than Crohn’s.  I’ve heard a couple of people who I would consider to be b-list opinion leaders saying this shows you that there are different targets in each, and that is just non-sense.  Speaking as someone who studies JAK signaling pathways in the lab, I can’t think of any possibility why it should not be as good a target in Crohn’s as in UC.  I would go as far to say that maybe not even poor clinical trial design, I think that it just illustrates that it is a hell of a lot harder to do a proof of concept study in Crohn’s disease.  Being familiar with the clinical trial design, with the findings they have, and the fact that there was at least a biomarker response, I think they can be more clever if they move forward in Crohn’s with hitting the right clinical endpoints”.


Categories: Crohn's disease, gastroenterology, inflammatory bowel disease, ulcerative colitis
Tags: , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
Bookmark the permalink.

Post a comment

Comments on are monitored.

You may use these HTML tags and attributes:
<a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>