Posted by Jeff Berk; BOLT International
Today’s Photo: Scottsdale Municipal Landfill.
Today’s Temperature: “Dry Heat”
Woman’s face tightens.
Releases horrific gas.
Checkout line faux pas.
Okay, before you send me an email asking if this is based on a personal experience, or just another pebble chipped off of my warped boulder…
Nothing ’bout Facebook is real.
Pretend to be what you feel.
So seek your desires.
You know we’re all liars.
Churning out bullshit with zeal.
Now, using the principle of combining literary techniques so as to blur the lines of truth and fiction, here are a couple of insights from BOLT’s 12th installment of our Gastroenterology Thought Leader Panel. These are clips from our just published post-DDW edition (and soon to be available on the pay side of BOLT’s website; email me now, or check back in a couple of days), dealing with inflammatory bowel disease: Crohn’s and ulcerative colitis. Enjoy.
Stelara (ustekinumab / CNTO-1275; Janssen)
- Word from the DSMB is that Stelara (ustekinumab) does not appear to have cardiovascular toxicity in IBD patients, and it is obvious which patients are on active drug because they are flaring when discontinued. Janssen is positioning Stelara as 2nd-line biologic therapy after TNF failure in Crohn’s. They will not imminently develop the drug for ulcerative colitis, as they do not want it to compete with Simponi (golimumab). They also won’t develop ustekinumab at a higher dose because of the concern that they are going to move out of the therapeutic window, and into the realm of cardiovascular events. There is also the confusion that would create with the dermatologists who are using Stelara for psoriasis, and the possibility that payers will direct prescribing toward the lower cost option; whichever it would be. At $32,000/yr for psoriasis, Stelara is already priced in the top tier of its competitive universe.
“There were TNF failures in their study. I think the study they presented I think they all had been on TNF and 50 percent two or more TNFs. So it looks like these were people who were not responding to TNF”.
“When I ask about ustekinumab there have been a lot of concerns raised by the dermatologists in psoriasis patients about the cardiovascular. Yeah, but you talk about a population again that has cardiovascular events where the underlying disease, the psoriasis, from patients who have that. So as soon as you are diagnosed with psoriasis you have increased rate of cardiovascular events. This is a high risk population to begin with. I don’t think this applies to Crohn’s disease. For me, the picture evolved as following. We do have the anti-TNFs at the moment. The anti-TNFs have been profiled and to complicated disease. And the anti-TNF gives the patients some drawbacks through its mode of application. It is parenteral. And now you have an oral substance that could replace parts of that anti-TNF world. And you have ustekinumab that can be applied to those individuals who are anti-TNF refractory and in whom the mechanism escape is happening. So these are two enrichment therapies”.
“It looked clean in the Crohn’s studies. Actually the head of the DSMB came up to me and told me that he knew who was on drug and not because they were flaring up when they stopped it. In our trials we didn’t see that”.
tofacitinib / tasocitinib; CP-690550 (Pfizer)
- 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. 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.
“What was your perception of mucosal healing data? I thought it was very similar to anti-TNF. It was good”.
“So let’s assume that Pfizer is successful by 2013 getting an ulcerative colitis approval for tofacitinib. So then you have these other companies that are at least two years behind them. When you look at the possible approval for tofacitinib – the reason I was so excited is because I can look at this slotted in after a 5ASA but as an alternative to you going on infliximab. Now that is very optimistic. And just in discussions, so this is not breeching any confidentiality, is what they need to do and what they are going to be forced to do is have the same package as an anti-TNF up front in their development package, moderate to severe Crohn’s disease. But given the fact, again, if they don’t see any toxicity data what has been recommended is that the next series of studies, which because they are a behemoth like Pfizer they don’t mind thinking about this, is to go into earlier disease states where you may supplant prednisone and you may go into milder disease. That is all going to be predicated on I think some of the results in making sure that they don’t see anything on the toxicity side. And as opposed to other companies, what I think Pfizer is now making a big play to become a major player in the immune-mediated disease and because they have the resources they will probably launch those type of trials before finishing a full phase III in moderate to severe disease just because that is the way that Pfizer is. And that has been the recommendation from the advisors to the company is think about doing this because you will have competition at your heels, there may be a three-year window. You may need one or two years just to start people getting used to using a different mechanism of action other than an anti-TNF, you may have vedolizumab in that space before you. So all of those things considered they need to be a little bit more novel in their approach to their development program. If you were on the regulatory side and someone wanted to come to you and say we should be used in TNF-naïve patients how would I design that trial? The problem now is that if you are looking for that pure TNF-naïve patient population I think that most of these drugs will get a label that is in both TNF-exposed and both TNF-naïve. I don’t think you need to do a pure TNF-naïve patient population. So then it is going to become a marketing issue? Yeah, it will become a marketing issue. And when general people talk it doesn’t matter if it is other physicians, you talk to analysts, no one is going to do a head-to-head trial. It is almost going to be impossible to do it in IBD in general just because the patients are not there. One of the things that I think is very, very important to consider and a group of us were talking about this about a week ago is there are so many things that are potentially coming down the pipeline that where are we going to get the patients to do these trials. So at least you may not be able to get those patients in traditional markets or traditional clinical trial centers so then you are going to look at potentially non-experienced or less experienced sites and then, once again, you run into the issue of quality of data”.
“Here is my prejudice, I love this JAK inhibitor tofacitinib. Am I…? No, I think you should love it. I think that what are the reasons to love it? The ulcerative colitis data is pretty strong. The Crohn’s disease data probably suffered maybe from a little bit of a dosing issue and now you have a compound that you can deliver easily and has a biologic effect. It is pretty consistent that it has a biologic effect. The only thing obviously that maybe concerning is there was a little question about liver toxicity. You have great data in rheumatoid arthritis and you have a company that has a huge pipeline that is going to invest heavily in the development of this going forward. So this is a winner. I think that unless something surprising comes up in the toxicity side this is something that I think we back all the way in both diseases, not only ulcerative colitis, to come through in three or four years time once they can finish their development program. So one of the panelists had mentioned mucosal healing data and I didn’t remember reading it. They said it was on the poster and I didn’t catch that. So what was said? It looks like an anti-TNF basically. You made the comment a few moments back that you expected with anti-TNFs to need higher dose for ulcerative colitis. And yet here… Because the mechanism and where it interacts is a bit different. So the dosing schedules in the Crohn’s study was a bit different than the dosing schedule in the UC study. I think they were trying to manage potential toxicity issues at that time. I think they get a better feel for the molecule now and based on that, again, I think it is going to be a winner here”.