Top line results from Redhill's Triple Antibiotic for MAP study

RedHill Announces Positive Top-Line Results from Phase III Study of RHB-104 in Crohn’s Disease

For any interested or that have been following.

Here is what has been released so far:

/www.redhillbio.com/RedHill/Templates/showpage.asp?DBid=1&LNGid=1&TMid=178&Fid=1384&Pid=0&Iid=8178

surprising small Phase III sample, and surprisingly large benefit from placebo. Higher than usual.

I think any treatment focused on the cut microbes has potential. The effect here is weak. If they fold this treatment into the other information known about the immune system and IBD, progress could be made.

I hope anti-science creeps don't piss this up.

I'm sure they need to spin this as a good result (to keep the business going) but it isn't.

If the aim was to show that MAP was causative, this has done nothing in that regard (and perhaps shows the opposite.)

At 52 weeks, 27% versus 20% placebo, is unremarkable. And the fact that patients were on other medications, makes it even worse.

It is already known that even single strain antibiotics can help around 20% of patients to achieve remission.

And it is already known that wiping out the gut microbiome can have a positive effect for IBD.

All in all it has not yielded any new information, nor any ground-breaking new treatment.

I hope they keep working on antibiotics as treatments, but not with such a scatter-gun approach.

Mark, what is your take on the results of this study in relation to the MAP hypothesis as the cause of Crohn's, and the great expectations formed in time before the announcement of the results?

I think the safety data is interesting. I would expect much higher (than placebo arm) side effect and related issues with this treatment.

Secondly, were all/majority of the study participants tested for MAP before or during enrollment, and which testing procedure was used (the old ones or the newly developed ones)? How many of them were tested positive for MAP? Why not all of them were tested positive for MAP, if MAP is the causative agent? How many of the MAP positive subjects responded to the anti-MAP treatment, and how well did they respond?

What do these data say to us for the age-old MAP problem, and also the possibility of a cure for Crohn's?

By the way, stock analysts were underwhelmed with the results. I think many gastroenterologists will also be underwhelmed by the results as well. I mean, even though they said "This study was powered for 26 weeks and was not sufficiently powered for 52 weeks" in their presentation, I think that's just an excuse for the miserable treatment effect at the one year mark.

ir.redhillbio.com/static-files/35b7a3f0-37d1-47bf-8a7d-7f8dce159732

/seekingalpha.com/article/4192004-redhill-biopharma-crohns-data-leaves-lot-desired

EDIT: I found these now:

RedHill Biopharma (NASDAQ:RDHL) says the market may be "confused" with the week 52 remission secondary endpoint from its Phase 3 clinical trial evaluating RHB-104 in Crohn's disease patients. Shares, initially up, sold off in apparent reaction to the endpoint which appeared to show only a modest separation from placebo.

The company says the endpoint measured "late induction of remission" and did not evaluate the preservation of remission over time. In other words, the endpoint meant to capture those patients who may have needed more than 26 weeks of therapy for initial induction of remission.

From: /seekingalpha.com/news/3376619-redhill-clarifies-52-week-data-phase-3-study-rhbminus-104-crohns

Regarding the standalone week 52 remission secondary endpoint, we believe there may have been some confusion. The standalone week 52 remission endpoint measures “late induction of remission” and does not evaluate preservation of remission over time. As such, this specific endpoint is neither a clinical nor a regulatory relevant endpoint. The standalone week 52 remission secondary endpoint was merely included by RedHill in the study to investigate whether certain individual patients might require more than 26 weeks of therapy for initial induction of remission. Accordingly, the analysis of standalone week 52 remission is an isolated exploratory outcome.

To emphasize, the clinically and regulatory relevant endpoint pertaining to week 52 is “maintenance of remission”, which by definition evaluates the maintenance (preservation) of remission from the induction of remission or response at an earlier time point to week 52. This “maintenance of remission” endpoint, in conjunction with a separate early “induction of remission” endpoint, has served as the basis for approval of current standard-of-care therapies for Crohn’s disease. In this endpoint, maintenance of remission from the induction of remission at week 16 to week 52, RHB-104 was twice as effective as placebo with high statistical significance (25% vs. 12%, RHB-104 and placebo, respectively, p= 0.007).

From: /seekingalpha.com/pr/17232359-redhill-biopharma-elaborates-announced-positive-top-line-results-phase-iii-study-rhbminus-104

Post Edited (xy123) : 8/1/2018 1:21:31 PM (GMT-6)

I will wait for the anti-MAP vaccine trials for a better answer to the MAP problem.

Hi xy

I don't have those answers. However many of those questions will be answered and released over time - a few months. They tested everyone. Multiple times I believe according to a few participants. I think (or am pretty sure) there will also be results with endoscopic examination and how this correlates to the diagnostic test will also be released over time. One patient was speaking recently about his colonoscopy results during the test. He/she was a responder. As for the blood test, it was a diagnostic test that was developed specifically for this study by a third party lab. This part of the study was being used as a proving ground for the test itself. I forget the lab name, but it is a big name lab for other IBD tests. It is in their literature somewhere.

Depending on current tests about 20-30% of general population test positive I believe. Interestingly the same as good old Tuberculosis. (~1/3 of population). They have a latent infection. Same situation is proposed.

Personally, and it's just me, but I would wager a very high bet that there will be a strong correlation between responders and their levels. I say this because many of the people on the individual triple abx have gone through this testing and the results have always corresponded. Those that do not respond to individual triple abx continually have high levels in their white blood cells and/or antibodies after subsequent testing depending on which test was used.

Three things were well known prior anyway: 1) That a decrease in bacteria (MAP levels) correspond with remission and healing status 2) That entering remission even for those taking the stand alone (separate triple abx) can take upwards of a year. 3) That triple abx do not, for whatever reason completely eradicate the bacteria inside white blood cells even in most responders. And have no effect on the bacterial levels in some (resistance).

I wouldn't call the one year mark miserable at all.

My take is simply that it might be enough at least to finally get researchers and GI's to think about something that is not 'auto-immune' and a therapy revolve around suppressing our immune systems. And open up funding grants. Also hopefully over time once he rest of the study data is released, it will spur some veterinary/dairy groups into action.

Yes, I think the vaccine results will be super interesting as well for the same reasons as you.

I haven't touched on the safety concerns with the long term antibiotic combination either. I think this should be adressed very carefully. It is now known through scientific studies and many articles that bactericidal antibiotics induce mitochondrial dysfunction, which should be expected based on the endosymbiotic theory. They have toxic effects on your mitochondria, one of the known mechanisms for that is oxidative stress. I can't remember right now about clofazimine and rifabutin; but there are many in vivo and in vitro studies demonstrating that macrolides (clarithromycin) have bacteriostatic and bactericidal effects.

Ask another question: How do these antibiotics combination affect brain physiology in the long term (since this is meant to be a long term antibiotic treatment)? Do they cause any permanent changes in your brain? It is known through scientific studies that clarithromycin has excellent CSF penetration.

Macrolides are one of the most potent antibiotics for causing antibiotic induced serious psychiatric problems, for example.

How do these antibiotics affect your cognitive function? How do they affect you neuroendocrinologically?

I have asked these to Dr. Chamberlin, and he said he doesn't have knowledge about these, but he thinks
the long term antibiotics treatment is safer than the standart Crohn's treatments.

This one year old study will not do it for me in terms of safety concerns. They don't look at these and many other possible physiological changes in the treatment subjects. They probably did very standart blood tests and if something very suspicious occurs, then looked for that isolated problem. I don't expect a drug company to do a thorough examination of a drug's effects on the trial subjects based on its molecular structure, and the literature about its possible mechanisms of action, its effects on various organisms, hypothetical questions and safety concerns raised about it etc.

Compare this with Humira, for example. Humira has no direct toxic effect on human cells and tissues. Anti-tnf's have been used for a long time to collect a good amount of pharmacovigilance data. The only problems that occur with the anti-tnf's are actually secondary effects of the tnf inhibition (slightly increased risk of cancer and fatal infections).

Post Edited (xy123) : 8/4/2018 1:29:31 AM (GMT-6)

OM it's very simple, and related to the article I posted above. In fact, that article discusses that issue as well.

You eliminate the immunogenic, irritant, and fermentable food particles from your diet. You eliminate the local food-driven inflammation, and massively decrease microbially-driven inflammation (because of the serious microbial reduction in the gut through enteral feeding).

Theoretically, gut sterilization and fully elemental enteral nutrition would cure Crohn's. The microbiota and the immunogenic, irritant, toxic (think plant toxins or microbial toxins in your food) foods are the only generators of inflammation in Crohn's.

I remember that study very well. You posted that a few years ago in the forum. They used Elemental 028, a fully elemental enteral nutrition product, in that study. You can't achieve the same results with a semi-elemental enteral feeding product like Modulen, because of the immunogenicity of the milk protein in it (also carageenan, maltodextrin etc.). Elemental 028 is a very clean product compared to others, it's probably the cleanest on the market.

Post Edited (xy123) : 8/3/2018 12:27:54 PM (GMT-6)

Veggies, especially raw, irritate the gut lining and increase bacterial population. Both of these cause increased serotonin levels in the gut, increasing inflammation. Increased bacteria in the gut means increased lactic acid, endotoxin, and nitric oxide; all inflammatory and metabolically suppressive (thus prevent healing). Except for the carrots (because carrots have antimicrobial effect) in moderate amounts, all the other vegetables they added are harmful for intestinal health because of their fermentability, their gut-irritant effect, their toxins, their goitrogenicity, lack of nutrients etc.

Post Edited (xy123) : 8/3/2018 9:06:19 AM (GMT-6)

OM, would you be concerned about the possible health effects of using the triple antibiotic therapy for years, if you or your son were to use them?

Post Edited (xy123) : 8/3/2018 2:05:56 PM (GMT-6)

Currently the generally accepted practice is that you need to be on them indefinitely. If you stop taking the antibiotics, you are likely to relapse.

Old Mike said...


...still cant figure it out.

oldmike

I think a lot of research focuses on treating IBD by suppressing the immune system, rather than getting at the cause. There is tons of money in biologics, so a lot of the best minds are wrapped up in that kind of research.

Johne's disease (in cattle) is so similar to Crohn's. Also MAP levels are higher in Crohn's sufferer's than controls so there again, seems logical that there is some link.

Edit: Oh, and MAP is the consensus cause of Johne's BTW.

Post Edited (C_G_K) : 8/9/2018 8:49:27 AM (GMT-6)

If they can show a distinctly positive correlation between the level of MAP in the blood of Crohn's patients before and after the treatment, and a distinguished treatment effect; that would be interesting.

Mark, I will ask the same question I asked to OM: Would you be concerned about the possible health effects of taking the antibiotics for years?