Patrick McLean Symposium Presentation Transcript

Thank you all for listening to us today. We’ve all got a lot to say. I’m here on behalf of Professor Tom Borody from Sydney, Australia and he’s the one that actually got me involved in it about 11 years ago and my retirement went into a passion for trying to solve this disease, solve this problem, and eradicate this disease. So I look on Tom as the father of MAP. Tom always says, well no, his mentor was John Hermon-Taylor and I guess that makes Dr. Amy my aunt.

So without further ado, I’d just want to say that I’d like to leave you with two thoughts today. One is that Anti-MAP therapy works in Crohn’s disease, and I will hopefully show you some pretty convincing evidence in the number of studies that have been run. The other thought that’s really important is that we won’t be able to resolve this until we have an effective diagnostic that can detect MAP and detect MAP in human beings.

What Dr. Collins talked about in terms of the animal kingdom; they’ve got a good system because MAP is a live bacterium and they can culture it. We don’t have that luxury in humans, unfortunately. Until we do, it’s going to be a very difficult road to convince enough people that this is a causal effect and that we have to have that before we go forward.

So, all that being said, I’ve got a couple of things to comment on because this is a CME event. I have to declare my financial exposure here, my disclosure. So I’m actually working, consulting Product Manager for RedHill Biopharma, an Israeli company based in Tel Aviv that is developing what we call RHB-104, which is a triple antibiotic therapy for the treatment of MAP infection. And I’m also still the CEO and the acting chairman of the company that Professor Borody and I set up when I went to Australia: Giaconda Limited, so just to let you know.

As a public company representing RedHill here today I have to put up this disclaimer. We’re not trying to sell you any shares. We’re not trying to sell anything. This is informational purposes only. And it’s a tour de raison of what’s happened with treating, studies, published studies in peer reviewed journals in treating patients with Anti-MAP therapy.

Tom’s mantra is, you know, where you see inflammation, look for infection. RHB-104 is a combination antibiotic therapy, this is the definition part of things, targeted towards treating  Mycobacterium avium paratuberculosis, or MAP. What we’re talking about here and when Dr. Chamberlin was talking about paradigm shifts, we’re talking about shifting a paradigm, not unlike what happened in the 80’s and 90’s with Helicobacter pylori. Where everybody said, well you can’t have a bug live in the stomach. It’s too hostile. You’ve got acids and you’ve got enzymes and you’ve got all these other things. Bugs won’t live in the stomach. Well, two Australians, Barry Marshall and Robin Warren proved that wrong and ended up winning the Nobel prize for it. Tom was actually a colleague, is a colleague of Barry Marshall’s and it was that work that set him off on a path towards looking at MAP, the potential for MAP infection to cause Crohn’s disease, and that’s where we are today. So to change the paradigm from auto-immune disease to dysbiosis to infection cause is as difficult as it was for Helicobacter pylori.

I think we’re all here because we understand what a devastating disease Crohn’s is. There’s no cure. The cause, or the etiology and the pathogenesis we don’t know, as Professor, or Dr. Chamberlin explained. There are over 1.2 million patients just in North America and Europe, because that’s where we can measure it, and that’s how we get those estimates. It’s well characterized, and I won’t go through all the characters of Crohn’s disease because many here know it.

This is what happens in the gut. And Professor Borody says, look, if you count up all the cells in our body, there are, 90% of them are in the gut, in the digestive system. So what he says, that makes us 10% human, and 90% something else. So going on to…I won’t say the word.

But going on to what the current therapies are, none of the therapies that are out there today, whether the anti-inflammatories or the biologics, are designed or they don’t claim to cure Crohn’s disease. The focus is on the modulation of inflammation. And what they essentially do is they turn down the volume. Turn down the volume of pain, of inflammation, of diarrhea and all the other aspects of Crohn’s disease that we see.

Looking back in time, looking at the early antibiotic trials, this is explained, I think Dr. Mike talked about the fact that in looking back when Dalziel first looked at, or got the idea of looking at the colon of an infected cow with Johne’s disease and the colon of a human being with Crohn’s disease, they looked quite a bit alike. So he hypothesized that maybe it’s the same cause but they weren’t able to find it in human beings, therefore we haven’t been able to nail that down. But what they started looking at in the 1980’s when PCR came up as a technique for finding DNA in various systems, and they were looking at the DNA in Crohn’s disease. And they thought, well if this is a bug, that’s a tuberculosis type bug, let’s throw some antibiotics at it that work on tuberculosis. Well, there were 15 of them, some of them used a single drug, some used up to four drugs, but in effect Mycobacterium tuberculosis and TB is significantly different from MAP and that means they’ve got different antibiotic sensitivities. So what normally worked for TB doesn’t work for Crohn’s, doesn’t work for MAP. And there’s no effective anti-tuberculosis combination that really works on MAP.

When HIV and AIDS came on the scene, and HIV/AIDS patients started to suffer a pulmonary condition called MAC, Mycobacterium avium complex, there’s a lot of money put forward and they discovered some intracellular acting antibiotics that work in MAC. And those now have turned out to be effective in, we believe they’re effective in treating MAP. So they took those antibiotics and included things like Clofazimine and Rifabutin and Clarithromycin, some Metronidazole, and they started using them on patients, on Crohn’s patients. And these are just some results, and underneath each of these studies.

Gui used Rifabitin, Clarithromycin or Azithromycin, so he went back and forth between the two. He got 68% of the patients, albeit a small study, into remission. Douglass got 20 out of 28 who responded. Response is different from remission. Response is just turning down the volume; a reduction of like 100 points, or at that point time it was 70 points in the CDAI, but not getting them into remission. Ira Shafran in Florida got 20 out of 29 to respond. And Professor Borody, when he published his paper in ’02, he was actually showed that he got 8 out of 12 to respond, and 6 of them went into remission.

When I retired from my last job and Tom invited me down to Australia, I met five of the six patients that he got into remission and that’s what turned me on to doing this and spending the rest of my life getting this therapy to the patients, because it worked. And if you listen to their stories like I have listened to them, then you become a believer as well.

So the rationale for the triple antibiotic therapy that’s constituted in RHB-104 is that mycobacterial infections in humans are very complex. I think that some of the messages you’ve heard so far demonstrate that. And what really happens is that effective antimycobacterial agents have to work inside the cell, because that’s where the infection happens with MAP. And you can’t use one because even all of the big people like World Health say that you have to use three, because if you just use one you’re liable to start creating some resistant MAP.

This was Tom’s first paper. I won’t spend a lot of time on this, but pictures tell 1,000 stories. If you look on the patient on the left, the deep colonic ulcers and twenty months later after therapy, healing. It’s interesting that that scarring there, this is like if you get a cut on your arm and it heals up you get a scar. Over time that scar will disappear. Well, that’s what happening, what’s probably happening here because you can see the deep ulcerations, cutting ulcerations and making deep cuts into the gut. This patient here, we’ll talk about him in a few minutes later. Extensive pseudo polyps and look at this, 20 months later.

So that was very impactful if you will, and started turning me on. And then there was this study published. This was a 63 year old male. And this is a one patient study. It’s the only one that’s been published where they looked at infection with MAP before, they found MAP before, and they treated him with Anti-MAP therapy and they looked at the MAP and they looked at the progress of the patient, and I’ll show you the results in a minute. This is actually a publication of Dr. Chamberlin. It was a 63 year old male with all this. Look at this. This is a key finding of the study, of this publication. So this is before. Big ugly ulcer and MAP. After, 6 months after, healed up. Still some healing to go, but no MAP. So that’s the only one that’s been published on treating MAP, determining MAP infection in a patient, treating the patient with Anti-MAP therapy and seeing the results.

This is; Professor Borody went back and looked at some of the work that, some of the patients he had treated over, there’s 22 patients that he had treated over 20 months and you can see here that the response rate went from an average, amongst these 22 patients, they had an average CDAI of 241. So that’s a moderate to severe Crohn’s patient. Within 1-3 months that was down to 102, so they’re in remission and it kept going down over time. So it’s again, more evidence of the fact that I believe and the publications demonstrate that Anti-MAP can be.

The one with all of the polyps I was talking about, that’s David. He’s been on AMAT and in remission since 1996. He will not give up his AMAT because the steroids did such a job on him that he had to have both hips replaced, and when he got into remission and stayed there , he said I’m not giving this up. I’ve met David a number of times. I’ve talked to him. This is the Australian is the equivalent to the Wall Street Journal in the United States, so it’s a national newspaper, it’s very well read, and he told his whole story there. So, 1996 he’s coming up on 20 years of therapy that he won’t get off of because of the benefits.

So the rationale for the RHB-104 treatment is it’s a combination of Rifabutin, Clarithromycin and Clofazimine, as I mentioned before. They’re active against MAC as demonstrated by the work done against HIV/AIDS in the 80’s. And MAP is a actually a subspecies of MAC. So you’ve got MAC, you got MAP; you got Mycobacterium avium and a couple of other things. They all, these three work intracellularly. The interesting thing that Robert Greenstein from New York, actually took and plated out some MAP and he took some of the existing therapies, so he took Azathioprine, he took 5-ASA, and he determined that those therapies that are commonly used in treating Crohn’s disease today, actually have anti-MAP therapy. They actually kill MAP when exposed, so interesting that he did that.

Previous clinical experience: all clinical efficacy studies with CD have included all comers. Why? Because as I said at the beginning, we don’t have a very accurate, actual, clean, effective MAP diagnostic. So we can’t tell if the patients are infected. I think you’ll hear more; some exciting news about that to come up with some of the future speakers. So all the studies that have been done have been done with all comers because we couldn’t sort out who’s got the MAP infection and who doesn’t. RHB-104 is intended for all CD patients for the same reason, okay. We can’t determine if they’ve got MAP or not. We’re testing for MAP, but we can’t going in say that we’re going to only treat these patients.

One of the things that happens, and this is important I think; If you look at the combination, one of the things that’s important with this therapy is that they ramp up. And Tom Borody will say this time, and time, and time again, is if patients started this therapy they’ve got to ease into it otherwise there’s some fairly significant side effects in terms of ague, flu-like symptoms, whatever. So it’s important that you ramp them up.

Let’s take a look at the Pfizer study, otherwise known as the Selby study, because Professor Warwick Selby in Australia was actually the first author. And what they wanted to do was determine whether or not, if they got, once they got the patients, if they could drive them into remission, then they would see how long they could keep that remission. How long can they maintain that remission. And the belief at that point in time was because they thought they had a cure. They thought that Anti-MAP therapy was the cure for all Crohn’s. They thought that everybody’s infected with MAP. I don’t personally believe that, and a lot of people would agree with me. Some people would argue with me but at the end of the day that’s what they thought and that’s the way they went.

So they were looking for relapse and between weeks 16 and 52 given proven remission at 16. So if they drive the patients into remission, and they did that with 40mg a day of Prednisolone, starting with the Anti-MAP therapy and then started weaning the Prednisolone over time. At the end of 16 weeks the Prednisolone was gone. Those patients who were in remission were then allowed to continue in the study.

And these are the results. If you look at it, it’s really interesting because comparing to placebo, they had 213 patients. They put 111 on placebo and 102 on active therapy plus the Prednisolone. At 16 weeks, look at this, 66% of the patients were in remission on the active therapy, but only 50% on the placebo arm that was caused by, again because they were given the Prednisolone. And the p value, if you get a p value of less than .05 that means you’re really, you’ve got some significant benefits over placebo; p value is significant at .017. But then, because they were only looking at the patients who were in remission from week 16 on, their denominator came down and they ended up with losing that, Although very closely to .05 so not too far off the significance, but not there. And at 2 years they were at .14 so they were way off. And that’s the results of that study, where as stated by Professor Selby, was that there’s no relationship to the treatment of MAP and Crohn’s disease. Although he had never tested any of the patients for MAP infection so he didn’t know that, but he just assumed that they all were.

So Professor Marcel Behr at McGill University from Montreal then took that data and reanalyzed it. Said, let’s take a look at it differently, and he used the term in his publication, his paper, he said let’s take a look at it in almost an intent to treat basis. What happens if you keep all the patients in here and you don’t take them out at week 16? Well, he changed the denominator and you end up with remission at 40% here with a p value .003. Very significant, very positive over placebo. You look at 2 years, .005. Two years you still got 39% of the patients in remission. So there are the naysayers saying Selby was right. There’s no relationship. But Marcel Behr said some of the data doesn’t bear that out. It looks like there’re some positive things.

One of the interesting things here, and these are two different studies. I don’t want to say that they were comparative studies. But just in terms of the outcomes. If you look at the biologic, the Accent I study that Remicade used to get their approval and the way they did it. They actually had it on an intent to treat basis, if you want to look at it that way, going back to all of the patients they looked at. 23% in remission at 30 weeks and 16% at 54 weeks. Again, compare that to 66%, 40% and 30% [with antibiotic therapy in the Selby study.]  All this say, is compared to all the treatments that treat the symptoms, if we  get this working, that we think that we’d have a very effective therapy if we treat the MAP infection in Crohn’s patients.

So what’s RedHill doing? They’ve got a Phase III clinical study going on against 270 patients, randomized 1:1 to placebo. Again, moderate to severe, and it’s add-on therapy. So the patient has got to be on something else. If they’re on 5-ASA, or they’re on 6MP or Azathioprine or Humira or Remicade, this is add-on therapy to that. So you take that and we’re looking at 120 sites in the U.S, Canada, Israel, Australia, New Zealand and selected EU countries. So it’s very expansive. When we started this study we found out that there were 72 competing Crohn’s studies out there, so getting patients into the study was difficult because they were already committed to something else. So it’s, we’ve had to expand a number of sites.

Primary endpoint is remission at 26 weeks. Remission at 26 weeks because we want to make sure that we give them a chance. MAP is a very slow growing bug, and we want to make sure we give them a chance to grow and to get at those bugs and get them into remission. Professor David Graham from Baylor School of Medicine in Houston is the lead investigator. And if you want more information just go to Clinicaltrials.gov. All of the studies are listed there and you can find out more of the specifics of the study.

Some of the interesting points, the secondary endpoints, we’re looking at maintenance of remission which is what Selby was really concerned about. We’re looking at the time and duration of remission; how durable is it. Looking at other indicators like C – reactive protein or fecal calprotectin; Efficacy outcome measures in relation to MAP. So we’re testing for MAP, but we don’t know if we’ve got the perfect test. And other things: population, we’re doing some pharmacokinetic studies, we’re looking at some CDEIS, which is looking at the mucosal healing, and we’re trying to validate a MAP assay in the process.

So in conclusion, H. pylori were strongly associated with ulcers. Although, if you look at the numbers, H. pylori is thought to be responsible for 70% of the duodenal ulcers, 50% of the gastric ulcers. What about the other 30% of duodenal ulcers? The other 50% of gastric cancers? And that’s why I firmly believe, and I think Dr. Chamberlin and I have talked about this numerous times, that Crohn’s is not a disease. It’s a syndrome. A good portion of the patients are suffering from a MAP infection and that’s what we’re trying to resolve for a lot of patients. Not for everybody, but for everybody that we can. Thank you very much for your time. Much appreciate it.