Dr. Sandborn presents effective therapies for the treatment of Crohn’s disease and ulcerative colitis.
I've been tasked with giving an update on therapies for moderate to severe disease that are in late stage development. So this stuff is all sort of experimental as opposed to the stuff you'll use in practice. There's my disclosures. So here's a kind of intimidating pipeline of therapies and inflammatory bowel disease. Uh anti immigrant, you're of course used to vandalism, mob, literalism mob, which is an anti beta seven antibody, failed to meet its end points and all sort of colitis. We're still waiting to see the Crohn's Disease data the next to products our orally administered but local acting anti alpha four beta seven drugs and then the uh M O R F 057 is a systemically bio available oral anti alpha four beta seven inhibitor that is in phase one clinical trial. So that could be really interesting. And we'll see how that whole place out. The next category of drugs is Janice kind nacer, jak inhibitors. I'm gonna show you data for one of these. You've had to sit in iB forgotten iB did meet its primary endpoint and all sort of colitis but due to some reproductive toxicity issues and males isn't going forward in the United States. Eisen Sittin NiB recently failed to meet this was a topical or got delivered Jak inhibitor that recently failed to meet its end point and all sort of politis Uh and then I'll introduce replace sedative and represented a little bit later tick two inhibitors. Uh think of this as an oral anti p. 19 drug. This has shown real promise in psoriasis. Uh so anti interleukin 23 very effective therapy and psoriasis. And this oral class of drugs shows promise as well. And it's being tested in inflammatory bowel disease. Well spending quite a bit of time on S. one p. modulators. So I won't the labor as an um Ahmad was just approved. I'm going to talk a little bit about that in a trace. Ahmad. And there's several other drugs entering the clinic in Phase two now uh anti interleukin uh that should be 23 drugs. So anti P. 19. There are many of these. I'll show you data for a few of them. God's Sake members and Kiss, a modern miracle mob that are in late stage development. Pt G. 200 is a rural topically administered and Tile 23. We'll see what happens with that microbiome. You maybe know that the series anaerobic spore fraction product scr 287 regions recently failed to achieve its primary endpoint G. V. C. S. R. Four is a gut gut stabilize our gut targeted hip stabilizer. You may know that systemically available 50 stabilizers are used to treat anemia and drive up erythropoietin concentrations. But this is sort of an anti inflammatory approach in the gut. There are several anti till one a antibodies PF 064. Recently data from phase two published in clinical gastroenterology and hepatology looks very promising and all sort of colitis A. B. X. 464. Face to a trial recently published big effect and then the data have been released for phase two B and this looks like it really works. We're sort of waiting to see what the safety looks like in larger numbers of patients. Uh anti sense against T. LR nine called battle ahmad and phase three for all sort of colitis. This Lance L two compound to topical anti inflammatory actually didn't meet its end point in base two but it looks like there might be something in the subject of patients and that went forward and uh it's going forward in ulcerative colitis and Crohn's disease. And then there's some strategies to deliver. I'll 10 locally to the gut. So pretty big pipeline. Um and then coming back to this concept of local delivery, you're of course used to miss salome and be destiny died. People have tried the local delivery of jak inhibitor TD 1473 that ended up not working but it's pretty hydrophobic. So it may be unique to the molecule other compounds are being tested Biologics, both carrier proteins for I'll 10 got targeted antibodies, interesting peptides and microbiome. So the efficacy of this sort of approach has been kind of mixed some of the things that have failed and some were still waiting to see but it's always attractive from a safety perspective. So let's now with that overview of what's going on. I'm not going to go through all those things that detail. I want to focus on three classes of drugs. Anti 19 or interleukin 23 antibodies recalled that the drug use all the time used to kenya mob blocks P 40 which is shared by interleukin 12 and 23. So anti P. 19 is the other sub unit that is unique to interleukin 23. So it's more selective. You would have thought that more selective would be less effective than in Psoriasis. That's turned out not to be the case. The anti p. 19 just flat out beads used to the mob. And so um you know, we're interested in whether that might be true and inflammatory bowel disease as well. And we'll look at the data jak inhibitors. You're used to the pan jak inhibitor, Tokyo City NEB which has been sort of limited by toxicity for pushing up the dose. And we'll see some data with Jack one selected drugs without a sitting there that maybe you can push the dose higher. And finally we're going to talk a little bit about SNP modulators. Actually it was an Ahmad just got approved. This actually is in the clinic now and I suspect our subsequent speakers will talk about positioning it but I want to reduce the class a little bit. So let's start with the interleukin 23 or anti p. 19. Um And as I mentioned uh if you look on the left half of this interleukin 12 and 23 share the P 40 sub unit which is targeted by use to kenya mob. Whereas Interleukin 23 alone has the P. 19 sub unit which is targeted by the drugs that were just about uh talk about. So there are three drugs that are in late stage development that I want to talk about. One is risk and tissue mob. The second is the second mab. Both of those drugs are already approved for psoriasis. And on the market generating safety data and being used in clinical practice and repetition. NeB is in late stage development for psoriasis but also for IBD. So we'll start with Ryzen Kitchen that this was a study led by brian Fagan published in the Lancet. Um that compared placebo 200 mg and 600 mg dose ng. Uh And here we can see clinical response and clinical remission. Over 12 weeks. I'm going to draw your eye to the upper right panel where you can see a remission rate. Clinical remission rate at 12 weeks of 15%. 24%. For reason could you have 200 mg and 36% for Ryzen cousin had 600 mg. This isn't an entirely anti TNF refractory patient population. So you have the delta 15 versus is almost 37. Uh So about 17% different for drug and placebo In a pure refractory population. And then I'll draw your eye to the lower right panel again at week 12 her clinical response. And here it's 20% versus 41%. So just over 40% of patients that were tight enough refractory at a clinical response. And then if you look on the right top to bottom you can see that the majority of patients who responded were actually remembers. So this is really interesting and then you can also see that there you know it wasn't clear that you shoulder the dose response curve. So placebo 200 mg 600 mg. So The of interest in Phase 3 to explore even higher doses which is in fact what happened. Um So then here's data. I don't think this is actually maybe it got presented an echo this summer. Um But I think most of this has just been presented as press releases and you're going to see the data at the U. G. W. Meeting and maybe a C. G. Uh this fall. So there were two Phase 3 trials the advanced trial and the motivate trial. The advanced trial is a mixture of conventional and biologic failure patients about half and half and the motivate trials. The pure biological failure trial. Now think about you know we had something similar to that with the use to kenya mob pivotal studies and as you recall all the absolute response and remission rates in failure patients were not that high better than placebo but you know you took a real hit on efficacy and the failure patients. So let's see what happened here. So we'll walk across the top starting with clinical remission. So, in the mixed biologic failure plus biologic naive the placebo remission rate at 12 weeks, 25%. And then the two doses of presentation, we have 612 100 each, 45 42%. So about 20% better than placebo. And this is, you know, that mixed population and remember in face to 600 mg was better than 200 mg. But we didn't know what would happen above 600 mg. And here you can see that there's no advantage to going above 600 mg. Now let's walk across to the the first row on the right side. Uh you know, pure failure populations, we have 19% Placebo, 41 42%. So again, no dose response. But so what's called 600 mg? The optimum dose. Um This is 23% better than placebo for full on clinical remission. That's kind of amazing. Uh in a failure population. And you can see compared to the mixed clinical trial population in the advanced trial, there was no hit on efficacy. So this is the first time we've seen this in Crohn's Disease that you would have a drug class that would be as good and failure patients as it wasn't naive patients. Then we can hop down to the second row clinical remission. And there again, it's about a 20%. This is just a different definition of clinical remission. Again, about a 20% difference between drug and placebo and no dose response and the mixed population and 15-19% difference between drug and placebo with a different definition of clinical remission. And again, not much dose response uh in the failure population. And then um this is the first trial as I recall that had cereal colonoscopy and all the patients as a co primary endpoint increases disease. All the other approved drugs they're either aren't endoscopic data. Think that Eliza mob or the endoscopic data or seven group analyses and small trials think influx a mob. Adeline a mob and used to kenya mob. So all the patients got scoped here and you can see that 12% of patients that we 12 had any evidence of endoscopic improvement as compared to 40% and 32% in the mixed population. And then on the right and the failure population 11% placebo, 29 and 34% in the two years depending have doses. So it looks like um that uh Anti p. 19 therapy with resin kitchen mob is about 30% better than placebo for inducing endoscopic response. So this is this is really kind of game changing I think especially for the failure patients with chronic disease. Then. What about maintenance? So the one thing I would say in psoriasis that this drug has a long half life. It's 20 some days as I recall. But in psoriasis there is a carryover effect that extends beyond the pharmacogenetics. So it does something to the in a disease modification way in in psoriasis that there's a durable effect after the drug is gone. That's different from used to kenya mob, especially different from TNF blockers. So in uh Crohn's disease, then the maintenance trial, they took the patients who had responded to intravenous induction therapy with Ryzen kids to mob and re randomized them to drug withdrawal or placebo. But remember that these guys all got induced with risen cash mob and you just saw that it was a highly effective induction agent. And then and then they were either got that or they continued either 180 mg or 360 mg of reciprocation job. And they were treated out through Year. And here here you can see the endoscopic response uh much better with Ryzen Kiss, you have been placebos with 22% carry over effect on placebo and almost 50% of patients having endoscopic response at the end of the year. Uh clinical remission here. You can see that there was a pretty substantial carry over effect from the ivy induction. So 41% versus 52 55%. So this is uh statistically significant, but it's a smaller delta because of the carry over benefit than in Skopje permission, only 13% on placebo at the end of the year versus 30 30% and 39%. So you can see this nice uh and then deep permission means in the same patient that you're having both clinical remission as well as uh endoscopic improvement. And here you can see that's just 10% of the placebo and 25 to 29% on the two doses of resin kitchen. And so I think overall a very robust maintenance effect as measured by endoscopic response, endoscopic improvement and deeper mission. But some placebo effect from the carry over for just a pure clinical endpoint. So very interesting. And I anticipate that this will be filed for approval in the near term and you would see this coming into your practice next year. Um Next drug in this class is the second mob. So again this has already approved for psoriasis. This is a Phase two study that we reported that U E G W last fall. And it's interesting because it has a used to kenya mob active comparator arm in purple. So this is a mixed population. It's about 55% or so. As I recall anti TNF failure patients and then biologic naive patients for the balance. So almost 50 50 here you can see the placebo rate is 15%. There were three different doses of the second mob and they all did similarly well for the endpoint of clinical remission. The used to kinsey mob was about 10% less effective although still much better than placebo. And then if you split it out into the bio failure population 12% on placebo, 50 some percent on drugs. So just exactly what we saw with Ryzen Kiss, you mob huge effect in bio failure patients. Much more than we've seen with other classes of drugs. And then it looks like it's again about 10% better than used to Kenya mob. And then in the conventional therapy failure now you're getting into clinical remission rates, pushing up towards 60% versus 18% of the placebo. And again, somewhere in the range of 10% better than uh used to kenya map. Now, the study wasn't really powered to compare God's sake mob versus used to kenya mob in phase two. But in phase three, they're actually doing two big trials where they have a smaller group of placebo because you can see it's very easy to beat placebo here and then it's actually powered for a head on head comparison Of the 2nd Mab vs Used to Kenyan Lab. And so you know, we'll see as we power up, will this 10% difference be statistically significant. I think it would be clinically significant. Uh thank you ma'am versus um used to a good standard of care currently used to kenya. So let's go to the third drug in this class miracles. You mob. So one of the speakers to follow lead this study, Bruce stands uh, in Crohn's disease looked at um, placebo, 206 101,000 mg of miracles, You mob again a mixed population of anti TNF naive and biologic Failure patients. And here you can see that the higher two doses 600 and 1000 mg Are significantly better than placebo and trending better than the 200 mg dose. So this ends up looking very much like what we just saw with presentation Bob that it seems like the dozing starts to plateau at about 600 mg or so. And you can see nice efficacy and a failure population. So it's very similar to the other two drugs. 40% commission rate versus 9.4% on placebo vs The 600 mg dose. And then um here's endoscopic endpoints. Uh So it's simple endoscopic score for Crohn's disease sc sc d here you can see endoscopic response or improvement on the left, just 10% on placebo dose response up to 600 mg. And then kind of a flattening of this response at about 600 mg. And then full on in discussed topic. Remission. So normalization of the endoscopy 1.6% of the placebo as you might guess Dose response up to about 600 mg and 600,000 or pretty similar. So this is now moved on into face three. And we're looking forward to seeing the data. Um The other. So you can see so far, I haven't talked about all sorts of colitis for anti p. 19. You know much less. Uh there's been one Phase two study published last year from Erica's Ahmad and all sort of colitis. We don't yet have anti P. 19 data for reason, Kesha Maverick a second here. We can look in the upper left at clinical remission. Uh 4.8% on placebo. Uh 200 mg dose uh which actually allowed for some therapeutic drug monitoring adjustment 22%. And then uh for clinical remission, that number was a little bit lower at the 600 mg dose. But higher than placebo. Then if you go to to the top of the middle column, we can look in naive patients and here you can see even a better separation and then numeric separation for clinical remission at the 200 mg dose and the failure patients. Again, this is phase two, it's fairly small numbers as you can see in the sample size there. So this is a little hard to read the tea leaves, it looks like it works. Um but you know, if you, when you have a trial, this had 60 patients in arms, think about what I just said you with Cosecha mob in uh Crohn's disease was easy to see a difference with 50 patients an arm here, you can see a difference, but it's not as dramatic with 60 patients an arm. So I think we're kind of waiting to see face three data to get a feel for whether on a relative basis. Anti P 19 is as potent and all sort of colitis as it is in Crohn's disease. I think it's definitely going to work. But whether it will be a breakthrough therapy will see lily recently announced that they have completed phase three and ulcerative colitis with Russian mob and they hit all the primary and secondary in points. The data have not yet been released to get a feel for how big the the factors. But I guess we should know soon. So now moving on to this just makes that point. So let's move on to the next class of drugs Janis kindness or jak inhibitors recall that there are four different Janice Kinney says Jack 12 and three and two. Um and you can basically, through MS medicinal chemistry you can make a small molecule Jak inhibitor relatively more potent for binding uh individual Jack subtypes. So you can either have a pan jak inhibitor that sort of blocks everything like Tokyo City neB, which in principle could have good efficacy but might be limited inducing by side effects from blocking everything. Or you could have more selective inhibitors for instance, blocking Jack one, which is going to give you blockade of and are looking to interfere on gamma interfere on alpha and Interleukin six for instance, but it will stay away from Jack to signaling with erythropoietin which can lead to anemia some humans logic side effects. So you're used to Tofu City neb but I want to review Jack one in addition with with you parasitic. So here's some of the things in the pipeline talked about 2% in the forgotten at a repre tox issue. So we won't talk more about that. You've got a citizen of review in detail, Eisen said in a got restricted jak inhibitor which is quite hydrophobic and maybe ended up being under dose missed its 10 point. And then I'll talk a little bit about a Jack three blocker, replace it in a And a tick to Jack one representative at the end there's some Phase two data. So let's focus on on UK to Sedona. These were um phase one sorry phase two data and all sort of flight us this is an extended release once a day oral formulation and we looked at placebo 75 mg 15 mg 30 mg and 45 mg. And you can see A linear dose response. Um remission is panel C and the left lower. And for that endpoint which is the primary endpoint for induction and also flight 0% of placebo. And this linear dose response up to about 20% on the drug. This is a mixed population about 5050 of Failure and naive patients. So this then said that 45 mg once a day would be the best dose for induction and then you would want to test different doses the withdrawal design for maintenance in Phase three. So here are Data for one of the two pivotal studies um in all sort of colitis. This was the mixed population as I recall. And here you can see that the face to data were absolutely replicated. So five Remission rate on placebo, 26% on drugs. So about 21 difference between drug drug and placebo. And given that this has lots of failure patients and that this is really Strong data. And then look at the next level clinical response, 73% of patients had a political response over eight weeks. So that's pretty remarkable as well. And then you can see robust differences for endoscopy and the combination outcome of histology and endoscopy. And here's the second trial which is I recall what's a failure population. And here it's 4% versus 33% for remission. So again, really big delta for a mission and a failure. But this is as good as we've seen with anything given that there's lots of failure patients in here. Again, 75% of 3/4 of patients having a clinical response and robust endoscopy and combined endoscopy and histology outcome measures. So that's induction replicated phase two and it's clear that 45 mg once a day for Eight weeks is a highly effective induction agent in both naive and failure patients. What about maintenance? Well with Jak inhibitors, we know there can be toxicity issues. You want to test lower doses and I'll remind you that the FADA approved dose for rheumatoid arthritis is 15 mg once a day. So for maintenance patients stepped down after induction therapy with 45 mg to either 15 or 30 We're withdrew to placebo. And here you can see for clinical remission. At the end of the year, only 12% of patients who had initially responded to you had a citizen of induction therapy were in remission compared to 42% on 15 mg, the rheumatoid Arthritis does and 52% on 30 mg There's a little bit of dose response. It looks like the higher maintenance dose, 30 mg is about 10% better. 10 to 15% better across the various outcome measures compared to the lower dose. But the lower dose still beats the pants off placebo 12% versus 42% for the point of clinical emissions. So again, this is substantially biologic failure population. So this is efficacy. You just don't see very often interestingly, the FDA came out just in the last week with sort of a class warning for Tofas sedative but also you had a citizen of Jack One inhibitor and another rheumatoid arthritis drug barris It in a which is a Jack one Jack to blocker and has highlighted some risk around dipping industry emphasis, pulmonary embolus, um and potentially a higher risk of infection and malignancy. And so they, as I understand the recent FDA communication and it restricts those three drugs including this drug to patients that have failed TNF blockers, trying to get the relative balance of safety and efficacy. So this drug I anticipate will be submitted for reviewed FDA sometime soon and would come to you and practice next year as I understand it today and we can talk more about this in a panel discussion. It will likely be restricted to patients that have failed the TNF blocker. But then you can see once you're into that setting you can tolerate some side effects and the benefit is really robust. Um what about Crohn's disease? This was a Phase two study in modern sphere. Crohn's disease with an earlier version of the drug that was not extended release. So we were giving twice daily dose ng 24 mg twice a day, remember. And also sort of colitis, we tested 45 mg once a day, so that 24 mg twice a day, which is a total that daily dose of 48 mg would be very similar to the, To the once daily dosing with 45 programs. And what you can see here is sort of the linear dose response um with Crohn's Disease up to that 48 mg total daily dose relative to placebo. So this drug has been taken forward in uh Crohn's disease face three. The trials are still running, it's 45 mg once a day induction and again, 15 and 30 mg, maintenance versus placebo. And we're looking forward to seeing the results in Crohn's disease. This was a pure failure population as well. So I think this drug could end up playing a nice role in refractory Crohn's disease as well. We'll see. Um and lastly, in the jak inhibitor class, replace that uneP which is a Jack three tech, which is a form of tyrosine kinase and breakfast at an event, which is take to Jack one selective. I'll take your eye to the Lower left. Um so reclusive deneb, the Jack three drug, placebo remission is zero. And with the conventional mail remission in .34% at the highest dose. And then if you look in the upper, sorry, in the lower right, using the definition that we would use today and in clinical trials, the definition that was used in the in the capital city in trials that we just looked at For remission 0% vs 38%. So this is a huge delta. We've never really seen anything quite like this. And it's uh this is about a half failure population. So it's a robust patient population. And then you get a feel to compare Jack one versus Jack three. So representative is a Jack one inhibitor which should be pretty similar to you participated, you've got to sit in. Um And if you remember you better sit in it, it was sort of 0% versus 21%. So it was a 20 21%. So it was about a 21% delta. That looks very similar to the higher to higher doses that represented. And and then it looks like with Jack three In addition you're getting another 10% of remission induction on top of that on a relative basis. So we don't have these trials are too small to have a good feel for the relative side effects. Um And so you know how safe Jack three in addition with representative is and whether it's going to have the same sort of class warnings that Jacqueline inhibitors have going forward, I think it's too soon to tell. But this is really remarkable induction efficacy. Last class of drugs will talk about is focusing one phosphate or S one p modulators. Um So this is sort of the hotel California drug. Um In ordinary circumstances there's a subset of lymphocytes that circulate through the lymphatic system through lymph nodes. They express the S one P. One receptor on their surface. And there is a gradient of S one P. And the circulation in the e fairer interest for the exit lymphatic system that through a concentration gradient draws the activated t cells out of the lymph node. So what s won t modulators do is cause an internalization of the receptor that you see on the bottom. And then these activated t cells can't sense this thing. I've seen one phosphate gradient and they just remain trapped in the lymph node and they can't exit the lymph node through the lymphatic and recirculate to and then flying tissue that gut in the case of all sort of colitis. So uh thus the hotel California. You can check any check in anytime you like but you can never leave. So what does this look like in practice? I told you there's four or five drugs actually in clinical trials but we have one that's finished. Phase three will look at those data just got approved and um attract someone. So here's uh face to induction with the san ahmad. You can see that one mg was more effective than placebo for all the conventional outcome measures. And when we traded straight through um that uh you could see those benefits extending out to 32 months. So this led to a phase three clinical trial program where patients got one mg for 10 weeks. And here you can see that this world drug had all the outcome measures. Clinical remission, clinical response, endoscopic improvement and I'm your postal healing. And then patients who responded to induction therapy were re randomized to continuous and Ahmad one mg or drop down to placebo and followed out through a year. Primary endpoint is remission. And again you can see that all the endpoints are hit for clinical remission and dystopic improvement etcetera. So this led to the recent approval of those and ahmad for moderate sphere all sort of colitis. There's a second drug that's just completing clinical development of trash. damaud. I will uh take your eye to the upper left corner. 12 weeks of their classified into two mg dose. It's 8% versus 33%. So that's a pretty big delta about what was seen with. You had a synonym, maybe even just a little bit more. And so if this gets replicated in Face three, this is another oral class of drugs that could look like JAK inhibitors in terms of efficacy but without the safety warnings of the jak inhibitors. So stay tuned for this class of drugs because I think because the rural this has a real chance to make a difference in your practice. And with that we will stop. You can see there's lots of things coming in the clinic, Those animals just arrived and many more over the next year or two. So pay attention. You're going to have a lot of new therapies. Thank you.
