Okay, good afternoon, and welcome to Insight's 2018 investor and analyst event. Thank you all for joining us today. My name is Mike Booth, and I'm Head of Investor Relations for Insight. We have a full schedule over the next 3 hours, but a few housekeeping items before we begin. Firstly, please note that Safe Harbor rules govern our remarks today and any forward looking statements that we may make.
I therefore encourage you to review the risk factors detailed in Insights' SEC filings, including in our Form 10 Q for the quarter ended March 31, 2018. Today's presentation will feature 4 main speakers from the panel table, Herve Oppenou, our CEO, Stephen Stein, our Chief Medical Officer and Reed Huber, our Chief Scientific Officer, are familiar to many, if not all of you. And they are joined today by Peter Langmuir from our Clinical Group. There are also several other members of the Insight leadership, clinical and discovery teams in the room with us today, and they'll be available to answer questions if needed during the Q And A sessions. There are 2 Q and A sessions in the schedule, one after around 90 minutes and the other at the end.
During the Q and A, which I will moderate, I ask that you limit yourself to a single question and state your name and organization before asking your question. Please wait for the microphone before asking your question because today's event is being webcast, and that will allow all participants to hear the questions. For those of you on the webcast, thank you for joining us. And please note that the slide deck being used today at today's event is available for download on the Insight website. If you are unable to download or find the file for any reason, please email irinsight.com and we'll send it to you.
With that, I'll start the formal program and we'll begin with Herve.
Yes, thank you, Mike. Thank you, everybody, for being here today. So we will spend the next 3 hours to discussing a number of subjects. So I want to first introduced to use the agenda of the day. So it is speaking about the number of, parts of our pipeline, and the project that we have ongoing that are have not been described in a lot of details over the past few years.
So first, we'll speak about our MPN franchise. So it's about Jakafi, obviously, in the U. S, but it's also about a number of projects that we have ongoing. With the goal of extending our leadership in the treatment of MTNs. You will see there for the first time some data of the PI3 kinase delta plus Roxolitinib combination.
So that's certainly something interesting. It's one of the pieces of that portfolio. Then we'll speak about GghD And there we'll show for the first time the data from our Reach 1 pivotal study in acute steroid refractory GVHD with oxolitinib, then we'll speak about FGFR. So that's a program that we have ongoing in the two indications and where, for the first time, we'll be showing the data from our study in cholangiocarcinoma and the ongoing study we have polymerized data on the ongoing study we have in bladder cancer. And then we'll be speaking about PI3 Kinase Delta in B cell malignancies where We have a number of studies ongoing, and we will be also speaking about some of the data we have done with the paired biopsy studies that is ongoing with PI3 NS Delta and PD-one, then we'll have a break, and then we'll go in to the PD-one program that is ongoing and the non oncology franchise, which is something that we have not spoken about very much in the past, and we are today, we'll be also showing for the first time data with topical roxolitinib in atopic gamma it should be a sort of a fairly dense program over the next 3 hour with a number of interesting data points that we can look at together.
Now before we do that, I wanted to go back a little bit to insight over the past 5 years because I think it's a fairly important picture to have in mind when we think about what has happened. The first most important thing is obviously growth high growth of the revenue line. As you can see, we went from 500 to what this year in total revenue will be based on the guidance close to 1,000,000,000. So we multiply the top line by 4 4 years. And at the same time, we have started diversification of the top line with multiple lines of revenue coming from Jakafi U.
S, which is obviously the main part, but also meaningful contribution from the Jakavi royalties we are receiving from Novartis, highclosing, also in Europe and now we are starting to see Ollumiant. So that's important to realize that the sort of this picture of the top line growth is really something we are very proud of and something that has been very successful over the past few years. The second thing is obviously the diversification of our portfolio during that time, not only on the revenue side, but also on the clinical portfolio where we have now 19 compounds. We also, at the same time, have diversified our discovery programs from just small molecule to include now antibodies, large molecule and bispecifics. And at the same time, we have organized our company across three continents with not only the U.
S, but also Europe and Japan. So I think it's a picture that gives you sort of a good idea of the strategy we have been following over the past 4 years and the success we have had on many of these dimensions. Now obviously, the subject of the day is our portfolio. So that's the picture of the portfolio today of the pipeline, if you want. So if you take it from left to right, you will see the 3 technologies we are using at the level of covery.
So small molecule, which is where, obviously, Insight has a lot of own capabilities, monoclonal antibodies, where now we have also our own capabilities and where we have had partnership to get where we are today and the bispecific program we are doing with mirrors where we have up to 11 products that will be coming from that research program. In clinical development, which is the center of the slide, we are organized in 3 divisions, in fact. So since time has 3 groups working for him. One of them is immuno oncology, and we have spoken about that a lot in the past few years, months years. The second one is pit led by Peter He is on targeted therapies.
So that's all the programs that we have in the field of cancer that are, most of them are targeted, we speak about FGF, FGF, and there are a number of other program we have there. And then we have a 3rd division in clinical development for what we call now, inflammation autoimmunity, which is what we call the non oncology programs in the past, which is obviously about topical ruxolitinib. We'll speak about that today, but you will see also today that we have a number of other programs that are now starting taking programs from research that have an immuno application outside of cancer and looking for this application. So that's really what you can see here. We have 11 projects at the prepock level.
And obviously, you can see the 7 projects that are at later stage of development post, proof of concept. And that will be the most of what we will be discussing about today, I must say, but also a word about Resource the way we are, we are applying resources to each of the policies, development program from research to to late development. And it must be clear to everybody that most of the investment is going to this right part of the slide here where in fact, when you look at the resource allocation for project at the early stage, it's in fact relatively very much smaller than what we have on the right side of that graph here. Is the other interesting thing, and we just it's just the same graph with a coloring of the products that came from our internal discovery. And as you can see, From the late stage portfolio, 6 of the products we have discovered at Insight by Insight researchers, 3 of, I think, 2 of the products on the market today are already two products discovered by inside are already on the market today with roxeltinib and baricitinib.
And most of the pipeline coming through our products that are coming from our own internal research. I think it's important for two reasons. One of them is speed because in fact, you can move projects through the different phase faster if you control the entire process, from the beginning to the end, but it's also very important in terms of economics because, obviously, none of this product has, have royalties and milestones attached to them, which makes them as they become commercial of the see very much more profitable. So just speaking of the revenue, so the right side of the previous slide looking at the products we have, already on the market. I think it's important.
I was saying we just multiply the sales by 4 over the past 4 years. This growth rate you are seeing here of 25 percent for Jakafi, 51 for Iclusig, 41 for Jakavi royalties, our growth rate from Q1 of this year compared to Q1 of last year, so that the yearly growth rate in the last quarter And what it is showing in fact is that the entire portfolio is moving with a fairly dynamic growth rate even after a number of years on the market in the case of Jakafi, it's also interesting to see from the numbers that 30% of the revenue today is not Jakafi U. S. So Jakafi U. S.
Is 70%. So it's a large majority of our revenue. But in fact, the diversification is starting to be visible at the top line level. Obviously, Jakavi, royalties are also a big part of the remaining study. But now Iclusig and Olumiant are starting to contribute to the growth and to the diversification of our of our top line.
So one of the things we'll be speaking about today is, is the performance of Jakafi and the next few years coming ahead of us. So you know the long term guidance we have on Jakafi is 1,000,000,000 to 1,000,000,000 We represented it graphically here. What we could also say about that is that there is certainly upside opportunities versus that guidance. It is a guidance that is mostly based on patient growth in MF and PV. So obviously, the numbers are highly dependent on that and they will be impacted by improved duration of the therapy general and the rate of penetration in polycytecniavera, where we know there is a fairly large potential.
Concerning GVHD and we'll be spending a lot of some time today speaking about it. There is always a question of duration of treatment in GVHD, which frankly is an evolving has been evolving knowledge about it as the clinical program are moving forward. And there is obviously a potential for longer duration of treatment there than maybe have been expected from the beginning. What we also want to speak about is how we are going to expand this leadership we have in MPM. And part of the presentation we will be, listening to today are related to that subject saying before 2027 and beyond 2027, how do we extend our leadership in the field with novel targets beyond JAK inhibition.
And I think it's very important to realize the benefit of a JAK inhibitor in MPN. It has transformative for this patient, but there is still a medical need that is very present there. And that's something where we believe new targets will be new mechanism will be required Roxelitinib based combination, obviously, as Rox is established today as a standard of care in the field and potentially any kind of novel formulation that could improve the benefit ratio of roxolitinib. So that's a subject that we will be addressing first in this presentation. Before we do that, I wanted to just put in perspective the overall presentation of today.
So you can see at the bottom what we just discussed, which is the leadership in MPN, we will be speaking about 5 new product candidates. That could be potentially contributing to our top line over the next few years. So we did a graphic representation here and don't try to measure every, the size of each of this field on the graph. In fact, what we did is look at the the programs we are speaking about, we believe most of them are somewhere between 500,000,002,001,000,000,000 in potential in commercial potential over time. And we will know more and we'll be giving precise guidance as we are running the phase threes and being able to calibrate the different elements of the product.
So what we did here is take a 1,000,000,000 number for each of them. So that's the way the graph was built to illustrate the fact that if as we will be launching each of these products over the future, it's going to have a very massive contribution to the growth rate of the corporation, even without counting any of the early stage portfolio, which as we know is very promising and could be also moving to late stage in the same time period. So that's a sort of a picture of what we wanted to communicate today. There is an MTN base that we have that we intend to extend over the next few years. There is a number of candidates, 5 of them are coming also in the short term.
And obviously, we have the optionality from our early stage portfolio, in addition to that. So that's the timeline basically for what I'm speaking about so that the 6 opportunities are described here. You can see the studies, in gray on this graph. It's basically 6 products, 6 different products, 15 potential indication. I'm not going to describe it in details because that's what we will do over the next two and a half hours left now.
So let's move to that first with the question about leadership in NPN and how we are going to extend it over the next few years.
Great. Thanks, Herve. So as Herve just outlined, an insight in research and development, we have a very keen focus on maintaining our leadership position in MPMs. And that reflects not only the importance of Jakafi as a franchise to us, of course, but it also reflects our continued commitment to patients and trying to drive benefit in a new and important areas in that patient population. I'll describe to you the next few slides into the work that we're doing there.
The goals for these therapies are outlined on the top, and I think it's safe to say that there's room to improve benefit. And if you just think about things like, reducing the disease burden, whether it's related to molecular remission, improvements in fibrosis or actually improvement in hematologic parameters, these in many respects are the North Star that we have in research as we set out to continue to innovate in this space that really we started an insight back in 2005. That includes initiatives both in discovery and in development. Some of these things are in research and so we won't be talking about them specifically. But I will talk about a recent relationship that we signed with Syros, just to give you an orientation as to some of the things we're doing.
I think they'll be illustrative of the thinking there. We'll also spend some time talking about the ruxolitinib combinations in patients who have an inadequate response to ruxolitinib at present I already mentioned those, those are much nearer term opportunities. And I'll describe to you some of the science behind those programs and Stephen will describe to you some of the emerging data. In one of them. So just beginning at the earliest stage in research, this is, the basic premise behind the Syros collaboration The JAK2 mutation is often synonymous with MPNs, right, Felisso.
It's mutated in the majority of those patients. What we don't often talk about and it's illustrated on the left hand of this slide is that these patients actually harbor a number of other mutations. And very, very frequently. In fact, the majority of patients have mutations, in epigenetic proteins are those that alter the packaging of DNA. And these are not just bystander mutations.
In fact, they're seen in acute myeloid leukemia as an example, And those are very important to the initiation and the progression of myeloid malignancies. And we have every reason to believe that they're very important in MPNs. On the right side of the slide, highlights the basic thinking with the silos collaboration by studying those mutations either individually or collectively with activated JAK2 signaling, we can understand better how this Chromatin is rearranged and repackaged platform for the identification, the characterization, and even the validation of these types of programs. So while this is a very long term program, I think it illustrates some of the innovative thinking that the field requires for us to make a meaningful leap forward in patient benefit in the MPN space. Turning now to some of the science behind the slitinib combinations that are a little bit near term, I'll remind you of the very simplified view that we had of this pathway circa 2005 2007 that led us to ruxolitinib.
Mutations in JAK2 in the receptor, thrombopoietin receptor or in calreticulin, drive JAK2 activation, which constituency leads to stat activation and the NPN phenotype. And there's a lot of truth to this that led us to a very important therapeutic in ruxolitinib, obviously making an important difference for patients today. But in fact, this dysregulated signaling pathway is far more complex than JAK STAT, and we now appreciate this with the research over the last decade activation of the PI3K AKT pathway down the center of this, graphic is very important for the growth and survival of the malignancy itself. And we are interested in targeting either the upstream delta kinase or the downstream PIM kinase in concert with ruxolitinib to more effectively block this dysregulated signaling network. Also, JAK1 is an important mediator of inflammatory cytokines which we know are highly dysregulated in patients.
In fact, this probably is the number one driver of the constitutional symptoms that patients have. It may also be an important driver of their, their hematologic components of disease could we, with a JAK1 selective inhibitor, drive much more complete inhibition of those cytokines in the face a tolerated level of JAK2 inhibition provided through ruxolitinib. So I'll walk you through some of the data to underpin these 3 combination trials. First with the PIM kinase inhibitor, this is work that's been conducted with Moffic cancer center, and I'll focus your eyes on the light blue bar where the arrow is pointing, these are the effects of combined inhibition of the Tim Kinase pathway and ruxolitinib in patient CD34 progenitor These are the actual malignant cells. The cells in this case came from a post ET myelofibrosis patient who is V617F positive And you can see compared to the dark blue bar next to it, a dramatic decrease in the ability of these cells to grow.
On the right, that translates into in vivo efficacy And we've now seen this with numerous patient samples, collected through this collaboration. And it really underpins the notion that combined blockade of this pathway could have a differential effect than monotherapy, JAK inhibition. On this slide, recently published by John masquerinas in 2017, it comes from a trial that we did of itacitinib in myelofibrosis patients. So this is a JAK1 selective inhibitor in MF. And what you can see on the left is a substantial improvement in the total symptom score, the symptomatic burden in patients.
The bar is going down below the X axis reflect improvement. And that is what we anticipated going into the trial and in on the far right. In that heat map, you can see that all those cytokines in the placebo arm that are bright red are decreased with the itacitinib arm. In fact, they're decreased in a level that's comparable to what you see with ruxolitinib underscoring the importance of the JAK1 inhibition, component in driving symptomatic benefit. Maybe what's most interesting about this study, and it's shown in the middle of the figure, is the lack of a deleterious effect on hemoglobin, and that's shown in the top middle panel over time.
And you can also see a similar effect, especially at the 102 100 milligram doses at preserving patients platelet levels. I'll draw your eye to the hemoglobin levels, which were actually trending to an increase over time, which may suggest the deleterious effect of this heightened cytokine activity in driving anemia in patients. So this underpins the notion that JAK1 selective inhibition on top of ruxolitinib may be able to have symptomatic and hematologic benefits in patients, and that's an important part of the clinical trial that we're doing now. Finally, for PI Kines Delta, this was a little bit of a detective exercise over the last 5 years or so. It's been known in the upper left that Stromel sells These are the bone marrow cells that support the malignancy actually attenuate the effects of ruxolitinib and The question was why is that?
And in this study, using a pan inhibitor of that PI3K AKT pathway, I mentioned that the outset prevents that. So that tells us that that signaling cascade may be particularly important in the malignant cells as they grow in the marrow niche. And that translated in vivo. These are preclinical studies using blockade of the PI3K AKT pathway with 2 Novartis compounds showing benefit that well exceeds what you would see with ruxolitinib alone. The question was, what is the operative PI3K isoform in MF we have to inhibit all of them?
Or is there one that's operative? And these results are in the bottom and the middle figure really drive home the fact that the delta isoform is the most important isoform. On the y axis, you have the activation of the signaling cascade in response to thrombopoietin where activates the JAK STAT and PI3K pathway. And as you titrate in increasing concentrations of a delta selective inhibitor, you can completely aggregate the signaling in that, in that cascade in primary patient CD34 progenitor cells. We think that the delta isoform is the key isoform that's governing this biology and the question is whether combined blockade with ruxolitinib can lead to differential benefits for patients.
So, Reed just outlined for you the preclinical work that then enables us undergo the clinical study. So this is our PR3 kinase delta inhibitor 50465 plus ruxolitinib in a myelofibrosis setting These are patients with a suboptimal response to monotherapy ruxat study entry. I just want to spend an extra second on the definition we used here one of the dangers in this particular field is there'll be cross study comparisons where people define their RUX failure patients slightly differently. For this particular study, patients needed to be treated with RUX for at least 6 months or greater and on a stable dose for at least 8 weeks or greater. The RUX doses before coming on study range from 5 milligrams BID up to 25 milligrams BID and the induction dose for the PI3 kinase delta inhibitor was 20 milligrams daily.
This is an early data set and a cut this year, the more complete data set will follow later this year, There were 28 patients in the safety population and there was nothing unexpected in terms of the safety signal seen and in keeping with the read pointed out pre clinically. What's enticing in the early data set, although it's 10 patients at the moment, in terms of the 2 efficacy endpoints that we know to be relevant in this field, spine reduction and then symptom improvement, you can see for those 10 patients, almost across the board a degree of of spleen reduction when you've added the PR3 kinase delta inhibitor to RUX in patients who've already had an inadequate or suboptimal response to RUX and there's clean length reduction upward of 60 plus percent in some of these patients. In terms of symptom improvement using the standard, validated scale, the NPM symptom assessment form, again, there's patients who have upwards of 50%, 60% improvements in their symptom burden. With the addition of Delta to RUX in this population. Over towards the end of this year, we hope to update this data set for you with a much greater number of patients.
So the entirety of the clinical program feeds off Reed's preclinical work that he outlined for you, the study at the top I just spoke about should have data in second half of this year. And then the ongoing work below with rux plus our perm inhibitor in an open label phase 1two, the number is 53914 in patients with advanced myelofibrosis. And then the addition of the JAK inhibitor, itacitinib, 39110, needing patients who have an inadequate response to RUX or cannot tolerate it and are then switched to atacitinib and this data will deliver in 2019.
Okay. So that was the first chapter about MPN, so expanding our franchise in MPN. So as you can see, I mean, we have a number of preclinical programs with Cyros, but vendor built and Moffit and internally in research, we didn't speak very much about that today, but this is something that overall longer period of time can give us opportunities to bring completely new mechanisms, not only different from JAK, but also different from Delta PIM and there's a Jack one here that we are discussing. And then in the short term, so so long half of this year and beginning of next year, we'll start seeing the clinical data with Roche plus PRIMROG plus JAK1, ICacitinib, and the second half of this year, the PI3K and Delta, you saw some of the preliminary first ten patients. And I think all of that is giving us a number of opportunities to spend in the short term and improve outcome for patients with MTNs because at the end of the day, the medical need in that disease is about identifying new combinations and new mechanism that will help, complement the JAK2, JAK1, JAK2 inhibition that you can mind with Roxolitinib.
So the next chapter will be Peter will take the lead to speak about GVHD, the program we have, the comprehensive program, we're having that field with ruxolitinib and Intensity.
Great. Thank you. So, what I'd like to do over the next couple of minutes is provide an introduction to graft versus host disease and an overview to the programs that we have both with ruxolitinib and with itacitinib. So we know that stem cell transplants can be a potentially curative therapy for leukemia and other hematologic malignancy And essentially, it's a 2 pronged approach. The first prong is very high doses of chemotherapy, with or without radiation to eradicate the disease, reduce the patient's immunity and essentially wipe out their bone marrow.
Following that, allogeneic stem cell infusion, so stem from another person with a similar genetic profiler infused. And those donor stem cells then reconstitute the bone marrow and the host immune them. So the second prong of the treatment of leukemia is that those donor T cells target the recipient tumor cells and prevent relapse. But the downside of this is that those same donor T cells or different donor T cells attack recipient tissues, and that causes graft versus host disease, and this is one of the leading causes of morbidity and mortality for patients after allogeneic stem cell transplant. So this slide summarizes the incidence of graft versus host disease.
So across U. S, Europe and Japan, There are about 23,000 patients who undergo allogeneic stem cell transplant, and about half of those develop acute GvHD. So, the incidence of acute GvHD is about 11,500. You see the incidence here of chronic GvHD in the steroid naive setting is about 9200, about 1 third of those patients are developed chronic GvHD with no prior GvHD, but about twothree of them will have previously had acute GvHD. Now steroids are the mainstay of therapy for GvHD.
The downside of steroids. So first of all, is they only work at about half a patients. And secondly, even when they work, in many patients, it's very difficult to reduce the dose of steroids and they need to be on steroids for months or years. And this can lead to a significant long term locations, from chronic steroid use. So you see here a substantial proportion of patients develop steroid refractory disease, and there's a huge unmet need in this place population, where there are very few effective therapies.
GVHD used to be divided into acute and chronic just simply based on the time of when it occurred, whether it occurred before day 100 or after day 100. But today, it's actually classified more on the basis of clinical and histologic features. So acute GvHD involves really 3 organ systems, the skin, the gastrointestinal tract and the liver. And the disease is primarily mediated by mature donor T cells. Product GVHD is far more complicated involving T cells, B cells, macrophages and can pretty much involve any organ system in the body.
Skin is most common. Patients can develop a sclerodermatous like finding on the skin. Their oral mucosa become very dry. They can get sclerosis in their GI tract. They can have liver disease, can have lung disease, they can have contractors of their muscles and ligaments, and it can be a very debilitating, disease over many months to years.
The prognosis of GVHD can be very poor, particularly in patients with severe GVHD. If we look at acute GVHD on the left, you see the survival, the 1 year survival, depending on the grade of GVHD. So about 2 about 1 third of the patients will have a grade 2 GVHD and that has a 75% 1 year survival. But if you move to grade 3 or grade 4 GVHD, the survival becomes much less. One thing I will point out here, and we'll come to this in a minute when we talk about the results of our Reach 1 study in GvHD, is that while we expect about 2 thirds of the patients to have grade 2 GvHD, in fact, in our study, it was a much higher risk patient population about twothree of the patients having Grade 3 or 4 GVHD.
It's very similar in the chronic GVHD setting, those patients who have severe chronic GVHD have a much higher risk of death compared to those who have mild or moderate GvHD. So clearly a high unmet need and a need for treatments that can be given over the long term.
So if we think about the molecular pathophysiology of GvHD, that's sort of outlined on slide. And again, we'll break it down by acute in chronic GvHD. And Peter nicely walked through the conditioning phase and the transplant phase and then the actual phase of disease. The important take home message as illustrated on the left of the slide is that the Janus kinases play very important roles in mediating this T cell driven acute GvHD and actually providing the signaling pathways, the key signaling nodes to lead to the inflammation that ultimately causes tissue damage in the acute GvHD setting. On the chronic GvHD side, you can think of it as a much more complex immune disease T cells are still very important and they maintain obviously their JAK dependence, but you also have B cells producing auto antibodies macrophages that are important in facilitating, for example, the fibrotic features of the disease, importantly, Jack signaling is also underpins many of the cytokine driven events that can lead to the T cell, B cell and macrophage activation and chronic GvHD.
So this underpins really the excitement I think we and also the field have in terms of Jack inhibition of the disease. Let me walk you through some of the data that then supports, some of the, the, the cartoon diagrams here. And I'll start with just, activity at the top in, in a contrived system and in vitro system where we take one patient's T cells and we combine them with another patient's antigen presenting cells. And that leads to a significant increase in proliferation, as shown in the gray bars by the height of the y axis, And you can see that the addition of a JAK inhibitor, in this case, ruxolitinib, dose definitely decreases, that proliferation. If we take ruxolitinib and we dose it to an animal that's been given a major mismatch transplant, so taking the marrow of one strain, and introducing it into an animal, a recipient animal from another strain, you get a significant influx in gray of these effector T cells moving into the key target organs that will ultimately produce inflammation and tissue damage, namely the skin the small intestine in the liver.
And you can see that ruxolitinib treatment in every case significantly attenuates the ability of these cells to migrate into those organs. So, so molecularly then we have 2 important aspects of the disease, which appear to be addressed by ruxolitinib. The proliferation and activation of the T cells as well as their ability to migrate into and instead we run a full efficacy study, where here on the Y axis, we can actually score the levels of GVHD and that's done with a composite score that takes into out several aspects of the disease as well as the animal's whole body health, you can see that in red, itacitinib 2 different doses, whether the compound is dosed prophylactically, so that's before the transplant or dose therapeutically starting at day 14 after the transplant after GVHD has set in, you can see a complete resolution of the GVHD score all the way back to the levels of those open black circles. Are control animals that never got GvHD to begin with, just the syngeneic transplant. So this tells us that JAK inhibition can be highly efficacious in a in a very aggressive form of acute GVHD.
Molecularally, the events that are the curves subsequent to JAK inhibition all help to reinforce this efficacy data shown in the upper left is the blockade of the stat, JAK STAT pathway within, one of the secondary tissues that was studied, in this case, colon tissue, you can see a dose dependent decrease in JAK STAT signaling. And that also occurs importantly, in the infiltrating T cells, you can see the decrease in both doses of itacitinib. If we look at the serum inflammatory markers in particular three markers shown here, which have a strong role to play in driving the effects of GVHD you can see a substantial decrease in all cases following Jack inhibition. Now for any GVHD therapy, 2 things are very important to know whether or not there's any effect on donor cell engraftment that's very important to not have And obviously, we don't want to attenuate the ability of these donor cells to eradicate the leukemia. That's the reason we're doing the transplant to begin with.
And as we've studied JAK inhibition carefully, we don't see any deleterious effects on either one of these axes, and it's shown in this graph, you can follow the donor cells, comparing vehicle versus both JAK inhibitors. You can see that those donor cells engraft and maintain their cell count numbers all the way out several weeks after transplant and down below in that blue box, where the colored image from the bioluminescent image is the tumor, the lymphoma tumor that's being eradicated by, the graft itself. You can see the addition of, in this case, ruxolitinib at a high dose to those animals in the final column in no way allows those lymphoma cells to grow back suggesting or reinforcing that the graft versus leukemia activity is completely preserved. So in sum, there's a very strong immunologic and preclinical rationale for JAK inhibition and GVHD. And I think we've taken a lot of steps over the last few years to understand specifically how this mechanism is as effective as it is in the preclinical setting.
So let me go back to some of the incidence figures. Peter was talking about and point out some nuances. So firstly, graft versus host disease as Peter has showed you is a major cause of both morbidity and mortality in transplant patients with upwards of 50 to 70% mortality rates less than a year after high grade graft versus host disease. We estimate, if you look at Continental United states, Western Europe and Japan that approximately 23,000 allogeneic transplants take place on a yearly basis. And then you look at the way the disease is currently divided up, and there will be some double counting because patients can have both acute and chronic.
But in the steroid naive population that's newly diagnosed, there are approximately about 11,500 new cases a year in that bucket and that's looking at grade 2 versus grade 4 there, not grade 1. In the chronic setting, about 9200 cases, and about a third of those are de novo chronic. So they've never had acute or any other disease before that. In the steroid refractory setting, we are going to be presenting some of our results today from REACH 1, 2nd line plus new incidents in acute in those three areas is 5700 cases a year in the chronic setting at steroid refractory, about 4500 cases a year. Our program in its entirety as comprehensive as we could make it, and we're looking at all the settings.
So it's a busy slide, and let me walk you through the program. It's both looking at itacitinib, our relative JAK1 agent as well as ruxolitinib. So on your left in the prophylactic setting, we have a gravity study 119, which is looking at itacitinib in the prophylactic setting to try and prevent graft versus host disease coming primary endpoint. Secondary endpoints would be the incidence of graft versus host disease itself as well as relapse survival time to engraftment and safety and we'll look at biomarkers there as well. There's a large interest in the field in trying to predict at a biomarker level who will one get graft versus host disease and 2 prophylactically, who will get more severe disease versus others.
If you look at the rest of the gravitas program on top in both in acute and chronic setting, the first important one there is the phase 3 gravitas 301 study, which is ongoing and enrolling well as we speak. It's in steroid naive, newly diagnosed patients in the acute setting, the primary endpoint is an overall response rate at day 28. There'll be a chronic study as well with itacitinib and gravitas 309 in 266 patients looking at response rate at month 6 in that population. The REACH program is below in the steroid refractory setting and encompasses 3 separate studies, REACH 1, REACH 2 and REACH 3. Reach 1 is a single arm phase 2 study but a pivotal study with a primary endpoint of overall response rate at day 28 and then secondary endpoints that include duration of response and numerous non relapsed mortality endpoints.
And I'll be showing you that data in a moment. The REACH II study in the same setting is a randomized study against best available therapy in 308 patients Its primary purpose is running conjuncture with Novartis is to be used for approval of RUX ex U. S. In a randomized set in against best available therapy. And REACH3 is in steroid refractory chronic and is enrolling as we speak as well in 324 patients again looking at response rate at month 6.
So let's talk about REACH 1. The 1st prospectively designed pivotal trial JAK inhibitor in steroid refractory acute chronic graft versus host disease, sorry steroid refractory acute graft versus host disease. It's for patients 12 years and above. They've had their first allogeneic transplant. They've grade 2 through 4 steroid refract acute disease.
They've already demonstrated evidence of myeloid engraftment by having an adequate neutrophil count and was in 71 patients, The first seventy two hours of therapy was with rux5 milligrams twice daily. If that was tolerated and there were no side opinions, the dose was increased to 10 milligrams twice daily with steroids and if needed a calcium urine inhibitor as well. The primary endpoint in these studies is at day-twenty 8 response rate because that is felt to be the most predictive of long term outcome in the acute setting, particularly long term survival. But there are important secondary endpoints, duration of response at 6 months, overall response at different time endpoints, the incidence of chronic graft versus host disease and safety. We also captured very importantly the best overall response rate in the study because that'll enable you to compare it to other data sets, particularly the proof of concept data from the ZICE at Allpaper, which is done by investigator when they look at response at any time point.
So onto the actual data, the best overall response rate in this study, so response any time point is 73.2 percent and that gives you the comparative number to look at the proof of concept data elsewhere and in some ways in many ways other settings where the state is reported by others. The primary endpoint was the day 28 overall response rate very strictly defined with a 2 day window. So either that to have a response between day 26 day 30, that was 54.9%. 26.8% of patients had a complete response, nearly 10%, 9.9% had a very good partial response and 18.3% had a partial response. The duration of response for the day 28 responders has not been reached yet.
And you can see on the Kaplan Meyer plot on your right that patients who had a response, you get a plateau at around 70% there. The month 3 event 3 probability estimate was nearly 80% without relapse and at month 6 nearly 70%, 67% to be exact. We haven't reached a median yet for duration of response. This I'll remind you was a study conducted under breakthrough designation and met the primary endpoint, Hensa intend to submit it for supplemental new drug application to the FDA, sometime in the second half of this year. In terms of safety, there is nothing unexpected from this population with the use of ruxolitinib here and the 3 main signals in terms of grade 3, 4 treatment emergent adverse events onemia thrombocytopenia and neutropenia.
Thus the primary endpoint was met, we will submit it to seek approval The data is also being prepared for a major medical meeting in the second half of this year, which will show the other endpoints I mentioned, and it's under a breakthrough designation. The U. S. Only incidence for allergenic transplants are pulling that out from the overall data sets I gave you earlier. There's about 7500 allergenic transplants a year, acute GvHD estimated incidence in the U.
S. About 1700 patients that are steroid refractory and in the chronic setting, another 1500 who are steroid refractory. Reach 2 and Reach 3 are ongoing. Reach 2 is in the acute study and randomized against best available therapy and REACH3 in the chronic setting. Both those studies should deliver their data in 2019 to round out the program.
So turning to itacitinib, our wholly owned JAK1 inhibitor, this is a proof of concept study that was presented at ASH in 2016, looking at 2 doses of itacitinib 200 milligrams and 300 milligrams in conjunction with corticosteroids. Patients that had also a prior allergenic transplant had Grade 2 through Grade 4 graft versus host disease and could either be steroid naive first line or steroid refractory second line. And the data on your right for shows you there that in the first line setting, For itacitinib at both dose levels, the response rate in the steroid naive patients was 83.3% and the steroid refractory was 64.7 and this gave us a very strong proof of concept in steroid naive acute graft versus host disease and enable the gravitas-three zero one study to be designed. Furthermore, because of the relative JAK1 inhibitory nature of this compound where cytopenias are more important in the acute setting, there's a safety advantage for using a JAK1 agent here in terms of spare in patients from increased cytopenias in a setting where they're likely to be sicker. And that, gave us the reason to do the Gravitas 301 study.
There, the study is for you. It's for adults 18 and above and no more than 1 prior allogeneic transplant major criteria for a graft versus host disease from 2, to 4, and then they were stratified for standard versus high risk 4 36 patients, primary endpoint at day-twenty eight response rate. If you look at the 3 settings, again, United States Western Europe and Japan, allogeneic Transponds 23,000 in total, but an acute incidence overall of 11,500 patients who would be eligible for this therapy should this study deliver this primary endpoint. And if successful, this would be a global regulatory submission would follow from this data set.
Okay. So that's the sort of the complex picture of GVHD. So we have Roxolitinib in the U. S. In the steroid refractory population data, you saw the first, look at this data it will be filed at the FDA this year.
It could lead to assuming it's approved, launching the product in the U. S. Next year in this steroid refractory, relatively small population, you saw the number, we estimate. The estimates are very depending on where you look, you get different So we try to give numbers that have been vetted by many people to crossing different sources, but we estimate it could be slightly below 2000 patients with that steroid or refractory, very specific population in the U. S.
With drugs. And then itacitinib, gravitas, Phase III ongoing result in 2019 and where we have the rights worldwide. So that would be a launch that we would be doing in U. S, Europe and Japan. And where I think it is a very different size of the population.
We spoke about 11,500 here. So 50 percent of patients who receive bone marrow transplant will have some form of GVHD. And that number is not very different from what the MF number looked like when we launched Jakafi in the U. S. By the way.
So a lot of the potential will depend on the duration of treatment for itacitinib in the first line setting. And frankly, there we don't have data prospectively in the study yet to be able to tell you how long this duration will be. We have anecdotes from some of the roxolitinib use that we are seeing today. That is in fact making us more and more optimistic about what the duration of treatment in GVHD in general could be, and we can speak about that maybe in the Q And A, but I think it's sort of giving us a perspective. For the timing, from the commercial standpoint, now launching Itacitinib into VHG around the world is in fact something that we feel very prepared for based on the teams that we have today.
The U. S, the team are already very much directed to hematology center, including bone marrow transplant center, just happens that in Europe, the product Iclusig we have on the market is for a certain form of a CML. And again, the sort of the deployment we have of our account Salesforce is very much in the same DMT centers that will be a target for Hitacitinib And obviously for Japan, it will be the 1st commercial launch for us. And it is a very good thing to have a very narrow group of prescribers like transplanters because it will help very much size the team in a way that will be a reasonable based on the on the size of the opportunity. So I see itacitinib when you think of it 'nineteen and 'twenty, it could be the 1st global product that be launched by Insight, maybe with the FGFR, we'll look at the data next.
So that's probably the 2 of them could come somewhere in the same timeline. And the beauty of this GVHD indication is that it is allowing us with the size of our organization to be very successful launching it based on obviously the clinical profiles that needs to be confirmed is a Phase III, but also an understanding of what this market looks like that makes it very, very feasible for us. So we will stop on GFG. Now if you have questions, we'll have a break for question after the next two presentation and the next one is about GFR.
So we'll turn now to our FGFR 123 selective inhibitor called incb54828. And I'll walk you through, it's it's preclinical profile and why we're excited about the emerging profile of this drug and Stephen and Peter will share some of the, emerging data in the targeted histologies that we're focused on those patients with FGFR mutations. So the FGFR or fibroblast growth factor receptor is a family actually of 4 receptors. They're called 1, 2, 3, and 4. This compound we're talking about is a selective inhibitor of 1, 23, and I'll talk a little bit in a second as to why that selectivity is particularly important In terms of the normal function of these FGFRs, they're important in skeletal development in vascular development.
They have important roles in angiogenesis And as you might expect, as a receptor tyrosine kinase sort of like the EGFR receptors, they activate a number of downstream signaling pathways and that's traded in the cartoon on the right. Most importantly, as it relates to cancer, tumor cells at times can coop these pathways to drive their uncontrolled growth and proliferation. EGFR driven lung cancer or ALK driven lung cancer or BRAF driven melanoma. The FGFR is can be classic oncogenes and therefore give rise to the possibility of targeted inhibition where now the molecules that we would use to target the FGRs can be used to specifically treat patients that have those underlying mutations. It turns out there are a number of genetic events that can activate FGFRs and emerging clinical data both in our own hands as well as from others in the field have shown that not all mutations are created equal.
Some predict sensitivity much better than others. And specifically, if the FGFR gene is translocated and activated, that means fused to another unrelated protein or there are specific mutations in the FGFR receptor itself, those are much better predictors of sensitivity than just amplification of the receptor itself. That's very distinct and that's unique to FGFRs. It's not seen with other genetic events. For example, the C Met kinase that we're targeting with Kamatinib in a program with Novartis, that's driven entirely by amplification.
So here, the translocations and the mutations are what are important to track in order to predict sensitivity. So we take a look at these genetic events across the various histologies, what types of patients harbor these events? There can be events in FGFR1 and that's the top of this table. In the middle is FGFR2 and at the bottom is FGFR3. And you can see that you can have translocations, amplifications and mutations in any one of these.
We've highlighted in bold those specific patient populations that our program is focused on. And if we begin at the top, you have FGR1 translocated 8p11 MPN. So this is a myeloproliferative neoplasm in the same general family as myelofibrosis It's a very rare disease, but it's, it's, definition as AP11 is entirely defined by the activating FGFR event. That's how these patients are defined. So you can see the prevalence is 100% because that is the sinequaquanone of diagnosis.
FGFR2 can be translocated in intrahepatic cholangiocarcinoma. This is bile duct cancer and you can see that 13% to 20% of patients can have the translocation, which would predict sensitivity to FGFR inhibition. And finally, bladder cancer is frequently driven by FGFR3 and that can be a translocation event, which is occurs somewhat infrequently around 5% to 6% or more commonly mutations in FGFR3 that drive oncogenesis and bladder cancer. And here you have 10% to 15% of patients harbor those mutations. So again, these four areas are where the key clinical program and our efforts are focused around INcb54828.
So important thing to mention is that it's a competitive field there are a number of FGFR inhibitors that are out there. And what we've tried to do on this table is give you a little bit of a kind of a head to head comparison of the key attributes of their profile. Compounds against the key 3 receptors 1, 23. And you can see that the 54828 highlighted in that first column compares quite favorably in terms of just an absolute potency standpoint. In the middle of the table is the activity against unrelated kinases that you'd like to avoid for various safety reasons, FGFR4, which can give rise to transaminitis and GI toxicities like nausea and diarrhea because of perturbation of bile acid homeostasis you can see the selectivity for 54828 is quite significant upwards of 30 fold against FGFR3 all the way to 70 fold if you compare FGFR1 potency to FGFR4 potency.
VEGFR2 is another, important cross reacting kinase because of its similarities to FGFR 1, 23. There, the key side effect is hypertension and you can see about a 2 or and a half fold improved potency or selectivity for 828 against those 2 kinases. So from a potency and selectivity standpoint, 828 has we think the attributes our best in class profile. And that of course translates then into cellular activities where we have very potent and balanced activity against all of the various cell types that harbor the relevant FGFR translocations. In terms of preclinical data that would support the activity of the compound, shown here are 3 model systems, They're all xenograft systems and highlighted are the various genetic driver mutations that each one of these cell systems has when grown in vivo.
First, an 8p11 MPN xenograft and in the middle, a cholangiocarcinoma harboring a specific FGFR2 translocation And finally, on the right, the FGFR3 driven bladder cancer. And you can see in every case, if you compare the colored lines against the gray or the black lines, that, 548 to 8, yields demonstrable anti tumor activity and in many cases, regressions in the right tumor models and these data really supported the advancement of 54828 into the clinic as a targeted therapy for patients that harbor FGFR activating events.
So I'm going to provide an introduction to cholangiocarcinoma, which is one of the key tumor areas we're focused on for our FGFR inhibitor. Kolangiocarcinoma is a cancer involving the epithelial cells that line the bile ducts, that root bile from the liver to the intestines. And There are two main locations where cholangiocarcinoma can occur. It can occur in the extra hepatic bile ducts outside the liver or it can occur intrahepatically. What we're particularly interested in is the interhepatic cholangiocarcinoma because up to 20% of these patients will have fusions involving the GFR2 gene, which we think are key drivers of the tumor and therefore a perfect target for an FGFR inhibitor.
The incidence of FGFR2 fusion, cleanser carcinomas, about 2500 to 3000 patients, Across the U. S, Europe, and Japan. And it looks like the incidence is increasing of these, of these tumors. Now the diagnosis of cholangiocarcinoma can be very difficult because of, the bile ducts location deep in the abdomen, symptoms can often be very non specific initial presentation. The extra hepatic form tends to be diagnosed somewhat earlier because it causes obstruction of the common bile duct.
And so patients can get so fairly acute symptoms related to that obstruction, but the intrahepatic form tends to be much more difficult to diagnose you see a lot of the symptoms on this slide are very non specific. And so the result for the patients can be devastating. What this means is that most of the patients who are diagnosed with cholangiocarcinoma have very advanced disease at the time of diagnosis And unfortunately, the treatments that we have for these patients are not very good. The front line standard of care is chemotherapy, generally with gemcitabine and cisplatin. And you see that the average outcome for those patients with response rates of about 26% progression free survival of 8 months and overall survival about a year.
And you see on the right hand graph there, you see how poorly the patients stage 3 and stage 4 disease, how poorly their outcome is. And unfortunately, most of the patients are diagnosed with this advanced stage. Now unfortunately after 1st line chemotherapy, there are really no effective options for these patients. So second line chemotherapy has been studied with disease control rates of about 30% response rates in the single digits and progression free survival of no more than 3 months. So again, clearly here there's a very high unmet need and the opportunity to study a targeted therapeutic approach for some of these patients.
So turning to the clinical program, which goes under the acronym FIT, this is the FIT-two zero two study using, 548 to 8 IFR in inhibitor in patients with intrahepatic cholangiocarcinoma. The target enrollment for this study is 140 patients and there are 3 cohorts within the study. The important one is the FGFR2 translocation has just been pointed out to you. Its cohort a and the target enrollment there is 100 patients. I'm going to show you some early data from that cohort.
There are 2 internal control within the study, cohort B, consists of patients with other FGF or FGFR alterations and that enrolled 20 patients and cohort C is patients without an FGFR or FGFR alteration and that also enrolled 20 patients. The dosing schema for this set study and schedule is 5482813.5 Milligrams daily, 2 weeks on, and 1 week off and the primary endpoint is an overall response rate in patients with the FGFR2 translocation, the cohort A population, and we did this by an independent reviewer. Again, when you compare data sets from some of the competitors, that that we showed you upfront, just look at whether they report an investigator or independently reviewed data sets. The secondary endpoints were response rate in the patients other alterations, progression free survival and obviously safety. Should this continue to produce the results I'm about to show you we feel this would be, adequate for a new drug application in 2019 in the United States from the study alone.
And as the potential to be the 1st selective FGFR inhibitor approved for cholangiocarcinoma that's FGFR2 translocated. The safety, just one thing to bear in mind here, the cohort A exposures are much longer than cohort BNC for which there was really no benefit from the use of the agent hyperphosphatemia is an on target effect and expected from the drug in terms of its mechanism of action. And in the other treatment emergent adverse events are there for you. The differences seen, for example, in alopecia are largely due to the much increased exposure in cohort A versus cohort B and C which actually served as internal controls, as I said earlier. In terms of the data, the disease control rate is 82% that's this complete response, partial response, unstable disease rate.
You can see on the waterfall plot that the vast majority of the patients are having some degree of side reduction. And this is an early look at the 100 patients. This is the first 45 evaluable patients with an FGFR2 translocation. The best overall response rate using resist criteria, the gray line 24% and at this early juncture includes unconfirmed responses. 8 of them are confirmed, 3 are unconfirmed, but are all ongoing awaiting confirmation, and the median progression free survival at this juncture is 6.8 months.
Compared to what Peter was telling you about 2nd line chemotherapy with an overall response rate of 10% and a progression free survival in the 3 month and you can see why we are excited about this compound in the setting. In the control groups, the cohort B, with other alterations or C, without any, There was really no response whatsoever and a median progression free survival of 1.41.5 months, thus serving as the internal control within the study. This is the swimmer plot of the duration of treatment. The arrows indicate that the patients are ongoing at this juncture The, green is a partial response. The orange triangle is stable disease.
The red is progressive disease. And as I said, the arrows are ongoing. You can see at this point in time, obviously, the patients right at the bottom have come on study earlier than the ones at the top, but the ones at the top are ongoing now in excess of 8, 9, 10 months. And that's how we get in a PFS at this point in the north of the 6 month territory. We are preparing a what should ultimately serve, hopefully, as a confirmatory study in the phase 3 setting potentially against chemotherapy but this design still is to be worked out in FGFR2 translocated cholangiocarcinoma in conjunction with regulatory discussions.
In terms of bladder cancer, so turning from the cholangiocarcinoma data, I showed you to metastatic bladder cancer, again, under the FIGHT ACronym. This is 5201. The original phase 2 trial design is metastatic or surgery unresected bladder cancer again a target enrollment of 140 patients. The first 100 in cohort A had an FGFR3 mutation or fusion and then the second cohort is without that and again serves as an internal control with 40 patients and the same dose in schema has outlined there for you 13.5 daily, with a 2 week on 1 week off schedule. The primary endpoint is an overall response rate in patients with FGFR3 mutations and the secondary endpoints are outlined there for you.
This is a more common patient population in total you look at the U. S, Western Europe and Japan, there are about 60,000 new patients with metastatic, bladder cancer. As we said earlier, about 15% to 20% of these are expected to have a FGFR3 mutations or translocations. The safety from the study at this point in time with that intermittent dose scheduled is there for you. Again, expected given the class with diarrhea, alopecia and a dry mouth being the main signals, again, the exposure is higher in the cohort versus the cohort B population here for you.
In terms of activity, there's a waterfall plot there for you. The first 47 evaluable patients. And to be evaluable in this, you had to have an FGFR 2 trans excuse me, an FGFR 3 mutational fusion plus receive at least one dose of the drug. It's a 28% response rate at this point in time. Including unconfirmed responses.
The 7 confirmed partial responses are all ongoing and the 6th unconfirmed at this juncture just haven't had the second scans yet and are all ongoing. You can see in the waterfall plot for you there. If you add them up, there were 5 who were not evaluable, because some of them did not have a baseline measurable disease and a couple of them didn't have any scan data available at this juncture. We are gonna adjust the study based on what's happening in the competitive space. So if you look at the J and J compound, they now have breakthrough designation and they made a switch in their program from intermittent dosing to continuous dosing.
They use an investigator reported endpoint, but from their increase towards continuous dosing, they they went from a 25% response rate to the mid-30s and now reporting a 40% response rate with continuous dosing. So you can see our modification below for cohort C will be again patients with FGFR3 mutations of fusions and will treat another 100 patients with a 13.5 milligram dose continuously. This state is expected in 2019. This may additionally given the data just shown you support our regularly submission in the United States and our ultimate intention is to develop 548 to 8 as a first line treatment for patients with FGFR3 mutated bladder cancer. The field's a little bit further complicated about what's happening with the PD-one and PD L ones.
For those of you who've seen the labels were actually issued this morning, by the FDA and European agencies on how to dose these agents in metastatic bladder cancer given the complexities around being either eligible for cisplatin chemotherapy or not and then platinum therapy in general. There is a warning on using these agents as monotherapy in patients with PD L1 low bladder cancer. It's interesting that if you look at the FGFR3 mutated setting, the one we're interested in with the FGFR inhibitor, PD L1 highs are very small amount of these patients. They're mostly PD L1 low. And obviously now given how this field is developing will be developing potentially a multi arm study in the setting to account for whether or not you chemotherapy eligible and whether or not you're a PD L1 EXPRESSor.
Okay. So again, so that's a product, discover that insight where we have the rights globally, where as programs that we are doing is prosecuted in the U. S, Europe, and in Japan, it could have its first result in Colombia carcinoma in 2019 and a filing, assuming the data is justifying it also in 20 and 'nineteen. I think it's important to, when you think about FGF, to look at it in two buckets, so Colanger Castinoma and bladder cancer AP11, the first indication will probably go through, but it's a number of patients. It's so small that in fact in some way, it does not impact the overall picture.
So 1st, Kolangiocarcinoma, we spoke about around 3000 patients between U. S. Europe and Japan. So that's a population we can calibrate today. It is growing fairly quickly.
And the rate of diagnosis is also obviously dependent on the number of treatment that you have available for this patient. So I still assume that this will continue to grow over time. I think what's important for the data we just is that 80% of patients benefit in some way from the treatment, which is obviously very in the line of what we have seen recently with this target therapy for specific mutations that has been identified. And that's really something very similar we find here with an FGFR inhibitor where We have this specific tumor type of cholangio and bladder cancer, but where we can see the same, a very large majority of patient benefiting from the treatment In terms of the duration, we spoke about early data showing a median of around 7 months, 6.8 months. For, in term of time to progression, which is giving you an idea that it will be counted in months and not in weeks.
Frankly historical comparison in conjugarcinoma is such a short effect that I think it's a very good news for this project to see this kind of this kind of number. I must say also from the commercial standpoint, when you introduce a new product in each of these 3 countries or continent like Europe, Japan and U. S, having a small narrow indication at the beginning of the life of the product and experiencing in term of ability to get a good price. Now the bladder situation, as you saw, we have an active drug. We have a profile of a potential best in class.
We are working on the schedule of administration because it is apparently visible from the class. That continuous administration could be in fact providing a better response rate. So that's part of the program that we have here. And frankly, the challenge is how to go to the first line setting in that population. It's a population north of around 12,000 patients around the world.
In the first line setting. And as Stephen was describing, it's a very quickly evolving field where this morning, in fact, some new labeling was published about the use of PD-one in this setting. So the design of the first line study is ready for us and the discussion with FDA is ready for us the next the next step for this program in bladder cancer with an optionality of an earlier approval based on the phase 2 that you have seen with 100 patients with intermittent under 100 patients with continuous administration. So again, second sort of slice of potential business for the next few years starting in 1920 20 with FGFR. And now we'll close that chapter and go to our Page Freaking is Delta.
Okay. So we we you heard already the work yesterday, I missed data on our program and you saw some of the data on our program with ruxolitinib in MPN. What I want to do with this slide is trying to describe all the components of the program with PI3 and East Delta. It's a class of products that has been frankly, damaged by over the past 2 years by the clinical profile of the first product to reach the market, if I may say that, but that's really something you can observe. We believe it's a mechanism that have that has multiple indication across all kinds of different types of disease and I'll speak about that.
And we believe specifically in decel malignancies that it has already proven its efficacy with fairly substantial response rate across a number of a type of B cell malignancy. The issue that we have been facing was related to safety, and there were 2 components to the safety issue with GSvik and its Delta. It's liver toxicity, it's cumulative toxicity, colitis like cumulative toxicity immune over time. And what you will see from our program is that we have taken the time over the past 18 months to So we tended to sort of decide 18 months ago or almost 2 years ago to go back to re establishing a new benefit risk ratio for PI3 can use Delta for the one we have, where we don't have the lever signal and where we believe now we can manage in a very different way, the cumulative toxicity. You heard about the first I mentioned, the gray on the left, which is PS III and S Delta has a complement to JAK inhibition in MPN.
You saw some of the data, which is not yet a very large number of patients, but somewhat promising. So that's a program that we have ongoing. What we will be speaking about right now is a B cell malignancy program with 3 types of lymphoma where we have studies ongoing. And then later, we will have a short discussion on another dimension of PI3 kinase delta, which is a type of studies we did with spare biopsy looking at the impact of PI3 kinase delta on the microenvironment of the tumor and how it can be combined. In fact, in that case, with the PD-one, with potential promise on that front.
And then later at the end of the non oncology or inflammation autoimmunity presentation, we will speak of the use of Plastics, Delta, in benign indication, non cancer indication, where in fact, there is also a lot of potential. So it's a complex product The complex series of products, in fact, with very independently moving parts, and I just wanted to start the presentation showing this graph so that when we speak about PS3 and Es Delta, it's not just a Bicel malignancy dimension, but in fact, it has a lot of potential across Numer's other indication. And this, Peter will start the presentation on the project.
So I'll summarize, to finish off this section, summarize, our plans for our PI3 kinase delta inhibitor and non Hodgkin's lymphoma Basically, these non Hodgkin's lymphoma represent the vast majority of all lymphomas, can be divided broadly into T cell malignancies and B malignancies and for the Delta inhibitor, we're really focused on the B cell malignancies. There are multiple different subtypes and classifications of these types of lymphoma, but very broadly they can be divided into those that are more indolent and those are more aggressive. The indolent lymphomas are generally not curable. At early stages, they can be fairly slow growing and relatively benign. But as they become more advanced, they can become very problematic, and there's really an unmet need for effective treatment in these patients.
And in the aggressive, lymphoma setting. There are some treatment of treatments available with the potential for cure, but there are still significant number of patients that don't respond to those treatments for whom there's still a high unmet need. We're looking at 3 main subtypes of non is lymphoma for our monotherapy development program. The first of these is follicular lymphoma, probably one of the most common types of lymphoma with an imbalance, not that problematic, but as they get more advanced and more widespread, the patients are going to need treatments and there's not much that's very effective And ultimately, many of these patients will transform into a more aggressive, lymphoma. We'll look at Marginal Zone Lymphoma, which is relatively uncommon incidence about 5000 per year and can involve multiple different sites within the body.
And then in terms of aggressive lymphoma, we're focused on mantle cell lymphoma and incidents about 4500 per year, relatively uncommon a very aggressive form of lymphoma and about 3 quarters of these patients were already have diffuse lymphadenopathy at the time that they're diagnosed. In our initial phase 1 study without Delta inhibitor, we are very encouraged to see, very rapid deep and durable responses in these 3 subtypes of non Hodgkin's lymphoma. And again, this is looking at the Delta inhibitors therapy. As everybody alluded to, we know from this class of agents that there's a problem as you treat out for longer once you get out to 6 to 9 months, many of these patients would develop immune like adverse events, particularly diarrhea and colitis. And so we took the time to explore different dosing regimen so that our paradigm now is that these patients start with a very high potent dose of the Delta inhibitor to drive them into response And then after 2 months, we go to a less dose intense dosing regimen to try and maintain that response and avoid the toxicity.
And the graphs on the right hand side of this slide where the hash marks are show how this reduced, dose intensity was able to sustain the response in many of the patients and most importantly avoid the colitis in all of these cases. So as we move into phase 2 studies, we're exploring this treatment paradigm of upfront potent inhibition followed by a reduced dose intensity to try and maintain a sustained response while avoiding some of the long term toxicities. So we're expecting data from this initial monotherapy trial program next year. Again, the 3 settings we're looking at: 1st, follicular lymphoma where we have a phase 2 monotherapy study with 100 patients that's ongoing. The primary endpoint is objective response rate In marginal zone lymphoma, we're looking at a study of 120 patients, again, with response rate as primary endpoint.
And here, we're looking at 2 cohorts of patients one in patients who have not previously received a BTK inhibitor like ibrutinib and another cohort in those who have. What we know is that BTK inhibitors are being used to a certain extent in this disease, they're not widely used, so potentially we could show effect in a patient who hasn't received 1, and the patients who have received them, their prognosis once they progress on those agents tends to be really terrible. And so we are able to show benefit in patients who have received those, that would be a major advance. But, data will be available next year. And then for the aggressive mantle cell lymphoma, we have a similar study 120 patients.
Again, patients can or cannot have had a prior BTK inhibitor. Again, we're looking objective response rate. Each of these trials is designed to support a registration in the successful. Now having said that, our focus initially is on monotherapy based on the encouraging phase 2 data that we saw from the phase 1 study but we know that the paradigm for lymphoma treatment is combinations with other, chemotherapy or immune therapies. And so we are currently have studies ongoing looking at combinations of our Delta inhibitor with standards of care, like rituximab, bendamustineplus rituximab, Bender Mustine plus open etuzumab and ibrutinib.
And these studies are designed hopefully to show the safety of the delta inhibitor with these combinations and support future, randomized Phase III studies. And so we should have data available from these combination studies later this year or early next year. So that basically summarizes the program we have for lymphomas.
Okay. So again, as a conclusion, so 3 different types of lymphoma data in 2019 potentially fighting NDAs if the data is sufficient for that in 2020. And again, we are in the field of relatively not rare disease, but relatively limited patient population where the commercial aspect of launching this product, ourselves, as inside. It's totally feasible both in the US, Europe and also in Japan. And, and that's something that, you know, we are looking forward to and that we will be triggering as we get, as we get the result from, from this study on that.
You know, quite round of the Fiesta candidates that are programmed. So we would be, having a a Q and A coming in the next few minutes. Just a reminder, take away from what we discussed, which is the MPM leadership and how this franchise can be renewed and expanded over the next few years with multiple defense initiatives, the GVHD, rocks, and tessitinib, Decitinib Worldwide, FGFR, and Collinjure and better, and PS3 can use Delta in that case, the recommendation on top of the MPM we discussed in the first on the T7 ERCs where we have ongoing studies. So I think we will stop on this and, Yeah.
Now we have some questions. And so now we'll take a break for questions. I ask those of you in the room here to put your hand up if you would like to ask a question. We have a couple of folks with microphones that will come to you, please remember, wait for the microphone. Please state your name and your organization and please just ask one question.
And if there needs to be a follow-up, then so we'll do that. Let's take a question, Brian, on table 12 or table 13.
Thanks. Ryan Abrams, RBC Capital Markets. On the graft versus host program, I'm just wondering sort of your sense as to the FDA's bar with the open label study for 28 day response rates and then 3 6 months durability, how definitive is that And what kind of sense, have you gotten from the study as to what the average treatment duration might be in the real world in this setting?
Brian, it's Steven. Thanks for the question. Just a few things upfront. Obviously, I can't speak for the FDA itself. The program is under break designation.
The program was designed with the FDA, with the personal internally there, there's a huge interest in the disease itself. The endpoints agreed. The studies agreed. So it's as robust as it can be day 28 response it's felt to be a really good surrogate for long term benefits, particularly survival. And then in terms of the endpoints, it was felt that anything north of 50% would, would be a really good surrogate or clinical benefit, coupled with, as you said, durability of response.
In terms of
the data I've shown you,
you know, the, the event free endpoints at 3 6 months currently are are really healthy. So at 3 months, 80% haven't, had an issue and and at 6 months, 70%. So we haven't reached the median yet. So we think this is a data set as good as it can be, in terms of submitting it for an approval and ultimately the FDA will judge whether that's the case or not. But, as confident as we can be into are putting in a supplemental NDA here.
That's, the best overall response, as you said, which, as we pointed out, at any time point, is 73%. That includes a few patients who had it earlier than day 28 and then many others that have it later. That's also pretty predictive for long term benefit. It's just not as well agreed to as a date 28 number. And that's why that's the primary endpoint.
So very high probability of success from where we sit and ultimately it'll be to the food and drug administration. I'll remind you also, Brutinib and chronic was approved very, very quickly. And it's not just similar setting when you have a marketed compound used, you know, thousands of patients elsewhere, so the safety is well established. So that's our hope here as well.
Okay. Regarding the duration of, the duration of treatment, we are anticipating. I just spoke about it briefly. We have, obviously, the study you have seen. So the median is reach.
So you have to see 70% of patients continue treatment, which is frankly a little more than what I was on this. Paving when we are sort of calibrating. If you want the size of this opportunity in term of rock solid yield, I think that's better, maybe than what we were expecting there. We have also a few other data points because there is an open,
Yes. So what what Urvi is alluding to is, there's a large amount of requests for, for RUX in the United States and graft versus host disease either through expand access for compassionate use, and although not a controlled study, we have some sense of, duration of use there. And while going into that, you know, at least in the acute setting, we thought, you know, probably around 6 months a year would be where people would use it for turns out, maybe not unexpected now, but at the time it was that people are tending to use it for a lot longer. And what happens in the real world, and Peter can speak as better than me, is that the main aim is to get them off steroids, in terms of toxicity And then one step of that and people think about whether or not maintaining JAK inhibition. But the little bit of real world data we have points to longer use at the moment.
Okay, great. Let's have a question from table 8. That's Corey, I think. And if we'd say, Mark, you can come next.
Thanks, Corey Kasimov, JP Morgan. I'm curious for the Jakafi combination work that you described at the beginning in MPNs. Is there potential to create maybe fixed dose combinations? Are these various strategies or any of these various strategies? So that would in addition to improving outcomes also have the potential added benefit of extending Jakafi related IP?
It's clearly something that, you know, as you've seen, some of these products are twice a day, some are once a day. So that would require a a lot of, some work at least in term of formulation to get there, but there is some perspective of adding to the slack inhibition with a new mechanism doing a those combination and being able to have clear superiority in term of patients, benefit, and outcome is that, with that new combination, but still that's part of the thing. We are at a stage where we are still establishing the proof of the proof of concept. You can see that the population where everybody would zoom is a population where Jakafi is not used after Jakafi kind of setting. And there we believe they're strongly subject to inhibition.
It's really not the solution for that setting. It's a solution of other mechanism to lead the body, you know, change the course of the disease at that stage after treatment with checkify. And then you have a group of patients with suboptimal response to checkify. And then you have the first line setting, and that's the natural flow of how these programs will house brands will move over time from the source of the refractory plus Jakafi to earlier stage, potentially with fixed dose combination, if able to do that, you know, depending on the mechanism, you can see the schedules are not exactly always available, but it should be feasible.
Mark Fran from Cowen. When we think about this either post or on top of ruxolitinib setting in MF, do you think there's approval possibilities with just symptomatic scores? Or do you also need the spleen reductions that we're seeing with Jakafi in their phase threes?
I think, those are discussions that
I think we need to have with FDA, but
I think based on our previous discussions, we're probably having some degree skeen reduction would be necessary. But in that sort of suboptimal setting or in a second line setting, would we need the same degree of spleen from frontline setting, probably not, but those are discussed that we do tend with FDA at any time.
Okay. Then we'll go Carter from UBS and then Lisa, I think you had a question too. So we'll go to you next.
Carter Gould, UBS, for Ervin and team. Regarding those phase 2 readouts and MPNs, or an MF, when you think about the strategy there, is that something you could take multiple combinations into phase 3 or sort of wait for all the data to come out and then
pick your best shot?
I would say at this stage, we don't know. I mean, what you're seeing, right? We have mechanistic reasons to be motivating to do
the studies we are doing, and there
are single arms that is fairly small, both with itacitinib, so that one type 2, it's a subtle neutral. It's propagated in some way, but it's all interesting. And then you have a beam and delta that already on drawing. And, frankly, if we get more than one success I mean, that would be, sort of a a good, a good program to have, but, I don't know if I I don't know. I really don't know.
I think we'll take it as the comment and we'll decide what the next steps are because we immediately have not discussed yet if we win on every study that we have ongoing, which would be surprising.
Hi, Lisa Baker from JMP. Just two questions related to the FGF program. Number 1, for the, FGFR2 fusion, is that part of the, bile cancer is derived from C. And then also for the FIGHT 201 study, do you also have the other alterations as a control like you described for the other study there? Thanks.
So, Lisa, do you mind re asking the first question? I'm not sure we had stood what you were saying.
Yes. Some of the, the bile duct cancer comes from PSC.
I'm just wondering. Right.
And I'm just wondering if that mutation is along that pathway
somewhere. That out.
Yeah. And then your second question on 5201, So, you know, initially, it's now obviously very clear that the activities where, as Reid pointed out preclinically, where you see, you know, the driver And when you don't, there's little to no activity, but going in, you don't know that. Plus, you know, it's often, that regulatory agencies will require you to prove that you that you does work in those settings, LVX in a more limited patient population. So they do have those internal controls, both, the cholangio has 2 extra cohorts and then ladder as well. But it's, you know, once you hit at least in the cholangio, the 220 patient subsets in bladder, there's a 40 patient subsets.
Once you have little to no activity there, you can stop. You don't have to keep going. So they do have those controls.
Let's go to Ying on Table 3.
Thanks. I'm Ying Huang, Bank of America Merrill Lynch. I have a question also, Claudio Casinoma. Program. You're already planning for confirm through 12.
Does that mean you're seeking, the accelerated approval with the FDA, with that separately? You're going to increase those 2 continuous dosing. Have you observed any dose limiting toxicity at all from previous trials?
Just to be clear, your second question first. In cholangio, we're staying with the intermittent dosing. The continued dosing switch is in bladder. In terms of, the likely approval setting, you know, the usual feeling is for a single arm study of the size that you're going to be looking at an accelerator approval scenario. Is it possible to get full approval?
Absolutely, yes. You know, if, if the agency thinks your, your response rate is robust, your durability is dispersed, robust and that demonstrates clinical benefit by the letter
of the law from a
regulatory point of view. You could get a full approval there. You cannot get accelerated approval without having an ongoing confirmatory study. So that's one reason. The other reason is to move to a I set in.
So remember, the studies in 2nd line and beyond, first line patients aren't captured for the most part. So there's multiple drivers. There's, to secure your accelerated approval to have it ongoing and then to capture a first line market as well.
But I know, have you ever seen any toxicity? The the the
main one and Peter may wanna add to what I say, is, you know, once you get to a high enough dose continuously almost universal hyperphosphatemia. And it's just how to manage that. Does everybody get primary prophylaxis? It etcetera, etcetera. That that would, I think, be the main one, anything else
to add?
Yeah. We think
we we haven't reached a maximum tolerated dose officially according to the protocol. It was either the interim or continuous dosing. However, with continuous dosing, we do see more discontinuations. Through the hyperphosphatemia, the the common toxicity, but we also see some diarrhea. We see some alopecia.
We see some nail changes. And those things all occur more commonly at the continuous dose So we still think in a setting like bladder cancer, we can increase the response rate that that risk benefit profile is still favorable with continuous dosing regimen. But we definitely expect more side effects in those nations. But to answer your question, we haven't strictly speaking met at the maximum tolerated dose in life.
Okay. Yeah, let's go, Asthika on the table
Thank you. Arctic Equinor and the Blooming Intelligence. Sticking with FGFR, I'm curious if you can sort of get into a cross trial comparisons. What the Grade 34 toxicity look like for FGFR, new data to date? And then sort of related, In the bladder cancer patient population that you treated, do you have any patients who were pretreated with IO?
And if so, what did the response rates look like in IO pretreated patients versus those who did not? Thank you.
In terms of grade 3 and 4 toxicity, I mean, generally the things that we've seen and, are are around diarrhea. We've seen some sotitis and mucositis, and that's commonly some, nail changes. So those have probably been the things that we see out of most commonly or their most bothersome to patients. Now how they compare to other drugs is a little difficult to tell. It doesn't look like what we're seeing is is certainly any higher than what's been seen with other agents.
Generally, it appears the toxicity profiles appear fairly similar across the different FGFR targeted, compounds. In terms of the IO, that's actually something we're gonna go back and look at. I know there are a couple of patients that were had been previously treated with IO agents, but I don't know the response rates off the top right now.
Yeah. Just to be a a a little additive to what said, the the J and J reported continuous dosing, discontinuation rate to 20%. Our intermittent dosing current discontinuation rate is 8%. When we go to continuous, would we get just similar territory? We'll we'll wait and see.
In terms of IO exposure, we know that about, 30 patients to date have had prior PD-one therapies, in the bladder setting. We're still going to examine the data a little more closely, but we know of at least one path response in somebody who had a prior partial response to a PD-one inhibitor. And that may be of interest on how the program develops in terms of studies. It's still too early to comment further.
Hi there. Evan Seagerman from Barclays. So with the PI3 kinase delta program, can you help me better on understand what was in the data of the DLBCL trial that caused you to discontinue their development? And are there any read throughs to some of the other indications that you had mentioned here?
Let me go first and then Peter may want to add in as well. Just to be clear, the compound is active across all B cell tumors. You saw Peter show, you know, follicular data, mantle, and marginal zone. In diffuse large B cell, we saw a 25% sponsrate. That's that's an active drug.
The issues around, monotherapy and monotherapy approvability and use thereafter in diffuse large B cell. And there really isn't a pathway there given that combinations have higher responses, B cell 2, BTK, CAR T therapies, etcetera. So it's a development decision to discontinue, not a lack of activity in diffuse B cell. It's as active as other have to be kind of delta inhibitors have been or maybe even a little more so in terms of monotherapy use there.
Any further questions
Yes.
So let's go to Jay over in the corner there from Oppenheimer.
Thank you for taking
the questions. Shales from Oppenheimer. For Reach 1, can you comment on what percent of patients titrated up to the 10 milligram dose? And then for FGFR, can you just comment on, potential registrational study designs? You mentioned the changing treatment guidelines with regards to PD L1 status, does it mean that you might have one treatment arms that could be in combination with a PD-one antibody?
Thank you.
So, just your second question, first, in terms of bladder cancer, you know, I think given this morning's label, updates, we'll think about each group carefully. Now there are, cisplatin ineligible platinum ineligible, which seems to be a different definition, which may allude to Cabo. And then there's PD L1 low and PD L1 high. In terms of labels this morning, it looks like, for the platinum ineligible, even if you PD L1 low, you can still get PD-one inhibitors. So we are thinking of a multi arm study there potentially in trying to segment the groups and potentially in in combination.
In terms of, Calandio, do you want to comment
on what James asked for?
I don't I don't have the, precise number in front of me. What we know is there was a proportion of patients who did escalate from 5 up to 10. We also know that there was a lot of dosage titration up or down based on cytopenias or other, you know, infections and things that were going on patients. So, what we know from from the dosing regimen is that that average is between 5, twice a day and 10, twice a day, but,
there was a lot of those just based
on the patient's condition, which is sort of what we would expect for those patients. But I I I'm sorry I don't have that number on top.
Any further questions before we close for a quick break? In that case, no, I'll Thank you all very much right now. It is 2:43. We'll be back for a hard start at 3 o'clock. Please grab some snack outside for those people here in the room, for those of you on the webcast, we'll see you again in about 15 minutes.
Okay. Welcome back to part 2 of Insights, investor and analyst event 2018. We'll kick off part 2 with some comments by Abe on our PD-one development program.
Okay. Thank you, Mike. Welcome back. And, so yes, the second part of this will be about, in fact, immunology. First, we'd speak about cancer immunology and specifically about our PD-one program and then we'll be discussing, so non oncology, so called information to immunity.
So obviously every time you start the presentation about our PD-one, the question is why is it important to have a PD-one in your portfolio? And I think I recognize that question completely. So it's something that I think it's important to describe. So we have this product that was his license from a microGenics and what it gives us is a number of very important competitive advantage in the field of cancer treatment in general. You heard about some of the discussion about FGF plus PD-one in the first line treatment of bladder cancer.
It's just a small example of what we mean here when we are discussing about the optionalities that you have when you have it in your portfolio. It's also a product that could potentially have a relatively rapid market entry as a monotherapy. So before we speak about the combination, there is a monotherapy aspect to it and we will be speaking about that over the next few slides. And then as a monotherapy, there is also the opportunity to develop it beyond the so called niche small indication where in fact usage is very broad. And if you look at the way usage of PD-one inhibitors has been spreading across a number of tumor type across a number of lines of treatment it's clearly also creating a commercial opportunity at that level.
In terms of combination, it's very important to realize that doing combination therapy without having a PD-one in your portfolio requires 1 of 2 things. Is either an enormous amount of money to buy it on the market or to work in agreement with other company, which is obviously creating complex cities and potentially slowing down your process. So I think a PD-one in your portfolio for us with the multitude of different mechanisms that we have with which it could be combined is a clear competitive advantage and we'll speak about that in the next few slides, specifically about what we can do as a monotherapy.
So the goal in, when we a look at the MGA012 program which originated from MacroGenics is a me too PD-one. At least in a monospecific antibody format, it doesn't appear that there's any clear way that you can differentiate around that. And so our goal is quite simple. Make sure that this PD-one antagonist is equivalent to pharmacologically pharmacokinetically to other canonical PD-1s in the space And so I just show on this slide, at the top, some preclinical in vitro data and the bottom, some clinical pharmacokinetic data to illustrate that. So on the top, you're looking at the ability of an antibody and in the red field circles as MGA012, our PD-one antagonist and their ability in a dose dependent fashion to block the binding of the PD-one receptor to one of its ligands, PD L1 on the left, or its other ligand PD L2 on the right, the more potent the compound is the earlier the compound will reflect or inflect downward And you can see that if you compare the red curve to the blue and the green, that's being nivo and pembro.
They're virtually superimposable in terms of their both their ability to maximally block PD L1 and PD L2 binding as well as the affinity or the potency with which they, they block those events. So from an in vitro biochemical standpoint, spot on similar. Now when we dose these antibodies in the clinic, obviously, we have to have a dose in schedule, it allows us to saturate PD-one on the patient's immune cells, specifically their T cells. And so shown on the right, are 2 different ways to measure that, the top panel is looking at maximum binding of the antibody on the cells themselves. So you want that to go to 100% and on the bottom is looking at, the ability to competitively inhibit binding of another antibody onto those same cells.
And so you want that to go to 0% And we've studied 1 mgs per kg, given every 2 weeks, 3 mgs per kg in green, giving every 2 weeks or 10 mgs per kg, giving every 4 weeks you can see in every case that we can completely saturate binding with PD-one, which is what you'd expect based on the PK, and helps to, convince us and the investigators that this antibody is able to effectively bind the target It does so with a high affinity similar to pembro and nivo, and we have multitude of doses and schedules that we can work with, that can be 100 percent saturating in terms of PD-one and therefore block the pathway completely. And that'll guide, subsequent clinical development that Steven will talk
So we inherited the compound fully in the United States with the IND transfer in March of this year, but this is a dose escalation data in 37 patients just to tell you that the safety profile is typical of what one would from an anti PD-one therapy. There's color code in there of the treatment related adverse events from grade 1 through grade 4. And again, again, typical for what an anti PD-one would expect to give you, including very importantly likely immune related adverse events, which although obviously not good for patients, but that's something you want to see in terms of the drug having the effect you want within the body. And then in terms of, adverse events of a grade 3 nature or higher or serious adverse events or any treatment related ones, expected and adverse events of special interest expected as well for the agent. In terms of the dosing escalation, the program is complete and redeluded to the different dose and scheme is used.
It started 1 milligram per kilogram every 2 weeks a build through 3 milligrams per kilogram, both Q2 and Q4 and then at 10 milligrams per kilogram to Q2 and Q4. With expansion cohorts in endometrial cancer, cervical cancer, sarcomas, non small cell lung cancer, and then a flat dosing regimen done in a tumor agnostic faction just to get as rapidly as possible the required safety data plus PK data and receptor occupancy data. The MSI High, the micro satellite instability high endometrial cohort is going to be further expanded at a 500 milligram Q4 dose and schedule and this will be with registration intent. So this will be one of our niche tumor monotherapy pursuits for this agent. And the indication is still open for this given that it's only currently under accelerated approval in the United States.
Furthermore, we will take, beyond InterMutual, we'll be looking at 2 other niche tumor indications in terms of registration pursuits. But just to spend a little bit of time on the MSI high endometrial cancer, about 28,000 patients a year get endometrial cancer, about a third of microsatellite instability high by standard definitions. Pembroluzumab as monotherapy has provided proof of concept in its MSR high indication as a 36% response rate, which was 5 actually of the 14 endometrial patients within that cohort in total. The disease itself is well recognized as a companion diagnostic already approved in conjunction with Pembro, so that wouldn't be required here. And we aim to enroll this as quickly as possible throughout this year in share with data in 2020?
And should that be what we expect from the agent that could be a monotherapy niche indication? We'll also be looking at Merkel cell carcinoma, a much rarer entity about 1300 patients a year, Avilumab, a provides the benchmark proof of concept data here, having obtained an accelerated approval here with the 33 percent response rate and a duration of response at 6 months that had 86% of patients that were without progression. It's an aggressive cancer with a with a poor prognosis with current standard of care. And again, although not easy patients to find, we expect to do the study in a through the end of this year and next year with data in 2020. And again, another shot at the goal for monotherapy indication.
And then our third one that we picked is anal carcinoma, 2500 patients a year, both Pembro and nivo provide the proof of concept benchmark here with response rates around 20 percent to 25 percent. It's a virus, associated cancer with human papilloma virus. Been implicated again in terms of his etiology, but patients who immunosuppressed as well with, HIV also tend to get more anal carcinoma and can have high mutational burdens, which actually obviously increased response rates. And this will take a little bit longer to fully complete with data in likely in 2021. So those are the 3 monotherapy indications, and all currently have accelerated approvals.
And under that regulatory framework, it is open then for other drugs to pursue until a full approval is obtained. The designs are relatively standard, but just to walk you through. We're using the 500 milligram IVE every 4 weeks. It's a 1 hour infusion, the metastatic murk studies there for you. Patients are required to have 3 or less prior regimens, no prior PD-one with a target enrollment of 100 and then the anal carcinoma study is either locally advanced or metastatic squamous cell anal carcinoma they are required to have a prior platinum, which is usually administered for anal carcinoma in conjunction with radiation therapy.
Unless they were either intolerant or ineligible for this, but less than 2 prior therapies, no prior PD-one, the target enrollment of AD. Both these studies have response rate as the primary endpoint with durability of response to accompany it to them, hopefully suffice should we get the data we anticipate as accelerated approvals. Again, Merkel would be in 2020, and anal carcinoma in 2021. Because we now have this agent sits in our hands and we're using it across the board in upwards of 7 of our internal molecule combinations, both our small molecules and our large molecules. And beyond the internal ones that you know about, we have the ability now to combine it with arginase and Axlemir, which has just gone into the clinic as well to look at both the microenvironment and myelod derived suppress the sales to allow hopefully complimentary and synergistic approaches.
Because of we've a little behind in the for example, in the LAG 3 space, we can look at competitor data there and LAG 3 is obviously from BMS and sort of do a fast follower approach there. And that's something we'll be doing. And as Erve said upfront, the ability to have our own compound not deal with a co development partner have it readily available to users, made things a lot easier. Given the AACR data we presented with Piafikanez Delta, that combo in our platform study at AACR this year. We also have the ability now with 1, 2, should we want to to combine with our Delta inhibitor going forward, from now on?
Yes, so this will be, I guess, the third of four pieces that we're talking about PI3 Counties Delta. We mentioned the MPN work and the lymphoma work in the previous session. So We also have an interest in using K3 kinase delta as a potential way to modulate the host immune system locally in the tumor. Those data actually start back in 2014 from some seminal work in the published literature from an academic lab, several labs showing that delta inside of regulatory T cells actually are very important to their function and their expansion in the tumor. And if you just knock out the enzyme only in those cells, you can shift the immune balance in favor of anti tumor immunity.
Late year after that, we confirmed those data in house, with small molecule inhibition and really showed that the compounds themselves improve the ratio of the effector cells to the regulatory cells. So the good guys, to the bad guys, that ratio has shifted. And the question for us is whether or not in humans and in patients, you could see the same change And so we designed this trial specifically to ask that question. So dose escalation trial fairly standard design on a fixed dose of pembrolizumab with escalating doses of our Delta inhibitor 50465, then with ultimately a safety expansion into either patients that had prior progression on a PD L1 inhibitor or were ultimately naive to, to, treatment to PD-one The translational assessments were the key endpoints of the trial, namely paired tumor biopsies. These are done pre and after treatment after 3 to 5 week on therapy.
And the key question we were asking was, do we change the ratio of those effector versus suppressor cells? As we saw in the knockout mouse and as we saw in our own labs with small molecule inhibition. And there were a host of other, translational endpoints as well. The data, shown here, some of you may have seen this at AACR, a representative patient is shown on the left side This is a melanoma patient actually had prior PD-one therapy, best response was a stable disease and ultimately progressed This is now being treated for 5 weeks on pembrolizumab plus 50465. And the FOX P3 column are the suppressor cells.
Those are the bad guys. Those are the cells that we'd like to decrease and they diminish a number, substantially over this treatment period. And you can see there can comment an increase in the CD8 effector cells. These are the cells that we believe will ultimately drive antitumor community. And if you look at the small cohort of patients that we studied, there were only 8 patients here, but we saw the preponderance of them 6 all with an increase and the mechanism and will help to guide us forward as we understand how dose affects this, how different histologies affect this, and, will form the basis potentially of PD-one combinations going forward.
I also had mentioned that I think this trial design is an important one for us in the sense that it helps us credential the mechanisms that we're bringing forward in the clinic which are often pre proof of concept there. They haven't been validated yet in man. This sort of a translational setting allows us to ask some key biological questions and can obviously help with decision making and prioritization as we go forward.
Okay. So is that 012 PD-one and other global opportunity for us. Data in 2020, we spoke about NDA submission, maybe 21. And for U. S, Europe and Japan, as we said, there is this niche approach, which is trying to find a way to get regulatory approval quickly that is ongoing already.
We have the opportunity as a single agent or combo with chemotherapy, let's say that is already open and that we are reviewing as we speak. And then you heard this morning about Jakafi, this afternoon about the PI3, sorry, PSB and its Delta combination is just an example of what, why we can see a number of very meaningful opportunity for this product. FGF earlier, Plia speaking is Delta, we just spoke about, and you have our G And A's, and you have a number of other mechanisms that we will be combining. So the picture we have, the picture I have for this project is certainly not, I recognize it's a very competitive environment. So that's something easy to see.
But at the same time, we have an opportunity to get it on multiple markets and we have an opportunity to expand it with proprietary combination coming from our pipeline. So I think it can, at the end of the day, end up being a meaningful contributor to the growth of the corporation over the next 5, 6 years. So that being said, we'd be moving to completely different field, which is something that we have been working on now for the past 2 years. And the idea is the following is that we have a very productive search group. As we know, we have a number of molecules that have been taken to the clinic and many of them have mechanism in the field of inflammation and immunology.
So the question is, can we find and can we identify opportunities for these products that are already gone through the discovery process and some of the toxicology process and apply them across a number of different indication. So what we'll be discussing in the next few minutes are 3 of them, one is very simple to understand because we spoke about it already at least in some indication, it's topical oxalitinib. So it's a new formulation, again, where we have the rights around the world. The second one is the JAK1 selective inhibitor that is now also in the clinic. And the last one is a PS3 kinase delta that we are also testing in a number of this indication.
The vision we have here is to develop the clinical proof of concept. So that's what we are in the process of doing. And then depending on which indication we'll be pursuing, the commercial aspect of it will be obviously decided at a later time as when we start, when we speak about following the science, this one is very typical. We don't have any selection about type of indication where these projects could go. We just follow the way the biology is hitting us.
We try to establish the clinical proof of what we are thinking could be the benefit of these products. And obviously, the next steps will be, depending on the type of indication that we will be, obtaining from this project. So we will start with topical oxalitinib as a first one and read with we'll introduce, mechanism.
So again, just to reinforce what Arvay just said, the idea here is relatively straightforward. We know that Jack inhibition can be a potent anti inflammatory agent. We know that there are a number of diseases of the skin where inflammation is the root cause of the pathophysiology. And one advantage we have with a topical formulation of ruxolitinib is the opportunity to minimize systemic exposure So that can change the type of diseases we could go into, the type of patients may want to treat in terms of their stage of disease and also alter the benefit risk potentially in terms of minimizing systemic rated here and just schematically at a high level, some of their biological underpinnings. So atopic dermatitis is a th 2 driven disease IL-four thirteen are critical there.
JAK STAT's play an important role, as I'll show you, Vitiligo, a th1 driven disease again, driven by interferon gamma, primarily in the skin and effector T cells attacking the melanocytes. And then finally, hygienitis suprativa a sort of more complex immune disease, th17 and th1, where IL-seventeen and IL-twenty two downstream of JAK STAT signaling are very important. So let's start first with atopic dermatitis. This is a figure that, nobody is intended to memorize, but what it illustrates in those red boxes are all the key driver cytokines of the disease. And the important thing to note is those ones in red, and importantly IL-four thirteen are sort of top of the pyramid in terms of driving the etiology of atopic dermatitis.
Also IL-thirty one and IL-twenty two and driving the itching and the dermal thickening, those are all signaling through the JAK STAT pathway. And so our belief is that topical ruxolitinib in this condition could be a unique therapy for patients with mild to moderate disease. And so these are not the moderate to severe patients you may treat with systemic therapy. And in fact, the mild to moderate, patient population may be an important one to minimize systemic therapy in order to enhance overall benefit risk for the patient. So this is the first positioning that we have for topical ruxolitinib.
So just to talk about the clinical side to this, topic dermatitis itself represents our earliest to market opportunity for topical ruxolitinib. The prevalence of atopic dermatitis in the U. S. Is typically up to 5% to 10% of adults and a little more 15% of children. It's under diagnosed in general with an average diagnosis rate of 50% to 60% And about 11,000,000 people in the United States who felt to have atopic dermatitis with the majority of that having mild to moderate disease, not severe disease.
It's represented by the pictures you see on the right with erythema, oozing, crusting, scaling, again, thickening of the skin like canification, as well as intense pruritus itching which can really affect the quality of life of these patients. Many of the patients skins are colonized with staphylococcus Aureus and they can have recurrent bacterial infections of these lesions and many of the patients have elevated serum IgE levels and increase allergen specific responses that go with that. In terms of a study that we did to look at the the use of topical ruxolitinib in this condition, this was actually a study done in 307 patients. It's a randomized dose ranging study with both vehicle and an active control. The active control is try and similar in cream of 0.1% PID for the 1st 4 weeks and then they were switched to the vehicle, the ID for the following 4 weeks.
The vehicle arm get vehicle all the way along for 8 weeks and then the active arm in terms of the the topical rux has 4 doses, 0.15 percent daily, 0.5% daily, 1.5% daily, and then a 1.5% PID on. This is a study in adults, 18 and above. They had to have atopic dermatitis as a diagnosis for at least 2 years. That did have what's called an investigator global assessment score of 2 to 3, that screening and baseline which signifies the mild to moderate disease. So this is mild to moderate erythema with some other features attached to it.
The involvement was allowed to be from a body surface stomach therapy. And as I said, an N of 307 patients. The primary endpoint was the efficacy of each dose level of RUX compared with the vehicle. And then the secondary endpoints is the efficacy of each dose level of rux compared with the a steroid cream, the triamcinolone cream then obviously safety. So it's a little complicated in terms of the endpoints and I'm going to spend a little bit of time walking you through this data which again will be presented at a major medical meeting in the second half of this year.
So on the left is the eczema area severity index. EZ score on the right is the investigator global assessment responder. So let's look at the EZ score first. The 2 control arms are below the on your left. Vehicle BID at week 4 week 8 and then the transsimilar in cream, the 0.1% cream used BID at week 4, but remember at week 8, they had stopped and switched to vehicle.
And those are the easy scores for that. And then the RUX arms for all four dose levels. Let me just point you for ease to it's the 1.5% daily and the 1.5% BID. You can see if compared to vehicle, overwhelmingly a much higher so 67 percent and then 78.5% at week 8 versus the vehicle scores again of 15.5% and 26.9%. For the active control arm, you've got for the 1.5% daily numerically slightly higher.
So 67 versus 60 and then 67 again, versus 60 for the 8 week off. But for the 1.5% PRD for the EZ score, These are both numerically high and statistically significantly higher versus obviously the vehicle easily so, but as well as in the steroid arm as well. The investigator global assessment responder rates are there for you. So for patients to be called a responder, they had to improve by at least 1 or 2 grades to a level of 0 or 1 in terms of an IGA responder. So you can see those rates for the control arms are very low vehicle single digit and then the Transimilar arm at week 4 was 25% 25% IGA responder rate.
And then again, just for ease, let me point you to the 1.5% daily in the BID arms. You can see easily beat out vehicle both at week 4 week 8 And then again, numerically and statistically significant, he beat out the Transinlone arm as well with rates of 38% 48% at week 8. So very encouraging efficacy data for our use of topical rugs, both the daily 1.5% as well as a 1.5% BID arms both compared to vehicle as well as the active arm for the 1st 4 weeks in terms of try and similar. Safety wise, as you would expect, from a topical regimen, very little to no, adverse events In fact, there are no grade 3 or 4, so very different population from what we used to in oncology and certainly graft versus host disease We can tell you now because it's publicly available online that has been accepted for an oral presentation in total at EADV in September. And that the regulatory discussions to, for a phase 3 design, again, are underway as we speak.
And we obviously, given this data, intend to pursue a Phase III program with the compound in atopic dermatitis.
So now we'll shift to another dermal inflammatory disease. This one is vitiligo, and it's driven primarily by interferon gamma, and a little bit of the biology is shown here. And what interests us in this disease is that, the stressors that ultimately damage and create a cellular response be it, oxidative stress, cellular damage, even genetic predisposition, drive the secretion of cytokines and chemokines, which help to pull in T cells, immune cells into the skin. And through interferon gamma secretion and activation of those T cells, you actually create effector T cells, which attack your pigment producing cells. Your melanocytes.
And that creates the characteristic loss, the depigmentation, which is just a, a terrible burden for patients who suffer from this disease. Importantly, the molecular pathology here is very much dependent on interferon gamma and CXCL10 and intracellular JAK STAT signaling within T cells. And so the hypothesis we have is JAK inhibition in a topical format would be an ideal modality for these patients where obviously efficacy is paramount, but also lack of systemic exposure and and benefit risk is equally important given that it's not a life threatening condition.
In terms of the clinical profile, for patients with Vitiligo, again, just focusing on the United States for the moment, this inflammatory disorder is felt affect up to 5,000,000 patients in the United States of which about 200,000 currently actively seek treatment about half the patients develop Vitiligo before the age of twenty and then the overwhelmingly majority about 95% before the age of forty. It can be, as depicted by the picture is quite cosmetically disfiguring with associated quality of life changes, including depression and anxiety that patients have. And it's characterized by the pigmentation in patch of skin all over the body, typically the face, the neck, the scalp and around body openings, so particularly the mouth and the gentle area as well. And the course tends to be progressive for Vitiligo with repigmentation of a spontaneous degree extremely low and usually not fully restorative in terms of what happens, an investigator initiated study was done with the ruxolitinib cream, the 1.5% PID cream, for 20 week duration was a proof of concept study, open label, 11 patients only. But in terms of the Vitiligo a severity index.
There was a 23% improvement in the mean score across the 11 patients and particularly in the part that's often most important to patients, 4 of these patients had a 76% improvement in the facial area severity score and it's depicted in the picture below at baseline week 8 and week 20 where you get almost complete resolution of it lager the face with continuous use of 1.5% BID over that 20 week duration. Again, as we would expect for a topical cream, there was minimal, safety in terms of some local erythemia and some transient acne from the use of rux topically, but nothing else to speak of in terms of safety. There is an ongoing phase 2 effort, again, a randomized double blind vehicle control study in adults, 12 above, with Vitiligo, they have to have deep pigmented areas at least 0.5% of the total body surface area on the face. No use of systemic immunosuppressives. No use of investigational agents.
There'll be 150 patients. The 4 dose levels of rux that you saw action atopic derma have been studied 0.15 percent daily,0.5 daily, 1,500,000,000 in the 1.5 BID. It's a total of 52 weeks to study. There's a primary endpoint at week 24 which is a 50% or greater to get to the other endpoints, which are there below for you, which include the total score, at week 52. And as I said, has its compared to vehicle control with data expected in 2019.
What's important with this agent that we see in Vitiligo is it takes a while to see response. And so continuous use over time should give you continuous improvement, which is why the study endpoint is initially a little longer than what we've already shown you with both the 24 and a 52 week endpoint. And again, we are actively because we already have proof of concept from the investigator study looking at phase 3 preparations, which we hope to start in 2019 in this entity, which has a large unmet need, as I said, particularly because of the quality of life effects as well as Vitiligo in these patients.
Okay. So one more, aspect of the dermal inflammation program we'll talk about today. And now we'll shift gears just a little bit away from topical ruxolitinib to another a very selective JAK1 inhibitor for oral administration, and that's called 54,707. And one of the benefits of having such a robust medicinal chemistry effort against the JAKs over the years is the ability to advance multiple compounds into the clinic. You can see ruxolitinib and baricitinib as examples of that but also you have itacitinib, the JAK1 selective inhibitor we talked about earlier for graft versus host disease.
And here, another, cousin to itacitinib called 54707, that we're bringing forward for development in one of these dermal inflammatory diseases that I'll talk about in just a second. So first, a little bit on the profile of of, 54,707, and highlighted in a orange box is probably some of the key aspects. And first, if you focus on the top number, that's the enzyme selectivity for JAK1 over JAK2, just to give you a sense, and that's in comparison to itacitinib and ruxolitinib for context. 50 foot 52 fold selective, for the JAK1 enzyme over JAK2. That's a little bit better than, itacitinib at 22 fold.
And also very potent activity against the IL-six JAK1 access in whole blood, 690 nanomolar compared to 100 nanomolar for itacitinib and ruxolitinib. Importantly, down below, you see the half life of the drug and 54,707 has quite a long half life upwards of 30 hours, which is one of the longer half lives we've ever seen in a JAK inhibitor, certainly longer than what you see with ruxolitinib and baricitinib. And so even with the slightly decreased potency, you still have a nice double digit once daily dose that allows for what we think will be pharmacodynamically active coverage of the enzyme for any kind of JAK1 inflammatory condition. So the disease that we're focused on and Stephen will talk about
it in a little bit
more detail on the coming slides is called Hydrogenitis Superurativa. So this is a dermal inflammatory disease. And the important thing from a biology standpoint is that it's, driven by IL-seventeen and IL 22, which are both produced downstream of activated JAK STAT signaling. We think with an oral JAK1 inhibitor in this case, we can go after moderate to severe disease and, and have a differentiated approach, not only in the disease, but also relative to the types of autoimmune and inflammatory conditions that others are pursuing their oral JAK1 inhibitors. Now let's even walk you through the aspects of the disease.
So this inflammatory follicular skin disease is again, commonly diagnosed in the U. S. Upwards of 300,000 so diagnosed in the United States yearly about 120,000 are actively on treatment. The lesions themselves develop in Exela in growing and under the breast area as a result of inflammation and infection of the sweat glands there and are characterized by these disfiguring recurrent boil life nodules and abscesses that can actually have a pus like discharge and are very difficult to heal can actually have open wounds with sinuses as reflected in the one picture there in scarring. They are amenable because they're on the skin to biopsy and further investigation that at a translational level.
So we know that they are characterized by the increased th1 that we describe with IL-twelve and interferon gamma as well as TH17 cytokines IL-one IL-seventeen IL-twenty three. Humara@alumab has an indication here, but does fail to regulate multiple inflammatory cytokines, particularly 22, 2017 and the gamma ones and is not as widely used because its activity is felt to be at best modest So there is an unmet need here and why we are so interested in studying this disease further. The phase 2 trial is about to begin and we'll go up on clinicaltrials dotgov soon, again, adults, men and women, they have to have moderate to severe hydrogenitis Supertiva by a grading system of at least 6 months duration. And then, there is an abscess and inflammatory count done left out at least 3 of these or more. We have a dose ranging study, that'll start initially at the bottom in cohort 1 with the first twelve patients at 30 milligrams daily, with a placebo randomization with a safety follow-up and then we'll go up to 60 milligrams and then 90 milligrams averse placebo with a safety follow-up to look at both safety and efficacy for the use I'm going to speak a little bit further now about the use of PI3 kinase delta beyond oncology in the setting of immunity and inflammation.
And here, we'll be introducing further clinical programs this year for other B cell mediated and antibody driven diseases. We feel that there's a potential to differentiate from CD20 antibody here, particularly rituximab based upon the mechanism of action and the ability to do reversible suppression versus long lasting depletion. So we're initially going to do proof of concept work in 3 entities listed there for you. The first one is a rare and potentially life threatening autoimmune disease of the skin that causes blistering of the skin in the mucous membranes called Pemphigus Vulgaris. We'll be using the delta inhibitor to antagonize delta signaling there and the TB cell interaction that's pathogenetic care for the disease.
And hopefully then inhibit auto antibody generation and ameliorate the condition. Driven against red blood cells. There's proof of concept already for CD20 antibodies here, particularly rituximab, The idea is to use Delta to suppress auto antibodies that are targeting the red cells, and see whether we'll have an effect here from PR3 kinase delta. And then the last condition we'll be studying is sjogren Syndrome, which is extreme dryness, as a result of destruction of the lacrimal and salivary glands, which can result in quite debilitating symptoms from dry eyes and dry mouth with can then result in both the difficulty swallowing and abnormality of taste. And, again, using PI3 kinase ELT inhibition to suppress inflammatory response here and hopefully ameliorate the condition further.
Okay. So as you can see, I mean, there are a number of opportunities beyond the oncology portfolio at Insight. We have obviously, the topical Roche program where we have Phase III studies starting this year for atopic dermatitis, potentially next year for Vitiligo, Both of them are very large indication in terms of number of patients. Vitiligo has the specificity of being a is with a very unique medical need, whereas there is no good approved product today. And obviously in atopic dermatitis, opportunity of a very favorable efficacy, safety profile due to the topical administration of ruxolitinib.
So they are exciting projects where we have short term value creation studies that would be initiated between today and beginning of 2019 or mid-twenty 19. On top of it, we have this proof of concept studies we are doing with our selective JAK1 inhibitor, which I think sorry, in HS that can be also very powerful. So we need to establish the efficacy, but we have good mechanistic reason to go there. And as you heard, through indication with PHHbeck and its Delta. So all of that is part of this effort we have made over the past years to look at diversification of our portfolio and how we can create new opportunities from mechanisms that have been already proven in the field of immunity and inflammation.
And we'll continue to do that with, with our pipeline as we go is that there is a team dedicated in functional medicine to take the projects coming from research and apply them across indication outside of the field of cancer. So just a reminder of what we discussed from the beginning of presentation today. The last two at the bottom are what we just discussed after the break about immuno oncology, the PD-one the opportunities for combination and the new portfolio in some way outside of the field of cancer. So before, we go to the final Q and A. I wanted to give you a picture of the next few weeks months in term of a news flow So atopic dermatitis, we just spoke about it.
We'll be presented at the medical conference in September. We have, obviously, the Columbia carcinoma and data can serve data with our FGF R inhibitor and potentially moving to the next steps in term of history. Roxolitinib fighting in acute GvHD steroid refractory in the U. S. Will be before the end of the year.
And we will have additional data with our PS3 K delta in combination with ruxolitinib, we showed you the 10 patient kind of efficacy data. We'll have a more complete set of data also in the first quarter. So fairly busy, next few weeks, reaching data and events and filing and submissions that obviously will put us in a good position for the next few years. A bit the picture we were trying to draw versus 3 hours. It's a portfolio with a base with Jakafi that is obviously very important.
Our leadership in MPN is something that we plan to expand, not just to keep as a Jakafi franchise, but to go beyond that, and over time to sustain and that's a very important part of our program. And then we have 5 new candidates that are coming with important data. Some of them are fairly de risked. We spoke about GVHD and the whole program with JAK, Some of them are more hypothetical at this point, but we are coming at the stage where we will have pivotal data over the next 24 months And that's what will help us accelerate the growth of insight over the next 3 to 4 years. So thank you for your attention, and we'll take your your question.
Now we have, we'll finish up the event with a Q and A period. Again, please wait for the microphone so those on the webcast can aid the discussion. Please give your name and your organization and please raise your hands if you wish if you have a question. So we'll start with Jay from Oppenheimer.
Thank you for taking the questions, Jay Olson. You mentioned earlier the commercial infrastructure required to commercialize your oncology pipeline, which you already have in place. I'm curious about your plans to commercialize your non oncology pipeline or Is that also a commercial infrastructure you plan to put in place or will you look for a commercial partner? Thank you.
So it's totally open at this point. So we obviously look, as I said, we are not targeting specific indications So some of this mechanism could lead us to fields where we would not want to be commercializing ourselves, but we don't want to eliminate that from the optionality is too early in the process. So we will tend to go. We have a clinical team preclinical biology. We have the entire team to prosecutes the development process.
So at this point, we will plan to go as far as we can by ourselves. It just happened that there are a number of this indication in dermatology, which is sort of interesting. It was not by design. I can absolutely tell you that. It was coming from where the drugs were leading us.
So that's sort of creating a sort of a new propagative question of saying is there a dermatology group that could be taking care of that? And that's absolutely possible and we are looking at that. Is it true for every part of the world or is it just true for some geographies? Is also another way we are looking at it? U.
S, Europe, Japan. I mean, so all of that is open. At this point, what we are doing is moving forward, as as we can with the atopic dermatitis phase 3. It will be followed by the Vitiligo phase 3 with a topical formulation and that is like real and concrete as we speak. And assuming the Vitiligo data as a final data is consistent with what we have seen, And then we have all of this proof of concept with other mechanism.
And as we see the result of that, I think it can lead to different commercial optionalities for us. But at this point, we don't reject the idea of doing it ourselves versus partnering it at some point.
Let's go to, I think the table 14.
Hi. Thanks for taking my questions. This is Binu on behalf of Reni Benjamin from Raymond James. Just a couple of questions for the atopic dermatitis. Phase 2 study, okay?
You sort of clarified, maybe provide some comments on why the active control was only those for like 4 weeks and if you dose them like those the drug for 8 weeks and what would be the results be as compared to, Rux? Thank you.
Yeah. It's it's the the question around why the triumph similar in control was only situation of time. And it's really around the ability to use that level of steroid on the face for any time longer. You can't. So that's the reason it was stopped at that time and then switched to vehicle.
In terms of the phase 3 designs, the question is do you even need an active control or can you go in mild to moderate against Placebo? That's going to be worked out. But it was important for us. The primary endpoint was against vehicle and you can see the numbers for yourself, but it was important for us to see how we compare to a steroid in that setting and then look at the tolerability as well because, steroids themselves aren't without side effects. That was the importance of doing that, but you can't do beyond 4 weeks on the face.
Thanks.
Can you turn the microphone on? Excuse me. Microphone.
Can you hear me?
Yes. You're on you go.
Oh, new one from David Merrill Lynch.
Just ask the question, please.
My question has to do with that given the pattern,
Jen, can you bring your microphone to? Let's try that. We got most of the way through the day.
Thank you.
Thanks. Jingha with PFA Merrill Lynch. Just a quick question on the fact that Ruxolitin does not have a lot of years of patent exclusivity left. So why not develop the 54707, in the dermatology indications instead of looking at ruxolitinib in the dermatology indications. Because you're still running the phase 2 trials, maybe still?
So it's a question about the exclusivity on ruxolitinib, it's still fairly long. Yes.
I thought it.
So we are speaking of 10 years. So
Right. But this is still phase 2, right, for the few It's
a question like why not
Go direct to
a sort of a topical form of another JAK inhibitor instead of doing it with a
With the Russell listening.
Jack Russell is in the words that has been done in formulation and in term of clinical has been done with Ruxoliti today. So that's what we are speaking about here. I think switching to another active ingredient at this point, which probably delays the entire program even further. Yes, I think the bigger Roxade team has a pattern to 2 1031.
Any other questions?
No, I'm just going to reinforce the fact that you have the cream formulation and the patents that are around that take you beyond just what the oral ruxolitinib is out to 2031?
Hi, Mark Fran from Cowen. When we think about the Vitiligo data in 6 months or so, what
do you
what else is used there off label and kind of what are the efficacy that are seen and therefore, like, what's the commercial hurdle to be a viable product?
Yes. So the, so patients do various things. 1 of the dominant therapies used in the U. S. Is phototherapy.
It's actually reimbursed by insurance. It often involves, sometimes setting up actually a tanning booth of so in a patient's home with UV radiation given their way costs around $6000 a year or north of that. And has some effect. But other than that, there's not much else to use as sort of a commercial comparison there. And that's why it became as we realized this as we spoke to patients, such an interesting need us to explore further?
We don't see a lot of use of systemic rugs in the off label setting for Vitiligo. I mean, that's something we don't observe
Okay. Michael from Guggenheim.
Hey, it's Michael Schmidt with Guggenheim. A question on the development strategy for the PD-one Heather. Why are you limiting, development to MSI high endometrial cancer as opposed to going in a broader MSI high patient population diagnostic or pain specific action or type?
Thanks, Michael. I think it's a good question. It's just about efficiency getting the monotherapy niche indications done. And then even more so that the fact that it was already in the study the dose escalation parts are very easy to just do the dose expansion and keep going. So it's around practicality.
Would we expect it to work beyond endometrial and MSI high in general? Yes, given what Pembro has already shown there. But it's chasing, as Erve said, monotherapy indications with speed in something that was already ongoing and expand and just keep going.
Can we have a question here on number 4? We need roller skates.
Is that the working mic or
Hi, Jeff. Thank you.
Jasper Deloig with, Argus Research. About the IMcb 5470 7. You talked a little bit about how it compares with ruxo and itacitinib. I'm curious if you guys will be sticking more with the dermatology side of things or, looking also into, other MPNs for that as well, and if it has sort of any, risks of cannibalization, with any of the other products.
So right now, 54,707 is sort of focused in areas outside of oncology. So we don't have any intention of developing it and NPNs. The other JAK1 itacitinib is the drug that is being positioned in combination with ruxolitinib and those studies are ongoing as we speak. So, no, I don't think there's any risk of sort of cannibalization or activity of taking, 54707 into oncology indications. I mean, I think the, I was just going to say that, you know, and I wouldn't think of it only as sort of dermal focus as a dermal focus as, as Urvi mentioned, there's sort of interesting collection of dermal opportunities we see over the near term.
Part of those are driven by, the fact we have a topical formulation of rux. So that's the kinds of indications you think about, with a selective JAK1 inhibitor like 707 as we understand its safety and efficacy profile in HS first, we'll look for other opportunities to explore it and that, that could be, or autoimmunity that are not focused on the skin. So we'll be opportunistic there and just follow the science and there'll be an effort that is led by research to understand a little bit more about what other opportunities could exist.
Jinko from Gabelli. I'm just wondering whether you could give us an update on your thoughts on your IO combination strategy, are you open to approved IO combined with Xerox40 Gator program or What's the plan there and what's the timeline?
Yes. So thanks for the question. Currently within the IO portfolio as a post proof of concept asset we have PD-one and that's the reason we focused on it and spoke about it today. In terms of pre proof of concept assets, we have 4 other large molecules. We have OX40 Gitter, TIM3, LAG3.
We have 2 other small molecules. The arginase inhibitor and axel for all of those earlier programs going looking at proof of concept in different areas and learning from if we're behind somewhere what competitors are doing and then leveraging that and going forward fast. Most of what I mentioned is combination work. That will need to be done. One of the ways we can do that as Reid was alluding to is to these platform paired biopsy studies, which would become very good at.
We can do the patients, we can do the biopsies, we can do the translational work and get to that endpoint that we showed you at AACR and then decide whether or not to go and then couple that if there's any efficacy data as well. But we'll be very efficient for those programs, particularly when we're behind. We'll be very focused on trying to get proof of concept or not. And maybe doing more randomized phase 2 work we needed, but for example, in a PD-one well defined refractory set in a single arm there may be okay as long as you see an efficacy pop. They're all early pre proof of concept work but we we now have a large amount of them.
We have the ability to do them, the people to do them and we can do this translational work really efficiently.
Okay. With that, I think we'll close. We're remarkably on time. Thank you all very much indeed for your attention and your questions today. And thank you also to the insight team for putting up in my customers.
And, with that, we will close the official portion of today and, we'll stick around for a few minutes afterwards if you have some additional