Good afternoon, and welcome to Incyte's 2018 Investor and Analyst event. Thank you all for joining us today. My name is Michael Booth, and I am Head of Investor Relations for Incyte. We have a full schedule over the next three hours, 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 Incyte's SEC filings, including in our Form 10-Q for the quarter ending March 31st, 2018. Today's presentation will feature four main speakers from the panel table. Hervé Hoppenot, our CEO, Steven Stein, our Chief Medical Officer, and Reid Huber, our Chief Scientific Officer, are familiar to many, if not all of you. They are joined today by Peter Langmuir from our clinical group.
There are also several other members of the Incyte leadership, clinical, and discovery teams in the room with us today, they will be available to answer questions if needed during the Q&A sessions. There are two Q&A sessions in the schedule, one after around 90 minutes and the other at the end. During the Q&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. We will allow for a follow-up if necessary. 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, please note that the slide deck being used today at today's event is available for download on the Incyte website.
If you are unable to download or find the file for any reason, please email ir@incyte.com we will send it to you. With that, I will start the formal program, we will begin with Hervé.
Yes. Thank you, Mike. Thank you, everybody, for being here today. We will spend the next three hours to discussing a number of subjects. I want to first introduce to you the agenda of the day. It is speaking about a number of parts of our pipeline and project that we have ongoing that have not been described in a lot of details over the past few years. First, we will speak about our MPN franchise. It is about Jakafi, obviously in the U.S., it is also about a number of projects that we have ongoing with the goal of expanding our leadership in the treatment of MPNs. You will see there for the first time some data of the PI3K-delta plus ruxolitinib combination. That is certainly something interesting. It is one of the piece of that portfolio.
We'll speak about GVHD, and there we'll show for the first time the data from our REACH1 pivotal study in acute steroid refractory GVHD with ruxolitinib. We'll speak about FGFR. That's a program that we have ongoing in two indications and where for the first time we'll be showing the data from our study in cholangiocarcinoma and the preliminary data on the ongoing study we have in bladder cancer. We'll be speaking about PI3K-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 PI3K-delta and PD-1.
We have a break, we'll go into the PD-1 program that is ongoing and the non-oncology franchise, which is something that we have not spoken about very much in the past and where today we'll be also showing for the first time data with topical ruxolitinib in atopic dermatitis. It should be a sort of a fairly dense program over the next three hours with a number of interesting data points that we can look at together. Before we do that, I wanted to go back a little bit to Incyte over the past five 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 $2 billion. We multiplied the top line by four in four years. At the same time, we have started the 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, ICLUSIG also in Europe, and now we are starting to see Olumiant. 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. At the same time, we have organized our company across three continents with not only the U.S. but also Europe and Japan. I think it's a picture that gives you sort of a good idea of the strategy we have been following over the past four years and the success we have had on many of these dimensions. Obviously, the subject of the day is our portfolio. That's the picture of the portfolio today, of the pipeline, if you want.
If you take it from left to right, you will see the three technologies we are using at the level of discovery. Small molecule, which is where obviously Incyte has a lot of own capabilities. Monoclonal antibodies, we have now also our own capabilities and where we have had partnership to get where we are today. The bispecific program we are doing with Merus, 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 three divisions, in fact. Steven Stein has three groups working for him. One of them is immuno-oncology, and we have spoken about that a lot in the past few months and years. The second one is led by Peter here, is on targeted therapies.
That's all the programs that we have in the field of cancer. Most of them are targeted. We'll speak about FGF, JAK, and there are a number of other program we have there. Then we have a third 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. 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. That's really what you can see here.
We have 11 projects at the pre-POC level, and obviously you can see the seven 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 about, also a word about resource, the way we are applying resources to each of the parts of this development program, from research to late development. 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. The other interesting thing, and it's just the same graph with coloring of the product that came from our internal discovery.
As you can see from the late-stage portfolio, six of the products were discovered at Incyte by Incyte researchers. Two of the products on the market today already are two products discovered by Incyte are already on the market today with ruxolitinib and baricitinib. Most of the pipeline coming through are products that are coming from our own internal research. I think it's important for two reason. 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. It's also very important in term of economics because obviously none of this product have royalties and milestones attached to them, which make them, as they become commercial, obviously, very much more profitable.
Just speaking of the revenue, 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 multiplied the sales by four over the past four years. This growth rate you are seeing here of 25% for Jakafi, 51% for Iclusig, 41% for Jakavi royalties, are growth rate from Q1 of this year compared to Q1 of last year. That the yearly growth rate in the last quarter. 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. Jakafi U.S. is 70%, it's a large majority of our revenue.
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 30%, but now Iclusig and Olumiant are starting to contribute to the growth and to the diversification of our top line. One of the thing we'll be speaking about today is the performance of Jakafi and the next few years coming ahead of us. You know the long-term guidance we have on Jakafi is $2.5 billion to $3 billion. 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.
Obviously the numbers are highly dependent on that, and they will be impacted by improved duration of the therapy in general, and the rate of penetration in polycythemia vera, where we know there is a fairly large potential. Concerning GVHD, and we'll be spending some time today speaking about it, there is always the question of duration of treatment in GVHD, which frankly there is an evolving knowledge about it as the clinical program 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 MPN.
Part of the presentation we will be listening to today are related to that subject of saying, before 2027 and beyond 2027, how do we extend our leadership in the field with novel targets beyond JAK inhibition? I think it's very important to realize the benefit of a JAK inhibitor in MPN. It has been 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, new mechanism will be required. Ruxolitinib-based combination, obviously, as Rux is established today as a standard of care in the field, and potentially any kind of novel formulation that could improve the benefit risk ratio of ruxolitinib. 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.
You can see at the bottom what we just discussed, which is the leadership in MPN. We will be speaking about five new product candidates that could be potentially contributing to our top line over the next few years. We did a graphic representation here, and don't try to measure the size of each of these field on the graph. In fact, what we did is look at the programs we are speaking about. We believe most of them are somewhere between $500 million and $2 billion in commercial potential over time. We will know more, and we'll be giving precise guidance as we are running the phase IIIs and being able to calibrate the different elements of the product. What we did here is take a $1 billion number for each of them.
That's the way the graph was built to illustrate the fact that as we will be launching each of these product over the next few year, 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. That's the sort of the picture of what we wanted to communicate today. There is an MPN base that we have, that we intend to extend over the next few years. There is a number of candidates, five of them that are coming also in the short term. Obviously, we have the optionality from our early-stage portfolio in addition to that. That's the timeline basically for what I'm speaking about.
That the six opportunities are described here. You can see the studies in gray on this graph. It's basically six different products, 15 potential indication. I'm not going to describe it in details because that's what we'll do over the next two and a half hours that are left now. Let's move to that first with the question about leadership in MPN and how we are going to extend it over the next few years.
Great. Thanks, Hervé. As Hervé just outlined, at Incyte in research and development, we have a very keen focus on maintaining our leadership position in MPNs, 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 in trying to drive benefit in a new and important areas in that patient population. I'll describe to you over the next few slides some of the work that we're doing there. The goals for these therapies are outlined on the top, I think it's safe to say that there's room to improve benefit.
If you just think about things like reducing the disease burden, whether it is 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 at Incyte back in 2005. That includes initiatives both in discovery and in development. Some of these things are in research, we won't be talking about them specifically. 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 are doing. I think they will be illustrative of the thinking there. We will also spend some time talking about the ruxolitinib combinations in patients who have an inadequate response to ruxolitinib at present. Hervé mentioned those.
Those are much nearer-term opportunities, I will describe to you some of the science behind those programs, Steven will describe to you some of the emerging data in one of them. 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, rightfully so. It is mutated in the majority of those patients. What we do not often talk about, and it is illustrated on the left-hand of this slide, is that these patients actually harbor a number of other mutations. Very frequently, in fact, the majority of patients have mutations in epigenetic proteins or those that alter the packaging of DNA. These are not just by standard mutations. In fact, they are seen in acute myeloid leukemia as an example, and those are very important to the initiation and the progression of myeloid malignancies.
We have every reason to believe that they are very important in MPNs. On the right side of the slide highlights the basic thinking with the Syros collaboration. By studying those mutations, either individually or collectively with activated JAK2 signaling, we can understand better how this chromatin is rearranged and repackaged in a malignant fashion in MPNs and identify druggable targets. The Syros platform is a quite a robust platform for the identification, the characterization, and even the validation of these types of programs. 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 ruxolitinib combinations that are a little bit near term.
I will remind you of the very simplified view that we had of this pathway circa 2005 to 2007 that led us to ruxolitinib. Mutations in JAK2, in the receptor, thrombopoietin receptor, or in calreticulin drive JAK2 activation, which constitutively leads to STAT activation and the MPN phenotype. There is a lot of truth to this that led us to a very important therapeutic in ruxolitinib, obviously making an important difference for patients today. 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. We are interested in targeting either the upstream PI3K-delta kinase or the downstream PIM kinase in concert with ruxolitinib to more effectively block this dysregulated signaling network.
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, and may also be an important driver of their hematologic components of disease. Could we, with a JAK1 selective inhibitor, drive much more complete inhibition of those cytokines in the face of a tolerated level of JAK2 inhibition provided through ruxolitinib? I'll walk you through some of the data to underpin these three combination trials. First, with the PIM kinase inhibitor, this is work that's been conducted with Moffitt 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 PIM kinase pathway and ruxolitinib in patient CD34 progenitor cells. These are the actual malignant cells.
The cells in this case came from a post-ET myelofibrosis patient who was V617F positive. 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. It really underpins the notion that combined blockade of this pathway could have a differential effect than monotherapy JAK inhibition. On this slide is a reminder of some data some of you may know was recently published by John Mascarenhas in 2017. It comes from a trial that we did of itacitinib in myelofibrosis patients. This is a JAK1 selective inhibitor in MF. What you can see on the left is a substantial improvement in the total symptom score, the symptomatic burden in patients.
The bars going down below the X-axis reflect improvement. That is what we anticipated going into the trial, and in fact, 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. You can also see a similar effect, especially at the 100 and 200 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. 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 PI3Kδ , this was a little bit of a detective exercise over the last five years or so. It's been known in the upper left that stromal cells, these are the bone marrow cells that support the malignancy, actually attenuate the effects of ruxolitinib. The question was, why is that? In this study, using a pan inhibitor of that PI3K/AKT pathway I mentioned at the outset prevents that.
That tells us that signaling cascade may be particularly important in the malignant cells as they grow in the marrow niche. That translated in vivo, these are preclinical studies, using blockade of the PI3K/AKT pathway with two 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? Do we have to inhibit all of them, or is there one that's operative? These results in the bottom, in 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, which activates the JAK-STAT and PI3K pathway.
As you titrate in increasing concentrations of a delta selective inhibitor, you can completely abrogate the signaling 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.
Reid just outlined for you the preclinical work that then enables us to undergo the clinical study. This is our PI3Kδ inhibitor, 50465 Plus ruxolitinib in a myelofibrosis setting. These are patients with a suboptimal response to monotherapy Rux at study entry. I just want to spend an extra second on the definition we used here, because 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 six months or greater, and on a stable dose for at least eight weeks or greater. The Rux doses before coming on study range from five milligrams BID up to 25 milligrams BID, and the induction dose for the PI3Kδ 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 what Reid pointed out preclinically. What's enticing in the early data set, although it's 10 patients at the moment, in terms of the two efficacy endpoints that we know to be relevant in this field, spleen reduction and then symptom improvement, you can see for those 10 patients, almost across the board, a degree of spleen reduction when you've added the PI3Kδ inhibitor to Rux in patients who've already had an inadequate or suboptimal response to Rux. There's spleen length reduction upward of 60-plus % in some of these patients.
In terms of symptom improvement, using the standard validated scale, the Myeloproliferative Neoplasm Symptom Assessment Form, again, there's patients who've had 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. The entirety of the clinical program feeds off Reid's preclinical work that he outlined for you. The study at the top I just spoke about should have data in the second half of this year, and then the ongoing work below with Rux plus our PIM inhibitor in an open label phase I/II, the number is 53914, in patients with advanced myelofibrosis.
The addition of the JAK inhibitor, itacitinib, 39110, is in patients who have an inadequate response to Rux or cannot tolerate it and are then switched to itacitinib. This data will deliver in 2019.
That was the first chapter about MPN, expanding our franchise in MPN. As you can see, we have a number of preclinical programs with Syros, with Vanderbilt and Moffitt, and internally in research. We didn't speak very much about that today, but this is something that over a longer period of time can give us opportunities to bring completely new mechanisms, not only different from JAK, but also different from delta PIM. There's a JAK1 here that we are discussing. In the shorter term, second half of this year and beginning of next year, we're starting the clinical data with Rux plus PIM, Rux plus JAK1 itacitinib. In the second half of this year, the PI3K and delta, you saw some of the preliminary first 10 patients.
I think all of that is giving us a number of opportunities to expand in the short term and improve outcome for patients with MPNs. 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 inhibitions that you can find with ruxolitinib. The next chapter will be Peter will take the lead to speak about GVHD and the comprehensive program we have in that field with ruxolitinib and itacitinib.
Great. Thank you. 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. We know that stem cell transplants can be a potentially curative therapy for leukemias and other hematologic malignancies. Essentially, it's a two-pronged approach. The first prong is very high doses of chemotherapy, with or without radiation therapy, to eradicate the disease, reduce the patient's immunity, and essentially wipe out their bone marrow. Following that, allogeneic stem cell infusion, stem cells from another person with a similar genetic profile are infused, and those donor stem cells then reconstitute the bone marrow and the host immune system. The second prong of the treatment of leukemia is that those donor T-cells target the recipient tumor cells and prevent relapse.
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. This is one of the leading causes of morbidity and mortality for patients after allogeneic stem cell transplant. This slide summarizes the incidence of graft versus host disease. Across U.S., Europe, and Japan, there are about 23,000 patients who undergo allogeneic stem cell transplant. About half of those will develop acute GVHD. The incidence of acute GVHD is about 11,500. You see the incidence here of chronic GVHD in the steroid-naïve setting is about 9,200. About one-third of those patients develop chronic GVHD with no prior GVHD, but about two-thirds of them will have previously had acute GVHD. Steroids are the mainstay of therapy for GVHD.
The downside of steroids, though, first of all, is they only work in about half of patients. 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. This can lead to significant long-term complications from chronic steroid use. You see here a substantial proportion of patients develop steroid refractory disease, and there's a huge unmet need in this patient 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. Today, it's actually classified more on the basis of clinical and histologic features. Acute GVHD involves really three organ systems: the skin, the gastrointestinal tract, and the liver.
The disease is primarily mediated by mature donor T cells. Chronic 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 sclerodermitis-like finding on the skin. Their oral mucosa become very dry. They can get sclerosis in their GI tract. They can have liver disease. They can have lung disease. They can have contractures of their muscles and ligaments. 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 one-year survival depending on the grade of GVHD. About one-third of the patients will have Grade 2 GVHD, and that has a 75% one-year survival.
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 REACH1 study in GVHD, is that while we expect about two-thirds of the patients to have Grade 2 GVHD, in fact, in our study, it was a much higher-risk patient population with about two-thirds of the patients having Grade 3 or 4 GVHD. Very similarly 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. Clearly a high unmet need and a need for treatments that can be given over the long term.
If we think about the molecular pathophysiology of GVHD, that's sort of outlined on this slide. Again, we'll break it down by acute and chronic GVHD. Peter nicely walked through the conditioning phase and the transplant phase, 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.
You also have B cells producing autoantibodies and macrophages that are important in facilitating, for example, the fibrotic features of the disease. Importantly, JAK signaling also underpins many of the cytokine-driven events that can lead to the T cell, B cell, and macrophage activation in chronic GVHD. This underpins really the excitement I think we and also the field have in terms of JAK inhibition of the disease. Let me walk you through some of the data that then supports some of the cartoon diagrams here. I'll start with just activity at the top in a contrived system, an in vitro system, where we take one patient's T cells, and we combine them with another patient's antigen-presenting cells. That leads to a significant increase in proliferation, as shown in the gray bars by the height of the y-axis.
You can see that the addition of a JAK inhibitor, in this case, ruxolitinib, dose-dependently decreases that proliferation. If we take ruxolitinib and we dose it to an animal that's been given a major mismatched transplant, taking the marrow of one strain and introducing it into 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, and the liver. You can see that ruxolitinib treatment in every case significantly attenuates the ability of these cells to migrate into those organs. Molecularly then, we have two 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 the key organ systems.
If we take that major mismatched model 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 account several aspects of the disease, as well as the animal's whole body health. You can see that in red, itacitinib at two different doses. Whether the compound is dosed prophylactically, so that's before the transplant, or dosed therapeutically, starting at day 14 after the transplant and 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, which are control animals that never got GVHD to begin with, just the syngeneic transplant. This tells us that JAK inhibition can be highly efficacious in a very aggressive form of acute GVHD.
Molecularly, the events that occur 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. That also occurs, importantly, in the infiltrating T cells. You can see the decrease at 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 JAK inhibition. For any GVHD therapy, two things are very important to know. Whether or not there's any effect on donor cell engraftment, that's very important to not have.
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. 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. 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. In sum, there's a very strong immunologic and preclinical rationale for JAK inhibition in 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.
Let me go back to some of the incidence figures Peter was talking about and point out some nuances. Firstly, graft-versus-host disease, as Peter showed you, is a major cause of both morbidity and mortality in transplant patients. With upwards of 50%-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. 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. 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 9,200 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, where I'm going to be presenting some of our results today from REACH1, second-line plus, new incidence in acute in those three areas is 5,700 cases a year. In the chronic setting, that's steroid refractory, about 4,500 cases a year. Our program in its entirety is as comprehensive as we could make it, and we're looking at all the settings. 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.
On your left in the prophylactic setting, we have a GRAVITAS study 119, which is looking at itacitinib in the prophylactic setting to try and prevent graft-versus-host disease coming about in the first place and looking at hematologic recovery at day 28 at the primary endpoint. Secondary endpoint would be the incidence of graft-versus-host disease itself, as well as relapse, survival, time to engraftment, and safety. 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 two, prophylactically, who will get more severe disease versus others.
If you look at the rest of the GRAVITAS program on top, in both an acute and chronic setting, the first important one there is the phase III 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 that'll be GRAVITAS 309 in 266 patients, looking at response rate at month six in that population. The REACH program is below in the steroid refractory setting and encompasses three separate studies: REACH1, REACH2, and REACH3. REACH1 is a single-arm phase II study, a pivotal study with a primary endpoint of overall response rate at day 28, secondary endpoints that include duration of response and numerous non-relapse mortality endpoints.
I'll be showing you that data in a moment. The REACH2 study in the same setting is a randomized study against best available therapy in 308 patients. Its primary purpose is run in conjunction with Novartis, is to be used for approval of Rux ex U.S. in a randomized setting against best available therapy. 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. Let's talk about REACH1, the first prospectively designed pivotal trial of a JAK inhibitor in steroid refractory acute graft versus host disease. It's for patients 12 years and above. They've had their first allogeneic transplant. They have Grade 2 through 4 steroid refractory acute disease.
They've already demonstrated evidence of myeloid engraftment by having an adequate neutrophil count and was in 71 patients. The first 72 hours of therapy was with Rux five milligrams twice daily. If that was tolerated and there were no cytopenias, the dose was increased to 10 milligrams twice daily with steroids and if needed, a calcineurin inhibitor as well. The primary endpoint in these studies is a day 28 response rate, because that is felt to be the most predictive of long-term outcome in the acute setting, particularly long-term survival. 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 Zeiser et al paper, which was done by investigator when they look at response at any time point. On to the actual data. The best overall response rate in this study, so response at any time point, is 73.2%, 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 this data is reported by others. The primary endpoint was the day 28 overall response rate, very strictly defined with a 2-day window, so either they had to have a response between day 26 and 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. You can see on the Kaplan-Meier 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. At month 6, nearly 70%, 67% to be exact. We haven't reached the median yet for duration of response. This, I'll remind you, was a study conducted under breakthrough designation and met the primary endpoint. Hence our intent 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 three main signals in terms of grade 3/4 treatment emergent adverse events, anemia, thrombocytopenia, and neutropenia. 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. It's under a breakthrough designation. The U.S.-only incidence for allogeneic transplants, pulling that out from the overall data sets I gave you earlier, is about 7,500 allogeneic transplants a year. Acute GVHD estimated incidence in the U.S., about 1,700 patients that are steroid refractory. In the chronic setting, another 1,500 who are steroid refractory. REACH2 and REACH3 are ongoing.
REACH2 is in the acute setting, 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. Turning to itacitinib, our wholly-owned JAK1 inhibitor. This is a proof of concept study that was presented at ASH in 2016, looking at two doses of itacitinib, 200 milligrams and 300 milligrams, in conjunction with corticosteroids. Patients that had also a prior allogeneic transplant had grade 2 through grade 4 GVHD and could either be steroid naive, first-line, or steroid refractory, second-line. The data on your right 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%. In the steroid refractory, it was 64.7%.
This gave us a very strong proof of concept in steroid naive acute GVHD and enabled the GRAVITAS-301 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 sparing patients from increased cytopenias in a setting where they're likely to be sicker. 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 one prior allogeneic transplant. MAGIC criteria for GVHD from 2 to 4. They were stratified for standard versus high risk. It's 436 patients. Primary endpoint at day 28 response rate.
If you look at the three settings again, U.S., Western Europe, and Japan, allogeneic transplants, 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. If successful, this would be a global regulatory submission, would follow from this data set.
Okay, that's the sort of the complex picture of GVHD. We have ruxolitinib 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 numbers. We try to give numbers that have been vetted by many people to crossing different sources. We estimate it could be slightly below 2,000 patients with that steroid refractory, very specific population in the U.S. with drugs. Then itacitinib, GRAVITAS, phase III ongoing, result in 2019, and where we have the rights worldwide.
That would be a launch that we would be doing in U.S., Europe, and Japan. Where I think it is a very different size of the population. We spoke about 11,500 here. 50% 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. A lot of the potential will depend on the duration of treatment for itacitinib in the first-line setting. 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 ruxolitinib 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&A. I think it's sort of giving us a perspective for the timing. From the commercial standpoint now, launching itacitinib in GVHD around the world is, in fact, something that we feel very prepared for based on the teams that we have today. In 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 CML.
Again, the sort of the deployment we have of our account sales force is very much in the same BMT centers that will be a target for itacitinib. Obviously, for Japan, it will be the first commercial launch for us. 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 reasonable based on the size of the opportunity. I see itacitinib, when you think of it, 2019 and 2020, it could be the first global product that will be launched by Incyte, maybe with FGFR. We'll look at the data next. That's probably the two of them could come somewhere in the same timeline.
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 profile that needs to be confirmed in the phase III, but also an understanding of what this market looks like that makes it very, very feasible for us. We will stop on GVHD now. If you have question, we'll have a break for question after the next two presentation, the next one is about FGFR.
We'll turn now to our FGFR one, two, three selective inhibitor called INCB54828. I'll walk you through its pre-clinical profile and why we're excited about the emerging profile of this drug. Steven and Peter will share some of the emerging data in the targeted histologies that we're focused on those patients with FGFR mutations. The FGFR or fibroblast growth factor receptor is a family actually of four receptors. They're called one, two, three, and four. This compound we're talking about is a selective inhibitor of one, two, and three. 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.
As you might expect, as a receptor tyrosine kinase, sort of like the EGFR receptors, they activate a number of downstream signaling pathways. That's illustrated in the cartoon on the right. Most importantly, as it relates to cancer, tumor cells at times can coopt these pathways to drive their uncontrolled growth and proliferation. This is called oncogenesis. It's a process that is exactly similar to EGFR-driven lung cancer or ALK-driven lung cancer or BRAF-driven melanoma. The FGFRs 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 FGFRs 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. 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. 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 capmatinib in a program with Novartis, that's driven entirely by amplification. Here, the translocations and the mutations are what are important to track in order to predict sensitivity.
If 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. 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. If we begin at the top, you have FGFR1 translocated 8p11 MPN. This is a myeloproliferative neoplasm in the same general family as myelofibrosis. It's a very rare disease, but its definition as 8p11 is entirely defined by the activating FGFR event. That's how these patients are defined. You can see the prevalence is 100% because that is the sine qua non of diagnosis.
FGFR2 can be translocated in intrahepatic cholangiocarcinoma. This is bile duct cancer, and you can see that 13%-20% of patients can have the translocation, which would predict sensitivity to FGFR inhibition. Finally, bladder cancer is frequently driven by FGFR3, and that can be a translocation event, which occurs somewhat infrequently, around 5%-6%, or more commonly, mutations in FGFR3 that drive oncogenesis in bladder cancer. Here you have 10%-15% of patients harbor those mutations. Again, these four areas are where the key clinical program and our efforts are focused around INCB54828. Important thing to mention is that it's a competitive field. There are a number of FGFR inhibitors that are out there. What we've tried to do on this table is give you a little bit of a head-to-head comparison of the key attributes of their profile.
At the top of this table are the activities, the enzymatic activity, the potency of the various compounds against the key 3 receptors, 1, 2, and 3. 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 the FGFR1 potency to FGFR4 potency. VEGFR2 is another important cross-reacting kinase because of its similarities to FGFR 1, 2, and 3.
There, the key side effect is hypertension, and you can see about a two or two and a half fold improved potency or selectivity for 828 against those two kinases. From a potency and selectivity standpoint, 828 has, we think, the attributes for a 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 pre-clinical 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.
You can see in every case, if you compare the colored lines against the gray or the black lines, that 54828 yields demonstrable anti-tumor activity and in many cases, regressions in the right tumor models. These data really supported the advancement of 54828 into the clinic as a targeted therapy for patients that harbor FGFR-activating events.
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. Cholangiocarcinoma is a cancer involving the epithelial cells that line the bile ducts that route bile from the liver to the intestines. There are two main locations where cholangiocarcinoma can occur. It can occur in the extrahepatic bile ducts outside the liver, or it can occur intrahepatically. What we're particularly interested in is the intrahepatic cholangiocarcinoma, because up to 20% of these patients will have fusions involving the FGFR2 gene, which we think are key drivers of the tumor and therefore a perfect target for an FGFR inhibitor. The incidence of FGFR2 fusion cholangiocarcinoma is about 2,500-3,000 patients across the U.S., Europe, and Japan. It looks like the incidence is increasing of these tumors.
The diagnosis of cholangiocarcinoma can be very difficult. Because of the bile duct's location deep in the abdomen, symptoms can often be very nonspecific at initial presentation. The extrahepatic form tends to be diagnosed somewhat earlier because it causes obstruction of the common bile duct, patients can get fairly acute symptoms related to that obstruction. The intrahepatic form tends to be much more difficult to diagnose. You see a lot of the symptoms on this slide are very nonspecific, 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. Unfortunately, the treatments that we have for these patients are not very good. The frontline standard of care is chemotherapy, generally with gemcitabine and cisplatin.
You see that the average outcome for those patients with response rates of about 26%, progression-free survival of eight months, and overall survival about a year. You see on the right-hand graph there, you see how poorly the patients with stage 3 and stage 4 disease, how poorly their outcome is. Unfortunately, most of the patients are diagnosed with this advanced stage. Unfortunately, after first-line chemotherapy, there are really no effective options for these patients. 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 three months. Again, clearly here, there's a very high unmet need and the opportunity to study a targeted therapeutic approach for some of these patients.
Turning to the clinical program, which goes under the acronym FIGHT, this is the FIGHT-202 study using a 54828 FGFR inhibitor in patients with intrahepatic cholangiocarcinoma. The target enrollment for this study is 140 patients, and there are three cohorts within the study. The important one is the FGFR2 translocation that's just been pointed out to you. That's cohort A, and the target enrollment there is 100 patients. I'm going to show you some early data from that cohort. There are two internal controls within the study. Cohort B consists of patients with other FGF or FGFR alterations, and they enroll 20 patients. Cohort C is patients without an FGF or FGFR alteration, and they'd also enroll 20 patients. The dosing schema for this study and schedule is 54828, 13.5 milligrams daily, two weeks on and one week off.
The primary endpoint is an overall response rate in patients with the FGFR2 translocation, the cohort A population. We did this by an independent reviewer. Again, when you compare data sets from some of the competitors that we showed you up front, just look at whether they report an investigator or independently reviewed data sets. The secondary endpoints were response rate in the patients with 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 U.S. from this study alone, and has the potential to be the first 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 B and C, 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. 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 the complete response, partial response, and stable disease rate. You can see on the waterfall plot that the vast majority of the patients are having some degree of tumor reduction. 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 RECIST criteria, the gray line, 24%. At this early juncture includes unconfirmed responses. Eight of them are confirmed, three are unconfirmed but are all ongoing awaiting confirmation. The median progression-free survival at this juncture is 6.8 months. Compared to what Peter was telling you about second-line chemotherapy with an overall response rate of 10% and a progression-free survival in the three-month territory, you can see why we are excited about this compound in this 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 1.4 and 1.5 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, 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. The ones at the top are ongoing now in excess of eight, nine, 10 months. That's how we're getting a PFS at this point in the north of the six-month territory. We are preparing what should ultimately serve hopefully as a confirmatory study in the phase III 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, turning from the cholangiocarcinoma data I showed you to metastatic bladder cancer, again, under the FIGHT acronym. This is FIGHT-201. The original phase II 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, the second cohort is without that, again, serves as an internal control with 40 patients. The same dosing scheme as outlined there for you, 13.5 daily, with a two week on, one week off schedule. The primary endpoint is an overall response rate in patients with FGFR3 mutations, the secondary endpoints are outlined there for you. This is a more common patient population in total. If 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%-20% of these are expected to harbor FGFR3 mutations or translocations. The safety from this study at this point in time with that intermittent dose schedule 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 A 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, to be evaluable in this, you had to have an FGFR3 mutational fusion, plus receive at least one dose of the drug. 28% response rate at this point in time, including unconfirmed responses.
The seven confirmed partial responses are all ongoing, the six unconfirmed at this juncture just haven't had their second scans yet and are all ongoing. You can see in the waterfall plot for you there. If you add them up, there were five who were not evaluable, because some of them did not have baseline measurable disease, a couple of them didn't have any scan data available at this juncture. We are going to adjust the study based on what's happening in the competitive space. If you look at the J&J compound, they now have a breakthrough designation, they made a switch in their program from intermittent dosing to continuous dosing. They use an investigator-reported endpoint, from their increase towards continuous dosing, they went from a 25% response rate to the mid-30s and now reporting a 40% response rate with continuous dosing.
You can see our modification below for Cohort C will be again patients with FGFR3 mutations or fusions, we'll treat another 100 patients with a 13.5 milligram dose continuously. This data is expected in 2019. This may additionally, given the data I've just shown you, support a regulatory submission in the U.S. Our ultimate intention is to develop 54828 as a first-line treatment for patients with FGFR3 mutated bladder cancer. The field's a little bit further complicated by what's happening with the PD-1 and PD-L1s. For those of you who've seen the labels were actually issued this morning by the FDA and the European agencies on how to dose these agents in metastatic bladder cancer, given the complexities around being either eligible for cisplatin chemotherapy or not, 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 a very small amount of these patients. They're mostly PD-L1 low. Obviously now, given how this field is developing, we'll be developing potentially a multi-arm study in this setting to account for whether or not you're chemotherapy eligible and whether or not you're a PD-L1 expressor.
Again, that's a product discovered at Incyte where we have the rights globally, where the programs that we are doing is prosecuted in the U.S., Europe, and in Japan. It could have its first result in cholangiocarcinoma in 2019, and a filing, assuming the data is justifying it, also in 2019. When you think about FGF, to look at it in two buckets. Cholangiocarcinoma and bladder cancer. 8p11, the first indication will probably go through, but the number of patients is so small that in fact in some way it does not impact the overall picture. First cholangiocarcinoma, we spoke about around 3,000 patients between U.S., Europe, and Japan. 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 treatments that you have available for these patients. What's important for the data we just saw 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 targeted therapy for a specific mutation that has been identified. That's 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 very large majority of patients benefiting from the treatment.
In terms of the duration, we spoke about the early data showing a median of around seven months, 6.8 months in terms 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 cholangiocarcinoma is such a short effect that I think it's a very good news for this project to see this kind of number. I must say also from the commercial standpoint, when you introduce a new product in each of these three countries or continents like Europe, Japan, and the U.S., having a small narrow indication at the beginning of the life of the product is an excellent thing in terms 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. That's part of the program that we have here. 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 Steven was describing, it's a very quickly evolving field where this morning, in fact, some new labeling was published about the use of PD-1 in this setting.
The design of the first-line study is really for us, and the discussion with FDA is really for us, the next step for this program in bladder cancer, with an optionality of an earlier approval based on the phase II that you have seen with 100 patients with intermittent, 100 patients with continuous administration. Again, second sort of slice of potential business for the next few years, starting in 2019 and 2020 with FGFR. Now we'll close that chapter and go to our PI3Kδ . You heard already the word PI3Kδ 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 try to describe all the components of the program with PI3Kδ .
It's a class of products that has been, frankly, damaged over the past few 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 has multiple indications across all kinds of different types of disease, I'll speak about that. We believe specifically in B-cell malignancies that it has already proven its efficacy with fairly substantial response rate across a number of type of B-cell malignancies. The issue that we have been facing was related to safety, and there were two components to the safety issue with PI3Kδ . It's liver toxicity and it's cumulative toxicity, colitis-like cumulative toxicity, immune over time.
What you will see from our program is that we have taken the time over the past 18 months to try to manage this cumulative toxicity with a new schedule of administration. We started to sort of decide 18 months ago, or almost two years ago, to go back to reestablishing a new benefit risk ratio for PI3Kδ for the one we have, where we don't have the liver signal and where we believe now we can manage in a very different way the cumulative toxicity. You heard about the first dimension, the gray on the left, which is PI3Kδ as 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. That's a program that we have ongoing.
What we will be speaking about right now is a B-cell malignancy program with three types of lymphoma where we have studies ongoing. Later we will have a short discussion on another dimension of PI3Kδ , which is a type of studies we did with paired biopsy, looking at the impact of PI3Kδ on the microenvironment of the tumor and how it can be combined, in fact, in that case, with a PD-1, with potential promise on that front. Later at the end of the non-oncology or inflammation autoimmunity presentation, we will speak of the use of PI3Kδ in benign indication, non-cancer indication, where in fact there is also a lot of potential. It's a complex product. It's a complex series of products, in fact, with very independently moving parts.
I just wanted to start the presentation showing this graph so that when we speak about PI3Kδ , it's not just the B-cell malignancy dimension, but in fact it has a lot of potential across numerous other indications. On this, Peter will start the presentation on the project.
I'll summarize to sort of finish off this section, summarize our plans for our PI3Kδ inhibitor in non-Hodgkin's lymphoma. These non-Hodgkin's lymphoma represent the vast majority of all lymphomas, can be divided broadly into T-cell malignancies and B-cell malignancies. 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. Very broadly, they can be divided into those that are more indolent and those that are more aggressive. The indolent lymphomas are generally not curable. At early stages, they can be fairly slow-growing and relatively benign. As they become more advanced, they can become very problematic, and there's really an unmet need for effective treatment in these patients. In the aggressive lymphoma setting, there are some treatments available with the potential for cure.
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 three main subtypes of non-Hodgkin's lymphoma for our monotherapy development program. The first of these is follicular lymphoma, probably one of the most common types of lymphoma with an incidence of about 12,000 patients per year. Again, as I said, the early stages of this disease are relatively indolent, 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. 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 5,000 per year, and can involve multiple different sites within the body.
In terms of aggressive lymphoma, we're focused on mantle cell lymphoma, an incidence of about 4,500 per year. Relatively uncommon, but tends to be a very aggressive form of lymphoma. About three-quarters of these patients will already have diffuse lymphadenopathy at the time that they're diagnosed. In our initial phase I study with our delta inhibitor, we are very encouraged to see very rapid, deep, and durable responses in these three subtypes of non-Hodgkin's lymphoma. Again, this is looking at the delta inhibitor as monotherapy. As Hervé 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 six to nine months, many of these patients would develop immune-like adverse events, particularly diarrhea and colitis.
We took the time to explore different dosing regimens 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, then after two months, we go to a less dose-intense dosing regimen to try and maintain that response and avoid the toxicity. 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. As we move into phase II 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.
We're expecting data from this initial monotherapy trial program next year. Again, the three settings we're looking at, first is follicular lymphoma, where we have a phase II 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 a primary endpoint. Here we're looking at two cohorts of patients, one in patients who've 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 one. In the patients who have received them, their prognosis, once they progress on those agents tends to be really terrible.
If we are able to show benefit in patients who have received those, that would be a major advance. Data will be available next year. 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 are looking at objective response rate. Each of these trials is designed to support a registration in the U.S. if they are successful. Now, having said that, our focus initially is on monotherapy based on the encouraging phase II data that we saw from the phase I study. We know that the paradigm for lymphoma treatment is combinations with other chemotherapy or immune therapies. We currently have studies ongoing looking at combinations of our delta inhibitor with standards of care like rituximab, bendamustine plus rituximab, bendamustine plus obinutuzumab, and ibrutinib.
These studies are designed hopefully to show the safety of the delta inhibitor with these combinations, and support future randomized phase III studies. We should have data available from these combination studies later this year or early next year. That basically summarizes the program we have for lymphomas.
Okay. Again, as a conclusion, three different types of lymphoma, data in 2019, potentially filing NDAs if the data is sufficient for that in 2020. Again, we are in a field of relatively, not rare disease, but relatively limited patient population where the commercial aspect of launching this product ourself as Incyte is totally feasible both in the U.S., Europe, and also in Japan. That is something that we are looking forward to and that we will be triggering as we get the result from the study on that quadrant of the PI3K delta program. We will be having a Q&A coming in the next few minutes. Just a reminder, take away from what we discussed, which is the MPN leadership and how this franchise can be renewed and expanded over the next few years with multiple different initiatives. The GVHD, Rux, and itacitinib.
Itacitinib worldwide, FGFR in cholangiocarcinoma, and PI3K delta. In that case, the presentation on top of the MPN we discussed in the first category on the B-cell lymphomas where we have ongoing studies. I think we will stop on this and-
Yeah, now we have.
Open up for questions.
Yeah, 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 and they'll 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 we'll do that. Let's take a question. Brian on table 12, or table 13.
Thanks. Brian Abrahams, 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 three and six 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? Thanks.
Brian, it's Steven. Thanks for question. Just a few things up front. Obviously, I can't speak for the FDA itself. The program is under breakthrough designation.
The program was designed with the FDA, with a person internally there who has a huge interest in the disease itself. The endpoints agreed, the studies agreed, it's as robust as it can be. day 28 response is felt to be a really good surrogate for long-term benefit, particularly survival. In terms of the endpoint, it was felt that anything north of 50% would be a really good surrogate for clinical benefit. Coupled with, as you said, durability of response. In terms of the data I've shown you, the event-free endpoints at three and six months currently are really healthy. At three months, 80% haven't had an issue, and at six months, 70%. We haven't reached the median yet.
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. As confident as we can be in terms of putting in a supplemental NDA here. 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 had it later. That's also pretty predictive for long-term benefit. It's just not as well agreed to as a day 28 number, and that's why that's the primary endpoint. Very high probability of success from where we sit, and ultimately, it'll be up to the Food and Drug Administration.
I'll remind you also, ibrutinib in chronic was approved very quickly, it's not a dissimilar setting when you have a marketed compound that's used in thousands of patients elsewhere, the safety is well established. That's our hope here as well.
Okay. Regarding the duration of treatment we are anticipating, I just spoke about it briefly. We have, obviously, the study you have seen, the median is not reached. You can see 70% of patients continued treatment, which is frankly, a little more than what I was anticipating when we were sort of calibrating, if you want, the size of this opportunity in term of ruxolitinib. I think that's better maybe than what we were expecting there. We have also a few other data point because there is an open
Yeah. What Hervé is alluding to is there's a large amount of requests for Rux in the U.S. in graft-versus-host disease, either through expanded access or compassionate use. Although not a controlled study, we have some sense of duration of use there. While going into that, at least in the acute setting, we thought, probably around six months to a year would be what people would use it for. It turns out, maybe not unexpected now, but at the time it was, that people are tending to use it for a lot longer. What's happened in the real world, and Peter can speak to this better than me, is that the main aim is to get them off steroids, in terms of toxicity. Once they're off that, then people think about whether or not maintaining JAK inhibition.
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 eight. That's Cory, I think. We'd stay, Marc, you can come next.
Thanks. Cory Kasimov, JPMorgan. I am curious for the Jakafi combination work that you described at the beginning in MPNs. Is there potential to create maybe fixed-dose combinations of 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 is clearly something that, as you have seen, some of these products are twice a day, some are once a day, so that would require some work at least in terms of formulation to get there. There is a perspective of adding to the JAK inhibition with a new mechanism, doing a fixed-dose combination, and being able to have clear superiority in terms of patients' benefit and outcome with that new combination. That is part of the thinking. We are at the stage where we are still establishing the proof of concept. You can see that the population where everybody would assume is a population where Jakafi is not used after Jakafi kind of setting. There we believe very strongly that JAK2 inhibition is really not the solution for that setting.
It is a solution of other mechanism to literally change the course of the disease at that stage after treatment with Jakafi. You have a group of patients with suboptimal response to Jakafi, then you have the first-line setting, that is the natural flow of how these programs will move over time from the sort of the refractory post Jakafi to earlier stage, potentially with fixed-dose combination if we are able to do that. Depending on the mechanism, you can see the schedules are not exactly always ideal, but it should be feasible.
Marc Frahm from Cowen. When we think about this, either post or on top of ruxolitinib setting in MF, do you think there is approval possibilities with just symptomatic scores, or do you also need the spleen reductions that we are seeing with Jakafi in their phase III?
I think those are discussions that I think we need to have with FDA. I think based on our previous discussions that probably having some degree of spleen reduction will be necessary. In that sort of suboptimal setting or in a second-line setting, would we need the same degree of spleen from a frontline setting? Probably not, but those are discussions we need to have with FDA at the time.
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 Hervé and team. Regarding those phase II readouts in MPNs or in MF, when you think about the strategy there, is that something you could take multiple combinations into phase III, or you're going to 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. You have seen we have mechanistic reasons to be motivated to do the studies we are doing, and they are single-arm studies, fairly small, both with itacitinib. JAK1/JAK2, it's a sort of an interest. It's provocative in some way, but it's sort of interesting. You have the PIM and Delta that are already ongoing. Frankly, if we get more than one success, that would be a sort of a good problem to have. I don't know. I really don't know. I think we'll take it as they come, and then we decide what the next steps are because we literally have not discussed it yet if we win on every study that we have ongoing, which would be surprising.
Lisa.
Hi, Lisa Bayko from JMP. Just 2 questions related to the FGF program. Number 1, for the FGFR2 fusion, is that part of the bile cancer that was derived from PSC? 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.
Lisa, do you mind re-asking the first question? I'm not sure we understood what you were saying.
Yeah. Some of the bile duct cancer comes from PSC. I'm just wondering-
Primary sclerosing cholangitis.
Right. I'm just wondering if that mutation is along that pathway somewhere.
I don't know the answer to that. I'd have to find that out. I'd have to look that up.
Then your second question on FIGHT-201. Initially, it's now obviously very clear that the activities where, as we pointed out pre-clinically, where you see the driver and where you don't, there's little to no activity. Going in, you don't know that. Plus, it's often that regulatory agencies require you to prove that you don't work in those settings, albeit in a more limited patient population. They do have those internal controls. Both the cholangio has two extra cohorts and then bladder as well. Once you hit, at least in the cholangio, the 220-patient subsets, in bladder there's a 40-patient subset. Once you have little to no activity there, you can stop. You don't have to keep going. They do have those controls.
Questions.
Let's go to Ying on table three.
Thanks. Ying Huang, Bank of America Merrill Lynch. I have a question on also cholangiocarcinoma program. You are already planning for confirmatory trial. Does that mean you're seeking the accelerated approval with the FDA? Secondly, you're going to increase dose to continuous dosing. Have you observed any dose-limiting toxicity at all from previous trials?
Yeah. Just to be clear, your second question first. In cholangio, we're staying with the intermittent dosing. The continuous dosing switch is in bladder.
Right.
In terms of the likely approval setting, the usual feeling is for a single-arm study of this size that you're going to be looking at an accelerated approval scenario. Is it possible to get full approval? Absolutely yes. If the agency thinks your response rates is robust, your durability is 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. That's one reason. The other reason is to move first earlier settings. Remember the studies in second-line and beyond. First-line patients aren't captured for the most part. 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.
Have you ever seen any dose-limiting toxicity with this compound?
The main one, and Peter may want to add to what I say, is once you get to a high enough dose continuously, you see almost universal hypophosphatemia, and it's just how to manage that. Does everybody get primary prophylaxis, et cetera? That would, I think, be the main one, unless anything else you want to add.
I think we haven't reached a maximum tolerated dose officially according to the protocol with either the intermittent or the continuous dosing. However, with continuous dosing, we do see more discontinuations. The hypophosphatemia is the common toxicity, but we also see some diarrhea. We see some alopecia. We see some nail changes. Those things all occur more commonly in the continuous dosing. 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. We definitely expect more side effects in those patients. To answer your question, we haven't, strictly speaking, met a maximum tolerated dose in life.
Thank you.
Let's go Asthika on table 11.
Sorry. Thank you. Asthika Goonewardene on the Bloomberg Intelligence. Sticking with FGFR, I'm curious if we can do a cross-drug comparisons of what the grade 3/4 toxicity look like for FGFR inhibitor to date. Sort of related, in the bladder cancer patient population that you treated, do you have any patients who were pre-treated with IO? If so, what did response rates look like in IO pre-treated 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 are around diarrhea. We've seen some stomatitis and mucositis, and less commonly, some nail changes. Those have probably been the things that we've seen either most commonly or they're most bothersome to patients. How they compare to other drugs is a little difficult to tell. It doesn't look like what we're seeing is certainly any higher than what's been seen with other agents. Generally, the toxicity profiles appear fairly similar across the different FGFR-targeted compounds. In terms of the IO, that's actually something we're going to go back and look at. I know there are a couple of patients that had been previously treated with IO agents, but I don't know the response rates off the top of my head.
Yeah, just to be a little additive to what Peter said, the J&J reported continuous dose in discontinuation rate is 20%. Our intermittent dose in current discontinuation rate is 8%. When we go to continuous, would we get to similar territory? We'll wait and see. In terms of IO exposure, we know that about 30 patients to date have had prior PD-1 therapies in the bladder setting. We're still going to examine the data a little more closely, but we know of at least one partial response in somebody who had a prior partial response to a PD-1 inhibitor. That may be of interest on how the program develops in terms of further studies. It's still too early to comment further.
Hi there. Evan Seigerman from Barclays. With the PI3Kδ program, can you help me better understand what was in the data of the DLBCL trial that caused you to discontinue their development? Are there any read-throughs to some of the other indications that you had mentioned here?
Yeah. Let me go first, and then Peter may want to add. He knows well. Just to be clear, the compound is active across all B-cell tumors. You saw Peter show follicular, data, mantle, and marginal zone. In diffuse large B-cell, we saw a 25% response rate. That's an active drug. The issue is around monotherapy and monotherapy approvability and use thereafter in diffuse large B-cell. There really isn't a pathway there given that combinations of higher responses, BCL-2, BTK, CAR T therapies, et cetera. It's a development decision to discontinue, not a lack of activity in diffuse B-cell. It's as active as other PI3Kδ inhibitors have been or maybe even a little more so in terms of monotherapy use there.
Okay. Any further questions? Yes. Let's go to Jay over in the corner there from Oppenheimer.
Thank you for taking the questions. Jay Olson, Oppenheimer. For REACH1, 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 arm that could be in combination with a PD-1 antibody? Thank you.
Just your second question first in terms of bladder cancer. I think given this morning's label updates, we'll think about each group carefully. Now there are cisplatin ineligible, there are platinum ineligible, which seems to be a different definition, which may allude to carboplatin, 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're PD-L1 low, you can still get PD-1 inhibitors. We are thinking of a multi-arm study there potentially and trying to segment the groups and potentially in combination. In terms of cholangiocarcinoma, do you want to comment on what Jay was asking?
For REACH1 and the titration?
Yeah. Sorry.
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 five up to 10. We also know that there was a lot of dose titration up or down based on cytopenias or other infections or things that were going on with the patient. What we know from the dosing regimen is that the average is between five twice a day and 10 twice a day. There was a lot of dose adjustment just based on the patient's condition, which is sort of what we would expect for those patients. I'm sorry, I don't have that number off the top of my head.
Okay. 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 P.M. We'll be back for a hard start at 3:00 P.M. Please grab, there's some snacks outside for those people here in the room. For those of you on the webcast, we'll see you again in about 15 minutes. Thank you very much. Okay. Welcome back to part two of Incyte's Investor and Analyst Event 2018. We'll kick off part two with some comments by Hervé on our PD-1 development program.
Okay. Thank you, Mike. Welcome back.
Okay.
Yes, the second part of this will be about, in fact, immunology. First, we'll speak about cancer immunology, and specifically about our PD-1 program. We'll be discussing the non-oncology, so-called inflammation, autoimmunity. Obviously, every time you start a presentation about our PD-1, the question is why is it important to have a PD-1 in your portfolio? I think I recognize that question completely. It's something that I think is important to describe. We have this product that is licensed from MacroGenics, 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-1 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. 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. 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. If you look at the way usage of PD-1 inhibitors has been spreading across a number of tumor types, 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-1 in your portfolio requires one of two things. It's either an enormous amount of money to buy it on the market or to work in agreement with other company, which is obviously creating complexities and potentially slowing down your process. Having a PD-1 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.
The goal when we took a look at the MGA012 program, which originated from MacroGenics, is a me-too PD-1. At least in a monospecific antibody format, it doesn't appear that there's any clear way that you can differentiate around that. Our goal was quite simple. Make sure that this PD-1 antagonist is equivalent to pharmacologically, pharmacokinetically to other canonical PD-1s in the space. I just show on this slide, at the top, some preclinical in vitro data, and the bottom some clinical pharmacokinetic data to illustrate that. On the top, you're looking at the ability of an antibody, and in the red-filled circles is MGA012, our PD-1 antagonist, and their ability in a dose-dependent fashion to block the binding of the PD-1 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 inflect downward. You can see that if you compare the red curve to the blue and the green, that's being evo and pembro, they're virtually superimposable in terms of both their ability to maximally block PD-L1 and PD-L2 binding, as well as the affinity or the potency with which they block those events. From an in vitro biochemical standpoint, spot on similar. When we dose these antibodies in the clinic, obviously we have to have a dose and a schedule that allows us to saturate PD-1 on the patient's immune cells, specifically their T cells. Shown on the right are two different ways to measure that. The top panel is looking at maximal binding of the antibody on the cells themselves. You want that to go to 100%.
On the bottom is looking at the ability to competitively inhibit binding of another antibody onto those same cells. You want that to go to 0%. We've studied 1 mg/kg given every two weeks, 3 mg/kg in green given every two weeks, or 10 mg/kg given every four weeks. You can see in every case that we can completely saturate binding with PD-1, which is what you'd expect based on the PK. It helps to convince us and the investigators that this antibody is able to effectively bind the target and does so with a high affinity similar to pembro and epacadostat.
We have multitude of doses and schedules that we can work with that can be 100% saturating in terms of PD-1 and therefore block the pathway completely, and that'll guide subsequent clinical development that Steven will talk about.
We inherited the compound fully in the U.S. from MacroGenics with the IND transfer in March of this year. This is a dose escalation data in 37 patients. Just to tell you that the safety profile is typical of what one would expect from an anti-PD-1 therapy. There's color coding there of the treatment-related adverse events from grade 1 through grade 4. Again, typical for what an anti-PD-1 would expect to give you, including, very importantly, likely immune-related adverse events, which although obviously not good for patients, that's something you want to see in terms of the drug having the effect you want within the body. 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 dose escalation, the program is complete. Reid alluded to the different dosing schemes used. It started 1 milligram per kilogram every 2 weeks, a build through 3 milligrams per kilogram, both Q2 and Q4, then at 10 milligrams per kilogram, Q2 and Q4. With expansion cohorts in endometrial cancer, cervical cancer, sarcomas, non-small cell lung cancer, a flat dosing regimen done in a tumor-agnostic fashion just to get as rapidly as possible the required safety data plus
PK data and receptor occupancy data. The MSI-H, the microsatellite instability high endometrial cohort is going to be further expanded at a 500 milligram Q4 dose and schedule. This will be with registration intent. 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 U.S. Furthermore, we will take beyond endometrial, we'll be looking at two other niche tumor indications in terms of registration pursuits. Just to spend a little bit of time on the MSI-H endometrial cancer. About 28,000 patients a year get endometrial cancer. About a third are microsatellite instability high by standard definitions. Pembrolizumab as monotherapy has provided proof of concept here.
In its MSI-H indication, there's a 36% response rate, which was five 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, that wouldn't be required here. We aim to enroll this as quickly as possible throughout this year and next year with data in 2020. 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 1,300 patients a year. Avelumab provides the benchmark proof of concept data here, having obtained an accelerated approval here with a 33% 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 poor prognosis with current standard care.
Although not easy patients to find, we expect to do the study through the end of this year and next year with data in 2020, again, another shot at the goal for monotherapy indication. Then our third one that we have picked is anal carcinoma. 2,500 patients a year. Both Pembro and Nivo provide the proof of concept benchmark here with response rates around 20%-25%. It is a virus-associated cancer with human papillomavirus being implicated here in terms of its etiology. Patients who immunosuppressed as well with HIV, also tend to get more anal carcinoma and can have high mutational burdens, which actually obviously increase response rates, and this will take a little bit longer to fully complete with data likely in 2021. Those are the three monotherapy indications, and all currently have accelerated approvals.
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 are using the 500 milligram IV every four weeks. It is a one-hour infusion. The metastatic Merkel study is there for you. Patients are required to have three or less prior regimens, no prior PD-1, with a target enrollment of 100. 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 at less than two prior therapies, no prior PD-1, a target enrollment of 80.
Both these studies have response rate as a primary endpoint with durability of response to accompany it to then hopefully suffice should we get the data we anticipate, as accelerated approvals. Merkel would be in 2020 and anal carcinoma in 2021. We now have this agent, it is in our hands and we are using it across the board in upwards of seven of our internal molecule combinations, both our small molecules and our large molecules. Beyond the internal ones that you know about, we have the ability now to combine it with arginase and AXL/MER, which has just gone into the clinic as well to look at both the microenvironment and myeloid-derived suppressor cells to allow hopefully complementary and synergistic approaches.
We are a little behind in, 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 is something we will be doing. As Hervé said upfront, the ability to have our own compound, not deal with a co-development partner, have it readily available to use has made things a lot easier. Given the AACR data we presented with PI3Kδ, that combo in our platform study at AACR this year, we also have the ability now with 012, should we want to combine with our delta inhibitor going forward from now on.
Yeah. This will be, I guess, the third of 4 pieces that we're talking about PI3Kδ . We mentioned the MPN work and the lymphoma work in the previous session. We also have an interest in using PI3Kδ 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. If you just knock out the enzyme only in those cells, you can shift the immune balance in favor of antitumor immunity.
A 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. The good guys to the bad guys, that ratio is shifted. The question for us is whether or not in humans and in patients, you could see the same change. We designed this trial specifically to ask that question. It's a dose escalation trial, fairly standard design on a fixed dose of pembrolizumab, with escalating doses of our delta inhibitor INCB050465, then with ultimately a safety expansion into either patients that had prior progression on a PD-L1 inhibitor or were ultimately naive to treatment to PD-1. 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 weeks on therapy. 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? 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-1 therapy. Best response was a stable disease and ultimately progressed. This is now being treated for 5 weeks on pembrolizumab plus INCB050465. The FoxP3 column are the suppressor cells. Those are the bad guys. Those are the cells that we'd like to decrease, and they diminish in number substantially over this treatment period.
You can see the concomitant increase in the CD8 effector cells. These are the cells that we believe will ultimately drive antitumor immunity. If you look at the small cohort of patients that we studied, there were only eight patients here. We saw the preponderance of them, six, all with an increase in that ratio. This sort of provides the early stages of the underpinnings for some translational conviction in the mechanism and will help to guide us forward as we understand how dose affects this, how different histologies affects this, and will form the basis potentially of PD-1 combinations going forward. I also would mention 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.
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, MGA012, PD-1, another global opportunity for us. Data in 2020. We spoke about NDA submission maybe 2021. 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. You heard this afternoon about the PI3, sorry, the PI3Kδ combination. It's just an example of why we can see a number of very meaningful opportunity for this product. FGF earlier, PI3Kδ we just spoke about, and you have arginase, and you have a number of other mechanisms that we will be combining.
The picture we have, the picture I have for this project is certainly not I recognize completely it's a very competitive environment, so that's something easy to see. 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. 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 five, six years. That being said, we'll be moving to a completely different field, which is something that we have been working on now for the past two years. The idea is the following, is that we have a very productive research 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. 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 indications. What we'll be discussing in the next few minutes are three of them. One is very simple to understand because we spoke about it already, at least in some indication, is topical ruxolitinib. It's a new formulation, again, where we have the rights around the world. The second one is a JAK1 selective inhibitor that is now also in the clinic. The last one is the PI3Kδ that we are also testing in a number of these indication.
The vision we have here is to develop the clinical proof of concept. That's what we are in the process of doing. Depending on which indication we'll be pursuing, the commercial aspect of it will be obviously decided at a later time. When we start, when we speak about following the science, this one is very typical. We don't have any selection about the type of indication where these projects could go. We just follow the way the biology is leading us. We try to establish the clinical proof of what we are thinking could be the benefit of these products. Obviously, the next steps will be depending on the type of indication that we will be obtaining from this project. We will start with the topical ruxolitinib as a first one, and we'll introduce mechanism.
Again, just to reinforce what Hervé just said, the idea here is relatively straightforward. We know that JAK 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. One advantage we have with a topical formulation of ruxolitinib is the opportunity to minimize systemic exposure. That can change the type of diseases we could go into, the type of patients we may want to treat in terms of their stage of disease, and also alter the benefit risk potentially, in terms of minimizing systemic therapy. The three inflammatory dermal diseases that we'll talk about over the next few minutes are illustrated here, and just schematically at a high level, some of their biological underpinnings. Atopic dermatitis is a Th2 driven disease. IL-4 and 13 are critical there.
JAK-STATs 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. Finally, hidradenitis suppurativa, a sort of more complex immune disease, Th17 and Th1, where IL-17 and IL-22 downstream of JAK-STAT signaling are very important. 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. The important thing to note is those ones in red, and importantly IL-4 and 13 are sort of at the top of the pyramid in terms of driving the etiology of atopic dermatitis. Also, IL-31 and IL-22 in driving the itching and the dermal thickening. Those are all signaling through the JAK-STAT pathway.
Our belief is that topical ruxolitinib in this condition could be a unique therapy for patients with mild to moderate disease. These are not the moderate to severe patients you may treat with systemic therapy. 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. This is the first positioning that we have for topical ruxolitinib.
Just to talk about the clinical side to this. Atopic 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%-10% of adults and a little more of children, 15% of children. It's underdiagnosed in general, with an average diagnosis rate of 50%-60%. About 11 million people in the U.S. are 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. You get thickening of the skin like lichenification, as well as intense pruritus, itching, which can really affect quality of life of these patients.
Many of the patients' skins are colonized with Staphylococcus aureus. They can have recurrent bacterial infections of these lesions. Many of the patients have elevated serum IgE levels and increased allergen specific responses that go with that. In terms of a study that we did to look at 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 a vehicle and an active control. The active control is triamcinolone cream of 0.1% BID for the first four weeks. Then they were switched to the vehicle BID for the following four weeks. The vehicle arm get vehicle all the way along for eight weeks. Then the active arm, in terms of the topical rux has four doses, 0.15% daily, 0.5% daily, 1.5% daily, and then a 1.5% BID arm.
This is a study in adults 18 and above. They had to have atopic dermatitis as a diagnosis for at least two years. They had to have what's called an investigator global assessment score of 2 to 3 at screening and baseline, which signifies the mild to moderate disease. This is mild to moderate erythema with some other features attached to it. The involvement was allowed to be from a body surface area aspect, anywhere between 3%-20% of their skin, and no use of topical treatment within two weeks of baseline or any systemic therapy. As I said, an N of 307 patients. The primary endpoint was the efficacy of each dose level of rux compared with the vehicle. The secondary endpoint is the efficacy of each dose level of rux compared with the steroid cream, the triamcinolone cream, obviously safety.
It's a little complicated in terms of the endpoints. 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. On the left is the Eczema Area Severity Index, the EASI score. On the right is the Investigator Global Assessment Responder. Let's look at the EASI score first. The two control arms are below, on your left. Vehicle BID at week four and week eight. The triamcinolone cream, the 0.1% cream used BID at week four. Remember at week eight, they had stopped and switched to vehicle. Those are the EASI scores for that. The RUX arms for all four dose levels. Let me just point you for ease towards the 1.5% daily and the 1.5% BID.
You can see if compared to vehicle, overwhelmingly much higher numbers, so 67% for the daily versus the vehicle of 15.5 and 26.9. For the BID, 71.6% 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 arm. For the 1.5% BID, for the EASI score, these are both numerically higher 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. 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.
You can see those rates for the control arms are very low. Vehicle, single digit, and then the triamcinolone arm at week 4 was 25% IGA responder rate. Then again, just for ease, let me point you to the 1.5% daily and the BID arms. You can see easily beat out vehicle both at week 4 and week 8. Then again, numerically and statistically significant, they beat out the triamcinolone arm as well with rates of 38 and 48% at week 8. Very encouraging efficacy data for our use of topical RUX. Both the daily 1.5% as well as the 1.5% BID arms, both compared to vehicle as well as the active arm for the first 4 weeks in terms of triamcinolone. 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're used to in oncology and certainly graft-versus-host disease. We can tell you now because it's publicly available online, that it's been accepted for an oral presentation in total at EADV in September, and that the regulatory discussions for a phase III 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.
Now we'll shift to another dermal inflammatory disease. This one is vitiligo. 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. Through interferon gamma secretion and activation of those T cells, you actually create effector T cells which attack your pigment producing cells, your melanocytes. That creates the characteristic loss, the depigmentation, which is just 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.
The hypothesis we have is JAK in hibition in a topical format would be an ideal modality for these patients where obviously efficacy is paramount, but also lack of systemic exposure 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 to affect up to 5 million patients in the United States, of which about 200,000 currently actively seek treatment. About half the patients develop vitiligo before the age of 20, then the overwhelming majority, about 95% before the age of 40. It can be, as depicted by the pictures, quite cosmetically disfiguring with associated quality of life changes, including depression and anxiety that these patients have. It's characterized by depigmentation in patches of skin all over the body, typically the face, the neck, the scalp, and around body openings, so particularly the mouth and the genital area as well.
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% BID cream, for a 20-week duration. It was a proof of concept study, open label, 11 patients only. In terms of the vitiligo severity index, there was a 23% improvement in the mean score across the 11 patients, particularly in the part that's often most important to patients, four of these patients had a 76% improvement in the facial area severity score, and this is depicted in the picture below at baseline week eight and week 20, where you get almost complete resolution of vitiligo of 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 erythema 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 II effort, again, a randomized double-blind vehicle control study in adults 12 and above with vitiligo. They have to have depigmented 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 will be 150 patients. The four dose levels of Rux that you saw actually in atopic derma have been studied, 0.15% daily, 0.5 daily, 1.5 daily, and then 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 improvement in the facial score.
A further 28 weeks of use 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 comparator 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.
We are actively, because we already have proof of concept from the investigative study, looking at phase III 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 with vitiligo in these patients.
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 very selective JAK1 inhibitor for oral administration, and that's called INCB054707. 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. Also you have itacitinib, the JAK1 selective inhibitor we talked about earlier for graft-versus-host disease, and here, another cousin to itacitinib called INCB054707 that we're bringing forward for development in one of these dermal inflammatory diseases that I'll talk about in just a second. First, a little bit on the profile of INCB054707, and highlighted in the orange box is probably some of the key aspects.
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. 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 IL6/JAK1 axis in whole blood. 690 nanomolar compared to 300 nanomolar for itacitinib and ruxolitinib. Importantly, down below, you see the half-life of the drug, and INCB054707 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.
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. The disease that we're focused on, and Steven will talk about it in a little bit more detail on the coming slides, is called hidradenitis suppurativa. This is a dermal inflammatory disease, and the important thing from a biology standpoint is that it's driven by IL-17 and IL-22, which are both produced downstream of activated JAK-STAT signaling. We think with an oral JAK1 inhibitor in this occasion, we can go after moderate to severe disease 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.
Let Steven walk you through the aspects of the disease.
This inflammatory follicular skin disease is again commonly diagnosed in the U.S. Upwards of 300,000 patients are diagnosed in the United States yearly. About 120,000 are actively on treatment. The lesions themselves develop in the axilla, in the groin, 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-like 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, and scarring. They are amenable because they're on the skin to biopsy and further investigation at a translational level. We know that they are characterized by the increased Th1 that we describe with IL-12 and interferon gamma, as well as Th17 cytokines, IL-1, IL-17, IL-23.
Humira adalimumab has an indication here but does fail to regulate multiple inflammatory cytokines, particularly IL-22, IL-17, and the gamma ones, and is not as widely used because its activity is felt to be at best modest. There is an unmet need here and why we are so interested in studying this disease further. The phase II trial is about to begin, and will go up on ClinicalTrials.gov soon. Again, adults, men and women. They have to have moderate to severe hidradenitis suppurativa by a grading system of at least six months' duration. There is an abscess and inflammatory count done. They have to have at least three of these or more. We have a dose-ranging study that'll start initially at the bottom in Cohort 1 with the first 12 patients at 30 milligrams daily with a placebo randomization with a safety follow-up.
We'll go up to 60 milligrams and then 90 milligrams versus placebo with a safety follow-up to look at both safety and efficacy for the use of INCB054707 in this population. I'm going to speak a little bit further now about the use of PI3Kδ beyond oncology in the setting of immunity and inflammation. 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. We're initially going to do proof of concept work in three 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 and the mucous membranes called pemphigus vulgaris.
We'll be using the delta inhibitor to antagonize delta signaling there and the T-, B-cell interaction that's pathogenetic here for the disease, and hopefully then inhibit autoantibody generation and ameliorate the condition. We'll also look at autoimmune hemolytic anemia, which is autoantibody-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 autoantibodies that are targeting the red cells, and see whether we'll have an effect here from PI3Kδ . The last condition we'll be studying is Sjögren's 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, which can then result in both a difficulty swallowing and an abnormality of taste.
Again, using PI3Kδ inhibition to suppress the inflammatory response here and hopefully ameliorate the condition further.
As you can see, there are a number of opportunities beyond the oncology portfolio at Incyte. We have, obviously, the topical rux 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 disease with a very unique medical need, where there is no good approved product today. Obviously in atopic dermatitis, the opportunity of a very favorable efficacy, safety profile due to the topical administration of ruxolitinib. They are exciting projects where we have no short-term value creation studies that will be initiated between today and beginning of 2019 or mid-2019.
On top of it, we have this proof of concept studies we are doing with our selective JAK1 inhibitor, which I think in HS that can be also very powerful. We need to establish the efficacy, but we have good mechanistic reason to go there. As you heard, three indication with PI3Kδ . 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. We'll continue to do that with our pipeline as we go. There is a team dedicated in translational medicine to take the projects coming from research and apply them across indication outside of the field of cancer.
Just a reminder of what we discussed from the beginning of this presentation today. The last two at the bottom are what we just discussed after the break about immuno-oncology, the PD-1, the opportunities for combination, and the new portfolio in some way outside of the field of cancer. Before we go to the final Q&A, I wanted to give you a picture of the next few weeks and months in term of news flow. Atopic dermatitis, we just spoke about it, will be presented at the medical conference in September. We have, obviously, the cholangiocarcinoma and bladder cancer data with our FGFR inhibitor and potentially moving to the next steps in term of phase III. Ruxolitinib filing in acute GVHD steroid refractory in the U.S. will be before the end of the year.
We will have additional data with our PI3Kδ 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. Fairly busy next few weeks, rich in data and events and filing and submissions that obviously will put us in a good position for the next few years. Back to a little bit the picture we were trying to draw over these three 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. Over time, to sustain, and that's a very important part of our program. We have five 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 Incyte over the next three to four years. Thank you for your attention, and we'll take your questions.
Now we'll finish up the event with Q&A period. Again, please wait for the microphone so those on the webcast can hear the discussion. Please give your name and your organization, and please raise your hands if you have a question. We'll start with Jay from Oppenheimer.
Thank you for taking the questions. Jay Olson from Oppenheimer. 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.
It's totally open at this point. As I said, we are not targeting specific indications. 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 optionalities too early in the process. We will tend to go We have a clinical team, pre-clinical, biology. We have the entire team to prosecute the development process. At this point, we will tend 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.
That's creating a new provocative question of saying, is there a dermatology group that could be taking care of that? 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. All of that is open. At this point, what we are doing is moving forward as fast as we can with the atopic dermatitis phase III. It will be followed by the vitiligo phase III with a topical formulation, and that is real and concrete as we speak. Assuming the vitiligo data, the final data, is consistent with what we have seen. Then we have all of this proof of concept with other mechanism.
As we see the result of that, I think it can lead to different commercial optionalities for us. At this point, we don't reject the idea of doing it ourself versus partnering it at some point.
Let's go to, I think, the table 14. Yep. There we go.
Hi. Thanks for taking my questions. This is Bin Lu on behalf of Benjamin from R.W. Baird. Just a couple questions for the atopic dermatitis phase II study. Can you sort of clarify, maybe provide some comments on why the active control was only dosed for four weeks, and if you dose the drug for eight weeks, what would be the results as compared to rux? Thank you.
Yeah. The question around why the triamcinolone control was only for that duration 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. That's the reason it was stopped at that time and then switched to vehicle. In terms of the phase III 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. It was important for us, the primary endpoint was against vehicle, and you can see the numbers for yourself. 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.
You can't do beyond four weeks on the face.
Okay, we'll go to Ying on table three.
Thanks. Is it on?
Can you turn the microphone on? Excuse me. Microphone.
Can you hear me?
Yeah. On you go.
Oh. Ying Huang from BofA Merrill Lynch.
Just ask the question, please.
My question has to do with that, given the pattern
Jen, can you bring your microphone, too? Let's try that. We got most of the way through the day.
There we go. Thank you. Thanks. Ying Huang with BofA Merrill Lynch. Just a quick question on the fact that ruxolitinib does not have a lot of years of patent exclusivity left. Why not develop the INCB054707 in the dermatology indications instead of topical ruxolitinib in the other dermatology indications? You're still running the phase II trials maybe still.
Is your question about The exclusivity on ruxolitinib is still fairly long. Actually.
Yep. I thought it.
We are speaking of 10 years.
Right. This is still phase II, right, for the few indications.
Is your question like why not-
Go directly to the-
Do a sort of a topical form of another JAK inhibitor-
Right
instead of doing it with-
With the ruxolitinib.
JAK ruxolitinib. The work that has been done in terms of formulation and in terms of clinical has been done with ruxolitinib to date. That's what we are speaking about here. I think switching to another active ingredient at this point would probably delay the entire program even further.
Yeah.
Topical ruxolitinib has a patent to 2031. That's what he just gave me.
Yes. 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.
Okay, let's go to Marc on table eight.
Hi, Marc Ferzan from Cowen. When we think about the vitiligo data in six months or so, what else is used there off-label, and what are the efficacies that are seen, and therefore, what's the commercial hurdle to be a viable product?
Patients do various things. One of the dominant therapies used in the U.S. is phototherapy. It's actually reimbursed by insurers. It often involves sometimes setting up actually a tanning booth of sorts in the patient's home with UVB radiation, given that way. Costs around $6,000 a year or north of that, and it has some effect. Other than that, there's not much else to use as sort of a commercial comparison there. That's why, as we realized this, as we spoke to patients, such an interesting need for us to explore further.
We don't see a lot of use of systemic drugs in the off-label setting for vitiligo. I mean, that's something we don't observe yet.
Okay. Michael from Guggenheim.
Hey, it's Michael Schmidt with Guggenheim. A question on the development strategy for the PD1 inhibitor. Why are you limiting development to MSI-high endometrial cancer as opposed to going a broader MSI-high patient population agnostic of the specific tumor type?
Thanks, Michael. I think it's a good question. It's just about efficiency of getting the monotherapy initial indications done. Even more so, that's a fact that it was already in the study. The dose escalation parts are very easy to just do the dose expansion and keep going. It's around practicality. Would we expect it to work beyond endometrial and MSI-H in general? Yes. Given what Pembro's already shown there. It's chasing, as Hervé said, monotherapy indications with speed in something that was already ongoing, and expand and just keep going.
Okay, we have a question here on number 4. We need roller skates.
Is that a working mic, or?
Hi. Thank you. Caspar Dolman with Baird Research. About the INCB054707, 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.
Right now, INCB054707 is sort of focused in areas outside of oncology, so we don't have any intention of developing it in MPNs. The other JAK1 itacitinib is the drug that is being positioned in combination with ruxolitinib. Those studies are ongoing as we speak. No, I don't think there's any risk of cannibalization or activity of taking INCB054707 into oncology indications.
Can you just speak about the JAK2?
Yeah. I was just going to say that I wouldn't think of it only as sort of dermal focused. As Hervé mentioned, there's a 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 RUC. 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 could be in other settings of inflammation or autoimmunity that are not focused on the skin. 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.
We have one on 12.
Hi, Jin Ho from Gabelli. I'm just wondering whether you could give us an update on your IO combination strategy. Are you open to approved IOs combined with your OX40 GITR program, or what's the plan there and what's the timeline?
Thanks for the question. Currently within the IO portfolio as a post-proof of concept asset, we have PD-1, and that's the reason we focused on it and spoke about it today. In terms of pre-proof of concept assets, we have four other large molecules. We have OX40 GITR, TIM-3, LAG-3. We have two other small molecules, the arginase inhibitor and AXL/MER. For all of those, they're 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 do these platform paired biopsy studies, which we've 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. We'll be very efficient with 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 II work where needed. For example, in a PD-1 well-defined refractory setting, a single arm there may be okay as long as you see an efficacy pop. They're all early pre-proof of concept work. 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. I think we'll close. We're remarkably on time. Thank you all very much indeed for your attention and your questions today. Thank you also to the Incyte team for putting up with my customers. We will close the official portion of today, and we'll stick around for a few minutes afterwards if you have some additional questions.