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Okay.
All right, well, welcome to the Fires ide Chat with Incyte. With us today, we have Pablo Cagnoni, President and Head of R&D, as well as Christiana Stamoulis, EVP and CFO. Welcome. Thanks for joining us today.
Thank you. It's good to be here.
I'm really excited to have this session here with Pablo today, who obviously, as I just mentioned, is the Head of R&D, and I'm really looking forward to spending time to go through Incyte's R&D pipeline and strategy and discuss some of the key value drivers in more detail. There's obviously a lot going on at Incyte right now. Jakafi continues to grow sales in its 13th year on the market now. Opzelura is starting to contribute meaningfully to the top line, and the pipeline has evolved quite a bit since you joined the company about a year and a half ago, Pablo. Maybe just starting out with a high-level question, how has Incyte's R&D strategy and pipeline evolved in the last year or so, and what are some of the initiatives that you have implemented since joining the company?
Certainly. First of all, thank you, Christiana and Hervé, and Michael, for having us here. It's wonderful to be here today, and those of you online, thank you for listening, so look, I'm very fortunate that I came into an organization that didn't need any massive restructuring or any massive changes. I think I'm very fortunate that there was a very strong pipeline that was evolving in the right way, and we had to make a few adjustments in the pipeline and a few adjustments in how we run the organization, and we'll continue to make those across the R&D organization, so a few of the things we did, which we thought were necessary, is focus on increased rigor in decision-making on the R&D organization, and that's simply, honestly, to really relentlessly challenge internal assumptions with external and internal sources in order to make better decisions.
I think as a result of that is that we terminated some of the programs that we did that we announced earlier this year in the third quarter because we didn't think that met a very high bar to continue to fund those programs, and we decided we could allocate that capital in other programs in the organization. The second is, and this is not entirely new, but we sort of recommitted to a focus on three major therapeutic areas with Graft-Versus-Host Disease as well. It's not that GVHD is not important for us, but we don't have a lot of programs in development in that therapeutic area. Our focus continues to be on expanding and accelerating our inflammation immunity pipeline, and that's not just dermatology. As we know, we have now a number of allergy programs. We have asthma in the clinic as well.
So that commitment continues and will continue to be expanded. We are committed to find what we define as a functional cure in myeloproliferative neoplasms. I think that through our existing programs as foundation, with the addition of our mutant CALR program, our V617F inhibitor program, we think we have a path to achieve that. And when it comes to oncology, we are recommitted or recommitting ourselves to solid tumor oncology. I say recommitted because obviously Zynyz is approved, Pemigatinib is approved, but now some of the solid tumor oncology programs I have put in place over the past few years are coming into view with our G12D program and our TGF beta receptor 2 by PD-1 program. So focus is critical. The third point is speed. We got to work a little bit faster.
I think by integrating decision-making across the entire journey of drug discovery and development, I think we're making speed gains that will be very important in the future. The final thought I would offer is we are accelerating the integration of AI and machine learning in R&D. We already have internal initiatives in target discovery on ADME property prediction, as well as on the drug development side when it comes to document generation, data visualization. That is based on some external collaborations, but we'll also continue to build that infrastructure.
Great, and can you talk about how you're balancing allocating resources internally versus looking at external sources of innovation? How do you balance capital allocation, perhaps as we think about additional acquisitions like the transaction that was announced early this year?
So this year, as you saw, we've done a few things on the capital allocation front. First of all, the acquisition of Escient that brought in two additional assets in IAI, one of them in multiple indications in development. And following that, we executed a very significant share purchase program. That was as a result of how the pipeline has been shaping up. And together with, once we added the Escient assets, we looked at the pipeline, and I think it's very fair to say that we have a well-balanced, a pretty full pipeline with programs well-balanced across the different areas of focus and also across different stages of development. So we felt that we had what we needed, and our focus from the capital allocation point of view in terms of the P&L cash flow or P&L capacity was on internal programs, pushing forward our current R&D programs.
At the same time, we looked at where we have been trading, and you could see that there was a very significant discrepancy between the trading levels and what we saw as the intrinsic value of the company. So the fact that we didn't need to bring in additional assets, the fact that we were trading at a significant discrepancy to the intrinsic value, and also we had a very strong balance sheet with a cash position following Escient of still in excess of $3 billion, it put us in a position to execute that significant share purchase and take advantage of the price dislocation, the value dislocation that we saw in the stock. So that was the other capital allocation activity that we did this year. Now looking forward, again, the focus is on investing in our internal programs.
We continue to have a strong balance sheet even after the share purchase, the $2 billion share purchase that we executed earlier this year, and that gives us the ability to opportunistically look at bringing in any additional technologies or assets that could make sense for what we're doing. The focus has changed from the past, the BD focus. We're either looking for complementary technologies and capabilities that will help with our discovery assets or any assets that are later stage of development, I would say actually commercial or near commercial, so that they don't add burn in our P&L, but add leverage and contribute to the top line in the near term, but there again, it's opportunistic, and only if we find assets where the valuation is such that we can create further upside versus paying full value upfront.
Right. And so in this context, was the share purchase a one-time thing, or is it something that could you envision taking advantage of in the future again?
Capital allocation decisions are revisited on an ongoing basis and change over time as the priorities of this company change. So we'll be looking at how those priorities evolve over time and then based on this, decide how we allocate between internal growth, BD, or any excess capital returning it to investors.
Great. Okay. Super. So Pablo, I wanted to talk about a few of your pipeline agents. And by the way, we have more time than the minutes up there, so just as a heads up. So I'm going to run through the list essentially. So maybe just starting out with Jakafi XR. And so the question there is, how do you think about Jakafi, the long-acting or the once-daily Jakafi opportunity? Is that still a focus? Is there still a focus on perhaps extending Jakafi's lifecycle beyond mid-2028, taking advantage of the long-acting form?
The Jakafi XR, the once-a-day formulation, just to get everybody caught up, we stated that we conducted a bioavailability study with different formulation, completed that, and as a result of that, we started the bioequivalence study, which is what we need for an approval of a once-a-day formulation. That data will be available in the early part of 2025. The importance there is potentially twofold, but the more straightforward one is the one you alluded to, which is Jakafi, as all of you know, has LOE at the end of 2028, very early 2029. It is important to remember that patients with MF, the average duration of therapy in Jakafi is somewhere around 20-24 months. For PV patients, that is about 40 months.
So the idea would be that once an XR formulation is approved, assuming a positive BE study, every new patient that starts on Jakafi is started in a once-a-day formulation. And therefore, when the LOE comes for twice-a-day Jakafi at the end of 2028, you have this large group of patients already once a day, and it's unlikely that everybody will be automatically switched to a generic twice-a-day. So in other words, instead of having an abrupt cliff, you have a more gradual reduction as those patients progress, and over time, the new patients get started perhaps on twice-a-day. The size of that area in the curve is hard to estimate, but it could be pretty significant. So that's the first point.
The second, potentially, and it's a harder road, is, we committed, and I think it's going to be probably one of the questions you have, to our BET inhibitor. We're going to disclose or discuss the more up-to-date data later this year, and we're going to give you clarity on the phase three path for that program, and potentially, there is a path by which you combine BET with Jakafi. You have a once-a-day either co-formulation with a fixed dose combination or a co-packaging. That's a longer road. For now, we're focusing on delivering the bioequivalency data, which we think is the first important step for that.
Great. So maybe good segue to talk about your BET inhibitor, which again, I think you previously already committed to sort of moving that into phase 3. And just in context of the recent disclosures from Novartis on some of the trial imbalances potentially in sort of secondary malignancies, has that changed at all how you look at your program and in terms of advancement?
It has not. Obviously, we know what has been made public for Pelabresib. We believe we have a really good BET inhibitor. We have seen data. We have shown you data in the past, and we will have a little bit more updated data later this year that suggests that it has a very strong effect on symptoms with the disclaimer or the caveat that it is open-label data as opposed to double-blind data, which is the Pelabresib data. Effect on symptoms, effects on spleen, and some effect on hemoglobin with an acceptable safety profile.
Based on that and our ability to dose daily, which is something you cannot do with Pelabresib, it is a two out of every three-week schedule, we think we have in our hands something that should be developed further in MF. So the question is, what phase 3 trial or trials we put in place, and we'll talk about that more later this year. But the Pelabresib data do not change our view of the path forward for our BET inhibitor. If anything, now we have the chance potentially to be first in class, which it's certainly attractive.
Right, and just remind us what additional clinical data you have been generating relative to last year's ASH presentation and how those data will support your planned Phase 3 program.
You know, unfortunately, I can't remember exactly how many more patients we have. We have a few more patients. We have longer follow-up, and we've seen very clear effect on symptoms, very clear effect on spleen. A lot of the patients have stayed on drug for quite extended periods of time, and nothing has changed in the safety profile that we've known. So it's almost, I would say, confirming that we're closer to the point where we transition this into phase three. That decision has been made to be clear. The only thing we haven't disclosed is what exact trial we will run.
Right. And so looking at last year's data, there actually was activity as a single agent as well. And so is there a single agent opportunity, or should we think about more of a Jakafi combination?
I think both are opportunities, right? We need to decide which one we do, whether we do one first or the other or both. And that decision has been made. We'll communicate it later this year. But you're right. There's very clear evidence of single agent activity. So that's a potentially very straightforward plan.
Okay. So we'll look forward to that. And then the ALK2 program is the other program that could potentially enhance sort of Jakafi's activity further. And just remind us where you stand with that and sort of what we should expect here at ASH for that.
So I don't think we submitted an abstract for ALK2 just to set expectations. And I think what we said at the last earnings call was that so far, the data that we've seen for ALK2 is not compelling enough for us to decide to move that into phase 3. We'll talk more about when we talk about the BET plan, but that's basically where we're at, and there will not be new data at ASH.
Great. Then just sticking with MF, so the mutant CALR antibody is one that I think was highlighted preclinically at ASH a couple of years ago in phase 1.
Yeah, phase two.
Yeah, for some time now. And just remind us again, why is it so interesting as a target, and where are you in your phase one study?
The phase 1 study is going well, and we are committed to disclosing data next year. That's the most important thing. We haven't decided the timing, and we expect to have a substantial enough data set to be able to give you clarity on further steps. That's the plan. Look, this potentially is a way to get to what I would define as a functional cure in patients with certain MPNs that have mutant CALR mutations. The reason is because what we've shown preclinically, which we expect to replicate clinically to some extent at least, is ability to selectively deplete the malignant clone MPN models in animals. If we can do that in patients, obviously, that allows the normal clone to overtake the malignant clone.
You basically have redefined from suppressing hematopoiesis with some degree, minimal degree of selectivity, malignant versus benign, to really eliminating the malignant clone, allowing the normal clone to replace the bone marrow hematopoiesis. If that happens, then you're changing the trajectory of this disease. Let's remember, Jakafi has been an extraordinary step forward in patients with MF and PV, but today, every patient with MF still dies of MF, basically. Jakafi hasn't cured patients. I mean, I'm sure there's anecdotes, but fundamentally, patients on Jakafi progress. Jakafi does prolong survival, to be clear. It does prolong thrombosis-free survival in PV, to be clear. But it still doesn't cure patients with MF. So we believe this, at least theoretically, has the potential to do that.
Can you talk about what are you looking for in phase 1? Is it as simple as SVR35, or are there other markers that are important?
No, we're looking at everything, right? We're looking at spleen. We're looking at symptoms. Obviously, we're looking at whether the hematopoiesis in the marrow is shifting, and we're looking at allele reduction, measured by variable allele frequency percentages, VAF, which we're measuring in patients, and so we'll know whether the malignant allele is coming down in patients with MF and ET as part of the study.
Okay. And then ultimately, how would this be developed? Would this be an add-on to Jakafi before or maybe after Jakafi initially?
You know, I'd rather answer that question once we have the data. Obviously, based on the mechanism I described, there should be a single agent path, and there should be a combination path with Jakafi. What Jakafi does very well, if you remember, is the symptom improvement on Jakafi is very rapid and very profound, and patients really like it because of that, so maybe there is a combination with Jakafi where you have an induction with Jakafi, and then you continue, or maybe it's a single agent or both, the single agent as well, so we'll talk more about that when we have the data next year.
Okay, and then where does your JAK2 selective V617F inhibitor fit into this plan?
Yeah. So the V617F inhibitor is a small molecule. The idea here and by the way, this is the only pseudokinase inhibitor. This is not just a little bit more selective JAK1, JAK2 inhibitor or anything like that. So it's a different approach to treating patients that have the 617F mutation, highly expressed in a percentage of patients with MF, obviously, as well as ET, and obviously, PV. More than 90% of the patients have V617F mutated.
So the plan is in a way the same. We've shown in animal models the ability to selectively deplete the malignant clone, in this case, 617F mutated. It's behind the mutant CALR program because we started in healthy volunteers to get the formulation work done. So that was completed and went out, I think, mid-year in the third quarter that we had entered patients. So it's behind CALR. We're still committed to having data with 617F next year, but just to be clear, it's behind the CALR program.
The endpoints or clinical assessments would be similar?
Similar.
Okay. Great, and then is there an opportunity to combine this with mCALR? Is it entirely different subsets of the market?
There's no overlap between the two mutations. So I'm sure there's, again, always a case report, but there's basically no overlap between V617F, CALR, and MPL mutations in MPNs.
Great. Okay. So maybe then shifting over to GVHD for a second on axatilimab, which was approved originally earlier this summer. And I know you've been waiting for the approval of the smaller vial sizes. So how are you progressing towards that and then ultimately the commercial launch?
Let me quickly comment on the vial, and I'm sure Christiana wants to comment on the commercial launch. So this is, and I'm glad to hear you put it exactly right. So vial size is not a formulation issue. The result of Agave was, to some extent, unexpected that the lowest dose in Agave was the one that we took forward, and it's approved. As a result of that, the vial that had been developed is too big, so we need a smaller vial. That information has been submitted to FDA. We expect that there will be a first quarter launch.
So in terms of the commercialization at this point, we expect to be launching in the first quarter of the year. And we have, as you know, expertise in the space. We have existing capabilities and infrastructure that we'll be able to leverage. And when it comes down to the potential size of the opportunity, we have said in the past that Rezurock, which is also approved for later usage in chronic GVHD, is a good proxy of how Niktimvo could look like in this indication. So you have a run rate of somewhere between $400 million and $500 million, and that's very much in line with how we are looking at the Niktimvo opportunity.
Right. And how do you expect the drug being used relative to Rezurock? Would you compete for the same patients, perhaps newly diagnosed patients in a third-line setting, I would say, or basically untreated patients, or would it be, is there opportunity to switch patients over from Rezurock? How do you think about sort of the market dynamics?
Sure. Look, graft-versus-host disease patients, especially with chronic GVHD, when you think about line of therapy, this is not like metastatic lung cancer that you get first-line therapy. You respond, you progress, you get second line, it's shorter, you're in third line, et cetera. Fortunately, a lot of these patients are cured of their primary malignancy that led to the transplant, and they have this chronic problem that needs to be dealt with, which is chronic graft-versus-host disease. Almost all patients, if not all, get started on steroids, and then the idea is, can you taper them off steroids? And when that happens, there are flares, and they need to be treated. And that's where Jakafi, Rezurock, and now Niktimvo come into play. So I think these medicines are going to get cycled through.
Probably Niktimvo is not going to be the first one used because of the label and because it's IV, but I think a lot of patients with chronic graft-versus-host disease will be exposed to Niktimvo in the course of their disease. So whether we compete directly with Rezurock or not, I don't think is the primary point. I do think there is room for a different mechanism. And that's a really important thing here, which is when patients progress or flare up on a particular mechanism, I think they're going to be looking for something different. And I think that's what Niktimvo brings into play.
We provided data, which we'll update, I believe, at ASH this year about some of the specific organ improvements and some of the more fibrotic organs, the improvement we've seen on Niktimvo, which we think is an important differentiation because of the monocyte macrophage-directed mechanism of action, which is different from the other competitors, but the really important thing for us is to move it to early lines of therapy. There is not only a combination with steroids, which is critical, but what providers tell us is they are really interested in having a steroid-free treatment regimen for chronic graft-versus-host disease, and that's our commitment to the combination with Jakafi, which we're trying to move as quickly as possible.
Yeah. Great. And then perhaps switching to your inflammatory and autoimmune disease pipeline or portfolio, starting with Opzelura, again, commercial drug. So the next thing that's going to happen here is probably the pediatric AD approval, right, in 2025. How much could that meaningfully change the commercial trajectory of Opzelura, you think?
First of all, we believe that there is a significant unmet need in pediatric mild to moderate. You have around two million children between the age of two and 11 with mild to moderate AD. Right now, most of them are on TCIs, TCSs. What has been differentiating Opzelura from other therapies is the very rapid itch reduction, and that would be even more valuable to children. We expect that it could help address a significant unmet need there. In terms of the size of the opportunity, we expect it to represent around 10%-15% of the overall AD opportunity for Opzelura, where we have said that in the U.S. is expected to be around $1.5 billion at peak.
Okay. Great. And then I know you have data coming up also for Opzelura in prurigo nodularis in the first half of 2023, actually. And so, yeah, can you just talk about that commercial opportunity, perhaps relative to AD or vitiligo over the drugs approved already?
Again, a significant unmet medical need. There are no other topical therapies for PN. They are at around 200,000 patients with PN, of which 100,000 are on some type of treatment, so we expect, again, Opzelura to be able to address a significant need.
What duration of therapy would one expect in PN relative to AD and vitiligo?
It's less clear because, look, in AD, it depends on the severity of AD, as you know, mild, moderate, or severe AD. Some patients with topical therapy have rapid relief, and they don't have flares frequent enough. So I don't think we've ever spoken about median duration of therapy in AD or vitiligo. We've talked about a number of refills per year that we think they're going to be much higher in vitiligo, which makes that opportunity potentially very significant. I don't think we have clarity on PN. Remember, for PN and Opzelura, we do not have phase 2 data, so we don't have that clarity. We believe since itch is the primary problem, then that leads to scarring and nodules in PN, that it makes a lot of sense to try a rux cream there. But in terms of duration of therapy, it's hard to assess.
I think in vitiligo, it's not only that duration of therapy is longer. Duration of therapy is key because if you don't really use the cream consistently for an extended period of time, you're not going to get the full benefit of it. And we have very clear data now, not only at 52 weeks, but even at two years, that there's continued improvement. I mean, even two years out, there's continued improvement in every measure, whether it's T-VASI 75, F-VASI 90, or F-VASI 75. There's continued improvement in patients with vitiligo. So part of our, not to get into commercial aspects too much, but part of our key commercial strategy is to educate patients and treaters that they need to stick with the twice-a-day regimen of Opzelura to get full benefit in vitiligo.
Great. Okay. Great. So then maybe switching over to Povercitinib, the oral JAK1 inhibitor, where we also expect a phase three readout early next year in hidradenitis suppurativa, which is obviously a rapidly evolving space. There's been recent approvals of Cosentyx and other agents advancing. And so beyond top-line success in phase three, how do you think about the competitive dynamics in this space and where Povercitinib could fit in dependent on the phase three data?
So first, let me talk a little bit about the data, and then Christiana can comment about the commercial prospects. Look, I think that we need to replicate the phase two data. And there isn't a ton of phase two to phase three transition in HS, so we have to be careful. But I think some of the data available suggests that that transition is pretty good in terms of translating phase two into phase three results.
I think if we can replicate the phase three data, then we have what I would define as comparable efficacy to biologic in a pill. And if we land there, I think we have a really good story to tell. In addition to that, the pain reduction, the NRS scores reduction with Povo in HS seems to be very rapid and perhaps superior to some of the biologics. So again, we need to see the data. We assume before we go there that we will have a black box. But if we replicate the phase three data, I think we have a very compelling story.
The efficacy profile is exactly what we need in order to be able to have the right placement, the right discussions on the access side. This is going to be critical.
Right, and so on the black box topic, obviously there's a class warning on oral JAKs. Do you expect there to be any kind of pushback or caution by patients based on the experience of oral JAK inhibitors right now, and how is the risk-benefit profile perhaps in HS relative to other indications where JAKs are approved?
Yeah, Michael, we need to see the data. Rinvoq seems to be doing pretty well commercially with the same black box that we expect to have. I would argue some of the indications are more "benign" at HS. So let's see the data. We're going to have a lot of randomized double-blind data with Povo. The HS program alone is about 1,200 patients. On top of that, as you know, we have PN, we have vitiligo, we have CSU, and we have asthma. It's going to be, over time, a comprehensive safety data set that we believe if it remains clean, it would be really a strong part of the story here.
Yeah, and then one question that comes up that Rinvoq obviously also doing a study in HS. It has a much more established market presence in other areas. Sort of how do you feel Povo is competitively positioned to Rinvoq?
I don't know the exact timing because we don't know their timelines. I don't think they're ahead of us. We go back to the phase 2 data. If we put side by side the RingVox and our safety data, I think it's very clear. We have better data, and if we both replicate our phase 2 data, I think we have a very strong argument that for the mechanism for a pill, Povo should be the first one you try, and I think that argument needs to be made to prescribers and patients.
Great. Okay. Super. And then there are obviously other opportunities for Povercitinib, including PN. We just talked about it where rapid itch resolution is perhaps an important factor. And we've seen some phase two data already for Povercitinib there. But yeah, how are you tracking towards launching that study?
I mean, we're enrolling this study. It's going well. We were very happy with the randomized phase two data, particularly, and you pointed it out because Dupi works in PN, but the time it takes to itch relief with Dupi is, at least in my conversations with prescribers, suboptimal, and we think Povo can help those patients with much more rapid provide relief. That's our hope that we replicate the randomized phase two data once again, and we have a path forward as comparable or better than biologic in a pill. It's the same story with Povo. I think that really fast and potent anti-inflammatory approach could lead to very rapid symptom improvement in a range of indications.
Okay, and then you've said you're also looking at CSU and asthma for Povercitinib. Just maybe talk about sort of the two respective phase two studies and what you're hoping to demonstrate.
The CSU story is interesting because we have another program, which is a mast cell-directed target drug, and obviously Povo is different. But there's an argument to be made about a contribution of T cells and the overall inflammatory reaction to CSU. It's one of the indications for which we have less data, but we're really encouraged by the way the study has accrued, and we'll have data early next year. I think for asthma, there's a very strong story to be told here.
Asthma is an inflammatory disease, and in patients with low or no eosinophilic disease, there is a path for obviously a T cells play, a very important role I would argue that T cells play. And there's a number of approvals with different targeted anti-cytokine approaches. And we believe the multi-cytokine approach of Povo in asthma could really form a compelling story. I have no data to convince you yet, but we'll have data in 2025.
All right. Looking forward to that, and then just on vitiligo, we just talked about Opzelura and how important the duration aspect is, the long-term use of the topical. But you also have obviously povercitinib, and then I believe an IL-15 receptor beta biologic in development. Can you just talk about how you envision your vitiligo portfolio to play out long-term in terms of different mechanisms that you're developing?
You're correct. Povo, it's been developed with vitiligo as well. We've shown the data. We've shown long-term follow-up data that shows very, very continued improvement in the efficacy if you stay on Povo for longer periods of time. I think that the interesting story there is there will be patients with limited vitiligo, and there's a little bit of overlap between the two potential labels. Obviously, Opzelura is approved, Povo is not. But the way we conduct the study, patients between 5% and 10% overlap in the two potential labels. But there will be patients with limited vitiligo area that might be better for Opzelura. It's simpler to apply. It has an absolutely clean safety profile. Even though it has a black box, there's really no concerns there because of the low systemic exposures.
Patients with either suboptimal response to Rux cream or with much more extensive disease, we think Povo is going to be a good option. The anti-CD122 or IL-15 receptor beta antibody, the idea there is sort of a more lasting benefit, right? Because the idea there is to decrease the number of autoreactive T cells, which are the cells that are attacking and destroying melanocytes. If we succeed with that approach, then not only will you continue to improve your vitiligo results, but you could potentially lead to drug-free long-term remission of the repigmentation. So that's the potential story there. We've shown preclinical data that supports that hypothesis. We're in the middle of a SAD/MAD study in healthy volunteers. We'll have more data. We'll have data at some point next year.
Okay. Super. And then shifting over to the two SCN assets, EP262 first. Yeah, could you just discuss MRGPRX2 as a target in mast cell-driven disorders and what makes it attractive perhaps relative to other approaches such as wild-type KIT?
The reason why we like MRGPRX2 is because it's not only cell-type specific, it is in mast cells, but it's also overexpressed in certain tissues, in mast cells in certain tissues, specifically the skin, connective tissue, and so we like that part of the story. We thought these are chronic diseases, not lifetime problems perhaps, but chronic diseases, CSU, CIndU, they tend to last two, three, four years on average, so it's a chronic problem. There are certainly diseases that affect patients in a number of ways, but they're not life-threatening, at least not most of the patients. Occasional CSU patients can have anaphylactic reactions, obviously, and so we thought that the balance of potential benefit that 262 can provide with a very clean safety profile could be a pretty compelling story, and we believe that today.
Obviously, we have no data to talk about yet, but the idea that you can have the next option after patients fail or progress after an antihistamine and/or Xolair, and you have an option that is very well tolerated, simple to take, that provides relief in a certain percentage of patients, we thought it was an important option. And that's what we've been discussing for the past few months since we acquired SCN.
Again, is the idea to have superior safety perhaps relative to BTK or KIT, or is there opportunity to improve on efficacy as well?
We're not going to concede the efficacy story yet, but my point is we don't need to beat them on efficacy to have a story here, which is, I think, something we've been very consistent about. If we have good efficacy with very clean safety and convenience of a pill, we think we have an important role to play in how these patients are treated. Even the best data with c-KIT antibodies doesn't cure everybody with these diseases. We've seen the CIndU data. The data looks very strong, but we think that there will be a sequence in how these patients are managed. Once we have our data, we'll discuss this in more detail, but that's the way we continue to view that area.
Right. Understood. And then can you set some expectations for the phase two data and CSU that you'll report next year? And how many patients are in the data set? I know I think you tested two doses initially. You added two doses in addition to that to talk about the phase two.
Yeah. So what we're going to report in the first part of the year next year are the three ongoing studies that have been put in place and required by the company, which is an atopic dermatitis study, a CIndU study, which is important, symptomatic dermographism, and cold-induced urticaria, and then the CSU data. And as you point out, the study that was ongoing, required by the company, was placebo versus 50 versus 150 of 262. And what we did is we decided to add, without having seen the data, we decided to add another study, basically a cohort, if you want, of 25 versus placebo.
That started enrolling when the first part completed enrollment, so we would not compete with each other. So the 25 versus placebo will not be available early in the year. It will be available later because it started much later. Whether we need the 25 versus placebo in order to advance further development of 262 depends on the data from the 50 and 150. So once we have that, we'll have more clarity on how important the 25 versus placebo is.
Great. And when we look at the data, I guess, what is the right bar or the right comp for six weeks activity? Presumably, are there other drugs that we could compare that against?
I'm not sure. I think we want to see clear evidence of proof of concept, meaning X2 inhibition improves the symptoms of patients with chronic urticaria. And if we have compelling evidence of proof of concept together with a clean safety profile, that would define the rest of the strategy for 262.
Okay. There are some other oral agents being developed, including a direct agonist, the EvoImmune asset, and then a negative allosteric modulator from Septerna. How much visibility do you have potentially into how differentiating your drug is versus theirs, or is it just impossible to say at this point?
It's really hard to say. They haven't presented a lot of data. It's hard to say. Our assumption with the EvoImmune is that it's not too different, but perhaps we're mistaken. I mean, we haven't seen a lot of data. So we're tracking them closely. We know we are ahead, and we're trying to move as quickly as we can in order to preserve that lead. But the truth is there's not a lot of clarity on how different they are.
Okay. And then how do you think about other potential opportunities for this class of drugs, including atopic dermatitis? And do you have plans to expand development into those areas?
The atopic derm trial is ongoing. It's going to read out, and we're going to report the results at the same time as the others at the chronic urticaria trials. It's a different biology, really, because we know that atopic derm is a T cell disease. There is a role for mast cells in flares, so we thought there was a very intriguing idea about the SCN team to test it. We look forward to seeing the data, and for now, that's the plan. We'll look at the data, and then we'll decide next steps. We have not discussed asthma internally. There's other indications as well. We're saving that story for next year. Once we have data and the lead indications, then we'll talk about other potential indications for 262.
Great. Makes sense, and then can you talk about the opportunity for EP547 and what are some of the areas where this could be potentially focused on?
Yeah. 547 is in a randomized double-blind phase two study in patients with cholestatic pruritus, cholestatic pruritus associated with two indications, PBC and PSC, primary biliary cholangitis and primary sclerosing cholangitis. And those are diseases where itching is intractable pretty much, in some cases even leading to liver transplant. And I think the idea that X4, which binds to cells in the trigeminal nerve that are agonized or are stimulated by bile salts and bile acids potentially can alleviate the pruritus, we thought it was a very intriguing idea that the Escient team put forward. So we're looking forward to seeing the results of that study.
I think that then the question would be how good the results are and whether there's a difference between PBC and PSC, and we decide on next steps. This is not a disease-modifying therapy, but pruritus is one of the major problems in patients with these two indications. Obviously, we're aware of the data of other medicines that have disease-modifying potential. This could be either used instead or as a complement or before patients go to transplant potentially if we saw the level of pruritus involvement that you need to see.
Okay. Great. So maybe then in the last 10 minutes or so, shifting over to oncology, starting with Tafasitamab. I know it's not been talked a lot about, but I'm just curious to understand the commercial opportunity in relapsed refractory follicular lymphoma, perhaps relative to the currently marketed indication based on the positive inMIND trial results.
Yeah. So, first of all, we will be discussing the data later in this year. So you will see more on the FL. In terms of the market opportunity, if you go back to the last call we had, we shared the slides showing how the three indications were two programs and the three indications that we or three programs, AXA, Tafa-FL, and Reti in SCAC in anal cancer could contribute to top line. And between the three, we said that there could be a contribution of $800 million plus in terms of big sales potential. We spoke about AXA in third line.
If you look at that opportunity and assume at around $400 million, that would imply that the two others are at around $200 million type of opportunities each. So that's how we see FL relative to what you're seeing now in relapse refractory DLBCL. It's not a huge opportunity, but it's incremental, and again, you have those smaller size indications coming together and contributing actually something that adds up to a billion-dollar type of revenue contribution.
Right. And then I think you may have guided to reporting phase 3 data of Tafasitamab in first-line DLBCL next year as well, right? So which is an indication that has been notoriously difficult for others to beat R-CHOP. And so, yeah, how confident are you in that study design?
I think you said it right. I think it's been really hard to beat R- CHOP in first-line DLBCL. And I think we need to be reminded of that. I do have a little bit of hope here because I think that the follicular study tested for the first time the combination of CD19 plus CD20 versus CD20. That's basically the idea. And it worked. And we'll talk about it at ASH how well it worked. So if you're a hopeful person, if you're an optimist, you say, "Okay, this should increase your level of confidence." But it's a really high bar. We really, obviously, we would love to have that additional indication for Tafasitamab, but it's a tough bar to crack.
But presumably not included in your $800 million.
No, that would be incremental. The 800 was just for the indications where we either have approval or we have positive data already.
Right. Okay. And then just on your CDK2 program, obviously, we saw some super interesting data at ESMO, especially in ovarian cancer. And so, yeah, I think the best data was at the lowest dose, the 50 milligram, if I'm not mistaken.
BID.
Yeah. Can you just remind us how you're tracking towards RP2D identification and then initiating some of the trials that you talked about?
Yeah. We showed really good efficacy at 50 BID, 100 QD on those two dose levels. And there was some efficacy at lower doses, and there was a little bit of efficacy at 125 QD. So that's the data we have. When you put together balance between efficacy and safety, it starts to emerge what the dose should be, but we're not going to make anything official yet. So the plan is, and I'll reiterate what we said at ESMO a couple of months ago, we will start one or more pivotal trials with CDK2 next year.
That's our commitment. We are ahead in this indication, and we want to remain ahead of everybody else and get the first CDK2 inhibitor in ovarian cancer approved. So what exactly that's going to look like, we'll talk about it after we finalize the in-depth analysis of all the data, not just the response data, but exposure response analysis and other analysis in the ongoing study. We sit down with FDA, and we have an agreement on what the path forward is. And then we'll talk about it next year.
Great. Yeah.
But we will start phase three studies next year.
I think of the studies you talked about, so platinum-resistant ovarian cancer and then first-line maintenance, which is obviously a significant opportunity. What gives you confidence in?
Pablo, and I have more confidence than I have data because we haven't done the combination with Bev. I don't expect a problem there, but we need to do the study that has started already, by the way, the phase 1 combined with Bev. CDK2 in our hands has a disease control rate in heavily pretreated platinum-resistant patients, maybe in our fourth line of 75%. The response rate was what it was, between 31% and 35% depending on the schedule, but the disease control rate was consistently a different dose that was about 70%-75%.
It would be shocking to me if a drug with that level of anti-tumor effect that keeps tumors from growing in so many patients for so long doesn't have an impact on progression-free survival. So we need to finish the combination with Bev, and we need to get going. But I agree with you. That is the long-term future of that drug, is to move as quickly as possible into platinum-sensitive disease. It's a much, much bigger opportunity. It's much better for patients because the magnificent benefit you can provide there is much more significant.
Right. And then others have looked at breast cancer for CDK2 inhibitors. Just talk about, in general, how you're planning to prioritize other opportunities for your CDK2.
Yeah. We prioritize ovarian cancer because we had early signals of efficacy, and we decided we can move fast here. We don't have a CDK4/6 in our pipeline. We don't have a CDK4 in our pipeline. So we thought in ovarian, we can move very quickly, and we have, and that's why I think we're in the lead. We are doing the combination work to understand how good of a breast cancer drug we have. Those are combinations with Faslodex and obviously with chemotherapy as well and CDK4/6 inhibitors.
We need to do the work, Michael. If this is combinable, as we expect it should be, like some of our competitors have shown, then we'll try to figure out the level of activity we have, whether it justifies accelerating that or potentially partnering with someone that has a CDK4/6, at least for breast cancer, not for ovarian cancer, CDK4/6 and doesn't have a good CDK2 inhibitor like we do.
Right. And then so what are the next disclosures from the program that investors should look forward to?
I think the next disclosure is that next year we will provide clarity on the timing and sequence of pivotal trials. I think that's it. And probably at that time, we may provide an update on the data, but that's basically it. And we don't have a specific timing for that yet.
Right. Okay. Great. Question on retifanlimab, your PD-1. And so I think we talked about these squamous cell anal cancer opportunity just now, but in non-small cell lung cancer, I think you reported a positive study, but it's unclear to me sort of what next steps are. So can you talk about if there's anything else for retifanlimab as investors think about some of the opportunities there?
Yeah. So from the regulatory perspective, we'll submit sBLA. Look, the drug is active. It's unsurprising. It's not the first PD-1 that shows efficacy in non-small cell lung cancer. It's hard to argue it's going to be a big commercial opportunity. Now, ex-U.S. and Christiana Stamoulis comment, their potential for taking Reti into other markets that are less competitive or one can compete on price. I don't know if you want to comment on that.
We haven't commented on that.
As investors think about the oncology pipeline longer term, what are other programs that you're actively investing in and where we could actually see some data at some point?
Yeah. The other programs that we've talked about are our G12D program. We think we have a very good G12D inhibitor. We're developing it as fast as we can. We're obviously aware of the recent data that was disclosed. We think now the bar has been set, at least in G12D-positive pancreatic, at about 30% by our colleagues at RevMed. So we think that there's still room if you achieve really, really high target coverage for consistent periods of time that maybe that number can be improved. So we have no data yet, and we'll talk about data next year. And the TGF-beta receptor 2 x PD-1 is a program that we continue to push forward. We haven't disclosed any data. We'll probably disclose data at some point in the future. But those are the two other key oncology programs that we have.
And then so earlier today, we talked about sort of the historic fast follow-up approach that Incyte had in terms of pipeline development. And so, yeah, how would you describe your approach today and what are other areas of focus for Incyte as you expand the pipeline going forward?
Yeah. Look, I think if you look at the programs we've been talking about for the past 45 minutes, I think that you'll see a strong emphasis mostly on either first or best, right? We have several first-in-class, what we expect to be first-in-class programs since CDK2 is one, TGF-beta receptor, PD-1, X2, X4. Those are all potential first-in-class. And then in cases where we followed others, we really have, at least so far, in some of them, clear data that suggests we might be best. And the best example there is Povo, right? Obviously, I didn't mention mCALR, JAK2 V617F. Those are truly first-in-class programs as well. For G12D, it's harder. Today, we have no data. We have a theoretical basis why we might be best in class, but it's a little bit of a softer call until we have some data.
So our goal continues to be to be first or best. Honestly, when you look at the competitive challenges, almost every indication these days with the challenges for access to markets and reimbursement, we think those two factors have to continue to be critical. And that's why we terminated some of the programs that we did, the LAG-3 by PD-1 program, the LAG-3 monoclonal antibody. The ora l PD-L1 program. We terminated those because we didn't see a way to be first or significantly better than what was out there. And we terminated those programs. So we'll continue to try to have that bar in every one of the decisions we make in R&D.
Great. All right. Well, Pablo, with this, I think it's time to wrap up. So really appreciate the.
Thank you.
Deeper dive into the pipeline, and Christiana, thanks for being here as well.
Thank you.
That was great. Thanks.