Greetings, and welcome to the Incyte Investor Conference Call. At this time, all participants are in listen-only mode. If anyone should require operator assistance, please press star zero on your telephone keypad. A question-and-answer session will follow the formal presentation. You may place into question queue at any time by pressing star one on your telephone keypad, and we ask that you please limit yourselves to one question and then return to the queue. As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Ben Strain, Associate Vice President, Investor Relations. Please go ahead, Ben.
Thank you, Kevin. Good evening and welcome to Incyte's Data Highlights from ASH 2024 Investor Call. The slides that follow today's discussion can be found on our website. On today's call, I'm joined by Pablo and Steven, as well as our two guest speakers, Dr. Pankit Vachhani and Dr. Laurie Sehn. Hervé and Christiana will also be available for Q&A. I would like to point out that we'll be making forward-looking statements which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. I will now hand the call over to Pablo.
Thank you, Ben, and good evening, everyone. On slide five, I want to highlight the continued transformation of our pipeline. On the left side of the slide are four products with important near-term milestones. As you all know, axatilimab, or Niktimvo, was approved in third-line plus chronic graft-versus-host disease earlier this year, and we anticipate this medicine being commercially available in the first quarter of 2025 for the approximately 6,000 patients with chronic graft-versus-host disease in third-line plus in the U.S. We also submitted the sNDA for ruxolitinib cream for pediatric atopic dermatitis and anticipate the potential approval in the second half of 2025. We remain on track for an sBLA filing for retifanlimab in squamous cell anal carcinoma by the end of this year, with the potential approval in the second half of 2025.
As a reminder, this will make the first ever PD-1, PD-L1 approved in SCAC and has the potential to become the new standard of care for advanced SCAC patients. And lastly, related to the data we're going to highlight today, we are on track to submit the sBLA for tafasitamab for the treatment of patients with relapsed or refractory follicular lymphoma by the end of this year, with a potential approval in the second half of 2025. This could represent an important treatment option for patients with follicular lymphoma, and Dr. Sehn will walk us through the data in just a moment. On the right side of the slide, we have a number of potential first-in-class programs that continue to progress with a number of important milestones in 2025. And before introducing our guest speakers, I'd like to quickly provide an update on our ALK2 program on the following slide.
Our initial hypothesis for zilurgisertib, our ALK2 inhibitor, was that by binding to ALK2, numerous downstream signals will be blocked, leading to the downregulation of hepcidin and the improvement of anemia through iron mobilization. Based on the dose escalation and dose expansion data thus far, zilurgisertib has demonstrated target engagement and hepcidin reduction but does not significantly improve anemia in patients with myelofibrosis. As a result, we have decided to cease development of zilurgisertib in patients with myelofibrosis. Moving to slide seven, as a reminder, over the next few years, we will deliver a number of pivotal readouts across the entire pipeline and will remain on track for more than 10 high-impact launches by 2030. Let me now introduce the guest speakers for today's call. Dr. Pankit Vachhani is an Assistant Professor of Medicine at the University of Alabama at Birmingham.
He leads the Leukemia and Bone Marrow Transplant Working Group and serves as Medical Director of the Clinical Research Unit. His primary research interest is in myeloproliferative neoplasms and systemic mastocytosis. He has also previously served as a panelist on the NCCN Guidelines for MPNs. Dr. Laurie Sehn is a Medical Oncologist and Clinical Professor with the BC Cancer Centre for Lymphoid Cancer and the University of British Columbia. She currently is the Chair of the Lymphoma Tumor Study Group and Chair of the Medical Advisory Board for the International Lymphoma Coalition, and previously she served as a member of the Editorial Board of JCO on leukemia and lymphoma and is currently an Associate Editor for Blood. We are delighted to have both on our call today, and I would like to thank both Dr. Pankit Vachhani and Dr. Laurie Sehn for joining us.
At this time, I'd like to turn the call over to Dr. Pankit Vachhani for an update on our BET inhibitor program.
Thank you for having me. This is Pankit Vachhani. Let's go to slide number one. That's the slide that talks about the natural history and time points for intervention. As you will see from the figure, patients who come in with myelofibrosis have symptomatology emanating from myelofibrosis. They also have organomegalies like splenomegaly and hepatomegaly, but also elsewhere, and they also frequently have cytopenias like anemia and thrombocytopenia, if not at the time of diagnosis, then eventually, and perhaps by intervening earlier and intervening with deeper and more targeted medications, as well as combination medications, we might be able to lead to disease modification as opposed to later interventions when the disease may have progressed more.
Now, the natural history of this disease suggests that over time, the fibrosis increases, the cytopenias get worse, patients also have more infections, there are thrombo-hemorrhagic events, and also overall there's a bone marrow failure-like state and a hint towards the leukemic transformation, which is a part of all myeloid neoplasms. So secondary acute leukemias also occur besides organ failure. So this is the overall natural history. Now, going to the next slide, we know that the current landscape in myelofibrosis has four different JAK inhibitors, ruxolitinib being the first one from 2011 and more recently momelotinib on the right side from 2023. They all have slightly different kinome profiles. They are all approved in line-agnostic fashions and have slightly different adverse event profiles.
The pros of these four JAK inhibitors are that they all improve spleen volumes, they all improve symptoms to one or the other extent, and we think that they all improve overall survival. However, I will preface that by saying that it's with ruxolitinib that we have most of that benefit documented and known. And maybe some of them also, not maybe, they do, some of these drugs also improve anemia. But on the other hand, what we don't know and don't have is an alteration of the natural progression of the disease, meaning we are not thwarting the disease. We are improving spleen volumes, we are improving symptoms, but we aren't doing much beyond that right now that we know of.
We are not really changing in a meaningful way the fibrosis or the clonal burden of the disease, and certainly we don't have any impact on the leukemic transformation rate. So much needs to be done along those lines. So going to the next slide, I think you have pictographically a representation of where things stand. So let's start from the leftmost side. On the leftmost side, you have the overall survival curves based on the risk stratification in primary myelofibrosis. What you will notice is that for Intermediate-1 risk patient population, the median survival is thought to be 10 plus years, and that's good. However, for Intermediate-2 and high-risk myelofibrosis patients, the survival is significantly lower, so less than five years, and in the case of high-risk MF, 1.5 years based on DIPSS stratification.
Things actually get worse when you look at that middle figure, which is showing and depicting the survival of patients who have discontinued ruxolitinib for one or the other reason. Now, when you combine all of those patients and look at that overall cohort from this study, the median survival was just 13 months after discontinuing ruxolitinib, and in fact, other studies have also shown that the survival post-ruxolitinib discontinuation is somewhere in that range of one year to one and a half years, so then what are the unmet needs in myelofibrosis? Well, first and foremost, we want more responses, both in terms of spleen and symptoms. We also want deeper responses, and we want these to be durable in nature beyond what we have, of course, and going beyond the spleen and symptom responses, we truly want to modify the disease course.
And that would mean improvement in fibrosis, improvement in cytokine levels beyond what we can do already, slow down the disease progression to blast phase or accelerated phase, and overall decrease the allele burden of the cooperating mutations as well as the driver mutations. The third bullet point talks about the management of cytopenic myelofibrosis, and that is especially true for anemia. Anemia is a big issue for patients with myelofibrosis, and that continues to be an unmet need despite the newer options. And of course, we in oncology, like with any other cancer, we want to improve the survival outcomes. So ruxolitinib does lead to survival improvement as shown by multiple studies, but we want to do even better than that in frontline management of patients with MF. And what about second line and beyond?
The graph in the middle shows that the median survival is 13.2 months, so certainly we want to do more than that. For accelerated phase, blast phase disease, the outcomes are terrible, and that's where we truly want to bring agents which may make an impact. Finally, and perhaps one that connects all of these above points is the fact that all our current treatment options are JAK inhibitors. Having drug options which have a mechanism of action other than JAK inhibition would be nice, but differently, targeting orthogonal or cooperating pathways which may synergize with the JAK-STAT pathway would be a nice thing to do. That's where the things are. Now, let's go to the next slide, which is where the study title is, and I'm presenting the results which were recently presented by my colleague, Dr.
Justin Watts, on behalf of all the group at the just concluded ASH meeting in San Diego. Going to the study design slide, you have it in front of you. This study is an ongoing phase one open label dose escalation and expansion study. Let me first and foremost make the point that this drug, INCB057643, is an oral drug that is taken continuously. So this should not be confused with some other BET inhibitors which may have different regimens. So I want to emphasize that this is a daily drug. Now, patients who are going on this study are adult patients with one or more of those diseases which are listed towards the left of the slide: relapsed/refractory, primary or secondary MF, essential thrombocythemia, MDS, and MDS-MPN overlap syndromes.
The focus of the study at the point where it is is primarily in MF as well as there's a cohort with essential thrombocythemia. Patients have to have a good performance status and platelet counts of 50 or more. There are two parts to the study. Part one is monotherapy, that's the green-colored cohort towards the top, and part two is in combination with ruxolitinib. Let's first look at the part one. Part one has dose escalation and expansion. Dose escalation is enrolling patients with relapsed/refractory MF, MDS, or MDS-MPN overlap syndromes, and there's an ongoing dose expansion in myelofibrosis and essential thrombocythemia. So that's the monotherapy cohort. Looking towards the bottom half, the blue-colored boxes, that's the combination therapy cohort. There too, there's a dose escalation and then a dose expansion.
In the dose escalation cohort, patients with myelofibrosis and suboptimal response to ruxolitinib were enrolled, and the INCB057643 drug was added to ruxolitinib. While in dose expansion, again, the same combination therapy is being delivered in patients with currently chronic phase myelofibrosis and subsequently down the line in accelerated phase myelofibrosis. There's also a cohort that is open to screening for patients who are naive to JAK inhibitor therapy, meaning first-line treatment. The primary endpoint is, of course, safety, tolerability, identification of DLTs. Secondary endpoints are what you would suspect: 35% spleen volume reduction, symptom improvement of 50% or more, anemia response with the definition that is shown on the slide towards the bottom. Let's go to the next slide now. This slide is showing the patient demographics and baseline characteristics.
There are a total of 25 relapsed refractory myelofibrosis patients who received monotherapy in part one and a total of 23 myelofibrosis patients currently receiving drugs but having suboptimal responses who got the combo therapy, the add-on therapy in part two. Patients with myelofibrosis were Intermediate-2 or high. Intermediate one-risk patient population is eligible only in part two combo dose expansion. Now, in this slide, we are only showing results of part two in the dose escalation phase. As you will see from the spleen and symptom rows, the patients had considerable splenomegaly at baseline with median spleen volumes around 2,000 cc. And also, the patients had considerable symptomatology with the mean MPN-SAF TSS score, the total symptom score of nearly 35 in part one and 20 in part two. Let's go to the next slide.
This slide is showing you pictographically the median duration that the patients in various different cohorts have been on INCB057643. The key point that I want to show and emphasize over here is that patients have been able to be on treatment for a relatively long period of time with both monotherapy and combination therapy. These are patients, of course, with relapsed refractory disease or suboptimal responses, and yet they've been on treatment for long periods of time. Let's go to the next slide. This slide is about the safety of the drug. Let's look first towards the left half of the slide. There were two DLTs with monotherapy. There was a patient with hyperbilirubinemia who had myelofibrosis and was in the 12-milligram monotherapy cohort, and then there was a patient with thrombocytopenia who had MDS-MPN overlap syndrome and was in the 12-milligram cohort.
Similarly, there was one DLT in the combination therapy cohort in a patient who had thrombocytopenia with myelofibrosis and was in the six-milligram cohort of combination therapy. Very importantly, let's focus a little bit more on the three cases of AML transformation for obvious reasons over here. There were three patients who had AML transformation. One was a patient with MDS-MPN overlap syndrome. One was a patient with MDS. Now, as anyone who treats myeloid neoplasms knows, these are patients who are at high risk for AML transformation in their natural journey. In fact, for example, the MDS-MPN overlap patient was someone who already had seen a hypomethylating agent and was destined in many ways to progress to AML. So this is not unusual to see. The myelofibrosis patient who progressed to AML was in the combination cohort with ruxolitinib 20 BID and four milligrams of the study drug.
Here too, the patient was at high risk for AML transformation. For example, this patient was an intermediate two-risk patient, in fact, had 10% blast at baseline, so it was accelerated phase to begin with, not even chronic phase, and when this happens, it's not unusual at all, and in fact, very much along the expected lines to see transformation to blast phase disease. Now, on the right side, what you are seeing is that the treatment-emergent adverse event rate was in total 14.8% for discontinuation. Overall, grade three or higher was about 60%. There were three fatal treatment-emergent adverse events, the two AML cases that I mentioned. Two out of those three had fatal outcomes, and one was a patient who had cardiac arrest post-discontinuation after already having had progression of disease. The most common treatment-emergent adverse events are again shown over there.
Thrombocytopenia and anemia were two of the more common ones. Bilirubin increase, nausea, dysphagia rates are as shown in the table. Let's go to the next slide now. This takes us to the efficacy slides. So the first efficacy slide is that of monotherapy cohort, and we are looking at spleen volume responses in 25 patients with myelofibrosis. First and foremost, patients other than the ones who got 4-milligram dose had some extent of spleen volume reduction. And what you are seeing is that the week 24 spleen volume reduction of 35% or more was achieved in three out of seven patients receiving the 10-milligram or higher dose of study drug.
Additional responses as 25% or more spleen volume reductions were seen in even more number of patients, and you can see those best available responses at any time of 35% or more spleen volume responses on the right side of the screen. Now, let's go to the next slide. This is the slide that shows the combination therapy spleen volume responses, so in this add-on cohort of 23 patients with myelofibrosis, spleen volume reductions were observed across all the dose levels. At 24 weeks, SVR35 rate was 24%, so 4 out of 17 patients had that. The best overall response, SVR35, was 5 out of 20, and of course, as you can expect, more patients had 25% or more reduction, showing that the drug is active. Now, moving on to the next slide, we are looking at symptom responses in 25 patients with myelofibrosis in the monotherapy cohort.
Here, you will see that the higher doses provided higher rates and deeper symptom improvements. At 24 weeks, the 50% or more reduction of total symptom score was achieved in 5 out of 8 evaluable patients and 7 out of 19 all evaluable patients. So those 5 out of 8 were the ones who got the study drug at 10 milligrams or more, and as the theme goes, more patients achieved spleen volume responses of, I'm sorry, symptom responses of 50% or more at any time, so 11 out of 20 such patients. Moving on to the symptom responses in the combination therapy or add-on cohort, you have the slide over there. Symptom improvements were once again observed across all the dose levels. TSS 50 rate at week 24 was 50%, so 8 out of 16 patients had that improvement in their symptoms.
Now, let's go to the next slide, which shows the hemoglobin level improvement. So we are now looking at anemia improvement or hemoglobin improvement. We are looking at patients who had either MF or MDS or MDS-MPN overlap syndromes who received monotherapy. As you will see from the graph on the left, for example, in part one dose escalation, there was a general trend towards an increasing hemoglobin level. In fact, anemia responses were observed in six out of 22 evaluable patients, leading to a response rate of 27%. This also included the two out of four baseline transfusion dependent patients who became transfusion independent. And now, moving on to the next slide, you have the hemoglobin level improvements from the combination therapy cohort. Here, you will see that four out of 18 baseline transfusion independent patients saw improvement.
So overall, the anemia response rate was 20%, so four out of 20 overall patients had anemia improvement as seen by this graph. Coming to the conclusion slide, treatment with INCB057643 monotherapy or in combination was generally well tolerated. Two DLTs occurred in the monotherapy cohort at 12 milligrams each, thrombocytopenia and hyperbilirubinemia. One DLT occurred in the combination therapy at 6 milligrams, and that was thrombocytopenia. There were few treatment-related serious TEAEs and no treatment-related fatal events. The three that occurred were not deemed to be from the study drug. The most common treatment emergent adverse events were thrombocytopenia, anemia, nausea, bilirubin increase, and dysphagia. Improvements in anemia, spleen size, and symptom burden, the trifecta that defines myelofibrosis in many ways, were observed in patients receiving the study drug both as monotherapy and in combination with drugs.
Dose expansion is ongoing for both the monotherapy and the combination therapy cohort, 6 milligrams and 10 milligrams as monotherapy, and there's also a cohort for essential thrombocythemia. The dose expansion is also ongoing in combination therapy groups at 4 milligram and 8 milligram doses of the study drug. Enrollment is ongoing for the JAK inhibitor naive combination therapy group as well. Thank you.
Thank you, Dr. Vachhani. I would now like to turn the call over to Dr. Sehn for an update on the results of the study of tafasitamab in patients with relapsed or refractory follicular lymphoma. Dr. Sehn?
Yes, great. So we're going to shift gears and talk about follicular lymphoma, and I'm going to present some data that was just presented at the ASH meeting two days ago in the late-breaking abstract session. But let's start with some background information on follicular lymphoma.
Follicular lymphoma is an indolent, usually slow-growing subtype of B-cell non-Hodgkin lymphoma, and it's quite common because it makes up about 15%-20% of all cases of non-Hodgkin lymphoma. Most patients, however, although we have multiple treatments for these patients, right now we would say that the disease remains incurable. Patients typically go on to experience multiple episodes of relapse or may even have refractory disease at the time of presentation and need to go on to multiple lines of therapy. In general, although this tends to be a slow-growing, well-behaving disease, we know that some people have a more, I would say, stubborn or aggressive form of the disease, and these are patients in general who exhibit refractoriness to their initial therapies, and particularly if they relapse within a short time from initial therapy, which is generally in the first two years.
These patients who are more refractory or have these early relapses within 24 months are really still very much a high unmet need in lymphoma management. Frontline therapy, so initial therapy, still relies on chemotherapy or what we call chemoimmunotherapy because it's usually chemotherapy combined with a monoclonal antibody. In the frontline setting, most people do get this very intensive type of treatment, but what we know is if you go ahead and reuse chemotherapy-based approaches with each time the patient relapses, they tend to get less benefit. Most of the development recently has focused on immunotherapies. Immunotherapies have shown a lot of promise in the treatment of follicular lymphoma, and now I think it's fair to say they're actually the preferred way to go in the relapse refractory setting because, as I mentioned, chemoimmunotherapy stops working very well after the frontline.
But there's still room for improvement with the immunotherapy options that we have, and the goal here is to increase the durability of benefit. One of the immunotherapy options that is commonly used for follicular lymphoma in the relapsed/refractory setting is the combination of lenalidomide, which is an immunomodulatory drug, together with a monoclonal antibody, tafasitamab. This has already been approved for the treatment of relapsed/refractory follicular lymphoma, generally anytime after the first line of therapy based on a study called the AUGMENT study. Now, what we're going to be talking about right now is tafasitamab, which is a monoclonal antibody targeting a different cell surface marker than rituximab, which has been around for a while. So this targets CD19. CD19 is commonly expressed on B-cell lymphomas and expressed virtually on all follicular lymphomas.
When the monoclonal antibody tafasitamab sticks onto its target, it actually induces not only a direct cell kill, direct cytotoxicity, but it actually enhances components of the immune system, specifically NK cells and macrophages, to fight off the lymphoma. We're going to be talking about a study that is looking at adding tafasitamab to lenalidomide and rituximab. We know that tafasitamab has already been approved in a different setting for an aggressive B-cell lymphoma in combination with lenalidomide. I'm going to the next slide that describes the epidemiology of follicular lymphoma. This is data from the SEER database, and it really speaks to the, really in my mind, the prevalence of follicular lymphoma.
We know that the rate of follicular lymphoma is generally 2.5 events per 100,000 people per year, but if you look at the death rate, it's much lower because people do often survive many, many years with their follicular lymphoma. For those of us who treat patients with follicular lymphoma, they do form a big percentage of the patients that we see because they fortunately can live for many, many years but do need to go on and get multiple lines of therapy. The next slide talks about the challenge of follicular lymphoma, and that is that, as I said, it's an indolent behaving disease, tends to grow slowly, responsive to many treatments that we have, but still, as I said, remains incurable.
Most patients live a long time, but there's this group of patients that have more stubborn refractory disease and also a group that can present with evolution to a more aggressive disease. They have a wide range of treatment options right now, but the goal of treatment, because none of those treatments really cure the lymphoma, is really to try and put it into a remission, get treatment benefit by shrinking down the lymphoma and sort of keeping ongoing control over the disease so that patients can have a good quality of life, and so the combination we're going to be talking about really is a novel immunotherapy combination that is really very promising.
Next slide, I'm going to be talking about the inMIND phase III study, which evaluated the combination of CD19 monoclonal antibody tafasitamab plus the commonly used current backbone of lenalidomide and rituximab for relapsed refractory follicular lymphoma. The next slide shows you the design of the study. This was a large phase III trial that was done internationally. Importantly, it was very robustly designed, so it was double-blinded and placebo-controlled, so neither patients nor their physicians knew what any individual patient was getting. But it broadly included adult patients with follicular lymphoma or a small subgroup of patients with marginal zone lymphoma, a different type of indolent B-cell lymphoma. And they were eligible to be on the study as long as they had had one prior line of therapy, so this was for a relapsed refractory disease.
Patients were randomized in a one-to-one fashion to tafasitamab or a placebo combined with the standard dosing of lenalidomide and rituximab for a total of 12 cycles. This is treatment that goes on for approximately a year. The study was stratified, so we made sure that there were equal numbers of the higher-risk patients on both arms by stratifying it for some of the higher-risk features that include that high-risk group of patients that progress within 24 months of diagnosis, patients who have already been shown to be refractory to prior monoclonal antibodies, and also stratified for the number of prior lines. This trial was powered for its primary endpoint, which was progression-free survival in the follicular lymphoma population as determined by the study investigator.
Importantly, there was a primary analysis planned to be done when 174 progressions were observed, and that is what was presented in the abstract and at the meeting and what I'll show you. Looking at the next slide, which is patient disposition, this is a very large trial that included 548 patients with 273 randomized to the tafasitamab arm and 275 to the placebo arm. The data cutoff date was in February of 2024. At that time, there were still some people getting treatment, so about 19% of people in the tafasitamab arm were getting treatment and about 15% in the placebo arm. Importantly, one striking difference that was observed at that time is that there were many more people that needed to discontinue or stop treatment due to progressive disease in the placebo arm.
That was 31% of the patients with a data cutoff block that had to come off treatment for progression compared to only 11%. Almost three times the number of people came off for progression at the time of this data analysis in the placebo arm. Now, the next slide shows the baseline patient characteristics. Importantly, this is a very large trial. It's randomized, and the two arms are very, very well balanced for the important patient characteristics. The median age was 64 years, and that's pretty much in line with sort of the average age of diagnosis of follicular lymphoma. I think one striking thing is that about 20% of people were 75 years and older.
This is a kind of treatment that could be delivered in even very elderly patients because that's quite a high percentage of patients in that age bracket for a clinical trial. The patients, I'd say, are fairly typical to the kinds I see in my clinical practice. Most patients had advanced stage disease. Many of them had what we would call a high-risk FLIPI score, which tends to be associated with higher-risk features. Importantly, they all had a reason for treatment, and most of them had a fairly high burden of their lymphoma that required treatment. The next slide talks about their prior treatment history. As I said, you were eligible to go on this trial if you had had at least one previous treatment, and the median number of prior treatments was one.
45% of people had at least two or more prior lines of treatment. In terms of the treatment characteristics, some of the things that point to the fact that this was quite a high-risk patient group is that 32% of people in this trial actually had that early refractoriness that we talked about, so had progression of their lymphoma within 24 months of diagnosis. Those are the patients that have the more stubborn behaving follicular lymphoma. Also, a pretty high-risk feature is that almost 40% of people would have been considered refractory to their last treatment. That means whatever they had for their last treatment, they actually did not respond to it. Finally, also quite noteworthy is that 43% of people were actually refractory to an anti-CD20 monoclonal antibody.
So that, again, is typically a patient that can be harder to treat with their next line of treatment. So if we move to the next slide, this is really the punchline of the results. So this is the primary endpoint of the study, which was progression-free survival as determined by the investigator. And you can see that the blue curve is the curve that represents the group of patients receiving the tafasitamab, and then the green curve represents the group of patients receiving the placebo. And what we can see is that the tafasitamab added to that backbone of lenalidomide and rituximab led to a very significant prolongation and progression-free survival, such that the median progression-free survival went from 13.9 months up to 22.4 months.
And the hazard ratio here is 0.43, but what the hazard ratio reflects is that really the degree of reduction meant that there was a 57% reduction in the risk of progression in this cohort. So very, very notable. The next slide actually is also very important, and that is that there was an independent confirmation of the improvement in progression-free survival by an independent review committee. And here you can see again that the tafasitamab curve is very much separated and on top of the placebo curve. Here, the median progression-free survival was not yet reached compared to 16 months in the placebo curve. And again, this p-value is highly significant at less than 0.0001, and the hazard ratio is 0.41. The next slide is an examination of individual patient subgroups.
So there was a plan in the protocol to look at some individual groups based on high-risk features or particular characteristics. And what you can see with those bars that sort of run down the middle of the slide is that they pretty much all line up in a vertical line. So what we're seeing is universal benefit across all of the subgroups that were tested. So this study is obviously not powered for all of these subgroups, but it is a way of trying to determine, is this benefit really only occurring in some of the patients, or is it occurring in all of the patients? And this type of analysis is very reassuring that we saw quite sort of consistent benefit across all of these subgroups.
And the big box at the bottom of this slide really reflects those three stratification factors on the trial, so the three important high-risk characteristics that the trial was stratified for to make sure that they were balanced between the arms. And we see that for that group of patients with progression within 24 months, the ones who are refractory to prior anti-CD20 monoclonal antibody, and those patients who have had more than one prior line of therapy, they all consistently benefit from the addition of tafasitamab. The next two slides is a bit of a breakdown on that just to show you the visual of these individual subgroups. So this slide, which says progression-free survival by POD24 status and refractory to anti-CD20 antibodies, the top of this slide reflects the subgroup that was either progressed within 24 months of diagnosis or not progressed.
You can see that those two top progression-free survival curves are fairly consistent. I mentioned that the trial's not usually powered for smaller subgroups, but what's quite striking here is that these curves really do separate, but it does meet statistical significance. So each one of these curves independently meets statistical significance. The lower part of this shows you the patients who, on the left, are refractory to anti-CD20 monoclonal antibodies and on the right who aren't. Again, you can see that there is a significant benefit regardless of whether or not patients are refractory to CD20 or not. Then finally, the next slide looks at the outcomes based on number of prior lines of therapy. On the left, patients who only had one previous line of therapy, which was 55% of the patients on this trial.
On the right side, patients who had two or more prior lines of therapy, about 45% of people on the trial, and both of those show a significant benefit to the addition of tafasitamab. The next slide talks about responsiveness, so with the addition of tafasitamab, we saw a significant increase in the number of patients that actually achieved a complete response by PET scanning and also a significant increase in the number of patients that were considered to have any response, either CR or PR. So the PET CR rate went up by approximately 10%, and the overall response rate went up by approximately 12%. The next slide talks about duration of response, so of those people who actually respond and achieve benefit, what we can see is that the patients receiving the tafasitamab have a longer durable benefit than the patients receiving placebo.
So tafasitamab with the lenalidomide and rituximab led to a longer response than placebo with lenalidomide and rituximab. And the next slide talks. I think this is a very clinically relevant slide. So one of the things we're always thinking about as lymphoma doctors is, when the patient, how much benefit will the patient get before they really need a next treatment. So this is time to next lymphoma treatment. And what we see here is very prolonged by the use of tafasitamab. So the median time to needing a next treatment was not reached versus 29 months in the placebo arm. And the next slide is overall survival. So this slide is a little premature because we know patients can live a very long time with follicular lymphoma. We don't necessarily expect to see any change in overall survival at a very early analysis.
But with 15.3 months of follow-up of overall survival, what we can see is there was a trend for improvement in overall survival for tafasitamab at this early time point. The next two slides really refer to the toxicity. So if we're adding a new drug in, we want to make sure that it's deliverable and safe and doesn't lead to excess toxicity. This first slide talks about any grade toxicity, whether or not it's minor or major in nature. And importantly, across both of the arms of the study, I would say that the side effects were quite comparable. And the most common side effect overall was neutropenia, so lowering of one of the white blood cell components. And it really wasn't that different between the arms, so 45% in the placebo arm and 48.5% in the tafasitamab arm, which is quite similar.
There's nothing really that stood out as being very, very different, but a slight increase perhaps of diarrhea and COVID-19 in the tafasitamab arm. But this trial, of course, was done during the height of COVID. The next slide pulls out the higher grade toxicity. So the toxicities that we refer to as grade 3 or 4 that are more notable. And here again, the most common grade 3 or 4 side effect or toxicity was, again, neutropenia, lowering of the white blood cell count, but almost identical between the arms, so 38% versus 40%. And any differences that stand out, there really is, as you can see, very minor differences. But if we had to point to something, maybe a slight increase numerically in the rate of pneumonia and COVID-19 in the tafasitamab arm.
On the right side of this slide, it speaks to the deliverability of the three drugs. So aside from side effects, we want to know whether or not adding a third drug in here is going to limit the ability to give the original two. And it's reassuring to see that there was no difficulty giving the whole combination together. So adding the tafasitamab in did not increase the requirement for dose delays or dose reductions. The lenalidomide and rituximab was able to be given on the general schedule. In terms of the next slide, so the next slide talks about number of deaths that were reported at the time of this analysis. There were 15 in the tafasitamab arm and 23 in the placebo arm.
Strikingly, if we look at the cause of death in the two arms, there were only five deaths reported due to progression in the tafasitamab arm compared to 17 in the placebo arm. So a higher rate of death due to progression was observed with this analysis. And importantly, no difference in the death rate due to any adverse events, which were typically related to infection. The next slide, I think, is quite important is that this slide compares the patients on this trial compared to the original trial that was done that initially led to the approval of the backbone lenalidomide and rituximab. So lenalidomide and rituximab is approved already. This trial is aiming to add the third drug in.
We did see that in the placebo arm of this trial, the curve was a little bit lower than would be expected based on the results of the AUGMENT original study of lenalidomide and rituximab. But this trial compares the characteristics of the population and generally really demonstrates that patients on the current trial we're talking about inMIND were much higher risk than that previous trial. So it really does explain why the curve in the placebo arm might be a little bit lower than anticipated. These were much higher risk patients. So the last slide I have is really the conclusion slide, and that is that this very large phase 3 inMIND trial met its primary endpoint of improving progression-free survival with the addition of tafasitamab to lenalidomide for patients with relapsed refractory follicular lymphoma.
It was a very significant improvement with a 57% reduction in the risk of progression, relapse, or death. The benefit was consistently seen across all the important patient subgroups, including the high-risk subgroups. It's too early to say anything definitive about overall survival, but it's quite notable that at this very early time point, there was a trend in favor of the tafasitamab for overall survival as well, and importantly, the safety profile was pretty much as we'd expect with the drugs being used and manageable and quite comparable between the two arms. This, I think, is a very important study because it's the first one to ever demonstrate and validate the approach of combining two monoclonal antibodies in the treatment of follicular lymphoma.
This is a regimen that can easily be administered, as I said, broadly to the general patient that we see, to older patients, but it can be administered in community settings as well as academic settings. It really stands to become a potential new standard of care for patients with relapsed/refractory follicular lymphoma.
Thank you, Professor Sehn and Professor Vachhani. I really appreciate your remarks and respect to studies. I'll now just spend a few minutes contextualizing a little bit in the context of Incyte and where we plan to go forward with these programs and give you some development updates. First, to talk about the BET phase 3 development plan. The intent of the entire program is to file a new drug application and secure the approval for patients with myelofibrosis before 2029 in the United States.
The initial pivotal program will initially evaluate the BET inhibitor in a phase 3 monotherapy study in a post-JAK population, the relapsed refractory intolerant population, in keeping with the data that was presented for you today by Professor Vachhani. Just to give you a sense with caveats on cross-trial comparison and small sample sets, but our data at 10 milligrams, as we're showing to you today for SVR35, had a 43% rate of SVR35, and for TSS50 had a 63% rate. And again, with those caveats, the competitor data, pelabresib, in the MANIFEST study was much lower, 17% SVR35 and a 38% TSS50. We think the ability to continuously dose our drug may be a differentiating factor and certainly may help in symptom control given that there's no off therapy period.
Our future plans, pending further safety data in early aligned settings, is potentially worth regulatory consultation to move forward in combination with ruxolitinib in a first-line JAK naive population. But we will see how that develops over 2025. The actual study that we'll show you has been submitted to the FDA for commentary, and we're ready to go in 2025, pending any other regulatory input. If you move to the next slide, I'll show you the actual proposed study schema here for you. It is a randomized open-label study versus best available therapy, traditional primary endpoint of SVR35 at week 24, a key secondary endpoint of TSS50 at week 24 as well. Target population is MF alone, so it's not including those MDS or MDS-MPN overlap patients, patients with platelets of above 100,000.
In terms of risk categories, these are the populations that, as Professor Vachhani showed you, intermediate-2 or high, with much worse prognosis and overall survival. Patients will have required to have one prior JAK therapy, but no more than two. The target end is 195 patients with a 2:1 randomization, and we will go with the 10-milligram dose given that is the best data in terms of therapeutic ratio and efficacy seen. The study will also be stratified by anemia and the risk category. After the week 24 endpoint, patients will be able to receive BET when appropriate in consultation with their physicians.
The next slide talks about tafasitamab and the practice-changing data just presented to you by Professor Sehn in follicular lymphoma, given the phase 3 inMIND study, with that primary endpoint of progression-free survival showing a 57% reduction in the risk of progression, relapse, or death, and observed across all the pre-specified subgroups. There's also the favorable trend in overall survival, although the data is still immature, and a manageable safety profile with the addition of tafasitamab to the R-squared regimen. And the first study to validate the approach of combining both a CD19-directed antibody with a CD20-directed antibody for the treatment of FL. It has the potential to address, if you look at the United States and Europe, upwards of 23,000 patients with relapsed refractory follicular lymphoma.
The filing for the sBLA will be in at the FDA before the end of this year, and thus we expect approval in the second half of 2025 given this dataset. I'll also remind you that the diffuse large B-cell lymphoma study in 899 patients with the IPI 3-5 risk groups of first-line diffuse B-cell lymphoma has completed. Again, there was Tafa-Len plus R-CHOP versus placebo R-CHOP, primary endpoint PFS by investigator. That study is anticipated to have data in the first half of 2025 and has the potential for that IPI risk group in first-line diffuse B-cell lymphoma to address approximately 32,000 patients in the United States and Europe. The next slide just gives you a sense from a good data source, looking again at tafasitamab in relapsed refractory follicular lymphoma, of how in the real world R-squared is used.
It's a very fragmented treatment landscape, as Professor Sehn was alluding to earlier, but despite that, R-squared is the most prescribed regimen in second-line follicular lymphoma, 23% in this dataset, another 8% in third line, giving you about 30% of patients receiving R-squared in the setting, so giving you the potential for tafa to achieve significant market penetration here. The next slide just gives you a sense of where we are in terms of development at Incyte. I'll just quickly go through it.
We did exactly what we said we would do in 2024 with the pediatric AD submission filed, axatilimab approved in third-line graft versus host disease, the BET and ALK data presented at ASH, the retifanlimab phase 3 data both in non-small cell lung cancer and squamous cell anal carcinoma, just showing you the follicular tafasitamab data, and the CDK2 data that we presented at ESMO with the intent to pursue registration in ovarian cancer in 2025. In the first half of 2025, and looking at the second half as well, we'll have RUX cream phase 3 data in prurigo nodularis. We'll initiate the RUX cream phase 3 in mild HS, and we expect the pediatric approval there in the second half of 2025.
Povorcitinib, a very important big year for the povorcitinib program with the phase 3 data in HS in the first half, as well as the phase 2 proof of concept data in CSU and then in asthma in the second half of 2025. Then just to reiterate what we spoke about today, the pivotal study initiation for BET in 2025 and various other important milestones there, including the bioequivalence data for RUX XR in the first half of 2025, expected approval for retifanlimab and squamous cell anal carcinoma in the second half of the year, as well as the follicular approval. With that, this will conclude our prepared remarks. We're nearly on the hour, so we'll keep the call open for as long as we're able to answer a few questions from the audience. Thank you. If you'll just give the instructions, Operator.
Certainly.
We'll now be conducting a question-and-answer session. As a reminder, in the interest of time, please ask one question and then return to the queue. If you'd like to be placed in the question queue, please press star one at this time. Once again, that's star one if you're placed in the question queue, and please ask one question and then return to the queue. Our first question is coming from Salveen Richter from Goldman Sachs on the line now.
Hi, thanks. This is Matt on for Salveen. First, I just wanted to see if you could confirm that the AML transformations are not a concern at all for moving forward. And then you highlighted the 10-mg dose as a potential go-forward for phase 3.
Could you share anything on what the safety or tox profile looks like for that, or should we just assume it looks like the dose escalation column? Thank you.
Yeah, Matt, that's Steven. So as Dr. Pankit Vachhani said, the natural history of this condition ultimately includes transformations. But in our dataset in MF, we have one case of AML out of 48 patients with about a 2% rate and a median exposure of 170 days. We think that, and Dr. Justin Watts said on the podium as well over the weekend, that that is in the acceptable range. Obviously, it is something we will continue to monitor very carefully, but that is something that we are not worried about, just to paraphrase your question, at the moment given the data we have seen. Our compound is not genotoxic in the three assays that are commonly done, so that is also reassuring.
The dose is pending some regulatory discussion, but the 10-milligram dose for us weighs the therapeutic ratio between the on-target thrombocytopenia and what we think is very compelling efficacy in terms of the SVR35 and particularly the symptom profile with a continuous dosing upwards of a 60% plus TSS50. So we like what we see there, and that's what we'd like to take forward pending regulatory discussions. Thanks.
Thank you. Next question is coming from Michael Schmidt from Guggenheim Securities. Your line is now live.
Hi, this is Paul on for Michael. Thanks for taking our question. We appreciate the slide that showed the R-squared usage rate right now in second-line plus follicular.
So would you largely expect the inMIND regimen to sort of take share from just that 20%-30% slice of patients who would otherwise get R-squared, or is there potential to be used more broadly given the efficacy benefits you saw? Thank you.
So if Hervé here maybe I can take that. I mean, we think it can be used broader than just the current R-squared share, if you want. But R-squared itself is already like 30% of patients. We spoke about 23,000 patients that could be potentially eligible for this. So it will be a meaningful contributor to the growth of the brand, obviously, and we think it would be meaningful to the overall portfolio. Now, how large could it be? What you heard is it's relatively easy to give.
The additional side effects that we have seen are not really preventing anybody from using this new combination, and we think it will be fairly broadly used, yes.
Thank you. Next question is coming from Tazeen Ahmad from Bank of America. Your line is now live.
Hi, good afternoon. Thanks for taking my question. For the BET inhibitor for the monotherapy cohort that you studied, you did have that 28% discontinuation rate. How is that comparing to what your expectations would have been, and how does that impact the dosing that you're considering going forward? Thanks.
Yeah, hi, it's Steven. I think from the dataset, just remember we're treating a phase one dataset of patients who are sort of heavily pretreated, pretty beat up.
So the expectation is, as we sort of narrow down and define the population more clearly with more clear dosing guidelines, given that we'll be on a set established dose, that that discontinuation rate will come down appreciably. We wouldn't want it to be 30% in a pivotal study at all. That was across all doses at different time points. So it's not a controlled phase three experiment discontinuation there. Just to complete that thought, if you look even the difference between the dose escalation and the dose expansion cohorts, the discontinuation due to adverse events drops from 27% to about 10%. So you would expect us to treat better patients that to come down.
Thank you. Next question is coming from Brian Abrahams, RBC Capital Markets. Your line is now live.
Hi, this is Kevin on for Brian. Thank you for taking our questions.
As you think about the regulatory path for your BET program, are you considering potentially absolute TSS for potential combination studies in the future as a key endpoint? And generally, what's your thought there on absolute TSS maybe versus TSS50? Thank you.
Yeah, Kevin, it's Steven. You see some movement in the field to capture that as a potential better way to look at symptoms as a continuous variable over time. It's something we capture anyway, so we can look at the TSS50 or the change over time and discuss that with regulators as to what's the appropriate point. We don't think that's in any way sort of a controversial area. It's something we'll capture both. And again, to reiterate and be somewhat repetitive, the symptom score in this open label study thus far with continuous dosing is really encouraging there, either way you calculate it.
Thanks.
Thank you.
Next question is coming from Kripa Devarakonda from Truist Securities. Your line is now live. Hello, Kripa, perhaps your phone is on mute.
Oh, sorry about that. Thank you for taking my question. So in the lymphoma trial, the triplet was compared to a doublet, but when we think about competition in the real world, what do you think are the right second-line benchmarks to compare the triplet to? And maybe this is the safety. When we're looking at the safety, when you add tafasitamab to the doublet, it does not seem to have worsened the safety profile versus the control arm, which I think is really impressive. But we've heard some concerns from lymphoma doctors regarding the safety of the doublet, the lenalidomide-rituximab doublet. Just wanted to see your thoughts given that you've seen all these data now. Is that a concern?
Have you heard anything at all on that?
So let me ask Dr. Sehn to comment on the two points you're asking, which is one, is this the appropriate comparator in patients with relapsed refractory follicular lymphoma? And second, the safety both of the doublet and the triplet in the context of the study. Dr. Sehn, if you could address those two points, it would be great.
Yes, definitely. So as I mentioned, I think there is a real move away from chemoimmunotherapy in the relapsed refractory setting. As with anything, as data emerges, practices sometimes can be slow. So what we saw is that maybe 30% of people are receiving R-squared, but I think moving forward, it will be much higher that there's definitely a message going out that reusing chemoimmunotherapy is just not the best thing you can do for patients anymore.
And so with immunotherapy becoming more and more desirable, R-squared is the only immunotherapy approved in the second-line setting. And this trial, of course, included patients second-line and beyond second-line. So I think R-squared is the most common immunotherapy currently used in practice in follicular lymphoma, and it's the only one that's approved second-line and beyond. So I think it is the appropriate comparator, but of course, in this trial, tafasitamab is being added to it as a backbone. So I would say that my expectations is the very positive message that will come out of this trial will make this approach with R-squared backbone more desirable and probably increase the use beyond where it is right now. But certainly, I think it's the right comparator.
This data sort of tells me that if you're going to use R-squared, you really would want to use the triplet combination because of the real improvement in efficacy with comparable toxicity.
Thank you. Next question is coming from Jessica Fye from J.P. Morgan. Your line is now live.
Hey, guys. Good afternoon. Thanks for taking my questions. For the planned phase three for the BET inhibitor in post-JAK patients, how do you think about the SVR35 response rate that you expect for best available therapy there, and what would represent a clinically meaningful improvement on SVR35 relative to the control in this post-JAK setting?
And then second, if I could, for the mutant CALR product and the JAK2 V617F product, the data boxes on the slide span both the first half and second half of 2025, whereas the other catalysts are mostly split up between first half and second half. Can you help us think about when to expect those updates and why it's sort of presented that way? Thank you.
But Steven, I'll do the first part. Pablo will answer your second question. So again, we're just pending some regulatory feedback. But should that go well, the BAT menu is a menu of five or six different therapies, including Hydrea, danazol, etc. The SVR35 response rate for that in this particular setting is often single digits at best, sometimes not even there.
Then if we replicate our data, even with the caveats around small datasets, you can see we should be appreciably more than that. So the delta should be more than encouraging, clinically meaningful, and significant to get it across the finish line in that regard. It's hard to give you an absolute BAT number, but it's probably at best in the 10%-15% range for BAT there. Your second question, Pablo will answer.
Yeah, happy to do that. So look, I think this slide is pretty consistent, Jess. When you look at phase two, phase three studies or approvals, we've given you a half, whether it's the first half or the second half, to give you to narrow a little bit the range of when you should expect that data.
When you look at the phase 1 ongoing studies, proof of concept studies like mutant CALR, 617F, G12D, TGF beta, and CD122, we are committed to providing data next year. Whether over time we can narrow that range, we'll decide in the future. There are ongoing dose escalation studies, so there's a lot of moving parts. And at this point, we didn't want to provide to really promise data at a very specific point in time. That's all. But if you look at this slide, all of the phase 1s, there's five phase 1 readouts next year. All are very wide bars, you can see.
Great. Thank you.
Yep.
Thank you. Next question is coming from Marc Frahm from TD Cowen. Is that live?
Hi, this is Alex. I'm from Marc. Thanks for taking my question.
In first-line DLBCL, we've seen limited adoption of the polatuzumab regimen despite it having beaten R-CHOP. What do you think Tafo's first-line trial needs to show in order to drive more significant adoption? Thanks.
Yeah, Steven, I can talk from a clinical point of view. If you look over the last few decades, it's been almost impossible until recently to beat R-CHOP with its 50% plus "cure rate" until the POLARIX reported data with PFS and event-free survival and then actually went to an advisory committee. I think the uptake from my vantage point has been pretty good given that and speaks to doctors will use drugs when you improve cure rates. If you look in our data, we'll deliver first half of next year in terms of 900 patients in this particular IPR 3 to 5 setting of first-line diffuse large B cell.
And we have to have both a statistically and clinically meaningful improvement in the endpoint to get use there. And we'll see. It's hard to estimate exactly what that magnitude has to be. Just to differ from you a little bit, I think, and being repetitive, that the uptake's been pretty good given what the data showed already for POLARIX. We think we have a more tolerable regimen than that. We don't see some of the side effects that are seen with the CD79 directed antibody. You just saw our side effect profile in line. So if you get the efficacy in a more tolerable regimen, it may even be better in terms of uptake. We'll see.
Thanks.
Thank you. Our final question today is coming from Jay Olson from Oppenheimer. Your line is now live.
Oh, hey, congrats on the progress, and thanks for providing this update.
Have you seen any evidence of fibrosis improvement with your BET inhibitor? And is there a potential to demonstrate fibrosis improvement in your registrational trial for potential inclusion in the FDA-approved label?
Jay, thank you. It's Steven. Really good question. In the phase one study, we didn't incorporate serial bone marrow biopsies to ascertain that. We know the prior BET inhibitor has done that. It is subjectively difficult to read, and it's hard to score fibrosis. And to date, it's not an established regulatory endpoint, as you know, but can help point to disease modification. The current intent is not to incorporate serial bone marrow biopsies at this point. Thank you.
Thank you. We conclude our question and answer session. I'd like to turn the floor back over for any further or closing comments.
Thank you for participating in today's call and for your questions.
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