Incyte Corporation (INCY) Earnings Call Transcript & Summary

All right. Good evening, everybody. Thank you for joining us. We'll start the meeting. It's really good to be here at the American Society of Hematology in person, in New Orleans, and this meeting is also joined by people on Webex as well. So thank you for being here. I just want to tell everybody from the beginning that safe harbor rules govern my remarks, those of my colleagues on the stage with me tonight and as well as any forward-looking statements, and I'd tell you to consult our SEC documents and for risks associated with anything we speak about. In terms of tonight's agenda, I am Steven Stein. I'm the Incyte Chief Medical Officer and Head of Development, and I'll be taking you through the agenda tonight and then at the end, wrapping up and -- as well as the Q&A, for which we should have about 15 to 20 minutes if everything goes according to plan. The presence we have at ASH is a really big deal for Incyte this year, both quantitatively and qualitatively. We had 57 abstracts accepted, 16 oral presentations, including oral plenary paper presented today at the plenary session and then 33 poster presentations. And that for us is an enormous effort, and we're very proud of everything we've done related to the American Society of Hematology and particularly the LIMBER program, which represents the bulk of what we'll be talking about tonight. Just to focus you on the pipeline and the areas we will talk about in some detail tonight as regards to what we call the LIMBER program is the PI3-kinase delta inhibitor and then the BET program, the ALK2 program and the mutant-CALR antibody that we unveiled for the first time publicly today, which we use the number 989 for. Just a reminder of the rest of our pipeline across the rest of Hematology/Oncology there for you and just to allude to tafasitamab, MONJUVI, a CD19 directed antibody in second-line diffuse large B-cell lymphoma, ongoing work in first-line diffuse large B-cell lymphoma as well as follicular lymphoma. And then very recently and something we're also very proud of is the orphan indication, the myeloid lymphoid neoplasm that's FGFR1-driven which we now have an FDA indication for pemigatinib. And then the rest of the pipeline in terms of dermatology, obviously, we're not speaking about tonight and other compounds, which are on the bottom right of your screen, for which you receive royalties. The agenda is here for you. Again, very happy to have with us tonight, Professor Verstovsek, a professor at MD Anderson Cancer Center, a recognized thought leader in the space and also Croatian by birth and allegiance in terms of soccer allegiance, which is really, really important in terms of the World Cup for those of you who follow it. And then following Professor Verstovsek will be Professor Yacoub from University of Kansas, who will talk about the Phase II data presented at this meeting for our combination of parsaclisib plus ruxolitinib, which enabled us to at least internally declare a proof of concept and then start our efforts in terms of registration efforts in a suboptimal study with ruxolitinib in combination randomized against rux and a first-line study using the same schema, Dr. Peter Langmuir, who is the physician in charge of all our LIMBER efforts, which are many, will talk tonight about the data we've shown at this meeting for our ALK2 inhibitor 928, and then our BET inhibitor, 57643 as well and show you where we are in terms of those programs currently and then potentially where we may head in the future in terms of those programs. Dr. Patrick Mayes will then present the mutant-CALR antibody, and then we'll wrap up with the Q&A. So that's the plan for this evening and the times associated with them. With that, I'll hand the podium over to Dr. Verstovsek to take us through myeloproliferative neoplasms.

Good evening, everybody, and I say, Go Croatia, go. Thank you for that note. This is very kind of you. So as you said, I'm Srdan Verstovsek from MD Anderson Cancer Center, and very much appreciate having opportunity to join you today for this wonderful gathering because it's a very exciting time, again, with us facing a new drug development in new directions. And particularly, the plenary session provided some insights to where the whole field is getting, and that is treating patients with the particular molecular signature to eliminate disease, and we're going to end up with that at the end. But for the beginning, we're going to talk a little bit in general what the myelofibrosis is. As you know, chronic myeloproliferative neoplasms, disease of the bone marrow that is driven by hyperactive JAK/STAT signaling related to different mutations, as I'm going to explain in a second, that leads to uncontrolled myeloid proliferation and uncontrolled inflammation, which means abnormal levels of cytokines. This uncontrolled growth and inflammation leads to several critical findings when you examine patients with myelofibrosis. And perhaps your focus is on the photo first because it's really what happens with that patient with the hematological disease, the anatomy of the body is completely changed, huge spleen and of course, the big liver as well. with the bone marrow fibrosis, which is left to the photo. And what then you have is abnormal blood count because the bone marrow doesn't really work well. The quality of life is extraordinary bad and it gets worse over time. It's not a nice picture to have an older person with such a big spleen and suffering from all the symptoms that are listed to the right. You can only imagine how that looks. And with the extraordinary effort, the team effort between the Incyte as in academia in patients, we were able to develop, as you know, first ever therapy approved for myelofibrosis and that was ruxolitinib. But when you ask the question, why do I treat the patient? You would say there are three reasons why to initiate the therapy. That would be improvement of the symptoms, of course, and then reduced splenomegaly to make it smaller and asymptomatic, but then there is also issue with the bone marrow production of the red blood cells and anemia is the #3. What ruxolitinib does very well is seen in the graph here, a very quick improvement in the quality of life within a month, 4 to 6 weeks, you get the maximum benefit, and that is usually described as half of the symptoms gone. And then you have a waterfall to the right, which we will tell you in very easy way to understand that almost every single patient has a degree of improvement in spleen with ruxolitinib when the control arm didn't do much at all. So the benefits are on two out of three critical parameters here, spleen and symptoms. And finally, as we now know, for a number of years, that the good control of proliferation and inflammation leads to prolonged life. That has been even recognized by the FDA in 2014 and was seen and has been seen since by many investigators around the globe. The critical evidence here from the COMFORT study shows you an easy-to-understand way that ruxolitinib in the green color would make people live almost 6 years on average. When these patients, by the way, by the reach of their pre-therapy characteristics would, on average, live 3 years. And that actually is true. If you look through the purple color, that would be in a simple way, a group of patients that have never ever received ruxolitinib, and the blue color is the survival patients that were in control arm, but majority of them crossed over to ruxolitinib. So we have three lines from no exposure to crossing over to ruxolitinib and fully from the day one exposed to ruxolitinib. So based on this data, I'm very comfortable usually to tell the patients and colleagues that on average, you would expect about 3 years of gain of life with ruxolitinib. Now we are not eliminating disease and there is a certain duration of the benefit, duration of response with ruxolitinib, as you see in the curve on the right, is about 3 years. Disease progresses, we lose the control of the disease features, the spleen starts to grow, anemia may worsen, platelets may go down. The management of anemia, while people are on ruxolitinib is another area of concern, area of unmet need to say. And finally, we would certainly like to up the bar from controlling the spleen symptoms or anemia to elimination of the disease. That would certainly make people live longer. So what do we do today? To address unmet needs with novel targets in development here at this meeting today, we go to PI3-kinase inhibition because there is a potential synergies with the cataract in PI3-kinase signaling along with the JAK2 signaling, and that would possibly then prevent disease progression and further control the signs and symptoms of the disease, or a BET inhibitor, which is, of course, epigenetic modifier and that would be a different angle in controlling the cytokine expression and genetic expression in bone marrow in general and possibly over time, decrease the fibrosis in the bone marrow. Both of them would be leading to control of the disease for much longer, with additional benefits on improving the anemia or decreasing the progression. But exciting part on the management of anemia for which we do not have any drug approved at all in myelofibrosis is development of ALK2 inhibitor. As you know, that is now a validated target for us to hope that with the inhibition of ALK2 or ACVR1, you would eventually have improvement in red blood cell production, which would easily then complement the therapy with ruxolitinib and with two medications. For example, you would be able to control the spleen symptoms and anemia at the same time. And finally, the calreticulin blockade and that is something that is completely novel, that's why it was on a plenary session, has the potential to eliminate disease to a large degree, and then we move to talking about partial response or complete response, where there is no evidence of disease. And of course, that would then lead to resolution of problems with the spleen symptoms or anemia. Now the driver mutations, this is how we call the mutations that activate the JAK/STAT pathway are, as you see on this slide, distributed in different percentages in patients with primary myelofibrosis to the left in the middle would be essential thrombocythemia, another disease of the bone marrow that manufacts itself with the high platelets and occasionally high vitals. And then the JAK2 mutation is predominant almost in all patients with PV to the right. And that's why we talk about extending the benefit of some of these therapies, particularly calreticulin directed therapy to ET patients. So this is the classic, one of the three classic MPNs, which is a little bit different than the myelofibrosis. In this disease, myeloproliferation is really present in everybody. Patients have a high platelets, some have white cells, some don't feel well and may have a big spleen. There are many, many more patients with ET than myelofibrosis. As you can see, maybe, of patients live, and I would say even more probably, with some risk of progression to myelofibrosis and acute myeloid leukemia. In this entity, we usually aim for control of the blood cell count as a surrogate marker for control of the blood clotting, and we do not have any evidence of any therapy, eliminating disease. So what do we do about these patients? We look at the thrombotic risk and we utilize this particular prognostic scoring system where to make it short at the bottom of the table, patients that we call high risk are the one that should be receiving cytoreduction therapies to decrease the blood cell count. These are people who had a blood clot in the past or are older than 60 and have a JAK2 mutation. We don't have any therapy again that would eliminate disease. So no therapies that would be able to eliminate disease or partially controlled disease where normalization of blood cell count symptoms and spleen would be normality as the control of that entity. So in that setting then, with ET to being a focus on this slide, we have some other medications in development. Ropeginterferon is in a Phase III study for approval as a second-line choice. Pelabresib, bomedemstat are in earlier stages. We do not really have a good understanding of pelabresib activity so far. There are some benefits, but unfortunately, a lot of toxicities with bomedemstat in new pilot Phase II study. And today, we're going to learn about our approach here together on the calreticulin possible elimination. There are others, you see a Phase I study with a vaccine that would be an effort to boost the immune response to possibly control the growth of these malignant cells. So in conclusion, to summarize the introduction on myelofibrosis and ET, ruxolitinib is worldwide standard of care for patients with myelofibrosis, by which we are reducing the spleen and improving quality of life. And it is truly the only therapy that we know proven to prolong survival of the patients with myelofibrosis. But the disease is progressive and therapies are needed for other indications like anemia, preventional progression, and novel agents that we talked about briefly now, and we're going to talk about them in much more detail are much welcome to change the standard of care. And most exciting, of course, this muted calreticulin antibody that we learn at plenary session has unique potential of elimination of the disease. So I thank you very much, and my good friend here, Dr. Yacoub, will take over and tell us about parsaclisib.

Good evening. This is definitely a week of celebration in which I got the opportunity to present this positive study in the ASH meeting and hopefully move the field a little bit forward. So I got the opportunity to present the final results of this Phase II study and show the positive findings that we identified. Dr. Verstovsek presented a very thorough review of how we approach myelofibrosis. Ruxolitinib has been our standard of care for myelofibrosis for good reasons. It's an active drug for spleen volume reduction, for improving the symptoms and for improvement of overall survival. Ruxolitinib has been and continues to be and likely will always be the standard of care for patients with myelofibrosis. All our approaches have been targeted at improving how ruxolitinib works. And many of those combinations aim to achieve a higher result with the same therapy and basically boosting the benefit that we get with ruxolitinib. And based on that concept, we identified that there's some optimum response in myelofibrosis that can be attributed to signaling through PI3K pathway in myelofibrosis cells. This is a very well understood pathway in cancer, and this has been addressed in many diseases actually. So this concept is a valid and it's been studied thoroughly in many diseases. And it could represent a pathway of escape. Parsaclisib is a unique PI3K-delta that is targeting the delta subunits, thus providing a very favorable safety profile, once daily dosing and would be a good partner for ruxolitinib. And the way we decided to study this is to add parsaclisib to a backbone of a steady dose of ruxolitinib. This way, any additional benefit will be attributed to parsaclisib per se since the patient already had been on a stable regimen of ruxolitinib, the standard of care. So why are we doing this? So ruxolitinib is an active agent. And in many of our clinical trials, a good proportion of patients, 40%, up to 60% of have actually achieved the maximum response, which we, arbitrary, define as a 50% reduction of symptoms and 35% reduction in spleen volume. And we know that the depth of response is the must predictor of the duration of response and patients' benefit. So for some of the patients who have not achieved the maximum response, how can we add an agent that does not have additional side effects that could bring those patients up to speed with the better performing patients. And that is the concept of add-on approach. Incyte was one of the first companies to design an add-on approach to ruxolitinib, and that model has been adopted by many other agents to copy and the same development design with add-on approaches to have standard ruxolitinib approach to patients. This scientifically made great sense. There's been in vitro evidence that the combination of a PI3K parsaclisib and ruxolitinib has significantly more activity than either agent alone in patients with myelofibrosis. And the design of the study was for patients on ruxolitinib receiving the standard of care ruxolitinib on a steady dose for at least 6 months, a stable dose for the last 8 weeks and continue to have disease-related symptoms, continue to have enlarged spleen. So the response will be described as favorable, but not optimum, suboptimum response. And in which -- in these patients, we designed a 4-stage study with different dosing schedules of parsaclisib to identify the optimum dosing schedule and the optimum dose in which we can help patients. So after this extensive design, the simple dosing of once a day ended up being the winner arm. So I'm going to go over some of those background details of those patients on that study. So these are patients who have lived with myelofibrosis for an average of 2 to 3 years and have been on a ruxolitinib therapy for 1.5 years, which is really the best therapy one can offer for those patients. And the average dose of ruxolitinib was roughly 15 milligrams twice a day, which is one of the higher dose levels for patients. So no one would disagree that this is an optimum -- optimized therapy with ruxolitinib. And despite all of that, they continue to have enlarged spleens, both by exam and by imaging, and they continue to have disease symptoms. So these are the patients who are benefiting, but could be optimized. And those are the patients who are eligible for this protocol. So what did we find? To start with, the combination was well tolerated. As you can see, patients have been on therapy for a 47-week by the time when the study ended, which is a testimony to the safety of the therapy. The median dose of parsaclisib was 5 milligrams, which is the planned dose. That means there has been very little intolerance or interruption of therapy. The median dose of ruxolitinib was unchanged. So we did not need to reduce ruxolitinib dose on therapy. So the combination really was not associated with any toxicities that required lowering the dose or interrupting the dose. And two, as we speak, there are 13 patients who continue on therapy even after the study has ended, they're on a compassionate care or open-label protocol. So in terms of activity, so for patients on an optimized dose of ruxolitinib, the addition of parsaclisib resulted in additional splenic volume reduction, both observed at weeks and at week 24. Some of those responses were deep, as you can see on the slide. In addition, the addition of parsaclisib resulted in remarkable improvement of symptoms, was observed in week and was further obvious at week 24 with the actual 50% reduction being observed in nearly 50% of patients. This is a bar that has not really been met by any add-on study that has been presented so far. In addition, this benefit is very almost immediate. It was observed as early as 4 weeks, which in our practice is the first visit you see the patient after you started their investigational therapy. So patients reported that as early as their first office visit after starting therapy. Now in terms of safety, we looked at, as a new agent, we're going to go over a thorough description of the side effects, but the adverse events that are of special interest that would be a concern in this setting were reported on that table on the right, and there's a lot of zeros on that table. There's really -- we haven't observed any of these stigmatic adverse events people would observe with this class of drugs. And in regard to the thrombocytopenia, we allowed patients with severe thrombocytopenia and anemia and transfusion dependence on the study and there was very little discontinuation because of that. If anything, most patients remain at the same gross level of platelets and red cells. And to demonstrate that further, this is the platelet count and the hemoglobin levels for patients on the study, which shows stability throughout the study. So to summarize, the addition of parsaclisib to patients on an optimized but dose of ruxolitinib, but suboptimum response resulted in further clinical benefits without additional toxicities and without loss of dose intensity of ruxolitinib. And then this positive data has led to two randomized Phase III clinical trial. One is investigating this combination in first-line setting, if that's positive, that will change the standard of care for our patients in which a combination would be the new standard of care. And the other study is the add-on approach in a Phase III setting in which when that study is positive, that also will be a standard of care in which we add parsaclisib to patients on ruxolitinib and suboptimum response. Thank you very much for your attention. Thank you.

Thank you, Dr. Yacoub. So again, my name is Peter Langmuir. I'm responsible of clinical development of our LIMBER projects in MPNs and GVHD, and I'll talk about our ALK2 inhibitor and our BET inhibitor. So first of all, the ALK2 inhibitor. So this is a slightly different approach from a lot of the other combinations that we're going to talk about today and that have been presented here at ASH. And that those other combinations are primarily focused on improving spleen and symptom response. But with ALK2, what we're looking at here is trying to improve anemia. And so we know that in patients with myelofibrosis, anemia is very common. It's one of the major complications of the disease. And in MF patients elevations in hepcidin are correlated with higher risk scores and associated with poor outcomes in myelofibrosis. And we know that a lot of the elevated cytokines that are present in MF stimulate excess levels of hepcidin. And this excess hepcidin leads to abnormalities in iron processing, ultimately leading to anemia. And so our hypothesis is that 928, which is a ALK2 inhibitor, will down-regulate hepcidin expression, mobilize iron for erythropoiesis and hopefully improve anemia. And the potential benefit here is twofold. First of all, primarily as the direct benefit on anemia, which again is one of the primary factors in myelofibrosis. But we also know that ruxolitinib causes anemia itself. And so there's a potential as well by ameliorating ruxolitinib-induced anemia is that we can optimize the dose of ruxolitinib and thereby improve splenomegaly, improve the activity against splenomegaly and improve symptoms as well. So it's a 2-pronged approach. 928 is very potent. It's very selective for ALK2 compared to the other ALK family members in our preclinical in vitro models. We show very clear inhibition and downstream effects of inhibition of ALK2. And so this -- the encouraging preclinical data led to the study that has been presented here at ASH or -- sorry, forget it, it's tomorrow let's say. So the ALK2 study is a two-part study. The first part is looking at 928 as monotherapy. These are patients who have previously been treated with the JAK inhibitor. It's a dose escalation study that is currently ongoing. And then following along behind that is a cohort looking at the combination of 928 with ruxolitinib. And this is in a very similar population to what Dr. Yacoub just described for the suboptimal responders for parsaclisib. So these are patients who are on a stable dose of ruxolitinib for at least weeks and are either transfusion-dependent or have symptomatic anemia. And again, this is a dose escalation part of the study that's currently ongoing. So we're presenting here data from the ongoing study, again, the dose escalation is still continuing for both of these. But if we look at the baseline characteristics, we have 14 patients so far in the monotherapy group. We have 4 patients in the combination group. All these patients at baseline have high levels of hepcidin. They're all anemic, you can -- it's fairly small inhibitor, the hemoglobin's range between about 7.5 and 8. So these are quite severely anemic patients, and the majority are transfusion-dependent. So this is exactly the population we're trying to target with ALK2. And what we've seen here is that the 928 as monotherapy reduces hepcidin levels. We see reduced hepcidin levels across all of the dose levels that have been tested. And we did see one patient at the 200-milligram daily level, and that's shown on the right, had a fairly dramatic improvement in hemoglobin from levels around about 7, up almost to normal levels. So this was very encouraging. In terms of the combination, again, relatively small number of patients so far, but early signals of clinical activity here. We again see hepcidin reduction shown in the chart on the left at doses of milligrams of 928 combined with ruxolitinib and two out of the four patients so far have achieved some initial anemia responses, and those are shown on the right-hand side, patients starting at hemoglobin about 8 and you see rises of 2 to 3 grams per deciliter in hemoglobin in those patients. So again, these studies are ongoing, but the preliminary data so far looks very encouraging, supporting the mechanism of action of 928 in ALK2 inhibition. In terms of the safety profile, so far, it seems to be very well tolerated. We've not seen any dose-limiting toxicity, either as monotherapy or in combination with ruxolitinib. We've seen no adverse events that have led to discontinuation of 928. And most of the adverse events have been Grade 1 or 2. Very few Grade 3 adverse events have been seen so far. And this study follows on from an original healthy volunteer study that was done, trying to estimate the doses we would get to. And in the single-dose study, we got up to doses of 500 milligrams. And then with days of dosing, we tested 300 milligrams BID. So you can see from that, that we still have a fair way to go in terms of dose escalation. So again, as I said, this is an ongoing study. What we've seen so far has been encouraging in terms of reductions in post-dose hepcidin levels at all of the dose levels have been tested. We've seen improvements in anemia in both monotherapy and in combination cohorts. And overall, the tolerability seems to be very acceptable. We have some room to go in terms of further dose escalation. So this study is ongoing. Right now, we're at 400 milligrams of 928 as monotherapy and 200 milligrams of 928 in combination with ruxolitinib. And so we hope to have further updates from this study to present to you next year. So moving on to the BET inhibitor. We've obviously heard a fair amount from [indiscernible], some data from that was presented here. So we also have data from our BET inhibitor. The BET proteins are a very interesting family of proteins that regulate a number of cell processes, including cell growth, survival, particularly relevant for myelofibrosis is the role of BET proteins in inflammation. And a lot of the activity of BET that's relevant for myelofibrosis seem to be through NF-kappa B signaling. We know that NF-kappa B is important in regulating the inflammation that we see with MPNs. And we know that abnormal JAK2 signaling in myelofibrosis leads to increased signaling through NF-kappa B. And so the expectation is that a BET inhibitor will reduce the NF-kappa B-induced inflammation as well as the bone marrow fibrosis, an;\d this has been shown in MPN preclinical models. And in mouse models of myelofibrosis, the combination of BET inhibition with JAK inhibition reduces the cytokine production, reduces the inflammation, reduces the overall disease burden and also eliminates bone marrow fibrosis. So this is the rationale for moving ahead into the clinic, and this is the study design. It's very similar to the ALK2 study design. We have two parallel cohorts, a monotherapy cohort as dose escalation. And then following behind that, a combination combining the BET inhibitor 57643 with ruxolitinib. And again, this combination is in the suboptimal responder population. So patients who are on ruxolitinib, are on a stable dose, but still have some residual splenomegaly symptoms. And so the data we're presenting here is some initial data from this ongoing study. When we look at the baseline characteristics, these are all quite advanced patients with myelofibrosis. For the monotherapy cohort, which is the data we're presenting here, these patients were heavily pretreated with JAK inhibitors and some other treatments in addition to that. Most of the patients were previously on ruxolitinib and importantly, there was no washout that was required in this study. The early data with monotherapy, what we're presenting here are results from patients that have been evaluated as monotherapy, 6 patients at 4 milligrams and 4 patients at 8 milligrams. On the right, we see changes in percentage, changes from baseline in LDH levels, which is a marker of inflammation. What we've seen here is some decreased levels of LDH at the 8-milligram dose. And as well on the table at the bottom, we've seen some patients with reductions in spleen length and volume compared to baseline, again, at the 8-milligram dose in particular. Overall, the BET inhibitor is well tolerated. This is a drug that's given continuously with no interruption. So far, we see no dose-limiting toxicities at the 4-milligram and 8-milligram doses. As is typical for this class of drugs, thrombocytopenia is the most common adverse event. We've also seen a couple of patients with some nausea in the study as well. But overall, it seems to be quite well tolerated. So in conclusion, again, this is an ongoing study. We're just showing data from the monotherapy cohorts here at ASH with doses up to 8 milligrams daily, where we see, again, reductions in LDH and some patients with reductions in spleen length and volume. And overall, the tolerability seems to be quite good at the 4-milligram and 8-milligram doses. So dose escalationing continues. We're currently enrolling patients at 4 milligrams of BET inhibitor with ruxolitinib in the combination and suboptimal responders and enrolling patients at milligrams as monotherapy. And so again, we hope to have more data to present to you from this study next year. With that, I'm going to hand it over to Patrick to talk about CALR.

Right. Thank you. I'm Patrick Mayes. I lead our biotherapeutics research. I'm going to be walking you through some of the data on our mutant-CALR antibody. This is just a reminder that when we speak about CALR, we're referring to approximately 25% to 35% of patients with ET and MF. It's important to note, these mutations are always mutually exclusive with mutations in either JAK2 or MPL. And this points to CALR being the key driver oncogene in those patients where mutations do arise. So mutations in CALR give rise to a novel C-terminus of the protein. This is a highly charged amino acid sequence, which allows it to act as a road chaperone. They will then bind to the thrombopoietin receptor in the ER and causes complexing of the thrombopoietin receptor and the dimers. And this complex is able to shuttle to the cell surface, where it's able to then institute constitutive signaling in a ligand independent manner, ultimately leading to oncogenic cell proliferation. Important to note that TPOR is the master regulator of megakaryocytes and platelets, hence, the association of these cell types with CALR-mutant MF and ET. So we've developed a monoclonal antibody, which binds specifically to the mutant calreticulin and disrupts the complex formation with TPOR, ultimately leading to inhibition of signaling downstream of this complex. So I'll walk you through a bit of the data with this agent. We refer to the monoclonal antibody is 989. This is a mutant-CALR-specific monoclonal. It's an IgG1 with a silent Fc. This means we've engineered out all the immune effector function associated with the molecule. As I said, it binds specifically to the mutant C-terminal tail with high affinity, has no cross binding to the wild type version of the protein. And then upon binding, it's access of potent antagonist of mutant-CALR function. So a little bit about the selectivity. This is an engineered cells system where cells have been engineered to express either the human thrombopoietin receptor in green or the human TPO receptor together with mutant-CALR as shown in blue. I think what you can clearly see on the graph on the right is that the 989 binds very selectively to cells only in the context of mutant calreticulin. So it binds selectively, but what's the function in cells. So this is the same engineered cell system. And these cells -- mutant-CALR induces signaling and proliferation in a cytokine independent manner. And then shown on the graph on the left is the ability of 989 to inhibit that CALR induced cytokine independent proliferation. In addition to growth of rest, as you can see from the graph on the right, 989 is able to ultimately result in cell death. These are cells stained with a viability dye that we can see the outcome over time. And again, this is very specific to transformation induced by mutant calreticulin. We see no effect in transformed cells with JAK2 V617F as shown in the left there. We've also looked at the effects of 989 in patient-derived cells from MF patients. This is a graph looking at CD34 cells from MF patients harboring different mutations and then looking at phosphostat signaling in these cells. So you can see from the yellow curve, the ability of 989 to potently inhibit phosphostat signaling in an MF patient with a CALR mutation, whereas no signaling inhibition was observed in patients with either a JAK2 or an MPL mutation is showing in green and red. And then importantly, in wild-type CD34 cells where phosphostat signaling is induced via ligand as shown in blue and light blue, we see no effect of 989. And this is distinct from what a non-targeted JAK inhibitor would achieve in these same cells. This speaks to not only -- the selectivity giving us not only more efficacious function in patients with mutant-CALR but potentially being a more safe therapy than existing therapies in these patients because of the avoidance of signaling inhibition in these wild-type cells. We've looked more closely at the Hematopoietic Stem, Progenitor population within these patients. These are again our CD34 cells harvested for myelofibrosis patients. And then if we track then the HSPC subclones within that -- within those patients, you can see the effects of 989 in blue on a patient with mutant CALR, whereas 989 had no effect on just normal wild-type HSPCs from a healthy individual. Likewise, looking at megakaryocytes. This is the lineage most affected by mutant-CALR on the right. We can see the effect 989 has on the ability of megakaryocytes to differentiate from HSPCs as shown in blue. Whereas, again, no effect was observed in the same sample harboring a JAK mutation. So this speaks to the ability of 989 to have direct effects on the cell initiating population within these diseases. We've gone on to utilize a surrogate of 989 in a mouse model of ET. And this is a bone marrow chimera model, where we take cells which harbor a knock-in version of the human calreticulin protein. We can mix those together with the GFP-labeled, wild-type bone marrow and then transplant those into a recipient animal and then track disease establishment over time. And what we observe in these mice is that if you look at the graph on the lower left, in the control-treated animals over a treatment time course, you see an outgrowth and an increase in platelet production, and this is indicative of the ET phenotype in these mice. Whereas in treatment with 989 completely blunt the increase in platelets over that period. If you look more specifically at the mutant calreticulin positive platelets in these same mice over that treatment time course, again, looking in control-treated animals, you see an increase of mutant calreticulin platelets every time to the point which at the end of that weeks, nearly100% of all platelets are mutant calreticulin positive, whereas a 989 treated mice, you see not only a blunting of that outgrowth of sales, but you see a steady decrease over time. This would be akin to what an allele burn reduction would look like in a patient from these mice. If you look at the bone marrows of these mice, after that weeks of treatment, these are control treated mice on the left, you see the highly abnormal bone marrows with signs of megakaryocyte hyperplasia, again, indicative of the ET phenotype in these mice. Whereas a 989 treated mice on the right, you see no effect of megakaryocyte hyperplasia, and we've seen normalization of the bone marrows with normal cellularity and no abnormal megakaryocites. So a final piece of preclinical data here, looking at the effects of the antibody in combination with ruxolitinib. And what we've seen is synergistic function of these agents in cells and patient cells harboring mutant-CALR. On the graph on the left, showing the dose response of 989 alone in blue. The combination of 989 together with the suboptimal concentration of ruxolitinib in red, you can see a tenfold shift towards increased potency with the combination. Looking in patient-derived material on the right, again, looking at megakaryocyte differentiation. You can see the effect of 989 alone as well as the combinatorial effect of 989 plus this suboptimal concentration of rux, whereas we see no combinatorial effects in wild-type cells in terms of megakaryocyte differentiation. This points to the ability of ruxolitinib to act in synergy with this monoclonal antibody, even with subtherapeutic or suboptimal concentrations of ruxolitinib. So in conclusion, we've developed a selective and potent antagonist of mutant calreticulin function. We're excited about this agent because it, we believe, offers the potential to alter disease course in patients, and it will be entering clinical trials next year. So I'll stop there and hand to Steven for closing remarks.

So just in an attempt to summarize what you heard tonight, firstly, thank you to all the speakers. I really appreciate the external speakers thoughts on myelofibrosis, particularly on the fact that ultimately, this is a progressive disease and can be viewed as not curable currently. And so eventually, patients will require further therapies to address the manifestations of the condition. So in terms of the parsaclisib plus ruxolitinib data you saw from Dr. Yacoub, there's, again, there have been improvements seen in patients who had stable doses for a long time, both in symptoms quite dramatically as well as spleen volume with the addition of parsaclisib to ruxolitinib. And then very importantly, because of the class and its history as regards, particularly lymphoma, just to show that in this population at these doses, it's been well tolerated in this data set with few drug-related adverse events and certainly none in terms of the class warring ones like colitis. The BET program, although earlier, again, shows encouraging signs of activity with monotherapy, both in terms of decreased inflammation and some spleen responses. And then no, again, worrying toxicity seen to date, there's no on-target toxicity in terms of thrombocytopenia certainly as you get higher with the dose. And we'll have to make strategic decisions on where to go with this program over the early part of 2023. And then ALK2, perhaps potentially huge benefit for patients should this pan out in terms of ameliorating the underlying anemia of myelofibrosis as well as the ruxolitinib-induced anemia. And then as was pointed out by Peter, potentially allowing you to maintain rux dose intensity and thus increase the benefits to patients. We certainly got more space to go with dosing. As you saw from Peter's data in single ascending dose studies, who went up to 500 milligrams in multiple ascending dose, who went up to 300 BID and in the clinic currently, we're in the, 200 range and no adverse events seen there. And then exciting from a preclinical scientific aspect, the mutant-CALR antibody with extremely elegant preclinical data showing evidence of hitting the clone and the cells affected by it, but unaffecting, at least in the preclinical models, normal hematopoiesis. So in a really good place for the LIMBER program to be at the moment. In terms of 2023, busy slide, but just to show you on your left, there are many catalysts coming. So firstly, just a reminder that our once-daily ruxolitinib is in an active submission at the FDA at the moment with the PDUFA date in late March 2023. And the suboptimal responder 304 study, the data from the Phase II that enabled that was presented by Dr. Yacoub, we'll finish enrollment soon, and we should have top line results towards the end of 2023 that needs a full 24-week follow-up there. Obviously, the ongoing first-line study with results to follow about a year later. It's about double the patient number there. It's about 440 patients are needed to complete that study. And then the ALK and BET program is now moving on to the combination phase with combination data in 2023 and then strategic decisions that need to be made there. And then mutant-CALR will enter the clinic as soon as the IND clears in 2023. So again, a big and busy year for us, which we're very proud of. Just a reminder on the right side there, not yet announced, but we're very actively working on novel targets in the PV [indiscernible], so stay tuned. Hopefully, maybe another ASH plenary, Dash, no pressure. And then the ET work related to mutant-CALR, which we can certainly talk about in Q&A, if you like. And just remember to round out the LIMBER program is a very important elements related to graft versus host disease, anti-CSF-1R antibody collaboration with Syndax, axatilimab, there the registration-directed Phase II study that AGAVE will deliver results in approximately middle of 2023 with enrollment being completed now and in combination with rux that will initiate. And ideally, because of non-overlap in MOA and hopefully, no toxicity that's worrying potentially a first-line effort in graft versus host disease and taking on steroids alone there. If you look at the value add here, obviously, as you've just heard, an enormously valuable drug to patients and then to Incyte and to shareholders is ruxolitinib and with its indications in MF, PV, steroid-refractory acute and chronic graft versus host disease, but now starting to see the light in terms of what's coming to not only replace this but grow this franchise, if you will, further in many spaces. So once daily rux, parsaclisib, ALK2. The Cellenkos collaboration we didn't talk about, that's now in the clinic, some umbilical cord cells that are enriched and then the mutant-CALR antibody and then the G -- CSF-1R antagonist axatilimab and novel targets in PV are coming. We'll move on to Q&A and just pause for a second. Remember, we have quite a number of people on a virtual feed, Webex. So please wait till the microphone is active to ask the question. So people online won't be able to hear you. And then one of us appear -- or potentially one of our experts will answer the question for you. So we'll take questions from the audience here. We have a few raised hands. The one I can see is Evan, but I don't know if the microphone is heading his way, [indiscernible]. We'll start at the front, person who has the microphone. Go ahead.

Great. Jess Fye, JPMorgan. For parsaclisib, what's the threshold for spleen reduction in the primary endpoint in the LIMBER-304 [ pro responder ] trial? Just trying to think about what we can learn from the Phase II data as it relates to that pivotal trial?

I mean I'm not going to even let Peter ask it because it's a question we actually have not addressed publicly on purpose. We view it as proprietary company information. So our primary end point there in terms of the percent reduction is not disclosed as opposed to a first line study, which is the same across all the sponsors, which is SVR35 plus symptoms. But for a suboptimal study, we haven't said the exact percent we are aiming for. So we haven't publicly disclosed that.

Okay. And for 928 ALK2, I know you said we'll get an update next year. Do you expect to have found a go-forward dose by the end of next year?

Peter, do you want to answer that?

Yes. So I think we'll see, I mean the dose escalation is continuing. And then obviously, it sort of depends whether we hit tolerability issues, whether we can continue to escalate to improve efficacy. But I think our hope is to have a dose and a decision on moving forward by the end of the year.

And just to be maybe a little bit additive there. I think when you do preclinical work on the modeling, it looked like we'd be potentially in the dose range now but you can see that we still have a ways to potentially go. We have more space. We've seen improvement with the higher doses that's even more encouraging. So I think it behooves us and as well as at the FDA at the moment with Project Optimus to keep going on dose exploration for the moment to maximize benefit, certainly when the therapeutic ratio is favorable and we're not seeing toxicity. That's where we'll keep going. I'll just leave it to people in the audience who have a microphone. It's hard for me to see. Evan?

Hey, Steve. Good to see you. Evan Seigerman from BMO. Would there ever be a rationale to combine, say, rux plus BET or the PI3 kinase delta plus an ALK, so triplet combination? And would you ever want to -- I guess, what would be the endpoint that you would have to see in these combination trials in the Phase III? Any thoughts there?

Peter, do you want to start addressing that and I don't know if one of the external experts want to talk about triplet combinations.

Yes. I mean it's interesting. I mean I think we'll see how these various studies pan out and where the benefits are on spleen symptoms? What the tolerability is? I think certainly, if there's a potential if we're seeing anemia in parsaclisib-rux combination and a BET-rux combination, we're seeing anemia as being a potential dose-limiting issue, then potentially adding an ALK2 on there could be a possibility. At this point, we're looking at the doublet combinations first, but there's going to be a lot more information coming over the next couple of years with our combination with other combinations that will help determine what the appropriate next steps will be from there.

Maybe one of the experts, Dr. Verstovsek you want to add?

Certainly, field is moving toward doublets. I think I like your thinking about triplets in the future as it happens in some other hematological malignancies. But the point here is that you need to really have an incremental benefit of significance, right? Doublet, as you see, most of them aim to improve the spleen and symptoms. And if you can add a third one to improve the anemia, you would cover all of it for a much longer period of time. Then you start talking about the survival benefit for real.

Marc?

Marc Frahm from Cowen. Maybe just to start on the ALK as you get to making that go -- no-go decision in the -- at some point next year. Just kind of what are you looking for? What's the kind of bar that you need to see? Is it a certain level of hemoglobin benefit? Is it a percent of patients hitting level, just how do you plan on evaluating the drug?

Do you want to start off, Peter?

Yes. Again, it depends a little bit what we see as we continue the dose escalation and what we see in the monotherapy and combination cohorts because there are a few different things we could look at. One is, and this is probably the severest group of patients who will be looking at transfusion-dependent patients. Can we make them transfusion independent, which would be a great benefit for a relatively small subset of patients that have particularly severe disease. The next level then would be, can we take all anemic patients and improve their outcomes, preventing the emergence of transfusion dependence, let's say. And then there's the possibility that we see better dose optimization of ruxolitinib through preventing or through treating the disease-related anemia as well as preventing the ruxolitinib-induced anemia, and does that lead to better outcomes in terms of spleen symptoms and ultimately, overall survival. So I think there's sort of there are a few different areas we could look at. And ultimately, assuming the data that we get from the ongoing study that will help us decide which path to take.

Okay. That's very helpful. And then maybe on the CALR antibody, one, congrats on getting a plenary for a preclinical presentation. But the -- as we think about that one moving into the clinic -- one, during that session, there was some pushback on just kind of the decision to have an Fc inactive antibody versus Fc active one, can you address that, but also maybe think more broadly, since you do have access to even other kind of formats of using antibody-based therapies bispecifics or other approaches. Just why is inactive Fc, the best way? And then related to that antibody for Dr. Verstovsek, when you were kind of talking about ET, the treatment goal there being kind of avoiding thrombotic events and kind of treatment decisions today. One of those risk factors is JAK mutation. So can you kind of explain what the unmet need is in the CALR ET patients?

Patrick, do you want to do first on the Fc-silent?

Yes, happy to. So thanks for the question about the Fc function. So this is something we explored. We looked at different formats of the antibody of different Fc isotypes, different formats in terms of killing function. Ultimately, wild-type versions of the antibody didn't add anything in terms of efficacy in the model systems. We believe this is likely due to the low level of expression CALR of the cell surface and the inability to kind of recruit immune cells to kill via ADCC functionality. So the decision was just to remove that function from the antibody itself, remove risk and we didn't believe it was adding anything in terms of efficacy.

Thank you for a very good question. As we approach the ET therapy, and the first line of worry is the blood clotting. The best way to eliminate the worry about the blood clotting is to normalize the bone marrow, eliminate the disease and aim for the molecular response. And so the potential of the calreticulin antibody in calreticulin-positive patients, about 30% of the patients and we are not only controlling the blood cell count, symptoms in the spleen by killing cells or preventing their growth, but to eliminate disease. That will be elevating the bar to PR and CR, and I hope that happens. And in that case, we would extend the applicability of this therapy to intermediate group of patients, which are defined by virtual having age over 60 without the molecular signature interfering with that. That is the gray area at the moment where some doctors would say I do and some say, I don't need to start the drug therapy. If you up the bar and say, I have a chance to eliminate disease, no question, I will go to use it and eliminate the intermediate group of questions.

Other questions?

Mara Goldstein from Mizuho. Two questions. Just a quick follow-up on the CALR. There also was a question around dosing in the plenary today. And I'm wondering if you might be able to comment on that, I think it was dosing about sort of a one-and-done type of therapy and maybe what you're envisioning for that? And secondarily, I had a question on the parsaclisib. On one of the slides discusses treatment emergent adverse events in patients entering study, some percentage entering the study at Grade 2 ended up with Grade 3 events and some folks entering the study a Grade 2 ended up with Grade 4 events. And I'm wondering what that means in terms of how physicians will look at baseline adverse events coming into treatment?

On the dosing first, Patrick.

Yes. So thanks for the question. So in terms of dosing, I don't think there is an expectation that this will be a one-and-done type therapy. This is an antagonist against a mutant oncogene. So it's a driver in these cells and the ultimate outcome has been discussed is to remove those mutant clones. And we know that this happens slowly over time. If you look at allele frequency reduction, this tends to happen on the order of months and years. So our anticipation is that we need to maximize inhibition of this pathway for as long as is necessary to alleviate that burden.

And then Dr. Yacoub on safety.

Yes. So thank you very much for that question. Actually, I was hoping somebody would talk about that a little bit. So thank you. So the reason this was actually, I spent a good while on this during the ASH presentation is that when we designed the study, we allowed patients with platelet counts as low as 50,. Some of them are actually below 50, once they enter the study. This is one of the lowest bar that any of the doublet clinical trials are allowing. Just out of confidence because we actually believe that parsaclisib has very little hematologic toxicity, so we allowed patients to get into the study with platelet counts that is that low that are qualified at Grade 2. So we already entered the study at Grade 2 thrombocytopenia. So we only worsened by 1 grade. I don't want -- when we count in Grade 3 side effects, that sounds like -- it does sound negative when you're having patients with Grade 3 thrombocytopenia, but 7 of those patients already were Grade 2. So they only went down 1 grade. Had we had a bar of plates count to, like the other doublets, you would have zero Grade 3 toxicities. So I wanted to emphasize that in the presentation. I'm glad you asked that, and this is definitely a topic that requires a lot of verification and the fact that we allowed patients with severe thrombocytopenia and with anemia and transfusion dependence is because this drug is that safe. It does not cause the hematologic side effects.

Gentleman in the front.

It's Leo on for Brian at RBC. So I had maybe a couple on the BET inhibitor actually. So if I remember correctly, in the past, you dosed it at 8 milligrams, milligrams, 16 milligrams. And as you sort of dose escalate out, you're getting -- approaching those same levels where you saw toxicity and advanced malignancies that caused you to stop the trial. So I guess what gives you confidence that now you're approaching this in the right way that you're not going to see some of those same signals? Is the patient population a little different? And then I guess, what are you looking for from the BET when you think about the kind of strategic decisions that you alluded to, that you'll be making?

Okay. No, very good question. So the question is asked and we should have mentioned that this compound was in the clinic years ago in a solid tumor paradigm, largely targeting MEK inhibition, we went up to the higher doses you allude to. So Peter, do you want to just talk about potentially differences in the profile we've seen?

I mean so in the original Phase I, it was all comers, it was a lot of solid tumor patients as well as some lymphoma, AML and a couple of MF patients. And we did escalate 8,, 16, 16 was not well tolerated. So 12 was going to be the dose we took forward. And so we're basically following the saying we're not going to go up above 12 in the current dose escalation. And obviously, now we're just treating patients with or primarily patients with MF. And so we're looking specifically at the tolerability profile there, the thrombocytopenia, which is the main dose-limiting toxicity. There can be more of an issue in MF patients or not -- so we're going to test that in the dose escalation. But we're not going to go above 12 because we already know that based on the original Phase I, that wasn't well tolerated. And then we'll see what the data look like. We'll have monotherapy data. We'll have combination with ruxolitinib and the suboptimal responders. We'll be able to look at spleen symptoms, anemia, all the typical endpoints and decide from there what the best perhaps take forward is whether it is a frontline study is it to do the suboptimal responder add-on. So we'll be able to decide once we have more data. So again, we would hope to make some decision later next year.

Thank you. Other questions? Yes.

This is Kripa from Truist Securities. So one question was about ALK2. So is there a threshold for hemoglobin level that you're reaching? Or is there a dose-dependent increase in hemoglobin? And given the fact that you're seeing on hepcidin, is there some sort of a dynamic or association with the disease severity and hepcidin levels in MF? And maybe for the 2 KOLs here. So with all these add-on therapies and the combinations that we're starting to see and probably in a couple of years, we're going to probably get some of them approved, is there sort of an algorithm developing as to how you're going to treat these patients, what's priority?

Peter, do you want to start off?

Yes. So maybe I can start with the ALK2 questions. So there's not really a specific hemoglobin threshold we're looking at. Again, as I mentioned earlier, we're going to look at the spectrum of benefits that we have and decide what to do from there. If we're seeing the major benefit being on converting a transfusion-dependent patients becoming transfusion independent. That may be the way we go independent what the actual hemoglobin levels are. If we're seeing patients with anemia, let's say, hemoglobin less than that we're able to consistently get them. Hemoglobin's above, avoid transfusions, avoid preventing them from developing a transfusion need, then that might be a way that we go there. But we don't have a specific target in mind for where we need the hemoglobin to be because, again, it depends on the other factors that may be involved. Are we in -- so I think in the graphs I showed where we had patients around, right. So we had patients around -- so it did look like it's stabilized. We have patients who are starting around 8 or so and getting up maybe to 11. I think one of it was close to 12 and did seem to stabilize. I think what will be interesting is we continue to dose escalate, do we get further improvements from there as we're able to continue. So I think that's one of the questions we'll be looking at. In addition, at this stage, we're seeing most of the patients with reductions in hepcidin and a few with anemia, but it will be interesting to see, again, as we go up the dose levels that we're getting not only maybe higher levels of hemoglobin, maybe continued increases in hemoglobin, we're also getting more patients that are having those increases in hemoglobin as well. So I think again, it's the challenge of having a study that's sort of midway through the dose escalation as we don't know where we're going to end up. In terms of the association with hepcidin and severity of disease, we know that elevated levels of hepcidin do predict poor outcomes, long-term outcomes with myelofibrosis. It's probably important to note that hepcidin is one of many parameters that's involved in the overall prognosis for MF. And so that's something as well we'll be looking at as we continue this study is to see how extensive those benefits are across many patients or are there select patients that seem to benefit more than others. So that's something we'll look at. And then maybe I'll turn it over the mic to our experts to talk about...

So a wonderful question, and you can only imagine how happy I am to answer the question when you say too many choices, potentially, and that's the key, right, and what they are for. So most of the combinations that we have are trying to improve what the JAK inhibitors do. And that will be improved the control of the spleen and symptoms, which is very valuable. But there are not that many that actually aim to improve the anemia. And as we were saying, there are 3 major problems. And we do cover with the JAK inhibitor alone pretty well actually the spleen and symptoms and anemia is compromising that control. If you would able to control the anemia, then you would be able to do better job with the JAK inhibitor in controlling the clinal symptoms. So enable the practice, what do we do? When we have anemia, either from the beginning of therapy with JAK inhibitor or the one that develops during the therapy, we would add anemia drug. We don't have one, but we use off-label danazol or ESAs or low dose thalidomide or prednisone, none really work well and not for too long, even if it works. But that's the standard practice, and that would be expectation of which of the combinations you would choose first. And in that case, ALK inhibitor is my favorite.

And I would like to add just a very short commentary is that once those studies are completed, additional medical information -- clinical information comes up, and this actually might be applicable in other situations. So just like ruxolitinib was [ appropriate to ] myelofibrosis and then the mechanism of action made it a reasonable medication for polycythemia vera and that was successful. And then the effective immunity was successful in GVHD. So some of those findings from the clinical trials might actually extrapolate to other diseases, such as the ALK inhibitor, when that study is completed and the anemia in myelofibrosis improved, that would have implication in other cancers with anemia. So that knowledge we gain from completing those studies can be expanded a lot bigger than the disease you studied it now. That would have been a smart question had you asked it.

My far left front of the room.

Steve Willey from Stifel. Maybe just a follow-up on the ALK2 inhibitor. Do we know what the association of correlation is between hepcidin reduction and then hemoglobin improvement? And I guess I asked the question because I know in the 200 mg cohort, you're seeing a pretty demonstrable improvement in hepcidin reduction, but I think there was only one patient that saw 1.5 gram per deciliter improvement in hemoglobin. So just trying to understand if there's an obvious disconnect there?

So I don't think there's a sort of clear linear correlation between hepcidin levels anemia because it is multifactorial. I think that, again, it will be interesting to see as we continue to dose escalate whether we can not only have consistent reductions in hepcidin, but ultimately have a more sustained and consistent increase in hemoglobin levels as well. So again, I think it's a challenge by not -- midway in the study. And again, as we continue to deescalate that will be something we look at. But we know there are many factors that are involved in the anemia, hepcidin is one of them. And so we'll see as we're able to get better and more sustained reduction in hepcidin where that translates into anemia benefits.

And then maybe for the physicians. Maybe you can speak to the threshold for initiating doublet therapy in a newly diagnosed MF patient. Do you think that you understand the risk stratification of the disease enough right now such that you would initiate doublet therapy right off the bat? Because I know like -- I think half of newly diagnosed MF patients, right, you're kind of watching and waiting, half will get single-agent rux, you get some kind of symptomatic and spleen benefit. Is there a clinical benefit, I guess, to initiating doublet therapy right off the bat as opposed to just laying on single-agent rux seeing who responds well, who doesn't and then just going after the inadequate responding population?

Very practical question. If you are talking about the combo that would be improving the symptoms and the spleen, I would say highly unlikely that at the moment, we would choose any of the combinations from the day one unless it's a very convincing reason that would be, for example, a much better response for much longer. That is not the case as we know so far. Otherwise, the current standard practice is to start with the ruxolitinib alone. It's very simple, it's very safe and it's very effective. And then after some time, in the case of parsaclisib study, you see that was after about 1.5 years. You say it's not working very well. But it's working to some degree, let improve it by adding an agent that would boost the spleen and symptom control. So for that particular purpose, it is much, much more likely to add an agent later in a course of therapy. But the combo for anemia would be something to consider from the beginning if the patient is already anemic, as we would usually do. In my clinic, we would -- for anemic patients who are starting ruxolitinib starts from the day one ESA or danazol.

And maybe you can just talk a little bit about I guess, maybe both from the company and from the physicians. What will be the plan with QD rux when that drug gets approved, presumably in the first half of next year? Is that something that you're going to try to detail as a single agent? And I guess to the physicians, I know that we often hear and you see it in the data all the time, right? I mean, rux is a very titratable drug in myelofibrosis and to what extent is having a QD version of that impair, if at all, your ability to titrate the drug?

Yes. I think they're good questions. I'm going to probably not satisfy you completely with the answer because it's still being worked out a little bit. There's the -- obviously, the actual approval that needs to be achieved, the fact that to date, we have bioavailability and bioequivalence data, but no other clinical data. And then thirdly, I guess, is the macro environment in terms of Inflation Reduction Act and other aspects commercially that may dictate on how we launch it. So we'll have to just wait a bit until we lean into it a bit more and probably tell you early next year exactly how we'll be potentially doing that. I think at an obvious level, it's once daily and has potential convenience in terms of that aspect. And then we have very good data showing equivalency with the BID dosing. So hopefully, the question around, if I understood you, the ability to switch from one to the other should be relatively easy but the other macro aspects, we're still working on a bit more, and we'll have to explain that to you early next year in terms of the launch dynamics and what we'll do with rux itself versus the once daily. So I'm not answering you completely at the moment. And I think we have time for one more question. So behind you there.

All right. Matt Phipps from William Blair. So on the CALR mutant antibody 989, maybe getting a little bit ahead of myself. But when you were trying to develop JAK1 in ET, there obviously were some issues with kind of completing that trial. Is there anything different you foresee about a development path in ET for 989 that you think would make it more feasible?

Yes. Maybe let me just lead off and then maybe Patrick. The level of excitement related to this compound, I actually haven't seen before. In my nearly 30 years of development, we literally have every investigator wanting to be the PI, et cetera. And I think it talks to why a preclinical asset made it to the plenary today, you saw mutant-CALR was cloned in 2013, and now we have a drug in the clinic in 2023 with this potential to alter the natural history as Dr. Verstovsek was saying. So I don't -- I'm not worried if your question was operational where we have problems executing the studies. I think enrollment, I'll predict from the podium now is not going to be a problem at all. MF, I think, is pretty clear cut. ET has some nuances, which we've been speaking about. I don't know if that's the essence of your question. So I'll let the experts maybe answer you there a bit on their thoughts.

So just zeroing down on the calreticulin antibody. And this has actually been an ask from doctors for years. We've been -- since we realized there is a new antigen and this could be immune targeted, there has been major advances in immunotherapy in cancer. You've heard about CAR-Ts and BiTEs and this has become the new era. So we're all waiting for an immune-based therapy for a new target. So this is something we've asked for. All physicians have been asking for it. I already have identified my patients with CALR waiting for a study. So it's that much that we're actually waiting for such an agent, if that helps answer your question.

Do you think a BiTE is overkill?

Okay. So -- and that question was raised earlier, but there is and the mechanism of action with this antibody is to prevent the dimerization of the receptor. Those are cancer cells that are dependent on the signaling. The minute you turn it off, that leads to cancer still dying. You might not need the extra kick that comes with immune system. And that actually might be counterproductive if you engage the immune system, they might actually resolve. And that was asked in the plenary session too, that actually that comes with other side effects. So if you can actually achieve the mission with just preventing the dimerization and cancer is just dying off, that will be all you need and that would just eradicate the disease.

So thank you very much to all the panel members for participating and thanks to the audience for the questions. Some of the company people will be around for a little bit if you want to ask us questions afterwards. Have a good and safe night in New Orleans. Thank you.