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. This meeting is also joined by people on Webex as well. Thank you for being here. I just wanna 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. Tell you to consult our SEC documents and 10-Q 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, I'll be taking you through the agenda tonight, then at the end, wrapping up and as well as a Q&A, for which we should have about 15-20 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 an oral plenary paper presented today at the plenary session, then 33 poster presentations. That for us is an enormous effort, we're very proud of everything we've done, related to the American Society of Hematology, 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 what we call the LIMBER program is the PI3Kδ 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 INCA033989 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.
Very recently, and something we're also very proud of, is the orphan indication, the myeloid/lymphoid neoplasm that's FGFR1 driven, for which we now have an FDA indication for pemigatinib. 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 we 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 this 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.
Following Professor Verstovsek will be Professor Yacoub from University of Kansas, who will talk about the phase II data he presented 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 sub-optimal study with ruxolitinib in combination randomized against ruxolitinib 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 INCB000928, and then our BET inhibitor INCB057643 as well.
Show you where we are in terms of those programs currently, potentially, you know, where we may head in the future in terms of those programs. Dr. Patrick Mayes will then present the mutant CALR antibody, we'll wrap up with the Q&A. 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. 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 very exciting time again with us facing a new drug development in new directions. Particularly the plenary session provided some insights where the whole field is getting, and that is treating patients with a particular molecular signature to eliminate disease. We're gonna end up with that at the end. For the beginning, we're gonna 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 a hyperactive JAK-STAT signaling related to different mutations, as I'm gonna explain in a second, that leads to uncontrolled myeloproliferation and uncontrolled inflammation, which means abnormal levels of cytokines. This uncontrolled growth and inflammation leads to several critical findings when you examine patient with myelofibrosis, and perhaps your focus is on the photo first because it's really what happens with that patient with the hematologic 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. What then you have is abnormal blood count because the bone marrow doesn't really work well.
The quality of life is extraordinarily bad and it gets worse over time. It's not nice picture to have a 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. With the extraordinary effort, the team effort between the Incyte, us in academia, and patients, we were able to develop, as you know, first-ever therapy approved for myelofibrosis, and that was ruxolitinib. 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 a reduced splenomegaly to make it smaller and asymptomatic. There is also issue with the bone marrow production of the red blood cells, and anemia is the number three.
What ruxolitinib does very well is seen in the graphs here, a very quick improvement in the quality of life. Within one month, four to six weeks, you get the maximum benefit, that is usually described as a half of the symptoms gone. You have a waterfalls to the right, which will tell you in very easy way to understand that almost every single patient has a degree of improvement in the spleen with ruxolitinib when the control arm didn't do much at all. The benefits are on two out of three critical parameters here, spleen and the symptoms. Finally, as we now know for a number of years, that a good control over 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 six years on average. These patients, by the way, by the virtue of their pre-therapy characteristics, would on average live three years. That actually is true. If you look through the purple color, that's would be in a simple way, a group of patients that have never, ever received the ruxolitinib. The blue color is the survival of patients that were in control arm, but majority of them crossed over to ruxolitinib.
We have three lines from no exposure to crossing over to ruxolitinib and fully from the day one exposed to ruxolitinib. Based on these data, I'm very comfortable usually to tell the patients and colleagues that on average, you would expect about three years of gain of life with the ruxolitinib. Now, we are not eliminating disease, there is a certain duration of the benefit. Duration of response with ruxolitinib, as you see in the curve on the right, is about three 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.
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. 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. There is a potential synergism with co-targeting 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. A BET inhibitor, which is of course epigenetic modifier, and that would be different angle in controlling the cytokine expression and genetic expression in the 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 the additional benefits on improving the anemia or decreasing the progression. 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 validated target for us to hope that, with the inhibition of ALK2 or ACVR1, you would eventually have improvement in the red blood cell production, which would easily then complement the therapy with the ruxolitinib and with the two medications, for example, you would be able to control the spleen symptoms and anemia at the same time.
Finally, the calreticulin blockade, and that is something that is completely novel, that's why it was on a plenary session, has a potential to eliminate disease to a large degree. Then we move to talking about partial response or complete response, where there is no evidence of disease. 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 manifests itself with the high platelets and occasionally high white cells. Then the JAK2 mutation is predominant almost in all patients with PV to the right.
That's why we talk about extending the benefit of some of these therapies, particularly calreticulin-directed therapy to ET patients. This is a classic, one of the three classic MPNs, which is 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 100,000 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.
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 ones 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 control disease where normalization of blood cell count symptoms and spleen would be a normality as a control of that entity. In that setting then, with ET being a focus on this slide, we have some other medications in development.
Ropeginterferon alfa-2b 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 a pilot phase II study. Today we're gonna learn about our approach here together on the calreticulin possible elimination. There are others. You see phase I study with the vaccine that would be an effort to boost the immune response to possibly control the growth of these malignant cells. In conclusion, to summarize the introduction on myelofibrosis and ET, ruxolitinib is worldwide standard of care for patients with myelofibrosis by virtue of reducing the spleen and improving quality of life.
It is truly the only therapy that we know proven to prolong survival of the patients with myelofibrosis. The disease is progressive, and therapies are needed for other indications like anemia, prevention of progression. Novel agents that we talked about briefly now, and we're gonna talk about them in much more detail, are much welcome to change the standard of care. Most exciting, of course, this mutant calreticulin antibody that we learn at plenary session has unique potential of elimination of the disease. I thank you very much, and my good friend here, Dr. Yacoub, will take over and tell us about parsaclisib.
Good evening. This is a definitely a week of celebration, in which I got the opportunity to present this positive study, in the ASH meeting. Hopefully, move the field a little bit forward. 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 splenic 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. Many of those combinations aim to achieve a higher result with the same therapy and basically boosting the benefit that we get with ruxolitinib. 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. This has been addressed in many diseases actually. This concept is a valid, and it's been studied thoroughly in many diseases. It could represent a pathway of escape. Parsaclisib is a unique PI3Kδ that is targeting the delta subunit, thus providing a very favorable safety profile, once-daily dosing, and would be a good partner for ruxolitinib.
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. Why, why are we doing this? Ruxolitinib is an active agent, and in many of our clinical trials, a good proportion of patients, 40% up to 60%, have actually achieved the maximum response, which we arbitrarily define as, 50% reduction of symptoms and 35% reduction of spleen volume. We know that the depth of response is the most predictor of the duration of response and patient's benefit.
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, with the better-performing patients? That is the concept of add-on approach. Incyte was one of the first companies to design an add-on approach to a ruxolitinib, and that model has been adopted by many other agents to copy and the same development design with add-on approaches to a 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.
The design of the study was for patients on ruxolitinib, receiving the standard of care ruxolitinib on a steady dose for at least six months, a stable dose for the last eight weeks, and continue to have disease-related symptoms, continue to have enlarged spleen. The response will be described as favorable but not optimum, sub-optimum response. In these patients, we designed a four-stage study with different dosing schedules of parsaclisib to identify the optimum dosing schedule and the optimum dose, in which we can help patients. After this extensive design, the simple dosing of once a day ended up being the winner arm. I'm gonna go over some of those background for details of those patients on that study.
These are patients who have lived with myelofibrosis for an average of two to three years and have been on a ruxolitinib therapy for one and a half years, which is really the best therapy one can offer for those patients. The average dose of ruxolitinib was roughly 15 mg twice a day, which is one of the higher dose levels for patients. No one would disagree that this is an optimum optimized therapy with ruxolitinib. Despite all of that, they continue to have enlarged spleens, both by exam and by imaging, and they continue to have disease symptoms. These are the patients who are benefiting but could be optimized, and those are the patients who were eligible for this protocol. 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 the study ended, which is a testimony to the safety of the, of the therapy. The median dose of parsaclisib was 5 mg, which is the planned dose. That means there's been very little intolerance or interruption of therapy. The median dose of ruxolitinib was unchanged, we did not need to reduce ruxolitinib dose on therapy. The combination really was not associated with any toxicities that required lowering the dose or interrupting the dose. Two, as we speak, there are 13 patients who continue on therapy even after the study has ended. They're on a, on a compassionate care open-label protocol.
In terms of activity, for patients on an optimized dose of ruxolitinib, the addition of parsaclisib resulted in additional splenic volume reduction, both observed at 12 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 at week 12 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-ons study that has been presented so far. In addition, this benefit is very almost immediate. It was observed as early as four weeks, which in our practice is the first visit you see the patient after you started their investigational therapy.
Patients reported that as early as their first office visit after starting therapy. In terms of safety, we looked at a new agent. We're gonna go over a thorough description of the side effects, the adverse events that are of special interest that would be a concern in this setting were reported on that table on the right, there's a lot of zeros on that table. There's really we haven't observed any of the stigmatic adverse events people would observe with this class of drugs. In regard to the thrombocytopenia, we allowed patients with severe thrombocytopenia and anemia and transfusion dependence on the study, there was very little discontinuation because of that. If anything, most patients remained at the same dose level, platelets, and red cells.
To demonstrate that further, this is the platelet count and the hemoglobin levels for patients on the study, which show stability throughout the study. To summarize, the addition of parsaclisib to patients on an optimized but dose of ruxolitinib but sub-optimum response resulted in further clinical benefits without additional toxicities and without loss of dose intensity of ruxolitinib. 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.
The other study is the add-on approach in a phase III setting, in which when that study is positive, there will also be a standard of care in which we add parsaclisib to patients on ruxolitinib and sub-optimum response. Thank you very much for your attention. Thank you.
Thank you, Dr. Yacoub. Again, my name is Peter Langmuir. I'm responsible for clinical development of our LIMBER projects in MPNs and GVHD. I'll talk about our ALK2 inhibitor and our BET inhibitor. Excuse me. First of all, the ALK2 inhibitor. This is a slightly different approach from a lot of the other combinations that we're gonna talk about today and that have been presented here at ASH, in that those other combinations are primarily focused on improving spleen and symptom response. With ALK2, what we're looking at here is trying to improve anemia. We know that in patients with myelofibrosis, anemia is very common.
It's one of the major complications of the disease. In MF patients, elevations in hepcidin are correlated with higher risk scores and associated with poor outcomes in myelofibrosis. We know that a lot of the elevated cytokines that are present in MF stimulate excess levels of hepcidin. This excess hepcidin leads to abnormalities in iron processing, ultimately leading to anemia. Our hypothesis is that INCB000928, which is a ALK2 inhibitor, will down-regulate hepcidin expression, mobilize iron for erythropoiesis, and hopefully improve anemia. The potential benefit here is twofold. First of all, primarily is the direct benefit on anemia, which again is one of the primary factors in myelofibrosis.
We also know that ruxolitinib causes anemia itself, 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. It's a two-pronged approach. INCB000928 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. This, the encouraging preclinical data led to the study that has been presented here at ASH or... Sorry, I forget, is it tomorrow? What is it? So the ALK2 study is a two-part study.
The first part is looking at INCB000928 as monotherapy. These are patients who have previously been treated with a JAK inhibitor. It's a dose escalation study that is currently ongoing. Following along behind that is a cohort looking at the combination of INCB000928 with ruxolitinib. This is in a very similar population to what Dr. Yacoub just described for the suboptimal responders for parsaclisib. These are patients who are on a stable dose of ruxolitinib for at least 12 weeks and are either transfusion-dependent or have symptomatic anemia. Again, this is a dose escalation part of the study that's currently ongoing. We're presenting here data from the ongoing study. Again, the dose escalation is still continuing for both of these.
If we look at the baseline characteristics, we have 14 patients so far in the monotherapy group. We have four 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 on here, but their hemoglobins range between about seven and a half and eight. These are quite severely anemic patients, and the majority are transfusion-dependent. This is exactly the population we're trying to target with ALK2. What we've seen here is that the INCB000928 as monotherapy reduces hepcidin levels. We see reduced hepcidin levels across all of the dose levels that have been tested.
We did see one patient at the 200 mg daily level, and that's shown on the right, had a fairly dramatic improvement in hemoglobin, from levels around about 7 g/dL up almost to normal levels. This was very encouraging. In terms of the combination, again, it's a relatively small number of patients so far, but early signals of clinical activity here. We again see hepcidin reductions shown in the chart on the left at doses of 100 mg of INCB000928 combined with ruxolitinib. Two out of the four patients so far have achieved some initial anemia responses, and those are shown on the, on the right-hand side. Patients starting at hemoglobin of about 8 g/dL, and you see rises of 2 g/dL-3 g/dL in hemoglobin in those patients.
Again, these studies are ongoing, the preliminary data so far look very encouraging, supporting the mechanism of action of INCB000928 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 INCB000928. Most of the adverse events have been Grade 1 or 2. Very few Grade 3 adverse events have been seen so far. This study follows on from an original healthy volunteer study that was done trying to estimate the doses we would get to.
In the single-dose study, we got up to doses of 500 mg, and then with 10 days of dosing, we tested 300 mg BID. You can see from that that we still have a fair way to go in terms of dose escalation. 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, and all of the dose levels have been tested. We've seen improvements in anemia in both monotherapy and in combination cohorts. Overall, the tolerability seems to be very acceptable. We have some room to go in terms of further dose escalation. This study is ongoing. Right now, we're at 400 mg of INCB000928 as monotherapy and 200 mg of INCB000928 in combination with ruxolitinib.
We hope to have further updates from this study to present to you next year. Moving on to the BET inhibitor, we've obviously heard a fair amount from the pelabresib. Some data from that was presented here. 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. A lot of the activity of BET that's relevant for myelofibrosis seem to be through NF-κB signaling.
We know that NF-κB 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-κB. The expectation is that a BET inhibitor will reduce the NF-κB-induced inflammation as well as the bone marrow fibrosis, and this has been shown in MPN preclinical models. 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. 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 INCB057643 with ruxolitinib.
Again, this combination is in this suboptimal responder population. Patients who are on ruxolitinib, are on a stable dose but still have some residual splenomegaly or symptoms. 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 pre-treated with JAK inhibitors and some other treatments in addition to that. Most of the patients were previously on ruxolitinib. Importantly, there was no washout that was required in this study. The early data with monotherapy, what we're presenting here are results from 10 patients that have been evaluated as monotherapy, six patients at 4 mg and four patients at 8 mg.
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 mg dose. As well in the table at the bottom, we've seen some patients with reductions in spleen length and volume compared to baseline, again, at the 8 mg dose in particular. Overall, the BET inhibitor is well-tolerated. This is a drug that's given continuously with no interruption. So far, we've seen no dose-limiting toxicities at the 4 mg and 8 mg doses. As is typical for this class of drugs, thrombocytopenia is the most common adverse event. We've also seen a couple of cases with some nausea in the study as well, but overall, it seems to be quite well-tolerated.
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 mg daily, where we see again, reductions in LDH and some patients with reductions in spleen length and volume. Overall, the tolerability seems to be quite good at the 4 mg and 8 mg doses. Dose escalation continues. We're currently enrolling patients at 4 mg of BET inhibitor with ruxolitinib in the combination in suboptimal responders and enrolling patients at 12 mg as monotherapy. Again, we hope to have more data to present to you from this study next year. With that, I'm gonna hand it over to Patrick to talk about CALR.
Thank you. I'm Patrick Mayes. I lead our biotherapeutics research. I'm gonna 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%-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. This points to CALR being the key driver oncogene in those patients where mutations do arise. 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 rogue chaperone. It's able to then bind to the thrombopoietin receptor in the ER and causes complexing of the thrombopoietin receptor in the dimers.
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. 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. I'll walk you through a bit of the data with this agent. We refer to the monoclonal antibody as INCA033989. 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. Upon binding, it acts as a potent antagonist of mutant CALR function. A little bit about the selectivity. This is an engineered cell 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 INCA033989 binds very selectively to cells only in the context of mutant calreticulin. It binds selectively, but what's the function in cells? This is the same engineered cell system. In these cells, mutant CALR induces signaling and proliferation in a cytokine-independent manner.
Shown in the graph on the left is the ability of INCA033989 to inhibit that CALR-induced cytokine-independent proliferation. In addition to growth arrest, as you can see from the graph on the right, INCA033989 is able to ultimately result in cell death. These are cells stained with a viability dye that we can see the outcome over time. 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 INCA033989 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 phospho-STAT signaling in these cells.
You can see from the yellow curve the ability of INCA033989 to potently inhibit phospho-STAT 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 as shown in green and red. Importantly in wild-type CD34 cells, where phospho-STAT signaling is induced via ligand, as shown in blue and light blue, we see no effect of INCA033989. This is distinct from what a non-targeted JAK inhibitor would achieve in these same cells. This speaks to 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 a signaling inhibition in these wild-type cells.
We've looked more closely at the hematopoietic stem progenitor population within these patients. These again are CD34 cells harvested from myelofibrosis patients. If we track then the HSPC subclones within that, within those patients, you can see the effects of INCA033989 in blue, on a patient with mutant CALR, whereas INCA033989 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 INCA033989 has on the ability of megakaryocytes to differentiate from HSPCs, as shown in blue. Again, no effect was observed in the same sample harboring a JAK mutation.
This speaks to the ability of INCA033989 to have direct effects on the cell-initiating population within these diseases. We've gone on to utilize a surrogate of INCA033989 in a mouse model of ET. 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 a GFP-labeled wild-type bone marrow and then transplant those into a recipient animal and then track disease establishment over time.
What we observe in these mice is that, if you look in the graph on the lower left, in a control-treated animals over a 10-week 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 INCA033989 completely blunts the increase in platelets over that period. If you look more specifically at the mutant calreticulin-positive platelets in these same mice over that 10-week treatment time course, again, looking in control-treated animals, you see an increase of mutant calreticulin platelets over time to the point which at the end of that 10 weeks, nearly 100% of all platelets are mutant calreticulin positive.
Whereas in INCA033989-treated mice, you see not only a blunting of that, of that outgrowth of cells, but you see a steady decrease over time. This would be akin to what an allele burden reduction would look like in a patient from these mice. If you look at the bone marrows of these mice after that, after that 10 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 INCA033989-treated mice on the right, you see no effect of megakaryocyte hyperplasia, and we see normalization of the bone marrows with normal cellularity and no abnormal megakaryocytes.
A final piece of preclinical data here, looking at the effects of the antibody in combination with ruxolitinib. What we've seen is synergistic function of these agents in cells and patient cells harboring a mutant CALR. On the graph on the left showing the dose response of INCA033989 alone in blue, the combination of INCA033989 together with a suboptimal concentration of ruxolitinib in red, you can see a 10-fold 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 INCA033989 alone, as well as the combinatorial effect of INCA033989, plus this suboptimal concentration of ruxolitinib. 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 at subtherapeutic or suboptimal concentrations of ruxolitinib. In conclusion, we've developed a selective and potent antagonist of mutant calreticulin function. We're excited about this agent because we believe offers the potential to alter disease course in patients, and it will be entering clinical trials next year. I'll stop there and hand to Steven for closing remarks.
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. Eventually, patients will require further therapies to address the manifestations of the condition. In terms of the parsaclisib plus ruxolitinib data you saw from Dr. Yacoub, 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 additional parsaclisib to ruxolitinib.
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 worrying 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. 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. We'll have to make, you know, strategic decisions on where to go with this program over, you know, the early part of 2023.
ALK2, you know, 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. As was pointed out by Peter, you know, potentially allowing you to maintain ruxolitinib dose intensity and thus increase the benefits to patients. You know, we certainly got more space to go with dosing. As you saw from Peter's data, in single ascending dose studies, we went up to 500 mg. In multiple ascending dose, we went up to 300 mg BID. In the clinic currently, you know, we're in the 100 mg, 200 mg range, and no adverse events seen there.
you know, 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. you know, 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, you know, there are many catalysts coming. 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. The suboptimal responder 304 study, the data from the phase II that enabled that was presented by Dr. Yacoub will finish enrollment soon, and we should have top-line results towards the end of 2023.
It needs the 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, so about 440 patients are needed to complete that study. Then the ALK2 and BET programs now moving on to the combination phase with combination data in 2023, and then strategic decisions that need to be made there. Then mutant CALR will enter the clinic as soon as the IND clears in 2023. 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 polycythemia vera space.
Stay tuned. Hopefully, maybe another ASH plenary dash, no pressure. Then, the ET work, related to mutant CALR, which we can certainly talk about in Q&A if you like. Just remember to round out, the LIMBER program is a very important element related to graft-versus-host disease, anti-CSF-1R antibody collaboration with Syndax axatilimab. Their, the registration-directed phase II study that, GRAVITAS will deliver results in approximately middle of 2023, with enrollment being completed now, then combination with ruxolitinib that will initiate. Ideally, because of non-overlapping MOA and hopefully no toxicity that's worrying, you know, potentially a first-line effort in graft-versus-host disease and taking on steroids alone there.
If you look at, you know, the value add here, obviously as you've just heard, you know, 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. Now starting to see, you know, the light in terms of what's coming to not only replace this, but grow this franchise, if you will, further in many spaces. Once daily ruxolitinib, parsaclisib, BET, ALK2, the Cellenkos collaboration we didn't talk about, that's now in the clinic. It's umbilical cord cells that are enriched, and then the mutant CALR antibody and then the CSF1R antagonist axatilimab and novel targets in polycythemia vera 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. Please wait till the microphone's active to ask the question, so people online won't be able to hear you. Then one of us up here or potentially one of our experts will answer the question for you. 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's in his way. There's Marc. We'll start at the front. Person who has the microphone, go ahead. Yeah.
Great. Hey, Jess Fye, JPMorgan. For parsaclisib, what's the threshold for spleen reduction in the primary endpoint in the LIMBER-304 poor 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 gonna 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. Our primary endpoint there in terms of the percent reduction is not disclosed, as opposed to first line study, which is the same across all the sponsors, which is SVR35 plus symptoms. For our suboptimal study, we haven't said the exact percent we're aiming for, so we haven't publicly disclosed that.
Okay. For INCB000928, the 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 wanna answer that?
Yeah. Is this on? I think, you know, we'll see. I mean, the dose escalation is continuing, obviously it sort of depends whether we hit tolerability issues, whether we can continue to escalate to improve efficacy. I think our hope is to have a dose and a decision on moving forward by the end of the year.
Yeah. Just to be maybe a little bit additive there, you know, I think, you know, when you do preclinical work on the modeling, it looked like, you know, we've potentially in the dose range now, but you can see that we still have a ways to potentially go. We have more space, and we've seen improvement with the higher doses that's even more encouraging. 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 because it's hard for me to see. Evan? Yeah.
Hey, Steve. Good to see you. Evan Seigerman from BMO. Would there ever be a rationale to combine, say, ruxolitinib plus BET or the PI3Kδ plus an ALK2, so a triplet combination? 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 wanna start addressing that? I don't know if one of the external experts wanna talk about triplet combinations of-.
Yeah. To me 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. You know, I think certainly if there's a potential if we're seeing anemia and parsaclisib or sorry, in a parsaclisib ruxolitinib 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. You know, at this point, we're looking at the doublet combinations first, but, you know, there's gonna 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 would be from there.
Maybe for one of the expert... If Professor Verstovsek, if you'd wanna add.
I certainly feel it's moving toward doublets. I like your thinking about triplets in the future as it happened in some other hematologic malignancies. The point here is that you need to really have an incremental benefit of significance, right? Doublets, as you see, most of them aim to improve the spleen and symptoms. If you can add a third one to improve the anemia, you would cover all of it for a much longer period of time. You start talking about the survival benefit for real.
Marc? Yeah.
Thanks, Steven. Marc Frahm from Cowen. Maybe just to start on the ALK, as you get to making that go, no go decision at some point next year, just kinda 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 a level? Just how do you plan on evaluating the drug?
Do you wanna start off, Peter?
Yeah. You know, 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, 'cause there are a few different things we could look at. One is, and this is probably the sort of severest group of patients, we'll 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.
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? I think there's sort of, there are a few different areas we could look at, and ultimately, it's gonna be the data that we get from the ongoing study that will help us decide which path to take.
Okay. That, that's very helpful. Maybe on the CALR antibody, one, congrats on getting a plenary for a preclinical presentation. 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? 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? For... 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.
Can you kind of explain what the unmet need is in the CALR ET patients?
Patrick, you wanna do first on the Fc silence. Yeah.
Happy to. Thanks for the question about the Fc function. This is something we explored. We looked at different formats of the antibody, both 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 of CALR at the cell surface and the inability to recruit immune cells to kill via ADCC functionality. 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, 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. The potential of the calreticulin antibody in calreticulin-positive patients, about 30% of the patients, that we are not only co-controlling the blood cell count symptoms in the spleen by killing cells or preventing their growth, but to eliminate disease. That would be elevating the bar to PR and CR, and I hope that happens. 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 a cytoreductive therapy. If you up the bar and say, I have a chance to eliminate disease, no question I was gonna use it and eliminate it in the intermediate group of patients.
Other questions?
Hi, 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 just dosing about sort of a one and done type of therapy and maybe what you're envisioning for that. Secondarily, I had a question on the parsaclisib. One of the slides discusses treatment emergent adverse events, and patients entering study at, you know, some percentage entering the study at Grade 2, ended up with Grade 3 events and some folks entering the study at Grade 2 ended up with Grade 4 events.
I'm wondering, what that means in terms of how physicians will look at, you know, baseline adverse events coming into treatment.
Why don't you dosing first, Patrick? Yeah.
Thanks for the question. 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. It's a driver in these cells, and the ultimate outcome as been discussed, is to remove those mutant clones. 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. Our anticipation is that we need to maximize inhibition of this pathway for as long as is necessary to alleviate that burden.
Dr. Yacoub on safety. Hmm.
Yeah. Thank you very much for that question. I actually was hoping somebody would poke that a little bit. Thank you. 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 50,000. Some of them were actually below 50,000 once they entered 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. We allowed patients to get into the study with platelet counts that is that low that are qualified Grade 2. They already entered the study at Grade 2 thrombocytopenia. They only worsened by one grade.
I know when we're counting Grade 3 side effects, It does sound negative when you're having 11 patients with Grade 3 thrombocytopenia, but seven of those patients already were Grade 2. They only went down one grade. Had we had a bar of platelet counts of 100,000 like the other doublets, you would have zero Grade 3 toxicities. In that, I wanted to emphasize that in the presentation. I'm glad you asked it, this is definitely a topic that requires a lot of clarification. 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.
Yeah. Thanks. It's, Leo, on for, Brian at RBC. I had maybe a couple on the BET inhibitor, actually. If I remember correctly in the past, you dosed it at 8 mg, 12 mg, 16 mg. As you sort of dose escalate up, you're getting approaching those same levels where you saw toxicity in advanced malignancies that caused you to stop the trial. I guess what gives you confidence that now you're approaching this in the right way, that you're not gonna see some of those same signals? Is the patient population a little different? Then, you know, 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. The question is asking we should have mentioned that this compound was in the clinic years ago in a solid tumor paradigm, you know, largely targeting MEK inhibition. We went up to the higher doses you allude to. Peter, you wanna just talk about potentially differences in the profile we've seen?
Yeah. In the original phase I, it was, you know, all comers. It was a lot of solid tumor patients and as well as some lymphoma, AML and a couple of MF patients. We did escalate 8 mg, 12 mg, 16 mg. 16 mg was not well-tolerated, so 12 mg was going to be the dose we took forward. We're basically following the same. We're not going to go up above 12 mg in the current dose escalation. Obviously now we're just treating patients with or primarily patients with MF. You know, we're looking specifically at the tolerability profile there. You know, is the thrombocytopenia, which is the main dose-limiting toxicity. Is that going to be more of an issue in MF patients or not? We're going to test that in the dose escalation.
We're not gonna go above 12 mg because we already know that based on the original phase I, that wasn't well-tolerated. You know, we'll see what the, what the data look like. We'll have monotherapy data. We'll have combination with ruxolitinib in the suboptimal responders. We'll be able to look at spleen symptoms, anemia, all the typical endpoints, and decide from there what the best, you know, path to take forward is, whether it's a, it's a frontline study, is it to do the suboptimal responder add-on. We'll be able to decide once we have more data. Again, we would hope to make some decision later next year.
Thank you. Other questions? Yes.
Hi, this is Kripa from Truist Securities. Thank you so much for taking my question. One question was about ALK2. Is there a threshold for hemoglobin levels that you're reaching, or is there a dose-dependent increase in hemoglobin? 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? Maybe for the two KOLs here. With all these add-on therapies and the combinations that we're starting to see, and probably in a couple of two 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? Thank you.
Peter, you want to start off on the hepcidin?
Yeah. Maybe I can start with the ALK2 questions. 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 patient to 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 10, that we're able to consistently get them hemoglobins above 10, avoid transfusions, avoid preventing them from developing a transfusion need, then that might be a way that we go there.
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.
Thank you.
Are we seeing? I think, you know, in the graphs I showed where we had patients around. Right. We had patients around, so it did look like it stabilized. We had patients who were starting around eight or so and getting up maybe to 11. I think one was close to 12 and did seem to stabilize. I think what will be interesting as we continue to dose escalate, do we get further improvements from there, as we're able to continue? 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.
It will be interesting to see again, as we go up the dose levels, are we getting not only maybe higher levels of hemoglobin, maybe continued increases in hemoglobin, but we're also getting more patients that are having those increases in hemoglobin as well. I think again, it's the challenge of having a study that's sort of midway through the dose escalation, is we don't know where we're going to end up. In terms of the associated hepcidin and severity of disease, we know that elevated levels of hepcidin do predict poorer 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.
That's something as well we'll be looking at as we continue this study, is to see, you know, how extensive those benefits are, you know, across many patients or are there select patients that seem to benefit more than others. That's something we'll look at. Maybe I'll turn it over to our experts to talk about.
A wonderful question, and, you can only imagine how happy I am to answer the question when you say too many choices, potentially. That's the key, right? What they are for. Most of the combinations that we have are trying to improve what the JAK inhibitors do, and that would be improve the control of the spleen and symptoms, which is very valuable. There are not that many that actually aim to improve the anemia. As we were saying, there are three major problems, and, we do cover with the JAK inhibitor alone, pretty well actually, the spleen and symptoms. The anemia is compromising that control. If you would able to control the anemia, you would be able to do better job with the JAK inhibitor in controlling the spleen and symptoms.
In everyday 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. That's the standard practice, and that would be expectation of which of the combinations you would choose first. In that case, ALK inhibitor is my favorite.
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. Just like ruxolitinib was approved for myelofibrosis, and then the mechanism of action made it a reasonable medication for polycythemia vera, and that was successful. Then the effect of the immunity was successful in GVHD. 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 will have implication in other cancers with anemia. That then, that knowledge we gain from completing those studies can be expanded a lot bigger than the disease you studied it in.
That would have been a smart question had you asked it.
To my far left, front of the room.
Yeah. Stephen Willey from Stifel. Maybe just to follow up on the ALK2 inhibitor. Do we know what the association or correlation is between hepcidin reduction and then hemoglobin improvement? I guess I ask the question because I know in the 200 base cohort, you're seeing a pretty demonstrable improvement in hepcidin reduction, but I think there was only one patient that saw a 1.5 g/dL improvement in hemoglobin. Just trying to understand if there's an obvious disconnect there.
I don't think there's a sort of clear linear correlation between hepcidin levels of anemia because it is multifactorial. I think that again, it'll 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. Again, I think it's a challenge by not be sort of midway in the study. Again, as we continue to dose escalate, that'll be something we look at. We know there are many factors that are involved in anemia. Hepcidin is one of them. We'll see as we're able to get better and more sustained reduction in hepcidin, whether that translates into anemia benefits.
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 and I think half of newly diagnosed MF patients right you're kind of watching and waiting. Half will get single agent ruxolitinib. You get some kind of symptomatic and spleen benefit. Is there, is there a clinical benefit, I guess, to initiating doublet therapy right off the bat as opposed to just laying on single agent ruxolitinib, seeing who responds well, who doesn't, and then just going after the inadequate responding population?
A very practical question. If we are talking about the combo that would be improving the symptoms in 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 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. After some time, in the case of a cyclics study, you see that was after about a year and a half. You say it's not working very well. It's working to some degree, let's improve it by adding an agent that would boost that spleen and symptom control.
For that particular purpose, it is much, much more likely to add an agent later in the course of therapy. 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 is starting ruxolitinib, start from the day 1, ESA or danazol.
Maybe you can just talk a little bit about and I guess maybe both for the company and for the physicians, what will be the plan with QD ruxolitinib when that drug gets approved, presumably in the first half of next year? Is that something that you're gonna try to detail as a single agent? I guess to the physicians, I know that we often hear and you see it in the data all the time, right? I mean, ruxolitinib is a very titratable drug in myelofibrosis. To what extent does having a QD version of that impair, if at all, your ability to titrate the drug?
Yeah. No, I think they're good questions. I'm gonna 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. Then thirdly, I guess, is the macro environment in terms of, you know, Inflation Reduction Act and other, you know, aspects commercially that may dictate on how we launch it. You'll have to just wait a bit till we, you know, lean into it a bit more and probably tell you early next year exactly how, you know, we will be potentially doing that. I think at an obvious level, it's once daily, you know, and has potential convenience in terms of that aspect.
You know, we have very good data showing equivalency with the BID dosing. Hopefully the question around, if I understood you, the ability to switch from one to the other should be relatively easy. 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 ruxolitinib itself versus the once daily. I'm not answering you completely at the moment.
Yeah. Thanks.
Thanks. I think, we have time for one more question. Behind you there.
All right. Thanks for including me. Matt Phipps, William Blair. On the CALR mutant antibody INCA033989, maybe getting a little bit ahead of myself, but, you know, when you were trying to develop Jakafi in ET, there obviously were some issues with kinda completing that trial. Is there anything different you foresee about a development path in ET for INCA033989 that you think would make it more feasible?
Yeah. Maybe let me just lead off and then maybe Patrick knows. You know, the level of excitement related to this compound I actually haven't seen before in my, you know, my nearly 30 years of development. We literally have, you know, every investigator wanting to be the PI, et cetera. I think it talks to why a preclinical asset, you know, made it to the plenary today. You know, you saw mutant CALR was cloned in 2013, and now we have a drug in the clinic in 2023 with its potential to alter the natural history, as Dr. Verstovsek was saying. I'm not worried if your question was operational, will we have problems executing the studies? I think, you know, enrollment, I'll predict from the podium now is not gonna be a problem at all. MF, I think, is pretty clear-cut.
ET has some nuances which we've been speaking about, I think that's the essence of your question. I'll let the experts maybe answer you there a bit on their thoughts. Yeah.
Just zeroing down on the calreticulin antibody. This has actually been an ask from doctors for years. Since we realized there is a new antigen and this could be immune targeted, there has been major advances in immune therapy in cancer. Heard about CAR- Ts and BiTEs, this has become the new era. We're all waiting for an immune-based therapy for a new target. This is something we've asked for, all physicians have been asking for. I already have identified my patients with CALR are waiting for a study. It's that much that we're actually waiting for such an agent. If that helps answer your question.
Okay.
Do you think a BiTE is overkill for the...?
Okay. That question was raised earlier. There is in this 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 result. That was asked in the plenary session too, that actually comes with other side effects. If you can actually achieve the mission with just preventing the dimerization and cancers just dying off, that would be all you need, and that would just eradicate the disease.
Thank you very much to all the panel members who participated, and thanks to the audience for the questions. Some of the company people will be around for a little bit if you wanna ask those questions afterwards. Have a good and safe night in New Orleans. Thank you.