Karyopharm Therapeutics Inc. (KPTI) Earnings Call Transcript & Summary

Good morning, everyone, and thank you all for joining us today for Karyopharm's Analyst Event at ASH. Following our webcast today, the slides being presented here will be made available on the Investors section of our website. I'm joined today by my colleague, Richard Paulson, President and CEO; Dr. Reshma Rangwala, Chief Medical Officer. I'm also very pleased to be joined today by 2 recognized global thought leaders in the area of MPN, Dr. Verstovsek and Dr. Ali. On this slide is an outline of what we will cover today. Before we begin, I'd like to remind you that various remarks we'll make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995 as outlined here. It is now my pleasure to introduce Richard Paulson, President and CEO of Karyopharm. Richard?

Thank you, Elhan, and good morning to everyone. And we are delighted that you're able to join us today for Karyopharm's analyst event during the 64th Annual Meeting and Exposition of the American Society of Hematology. And on behalf of all our presenters, I would like to thank you for taking the time to join us today. Karyopharm was founded in 2008 as an innovation and patient-focused company, developing first-in-class oral, selective inhibitors and nuclear export with target XPO1. Fast-forwarding to Karyopharm today, where we are successfully leveraging this fundamental mechanism of action to build upon our existing multiple myeloma franchise anchored around our commercial drug, XPOVIO. XPOVIO is now approved in 40 countries, and combined with increasing use in earlier lines in multiple myeloma, we are expecting revenue of between $155 million to $165 million in 2022. We are working to expand invitations through advancing our focused clinical pipeline. This pipeline is comprised of mid- and late-stage clinical development programs that has been purposely built and strategically focused to help patients who suffer from cancers with high-unmet need to demonstrate efficacy at lower doses, with improved tolerability and where we believe we will have the highest probability of success. Based on compelling data signals, we are pursuing opportunities in endometrial cancer, myelofibrosis and myelodysplastic neoplasms. Collectively, we believe we have the potential to achieve multiple product approvals over the next 2 to 4 years. We've also evolved our leadership with highly accomplished executives from across the biopharmaceutical industry, specifically with commercialization and mid- to late-stage clinical development experience to lead us in delivering our targeted mid- and late-stage pipeline. With a strengthened leadership team in place, we believe we can achieve both scientific and commercial excellence while executing on our key corporate objectives. I will now turn to Reshma to discuss the science that informs everything we do. Reshma?

Thank you, Richard. The nuclear pore is a complex gate between the nucleus and the cytoplasm, closely regulating the import and export of most large molecules, including many proteins. In humans, there are 7 known exportins or nuclear export proteins, the most well-characterized is called exportin-1 or XPO1. Karyopharm's lead investigational drug candidates are first-in-class, oral, selective inhibitors of XPO1. XPO1 inhibitors block the nuclear export of tumor suppressor, growth in regulatory as well as anti-inflammatory proteins, leading to an accumulation of these proteins in the nucleus and enhancing their anticancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. This novel mechanism is broadly applicable and foundational to cancer biology. We have prioritized and targeted core programs focused on improved patient outcomes in areas of high-unmet need using the science I just described for you. Today, we will be focusing on myelofibrosis, where our drug selinexor has the potential to improve patient outcomes in both frontline as well as the relapsed/refractory myelofibrosis patient population. We are very pleased to have with us today 2 guest speakers who are distinguished global opinion leaders in the field of MPNs. First, we will hear from Dr. Verstovsek, M.D., Ph.D. Director of Clinical Research for myeloproliferative neoplasms at the MD Anderson Cancer Center. Dr. Verstovsek?

Good morning, everybody, and it's a great pleasure to be here this morning with good friends and family here. And we say, "Go Croatia Go" for the World Cup, right? And I see in the public many people that I know well, and we follow each other. So it's really nice to be here to talk about exciting new products that may help our patients with myelofibrosis. I am with the MD Anderson Cancer Center since 1998. And it's true that I lead that clinical research center for myeloproliferative neoplasms, which is the largest single institution center, about 250 new patients every year in consultation, mostly with myelofibrosis. And I am engaging in a number of different activities related to new drug development. And after all, led to development of ruxolitinib as the first drug approved for myelofibrosis. So it's exciting time to talk about our new findings with early findings with selinexor. But before we go into the details of other findings, let me tell you a little bit more about myelofibrosis in short introduction. This is what it is. It is the myelofibrosis -- myeloid cells or the bone marrow cells in fibers in bone marrow. You can see the fibers by the black color. These are the fibers actually and the bone also is changed, bone itself, its call osteosclerosis and the 2 packed together, fibrosis and osteosclerosis prevent bone marrow from functioning leading to enlargement in the spleen in about 80% to 90% of the patients, which is a blood organ. So it's a reactive enlargement. That then would also result in the anemia, that's the blood film and unfortunately, some patients, about 25% of the patients would have a progression to acute myeloleukemia, and this would be blast in the blood as an indication of a progression. So if you want to summarize the clinical feature of myelofibrosis, we typically talk about 60, 65-year old person, that's the typical age of diagnosis. Myelofibrosis can be de novo after [indiscernible] basically, patients present with these findings or may have a history of polycythemia vera or essential thrombocythemia more benign myeloproliferative neoplasms with the annual incidence of about 1 new case per 100,000, which makes it about 20,000 people living in the United States with myelofibrosis. So clinically, because of fibrosis, you have splenomegaly with its own associated problems; big spleen, causes pain, inability to eat, loss of weight, and cachexia; then the cytopenias, anemia, thrombocytopenia, bleedings, transfusions, effect on multiple organs, constitutional symptoms of different sorts, night sweating, bone aches and pains, itching. You can imagine how this actually looks like in a 65-year-old with a big spleen and loss of weight and all the symptoms. It's not a very nice picture at all. The outcome is poor, the average survival 5 to 7 years, mostly because of progression of myelofibrosis, only about 1/4 of patients progress to acute myeloleukemia. So what does this mean? Bigger and bigger spleen, bigger and bigger liver, organ failure, pulmonary hypertension, heart failure, ascites, leg swelling, cachexia, slow death in the hospice or at home, not in acute setting. It's really not good at all. Okay. Now, we know now since 2005 a lot about biology, and we keep learning. But it is fair to say that in every single patient, there is a hyperactivity of the JAK/STAT pathway for different reasons and the JAK/STAT pathway is involved in a blood making inflammation and immune function. And in bone marrow, due to different mutations, it will make cells grow without control with the reactive fibrosis leading actually to 2 fuel cells being produced. The driver mutations, this is how we call mutations that activate the JAK/STAT pathway of different sorts, typically mutually exclusive of each other, the most common being the JAK2 mutations, but there are others. The bone marrow fibrosis, it's, as we say, usually a reactive process to presence of malignancy where cytokines in a bone marrow or stroma, the cells to support the growth of bone marrow cells, react in a way of autocrine and paracrine influence on what happens in the bone marrow through elevation in production of different inflammatory cytokines. Because the blood is not made, then anemia, thrombocytopenia over time slowly progress and contributes to the morbidity of the disease. And this extramedullary hematopoiesis is one of the hallmarks of the disease with big spleen and big liver, but 40% to 50% of patients have a big lever as well. So it is really unusual, very transformative physically for the patients and in terms of quality of life as well, very terrible condition. So what do we do? Well, we don't have a cure. The only cure is the bone marrow transplant, just to clear that up because you say, why don't we just send everybody to transplant, but less than 10% of the patients actually go to transplant. So realistically, that's not possible, right? So we have to manage patients and their condition. So as you see a circled part here, why do we treat the patients? We treat the patients for constitutional symptoms. We try to use a questionnaire to objectivize the quality of life and say, "Hey, your quality of life bad. Let's treat you for that quality of life." Progressive organomegaly, spleen and liver needs to be reduced to improve quality of life and possibly improve the longevity, as I want to mention later, and then anemia. So 3 areas of concern, anemia, splenomegaly and bad quality of life. What do we do today? This is the copy of NCCN guidelines. It's continuously updated, but there is not much update to provide for patients in myelofibrosis unfortunately, with the real new medications. Everything that we have so far is about the JAK inhibitors to control the signs and symptoms as much as you can, but they are lookalikes and they have a similar modes of actions. And you see here that we would first divide patients in the dose that are symptomatic or not. And then platelets would matter pacritinib is approved, as we all know, for patients with lower platelets for others to use ruxolitinib, fedratinib. And in second line setting, if one doesn't work, we could use the other. So more of the JAK inhibition. So what do actually JAK inhibitors do? And this is from the ruxolitinib a very old slide COMFORT-II study comparing ruxolitinib to best available therapy waterfall for a spleen response. Fair to say everybody have a degree of spleen response, primary refractory patients to ruxolitinib are very rare, maybe 2% or 3%. That's the orange color here. But my goal as a physician is to get this waterfall to be equally low to 80 to 100% elimination of the spleen in everybody. It's a waterfall. We wanted to have it a wall where everybody has a massive improvement in the spleen. So there is much work to do, right? The standard practice, by the way, which is in blue, which is hydroxyurea doesn't really work well. That's why the JAK inhibitors became stand the practice. But as you can see here, much room for improvement plus the standard frontline therapy with ruxolitinib causes anemia and thrombocytopenia and those adjustments and the management of patient's ruxolitinib is affective quite a bit and leads to underperformance of these drugs because of the anemia and thrombocytopenia. However, we can prolong the life of these patients with ruxolitinib on its label. How can we do that? One marker of the success is the degree of spleen reduction. Basically, the smaller the spleen becomes the longer the life of the patient that was done by measuring the spleen by volume by MRI to the left -- in the studies and by patients simply to the right, you see the palpation results, 50% screen gone or not in here and those that have a smaller spleen, live much longer. Now this is a marker of disease, not that there is some magic about the spleen. It is just the marker. I will usually say, look, you shrink the tumor as small as possible, it just takes much longer to come back and people live with the control disease much longer. So we want to optimize the care. Unfortunately, the durability of ruxolitinib in clinical studies is not that good. It is on average and the lines here are from different studies and how they drop out and when. And on average, you would see that most of the lines would say that about 3 years is average duration of ruxolitinib. The black one that is extraordinary bad is for patients with low counts. These are plated below 100. Why is this not longer, right? Well, under dosing because of anemia and thrombocytopenia and inability really to provide this effectively for much longer. In fact, we know now, if you follow the field very well, you would know that from a community standpoint, the average duration of therapy with ruxolitinib in the United States is about a year, 1.5 years, not 3 years. Studies role is better than the community practice, right? So there is much room to improve here. Once you stop ruxolitinib, the story goes down, I mean, it's really sorry to say, it's a little devastating for the patients. This is our own experience that is recapitulated by many other publications. The average survival once you stop ruxolitinib is 14 months. So you have, obviously, here a case to improve what ruxolitinib does, build on it or develop and/or develop another agent that would be very effective after ruxolitinib. And you see the reasons for -- and main reasons for loss of response, it's not only about the dosing, but the biology of the disease with the clonal evolution, new other mutations developing in the patients while they are on ruxolitinib leading to lose response. So many kinds of our action -- with a new mechanism of action is important topic. We need something different than another JAK inhibitor after JAK inhibitor. So obvious need for new therapy and this is just a cartoon from a serious review on the topic, identifying possibilities of attacking the malignant cells in myelofibrosis, where there are so many different abnormalities. And not to go through details here, but each white box gives you a name of the drug and the target. So it's a very active field to find something different that would be active and effective and simple to help our patients with myelofibrosis to build on the JAK inhibitors or to help after JAK inhibitors fail its control of the disease. And as we know, there are several drugs in the red box to the left that are already in Phase III studies for possible approval with a different mode of action, from BCL-XL inhibitor down all the way to telomerase inhibitor for different populations of the patients. Not every patient is the same. And this spans from the combinations in first line to adding medications to people who have suboptimal response, which is a very large group of people or the second line. Of course, each of these combination partners needs to fulfill some basic prerequisites, which would be safety and simplicity in delivery. Otherwise, you compromise further the delivery of the standard practice JAK inhibitor. And so that's why we are excited about today's presentation and we'll learn in detail about what's happening with the selinexor in combination with ruxolitinib in patients that have a treatment-naive myelofibrosis. So thank you very much for letting me introduce the next speaker to Dr. Ali, who will tell us all about the updates on the data. Thank you.

Thank you. Good morning, everyone. So I'll be talking about the results of the Phase I study of adding -- basically using selinexor-ruxolitinib as upfront treatment for patients with myelofibrosis. So myelofibrosis is driven by 3 mutations, JAK2, CALR, MPL mutations, which are most common mutations we see in the myelofibrosis patient. And usually, the JAK/STAT pathway is activated and that actually leads to activation of downstream pathway, including AKT and ERK pathway. And most of these pathways actually lead to activation of the nuclear transfer protein that are involved in the progression of the myelofibrosis. So with this, actually, we did the Phase I study using selinexor along with ruxolitinib in the previously untreated patient. And here's the key inclusion criteria patients with myelofibrosis dips one or higher -- intermediate one risk or higher with the spleen volume of 450 or above. And the performance status ECOG 0-2, platelet account more than 100. In dose escalation, we tested 2 doses, 40 milligrams weekly versus 60 milligrams weekly and the ruxolitinib was given at doses 15 to 20 milligram BID depending on the platelet count. And in the dose expansion, we had 18 patients with either 40 milligrams or 60 milligrams. And the objective of this routine was to explore the combination of selinexor and ruxolitinib and built on the single-agent activity of both compounds. We have presented this data in ASCO earlier and here, we presented the update safety and preliminary efficacy data at week 24. The primary endpoint was the medicine at tolerated dose and a recommended Phase II dose and looking at the AEs. And the secondary endpoint was -- were very common that typically you'll see in other myelofibrosis study SPL35, which is 35% volume reduction at 24 weeks. TSS50, 50% improvement in the total symptom score. Overall survival anyway response and also if we look at the PK analysis. As of October 21st, we currently have 24 enrolled patients and 10 patients on 40 milligrams arm and 60 patients -- 13 patients in the 16 milligrams arm, and there was 1 patient who received dose at 20 milligrams weekly in the 60-milligram but was included in the 40 milligrams arm. So here are the baseline characteristic, which is quite typical what we would see in myelofibrosis patient, media age 64 -- in 40 milligrams of 58 versus 65. More male patients that it's typically expected of the disease. There was a majority of the patients were transfusion independent. There was one transfusion-dependent patient and there was a good breakdown between primary and secondary myelofibrosis. And there was a good mixture of various risk categories, intermediate 1, intermediate 2 and high risk. And most common mutation that typically as -- typically would see in myelofibrosis JAK II followed by CALR and NPL mutation. And looking at the analysis, so we have safety population of patients who will see at least 1 dose. And in the efficacy, I mean, we had a patient who had at least 1 spleen volume measurable during the assessment and for symptoms who had at least one symptoms were collected. For the primary analysis included patients have been treated until the relevant time points and/or discontinued prior to the relevant important time points. And all patients who are hemoglobin stabilization population, all patients who had transmission independent at baseline or followed up at 8 weeks. And the data cutoff was October 21, 2022. So here's the swimmers plot. You can see that median duration of therapy was at 25 weeks, it was much longer in the 60-milligram arm the 29 weeks and the 40-milligram cohort was 17 weeks. And the reason for discontinuations are listed here, clinical progression to AML treatment-related adverse events, a patient proceeding to stem cell transplant or withdrawal of consent. And I mean, you can see in the -- some of the patients, especially in the 40 milligrams arm actually have not completed the 24 weeks, so data has continued to be corrected as of the cutoff date. And here are the primary analysis, so looking at the volume responses at 24 weeks of SVR35. So we see 11 out of 92 -- 11 out of 12 evaluable patients, about 92% of the patient had a spleen volume response. And looking at TSS50 in patients who actually submitted, we were able to collect the symptoms about 67% TSS response by 50% or more. So here's the waterfall plot for spleen volume response. I mean, at both dose levels, you see a very good spleen volume response at week 24. I mean -- and here to note actually -- all patients actually responded. There was -- as the Dr. Verstovsek showed that there was few patients in the ruxolitinib arm that did not respond, but here, we see the response in pretty much all the patients. And again, here is the curve showing the responses by 12 weeks and 24 weeks. You do see a rapid reduction in the very beginning of the treatment with a 45% spleen volume response median and that continues to proceed at 24 weeks. So -- and I mean here, some of the patients were at low dose, as low as 5 milligrams but still they continue to have response despite being on the low dose of 5 milligrams of ruxolitinib. Here, you see what happens to the hemoglobin in the patient. Typically, with ruxolitinib, you will see a dip in the hemoglobin in the first 2, 3 months. And subsequently, actually, it recovers. So this typically -- this is what we saw on the study as well, there was a drop in the hemoglobin eventually actually, it recovers. And in some of the [indiscernible], they show that when the hemoglobin recovers it may not go back to the baseline, but at least in the study what we saw is actually going up to the baseline. And if you look at the number of patients who had hemoglobin below 10, and they had a stabilized hemoglobin that actually did not drop from baseline by 2 gram per deciliter about 81% of the patient and -- so 100% in the 40-milligram and 60% in the -- 71% in the 60 milligrams arm. Here's a breakdown of adverse events. The most common adverse event was nausea, anemia and fatigue as well and -- but the majority of the adverse events was actually grade 1. There was only 1 grade 3 nausea that was observed. And 2 cases have grade 4 neutropenia that occurred at 60 milligram dose. And -- but it was not clinically relevant and there was no bleeding events that were seen in these patients. There was no treatment-related death. So in conclusion, I mean, a combination of selinexor-ruxolitinib demonstrated meaningful efficacy across relevant efficacy time points, including SVR35, 92%; TSS, 67%; and hemoglobin stabilization in about 55 -- 7% of the patient. AEs were generally manageable and grade 3 or 4, they were not clinically relevant and there was no bleeding, serious infection or a clinical sequalae. The both 40 milligrams and 60-milligram doses were well tolerated. Most common AE was nausea, fatigue, anemia and thrombocytopenia. And the combination led to a rapid reduction in spleen volume in these treatment-naive patients, and the data demonstrated that the combination of selinexor and ruxolitinib has the potential to be a novel first-line agent for treatment naive patients. Thank you.

Thank you, Dr. Ali and Dr. Verstovsek for those wonderful presentations. Let's recap these important findings from the Phase I portion of the export MF of the 3-4 study. selinexor in combination with ruxolitinib demonstrates meaningful efficacy across 3 relevant efficacy endpoints in treatment-naive myelofibrosis patients. Specifically, key highlights include a rapid sustained spleen response observed in 92% of efficacy evaluable patients who achieved an SVR35 at week 24. And 67% of efficacy-evaluable patients also experienced a greater equal to 50% reduction in their total symptom score at week 24. And then lastly, 57% of transfusion-independent patients either maintained or improved their baseline hemoglobin levels. The study also showed a generally manageable side effect profile at both the 40- and the 60-milligram doses with the most common AEs being nausea, fatigue, anemia and thrombocytopenia. This data build on the single-agent activity of selinexor observed from the essential study in the JAK inhibitor exposed myelofibrosis patient population and suggest selinexor could be utilized in both the treatment-naive and JAK inhibitor exposed patient populations. A 30% SVR35 was observed at week 24 and 40% SVR35 was observed at week 24 and beyond. In addition, we observed a 2-year probability of overall survival of 92%. Although the essential study is small and the data are still preliminary, the results build on compelling nonclinical and preclinical data by demonstrating monotherapy activity and highlights the potential of this novel class of therapy to improve outcomes, including durable screen volume reduction. We continue to enroll on our most advanced MF study, the ongoing Phase II MF035 study. Here is a preliminary schema for the randomized portion of the selinexor and ruxolitinib combination in treatment-naive MF patients. Specifically, we will compare the SVR35 and TSS50 at week 24 for the combination compared to ruxolitinib alone. We look forward to discussing this trial design with the FDA in early 2023 and expect to start the randomized portion of the study in the first half of next year. In closing, we continue to strive each day for patients with unmet needs as we advance our pipeline with a number of key near-term catalysts and corporate milestones. With that, I will open up to the Q&A, which Elhan will facilitate.

[Operator Instructions] We will first start taking questions from the audience here. Jonathan?

Jonathan Chang from SVB Securities. Congrats on the data. First question, how do you see the selinexor plus ruxolitinib combination comparing to other ruxolitinib combinations in development in the competitive landscape? And then secondly, could you just comment on how you're thinking about dose selection and the tolerability profile of each agent and to what degree dose modifications or discontinuations were reported?

So if I may start with the first question, multiple questions excellent -- thank you, Jonathan. So the comparison at the level of everybody having a different follow-up or a different level of development of their own assets it's somewhat limited. But when you see the results of this quality with such high percentages of control of the spleen and symptoms, we are very much intrigued and the efficacy is tied to the safety and the simplicity. This is a drug that is given once a week. So you already have a check on the simplicity. And the tolerability is something that can be improved on, but it's really good already, without major or new discoveries. So I would say that if you combine the 3 things together higher efficacy than any other, very simple unlike any other, and tolerability, which is acceptable this, in my view, is very compelling for further development. And others will talk about the dose selection.

I mean dose selection, we really want to wait for the 24 weeks data to have a pretty complete set of data to the dose selections. So I mean we have not decided what dose we're going to move forward with. Reshma?

Yes. Yes, I appreciate that. And I think this is sort of the next steps that we're going to be looking at is identify the recommended Phase II dose as Dr. Ali just mentioned, it really is going to be incorporating the efficacy, the safety as well as incorporating that pharmacokinetic data. We'll use those 3 data sets to, again, identify the dose that we want to take into the Phase III, of course, discuss that with the FDA and then all of that's going to drive to initiation of the study next year.

All right. Are you able to comment on the degree of dose modifications or discontinuations and the experience to date?

I think we have that on the slide. And for the reason of discontinuation. And I mean -- about the modification we did a…

We have -- yes, I can certainly take that one. We haven't provided the dose modification-dose reduction rates at this point. We are still waiting for the data to mature and of course, we will provide that data in future updates. With that said, we're very encouraged by the dose intensity that we're seeing. So 82%, 83%, respectively, for seli and rux in terms of the dose intensity. Those data suggests to me at least that the planned doses that the investigator had indicated for the patients, by and large, are getting administered to the patients. We don't see a lot in terms of dose modification reductions that will alter again that treatment plan. So to Dr. Verstovsek's earlier comment, this is a relatively simple, easy combination that ultimately can be provided to the patients, but we will provide additional data on that question going forward.

It's Leo on here for Brian from RBC. I just wanted to dive also a little deeper into the safety profile. I guess what are the kinetics of when patients were seeing these adverse events? Is it when they're taking that dose for the first time in a week that they're getting this vomiting? I guess is it something that they can keep dosing through? Does it fade over time? And then maybe for Dr. Verstovsek, do you see the need to maybe medicate the patients for the constipation, the vomiting and the nauseas adding to the complexity of the treatment? And could this impact real world use compliance and duration of treatment?

So I mean, in terms of the symptoms of nausea, not all this vomiting, but where nausea typically will happen on the day the patient would receive treatment and patient would get a pre-medication Zofran to help with the nausea and continue the post dose. Usually, the symptoms are predominantly in the first 2 cycles, but then after there actually is very tolerable. Patients don't even feel it that much. So there is actually an improvement in the symptoms after the first couple of cycles.

I can provide a little bit of color to the kinetics. So we've got a much larger data set, especially from a multiple myeloma experience. And it's exactly what Dr. Ali was describing is what we see in multiple myeloma too. So from the Boston study, we know that patients experience that nausea very early on with a substantial improvement at the end of cycle 1, by the end of cycle 2, almost 92% of patients resolve their nausea. So it is limited to the first 2 cycles and going forward, really not a problem for that patient population. Antiemetics too are also further controlling. In this study, we only provided -- we only required 1 antiemetic going forward will require the 2 anti-emetics and further hopefully have an opportunity to further improve that nausea. Last thing I will mention is that none of the patients discontinued due to nausea. Patients, by and large, while they were experiencing that grade 1, we're able to maintain their therapy, stay on, which ultimately drove that efficacy.

So learning along as we go in management of geotoxicity is certainly very important in providing a prophylactic preventative anti-nausea medications would be the key to start well and not allow the patients to have a toxicity that would then question the doctor's decision to prescribe this medication. But we see successful management of this program by others. We have, for example, pacritinib that causes about 60% patients having diarrhea that comes together with anti-diarrhea when you prescribe the pacritinib and you don't hear anything about diarrhea causing any problems with pacritinib for people with low platelet below 50. So I would predict that this would be something that would be a common practice here with selinexor comes together with anti-nausea medication, and patients just take it, and that resolves the issue of nausea.

This is Kevin Strang on for Maurice from Jefferies. I just had a question on the TSS50 more. Is there sort of a specific bar that you're looking for, for TSS50? And when could you have an update to sort of make a decision there? And then just given the better looking AE profile so far for the lower dose, do you think that, that would potentially influence the TSS50 score for those patients and potentially have those patients have a higher score there? And how do you sort of think about if the SVR35 is maybe numerically lower for those patients, but the TSS50 is higher? I guess what goes into that recommended Phase II dose decision?

I can take.

You want to take?

I can certainly answer that. This is a very good one. A very good question so far. The control of quality of life and the spleen are equally important. We can't have a drug that does 1 thing and doesn't do the other. We have problems with other drugs in development like that. That's why the question -- first question was how do you compare? Well, this one, as you can see in both arm -- both of the benefits is much more than what you would expect with ruxolitinib alone. But you don't want to have a discrepancy of -- a large discrepancy between the 2. So for example, it's good to have dose about the same, right, at the same level. So fine-tuning dosing perhaps or how the management of early introduction is with the lower and higher dose or perhaps finding a middle dose or there is work to be done on the part not to lose the sight of the both factors together. So your concept what you're asking about is crucial for overall success because you want to have a smaller spleen and a better quality of life together.

And we'll certainly be taking in. We are not identifying the recommended Phase II doses. As you know, based upon this data set, we are looking for more maturity, especially in that 40 milligrams. And to your point, I mean, that is exactly one of the factors that will into consideration. In terms of the -- I just want to also comment in terms of the AEs, what we know and Dr. Ali mentioned this, is that the median duration on treatment is quite different for the 60 milligrams and the 40 milligrams. So there too, that maturity in that 40 milligrams really will allow us to better compare the AE profile for the 60 and the 40. We may just see a numerically higher rate in the 60 milligram again just because they've had longer duration of treatment.

Eric Joseph, JPMorgan. The impact on anemia and the change in hemoglobin is pretty interesting. So I guess I'd be interested from Dr. Verstovsek's perspective, just sort of how anemia correction or management thereof is, how that ranks among endpoints like spleen volume and symptom score. And as for the data themselves, is there any indication of a dose response or dose sensitivity to the change in hemoglobin or the return of hemoglobin count that you're observing?

Well, I am not aware and we just talked about the dose modifications and how this works out very well in the patients. But overall outcome of the experience so far is particular. People don't have a reason to stop the therapy because of anemia, the degree of anemia that we saw on that graph is less pronounced than with ruxolitinib alone. And therefore, I'm happy to say that there is no contribution of myelosuppression to management of patients with ruxolitinib alone because that's a common problem. When you add another agent that is causing anemia or thrombocytopenia, in particular, compromising the simplicity and safety of the combination. So that does not appear to be concerned. Later on we will have a more detailed analysis of those adjustments and modifications to answer to some precision but first-look looks really favorable.

Do want to add on that typically patients when they present, I mean, with all the symptoms, fatigue and different things that are also being driven by the cytokines. So typically, if you see a drop in the hemoglobin in the patients, but generally, the symptom still continues to improve despite the drop in the hemoglobin because generally, patients are feeling better. The spleen is smaller, they're gaining weight, there's less night sweat. So it can correlate with the symptoms, but most of the time in the beginning of the treatment, it actually doesn't. So it gives you a time for the initial period for the hemoglobin to recover. So it does not become an issue.

Any other questions from the audience? We have a few questions from the webcast from Edward White from H.C. Wainwright & Co. He has 2 questions. Why did the one patient get 20 milligram for 3 cycles? And then the other question is, can you give us an update on the Phase II MF035 study? And the last question is pathway approval for combination of monotherapy and expected timing. So maybe we can start with the first one, 20-milligram or 3 cycles.

It was a very simple, answer the patient just took the 20 milligrams. So they were prescribed a higher dose, but they took the 20 milligrams and they took that 20 milligrams for the first 3 cycles, and then we just increased them up to the 60 milligrams. Ultimately, when we took the average of the dose, it came to 40 milligrams, which is why we included that patient in the 40-milligrams analysis. But yes, there was no greater explanation than an error. In terms of the 035 study, so the 035 study again is an JAK-exposed patient population. In this randomized study is comparing only monotherapy compared to physician choice therapy. This trial is currently enrolling in multiple sites throughout the world. And then in the last question was the registration path?

Yes, path to approval for combination of monotherapy and expected timing.

Yes. Great question. And this is going to be part of our discussion that we have with the FDA in the beginning of next year. So we'll be talking about our entire myelofibrosis program, including the design and the details of the design that I just mentioned earlier in the presentation today, but of course, also monotherapy opportunities for approval.

Yes, I don't see -- I mean there is another question from Michael from Morgan Stanley, but we already answered that, and it was about the 40 milligram versus 60 milligrams. So we're fine there. But I'll turn to the audience in case there is a last question from anybody. I think we're all set here.

Thank you, Elhan. Thank you to everyone for joining us today and great questions. Thank you to our guests, speakers and all the employees who help make this event possible today. We look forward to seeing many of you in person again. It's wonderful to be in person at the JPMorgan conference in January. So have a great day, everyone, and enjoy the rest of your ASH conference.