Ladies and gentlemen, welcome to the Sobi Investor Event, the Journey for Vonjo Conference Call and Live Webcast. I am Alice, the Chorus Call operator. I would like to remind you that all participants will be in listen-only mode, and the conference is being recorded. The presentation will be followed by a Q&A session. You can register for questions at any time by pressing star and one on your telephone. For operator assistance, please press star and zero. The conference must not be recorded for publication or broadcast. At this time, it's my pleasure to hand over to Guido Oelkers, CEO. Please go ahead, sir.
Yes, thank you so much, and welcome to this conference, which is dedicated to Vonjo. Before we start, I would like to provide you with a forward-looking statement, as per usual, and let's go straight to the next slide, and today, it's really about Vonjo and pacritinib in our recent acquisition that we got going with CTI, and as we discussed yesterday in our earnings call, we wanted to provide you with more information on Vonjo, and basically, today, I'm really blessed to be accompanied, and I'm just doing here the little prelude by Professor John Mascarenhas, from Mount Sinai, who is one of the world-leading experts in myelofibrosis and has many other academic credentials that we could spend all afternoon on. So forgive me, Professor Mascarenhas, that I keep it a bit shorter today, and Dr.
Sarah Buckley, who is our global head for the Vonjo franchise, and I'm very excited that she decided to join us from CTI, and you will see that there was a lot of exciting development ongoing, and Sarah symbolizes for me this deep and broad knowledge about the disease area, but also about the product, and then followed by the summary and the question and answers. Very brief, only one minute, one or two minutes from my side to the next. Let's move to the next slide. Basically, this is really Vonjo as part of our journey, but as you can see, we focus on hematology, and for us, as we have discussed yesterday, it just didn't, the acquisition of CTI did not happen by coincidence. It's right on strategy. It's a highly differentiated JAK2 inhibitor, as you will see later, with effect on IRAK1 and ACVR1.
And it is right on our area of not necessarily already expertise, but it connects extremely well with our franchise in hematology. Next slide. And where we are today, I'm really gratified that we were able to attract really the key talents of CTI to Sobi. Obviously, this is a journey, but we will do whatever we can to make this a very positive journey and experience for everybody. And there's no longer them and us; it's all us. And we are in the midst of preparing our life cycle management planning, as we outlined yesterday. And we're really very thoughtful of developing this product further, and we see a lot of utility of the product. This is really about developing the franchise, building a growth story, but also giving justice to the opportunity of the product. And this is not about cost saving. Next slide.
Yeah, with this having said, I would really like to refer now to Professor John Mascarenhas, who will take it on from here. Thank you.
Okay, thank you for the introduction. I'm thrilled to be here, working many years now with CTI BioPharma and Sarah Buckley directly, and look forward to working with Sobi in bringing pacritinib to patients with myelofibrosis. Next slide. So for those of you in the audience to familiarize yourself with myelofibrosis, this is a hematologic malignancy recognized by the World Health Organization as a neoplasm that's derived from the hematopoietic stem cell. So these are blood cancers. Myelofibrosis is an aggressive type of blood cancer, and there really are three main aspects of myelofibrosis that are often considered therapeutic targets. So due to activation of a signaling pathway called the JAK-STAT signaling pathway, there is abnormal hematopoiesis that compromises normal hematopoiesis.
This is reflected by often cytopenias, low blood counts, so thrombocytopenia, low platelet count, anemia, low hemoglobin at presentation in many patients, and often worsens with disease progression, but also as a result of many therapies that are given, including other JAK inhibitors. This becomes a very important point as we continue discussing the disease and the opportunity to capitalize on these aspects with drugs like pacritinib. Splenomegaly is another major hallmark of this disease that's driven by extramedullary hematopoiesis, and it's contributed to bone marrow fibrosis. You have abnormal trafficking of these malignant stem cells from the bone marrow to other organs like the spleen and the liver that cause enlargement. And this enlargement of the organs causes a lot of discomfort and contributes to the poor quality of life and ultimately the poor outcomes of patients with myelofibrosis. And this is a well-recognized therapeutic target. And then symptoms.
This is a highly inflammatory disease, again, driven by JAK-STAT signaling, results in significant pro-inflammatory cytokine production that results in a significant symptom burden to patients with myelofibrosis. These are some of the sickest patients we see in the cancer center with constitutional symptoms: fevers, night sweats, weight loss, and then other symptoms that can be related to the spleen: bone pain, itching, fatigue, and inactivity. These patients are quite unwell, and I'm hoping I'm conveying significant symptom and quality of life reduction in these patients with a short survival given the type of malignancy we're talking about. Next slide. So to reemphasize again that these patients are quite unwell and feel quite unwell, and those symptoms can be broken down broadly into symptoms that are centered around low blood counts. So for example, fatigue, inactivity. This is almost a universal symptom.
I would say every patient I have with myelofibrosis has some degree of fatigue. It's the most frequent, it's the most severe symptom, and often leads to inactivity and reduction in quality of life and interaction for many of my patients. Patients are also plagued by what are called constitutional symptoms. They're driven by cytokines such as night sweats, itching, bone pain. These symptoms really reduce quality of life and again, are a therapeutic target and goal of treatment when addressing our patients with myelofibrosis, and then spleen-related symptoms: early satiety, abdominal pain, and even vein symptoms like abdominal distention, inability to wear pants normally. It really affects many aspects of life that we take for granted. These patients, again, have a chronic myeloid malignancy, essentially a chronic leukemia that runs the risk of developing into an acute leukemia, which happens in about 20% of patients within 10 years.
This is associated with a dismal prognosis of three to five months. These patients are also considered hypercoagulable, meaning that they're at higher risk for having thrombotic complications, arterial and venous. This can happen in about a third of the patients, and the sad part is the median survival of patients with myelofibrosis is five to six years. Remember that number because we're going to also concentrate on a subset of patients that have a dismal prognosis that's far worse than this, that is typified by the cytopenic myelofibrosis phenotype. Next slide, so I've mentioned JAK-STAT signaling. This is recognized in 2005 with the discovery of the JAK2 V617F mutation as the fundamental hallmark, at least biologic hallmark of this disease that drives the cytokine production, the overproduction of blood cells that drives splenomegaly.
It is now increasingly recognized that there are other signaling pathways that are highly relevant to the biology of myelofibrosis. And many investigators, like Stephen Oh, have brought this to light with preclinical studies and correlative studies demonstrating the activation of the toll-like receptor IL-1 signaling pathway that signals through the myddosome complex and recruits IRAK, IL-1 receptor-associated kinase 1, which Sarah Buckley will talk more about in her presentation, which ultimately leads to NF-kappaB activity. NF-kappaB is a master regulator and transcription factor of cytokine production. So you have two pathways that are driving this pro-inflammatory state: JAK-STAT signaling and IRAK1 NF-kappaB signaling. Right now, the drugs that we normally give to address the disease are focused on the JAK-STAT signaling pathway and neglect the IRAK1 NF-kappaB pathway.
This becomes fundamental to appreciating the uniqueness and importance of pacritinib in treating patients with myelofibrosis, which we'll hit upon in the next slides. Next slide. It is also increasingly recognized, in large part due to the clinical trials and availability of pacritinib, that there is a spectrum of patients with myelofibrosis. These are not uniform disease. This is not a monolithic presentation of patients. Patients present in various ways, have various clinical presentations. And within that spectrum, there are those patients that have a very proliferative phase disease on the left, and then those patients who have a cytopenic phenotype on the right. The cytopenic patients are the patients that are typified by lower blood counts, so anemia, low hemoglobin, thrombocytopenia, low platelet count. They often have higher blast count. They're more likely to transform to leukemia.
They are often JAK2 mutated, but often with a lower JAK2 VAF, which becomes important when looking at some of the biologic mediators of these phenotypes, and they're often complicated by additional mutations. This group on the right, the cytopenic MF patient, unfortunately has the worst prognosis of patients with myelofibrosis. These patients do particularly poor. They represent an unmet need that was not met previously, in which pacritinib is uniquely suited to address. Next slide, so as I've been mentioning, cytopenias, which is the clinical aspect of the patient profile that we're talking about, is a frequent complication of the disease, and what I'm showing you on the top is thrombocytopenia, low platelet count, occurs in about at least 25% of patients at presentation, and as you can see, worsens through the disease course. Why does it worsen? It's part of the disease progression.
It's a mark of disease progression, but it's also complicated and exacerbated by many of the therapies, including pre-existing JAK inhibitors that we give our patients, and often limits the ability to effectively dose other JAK inhibitors, so it's an important aspect that is frequent and tracks with anemia shown below, which is a major hallmark of the disease as well. Also frequent at presentation and worsens through the clinical course, and again, often complicates therapeutic decision-making and exacerbated by most of the therapies we give and remains an unmet clinical need, so anemia and thrombocytopenia are clinical hallmarks of this cytopenic myelofibrosis patient, which is very frequent and worsens with disease course. Next slide. It is not only a hallmark and a frequent hallmark, but it also has prognostic significance, which is extremely important to consider.
So here I'm showing you the survival curves from retrospective studies looking at thrombocytopenia, low platelet count on the left, and anemia, low hemoglobin on the right. What you can appreciate is that the lower the platelet count, the worse the survival. The lower the hemoglobin, the worse the survival. In fact, if you look in that blue dotted line on the left for thrombocytopenia, you can see that the patients who have platelet counts less than 50,000, so this is extreme thrombocytopenia, an utter unmet and urgent need prior to the availability of pacritinib in the U.S., and median survival of 15 months, just a shy over a year. This is really a tragic situation in which we had very little therapies to provide, and these patients do very poorly, as you can see. Next slide.
It is increasingly recognized that thrombocytopenia, again, is not only frequent and progressive, is not only associated with a poor prognosis, but is also associated with a significant symptom burden, and no matter what symptoms you look at, and I love this graph because it really provides a very nice and simple snapshot to understand that in gold, which is thrombocytopenia, so these are patients who have platelet counts less than 100,000 compared to blue, greater than 100,000, there is significant worsening of each symptom in almost every case. It's not one symptom that drives it. Across the symptom burden, which you can see, these are many different symptoms that plague patients. The symptom is often worse in patients who have low platelets.
These patients not only have a poor prognosis, not only are limited in therapeutic options, but have a very poor quality of life with significant symptom burden that detracts from their functionality and ultimately contributes to their poor outcomes. Next slide. Where are we going with this? Obviously, this meeting is about pacritinib. This was a huge advance for the treatment armamentarium of myelofibrosis because it finally met an unmet need that had unfortunately persisted for many years. Ruxolitinib was approved in the US in 2011, fedratinib in 2019. Both drugs are approved for patients with platelet counts greater than 50,000 who have spleen and symptom burden. Finally, pacritinib meets that unmet need for patients with platelet counts less than 50,000 with intermediate or high-risk disease. This was based off the PERSIST studies, which we'll review. Next slide.
So as I mentioned in the previous slide, JAK-STAT signaling, fundamental, important to the biology and a therapeutic target, but also IRAK1 NF-kappaB signaling, which is also contributing to that pro-inflammatory state, which goes unquenched because the current JAK inhibitors are not hitting that pathway. Pacritinib is a selective JAK2 inhibitor. It's an IRAK1 inhibitor, so it downregulates NF-kappaB. It downregulates the other signaling pathway that contributes to the disease biology and the inflammatory state. It likely also explains why this drug can be delivered in patients with low blood counts. And importantly, and Sarah Buckley will hit on this further, it's also an ACVR1 inhibitor, which is also a fundamental pathway that governs erythropoiesis anemia.
There are distinctions with pacritinib that are important in terms of its ability to not simply be able to be delivered in patients with low blood counts, but in a proportion of patients, even improve hemoglobin levels, which we do not see with ruxolitinib and fedratinib. Next slide. What I'm showing you here is the study schema for the PERSIST-2 study. This was the pivotal registration study in patients with myelofibrosis with a platelet count less than 100,000. By definition, this is the cytopenic myelofibrosis patient population. These were the patients who would have been excluded from the pivotal COMFORT studies that led to the approval of ruxolitinib. The patients could have seen a JAK inhibitor before, so half the patients were already previously treated. Again, this represents an additional adverse prognostic factor.
Patients who've seen ruxolitinib previously have an even worse prognosis with a median survival that's approximately a year and a half at best, and patients were randomized to pacritinib 400 mg once daily, 200 mg twice daily. That's the approved dose or best available therapy, which could have been dealer's choice, whatever the physician thought was effective because it's a desperate situation. Patients were given ruxolitinib at low doses, hydroxyurea, in some cases no therapy. They could have gotten erythropoiesis stimulating agents to help anemia. They were essentially given whatever was at the disposal of the physician to try to improve the situation of the patient. This is one of the most stringent co-primary endpoints of a trial done in myelofibrosis with spleen volume reduction of 35% or greater. This is an important regulatory endpoint that the FDA recognizes.
This is a diminution in the spleen size by imaging after six months of 35% or greater, and that has been deemed an important clinical outcome measure, as well as a Total Symptom Score reduction of 50% or greater. This is filled out by the patient. This is a patient-reported outcome. It's a validated symptom score that's appreciated by the FDA and considered a primary or key secondary endpoint for these trials. In this study, it was two. It was the co-primary endpoints of spleen and symptom benefit in these patients with low platelets that have, even in some cases, half the cases seen a prior JAK inhibitor previously and have no other options. Next slide. Here is a snapshot of the patient demographics. The median age is 68 year. That's around the median age of patients with myelofibrosis. Importantly, the median baseline platelet count was 55,000.
This is very low. Almost half the patients had platelet counts less than 50,000. I will reiterate, these were patients who had historically been excluded from the COMFORT studies, the first JAK inhibitor. And many of these patients would have been excluded from studies like the JAKARTA studies that led to the approval of fedratinib and even the MOMENTUM study that led to the approval of momelotinib. A recurrent theme is that these patients have low platelet counts. They would have been given suboptimal standard of care therapies and never made it to a tertiary care center for clinical trial participation in many cases. Also, low hemoglobin, 9.5g/dL . Again, anemia is an adverse prognostic indicator. It's incorporated into many or most or almost all of the prognostic scoring systems along with thrombocytopenia.
Again, half of the patients saw prior ruxolitinib in an even worse patient population with an expected poor survival, and these patients had large spleens. Next slide. I think the slide speaks for itself. If you look at the data specifically in the patients with less than 50,000 who received pacritinib at 200 mg twice daily, the approved dose, the spleen volume response rate of 35% or greater was met in nearly 30% of patients compared to 3% of patients with best available therapy. So a very striking difference. I like the waterfall plot on the right because it gives a sense of the spectrum of responses. So even in the patients who did not hit that endpoint of 35% or greater, there was significant reduction in the spleen.
In fact, we've done ad hoc analysis demonstrating that even a reduction of 10% or greater with pacritinib affords patients a survival benefit when looking at outcome measures. So this is a drug that can be delivered in patients with low platelets that can achieve spleen responses hitting regulatory endpoints, but even when not hitting regulatory endpoints, I can assure you providing benefit that's meaningful to the patient and their quality of life and their outcomes. Next slide. This is a well-tolerated drug. I say that for a number of reasons. One, we're talking about a patient population that does not tolerate drugs well because they are typified by the low platelet count. These are patients that are more likely to have complications and adverse events that are often not even therapy-related and are simply treatment emergent. Pacritinib is a FLT3 inhibitor. There is expected GI toxicity.
This is low-grade GI toxicity seen mostly in the first two cycles of therapy. It rarely leads to discontinuation. It is very easy to manage with antiemetics or antidiarrheals when needed. And it is not a major obstacle for delivery of therapy for patients with myelofibrosis. And in hem-onc, it is not an extraordinary toxicity that we see. You can also see some of the other toxicities listed below. I will caution anyone who may look at the myelosuppression, the anemia, and the thrombocytopenia, and remember that these patients came into trial with significantly compromised blood counts. So even small diminutions in the hemoglobin level or platelet count could trigger an adverse event on a clinical trial such as this.
That would appear that the drug is contributing or worsening that, but in many cases, that's not what's happening, and the patients can be treated easily through these cytopenias, supported when they need to. And as I've seen in my own anecdotal cases, and we've seen in the clinical trial, there are patients over time that actually have improvements in their cytopenias on pacritinib in the setting of diminution of their spleen, improvement of their symptoms, and restoration of their performance status. This was rarely a reason for discontinuation. And the fatal adverse reactions were similar between the two arms, pacritinib and BAT. Next slide.
To better drill down on maybe the differences in adverse events, considering that the patients had a much shorter exposure to BAT because those patients on BAT almost universally crossed over to pacritinib, an analysis was done using events per 100 patient years at risk to provide a better, more even sense of adverse events as it relates to exposure and time at risk to experience those adverse events. What you can see is numerically, there were less adverse events with the pooled data from PERSIST-2 and the phase II dose-finding PAC203 study. Again, this is all at the approved dose of 200 mg twice daily. So there were actually fewer adverse events as it relates to cardiac events, even bleeding events, thrombosis, non-melanoma skin cancer.
This is a recognized complication that can occur in the setting perhaps of JAK1 inhibition, which is spared with pacritinib but not with ruxolitinib. And almost in every case, this was less frequent in patients treated with pacritinib with this type of analysis. I'll also just bring your attention at the bottom to deaths. There were fewer deaths with pacritinib than there were with BAT and even specifically with ruxolitinib. Again, I think highlighting the ability to effectively deliver this drug, maintain dose intensity, improve spleen and symptom, restore functionality, restore weight loss from cachexia, and patients who eat and move are likely to do better than patients who are suffering and cannot get adequate JAK-STAT inhibition and NF-kappaB downregulation. So I think this is a function of the mechanism of action of this agent. Next slide.
The PACIFICA is an ongoing phase III study with the study schema shown here, specifically targeting those patients with a platelet count less than 50,000. I'll remind you that the pivotal PERSIST-2 with patients with platelet counts less than 100,000. The accelerated approval was for patients with platelet counts less than 50,000. That was deemed the most urgent unmet need by the FDA, and that's what provided the accelerated pathway. But we have data, as I've shown you, for patients with 50,000 to 100,000. But this study is specifically enforcing what was seen in the PERSIST-2 data or is intended to do that with platelets less than 50,000, either JAK inhibitor naive or limited duration of prior JAK therapy. You can see it's a large study. Almost 400 patients will be enrolled in a two-to-one randomization. The dose is the approved dose, 200 mg twice daily.
The physician can either give low-dose ruxolitinib, which would be the common option given in the community, hydroxyurea, danazol, or corticosteroids to these patients. Again, stringent co-primary endpoints, spleen volume response. We've seen it with PERSIST-2. We know it's there. Reduction in symptom score, I can tell you that that's also there. So these are important co-primary endpoints, but also the secondary endpoints of survival, Patient Global Impression of Change, and obviously characterizing the safety profile. Next slide. This is a snapshot of the NCCN guidelines for the management of lower-risk patients with myelofibrosis on top and higher-risk patients on the bottom. I just want to bring your attention to a couple of squares. For lower-risk patients, you can see that the NCCN does endorse pacritinib for patients who have lower-risk disease by risk stratification for patients with platelet counts less than 50,000.
It is obviously approved and endorsed by the NCCN for patients with intermediate to high-risk disease with platelet counts less than 50,000, and I would say pacritinib could be used as a therapy in itself. It can also be used as a bridge to patients who are going to go on to get the minority patients who are going to get transplant, and then importantly, the NCCN authors have also endorsed and recognized the utility of pacritinib for patients with platelet counts greater than 50,000. Why? Because the data is there. It's from PERSIST-2. We have data for patients with platelet counts greater than 50,000. We have data from PERSIST-1 with platelet count of any platelet count in which benefit can be delivered to any myelofibrosis patient with spleen and symptom burden.
You'll also notice that, and although it's not highlighted well here, pacritinib can also be used as a second-line agent irrespective of the platelet count and endorsed by the NCCN guidelines. I'm happy to see that the physicians that comprise the NCCN guideline committee recognize the benefit of pacritinib and have integrated this therapy within their guidelines, which also helps prescribers in the community advocate for their patients and gain access to pacritinib even outside of the label of less than 50,000, in which increasingly I have seen many providers in the community move to because this remains an unmet need even beyond the less than 50,000 patient population. Next slide. Now I'll turn it over to Dr. Buckley. Thanks very much.
Thank you so much, John. Hi, everybody. My name is Sarah Buckley.
I'm the Medicine Development Lead for Vonjo, and I'm very excited to present some emerging insights that have helped us to better understand the potential role for pacritinib in myelofibrosis and also beyond, so on the next slide, you'll see that recently additional insights have been emerging on the benefit of pacritinib in myelofibrosis, and this is based on retrospective analyses as well as on investigator-sponsored studies. I'm going to describe some of these to you. Due to time constraints, there are a few that I won't be able to touch on. For example, there was a recent landmark survival analysis of PERSIST-2, and there was also a recent oral presentation at EHA on the HOVON-134 study that was looking at the use of pacritinib prior to allogeneic stem cell transplant. I would encourage you to review these abstracts on your own. They showed very encouraging results.
But let's just hit a few of these and take a look at the results. So on the next slide, you'll see we'll start by discussing some of the post-hoc analysis of symptom data from PERSIST-2. This is actually an important part of the NDA submission. So I need a little bit of background for this slide. PERSIST-2 was positive for one of its two co-primary endpoints. So it hit spleen reduction, but it was a near miss for total symptom score, or TSS. However, this is crucial. The version of TSS used in PERSIST-2 was not the same version that was used in the pivotal studies for approved JAK inhibitors. So unbeknownst to CTI at the time, these other JAK inhibitor studies for ruxolitinib or fedratinib, they used a modified version of the TSS that excluded the symptom of tiredness.
Why did they do this? Tiredness is complicated. There are so many confounding factors that impact whether you feel tired. So it's very challenging to use tiredness as a measure of treatment effect. For those studies, it got dropped from the total score. PERSIST-2 included tiredness. Not surprisingly, it's the most common symptom, and it's the most severe symptom of all of those reported. Once this discrepancy was recognized, there was a retrospective analysis performed from PERSIST-2 based on the modified TSS. Here's what we found. The percentage of patients in the pooled pacritinib arm who achieved a response was 31%, and this was significantly greater than the 14% who achieved response on best available therapy.
In other words, had the PERSIST-2 analysis been correctly pre-specified, meaning in line with all of the other JAK inhibitor trials, PERSIST-2 would have been a positive study. It would have hit both spleen and symptom endpoints. This data was not included in the Vonjo label, but it was listed by the FDA as evidence of benefit in the integrated summary, and we've subsequently published the results of this analysis. Now, on the next slide, I'll show you results of another analysis in which response rates were compared between patients who received pacritinib 200 BID, the approved dose, versus those who received ruxolitinib as their best available therapy on PERSIST-2. Now, of course, this PAC versus RUX study is a post-hoc analysis. It's not randomized or powered, but the results are still striking. Look at the response rates on pacritinib versus ruxolitinib.
Among these patients, and they had platelet counts of 100 or less, ruxolitinib had very low efficacy for spleen response. So that's the bars on the left, whereas pacritinib responses were quite good. Similar trends were noted for symptom response. So if you look at the middle bars, those show Total Symptom Score response. And then the right bars labeled PGIC show the percentage of patients who described their symptoms as being much improved or very much improved at week 24. And you can see on pacritinib, it's over a third of patients. And an important point in this analysis is that these patients who are very cytopenic, they were able to tolerate full-dose pacritinib. Median dose on study was the full 200 BID throughout the treatment course. And this was not the case with ruxolitinib.
Full-dose therapy with RUX was either not tolerated or it was not even attempted given the cytopenias in this population. Now, let's switch gears to the next slide. So here's some important anemia data that was presented at the American Society of Hematology in 2022. But before I can show you the data, I need to provide a little background on anemia. So one of the major causes of anemia in myelofibrosis is inflammation. We've discussed that myelofibrosis is an inflammatory disorder. And when the body is very inflamed, the liver produces a molecule called hepcidin that takes the body's iron and hides it. And when it does that, you can't produce new red blood cells, and so you become anemic. So inflammation causes anemia through hepcidin. That's where ACVR1 comes in. ACVR1 is a master regulator of hepcidin. So if you block ACVR1, you reduce hepcidin.
Now, the hypothesis is that if you have a drug that can target both the inflammatory pathways of myelofibrosis and it can block ACVR1, that can really lead to an improvement in anemia, so let's switch to the next slide, and we can see the results of the ACVR1 inhibition analysis. Now, this was after pacritinib was approved in 2022. It was discovered that pacritinib is a potent ACVR1 inhibitor. This was based on an in vitro assay, and this assay looked at the inhibitory potential of four JAK inhibitors head-to-head in vitro. These were pacritinib, momelotinib, fedratinib, and ruxolitinib. And the IC50 inhibitory concentration for each drug was calculated, and the experiment was duplicated just to check the results, and what we found is that pacritinib was the most potent ACVR1 inhibitor of all of those tested.
And when you consider the kinetics of pacritinib, and that's the graph on the left, you can see that in humans, pacritinib achieves levels well above this IC50. So it's inhibiting ACVR1 from the first dose, and this inhibition persists for 24 hours a day, the entire dosing cycle. The plasma level never falls below the IC50. And this is not the case. It does not appear to be the case with other JAK inhibitors based on this data. With momelotinib, the IC50 is higher, so it seems to be a less potent inhibitor in vitro. And the predicted plasma concentrations don't remain above that threshold for the full dosing cycle. Now, before I show you some new data on pacritinib's anemia benefit, let me step back for a second and say that data on pacritinib's anemia benefit is not new.
There were pre-specified analyses in PERSIST-2 that already looked at pacritinib's anemia benefit, and these results were already published five years ago as part of PERSIST-2. But what we did in 2022 was to look at a new measure of anemia benefit. Next slide, please. And that measure is transfusion independence. This is a retrospective analysis of transfusion independence, or TI. And we looked at patients on PERSIST-2 who were receiving red blood cell transfusions at baseline. And we looked at the conversion from requiring red cell transfusions to being TI, where TI was defined as a period of at least 12 weeks where you did not require red cell transfusions. And we looked through week 24. We found that TI conversion was more common on pacritinib at 37% compared to best available therapy at only 7%.
What's really striking about this data is that standard erythroid support therapies, meaning things that help improve your hemoglobin, things like EPO or danazol or steroids, all of these agents got used on the best available therapy arm, but they were not allowed on the pacritinib arm. Still, pacritinib showed significantly better results. We also assessed our results in multiple subgroups. That's the graph on the right, and the results were consistent throughout. Now, this analysis focused on patients who were very cytopenic. I think the median platelet count in this subgroup was 43. Pacritinib has been studied in broader MF populations. It's been studied in patients with normal blood counts, and there's been an open question of whether pacritinib works differently in patients who are more cytopenic or more proliferative.
If we take a look at the next slide, we can start to answer that. This was a retrospective analysis that highlighted pacritinib's consistency of response regardless of baseline cytopenias. This study was unique because it pooled patients on both PERSIST-1 and PERSIST-2. The reason to include both studies was that PERSIST-2 was limited to patients with platelet counts of 100 and less. In order to see effects in patients with higher blood counts, we wanted to look at all available data with pacritinib. Here's what we found. On the left, you can see the median percent change in spleen volume stratified by baseline platelet count, that's in shades of blue, and by baseline hemoglobin, that's in shades of red. As you can see, all of the lines are overlapping.
In other words, spleen reduction occurred similarly regardless of these baseline counts. Next, let's turn our attention to the graph on the right. This shows changes in symptoms. Well, let's go back a slide, please. So the graph on the right shows changes in symptoms measured by total symptom score, TSS. And once again, we see consistent symptom reduction across all subgroups. But interestingly, the improvement seems greatest in the most anemic patients. If you look at the subgroup with hemoglobin less than eight, that's that bar in the maroon color, you can see deeper, faster, and deeper symptom improvement. And when we showed this data to the investigators who were working with us on this publication, a question arose. Why do we observe seemingly better symptom improvement in patients with more severe anemia? And is there a link to anemia improvement in the subgroup?
So in order to answer this question, the study authors wanted to see a graph of hemoglobin over time in all these subgroups. So now we can go to the next slide, and I'll show you what we found. Overall, the median hemoglobin levels were stable. But in patients with baseline hemoglobin less than eight, these patients appear to have an improvement in their hemoglobin starting by around week three on treatment. So the authors of this analysis are planning to explore the connection between symptom improvement and anemia benefit further, and we're drafting a manuscript around these data. So on the next slide, I'd like to start thinking with you more broadly about how pacritinib can achieve its full therapeutic potential. We're committed to exploring the potential of pacritinib to benefit patients in myelofibrosis and beyond, and I'd like to share some thoughts on future directions with you.
Next slide. Pacritinib's current label is narrow, but pacritinib has the potential to address unmet needs in additional patient populations within myelofibrosis. This broader utility was already recognized by the NCCN panel, as Dr. Mascarenhas outlined, as they included pacritinib as a first-line option regardless of platelet counts for patients with higher-risk disease who are not eligible for transplant. But beyond that, emerging data has shed light on how pacritinib could impact patients with anemia, how it can be used to optimize patients prior to allotransplant, and additional studies could shed light on pacritinib's impact in accelerated or blast phase myelofibrosis, perhaps in combination with other agents. Next slide. So based on its mechanism of action and its unique kinome profile, pacritinib could be beneficial in other indications within malignant hematology or solid tumor oncology or benign hematology or inflammatory diseases.
This slide lists a few examples of disease areas where clinical studies could be considered. There's also strong interest from the medical community in many of these areas. We currently have over 20 investigator-sponsored studies, either ongoing or under review. Given Sobi's expertise in hematology and in immunology, we're exploring opportunities for indication expansion, and we hope to have more information at a later date on how this is progressing. Next slide. Pacritinib is a unique molecule, and it's well-positioned for further exploration of its benefits. We're currently assessing multiple opportunities. These include additional data generation to leverage real-world insights into pacritinib's benefits in myelofibrosis. In addition, we're exploring the possibility of new indications in malignant and in inflammatory diseases. There's also the opportunity to test combination therapies.
This is an area that I'm personally very passionate about because I believe that pacritinib could become the JAK inhibitor of choice for partnering with novel disease-modifying agents, and finally, there's an opportunity for geographic expansion. We're ramping up our regulatory teams, which have a strong track record of international expansion of our products, and that concludes our overview of emerging data and future potential for pacritinib. Thank you so much for your attention, and I'm now going to hand back to Guido.
Thank you, Sarah, and thank you, John. I mean, you know, when I promised you yesterday that we are excited about the product, I think you could sense, you know, from the previous presentations how excited we are and the utility that we see for the product. I mean, maybe you go to the next slide, if there is any.
And if not, let's, oh, yeah, there is one. You know, you could sense, you know, and why we talked yesterday about what Vonjo is right on strategy. I think we could hopefully share, you know, our view that Vonjo is a differentiated asset in myelofibrosis, that it is that thrombocytopenia in conjunction with myelofibrosis represents a higher unmet medical need, that there is an opportunity for us to build a broader pipeline around Vonjo or with Vonjo as a lead asset, as we explained in the later part of the presentation. And, you know, that this is that good medicine may also be good business, I think, is self-understood. Yeah, I think on this note, we want to give way to question and answer, and I understand from the moderator that there are quite a few questions already.
Maybe hand back to the moderator, and you know, now it's time for Q&A.
We will now begin the question and answer session. Anyone who wishes to ask a question may press star and one on the touch-tone telephone. You will hear a tone to confirm that you have entered the queue. If you wish to remove yourself from the question queue, you may press star and two. Questioners on the phone are requested to use only the handset and turn off the volume from the webcast. Anyone who has a question may press star and one at this time. Our first question comes from the line of Charlie Mabbutt with Morgan Stanley. Please go ahead.
Hi, it's Charlie Mabbutt from Morgan Stanley. Thanks for taking my questions. Two questions, please.
So firstly, Professor Mascarenhas, I'd be interested to hear if you see anemia or thrombocytopenia as more of a concern in your patients and why. I ask because, obviously, despite the strong anemia data, pacritinib is only indicated on label for thrombocytopenic patients, and soon we're going to likely have another drug indicated directly for anemia. It's just how you see the positioning there. And then secondly, are you able to provide any color on the treatment duration you currently see with patients on pacritinib, especially given their worst prognosis, which you outlined, and how this varies between the first line and beyond? Thanks very much.
Okay, so to address your first question, I think it's important to appreciate that both anemia and thrombocytopenia track together. So they're frequently present and worsen, you know, in parallel.
Usually, thrombocytopenia is considered the more complicated cytopenia to deal with because, again, it does limit the ability to adequately provide sufficient doses and dose intensity of ruxolitinib and fedratinib. You can transfuse platelets, but often their longevity is limited to days. So you're constantly trying to keep up the platelet transfusion part of it. And this, you know, I believe particularly in patients who are older, who are sick, that's in a closed compartment like the cranium from a fall is really a very significant risk and concern when we treat these patients with significant cytopenias and significant platelet count. What is, I think, important and, you know, perhaps not totally, and I think Dr. Buckley highlighted this, not totally appreciated initially, was that we did see anemia responses with pacritinib.
And I've seen this. I can speak anecdotally as well beyond the clinical trial that we've participated heavily in. Anecdotally, in the commercial space, I have patients, and I've shared this information with CTI previously. I have patients now who are out years to speak to durability, years on pacritinib, some of which now have hemoglobins that, you know, are not normal, but, you know, approaching nine and 10. Even one patient has 11, and these are patients who were transfusion dependent and had hemoglobins in the sixes previously. We've even seen patients have improvements in the platelet count. One of the things I think is important is that you don't get that significant treatment emergent thrombocytopenia with pacritinib. You have a certain degree of stability of the platelet count.
But as I keep pointing out, which is not captured in the clinical trials adequately, but I see it in clinical practice, is that if you treat the patients through particularly the first six months of therapy and continue to deliver the drug at 200 mg twice daily or even 100 mg twice daily, you start to see this slow but very reliable and reproducible uptick in the platelet count. So I have seen patients who were in the single-digit or low double-digit platelets now have platelet counts of 50,000 to even 75,000, very different from what they look like at treatment initiation with pacritinib. So I think both are important. I think platelet count is more worrisome from a clinical standpoint. As I showed you, platelet count also tracks and associates very neatly with symptom burden and is a poor prognostic marker.
So it is a challenging situation, to say the least. Both are prevalent, both complicate therapy. Pacritinib can be delivered at the full dose with minimal concern from a platelet count perspective and an upshot of potentially improving those cytopenias over time. And the durability is there. I don't know that I could give you, you know, median duration at this point, but what we do see are patients who remain on pacritinib mainly because there are not other therapeutic options. So these patients are doing well and continue to receive the drug day in and day out. And perhaps Dr. Buckley can speak to prescriptions and scripts that keep going up, but I personally cannot.
Yeah, I don't have any data on prescriptions or scripts.
Thanks very much. Good. Maybe we can move then to the next question. Thank you.
The next question comes from the line of Christopher Uhl with SEB. Please go ahead.
Thank you very much for taking my questions. I have quite a few, so I'll start and get back in the queue. But I guess, Professor Mascarenhas, to begin with, so I guess when one looks at the forecast that people have out there, it's clear that there are a lot of patients who the market, let's say, does not expect to get on pacritinib who are severely thrombocytopenic. So what proportion of these patients are on some kind of therapy, and what are the main obstacles to getting more of them on therapy and on pacritinib in particular? And I guess sort of so related to that, I mean, yeah, so what therapy do most severe thrombocytopenic myelofibrosis patients get today, and how much is off-label Rux? Thanks.
So I think, you know, historically, patients with extreme thrombocytopenia, we're typically getting nothing because nothing could be delivered effectively. And I hate to say it, many of these patients ended up in hospice and were simply getting supportive care or low doses of ruxolitinib, which, you know, provides minimal benefit, but definitely not maximal or optimized benefit. So you would have patients sitting on, you know, five milligrams once a day, five milligrams twice a day of ruxolitinib with some degree of symptom benefit, very minimal spleen improvement. It was suboptimal, to say the least. I think when pacritinib was approved, it was a welcomed addition because it was not simply another JAK inhibitor.
This was a JAK inhibitor that met a need in the less than 50,000, which was excluding, you know, so, you know, to answer your question of what percentage of patients would be eligible for pacritinib, probably 80% of patients with platelet counts less than 50,000. I couldn't tell you what percentage are actually getting pacritinib now. I can tell you that it's increasing. I do webinars with physicians across the country in different geographic areas in the U.S., and what is remarkable and consistent across those webinars with small groups of 10- 12 physicians is that there's already a recognition within the community for a drug that was only approved in March of 2022. There's already a recognition of pacritinib, the name Vonjo, the product label, where the drug would be used, and even a willingness and interest in using it in those patients.
I'm not seeing any resistance or concern about using pacritinib in those patients. And, you know, the reality is because it really isn't a great drug to use. So this drug becomes a very obvious choice for those patients. I think that to try to answer the rest of the question, I think that where this moves from now is for those patients who are sitting on inadequate low doses of ruxolitinib is the comfort level of the practitioners to then switch them over to pacritinib. And of course, you know, it's always hard, I think, when you have, you know, over a decade of experience with one JAK inhibitor, you know, this is a ramp-up of providing another option and the confidence to move to that option. So what I typically see are patients, physicians are prescribing pacritinib to the patients who couldn't get anything.
They get that comfort level, and then they start to look at the patients who are on suboptimal doses of ruxolitinib with an eye to start switching them to pacritinib to try to maximize benefit. So I think you'll see increasing utilization of patients switching from inadequate low doses of Rux to pacritinib. We also see a lot of bleed over. I myself for sure do it. I see a lot of my colleagues doing it where even if the label is 50,000 or less, if you have someone who has a platelet count of 75,000, you know that if you try to deliver effective doses of Rux, you will simply compromise the platelet count and then get into this cycle where you end up dose-reducing and then limiting the effect of ruxolitinib.
So even in those patients, many physicians now are adopting an approach where they are looking at to obtain pacritinib. And I have to say, it's, you know, it's not an obstacle to obtain pacritinib. So I wouldn't say that insurance approval has been an obstacle and getting pacritinib for their patients even, you know, slightly above that 50,000 range. And I think that that will continue to expand as the comfort level with the drug increases.
Thanks very much. I'll get back in the queue.
Thank you. Next one. Next question, please.
The next question comes from the line of Eun Yang with Jefferies. Please go ahead.
Thank you. So overall survival is not a primary endpoint in phase III, but it's a secondary endpoint. So can you kind of comment on what do you expect overall survival would be on Vonjo versus competitor arm in phase III?
So I can try to address that. Survival is a, I believe, a secondary endpoint in the PACIFICA study. We don't have the study power to detect survival difference one way or the other. Survival is both an efficacy and a safety endpoint, but I don't think I can comment further on what we expect to see. I would refer you to the PERSIST-2 study, which shows there is a difference in survival, not statistically significant, between pacritinib and best available therapy. I believe the hazard ratio was around 0.68 in that study for the 200 BID dose.
Okay, thank you. And then a question to Dr. Mascarenhas. So according to, like, outside from the label, per the NCCN guidelines, you can actually treat first-line patients not eligible for transplant regardless of the platelet count.
So in your current patients, what percent of patients who were previously on ruxolitinib actually switched to Vonjo? And second question is, as you mentioned, as the physicians' comfort levels of the drug improve, do you expect utilization would go up? But if you look out to the next three to five years, what percent of first-line patients not eligible for transplant do you expect to be on pacritinib? Thank you.
So to address the first question, you know, you have to take into account that you're speaking to a physician who primarily does myeloproliferative neoplasms, who has an array of clinical trial options, many of which would act to salvage patients who are failing ruxolitinib by adding on different strategies or monotherapy. So I'm probably not the best gauge of what it would look like in the second line.
I can tell you that 30% of patients in the second line, as a second-line therapy, I think are great candidates, at minimum are great candidates for pacritinib, in which I do present them with that option. I don't know what the percentage in my practice actually is. So we, you know, it is an option that's NCCN endorsed irrespective of the platelet count. I think 30% of patients already sort of meet that platelet count, that low platelet count, but it could be used even beyond that 30% that need it. In the community where the options are limited and clinical trials are not abundant, you know, that's a significant proportion of patients in the second line, which thrombocytopenia is even more prevalent. And then again, as NCCN endorses, even above thrombocytopenia.
So once the comfort level with pacritinib is there in the prescriber's hands, I would expect that a majority of patients, you know, will likely get pacritinib as a second-line therapy, even irrespective of the platelet count as endorsed by the NCCN guidelines. And I apologize if I didn't cover your second question.
Oh, that's helpful. And I just have one more question. So the phase II data, the basis for the accelerated approval, is pretty compelling. So phase III is a confirmatory phase III is underway. Is there any data, like a data point that you would like to see or you think that would be needed in order for the drug to be utilized a lot more significantly from current levels, or would that be just a confirmatory? Thank you.
I mean, if the question is asked to me as a clinician and a practitioner, someone who's had experience across the myelofibrosis disease spectrum and therapeutics and pacritinib specifically, I personally didn't see a need for another phase III study. The FDA did. So I had, you know, confidence in pacritinib as an effective agent in this patient's setting. So I, you know, without sounding, you know, too facetious, I mean, I personally don't need the specific study to endorse the use of pacritinib, and I would expect it to confirm what we saw and provide, you know, maybe some more texture and hopefully longer follow-up than the PERSIST-2 did. So I look forward to the longer follow-up. I think that will be helpful and will be added information both from a safety, durability, and efficacy standpoint.
But to me, the data from PERSIST-1, PERSIST-2, PAC203 really spoke for itself and didn't actually require another study, but that's beyond me as a clinician.
Thank you. Thank you.
Thank you. Maybe we can afford two more questions.
The next question comes from the line of Gonzalo Artiach with ABG Sundal Collier. Please go ahead.
Hi, and thank you for taking my questions. It's only one on pacritinib's mechanism of action, and it's linked to a potential use outside myelofibrosis. So knowing that pacritinib targets JAK2 both wild-type, but also JAK2 V617F mutation, I was wondering if you could give us some words on the importance of Vonjo in this mutation specifically, not only in myelofibrosis, but also in other diseases such as MDS, where the mutation is found on a large proportion of patients.
I mean, I think that Jakafi was tested in MDS, but the results were not super impressive. So given the specificity of Vonjo and JAK mutated, could we expect better results in MDS, for example, compared with other JAK inhibitors such as Jakafi? Thank you.
I think that there are certainly potential reasons to think that Vonjo could act differently from ruxolitinib in a variety of hematologic and inflammatory disease. And that relates not only to its target of JAK2, but also to IRAK1 and ACVR1, which may be important targets in other diseases. But as far as any plans for additional studies, those are currently being evaluated, and I don't want to speculate too far into how Vonjo would act in certain diseases versus other JAK inhibitors.
All right. Thank you very much.
Thank you. Thank you. Maybe to the next question.
The next question comes from the line of Emmanuel Papadakis with Deutsche Bank. Please go ahead.
Yes, thank you for the question. I just wanted to understand, just putting all that was presented today together, how do you see pacritinib being differentiated against momelotinib at the end of the day on the anemia front? And any further data in anemia? When can we expect that, please? And if there's room for one more, maybe on the first line, given the NCCN guideline update, just thoughts on the upcoming readouts from MANIFEST-2 and TRANSFORM-1, what kind of impact, you know, you expect they will have on your plans to increase uptake in first line? Thank you.
So I think the first part of the question was about pacritinib versus momelotinib with respect to anemia.
I think that it's hard to comment on relative efficacy because the studies for these two drugs were so different, both in terms of the endpoints and especially in terms of the patient population enrolled. I think that we've certainly seen an anemia benefit on pacritinib, and physicians have responded very positively to pacritinib data, but in terms of how to differentiate them or compare them head-to-head, I'm not sure that you can do that with the studies at your disposal. And then the second part of the question, I believe that you brought up some other emerging data.
And I think this would be, you know, I mentioned that one of the things that I'm most excited about with pacritinib or Vonjo is the possibility of using Vonjo as a backbone of choice for combination therapies because you may not see, you know, a lot of these novel agents have cytopenias as a toxicity, and so it would make sense to combine with pacritinib. But these are opportunities that we're currently evaluating right now. Yeah.
Thank you.
Yeah, maybe we can open up to one more question and then we close the session. Back to the operator.
The next question is from Mr. Viktor Sundberg with Nordea. Please go ahead.
Yes, hi. Thank you so much for taking my question. So I also had a question on momelotinib.
I think a matched indirect comparison was presented at EHA this year that seemed to favor momelotinib, looking at hemoglobin improvement. So maybe if you could comment on that, that would be great. And also on anemia, I don't think that's something that's mentioned in guidelines and pacritinib at the moment. Is that expected to be included, you think, given the strong data that you presented, for example, at ASH? Thanks.
Sure. So the indirect comparison that was presented, you know, they used momelotinib data, but there was no individual patient data from pacritinib that was used as part of this analysis. They were looking at the study in aggregate, and the pacritinib studies enrolled patients that were very different from the momelotinib studies.
You know, you can try to use sort of matching techniques to map one population onto another, but at no point did momelotinib studies really enroll patients that were that similar to the pacritinib patients. Certainly, they did have a lower threshold for platelet counts enrolled, whereas the pacritinib studies did enroll patients with platelet counts as low as six, which were not even considered on the momelotinib studies. The patient populations were different, and I'm not sure how well you can really extrapolate from the pacritinib data as a whole and do successful indirect head-to-head comparisons. I know people want head-to-head data. I don't think that there's a great way to get head-to-head data. I think that may come from people's individual experience if both agents end up on the market. The second question was about NCCN guidelines.
We've certainly provided the anemia data to the NCCN panel, but as far as what we expect, you know, the decision will be up to them as to where or how pacritinib is included.
Okay, thank you very much.
Yeah, thank you. I mean, you know, I think, I mean, I understand there's many more interests in this, but we have to be respectful of the timing, obviously, of the speakers' schedules, Professor Mascarenhas, and also your time. So what we would propose is that if you have questions, please refer them to Jennifer and to Tobias. We will then provide you with the answers or make experts available. And, you know, this was more of a snapshot, and as you can sense from Sarah's stipulations, there's more to come. So this is obviously for us a long-term commitment, as you can sense. So thanks for your interest.
You know, nothing more to say. We are very excited. Thank you so much, Professor Mascarenhas, for being available for this very inspiring and interesting talk. And thank you, Sarah, for bringing this alive. I think there's a lot to do for us. Thank you for your interest, and we look forward to reconnecting. Thank you.
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