Protagonist Therapeutics, Inc. (PTGX) Earnings Call Transcript & Summary

Good morning, everybody. Thanks for joining us. I'm Corey Davis with LifeSci Advisors. Welcome to our PV Day with Protagonist Therapeutics to review the current PV market and set the stage for the upcoming Phase III data that are expected in March. We've got 2 KOLs and a number of company executives to walk through what I hope will be a scintillating presentation. We've got about 40 people in the room and over 100 people listening on the webcast. The prepared remarks will last about 90 minutes. And after that, we'll leave 30 minutes for Q&A. For those of you in the room, feel free to stay afterwards for lunch, where you can ask the KOLs any additional questions that you'd like. Next slide are the obligatory forward-looking statements. Please read these as always. Today's presentation is going to be available on the Protagonist website afterwards, along with a replay from the event. And with that, it's my pleasure to introduce the CEO of Protagonist, Dinesh Patel, to make some introductory remarks, kick things off. And as we go through the presentation, we'll introduce the specific agenda and our speakers as well. With that, I'll turn it over to Dinesh.

Well, thank you, Corey. Good morning, everybody, and we are really pleased to see almost full attendance. For a while, we were worried that the snowstorm may steal the show, but I'm glad that we have a great audience, and we have some esteemed experts with us who will do most of the talking and help all of us increase our awareness towards the unmet need in PV and the potential role that rusfertide could play as a therapeutic -- as a new therapeutic option. Now before we dwell into PV and rusfertide, I thought it was probably a good thing to take a few steps back and look at the company overall and its pipeline. As you know, we are exclusively focused on peptide therapeutics. This is something we have been doing for the last 15, 18 years. And so it has been a slow and steady journey. But the good thing is like we are looking at 2 late-stage assets that are moving towards NDA filing this year. Icotrokinra, that's our first-in-class, best-in-class oral IL-23 receptor antagonist partnered with J&J. Recently, we got positive Phase III data in psoriasis. There is a lot more data coming in the coming months, and it's well on its way towards NDA filing. Rusfertide, which is the main topic for today. It's, as you know, being evaluated in multiple studies and the Phase III study results should be available next month. So talking about disclaimers, we have a very straight face, I can say that none of us know the data at this stage. We are all blinded to it. But we believe we are on track to share top line results sometime in the month of March. And as you know, this is also an asset that is partnered with a pharma company, Takeda Pharmaceuticals, and thanks to some of the Takeda folks who are here today in the audience. So the genesis of both of these drugs over the past decade or so has been our proprietary peptide technology platform, which we have now started put into use for other kind of products also. The common thing in general is that we want to work on biologically validated and commercially successful targets. And with our approach, we get an opportunity for a strong differentiation. We get an opportunity to address unmet needs. And hopefully, we will be a best-in-class, first-in-class in one of those or both of those categories. As a follow-up, rusfertide and as part of life cycle management, we also have an oral hepcidin program. As you know, rusfertide is a hepcidin mimetic. It's in general, once-weekly subcu administration. So an oral entity sounds like the next logical step, and we are well on our way, and we should have a development candidate sometime this year. Similarly, in terms of -- in the immunology space, besides IL-23, now we are also focused on IL-17, a greatly validated target. PN-881 is in IND-enabling studies as we speak, and it should enter Phase I study sometime this year. And then last but not least, definitely not least is the -- our presence in the anti-obesity space. As you know, there are 2 drugs approved. And chemically speaking, those are peptides, injectable peptides. Protagonist has carved out a name for itself in the field of oral peptides. So this is almost like right up our alley. So we are working on that as well. In terms of the upcoming events, there is a lot going on. There is a lot that will get unfolded in the coming months, starting with the PV Day today, top line results next month. And if those are positive, then we'll be on our way towards NDA filing with rusfertide. With icotrokinra, a lot of study initiations and study results, both in psoriasis as well as in ulcerative colitis in the coming months. The Phase III psoriatic arthritis study got initiated. It got posted on clinicaltrials.gov about 2 days ago. Fair to say that our partner and we are very committed to moving this towards NDA filing sometime this year. And then in discovery, we are starting with one development candidate, and we expect to end the year with at least 2 additional development candidates. I think this is my last slide. And as a biotech, we have seen our highs and lows and cash is always very precious. And thanks to the enthusiastic investors who are believers in us. We are now in a very admirable situation. We have cash runway at least through the end of 2028 and a big contributor to that is also our 2 partnerships with J&J on ico and then with Takeda on rusfertide. And in this cash runway forecast, we are not including anywhere from $200 million to $600 million plus that we could be earning a new milestones over that time period. And obviously, we're also not including the future royalties that may stem from these assets. So that's like a long way of saying that we feel confident about our cash position and our intent will be to redeploy that cash into our early-stage programs, take them on our own, at least up to clinical POC and then create a very robust and broad pipeline. So with that, then I want to thank you all. I really want to thank Dr. Andrew Kuykendall and Dr. Joseph Scandura for making the time for us. And I will hand it over to our Chief Medical Officer, Arturo.

Thank you Dinesh. So let me just give you a brief overview of the agenda for today. Dr. Scandura will review Polycythemia Vera and its symptoms. I'll give a brief presentation on the Phase II PACIFIC data. Dr. Kuykendall will review the Phase II REVIVE data and discuss the Phase III VERIFY trial design. Then I will review similarities between the VERIFY and REVIVE studies as well as highlight some potentially important differences in the study. Then Lopa Desai will review the rusfertide commercial opportunity. Dinesh will summarize or wrap up, and then we'll have 25 minutes for Q&A and then followed by lunch. And as you heard, you all are invited for lunch. So the objectives for today are to provide a high-level overview of Polycythemia Vera and highlight the clinical signs and symptoms of PV. We will also review the standard of care treatment options for patients with PV, which include therapeutic phlebotomy, aspirin and cytoreductive therapy. We'll also review the Phase II PACIFIC and REVIVE clinical studies that investigated rusfertide in patients with PV and key data from these trials. Then the study design of the Phase III VERIFY study that is investigating rusfertide in PV, again, highlighting key similarities and differences between REVIVE and VERIFY. Both of these are randomized studies. They're very similar, but there's also some important differences. And as I said, we'll also review the potential unmet needs in PV and an overview of the commercial opportunity for rusfertide in PV. This slide summarizes our clinical development plan. This is -- there's 3 studies, 2 Phase II studies are the PACIFIC study and the REVIVE study. Also the VERIFY Phase III study. And as Dr. Kuykendall will show, about 80% of the patients randomized in the REVIVE study have gone on to long-term extension, which is called the THRIVE study. We submitted this proposal to the FDA as what would constitute our data package for a safety database for submitting an NDA. And in principle, this is the data -- these are the components of the NDA that will be submitted. And if you look at the totality of patients, we will have data on more than 350 patients with PV who have been either treated or are still being treated with rusfertide. We'll focus a bit on the VERIFY study, which, as Dinesh mentioned, it's ongoing. We are -- remain blinded to the results of the study, and we will hopefully be unblinding in March and share the top line results with you. So both VERIFY and THRIVE are randomized study, but a key difference is the size of the study and where the study was conducted. The REVIVE study was conducted in 2 countries, the United States and India. The VERIFY study is being conducted in 19 countries across the world, 5 different continents. So it's truly a global study. So now I will pass it to Dr. Scandura, Associate Professor of Medicine at Cornell, to take us through the polycythemia overview and symptoms.

So I'm just curious why make it to sit at the table, and I have to come down here. I'm going to speak a little bit about Polycythemia Vera. What is Polycythemia Vera? It's a chronic myeloproliferative. Are you guys getting feedback? Okay. So what is Polycythemia Vera? It's a chronic myeloproliferative neoplasm. These are uncommon diseases compared to many other cancers. And it's characterized really by overproduction of red blood cells. So if you look at blood, it's comprised of the liquid part plasma and predominantly red blood cells that in a normal patient occupy around just under 50% of the blood volume. In Polycythemia Vera, there's too many red blood cells. And so what happens is that blood is 50%, 70% comprised of red blood cells, and that leads to what you can think of as vascular sludging or traffic jam in the circulatory system. And so like getting around in Midtown Manhattan, the traffic is not good for anybody. It's not good for your body either. It puts a lot of stress on the cardiovascular system. It can irritate the blood lining cells. And all those things lead to complications. Patients have symptoms. There's an excess risk of clotting and there's an associated shortened survival with this disease. So how many cases, about 155,000 cases estimated in the U.S. The median age is 61, meaning that half the patients are in their 50s or younger. And so these are working age people, and they do have symptoms as reported before, and they have a lot more need for medical care, and that ends up reducing productivity and interfering with function. Virtually all of the patients with Polycythemia Vera share one of a couple of mutations in a gene called JAK2. And the average life expectancy from the time of diagnosis is estimated to be about 16 years. So what does that mean? If you're 60 years old, 76. If you're 40 years old, that would mean 56. So these are shortened compared to what you would expect. Why -- what bothers patients? Patients have a lot of symptoms. Virtually 70% of them report some degree of fatigue. They are also very common complaints is difficulty in concentration that can interfere with work and life, difficulty sleep, sexual function, a lot of things on this list and not included on this list are what drive patients sometimes to seek care. But certainly, as they get into the course of therapy, they become increasingly common with certain therapies. So MPNs and PV, no exception, are diseases associated with a lot of inflammation. That inflammation and maybe other factors is associated with an increased risk of second malignancy. So these are non-hematopoietic malignancies, but solid tumor malignancies and including skin cancers, which I'll talk a little bit about here. And so there's about a 60% risk of any solid tumor cancer. Our therapies for Polycythemia Vera and predominantly hydroxyurea as a cytoreductive agent have known and well reported from randomized studies, from single-agent studies and increased risk of non-melanoma skin cancers. This is seen in MPNs [ writ large ] as well as in Polycythemia Vera. And this is also true for ruxolitinib, which is a JAK2 inhibitor that is mildly immunosuppressive and is associated with this increased risk of skin cancers as well. Probably the predominant problem and what used to kill most patients with Polycythemia Vera is this increased risk of blood clots. And so those clots can be in arteries and those are heart attacks, strokes, things like that or in veins, DVT/PE, which I've realized in watching playoff football that this is apparently a target audience is people who watch football because there's a lot of commercials for DVT/PE during football games. That and beer and trucks. When you look at this risk, it's nonlinear. In both of these curves, you see at the time of diagnosis, I'm using a point here. In the time -- from the time of diagnosis for the first couple of years, there's a vastly increased risk of clot versus the general population. So this is excess risk. Anything above the line here is excess risk. And you see it never normalizes during the course of these therapies. They always have excess risk of clotting, but it's particularly high around the time of diagnosis. So what do we do for that? We know from the cytoPV study that controlling hematocrit, I mean it makes sense, right? You have too many red blood cells, control reducing them that has favorable effects on this clotting risk. So reducing the hematocrit below 45, fourfold reduction in clotting events. So how do we manage this disease? Well, first thing is manage the other cardiovascular risk factors. We have to do that. Low-dose aspirin in everybody, unless there's a really good reason they shouldn't be on it, low-dose aspirin. So simple stuff. But then it comes down to like what is the day-to-day? Patient comes in, you're checking blood counts. If the hematocrit is above 45, always, you'll be doing phlebotomy. And then you cycle around. So there's exceptions to that. If patients have a prior blood clot, we put them on cytoreductive therapy. So these are drugs to reduce the need for phlebotomy. More commonly over time are these things. Patients often or they learn to hate phlebotomy, and they become intolerant to it. They become very iron deficient. And so iron deficiency and the increased fatigue following phlebotomy is pretty common complaint. And so some patients just don't want to continue down that course. And if you look longitudinally, phlebotomy alone, although often talked about as a therapy for PV, is seldom maintained long time as a therapy for PV. Virtually everybody progresses to some sort of cytoreductive therapy. And so what are cytoreductive therapies? Probably the most common worldwide is hydroxyurea, interferon, ruxolitinib and then obviously, for clinical trials for those not served by those drugs. So I just want to bring your attention back to this early phase. It's the same curve. But what's happening in this? Why is that increased risk in the beginning? And it's not a -- there's not a clear answer, but I can tell you what's happening with patients in this period, this is their most phlebotomy-intense period generally of their entire course. These are people who are coming in with abnormal blood counts who have to be brought down under control that requires a phlebotomy, and that's always associated with iron deficiency. If you look at people who are on cytoreductive therapy, in this case, hydroxyurea, who maintain on the right side portion, who maintain the need for phlebotomy, they do worse. So there's some biological selection here for patients who are just worse actors. But there's also -- it makes the point that ongoing need for phlebotomy does not address the fundamental problems. If you need phlebotomy, it's telling you something about the risks of this disease, and those risks are immediately read out in thrombotic risk. They can be read out in overall survival as well. So where is iron in the body? In a normal person, 75% of the total body iron is floating around in red blood cells. That makes sense. Red is iron. And so the red blood cells because of the fall of iron. And that leaves only 25% for the rest of the body to share. So where is that? A lot of it is in stores. So these are kind of -- you can think of them as the iron bank. And so it's stored there. When cells need it, they can communicate with each other, iron can be transferred, the cells can take the iron they need. And it's a very complex and highly regulated system. In PV, this complex and highly regulated system is completely out of whack because what happens is you're now 90-some-percent of the iron in the body is in the red blood cells. The iron stores are almost universally completely depleted. So all of the iron is getting shuttled into making red blood cells and the rest of the body often is suffering. And phlebotomy is literally taking that iron in the body, the total bio iron and throwing it in the garbage. And you can think of this as like if you have traffic, right, in the city, we have gridlock. You can do the intervention of having an exit ramp that goes off a cliff. You will get rid of some of the cars. It just isn't exactly solving the problem. Another approach would be to reduce the number of cars getting on to the highway, onto the roads. And that's where cytoreductive therapies and other therapies that we'll talk about today have a role. Why does iron deficiency matter? Because we know from the non-PV population. So this is often young women due to menstrual losses become iron deficient or for whatever other reasons. In that setting, there's a number of symptoms that are not related to anemia directly. So non-anemic iron-deficient women have cognitive problems. If you're a kid and you're iron deficient, you can have cognitive learning disabilities. Fatigue, obviously, is a big part. Fatigue, not explained by the level of anemia. So iron deficiency, every cell in your body needs iron to generate energy. And so they all have to share. Evolutionarily, nature has said red blood cells get first picked. What happens in the community? So phlebotomy, that sounds easy, right? For 3,000 years of human history, people have been doing phlebotomy. It's not as easy to pull off in the population as you would think. It's time-consuming, expensive, requires time. The time cost there is seldom accounted for, but people lose half a day due to phlebotomy. When we've looked at the actuarial survival, right, of patients and their matched set -- sorry, conversely, if you look at patients with PV treated largely in community outside of expert centers in the [ SEER ] database, survival is shortened by at least a decade or more by virtue of the Polycythemia Vera. At Cornell, we looked at our patients and they were doing much better. I don't think we have secret sauce other than scrupulous adherence to standards of care. And so that leads to and translates directly to a greater than 10-year survival benefit. So why isn't phlebotomy? Why aren't those standard scrupulously adhered to? Plebotomy is very inconvenient. It's kind of a pain. Patients have to go, they lose half a day, and they become iron deficient. They become symptomatic from that. They tend to hate phlebotomy. Normal iron flows, I'm showing in this. So most of the iron is in red blood cells. Red blood cells are produced in the bone marrow. Some of the older red blood cells get recycled into iron storage pools. And then from those storage pools through plasma, iron is returned to the marrow to keep this going. Since most of the iron is in the red blood cells, most of the iron flows are back to the bone marrow. But the rest of the body also has to share. So your brain, your muscles, all of these things need iron to generate energy, and so they get their pick too. Dietary iron plays a relatively small role in this. There's a little bit of dietary loss in iron from shed intestinal cells, etcetera. But most of the iron in use is recycled. In Polycythemia Vera, this is completely messed up. These flows are now pouring out unnecessary red blood cells. The recycling is happening. But because the marrow continues to want to make these red blood cells, the iron flows are predominantly going into the marrow. The iron stores are passed through. There's no bank here anymore. It's just you're taking the money and passing it on. And that leads to iron deficiency in the tissues. And I think that drives a lot of the symptoms we see in people who are on phlebotomy. And so how does that happen? Well, the bone marrow actually the erythroid precursors secrete hormone that basically tells the other cells to just cough up their iron. So the iron stores open the bank, whatever dietary stuff is coming in, it extracts the iron efficiently. And this is done through a hormone system that involves hepcidin, a suppressed hepcidin production. So what does hepcidin do? Hepcidin is kind of like it's the lock on the door. So if iron have to come in and out of the store -- in and out of the bank, right, it has to pass through the door. Hepcidin just locks the door. So the bank is closed. You can't get money out. Whatever is there can stay, cells, you don't absorb iron pretty well, kind of blocks that whole transfer. And as I told you before, hepcidin is low in PV. So everything in the stores is just flying out, flying off the shelves. You can't keep it in stock and making red blood cells. And so what does rusfertide do is basically just hepcidin. It's a hepcidin mimetic. And what it does is it closes the door. What does close the door do? Blocking ferroportin, reducing iron delivery to the bone marrow. So this is the raw material that the bone marrow needs to make red blood cells, and that leads to a reduction in red blood cell production. And that's really the secret sauce.

I'll keep you company over here. So I'm just going to talk briefly about the PACIFIC study. This is a Phase II study. It enrolled 20 patients. Key eligibility criteria for this study is uncontrolled hematocrit. So patients were required to have a hematocrit above 48%. There's no specific requirement for prior phlebotomies or cytoreductive therapy, although a lot of these patients were on hydroxyurea. If you look in the middle, you see that the starting dose of rusfertide is 40 milligrams subcutaneously twice a week, and patients were dosed twice a week until the hematocrit dropped below 45% and then switched to once a week dosing. And then the dose of rusfertide could be titrated to maintain the hematocrit below 45%. Here, you see the effect of rusfertide in achieving rapid hematocrit control to less than 45%. And this was achieved in 45 -- sorry, in less than 5 weeks. So the median time to first hematocrit control less than 45 is 5 weeks. The rate of hematocrit reduction is 1.7% per week. Prior to starting the study, none of the patients had a hematocrit below 45%, and you can see that in the figure. Orange denotes the time that rusfertide has started and the proportion of patients with hematocrit less than 45% is 85% at week 8. So what this shows is very rapid effect in bringing down the hematocrit. The safety profile in the PACIFIC study was very similar to what we've seen in the REVIVE and other studies. It's basically injection site reactions that are common. Some of the other symptoms are attributed to the symptoms of Polycythemia Vera. So in summary, the PACIFIC Phase II study resulted in rapid reduction in hematocrit levels. That was with rusfertide effect. The median time to achieve hematocrit less than 45% was 5 weeks or less. 85% of patients achieved hematocrit levels less than 45% within 8 weeks. And the pretreatment phlebotomy rate was 2.5 per year. But in the PACIFIC study, no patients received a therapeutic phlebotomy during the rusfertide treatment period. And finally, the safety profile and tolerability profile of rusfertide in the PACIFIC study is similar to what was observed in REVIVE. The most common treatment-emergent adverse events are injection site reactions, and these tend to improve over time. So this will set up the stage for the other studies. And now we'll ask Dr. Andrew Kuykendall, associate member of Moffitt Cancer Center to join us for the review of the Phase II study results.

All right. Thanks, Arturo. So I'm going to go through the Phase II REVIVE study, which really kind of set the stage for the VERIFY study that we're anxiously awaiting results from. So talking a bit about the REVIVE study. So this was a Phase II study. So going back and like what are we trying to establish with the Phase II, we're trying to get a sense for efficacy to set the stage for a kind of registrational or Phase III trial. And so if you look at the design of the REVIVE study, it enrolled patients that were phlebotomy requiring. So there were patients with Polycythemia Vera that needed some degree of requirement or necessitated repeated phlebotomies. And so that was defined as needing at least 3 phlebotomies in the 28 weeks prior to going on study. Importantly, these patients could be on cytoreductive therapy, hydroxyurea, interferon, ruxolitinib or they could not be. They could just be getting phlebotomies routinely as the main portion of their therapy. Patients then went through a dose-finding period in Part 1 of the study. So this was 28 weeks, whereby the kind of optimal dose of rusfertide was determined during this period of time. Then there was this very unique randomized withdrawal phase that were patients who -- everyone was on rusfertide, patients were randomized to half of them come off of rusfertide to go on to placebo or stay on rusfertide. This was up to 12 weeks of therapy. And this gave really a snapshot into maybe what we're going to be looking at with the VERIFY study. So a lot of Phase II studies do not have this design. And I think this was something that was unique and particularly, I think, enlightening as far as trying to analyze the study. So in this period of 12 weeks during the Part 2 part of the study, there was a primary endpoint looking at response. And I'll spend some time talking about response because that's really what we're trying to see is what was the response rate between patients who were on rusfertide versus those that were randomized to come off of rusfertide. So here, the response was defined in a couple of different kind of bullet points here, but basically not being phlebotomy eligible. So not requiring or being a candidate for phlebotomy. And that was defined as having a hematocrit greater than 45%. That was also 3% higher than their week 29 pre-randomization hematocrit value. So essentially, we talked about and Joe kind of mentioned the importance of keeping hematocrit controlled. But at the same time, we do know there are fluctuations for these patients. And so not only did the hematocrit have to be greater than 45%, it also had to be 3% higher than it was at the baseline. So in someone who was 44.9% per se, right, they're not going to meet that phlebotomy eligible requirement if it just goes to 45.1%. This had to represent an increase that was relatively significant. They also would be considered to be phlebotomy eligible if the hematocrit ever rose above 48% or if they had an increase in 5% or more in their hematocrit compared to that pre-randomization value. If they did not meet any of those criteria, then they were considered to be a responder. If they met one or more of those criteria, they were a non-responder. After this, patients were then went back on, if they were randomized to come off of therapy, they went back on to the open-label extension, which allowed patients to go back on rusfertide and has allowed us to get long-term data within the REVIVE study up to 3 years. And then also many of these patients, as we'll talk about, rolled over to the longer-term extension study, looking at the THRIVE study. So this kind of study design allowed us to find -- put all patients on rusfertide as we do in most Phase II studies, then allowed us to get a comparison between being on placebo versus rusfertide, then allowed us to get long-term data, which I think is very helpful in guiding kind of future development of an agent, especially in a disease we're talking about Polycythemia Vera where we're playing the long game with these patients. We expect them to live a long time. As Joe said, at Cornell, these patients are living very long. And I think it's happening at other academic centers, too. It's nothing special that Joe is doing. And so if we're thinking about these patients living a long time, then we need to understand kind of long-term safety data as well and make sure this is something that patients can continue to benefit from. So if you look at the demographics of patients in Parts 1 and 3 of the study, I would say, largely speaking, this is quite representative of the PV population. So you have a slight male predominance. You have most patients, 57% being high risk; that's pretty consistent with PV at large. Age of PV diagnosis, median age was 55, about 2.5 years on average from PV diagnosis to initiation on the clinical trial. Most of these patients, as you said, were requiring excessive amounts of phlebotomy. So here, we see that the mean number of phlebotomies over the 28 weeks prior to rusfertide treatment was 4.7. 42.9% of patients were requiring 5 or more phlebotomies over the 28 weeks prior to going on rusfertide as well. Importantly, I think you can see there's a pretty even split between patients that were on some sort of cytoreductive therapy as well as those who were just getting phlebotomy alone. So 50-50 essentially, and so quite a mixed bag of this adding to patients original therapy. I think one thing to note is while this is representative of PV at large, you could also argue this is representative of a higher risk portion of PV at large because as we talked about, to require consistent phlebotomies is really a poor risk factor. Those patients have more events. They have more progression of their disease. They typically just have more aggressive disease. Looking at the numbers of patients, 70 patients enrolled in Part 1, 59 patients enrolled in the randomized withdrawal phase or Part 2 and 58 actually made it to the open-label extension. So pretty good consistency of patients on study. If you look at the primary endpoint and the results, these were published in the New England Journal of Medicine last year, about a year ago. The primary endpoint, you could see a stark difference between the rusfertide treated patients and the placebo patients. So 69% meeting that primary endpoint of not being phlebotomy eligible versus just 15% of patients and 4 patients in the placebo group. If you look at this kind of sensitivity analysis, so this is an intention to treat analysis. This kind of accounts for patients that may have dropped out or not made it to the final endpoint. This is kind of a very stringent statistically appropriate way to look at the data. Still, you see this wide variability or wide gap between the rusfertide and the placebo-treated patients. So even with kind of the most statistically appropriate way of looking at the data, we see a huge benefit in terms of the rusfertide treated patients. Looking at that data kind of in a different way, we're now looking at the mean hemoglobin over time. The one thing I'd notice is this is a lot of time for a clinical trial. It's hard to run long clinical trials, especially in malignant hematology. But here, patients are followed out to 3.5 years. As we get out to 3.5 years, the numbers go down. But certainly, many of these patients, 71% of patients have been treated for 2 years or longer, 54 of 2.5 years or longer. So we're getting good long-term data in these folks. You can see here, if I kind of to level set -- that 45%, right, is up there at the top. That's -- we want to keep patients hematocrit less than that number. And on rusfertide, you could see very clearly that they're maintained in a stable regimen, honestly, between 41 and 42 for the most part. Here, you can see during that randomized withdrawal phase, how quickly the patients who were randomized to placebo, their hematocrit jumped quite rapidly. And then those patients, if they did require phlebotomy, went back on to the open-label extension and we were able to get their hematocrit back under control. Again, robust efficacy in terms of maintaining hematocrit control across different patient categories. We also saw symptom improvement. I think this is something we'll certainly touch on when we talk about patient-reported outcomes in patients who are coming in with moderate to severe symptoms at baseline. We know Polycythemia Vera patients have a good amount of symptoms at baseline. And as we're talking about living a long time, we need them to live well as well. And so we have a strong focus on maintaining and improving quality of life. And importantly, we saw a normalization of serum ferritin, which I'll get to in just one second. So looking at kind of key numbers and how this impacts blood counts and various other kind of lab values, erythrocyte, we can look at the red blood cell number. As Joe mentioned, we're making too many red blood cells. Here, patients who are on rusfertide were able to decrease the number of red blood cells they were making. This was a steady decrease over time. You can see there in the randomized withdrawal phase, what happens when you come off of rusfertide and go on placebo that iron becomes available and those red blood cells are made quite rapidly after discontinuation of rusfertide. If you look at serum ferritin or iron stores, that normalizes over time. These patients oftentimes with Polycythemia Vera, they're using up all of their iron to make red blood cells. So they come in mildly to moderately iron deficient. We then phlebotomize them and take further iron from them and they get more profoundly iron deficient. So to come up with a regimen that's able to control the hematocrit but allow iron stores to normalize is something that's certainly aspirational. We don't think rusfertide has much effect at all on white blood cell counts. The white blood cell counts remained quite stable throughout study. Here, slightly elevated just above 10, which is normal for patients with Polycythemia Vera. But here, white blood cell counts really remained quite stable. You see a little bit of a blip or some volatility there when patients were -- went to the randomized withdrawal phase. Likely, that's just due -- you can see from the [ arrow ] bars being quite wide because you've cut the sample size in half, so you're going to have more variability there during that brief period of time. Platelet counts, we know rusfertide increases platelets by about 15% to 20%. This occurs early on in therapy and then remains quite stable throughout. Again, you can see what happens when patients come off rusfertide that ferritin those platelet levels drop a bit and then come back as they go back on rusfertide. I think this is an interesting -- I mean, this is kind of the hematologist in me that's quite interested by some of these kind of more esoteric labs that we look at. I mean, if you've ever looked at your own CBC, there's like hemoglobin and white blood cells and hematocrit and platelets and then there's a lot of other things that are reported on there that no one knows what they are, but we get a lot of messages in the message center of like why is my MCHC different? So MCV stands for Mean Cell Volume. This is the size of the red blood cells. Healthy red blood cells are typically between 80 and 100 here, 80 and 94, I think, on this one. But we know that microcytic or small red blood cells occur in patients that are iron deficient. That's one of the ways that we get a real clue of that diagnosis when patients come in. They're anemic, their MCV is 60, 65. Oftentimes, these patients have iron deficiency. Patients with Polycythemia Vera don't have that anemia portion, right? They're making a lot of red blood cells, but they do have that microcytosis. So on average, these patients came in with small red blood cells. And over time, those blood cells actually came up to the normal size, suggesting there was a more effective, more optimal utilization of iron, more healthy red blood cells that are being created. When we look at long-term safety profile, Arturo mentioned this a bit when talking about the PACIFIC study. Here, we -- first thing we got to note no grade 4 or grade 5 treatment-emergent adverse events. 26% of patients did experience some form of SAEs. These could be related to skin malignancies as we talk about, which are quite common in our Polycythemia Vera patients and certainly multifactorial incidents there when we think about a lot of these patients being on hydroxyurea or ruxolitinib. Some of these SAEs referred to a mild number of thrombotic events, 6 arterial, 1 venous. Also, this was a study that was done in the era of COVID. So you can see here, 34% of patients had COVID infections during the course of the study. That certainly can contribute to SAEs as well. When you look at overall, the injection site reactions, again, these are quite common occurring at 87% of patients. This is not surprising any kind of injectable peptide. But these were quite manageable, very low grade. The one thing I would mention about -- I know we've already talked a little bit about the skin malignancies is secondary malignancies are quite common in PV patients. Skin malignancies is very common in PV patients, probably from the disease, from the inflammation, from the treatments they're on. I think that this is something that we paid close attention to on the study and on VERIFY is doing close skin exams throughout the study. I will mention that the more you look for something, the more you'll find it, too. So this is one of -- at least for my patients, like getting them in to see a dermatologist regularly is something that they were not necessarily as compliant with prior to going on study as that they should have been. We're in Florida, where it's much better weather than currently. And patients -- really, we advise them all to keep our dermatologists in business with large boats, and so we want them regularly seeing them in the clinic. When we look at the open-label extension of REVIVE, this is kind of a summary of the design that we talked about before, dose titration over the Part 1, randomized withdrawal, Part 2, Part 3 open-label extension. And then we have patients roll over on to the THRIVE study for continued follow-up. So really up to 5.8, almost 6 years of therapy with rusfertide, getting a sense for that long-term effect, long-term benefit, long-term safety profile, right? That matters as well. I think one of the things is we can show you a lot of different slides talking about efficacy, phlebotomy dependency, phlebotomy eligibility, decrease in hematocrit. We could show white blood cells not being effective. We could show MCVs coming up. I think sometimes the simplest kind of statements may actually speak more volumes, which is 58% -- or 58 patients who went on to the open-label extension, 80% transitioned to the Phase III THRIVE study. So this is an agent, a study that patients were motivated to stay on therapy. And this is actually a very like problematic issue we have in myeloproliferative neoplasm research and clinical research is keeping patients on study durably because we do want that follow-up. But here, not really an issue. Patients wanted to stay on study. 80% went over to the open-label extension. So with that, I will actually move over to talk very briefly about the VERIFY study. We can't talk too much about it because we don't know anything as far as results, which is what we want to know. But I can at least go into the study design and put it in context of the Phase II study. So here, a different study, but there's key similarities, some key differences as well. So here in a Phase III study, we're not trying to show preliminary efficacy. We're trying to show that this is better than standard of care. And so here, patients are actually randomized at the outset. They can be on cytoreductive therapy, not on cytoreductive therapy. It's very agnostic to that, but then patients are randomized between going on rusfertide or going on placebo. For the first 20 weeks of the study, it's going to be a dose titration portion of the study. And then from weeks 20 to 32 is this kind of main efficacy evaluation period, whereby the primary endpoint, at least in the U.S. is being evaluated. And then after week 32, there's -- everyone moves to open-label extension and goes on rusfertide as well. Inclusion criteria, quite similar to what we saw in the Phase II study. So 3 phlebotomies over the prior 28 weeks or 5 phlebotomies in a year. It doesn't require you to be symptomatic at baseline. Certainly, we're interested in symptom improvement, but it's not requiring that to go on study. Some questions I get often is why -- how do you define 3 phlebotomies, 5 phlebotomies, where does that come from? I mean some of that comes from prior studies done in the Polycythemia Vera space. Some of this also comes from kind of -- for patients, we often are following them every 3 months or every 6 months in the clinic. So we're seeing them maybe up to 4 times a year at baseline. We don't want them tied to the health care system, if possible. If they're coming in an extra time just to get a phlebotomy to get a lab check to go -- that's impacting their quality of life. It's impacting their autonomy. So to me, that's a reasonable definition as far as what is an excessive amount of phlebotomies. Looking at the primary endpoint here; again, primary endpoint is clinical response. So similar definition before, a responder is defined as the absence of phlebotomy eligibility, the absence of any phlebotomy and completing 32 weeks of therapy. So they have to stay on therapy, not get a phlebotomy, not be a candidate for phlebotomy. This is the primary endpoint in the U.S. In the EU, the primary endpoint is actually looking at the average number of phlebotomies over the 32-week period. So still kind of focused on the same thing, some slight differences in what's being looked at with the U.S. and the EU, still focusing on kind of controlling the need for phlebotomy, not being phlebotomy eligible and continuing on therapy. Some key secondary endpoints. Again, the average number of phlebotomies, which is the primary endpoint in the EU, key secondary endpoint in the U.S., a proportion of patients who maintain hematocrit less than 45% for the week zero to 32. That's a very stringent requirement to not need -- to not ever have a hematocrit that's confirmed over 45%. And then these key secondary endpoints looking at symptoms or patient-reported outcomes, PROs. Arturo will talk about these in a little bit more detail. But looking at the PROMIS fatigue score, this is something that's, I think, very intriguing to me in the sense that fatigue is the symptom that all of our patients tend to have to some degree, some can be quite debilitating. And I would say it's difficult to live every day of your life waking up with fatigue, and so something that we certainly hope to be able to improve. And then also looking at the MFSAF, which is the Myelofibrosis Symptom Assessment Form, total symptom score. This is a PRO that's been validated in prior studies and used in registrational studies before. So with that, I will actually turn it back over to Arturo to discuss some of those key Polycythemia Vera focused PROs in a little bit more detail. Thank you.

Thank you. So first, the similarities. REVIVE and VERIFY are both randomized studies, as I mentioned. They have very similar primary efficacy endpoints, very similar patient population, very similar inclusion and exclusion criteria, both randomized, both placebo-controlled. Here, what you see in REVIVE, just to remind you, all patients get started at -- with rusfertide and then the dose is optimized. So the randomization period, which is 12-week long, occurred after the dose was optimized, and it had a randomized withdrawal design. With VERIFY, the randomization period is 32 weeks. So it's quite longer. More time to compare rusfertide versus placebo, but it occurs at the very beginning of the study. And it is much longer. Important to note, in both of these studies, rusfertide is being used as an add-on treatment. But why would this be important? Well, patients in VERIFY need to complete all 32 weeks before they get crossed over. In REVIVE, the dose was optimized, then there was a randomized withdrawal period. But if patients didn't complete the 12 weeks, and that happened a lot, they became non-responders, but they could still go over to the open-label extension. So they didn't have to finish the 12 weeks. But here, they have to finish the 32 weeks before they are guaranteed to go on rusfertide. So we will have a lot more comparative data between rusfertide and placebo to allow us to interrogate the efficacy endpoints that Andrew discussed. Now where there are important differences are in the patient-reported outcomes because in REVIVE, we used the MPN SAF which has not been validated for use in PV. And we focused our analysis on patients with moderate or severe symptoms. And what I want to highlight here is that any improvement in scores, a decrease in the symptom score of 1, 2 or 3, that represents an improvement in symptoms. So you want to have these scores to the left. And so this data is after Part 1 of the REVIVE study. And you see improvement in level of fatigue, early satiety in activity, problems with concentration, night sweat, itching and pruritus. Then we're still in REVIVE open-label data. So there's not placebo-controlled. It's open-label data. We monitored those same patient-reported outcomes at different time points, 52 weeks, 100 weeks, 140 weeks, 188 weeks and then at the end of study. And what you see is that improvement in patients -- in symptoms in the patients with moderate to severe symptoms at baseline persists throughout the duration of the study. So this is very encouraging, but the limitation here is that it's all open-label data, which is subject to potential bias. So now we're going to focus on VERIFY. And the key secondary endpoints in VERIFY include PRO measurements, but you're going to see that now the key tool that we're prioritizing is the PROMIS fatigue SF. That was not used in REVIVE but we're using it here in consultation with the FDA. Also, the MFSAF was a request from the FDA, the rationale being that they're more familiar with that tool because it's been used for myelofibrosis, and it's been used to help with the approval in myelofibrosis. But one of the limitations for us in the MFSAF is that we're missing a very important symptom, which is problems with concentration. So we have additional endpoints that we've discussed with the FDA that we are analyzing in this study. Remember, I told you that for these key secondary endpoints, this is an intent-to-treat analysis. So we are assessing the differences in all patients irrespective of whether they had pain or not at the time of study entry. And we did not specifically select for patients with higher levels of pain. So the key endpoints in this slide are all-comers. But then we also have additional analyses in the subset of moderate -- patients with moderate or severe symptoms, where I showed you really nice data from REVIVE. Except here, it will be placebo-controlled data. We'll be comparing placebo and rusfertide for 32 weeks as opposed to 12 weeks. So again, with PROMIS fatigue, we're going to do all-comers, but also patients with moderate and severe symptoms. MFSAF all-comers, also patients with moderate to severe symptoms. And we're also proposing a TSS-4 score. Here, you see TSS-7, and these are 7 symptoms from the MFSAF. But as part of an exploratory analysis, we're proposing TSS-4. These are more focused or symptoms that are more focused for patients with PV. And we bring back our friend from REVIVE, the MPN SAF because that's how we're going to capture problems with concentration, which as was mentioned by Joe and Andrew are very important. It's a very important symptom for patients with PV that is not commonly seen with the other MPNs. So I think this gives you a good idea. The trials are very, very similar with respect to the primary efficacy endpoints, the patient populations. There are some differences in the trial design in terms of the duration of the randomization period. And the differences are primarily in the PROs. That's a little bit of an unknown because none of these tools have been used successfully in demonstrating PRO benefits for any of the agents that are currently used in Polycythemia Vera. So for HU, for interferon, for [ ROPEG ] in Polycythemia Vera, none of these tools have been successful in demonstrating a PRO benefit, in part because only about a third of the patients with PV have the moderate to severe symptoms. Many have no symptoms or only mild symptoms. But we'll be looking at, like I said, intend to treat all-comers, but also we'll be doing some subset analysis of the patients with moderate and severe symptoms. And there, we're optimistic because we do have really good data in those symptomatic patients. But for all-comers, that's an open area. So to summarize, before I pass it to Lopa, this again shows the clinical development plan. The REVIVE study has already been completed. 80% of the randomized patients went on to THRIVE, and that's ongoing. The PACIFIC study also has been completed. And the VERIFY study is ongoing, and we're looking forward to unblinding the study next month, sharing top line results and then submitting the results for major medical meetings. As a reminder, rusfertide has orphan drug designation and fast track status for Polycythemia Vera. So now I will pass it on to my colleague, Lopa Desai, who will be for Commercial Strategy Adviser, who will give you a commercial overview of rusfertide.

Can you hear me? Yes. Okay. Well, it's a pleasure to be here today. And of course, we're very excited as a commercial person to have a potential therapy for this patient population. I do want to point out one thing here that our colleagues over there at Takeda have primary control leadership of the commercial program for rusfertide. But along with them, we're working very closely to ensure commercial success. So as part of that, in this last year, we spent a lot of time refining our thinking around not only the unmet need but the patient journey as well as the market opportunity. So today, I'm going to share some of that information with you so that you can actually get a sense of what it's like to be a patient with PV and how that dovetails into the opportunity for rusfertide. So I'm not going to spend a lot of time here. We've heard a lot from Dr. Scandura about the unmet need in PV. We simply say that having uncontrolled hematocrit is not good. I think that's the point of this, right? There are consequences to that TEs, cardio issues, etcetera. But we know from real-world evidence that 78% of patients actually are uncontrolled. That's a pretty big number. And there are a lot of reasons for that actually. Obviously, getting a phlebotomy, then you wait to get your next phlebotomy. So you're not consistently controlled. One thing I do want to point out is the importance of rapidity of response because as it was shown earlier today patients actually are high risk in that first year. And so when you look at real-world data, what we actually see is that of the patients that have a TE, 70% of them have it in the first year. So that's very important to get control early on. So why do we think we have an opportunity? Well, there are other products out there. But given the fact that 78% of patients are uncontrolled, it gives us reason to believe that there is a place for rusfertide, a therapy that's very red blood cell specific to benefit these patients. So I'm going to walk through the patient journey. Hopefully, I'll interject the patient voice here. We see a lot of data today, but I really want to give you a sense of what it's like to be a patient because Polycythemia Vera is not very well known. I think that probably when you heard about this, you went in Google to find out what it actually is. That's not uncommon. I did the same thing. So, let's start off with the diagnosis. So, this generally happens in primary care, where primary care doctors don't actually see a lot of PV patients. And so either a patient goes in and gets a blood test, routine blood test, and lo and behold, hematocrit or they're not feeling great. They already have some symptoms of fatigue, they have brain fog or whatnot, and they go in and they get a blood test and hematocrit or they've had a TE. All of this lands you into primary care. So what happens next? Well, the physician who may or may not have seen a lot of PV patients and may actually not know a lot about PV even says, "well, you've high hematocrit. But don't worry, it seems like it's indolent." If it's an astute primary care doctor, they may say it's blood cancer. Otherwise they'll just say it's blood disease. But for the patient, what they're hearing is now they've heard maybe cancer, maybe not cancer, not quite sure, but it's not curable, it's chronic, it's long term. It's a life sentence that they're going to have to manage. So, generally, what happens is then the primary care doctor will refer the patient to a hematologist or a heme/onc. Get it. There's onc in it. Probably by now the patient realizes that it's blood cancer. So they go to see the heme/onc or a hematologist and they have blood work done probably again And the first thing they do is get a phlebotomy. So phlebotomies are actually good at reducing hematocrit pretty rapidly. But over time, they become problematic because they put a patient on a roller coaster. And that roller coaster is, you feel good, you don't feel good; you feel good, you don't feel good. And then all of a sudden you're starting to be very fatigued because you're becoming very iron deficient. And so, I want to describe what that fatigue feels like. It's not like being tired, sitting here and listening to a presentation. It's not like traveling long and far or running a marathon. It's deep fatigue where you can't get out of bed for days on end. So I have this great analogy that a physician said to me, "It's like telling a patient that has migraine, they have a headache." So, basically, if you tell a patient, well you're just tired, but that's not what fatigue is in this kind of situation. So that's why where there's a place for phlebotomy, of course, is initially, but maybe not over the long haul. So what happens to these patients? If you're low risk, you have phlebotomy. If you're high risk, you might get HU, which people go, "Oh, that's a chemotherapy." It's a cytoreductive, right? It can be useful. But over time, as hematocrit becomes uncontrolled, that dosage goes up. And so you see a lot more side effects from this. At that point, the patient needs to make a decision. Now maybe they're controlled, but most likely they're not because 78% of patients are not controlled. They have to decide, do I want to do something else? And so, they cycle through other cytoreductive therapies, whether it's interferon or Jakafi or something like this. So we believe that a product like Rusfertide has a place in this paradigm, this treatment journey, where it can actually be used across a broad spectrum of patients, based on our clinical trial design, it can be used as monotherapy, as add-on therapy as well. And so, that gives us hope that patients will be able to maintain the hematocrit. They'll do it rapidly, they'll do it consistently. And of course, it will be sustained over time. So let's talk about how we maximize this opportunity and what is the opportunity to start with. So this is real-world data, right? So you've seen prevalence numbers, but this is actually diagnosed patients. So there are 155,000 diagnosed patients. I'm going to divide that into 2 groups. There are the patients that are very active in their treatment. They're the ones that go out and get phlebotomies. They go to their doctor, they routinely get their blood checked to make sure hematocrit is controlled. Then there's the other half who for a multitude of reasons, have decided that they don't actually want to pursue more advanced therapies it's called, although phlebotomy is very old. They've decided that they're going to wait and see. They've decided they're going to stick to aspirin. They are going to maybe get the occasional phlebotomy. But just in general, they're like, "No way, I'm not going to go through the hassle of getting routine phlebotomies," which, as I mentioned, can create fatigue. So we view our primary group of patients initially as the 78,000 patients, right, because they're actively involved in their treatment. The remaining balance with a good option has the potential to actually move over into that bucket that is routinely regimented treatment. So if you look at the numbers, though, you see that the majority of patients are getting phlebotomy plus or minus HU. And then there's kind of this drop-off, right, of patients that are going on to other therapies. And there are a lot of reasons why this is -- if you can read the labels for these products, understand the side effect profiles and what you need to do to be on the product, whatnot. But as I mentioned before, we actually think we can be used at every step along the way. So that gives us access to initially that 78,000 patients. So, how do you maximize this opportunity? And our colleagues at Takeda have done a really great job of really mapping out what the need is in order to be successful commercially. So, first and foremost, explaining what PV is, because like I said, most of us have googled this. In addition to that, explaining why you need to control your hematocrit. What are the consequences of that? Why is it important? Then also building awareness for Rusfertide at the appropriate time. It's building value in Rusfertide so that it gets a nice place in those guidelines. Building advocacy among key stakeholders. And then, of course, activating patients so that they become owners of their treatment, doing that digitally and by other means. All of this together leads us to a peak revenue of $1 billion to $2 billion, which is a big number. But as I said, it's a product that can be used across all steps, as monotherapy or in combination, as add-on, right? So I'm just going to summarize here because I do want you to walk away with some key points after all this discussion. If you walk away with 155,000 patients, that's great. 78,000 who are actively involved in their treatment, are doing routinely regimen treatment. The fact that 78% of patients are uncontrolled, we know the importance of controlling hematocrit, the consequences of TEs and cardio issues, of course, and that other options are out there, but maybe they're not optimal because we do know that a lot of patients have chosen not to actually take those treatments. And then finally, Rusfertide, a product that, as I said earlier, provides rapid, consistent and then, of course, over the long haul, sustenance, right, control. So, that's why we actually believe that this product has a very nice place in this treatment paradigm and could result in peak revenue of $1 billion to $2 billion. All right? So, I'm actually now going to turn it over to Dinesh to give some final remarks, and then we'll move into Q&A.

I've just one slide, right? So this is just to kind of get ourselves reoriented in terms of key near-term Rusfertide-related milestones, PV-Day, work in progress as we speak. Phase III VERIFY top line results in the month of March. And while this was not highlighted early on, the Rat 2-year carcinogenicity study has been completed without any events. The final study. The draft audited report suggests no Rusfertide-related findings, and we expect to submit the final study report to the agency in the coming weeks. You can expect some presence from us at EHA and also at ASH. But the big moment will be assuming the VERIFY study results are positive, both Protagonist and Takeda look forward to NDA filing by the end of the year. Thank you for your attention.

Thanks so much. Thanks and we'll move into the Q&A session. If people could just identify themselves and ask their questions of interest.

Great. I'm Tara Bancroft from TD Cowen. So, my question is for the doctors. So I'm curious, which patients would you treat initially? Like right when Rusfertide would be launching and then over time, say, at peak? And in your answer, I'm kind of looking for the type of patients such as severity and the quantifiable maybe percentage of total patients that you would treat with this at both kind of time points?

If I can jump into talking about the types of patients, I'll leave quantifying it to Joe. I'm not a quant guy. So, first off, I would say that what we've seen with Rusfertide so far is its ability to eliminate the need for phlebotomy in a group of patients that has required consistently a lot of phlebotomies, despite being further along in the disease course, despite being on cytoreductive therapies. We've also seen a snapshot of patients that have felt better when you randomize them to either being on the medication versus not. I go back to the fact that it, to me, is difficult when I'm talking to patients initially when they come in to say, part of our treatment plan in 2025 is that we're going to drain blood from you every so often, right? And that's going to be great for you, like you're going to love that. And it's going to put you a goal. And I know you're iron deficient and you feel poorly, but we're going to drain blood from you on like a monthly basis or every month -- every other month. It's going to make you more iron deficient. But again, your number is going to look better, and we're going to be happy about that. But I have a hard time kind of selling that as how we're practicing modern medicine. So I think, first of all, the patients that are clearly going to be used in this are people that suffer from getting a lot of phlebotomies or they don't tolerate phlebotomies well. I mean we haven't gone into like the challenges with phlebotomies. But when you actually do a phlebotomy. It requires you to come in, get a lab work done. Okay, we're going to recheck it. Okay, now we're going to set you up in a lab. Where that happens is different. It happens in the infusion center at Cornell, happens in the lab at Moffett. And the community, maybe it happens in an infusion center, maybe it happens at a blood bank, but figuring that out is challenging. When you get the blood drawn, you get lightheaded, sometimes you need fluids afterwards. Some people pass out, some people vasovagal and that the chance of getting a needle near them and pass out. So, I mean, there's a lot of issues with that. So I think first off, the people that are requiring consistent phlebotomies, that's a slam dunk. Beyond that, people that maybe not require consistent phlebotomies are a ton of them, but just don't tolerate them well. That's another chunk. And then I think looking at the symptom factor, I would say -- I mean, in kind of large landmark patient surveys, 90% of our patients deal with some degree of fatigue, and that usually is the symptom that is probably -- is one of the symptoms that's most closely aligned with poor quality of life, right? There is a lot of symptoms people have they can live with. Fatigue is a tough one, on a day-to-day basis. So I think, you look at those phlebotomy requiring people or people struggle with phlebotomies, maybe that's 20%, 25% of patients. There's an additional amount of patients that like suffer from fatigue, where that's problematic, who are desperate for an agent that has shown some benefit there.

Yes. I mean, I would totally agree with the patients who are requiring phlebotomy. I personally think that phlebotomy is kind of failed therapy. So every time we do a phlebotomy, it is a number of things that have led into that and a number of consequences of that. So, we spoke a little bit about the lost time and potential productivity, the iron deficiency and things like that. There's another part is the unknown for the patient. So every time the patient comes to you when they're requiring phlebotomy, they don't know what that day holds for them. So they come in, they get the blood test. And then it's, I'm out of here, get on with my life or I'm stuck here for the rest of the afternoon. And they don't know. So, they can't plan. So even if they don't require a phlebotomy, they've kind of left themselves free that afternoon in case. There is anxiety that goes along with that as well. And it becomes -- they become much more patient instead of person with disease. And so, I think that phlebotomy to me is always a failure. If I can avoid phlebotomy, I want to avoid phlebotomy. I try to never use it. In the beginning of therapy, currently, everybody gets phlebotomy to varying degrees. And, if you look at the longitudinal, like how long people stay on phlebotomy-only therapy, although it's always there, right, in the NCCN guidelines, it's first line therapy for so-called low risk, which is a misnomer anyway, low-risk PV, it's first -line therapy. How many people maintain on that first line therapy for the long term? Very few. It becomes intolerable. As they become more and more phlebotomized, they become more and more iron deficient. They give up. They don't want that anymore. So I would say anybody who's still requiring phlebotomy on whatever therapy they're on or anybody who has symptoms referable to iron deficiency would probably be a person I would consider for Rusfertide, would it be available. The other population, which again, I think depends on the indication with the package insert and [ insurer ] and some practical aspect. But I would love to be able to start it right from the start with whatever else I'm going to do, but just get rid of phlebotomy.

Next question?

Can I just ask one clarifying question? From the first response when you said consistent phlebotomy, do you -- the way that I kind of understood your answer was that you wouldn't necessarily say somebody with 5 or more, but it would be kind of on an individual basis just -- because you said 20% to 30% and -- so just want to clarify that.

Yes. I mean -- so, yes, I mean, like people that are I think consistent, or it means like you've reached some sort of equilibrium where then you know they're going to be getting phlebotomies as part of their regimen, right? They're not free of them by any means. I always give like you're the king of metaphors. But I like -- I always tell my patients sometimes like -- and this is like a true story, but like I have my front left tire.

Those are the best ones.

I know [indiscernible]. So my front left tire is like consistently, I need to put air in it. Like that's probably an issue with the front left tire. But I'm like, phlebotomy zone right now where I'm like literally like every 3 or 4 weeks, I go and put air in the front tire. Like at some point in time, is that like a long -term solution? Is that how I want to live my life? Like not really, but it's how I'm doing it. When I tell people about it, they're like just get a new tire, put a patch.

Because you don't know stuff.

Well, I don't know. We don't have that at all. But yes, I mean, I think they are the patients where certainly you can optimize them in a much more sustainable plan, right, as opposed to these consistent phlebotomy.

Next?

Hi, Doug Tsao, H.C. Wainwright. I was just curious in terms of -- a question to the 2 physicians in terms of what leads to patients not being treated? And what is your sense of the availability of Rusfertide to potentially have them actually start treatment? And would that sort of -- the availability potentially of Rusfertide and if it shows what -- and verify what we've seen in REVIVE sort of drive you to be more of an advocate for initiating treatment? And I have a follow-up.

I think the short answer is, we don't exactly know. My personal belief is that these are uncommon diseases. So you have somebody with blood count abnormalities for some -- I mean, fatigue, right? It's not a very specific clinical sign. So, people come in with some complaint or they're found on routine blood testing to have abnormalities. This is generally happening with primary care physicians, and in that setting, [ PV array ] is just not the first thing that jumps to people's mind. So we find, about 20% to 30% of people are diagnosed because they've already had an event. They've had a stroke or they had an MI or they had a deep vein thrombus. And so they come in with a clot. That, because it's medically more urgent, triggers more detailed analysis. But when you look back, it's not uncommon. I'll be seeing somebody, I'm sure Andrew is the same. In a first visit, and they've had persistent abnormalities of the blood counts for years, sometimes decades. And it just never really came to the threshold where they were referred until either a clot or they become very symptomatic, something else kind of drives it. So I think that there is an awareness factor that plays a role in it. I think there's also people are reading from when they were in medical school, right? So it wasn't a cancer back then. So you still have people tell patients, well, don't worry, it's not a cancer. It just kills your life, right. So the -- I think there's information in the community would help. Information of patients. New York City, it's a little different. We have more like patients will have abnormal blood counts and we'll see 15 specialists reporting a diagnosis. But I think that's not typical across the country.

Yes. I'd say the other thing is good treatments make people better doctors, too. Like, it's hard when patients come in and talk to their primary care doctor or talk to me about fatigue. I think how many patients come in and see you and they've been told us because they're getting older or maybe it's their thyroid or maybe they need to sleep better. But like a lot of that because there's not a huge incentive to relate fatigue to the polycythemia vera because we're not good at treating it, right? And so I would love for it to be due to something else that we can treat. Now I can't treat getting older, right? That's -- maybe we will one day. But the -- like -- but if we have agents that we know help with some of these more vague symptoms, we're more likely to kind of be educated and knowledgeable and say, yes, this -- we know that 90% of our patients have fatigue. It's the most problematic symptom. There's good reasons behind it. It's easier to attribute it to the disease if we have a way that we can potentially manage it.

And I guess just as a follow-up, I mean, where do you see this falling into your treatment algorithm if it became available? How quickly would you anticipate using Rusfertide?

Well, I mean, the easy answer is we know that Joe referenced the NCCN guidelines that first line recommend phlebotomy, right, for all patients with polycythemia vera as needed. And so this is an integral part. If this is something that's showing that it's better than phlebotomy, then perhaps it can replace it in some senses, then I think it can be an option for most patients at some point in time during their patient journey, right? Is it going to be a part of every single patient's forever in their patient journey? Maybe not, right? And it's going to be more of a part of some patients' journeys than others. But I don't see necessarily a single polycythemia vera patient who might like never be a candidate.

Great. And then a couple of questions related to the -- already see the Phase II data and then pretty impressive on the efficacy side, and then we're about to see the Phase III. So what would be considered as a home run result from the primary endpoint in terms of the response rate and also the phlebotomy reduction. And then as a physician, you will think, okay, I will recommend this as the first line just like we suggested, even replacing [ a put ] in front of the phlebotomy, replacing all the cytoreductive therapy.

I guess from my viewpoint, if the results are of such nature that Protagonist and its partner, Takeda think this is good for NDA filing, we'll be satisfied with that.

Do you guys want to comment on the types of benefits that will be important to you in terms of determining who will get Rusfertide?

I mean -- so I would say from a home run standpoint, if we just see a continuation of what we saw in the Phase II, right? I think the Phase II to me was a home run as far as the drug doing what we hoped it would do for patients that need help. And so, if we -- if that story continues from the Phase III data, like, I mean percentages, it's tough to say, like 55% versus 45% versus 63%, like I don't know if those response -- I think it's hard to kind of necessarily put an exact number on some of these things. But if we see a significant difference, right, in a positive trial that shows that this does what we hope it does and helps patients, then it's certainly something we want to bring to the table for patients.

I agree. I mean, I think the Phase II data, which, in many ways, was stacked against Rusfertide, the comparison window, you could -- as soon as you require phlebotomy, you could jump back on to Rusfertide. So, there wasn't much opportunity for all the ill consequences of ongoing phlebotomy, right? So patients, even there we started seeing maybe some symptom benefit in patients. I think that, that would be quite helpful, and I think there's a -- maybe a chance of seeing that in this design of the Phase III? But even short of a proven symptom benefit in the Phase III study, eliminating the need for phlebotomy has a lot of profound benefits to a patient and their quality of life. So I would consider that a victory in itself. Although I expect/hope that we'd also see some symptom benefit.

Great. That's on the efficacy side. And then on the safety side, I'm very glad we see the 2 year carcinogenicity is no drug-related cancer incidence there. But we see some cancer case in the Phase II, how you think the cancer language in the label may change your view on how you will use Rusfertide with certain language in the AE side will change your practice?

I think the first thing I would say is that we already have agents that cause skin cancers. right, those known to cause skin cancers with ruxolitinib and Hydroxyurea, and those are probably the 2 of the most used agents we have. So here, we have an agent Rusfertide where we don't actually have any proof that it does cause excess skin cancers, like we're seeing them on study, which we would expect to see in this patient population. So even in -- with ruxolitinib, especially when you're seeing 3.8x, maybe 4x increased risk of skin cancers yet, it's still something that we know patients benefit from and we get, right? So I don't think that necessarily would impact my provision. Again, close monitoring, we have to be appropriate with all these patients and making sure they have routine skin exams and things like that. I mean, my first question would be, is there a signal there? So far, personally not convinced there is. The whole concern about skin cancer was based on an animal model where if you look at it with unkind eyes, they develop cancer. So, Rusfertide and the linkage there in non-cancerous skin lesions is kind of weak to begin with. And that's where this all came from. It wasn't from clinical findings, it was from an animal model. And so in terms of clinical care, yes, we do deal with this. And a lot of our patients are older and they live their lives. Some of them even go to Florida, the skin cancer state. We're protected here. And so we do have to deal with that as part of the routine care. I mean we generally are advising people to get routine skin care, particularly people who have had skin cancers or precancerous lesions, which is quite a few of them. I mean it's a pretty large percentage. And so it is part of the care now. So I don't anticipate it being something that dictates therapy even if there were a signal. And so far, I don't think there is a signal.

From the company perspective, it's fair to say that with the incorporation of periodic dermatologic exams as part of the Phase III study and also in REVIVE, we've been able to intervene and detect these lesions even at the pre-malignant stage. And although we haven't shared the data, we haven't -- unblinded, but prior to coming on study as part of a baseline dermatologic exam, we found some patients with skin cancers and melanoma before ever being dosed on Rusfertide. So, from a labeling perspective, if there's some wording in there recommending periodic derm exams, I think that's the long term good for the patient. And I'd like to see our colleagues in NCCN consider that for all PV patients because PV patients get HU and that increases the risk of skin cancers. And even the patients who are on phlebotomy only have an increased risk of skin cancer compared to the general population.

Next question?

Hi guys. Julian Harrison, BTIG. I have a few. I'll just go one by one. First, based on everything we know about Rusfertide's activity, pre-verified data, what do you expect payers to be most receptive to?

Payers?

Payers, yes.

Oh, don't ask me that. It's like crawling into the table.

Yes, it's hard to predict. And really, at least in my experience in New York, it really depends on the payer. You will have people who will recommend completely crazy things to do first before the drug that they don't want to pay for. Eventually, we win. I take it as a personal challenge to shave them into paying. But it is hard to predict. I think it depends on the package insert. If the package label says X, and we're trying to treat them with that indication, it's pretty smooth sailing. Sometimes one escalation. But it's not uncommon that we want to use it in a non-labelled indication, and then we have to argue a little bit. The more data there is, the better. But usually, we can win that, but it just kind of is a pain in the neck. So it depends a lot on the label would be my short answer.

And then thinking more about VERIFY sites all around the world. Is access to phlebotomy relatively consistent? Are there any nuances there in any geographies we should be considering?

Arturo, do you want to comment on that?

Yes. I think in Europe or ex-U.S., it's more problematic and challenging for the phlebotomies. Often, they cannot be done the same day. They need to be scheduled on a different day, sometimes at a different facility. And so it's more cumbersome, more time consuming. That's a general sense that we get. And what I hear is, well, the patient needs to spend the whole day for the phlebotomy, not in an afternoon, but like a whole day.

It's one of the reasons we went to Asia to do the PACIFIC study to find patients who are poorly phlebotomized.

Got it. And sorry if I missed it, are you commenting now on the split U.S. versus ex-U.S. enrollment for VERIFY?

No, not yet.

Okay. And one final question, if I may. The opt-in, opt-out on the co-promote, are you able to talk a little bit about what's informing that future decision? Is it something specific in VERIFY that you're looking for anything else?

Dinesh, do you want to comment on it?

Yes. Sure. So, again, I think it all boils down to simple and PV kind of math, right? So -- and we have roughly sticking up to the middle of next year to make that decision. And I think as Lopa gave the brief commercial perspective, those are the kind of things that will get more well refined this year. And of course, the Phase III VERIFY data, the quality of the data, the quantity of the data that will play a significant role in anywhere from increasing awareness around PV, increasing awareness around the potential availability of the first erythrocytosis specific agent ever out there. And then I guess the Protagonist has to do our own math and make a judgment call. So it won't be driven by "The financial stress" of Protagonist, because the reality is we don't have any at this stage and in the foreseeable future, it will just boil down to like what is the true commercial scope of Rusfertide.

Additional questions?

Rich Law from Goldman Sachs. So, just want to follow up to what you guys were thinking about the payers and try to learn a little bit about that. What do you think you need to show in terms of symptomatic improvement in the secondary endpoints? And how would those translate to health economic values that you think could lead to a broader payer coverage? And the reason why I ask is that when you look at like Besrami, it requires that additive phlebotomy, hydroxyurea and also Pegasus, even though NCCN guideline preferred it over Pegasus. And it also had better efficacy in a head-to-head study. They both have similar box warnings so that can't be that. So my guess is driven by price. So, just want to hear how you think about that and also what level of symptomatic improvement do you think you need to support broad coverage?

If you want to hear cynicism about payers, happy to launch into this. I mean I think -- it's really hard to kind of judge what payers are going to do. I don't know why ROPEG, occasionally, they require us to go through hydroxyurea, ruxolitinib, pegylated interferon. I mean, it's hard to even sometimes get pegylated interferon and ROPEG -- and it doesn't have an indication, right, like for PV. So, I don't think payers necessarily follow any kind of guidelines that are out there. That being said, I think when things do get a label, we use them on label. They get into guidelines. Patients become motivated based on data. I think that there's usually a -- it takes some time, but ultimately, we're able to get those agents, right? And sometimes that's probably because there's negotiating going on between payers, right, like while they get the price figured out. That being said, I think that the symptom part of thing that you referenced, I don't think that's -- I don't think you necessarily need a positive symptom endpoint right here to make this a positive trial. I think that would be nice, and I think that might resonate a ton with patients. There was, I don't know, what, 5, 7 years ago, a huge upwelling of, like, patients that came to me because they wanted to be on pegylated interferon based on the data that it was coming out about it. And so sometimes patients drive this, right? And so, I think if you have something that resonates with them, then I think that they -- that might push that forward a little bit and move things more quickly. But I think the symptoms are tough to look at and I think Arturo went through the different kind of PRs that are being used. And I think that the ones we settled on with PROMIS Fatigue and MFSAF are great. But ultimately, what we want to do is see some signal in there that we're making patients' lives better, right? And I don't know if there's the perfect symptom endpoint that's been created, but I think those are as relevant as we can get for things that have already been kind of accepted by the FDA.

I agree completely. The only other thing I would add is that phlebotomy independence is freedom for patients. And so although it's not quantified separately, it is quite meaningful for patients and their care and also their kind of approach to the disease. If every time they come in and I mentioned this before, they don't know if their day is blocked or they're in and out in 1.5 hours, 2 hours. It's a big burden on them. And if they're on something that's making them phlebotomy free and they're confident they're going to be phlebotomy free, they'll plan for the afternoon.

Fantastic. Just one more follow-up to that. What are the payer sort of the coverage assumptions behind that $1 billion to $2 billion peak sales guidance in terms of like step edits or stuff like that?

Premature to talk about any of that before we have seen the Phase III data. You can't really know what the label or payers are going to do until you unblind a Phase III study. Can we get up here and get some questions? Yes, go ahead, Brian, go ahead.

Hey guys. This is Brian Cheng from JPMorgan. A couple from us. Arturo, in the beginning of your talk, you said that there were 2 countries for REVIVE, which are U.S. and India. Now the Phase III VERIFY now recruit patients from 19 countries. So how might that change the background usage of cytoreductive agents? And can you also remind us whether background usage have any influence on the response to Rusfertide?

I'll answer the second question first. Rusfertide works equally well irrespective of whether you're on phlebotomy only or phlebotomy plus additional treatment like cytoreductive therapy. Just repeat your first question again, to make sure I got it correct.

Just because of the geographical location difference, does that change the way how the background of cytoreductive agent being used when these patients enter the VERIFY trial?

Yes. In some countries, not all agents are readily available. And some became available over time. But some countries did not have access to Besrami, but they could still get like Pegasus.

We're speaking generally now, not from actual knowledge of the demographics.

Yes. No. But I think stay tuned because we will share that information in about a month or so.

But it's fair to assume that something like hydroxyurea would be available [indiscernible] right.

Everyone, Yes. There's always Hu. That's always available.

It was an old drug when I was in medical school.

Just looking at the control arm performance in the past in Jakafi's RESPONSE trial and also your REVIVE trial. Obviously, there are some nuances to each of the respective trial design and also difference in baseline. Can you give us a better sense of how we should think about the stat powering and also the performance of the placebo arm? If we assume a ballpark of somewhere around the mid -teens to 20% range for the placebo control arm, does that make sense?

I'll ask my academic colleagues to answer first, and then I'll answer.

Yes. So, I mean, if you look -- if you're thinking about just again, looking at that weeks 20 to 32, how many patients are not going to be phlebotomy eligible, I think when we looked at the Phase II data, it's a smaller window, right, of that randomized withdrawal phase, and patients are coming off Rusfertide after getting kind of optimized and the rates there were kind of in the low teens or whatnot. I think one thing to note with any randomized study, we've learned this from myelofibrosis, so kind of going on a separate thing. We do a lot of trials in patients that are transfusion dependent, which is to be the inverse of phlebotomy requiring, right? And when we've done these trials, we'll say, oh, in the Phase II study, we saw patients that were transfusion dependent, 20% became transfusion independent. And then we'll go to a Phase III trial and we'll compare them to placebo. And invariably, we see that 16% of patients on the placebo arm become transfusion independent when they go on the study. And so there's always going to be this potential for the placebo to respond. And I think I average that kind of what you're saying, maybe 15% to 20%. Reasons for that, I mean, maybe in these patients who have been kind of managed with cytoreductive therapy beforehand haven't been as kind of on top of it and then they go on a clinical trial and they're better at taking it consistently or they get phlebotomized more consistently prior to going on study. And then for whatever reason, they just don't meet the criteria as discussed during that. So I think when you look at the Phase II and kind of compare to the Phase III, I think there still will be a phlebotomy response there, maybe slightly higher. If I was guessing, I mean, this is pure speculation, but maybe slightly higher than we saw in the Phase II because there's more period of time when they're randomized. But at the same time, there's such a wide gap in what we saw with the Phase II that I think that's built in where you have that ability for the numbers to change and still see a significant benefit there.

Just last one for me. Just going back to stratification for VERIFY, Jakafi's Phase III anchors on prior hydroxyurea [indiscernible] of screening and thromboembolic events. How different is that to you compared to yours?

Our stratifications are based on the type of cytoreductive therapy. And I think I just wanted to emphasize the point that Andrew made that you do expect the baseline effect of placebo in the teens, the 15% could be maybe a little higher. But the magnitude of treatment effect was so robust in the Phase II study the p-values of 0.0001 and 0.004 even when we include the patients who dropped out prematurely. And this is only in a 70 patient study with 59 randomized patients. So now you take a study that's targeting 250 patients, I think the efficacy we should -- I'm optimistic that if given the same patient population, given the same primary efficacy endpoints, inclusion/exclusion criteria, that if we replicate anything close to what we already showed in REVIVE, we'd be in good shape.

Can I just make one comment on that is when you look at the ruxolitinib approval, right, this HU resistant intolerance, we argue about this, how to even define that. But that study required a change in therapy, which is a big barrier. And we see this in all of our clinical trials is like if we have to stop a drug to start a new drug, there are people who might not be getting much benefit from something, but they're getting a smidge. And if we have to stop it and keep them off it for some number of weeks, it's a big barrier to study. This study is much more like we treat patients. They're on something, it's not enough, we add something to it to make it better. We don't necessarily stop the other thing beforehand unless there's a toxicity. And so I think that the way Rusfertide is being developed is much more real world. And it gives clinicians a knowledge base to know, okay, this person is on HU. Well, what do I have to do if I want to put them on Rusfertide? Well, just start the damn Rusfertide. You don't have to do anything else. We know that already. We know it's tolerated by patients. So it's different. You don't have to have this worry about the transition period.

And just to set up the Phase III expectation, remember because it's stratified in the final data analysis, you'll get data on every drug that's available with and without Rusfertide in similar numbers.

Kaveri Pohlman from Clear Street. My first question is about the duration of exposure. The previous study showed about 2.7 years of exposure for patients. Would you expect it to change significantly in the real world if it gets approved tomorrow, let's say? And what all factors would you consider for keeping patients on or off treatment?

The reason why it's 2.5 years is that's all the opportunity patients had on average to be on the drug. When there was the FDA hold for Rusfertide and we probably had the same experience, we had so many patients calling pissed off because all of a sudden, they stopped this study. I mean, like we don't even know if it was benefiting them, right? The patients were pissed off because they felt worse. Now that might not read out in the study, but it definitely read out in the secretaries calling me and sending us emails, because they're -- so when you think about duration, that's part of it. If you look at the -- Andrew hit on this, and I completely agree, if you want a very quick answer, is this drug doing something useful? Look at these extension studies. How many people go on? 80%. And why didn't the other ones go on? They were already off the study, not because they failed or didn't want to, but they got probably pissed off at some point during the hold or whatever it is. I don't know all those statistics, but a lot of the people who didn't have the opportunity who didn't go on, didn't complete the first part of the study, and that's why.

Look at the patients that stayed on the extension. Also, look at the centers that opened the extension, because it's not necessarily easy for us to open an extension study like we have to use a lot of resources...

I don't really know how many arguments I had with them about, please don't make us open an extension.

There's no academic credit for that.

Well, we had to close the revive study and lock the database and write a CSR because it's 1 of 2 adequate well-controlled studies. And the only option was to open up a new study, and 80% of these patients went on the study. It's very gratifying, when you're doing drug development, take care of these patients and you can keep them on treatment that's working for such a long period of time.

I mean we would have love to -- I mean, to open extension just from the background, I mean like for us to open extension study, we have to -- it's not like there's a separate route to open that as opposed to fighting with just new interventional studies, and we always want to open studies. There's a backlog. We can't -- we have to fight and like put our own, like credibility on the line within our departments to like choose this trial. And so, to choose an extension study, which is not going to enroll new patients, it's going to enroll patients over from the prior trial. The reason we did it is because the patients were demanding that they have that option, right? And so I think that speaks to the fact that this was open and patients went into that extension study because it was really driven by patients benefiting.

Our only argument is the patients are benefiting. That's our only argument, right? It's like, yes, just occupy -- from the cancer center standpoint, it's like this is a waste of time, don't do this. And we have to argue. Our only argument is, we think the patients are benefiting.

And another question just on some of the previous comments you made, Rusfertide works really well in patients who are just -- whether it's with cytoreductive agents or without. Is there a potential to replace those? Are there any cytoreductive agents you would want to keep with them or Rusfertide can take care of that?

I mean I have my biases. I think that phlebotomy is not just an ineffective therapy. I think personally, I think it's a dangerous therapy. I really try to avoid it. I do like interferons and use them a lot, but that's a really slow drug, right? So you're talking about having people on for best responses with interferons, they bottom out, they plateau in terms of best response, 6, 7 years, right? So there's a lot of time in between. This is where, for me, if I had access to Rusfertide, I would just put interferon and Rusfertide in the same syringe, inject them from the beginning and go forward. I mean...

You're advocating for putting both in the same syringe?

Yes, I am.

Alright. So I mean, I think the question is, can this replace cytoreductive therapy? I'm not ready to say that by any means. I think that this -- but it can certainly help you optimize cytoreductive therapy. There are patients who are in the lower-risk category who we put on cytoreductive therapy solely for the need to control their phlebotomies. And I think certainly, maybe in that group of patients, this could be an alternative. There's other patients that we also have on 2.5 grams of hydroxyurea right? Because we know that they're high risk, they should be on cytoreductive therapy, reduces thrombotic potential. But at the same time, that's the dose that's required to get them to not require a ton of phlebotomies. And those patients, you have the potential to substitute part of their hydroxyurea, have them on Rusfertide, bring the hydroxyurea down to a more tolerable dose, so they're not getting fatigue, mouth sores, ankle ulcerations and skin cancers and things like that. So maybe not full replace, but certainly optimize.

I want to echo that point because it's important. We often are kind of balancing toxicity and efficacy with these drugs. And so if I have to push the dose of whatever it is, and for instance, I'm causing a little bit of thrombocytopenia, maybe a little leukopenia at the same time, GI upset to some degree isn't uncommon with HU. If I have to push the dose to make somebody phlebotomy independent, that's a decision that the patient and I are going to make together. If I can just make them phlebotomy independent and I use HU for whatever I'm going to use it for, I don't have to push the dose anymore. And so I think that we don't know this yet, but my suspicion is there is a hidden benefit to that as well.

I would point out in the long-term extension data, we do allow people to alter the dose of cytoreductive, so we may get some data long term on doctors trying to reduce those doses in the setting of the long-term follow-up.

Got it. and sorry -- I just wanted to quickly ask, like, based on the mechanism that you explained and the biology here, how do you see the potential of Rusfertide in other indications like hemochromatosis and beta thalassemia?

So, I think we had done a beta-thal study and we concluded that, that would not be the place we would want to go. We have done a small hereditary hemochromatosis study, Phase II study. The data has been published. And of course, over there, we got positive results and that has been published.

And there are other rare conditions like patients with mutations of the EPO receptor who have very high hematocrit. And I think we're starting to map out a potential life cycle management plan that helps us explore adjacent indications. The problem with those like is we just don't have as good a data for the value there, right? Like so like in -- with polycythemia vera, we get a lot of [indiscernible] and we get a lot of referrals for people that have high hematocrit. They don't all have polycythemia vera. And the optimal way to manage someone with high hematocrit is not polycythemia vera is not well described right? Like whether it's testosterone, I mean, if it's from smoking or COPD or something, you probably don't want to lower their hematocrit maybe, because that's how your body kind of deals with that, right? But then other people who have oxygen sensing pathway mutations or who are on testosterone or some of these new SGLT2 inhibitors that cause erythrocytosis, maybe you do, right. But the problem is we don't have good data that says there's a goal hematocrit that you should be shooting for there. We have great data with PV that suggests this kind of 45 and lower is something we should be trying to optimize.

Last set of questions.

Hi, Srikripa Devarakonda from Truist Securities. Thanks for all your insights. You said that Rusfertide would be used at some point of time in a patient journey. If I were to ask you 3 to 5 years down the line, what percent of your patients do you think will be -- will have used Rusfertide or will be on Rusfertide?

I think I've said that it would be -- there would be all candidates at some point in time during that, right? So I think that there's certainly the potential to use it at different times. And I think we kind of showed that during one, everyone needs phlebotomies, right, during the course of their disease, typically early on more than later, but also sometimes later on for a lot of these patients. And so, overall, if you're talking about the number, a lot of it comes out to what the clinical trial shows, right? And I think that you could argue that there's an easy 20%, 25% of patients that I think are great candidates just from what we've seen on the Phase II setting. But I think there's additional data that can be created and additional kind of insights we can gather from Phase III. How -- what the symptoms look like early on in the disease, right, as far as patients presenting with like hematocrit of 60, right? You don't want to give them weekly phlebotomies for 8 to 12 weeks. Patients who don't have a controlled hematocrit, but they're starting on interferon, that's going to take 12 to 24 months to control things, right? Like there's a lot of these other patient populations that you could say, yes, it makes a ton of sense there. Do we have the data to say to support it as well as those 20% to 25%? Not yet, but I think that can be created.

And Dr. Scandura, I think you mentioned about low risk is a misnomer. I just wanted to double-click on that. What do you mean? And as patients progress through the disease, how do you change the treatment paradigm? And with Rusfertide, how do you think that's going to be incorporated?

So, if I were to tell you, if you walk through that door, there's a 4% chance that somebody is going to hit you with a sledgehammer. That's high risk. And there is a 2% chance somebody is going to hit you with a sledgehammer. That's low risk. But everybody else can pass through the door with no problem. That's the argument. It's not normal risk. it's lower, but it is not low. It's excessive risk. So -- and this is going to go away. I promise you in 5 years, we won't have this conversation anymore, because there was a study in -- it's actually, it's humorous and instructive. So, Ropeginterferon, interferons were not available in Italy at all. There was no availability of the drug. And in Italy, phlebotomy alone was always proposed as a suitable approach for so-called low-risk people and preferred. And so there was a study comparing Ropeginterferon to phlebotomy alone. And they very carefully built in stopping rules to that study so that they could say, "All right, well, look, if the interferon is hurting people, let's not hurt more people than we need to, let's stop the study early." So, as it turns out, the study was stopped early. Why was it stopped early? Because phlebotomy alone was more toxic than interferon. It's not a benign therapy. It's not a benign setting. And data emerging is -- that we discussed, it wasn't a long time. but if you look in the so-called high-risk group, some of these drugs are not just reducing phlebotomy requirements, but reducing the events of clotting events over time compared to standards of care high-risk HU being a standard of care. And so I think that the -- as that kind of data emerges and eliminating the necessity for phlebotomy entirely with drugs, we'll see but like Rusfertide, I think that will change practice and also eliminate this artificial discrimination of low risk [ heart disease ] kind of concept.

One last question. Anything else in the therapeutic development landscape for PV that you're watching closely?

We watch everything. I mean, I think that there's certainly excitement around agents that look at Hepcidin, right? I think that speaks to the benefit that I think people are seeing in these agents is there's potentially a path to look at other agents that do the same thing in different ways. And so, it's always a marker of success when people go, yes, that looks like it worked really well. Let's do that as well. We saw with JAK inhibitors and MPNs as well. So, looking at that and -- but yes, I think that certainly, this is an area that's touched the nerve with folks that we think that we can help patients through this.

One more question and then we got to wrap up. Go ahead.

Great. So, Yun Zhong from Wedbush. First question to the company, please, and on the Phase III study design. I think Phase II, the withdrawal design showed really clear benefit. And was there a possibility of running a similar withdrawal design for Phase III? Or was that randomization at the very beginning a request from the FDA? And I think you talked about titration. During that titration period, how are those placebo group patients going to be titrated?

So the more traditional design is what the FDA likes. And if you look at most other studies for Phase III, you randomize at the very beginning. So that's a pretty traditional design. Then the second question, I mean, for the placebo, we have recommendations in the protocol for all patients. We are blinded, investigators have been blinded. And if the hematocrit goes up by a certain amount, you can go up on the dose. And so there's upward dose titration and we're eager to look at the results after we unblind.

That placebo-controlled phase is necessary to adjudicate mild symptoms that can be part of the disease or part of daily living. So if I see 10% headaches at mild, is that drug related? I can only see that in a study that's randomized from the get-go.

And there's precedent also in other trials MPNs for that 32 week or so period of comparison between a placebo or your control versus the investigational arm. So we also took lessons learned from what's already been done before.

Okay. Second question to the KOLs, please. And I think 80% patient participating in the long-term extension study is certainly very impressive. But in reality, how often do patients get their hematocrit levels checked, and other than the reduction of the need for phlebotomy, anything else that you're hearing from patients that, again, in real clinical practice, do you think will be the strongest motivation for patients to stay on therapy?

I'll give you an anecdote, so take it for what it's worth. True story. I had a young patient, 40s or so, who came to me after maybe the first 3 or 4 months of his care, during which he had 10 units of phlebotomy. So basically, his blood volume had been taken out and made a new one. And at that time, he was so crippled from iron deficiency. This is a federal officer, right? So crippled, he couldn't climb the stairs at his home. He was saying, he had so many cardiologists, pulmonologists, all these people starting to get involved in his care; stress tests, echo, all kinds of things. What the hell is wrong with this guy? Young, was fit, in great shape, now terrible. Eventually, after -- I mean, he was pretty refractory to therapy. Eventually, he got on study with Rusfertide due to his phlebotomy dependence despite cytoreductive therapy. And within 2 years, the guy won an award for best officer across the country from the Secretary of his department. He's coaching his kids baseball team, and he's living his life. And that's a difference that is hard to pick up in these studies because his quality of life is like, are you better? He's better. Is he better like life changing better? It's not recorded that way, but he's life changing better. And so I think that when you think about what is motivation for people to stay on, a lot of people who have like this mild fatigue and it gets a little bit better, they're going to stay on. Even if they still have ongoing fatigue, which we don't know yet one way or the other. My personal suspicion is it's going to be good, but we'll see. But just avoiding phlebotomy is a benefit in itself. I mentioned that a few times, but just not having to come in and know and wonder whether or not your day is shot or you're going to get in and out relatively quickly is a benefit in itself that motivates patients.

Thank you very much. I want to thank our outstanding KOLs who contributed to this event. I think you can all see that if you or your family member had polycythemia vera, you would want to be taken care of by one of these very good physicians. So thanks for coming. Thanks for making this a great event, and we look forward to discussions at the lunch. Thank you.