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

Thank you for joining the Protagonist Therapeutics PTG-300 opportunity update webinar. The company will give a presentation followed by a Q&A session. Directions for the Q&A will be given at the appropriate time. With that, I'd like to turn the meeting to Dinesh Patel, CEO of Protagonist Therapeutics.

Good afternoon and thank you all for joining us. We would like to extend a warm welcome to everyone at today's event. We are pleased to provide an update today on clinical unmet needs in polycythemia vera, based on our market research, and potential commercial opportunities that it may present for our hepcidin mimetic PTG-300 or 300. Before we begin, I would like to acknowledge the constant challenges of the COVID era and would like to express our sincere gratitude for the health care workers who continue to serve at the front lines of the prevailing pandemic. It is the important work of these individuals that translates to safety and security for all of us in this challenging and uncertain times. I would also like to acknowledge that today is the anniversary of September 11, 2001. The events of that day were and are still tragic for our nation and for the entire globe. We would like to take a moment to share our sympathy and support for those who were most affected. And also remember, how our response to crisis like these reflect our core strengths and values as a society and nation. As a reminder, Protagonist is a publicly traded company, and today's discussion will include statements about the company's future expectations, plans, and prospects that constitute forward-looking statements. I would like to set the tone for today's discussion by highlighting our drug discovery and development approach and our clinical pipeline. Protagonist focuses exclusively on the development of peptide therapeutics, and we have a highly innovative technology platform that allows us to discover novel peptide candidates in a de novo fashion against almost any biological target of interest. The fact that we already have 3 different clinical assets illustrates the breadth of our capabilities. These 3 candidates fall in 2 broad categories of diseases. In the first category is PTG-300, a peptide mimetic of the natural hormone hepcidin for various blood disorders. 300 is currently being developed in 2 different indications. The first is polycythemia vera, which is our major focus and the main subject matter of today's event. And the second indication is hereditary hemochromatosis, a disease which results from the absence or deficiency of hepcidin in the body. The second category of development candidates are the oral, gut-restricted peptides for inflammatory bowel diseases or IBD, and they work through integrating the biological pathways that have already been validated by injectable antibody drugs on the market. As you may recall, PTG-300 is currently in a Phase II study in patients with Crohn's disease and we are pleased to have Janssen Pharmaceuticals as our partner on that program. The second IBD at PN-943 is fully owned by us. And it is currently in a Phase II study in patients with ulcerative colitis. While we are pursuing both of these studies aggressively globally, we will not be discussing this during today's event, which is focused on our hepcidin mimetic and the PTG-300 opportunity. To that point, we have designed today's agenda to highlight 3 important aspects of our hepcidin mimetic program. First, we believe there is a significant unmet need in polycythemia vera. More than half the patients do not have their hematocrit levels well controlled and this reflects the need for better therapeutic options for this disease. We are making this conclusion based on our market research data that we'll be sharing with you today. Second, we are very encouraged with the initial data we reported in early May from our ongoing Phase II study of 300 in polycythemia vera. We continue to be very pleased with the progress we have made with the trial to date. We will provide a general enrollment update today and anticipate providing more clinical data later this year at a major medical conference. Third, encouraged by the findings with 300 in PV, we are expanding our efforts by evaluating new potential indications, strengthening the IP and patent portfolio and exploring the potential to develop an oral hepcidin mimetic. We plan to detail each of these 3 points further during our presentations today. So here is the detailed agenda for today. First, Dr. Hoffman of Mount Sinai will speak on the background of PV. Then Tracy Woody, our executive VP of Commercial Strategy, will introduce our Symphony project, which we undertook in order to develop a deeper understanding of current real-world PV patient data and its relevance to the potential opportunities that it may present for 300 in the future. Sharing with you what we have learned so far is a primary objective of today's event, which includes a detailed analysis of the patient journey with current treatment options. After Dr. Verstovsek's presentation, Tracy will follow-up with information on how we may position 300 to address those patient needs and the potential commercial opportunity within that market. Our Chief Medical Officer, Dr. Sam Saks, will review the current status of PTG-300 development. We provided a fairly detailed clinical update on May 7 and while we aren't sharing any additional clinical data today, we will offer some qualitative guidance on the current status and our expectations for the path forward. Finally, Dr. David Liu, our Chief Scientific Officer, will describe our current understanding of the mechanism of action of PTG-300. David will also highlight our hepcidin mimetic franchise more broadly, including some of our new portfolio development and preclinical activities. After David's remarks, all of our speakers as well as Don Kalkofen, our Chief Financial Officer, will join the Q&A session as we take questions from those of you joining today's event. As you can see, besides various members of our Protagonist team, we have 2 prominent key opinion leaders who have gladly accepted to participate in this event. And I would now like to have our Chief Development Officer, Suneel Gupta, to introduce these individuals to you today. Suneel?

Thank you, Dinesh. Good afternoon. My name is Suneel Gupta. I'm Chief Development Officer of Protagonist. I'd like to extend a warm welcome to the highlighted speakers in today's program. Dr. Ron Hoffman, Director at Mount Sinai and Dr. Srdan Verstovsek, at MD Anderson. We are pleased to have both these highly regarded researchers and clinicians joining us today. Both individuals are also investigators in PTG-300, polycythemia vera study. Notably, Dr. Hoffman and his group have made significant contributions to understanding of hepcidin mimetic mechanism. And Dr. Verstovsek has provided highly valuable contribution to the design of PTG-300 study in polycythemia vera. Today, Dr. Hoffman will talk greater depth about polycythemia vera as a disease and provide an overview of the current treatment paradigm. Dr. Verstovsek will share the details of the Symphony data or the medical claims there and highlight their significance for new treatment options for polycythemia vera. Dr. Ron Hoffman, please?

Well, thank you for allowing me to summarize the ongoing clinical care of patients with polycythemia vera in order for you to be able to put into perspective the utility of PTG-300, which I think is a promising agent, novel agent for the treatment of patients with this chronic hematologic malignancy. Can I please have the first slide? Well, polycythemia vera is a specific type of chronic hematologic malignancy is called myeloproliferative neoplasms that's primarily characterized by the overproduction of red blood cells, but is also associated with increased numbers of platelets and white blood cells. Polycythemia vera is almost uniformly characterized by mutation in the intracellular kinase called Janus kinase 2. Although the JAK2 mutation drives increases in all cell types, the greatest increase is in the production of red blood cells. Polycythemia vera is diagnosed most commonly in individuals 50 to 70 years of age. The median survival of these patients is approximately 20 years and many of them progress to myelofibrosis, which is characterized by scarring at a bone marrow and extramedullary hematopoiesis, in an eventual evolution to a form of acute leukemia called MPN blast phase that is refractory to the standard of care. An elevated hematocrit is the hallmark of this disease. And patients are at a higher risk of thrombotic events. In fact, thrombotic events is really the major cause of morbidity and mortality. Next slide, please. Elevation in the hematocrit or thrombotic events often initiates the diagnosis, which is followed by a blood test to confirm the presence of a JAK2 mutation. The thrombotic events usually involves stroke or heart attack, which present the greatest risk to PV patients. However, patients can also have venous thrombosis and intraabdominal thrombosis, such as Budd-Chiari syndrome. The current treatment goal is to control the hematocrit level to a level below 45% to reduce the risk of thrombotic events. Significant evidence, both retrospective and prospective have been published that indicate that maintaining the hematocrit level below 45% is critical to minimizing the incidence of thrombosis in cardiovascular events and death. In most patients, clinically meaningful high white blood cell counts and platelet counts are not present. Splenomegaly is frequently a late manifestation of this disease and is infrequently symptomatic. Next slide, please. Here, one sees the schema or cartoon essentially showing the goals of treatment of how to keep the hematocrit less than 45%. These are guidelines for the cancer center -- from -- developed for American cancer centers for maintaining the patient's hematocrits below 45%. Maintaining hematocrits below 45% reduces the risk of stroke, myocardial infarction and death compared to maintaining hematocrits 45% to 50%. The patients are stratified based upon their risk of developing thrombotic events. Those who are considered low risk or less than 60 years of age and have not had a thrombotic event, while those high-risk patients are greater than 60 years of age and have had a prior thrombotic event. We'll focus initially on those patients who have the low-risk form of the disease. They are almost exclusively treated with phlebotomy, and if one is able to maintain hematocrits less than 45%, that phlebotomy is maintained throughout their clinical course. If, however, they have poor hematocrit control that is they require numerous phlebotomies or there's poor venous access to obtain phlebotomies, then a myelosuppressive agent is usually utilized at that time. And as you can see, that arrow then points to hydroxyurea. The therapeutic strategy with high-risk patients is somewhat different than those patients who have low-risk disease. Initially, they're phlebotomized down to hematocrit of 45. And then they are given 1 of 2 myelosuppressive agents, either hydroxyurea or interferon. If either of those agents are successful in controlling the amount in a prolonged fashion, the patients are maintained on those agents or if they are refractory or unable to achieve successful control, you're treated with 2 additional agents. One is a JAK1, JAK2 inhibitor called Jakafi or an alkylating agent, busulfan, which is used primarily in patients who are over 70 years of age. Alkylating agents, as you remember, are associated with secondary forms of leukemia. Next slide, please. This is an important slide that is taken from a paper from Dr. Marchioli from Italy, which is called the CYTO-PV trial. Patients were randomized to maintenance -- polycythemia vera patients, I should say, were randomized to maintain hematocrit less than 45% or between 45% to 50%. So the less than 45% patients are the low and the 45% to 50% are high. At a median of 31 months, 98 -- 9.8% of the high hematocrit group met the primary endpoint versus 2.7% with the low hematocrit group. And the endpoint is the probability of cardiovascular events. Patients with hematocrits below 45% to 50% -- between 45% to 50% were 4x more likely to die from cardiovascular causes or major thrombotic events. This seminal study emphasizes the need of strict hematocrit control in reducing the incidence of thrombotic events in patients with polycythemia vera, which is our goal with PTG-300 therapy. Next slide, please. Let's go over with what therapeutic phlebotomy is like. It's really the standard of care for treatment for low-risk patients. It's essentially giving a unit of blood as you do when you're voluntarily giving blood to a blood bank. It involves low-risk patients who require frequent phlebotomies more than 5 to 6 a year to keep their hematocrit below 45%, many of these patients also receive cytoreductive therapy in addition to phlebotomy. It's also used in high-risk patients who have incomplete responses to cytoreductive therapy. So frequently, a patient will receive cytoreductive therapy and then get supplemental phlebotomies in order to maintain hematocrit below 45%. Patients go to the clinic to have the unit of blood removed by venous section, removing whole blood and thereby reducing the overall red blood cell count. This is effective in part by depleting iron stores and thereby restricting iron availability for red blood cell production. The increased phlebotomy requirement is often a sign that pharmacological interventions are not effective. Newly diagnosed patients often receive a greater number of phlebotomies than those with a longer history of the disease. Next slide, please. There are numerous therapeutic challenges associated with phlebotomy therapy alone. Phlebotomy works in part by removing iron. 95% of PV patients are iron deficient at diagnosis with iron deficiency worsening after repeated and/or frequent phlebotomies. Iron deficiency leads to significant symptoms and secondary effects, including cognitive impairment, debilitating fatigue, decreased physical performance, decreased muscle function. Hematocrit levels also fluctuate between phlebotomies and can be difficult for patients and physicians to consistently control hematocrit guidelines. One can envision that a patient with polycythemia vera seen a 4 to 6x a year and at that point hematocrit level is elevated and triggers a phlebotomy. The question really remains what happens between these various visits and how long is the patient at risk of having an elevated hematocrit, which would lead to an increased risk of having a thrombotic event? PV patients in the REVEAL study, an observational study with PV in the U.S., continued to receive phlebotomies at an average of approximately 8 phlebotomies per year. Many PV patients, approximately 50%, report that phlebotomy had posed a burden to their overall quality of life, including anxiety, from having to manage their hematocrits below 45%. Next slide, please. There are numerous agents, including hydroxyurea, interferon and busulfan that are used as cytoreductive agents to treat those patients with high-risk polycythemia vera or those low-risk patients that have an excessive phlebotomy requirement. Although never studied in randomized clinical trials, hydroxyurea, at least in the United States, is first-line treatment for polycythemia. Cytoreductive agents like hydroxyurea worked through progenitor cells and reduce all the white blood cell types indiscriminately, that is red cells, white cells and platelets. High-risk patients are started on phlebotomy and cytoreductive therapy, which is most often hydroxyurea, at a dose of 500 milligrams daily as first-line therapy. Recently, interferon has really also been proposed as first-line therapy by numerous investigators. This drug is a biological agent injected once every 2 to 4 weeks. The FDA received a BLA for ropeginterferon alfa-2b for PV patients in the absence of symptomatic splenomegaly. Busulfan, a drug that has been available for decades as an alkylating agent is occasionally used in elderly patients with limited life expectancy that is greater than age 70, as I previously mentioned. Next slide. Cytoreductive therapies reduce all the cells, and this can lead to adverse effects such as thrombocytopenia and the accompanying bleeding. The main side effects of hydroxyurea therapy include bone marrow suppression, low red cell and white blood cell and platelet counts, hair loss, nausea or vomiting, diarrhea, and most importantly, mucocutaneous ulcers and anorexia. These mucocutaneous ulcers are not trivial and frequently require plastic surgery. The NCCN Guidelines recommend use only in high-risk patients due to the lack of solid demonstration of thrombosis or survival agent advantage for any of these agents. Up to 20% to 25% of patients who do not respond well or are intolerant of hydroxyurea require a different form of therapy. Patients who are taking hydroxyurea and receiving 3 or more phlebotomies annually, are thought to experience poor outcomes. Interferon, this biological agent, is an effective agent, but is not without its own side effects, and this can include low-grade fever, flu-like symptoms, night sweats, long-term myelosuppression, hair loss, exacerbation of autoimmune diseases, cardiac toxicity, hypothyroidism and depression. 1/3 of patients who initiate therapy with interferon discontinues such therapy because of the onset, unfortunately, of these side effects. Next slide, please. Recently, the JAK1, JAK2 inhibitor, ruxolitinib, also known as Jakafi, has been approved for the treatment of those patients who fail frontline therapy. Ruxolitinib has proven to be a useful drug in that it inhibits JAK2 -- kinase 2 or JAK2, a nonreceptor tyrosine kinase involved in the production of red blood cells. This drug is indicated in PV patients for adults who have inadequate responses or intolerant hydroxyurea. In a Phase III trial, a significantly greater proportion of ruxolitinib patients achieved a reduction of phlebotomy recurrent in splenomegaly as compared to those patients that receive best available therapy, which included phlebotomy and/or hydroxyurea. Most often used in the sub southern advanced PV patients who have been adequately disease controlled despite treatment with high doses of hydroxyurea and splenomegaly. Clinically relevant splenomegaly is really owing a problem and a real minority of patients with polycythemia vera. Jakafi is also often used for symptomatic patients with pruritus that is associated with water exposure, night sweats, early satiety or occasionally fatigue. It is appropriate for symptomatic or persistent splenomegaly in patients resistant or refractory to either hydroxyurea or interferon alfa. Next slide. Jakafi therapy or ruxolitinib therapy is indicated only in patients who have had an inadequate response to or intolerant to hydroxyurea. The most common hematologic adverse effects in the ruxolitinib group in a Phase II trial was anemia in a large proportion of patients, 53% of patients, or thrombocytopenia, 27% of patients. The most frequent non-hematologic events in this ruxolitinib study versus best available therapy over 32 weeks were headache, diarrhea, fatigue and pruritus. Next slide. So from what I've tried to express to you today, my conclusions are that physicians and patient treatment management goals are in polycythemia vera a decreased thrombotic events by maintaining chronically and persistently hematocrits below 45%. And Dr. Verstovsek will present the evidence that PTG-300 has some promise in this area. Phlebotomy alone or in combination with the cytoreductive therapy is the most common treatment for this particular disorder. Frequent phlebotomies can often lead to iron deficiency symptoms, including cognitive impairment, debilitating fatigue, decreased physical performance and decrease muscle function. And one must remember that this is a chronic illness and that virtually all of these patients are gainfully employed or leaving active lives and these secondary symptoms can really decrease dramatically their quality of life. Up to 20% to 25% of patients do not respond well are intolerant of hydroxyurea. Jakafi can be used in a subset of patients who have an inadequate response to hydroxyurea and with patients, and these are unusual patients who have symptomatic splenomegaly. A new non-cytoreductive option may address some of the unmet needs in polycythemia vera, including the potential to consistently maintain hematocrit below 45% by specifically living erythropoietic activity while reversing iron deficiency associated with phlebotomies. And I must emphasize the most important aspect of this is that the persistent maintenance long term of hematocrits below 45% might be the most important achievement that we can observe with such a potential agent. I'd like to thank you for your time, and hopefully, you've found these comments meaningful, and we'll now move on with the remainder of the program. Thank you.

I'd like to spend a few minutes laying the foundation for Dr. Verstovsek's patient analytics presentation by describing the Symphony database and our goal when we began this review back in February of this year. The company has been working with a number of thought leaders, including Dr. Hoffman, which you just heard from, and Dr. Verstovsek, not only on the clinical development program for PTG-300, but also increasing our understanding of how PV patients are being treated. Our overarching goals are to understand the greatest challenges facing prescribers and patients, and particularly to understand how patients are being treated in a real-world context. Specifically, we wanted to look at phlebotomy and cytoreductive therapies, which has been mentioned as the predominant treatments in PV and get a sense of how prescribers are using these therapies, either alone or in combination. We just heard from Dr. Hoffman, the importance of managing hematocrit in PV patients. These data allowed us to look at this important marker in a subgroup of patients and to see how hematocrit is controlled with the most commonly used treatments. The data also allowed us to look at patients moving between therapies and identify potential triggers for these events. Finally, as mentioned, it's well-established that PV diagnosis is associated with an increased risk of thrombotic events relative to the general population. This data set allowed us to look at these risks in the large set of patients pre and post treatment. So PV is treated with, as mentioned, either phlebotomy, cytoreductive therapies or a combination of these treatments. Lab results, including measuring hematocrit levels are a critical part of managing PV. Lab results help clinicians to adjust to a patient's treatment plan with the goal of either maintaining or reaching treatment guidelines. The Symphony Health database is one of the most comprehensive sources of health care data in our industry. By using the source, we are able to link treatments for PV with blood tests, specifically hematocrit and gain a deeper understanding of the entire PV patient journey. Within the data set, we focused in on the subgroups of patients who had 2 ICD-10 diagnoses of PV and received treatment consistently for over a 2-year period. These inclusion criteria provide a patient count, as you see here, of 28,306 PV patients treated in this 2-year window. Further, in the smaller bubble you see, we were able to obtain lab results or blood test for 4,264 of these patients, so a subset of the larger group and evaluate their hematocrit test over the 2-year period -- treatment period to review how these tests results impacted treatment decisions. This provide us with a group of PV patients, we feel, representative of the current landscape. Now Dr. Verstovsek will walk you through some of the highlights of this data.

Well, hello. I'm Srdan Verstovsek from MD Anderson Cancer Center in Houston, and I'm really pleased to join today a Protagonist team in discussing new therapies and opportunities for development of new therapies in polycythemia vera patients. We have heard from Dr. Professor Hoffman on the polycythemia vera and what is the problem with these patients, what do we do about it? And where are the problems in management? We have now also heard about Symphony data. And we have opportunity here to evaluate this data from a large population of patients to assess real-world treatment patterns. This is an amazing source of the information. Similar approach to what I have done in the recent past with the Optum database and presented at the major meetings where we utilize this source of information to uncover treatment gaps. In the data that I'm going to talk about today, we base diagnosis on ICD codes, and all patients that we're going to describe were receiving therapy over the course of a 2-year period. Lab data provides insights into the hematocrit and hematocrit management which, as you know, is a key for management of polycythemia vera patients, and this will provide us information relevant to a risk assessment, risk of thrombotic events, which is the risk that we talk about in polycythemia vera tied to control of the blood cell count. So this will then allow us to determine opportunities for improvement. So let's start with these 28,000 patients that we're going to talk about that were explained earlier on as the focus growth of patients that we can analyze and learn from. So here we go with the risk stratifications of these 28,000 patients. And as expected, and this is really a reflection of what we see otherwise in a community practice when we talk about PV patients, median age is about 65 years of age, that's normal. And therefore, a majority, 2/3 are what you call a high risk for thrombosis, almost about 70% actually of the whole sample is high-risk category patients, which is based on the 2 factors; one is age of 60 or more, and the other one is either or thrombotic event. And if you analyze the group of patients on the right side of the slide, in the purple colors, which are the high-risk patients, you'll see that about 50% are based on age being a high risk, and about 15% had prior thrombotic event and older than 60, and about 5% are younger with the prior thrombotic events, exactly like you would expect. And about 30% are low-risk patients, so younger than 60 and never had a thrombotic event. So what happens with these people? What therapies do they receive over 2 years of observation period? 67% of the patients started with phlebotomy. And remember, majority of these patients should actually be treated with cytoreductive therapy because they are high-risk for thrombosis. But you see what happens in real life. 67% of the patients are treated with phlebotomy alone regardless of the risk. And as you can see on the right side, over a period of time, 77% of these patients did not change treatment over the course of 2 years. I am actually really surprised about it. But if we focus and this is the point of this particular slide, all the patients that have a high risk, and this is almost about 20,000 patients. Remember, again, they should be treated with cytoreductive therapy to eliminate the need for phlebotomy, control the thrombosis very well, that is not the case. You see about 60% of these high-risk patients, although considered high-risk patients, were still started with phlebotomy alone. And majority, 73% did not change treatment over the course of 2 years, which is really mind boggling to me. I did not expect anything of this to happen. So hematocrit as the goal of therapy is not being managed according to guidelines. We look here on a smaller group of people for which we have precise hematocrit levels over 2-year period, and we have a breakdown shown in the box on the right side of the slide to see where are those hematocrit levels. Remember, the goal is to have it below 45%, all right? Occasionally, sometimes it goes above 45%. And we know what to do about it, adjust the dose of medications or phlebotomize. But look at the results. Hematocrits, the first-line in the box, above 50%, 50%, almost half of the patients had at least 1 hematocrit test over 50% and only about 22% in the lower part of the box had all the measures below 45%. So clearly, unsatisfactory management of the problem that polycythemia vera patients have. Now let's look into much more detail. We're going to here talk about the treatment challenges with phlebotomy alone, right? So the -- some patients, as we said, are treated with phlebotomy alone. And we know that with phlebotomy, you should be able to control the risk of thrombosis by maintaining hematocrit below 45%. Now we see that the number of patients, which is in purple color on the right upper part of the slide, a number of patients require a number of phlebotomies a year, about 17% require 6 or more phlebotomies a year. That's about every other month. That's quite a bit. Among those that require so many phlebotomies in a lower part of the slide in the yellow color, the orange color, actually, we see that even in those patients that they phlebotomize so often, the control of hematocrit is not satisfactory. About 42% of this paper that requires 6 or more phlebotomies still have all the measurements of hematocrit above 45%, really actually shocking. Now let's move on to the different group. Majority of the patients are high risk, as we defined earlier on, and they should be treated with cytoreductive therapy, which is the hydroxyurea, common first-line therapy. In this particular setting, even though the patients are on hydroxyurea, and even though the therapy should be eliminating need for phlebotomy, a number of patients are on phlebotomy. And not only 1 or 2 a year. As you see in a purple color on the right upper corner, 44% of the patients require 4-or-more phlebotomies a year, even though they're on hydroxyurea. And in the lower part of the slide, we see that 19% on these people who had 4-or-more phlebotomies a year still had all their hematocrit levels above 45%, clearly unsatisfactory. Now the bottom line with control of the blood cell count and control hematocrit, elimination either with phlebotomy, with therapy is to reduce as much as you can, the thrombotic risk, meaning you should see a decrease in the risk of having a thrombotic event. And that apparently, and that is here is, not really achieved in everyday practice. What you see here is if you follow really the high-risk patients in lower part of the table, you see that of patients with prior thrombotic event, therefore, they are high risk, 40% had at least another one while on therapy over 2 years of observation period. And of the patients without the prior thrombosis, 10% had at least 1 thrombotic event during treatment over 2 years period of time. So these percentages, particularly 40% in those with history of thrombosis is highly unsatisfactory and requires us to be aware of the problem and more of the analysis of this data is required for us to fully grasp the problem. And this is just the highlights of the problem that is obvious to everybody and requires us to act. So in conclusion, despite advancements made in the field of polycythemia vera, we have made progress. There is opportunity for significant improvement. New therapies, new differentiated interventions are potentially part of better treatment solution for the future. Hematocrit is a central theme in the treatment of PV with a goal of maintaining it below 45% to reduce risk of thrombotic events. But as you see, many patients that are managed with phlebotomy alone, may have unsatisfactory control of hematocrit. And furthermore, to my dissatisfaction specifically, many patients managed with hydroxyurea to eliminate need for phlebotomy, do not achieve optimal treatment goal of hematocrit control below 45% and still require many phlebotomies. So maintaining hematocrit below 45% is the key to preventing thrombotic events. I thank you very much. And we move on to this next presenter.

Over the next few minutes, I'd like to share an overview of the PV market and explain how an analysis of the data set just presented demonstrate the clear unmet need in PV and the potential market opportunity for PTG-300. It is estimated that there are approximately 160,000 people in the U.S. living with PV. This number is growing at an average of 14,000 patients that are newly diagnosed each year. The majority of diagnosed patients are treated and monitored frequently, seeing their physician on average 6 times annually. PV is a chronic disease, and although not curable, patients can be treated for decades with a median survival of 20 years. Jakafi was approved in 2014 for PV and is the only product in the U.S. with FDA approval for this indication. PTG-300 is unique as the only non-cytoreductive agent in clinical development for the treatment of PV. PV is predominantly managed by phlebotomy, cytoreductive therapies and a combination of both, which you see represented here. This data, the Symphony data set presented here looks at the treatment for the large 28,000 patients observed over that 2-year time period and what therapies they were receiving. As you can see, most patients would begin therapy on phlebotomy and used phlebotomy, and as their disease progresses, they move to cytoreductive therapies, primarily hydroxyurea or a combination of phlebotomy plus hydroxyurea. A small population of patients will be treated with interferon, busulfan or a JAK2 inhibitor. Over the last 4 years, the PV market has continued to grow, which you see here. This slide looks at the number of unique PV patients that have entered the market since 2016. The growth has most likely come from new treatments, bringing greater overall awareness of the disease and greater awareness of the revised guidelines. Hydroxyurea is the most used cytoreductive therapy in PV. And in the small purple bars here, it shows the number of unique patients initiating treatment with hydroxyurea or HU since 2016. And while we see a slight increase, it's fairly modest, with approximately 600 additional unique patients annually. This is consistent with what we saw in the Symphony Patient Journey data. The Patient Journey data suggests a potential reluctance, either maybe by the prescriber or the patient, to add hydroxyurea or switch to hydroxyurea despite a large proportion of patients not being managed to guidelines. We see this at Protagonist as a signal of a treatment gap and an unmet need. As I mentioned, Jakafi is the only FDA-approved treatment for PV. And Jakafi was approved in 2011 for the treatment of myelofibrosis initially, and then 3 years later, it was approved for PV. I'd like to highlight that the sales growth in PV outpaces that of myelofibrosis, despite the fact that the product is only indicated for use in a fairly small patient subset. Jakafi, as mentioned by Dr. Hoffman, is indicated for those patients who have failed or become intolerant to hydroxyurea, which is estimated to be somewhere around 20% to 25% of patients treated. Our interpretation of Jakafi sales data exemplifies that a focused effort, defined audience and engaged key stakeholders who all appreciate the unmet need in a patient population contribute to a successful commercial effort. So as we look at the treatment landscape here and overlay the findings of our own recent data, we at Protagonist see unmet needs for treatment advancements in PV across this landscape. While phlebotomy is predominant treatment in this disease, we know this treatment comes with limitations. Phlebotomy is not desirable for all patients. The MPN Landmark study showed that physicians reported that over half of their patients, about 56%, stated not wanting to continue their phlebotomy, because the frequency of visits is inconvenient. 37% of -- have a fear of needles and 34% report feeling worse after a phlebotomy. While the application of cytoreductive therapies or use of combination of cytoreductive therapy and phlebotomy is aimed at helping control of hematocrit, we know this can often be accompanied by unwanted side effects and may not always prove effective. In this slide, we are summarizing the PV market, showing you the potential positioning scenarios for PTG-300. Just as a reminder and recap, there's 100,000 people in the U.S. diagnosed and living with PV. Treatment is required in more than 90% of that population, either with phlebotomy or cytoreductive therapies. While these treatments may be effective in treating some of the patient population, the data that Dr. Verstovsek presented indicates that clearly there are treatment gaps to be filled. If we extrapolate the data set from Symphony and apply it to the broader PV population, we could estimate that there are potentially 70,000 patients not being treated to meet guidelines using the current treatment options. As our PTG-300 clinical data continues to evolve, we will identify the patients within this 70,000 segment that will best align with the potential benefits provided by our molecule. As we prepare in designing our Phase III pivotal study, we will continue to work with KOLs to understand exactly what problems 300 may solve in relation to the other available treatments, specifically phlebotomy and HU, what our strengths will be and what patients best fit out of this segment. Beyond the identification of the most appropriate patient subpopulations for PTG-300 treatment, we clearly understand that commercial success will also require compelling evidence for reimbursement. What we have presented today should give you a sense of the potential patient population that's likely to see a benefit from a treatment option like PTG-300. In the coming months, we'll continue to develop our understanding of this patient journey and the treatment landscape, while we also work towards clinical development. Now I'd like to introduce Sam Saks, our Chief Medical Officer, who's going to provide an update on the status of the ongoing study with 300 in PV. Then David Liu, our Chief Scientific Officer, will provide some background on the PTG-300 mechanism and future directions.

Thanks, Tracy, for that informative presentation about the unmet medical needs in polycythemia vera. Our Phase II proof-of-concept study is designed to continuously keep the hematocrit below 45 for all the reasons that you've heard so much about today. Of course, if we meet that goal, we would expect that phlebotomies would be reduced. In Part 1 of the study, we titrate patients to effect while monitoring patient safety. In Part 2, we have a placebo-controlled randomized withdrawal of the patients and have that part lasting for up to 12 weeks. After Part 2, they're eligible to enroll in Part 3, which is an open-label extension where they may receive the drug for up to 1 year. We demonstrated on May 7 some very important data that I want to remind you about. We were able to show in the red triangles on this slide, before 300, the infrequent and erratic process these patients go to get phlebotomized as part of their regular care. Once beginning 300, in this small sample size, we were able to see a dose-related ability to control the hematocrit continuously in these patients. Importantly, their ferritins rose. As was discussed earlier, ferritin is an important marker of iron status in the body that's used in a variety of diseases. These patients were initially treated with very low, below-normal ferritin levels. It rose into the normal range, in most cases, relatively rapidly. We are currently studying whether this rise in ferritin is associated with symptom improvements in this patient population. We also presented safety information that shows that the safety of PTG-300 is consistent with the over 50 patients with beta-thalassemia that were presented at the European Hematology meetings in June of this year. Pictured here, you see the centers that are currently participating in the study in the United States as well as those that are in the initiation phase. We have also begun to recruit ex U.S. centers as well. I want to thank all the patients and investigators who are participating in this study and helping us to do this important work. And you see the website for the study pictured on the slide. I also want to thank the entire Protagonist development team led by Dr. Gupta that's conducting the study. Of course, we've been very busy since the spring of this year when we came on to this data and presented it to the world. We have been expanding the study to 50 patients with the broad range of treatments that are available in the community, providing them on stable doses. We are -- you're going to see now in more centers in the U.S., and we've expanded that study ex U.S. And we're happy to say that we expect to complete that study by mid-2021 as we have 16 patients enrolled to date. We hope to present an update on this data at a medical meeting by the end of 2020. I also want to point out that we have obtained orphan drug status for PTG-300, one of several accelerated pathways available to us with this drug. Importantly, we are working with advocates and investigators to design the clinical plan that we hope to take to the FDA next year. With that, I'd like to introduce David Liu, our Chief Scientific Officer, who will tell you about the interesting mechanism of action of this mimetic of an endogenous hormone and will tell you about some advances in our hepcidin franchise. Thank you.

Thank you, Sam. It's a pleasure for me to be here to share with you some details of the mechanism of action for PTG-300, building on the clinical description of PV provided earlier by Dr. Hoffman. More importantly, I will also speak to our plans to build a franchise based on the regulation of a hepcidin pathway in the treatment of additional disease indications beyond polycythemia vera as well as progress on ongoing discovery projects. I would like to discuss the mechanism of action of 300 in the context of PV. There are several key points that cannot be overemphasized. Firstly, polycythemia vera with an uncontrolled abhorrent EPO-independent growth of red blood cells or erythrocytosis, where there is a high demand for iron as shown on the left panel. Iron recycling to meet this demand flows from macrophages in the spleen and the liver to the bloodstream under the control of ferroportin, shown here as a valve on the macrophage membrane. This exported iron is then chaperoned by the blue transferrin molecules to the marrow as a complex, where iron can then be taken up by the erythroblast or the RBC precursor cells to make hemoglobin and assist in the maturation of red blood cells. In turn, these red blood cells are then broken down by macrophages for recycling the iron from red blood cells to complete this cycle of erythropoiesis. Three, as shown in the right panel, the activity of 300 is to quickly reduce iron availability within hours by shutting off the ferroportin duct. 300 both blocks the transport of the iron as well as inducing the internalization of ferroportin away from the cell surface. This prevents ferroportin from serving as a portal for iron transport. As a result, RBC numbers are rapidly reduced within weeks, unlike the much longer time needed by the broad cytoreductive chemotherapeutics. 300 is intended to maintain an adequate consistently below the 45% level and avoid the fluctuations that are evident with frequent phlebotomies with or without accompanying broad cytoreductive chemotherapeutics such as hydroxyurea, interferon-alpha and ruxolitinib. Five and finally, frequent phlebotomy as part of its mechanism of reducing red blood cell levels leads to systemic iron deficiency, as was previously discussed by Dr. Hoffman, along with its detrimental effects on quality of life issues such as fatigue and cognitive impairment. In contrast to phlebotomy, 300 is expected to temporarily increase iron storage in natural macrophage depo sites, in the spleen primarily and then the liver secondarily. In this situation, iron is now still available throughout the body for supporting normal functions of organ systems. This was an important hypothesis first proposed by the Drs. Hoffman and Yelena Ginzburg at Mount Sinai. This unique mechanism is further highlighted by the observations that PTG-300 has been very well tolerated in clinical studies. Beyond PV, there are other indications characterized by erythrocytosis associated with a variety of other comorbidities. Because of its generalized mechanism, we believe that 300 may have similar beneficial effects in these kinds of additional indications. What will this look like? So allow me to focus your attention on 2 major categories of excessive RBC production that may or may not involve therapeutic phlebotomy. The first category is one that you're familiar with, and that is polycythemia vera, which is due to genetic mutations, which also includes polycythemia vera, where obviously there is a known JAK2 mutation; and importantly, idiopathic erythrocytosis with unknown mutations. The secondary category includes chronic obstructive pulmonary disease, cor pulmonale and others such as sinatic, congenital heart disease and arteriovenous fistula. We are currently working to better understand opportunities in this category, particularly COPD or cor pulmonale. In both settings, there can be erythrocytosis accompanied by pulmonary hypertension, driving an increased workload on the heart, leading to right heart failure. Phlebotomy may be used for reducing the high hematocrit that may be associated with hemodynamic issues. Finally, there are also ultra-rare indications, such as those associated with mutations in the oxygen sensing pathway that may be candidates for 300 development, depending on the commercial landscape. Beyond its effects on erythrocytosis, 300 may also facilitate the potential treatment of iron imbalance. For example, hereditary hemochromatosis or HH, driven by mutations in the hepcidin pathway and iron hyperabsorption. HH is the subject of our other Phase II trial with 300. An indication that exemplifies iron imbalance, not iron hyperabsorption is porphyria cutanea tarda. Our strategy is to continue to solicit KOL advice, while assessing the commercial opportunity before committing to clinical studies. Finally, I'd like to touch upon 2 other important aspects for our strategy to build the hepcidin franchise. Our peptide technology platform continues to drive the discovery of new chemical entities for intervening in the hepcidin pathway. Specifically, we are now engaged in a preclinical stage discovery project for the discovery of oral hepcidin mimetics as a complementary approach to that of the injectable PTG-300. Towards that end, we have demonstrated systemic activity in preclinical studies with a lead candidate, are optimizing based on the initial leads. And we intend to submit this data to a medical conference in 2020. We are very proud of our peptide technology platform from which PTG-300 was discovered. This has resulted in an extensive IP portfolio, highlighted here. We continue to file applications as part of the life cycle management strategy as another approach to strengthen the hepcidin franchise with an eye towards robust commercial opportunities. Thank you for your attention.

Thank you, David, and thank you, everybody. Just a quick clarification that for the current ongoing PTG-300 Phase II PV study, we expect enrollment completion and not the study completion by mid next year. We view this enrollment rate as a big, big accomplishment, especially in today's COVID era. So this concludes the formal presentations for today, and we will now move into the Q&A session of our event. Just a quick reminder that we will have the Protagonist team and our KOLs available to take the questions. Operator?

[Operator Instructions] Our first question comes from George Farmer with BMO Capital Markets.

Thanks so much for this presentation today. It was really helpful. I was wondering perhaps, Dr. Hoffman, could you comment on how you see PTG-300 being used in a real world treatment setting? Would the goal be to reduce -- ultimately reduce frequency of phlebotomies or maybe even going further and reduce dependence on cytoreductive therapy?

That's an interesting question. Thank you for that question. I think it has numerous potential utility in the PV patient community. Initially, I think that it would be very effective. I know it will be very effective in reducing the number of phlebotomies. My hope is that by maintaining chronically the patients with hematocrits lower than 45%, at least I anticipate that it will also reduce the incidence of thrombotic events, which is really one of the major causes of morbidity and mortality. We have some hints right now that it will also, to a certain extent, reduce the incidence of systemic symptoms that are associated with polycythemia vera. And at least based upon the animal model studies that were done several years ago by Dr. Rivella, who was at Cornell at the time, but also -- who's now at the Children's Hospital of Pennsylvania, there was some suggestion, at least in an animal model, that it could reduce splenomegaly. Most of the patients or the majority of the patients that we've treated so far have not had extensive splenomegaly. So we really don't have a clinical readout. I think the patients -- the drug can be useful in those patients that are being treated with phlebotomy exclusively or could be an adjunctive therapy to those patients that are being treated with hydroxyurea, interferon or ruxolitinib with a suboptimal response to those other agents.

Okay. And then one for the Protagonist team. When you -- your earlier studies with PTG-300 in thalassemia, the goal there was to elevate hematocrits. And here, you're having the opposite effect. I know we talked about this before, but how do we think about mechanistically, how do you reconcile 2 different mechanisms of action in the 2 different treatment settings?

I think that's a very fair question. And that's why our intent all along has been that we do small open-label proof-of-concept studies in multiple indications and then let the data drive us in the right direction. Having said that, I would like to have both David Liu first and then maybe Sam Saks afterwards respond to your question as well. David?

Sure. Thanks for the question, George. The issue really is that regardless of the situation that we find ourselves, whether it's thalassemia or PV, that in fact the mechanism is redistribution of iron, restoring iron homeostasis by PTG-300. In the case of thalassemia, the hypothesis was that there was actually too much iron causing oxidative stress in the bone marrow. So we would reduce that to allow the normal erythropoietic pathway to occur. In PV, it's the same thing. We are restricting iron further or maintaining it at a level that is low enough to reduce the erythropoietic pathway in the case of excessive erythrocytosis. So it's restoring iron homeostasis in both cases.

Sam, would you like to chime in?

I would just second what David said that, because it's a mimetic of an endogenous hormone, we're working through known mechanisms in the body. In this case, at least partly through ferroportin is what David is alluding to. So that being said, we're, as he says, reregulating it. And we saw in PV that we're able to control erythrocytosis. In thalassemia, we had a different intent, which was to increase the hemoglobin. But there, again, it was due -- we thought it was due through a mechanism of iron overload. The PV patient, of course, is, if anything, iron-deficient.

And once again, what I would read that, it is like the -- ultimately, the true answer comes from the actual data in these open-label studies. And George, as you know, the data we have shared so far, specifically on May 7 for PV, it's a small, but incredibly robust data set.

Our next question comes from Chris Howerton with Jefferies.

Frankly, echo George's sentiments. I thought that the session today was very informative, and I appreciate it. So I guess, maybe for -- I'm so sorry, I don't want to butcher your last name, the physician from MD Anderson, what percentage of patients out there in your either independent research or in the most recent Symphony exercise actually has splenomegaly? And maybe some indication in terms of what patients could Jakafi actually serve and what's kind of the white space there with respect to PTG-300?

Very good question. Thank you very much for such an interesting topic. Actually, the splenomegaly is certainly something that happens in polycythemia vera patients, but the question always is, is this clinically relevant. I'm not talking about just the slight enlargement, which you can find quite often if you do widespread ultrasound or CAT scan. It is about those that really clinically matter, that are big enough to cause symptoms or signs that are bothersome related to the quality of life for that patient. That particular aspect does not happen that often. In fact, I was leading the effort with ruxolitinib that you mentioned for approval in the second-line setting after hydroxyurea. And one of the issues was and the critique to studies that were done to approve ruxolitinib in a second-line setting was that there are not too many patients there with polycythemia vera that have a symptomatic and large splenomegaly. That's why that was the study. The late-stage approval was followed by another study where the spleen was not required, because again, that does not appear to be the major problem in majority of the patients. Minority in advanced setting with very high blood cell count not really the subject for PTG-300, which would have much broader, much, much broader utility in controlling the red blood cell count. Lychee is the problem in almost everybody.