Protagonist Therapeutics Inc

NASDAQ:PTGX

Earnings Call Transcript 2020-Q1

[Operator]

Good day and welcome to the Protagonist Therapeutics PTG-300 Development Update Call. Please note that today's conference is being recorded.

At this time, I would like to introduce Don Kalkofen, Protagonist's Chief Financial Officer. Please go ahead.

[Don Kalkofen, executive]

Thank you, operator. Good afternoon, everyone. Please note that a replay of today's call will be available at the Investors section of our website at protagonist-inc.com.

Before we begin, I'd like to remind you that today's discussion will include statements about the company's future expectations, plans and prospects that constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our quarterly and annual reports on forms 10-Q and 10-K, which are on file with the SEC. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our view should change.

With that, I will now turn the call over to Dinesh Patel, President and CEO, to provide you an update on the company's progress to date.

[Dinesh Patel, executive]

Thanks, Don. Good afternoon, everyone, and thank you all for joining us today. On today's call, we'll also hear from Samuel Saks, our Chief Medical Officer; and Dr. Ronald Hoffman, Professor of Medicine in Hematology and Medical Oncology at the Mount Sinai Hospital in New York City. Dr. Hoffman has been involved in the Phase II clinical study of PTG-300 in polycythemia vera, and he will provide a brief overview of the disease and his perspectives on PTG-300 and its potential benefits as the novel treatment for polycythemia vera or PV.

Also present for the call today are David Liu, our Chief Scientific Officer and Head of R&D; and Suneel Gupta, our Chief Development Officer. We are pleased to have all these individuals available to address questions during the Q&A session of today's call.

So let's start with Slide #3. As you are well aware, Protagonist started the year 2020 with 3 clinical assets, all of which have been discovered through the use of our peptide technology platform in 6 different clinical proof-of-concept studies. The 3 assets fall in 2 broad categories: PTG-300 for various blood disorders, most of which are rare disease; and oral GI-restricted targeted peptide PTG-200 and PN-943 for inflammatory bowel disease, or IBD. All of these assets have a multibillion-dollar potential in multiple indications.

PTG-300 peptide mimetic of the natural hormone hepcidin that serves as a master regulator of iron homeostasis storage and distribution in the body was being pursued in Phase II open-label proof-of-concept studies in beta-thalassemia, or beta-thal; polycythemia vera, or PV; hereditary hemochromatosis, or HH; and an investigator-sponsored study in myelodysplastic syndrome, or MDS. As you may recall, a major objective for 2020 was to pick our first clinical indication for PTG-300 that we can progress towards a pivotal study in 2021.

Today, we are pleased to announce initial but yet very robust clinical data from our polycythemia vera program. And the selection and prioritization of polycythemia vera as the first indication for a pivotal study with 300. This decision is based on 3 criteria: strength and consistency of the clinical data, favorable regulatory path forward and the commercial opportunity. This is our major announcement today. And while most of our discussion will be around 300 and polycythemia vera, let me also take this opportunity to talk briefly about our oral gut-restricted IBD assets, largely in the context of corporate update and cash runway.

The enrollment rate of Phase II studies of these agents, namely the oral alpha-4-beta-7 integrin antagonist PN-943 for ulcerative colitis and the oral interleukin-23 receptor antagonist PTG-200 for Crohn's disease are understandably going to be influenced by the current COVID-19 situation. Therefore, while these studies are continuing, we believe it is appropriate to remove future guidance on the timelines for top line data from these studies.

In addition to the decision to focus our efforts towards rapidly advancing 300 in polycythemia vera indication, we are continuing the ongoing proof-of-concept study of 300 in hereditary hemochromatosis as a potential second indication and are also deciding to now discontinue further development of 300 for beta-thalassemia as well as for myelodysplastic syndrome.

On the financial side, we ended the first quarter of this year with about $117 million in cash and investments. By factoring in the delay in enrollment and the associated clinical development costs, coupled with a reduction in operational needs and expenditures, we are now extending our cash runway by an additional 6 months through the middle of 2022.

Now let's go to Slide #4, and let me turn to PTG-300, a major highlight of today's call and to provide rationale for why we are pursuing polycythemia vera as our first indication. First and foremost, it's the robust and consistent clinical responses we have seen in our ongoing Phase II PV trial. Although small, the data set is very compelling and consistent. On 6 out of 6, dose compliant patients treated for up to 28 weeks with 300 are phlebotomy free as of today. These are very noteworthy results. Keeping in mind that prior to entering our study, these subjects were receiving frequent phlebotomies in the weeks leading up to enrollment. We are obviously very encouraged by these results, and the enrollment in the study continues with 8 patients enrolled to date. And we have also decided to now expand the current study from 30 patients to 50 patients.

The second factor is the regulatory path forward for the development of 300 in polycythemia vera indication. As you know, approved drugs for polycythemia vera fall into the orphan drug designation category by virtue of it being a rare disease in the U.S. and Europe. And orphan status provide certain benefits to the drug developer, including 7 years of market exclusivity upon FDA approval, prescription drug use of fee waivers and tax credits for qualified clinical trial.

The third factor besides the data and the regulatory path is the very significant commercial opportunity that lies ahead of us based on the significant unmet need that exists today for these patients. And specifically, by virtue of PTG-300 being a novel mechanism-based, first-in-class non-cytoreductive natural hormone mimetic agent. While PV is a rare disease, there are approximately 100,000 people in the U.S. living with this disease, and this number is unfortunately expected to grow as the population ages. The majority of PV patients are treated with phlebotomies, cytoreductive therapies or a combination of those treatments.

Jakafi is the only FDA-approved cytoreductive therapy in PV and despite having a limited indication in patients who have had an inadequate response to current treatment, Jakafi is expected to reach almost $2 billion in sales in 2020, and the largest percentage growth is in the PV population, 19% year-over-year based on their most recently quarterly update. PTG-300 has the potential to address a significant unmet need in this category where there is a lack of new cytoreductive agents in development. 300 offers the potential of keeping patients phlebotomy-free without causing iron deficiency.

So to summarize, we are incredibly encouraged by our preliminary but strong and consistent data and, therefore, are electing to focus our resources on expedited development of 300 for polycythemia vera.

To speak more about this, I would now like to introduce our Chief Medical Officer, Dr. Samuel Saks. Sam?

[Samuel Saks, executive]

Thanks, Dinesh. As Dinesh mentioned, we are really encouraged by the results we have seen in the ongoing Phase II study of PTG-300 in patients with polycythemia vera. Dr. Hoffman is going to walk you through the study results in detail, but I wanted to highlight why I believe this data has prompted us to focus on PV as the first indication for 300.

The majority of PV patients today are treated with phlebotomy, or phlebotomy in combination with cytoreductive therapies to control erythrocytosis and keep the hematocrit levels below 45%, as indicated in many treatment guidelines. There is a large body of evidence that shows that managing hematocrit is challenging and regardless of best available therapy, they're a substantial portion of patient segments that have poorly controlled hematocrit and therefore, a higher mortality rate compared to age match controls. The treatment paradigm of PV allows patients to enter what I call the danger zone before they get the next treatment. So even those people who are considered well-controlled have increased hematocrit leading up to their phlebotomy. Self-administered 300 may reduce doctor visits and the anxiety associated with the uncertainty of phlebotomy at that time. Phlebotomy is those of donated blood know, is associated with acute symptoms and difficulties. But the real problem in these patients is the potential for chronic symptoms related to iron deficiency in phlebotomized patients.

PTG-300 offers the possibility of putting the control of the hematocrit in the patient's hands with a weekly self-injected mimetic of an endogenous hormone mimetic. With a clear decision to focus PTG-300 development in PV, we are expanding the current study to include additional patients, and we'll be also hosting a scientific planning meeting with leaders in the field of myeloproliferative neoplasms. We will also be working with patient advocates to discuss pivotal and future studies in polycythemia vera.

I will close by saying that while further follow-up and data from additional patients will be needed to confirm the continuity of the robust clinical responses observed to date, we believe this study provides a compelling rationale to initiate planning for a pivotal program in PV. In the near term, we are expanding the current study to include additional patients as we focus on these encouraging results.

Finally, I want to express how proud I am of the entire clinical development team of Protagonist and all the Protagonist employees that helped us to get where we are today with this program.

With that, I would like to turn it over to Dr. Hoffman, who needs no introduction. He's a recognized expert in the field of myeloproliferative disorders and is Director of the Myeloproliferative Disease Program at The Icahn School of Medicine at Mount Sinai and an investigator in the 300 study. Dr. Hoffman?

[Ronald Hoffman;Mount Sinai Hospital]

Yes. Thank you very much, Sam. Thanks for the opportunity to present this really exciting data. So if we can go to Slide 7, I can educate the audience on what polycythemia vera is so they can have a better understanding of the potential for 300 and put this in context.

So as you can see here, this slide is entitled "What is Polycythemia Vera?" Well, polycythemia vera is a member of a group of chronic hematologic malignancies termed myeloproliferative neoplasms. And these neoplasms are unusual in that patients frequently live several decades. And these neoplasms occur at the level of the hematopoietic stem cell. And unlike leukemia, they are characterized by increased production of mature blood cells. In polycythemia vera, the cell that's most destructive to the patients are really the increased production of red blood cells. And that's the term erythrocytosis that you've heard previously and we'll hear subsequently.

Now the interesting thing about this disease is that there are 100,000 cases of polycythemia vera in the United States. This disease occurs across races and age groups. And the critical diagnostic warning sign is that of an elevated hematocrit, which is the hallmark of the disease. I think the importance of this drug is that although there's 100,000 cases of these patients, these patients, as I mentioned, live for several decades, so the usage of this drug would be quite prolonged over that period of time.

The disease occurs primarily in individuals who are 50 to 70 years of age. There is, however, a higher incidence in young females who present with life-threatening thrombotic events. The thrombotic events that occur in patients with polycythemia vera include strokes as well as life-threatening thrombosis of arteries or veins within the venus -- within the abdominal cavity. There's a very high incidence of acute myocardial infarction, cerebral vascular incidents and strokes. The women that we've talked about, the young women, they are particularly prone to develop thrombosis within the abdominal cavity, especially the hepatic vein, and that leads to a life-threatening condition called Budd-Chiari syndrome. In its most severe forms, it requires liver transplantation.

Over the last 15 years, there's been tremendous understanding -- new understanding of this group of myeloproliferative neoplasms. And they've been shown to be characterized by mutations in genes that are associated with myeloid blood cell production. So the myeloproliferative neoplasms are associated with 3 driver mutations: one involving JAK2, the other gene called calreticulin and the other MPL, which is a receptor for the hormone thrombopoietin. Virtually 99% of patients with polycythemia vera have a mutation in JAK2. Most commonly, it is a mutation that occurs at exon 14, which is the JAK2V617F mutation. A smaller group of patients have a mutation in exon 12, and those are referred to as exon 12 patients, and they have a similar phenotype, again, elevated hematocrits, increased thrombosis and shorter lifespan due to these thrombotic events and severe erythrocytosis.

Next slide, please. We're going to talk now about the diagnosis, symptoms and treatment of polycythemia vera, so that you can get an understanding of the role of -- the potential role of PTG-300. The diagnosis of polycythemia vera is triggered by finding an elevated hematocrit serendipitously or by a thrombotic event, and that initiates the physician looking for the diagnosis. So for instance, a patient could present within an acute myocardial infarction and be found to have hematocrit. These warning signs, then prompt, the blood tests to be performed that look for the presence of the JAK2V617F mutation or the exon 12 mutation of JAK2V617F is not present. And sometimes, a bone marrow examination is required to perform histopathologic confirmation of the diagnosis.

This disease is not only complicated by thrombotic episodes, but it's also complicated by burdensome systemic symptoms, including fatigue, headache, visual symptoms, night sweats and itchiness. And this itchiness characteristically occurs on exposure to water and has termed aquagenic pruritus. This might seem like a trivial symptom but aquagenic pruritus can be so severe that patients are unable to shower for months or can lead to such stress that occasionally, we've unfortunately had patients who have succumbed to suicide. Thrombotic events is the greatest risk to patients with polycythemia vera. These thrombotic events, as I mentioned, include heart attacks, strokes, deep vein thrombosis or pulmonary embolism or the Budd-Chiari syndrome. The cardinal feature of treatment and reduction of this thrombotic risk is to reduce the hematocrit below 45%. Again, the hematocrit is just the measure that we use of the number of red blood cells and the degree of erythrocytosis. And that assures that essentially the viscosity of the blood or the stickiness of the book is reduced, thereby reducing the incidence of thrombosis.

So normalization of the hematocrit using therapeutic phlebotomy is very common, and it is really the first treatment in newly diagnosed patients with polycythemia vera. Unfortunately, therapeutic phlebotomy leads to the removal of red blood cells, which contain iron and it leads to more severe iron deficiency contributing to many of the exacerbation, of many of the systemic symptoms that I referred to previously. And those patients that require frequent phlebotomies or at their advanced stage that is over 60 years of age or have thrombosis, a prior thrombosis, it is the recommendation of the standard of care that those patients all be treated with hydroxyurea, interferon or Jakafi. It is in this situation that 300 is especially attractive drug because it can be used to treat patients who are not requiring myelosuppressive agents or it could be a replacement for those myelosuppressive agents. Again, the site of the reductive agents are hydroxy and interferon, which are used in combination with phlebotomy, with supplemental phlebotomy, or an alternative drug is Jakafi or ruxolitinib, which is the only U.S. FDA-approved product for phlebotomy. Each of these drugs, and I can go into that in detail during the question-and-answer period are associated with significant adverse effects and have a question -- and have a questionable surrounding their tolerability. Significant evidence, as I've mentioned, shows that controlling the hematocrit below 45% is the most important factor in minimizing thrombosis, cardiovascular events and death due to thrombosis.

Please let's go to the next slide. So we're going to talk a little bit about phlebotomy, which many of you have probably experienced when you donate blood. So most patients receive phlebotomy initially. Phlebotomy is basically the removal of a unit of blood to reduce the hematocrit below 45%. So our target is to keep those patients always below 45% because it's been well demonstrated in the literature that, that reduces significantly the incidence of thrombosis. And the incidence of thrombosis has been shown to be reduced when the degree of time with an adequate of 45% is maximized. In addition, these would patients receive low-dose aspirin to paralyze their platelets and their -- or further augment this antithrombogenesis in patients with polycythemia vera. Patients who undergo phlebotomies will often report feeling tired or dizzy after the phlebotomy. And especially in the elderly, this is a major factor. Many of these patients become hypertensive, require long stays in our outpatient facility or require fluid infusions because -- or going to congestive heart failure because of their poor fluid balance. Furthermore, regular phlebotomy results in iron deficiency that makes -- the augmentation of iron deficiency that may have a debilitating -- that may have debilitating symptoms. As I mentioned, particularly severe fatigue, weakness and cognitive impairments. This cognitive impairment is a really big deal because many of the patients complain of having a fuzzy brain syndrome, and they cannot concentrate and do their jobs. In addition, some of the patients have craving for unusual substances such as ice or clay, which is termed pica. And then, unfortunately, some of the patients have a restless leg syndrome, which prevents them from going to sleep. Three or more phlebotomies in a year in those patients receiving hydroxyurea is associated with an inferior prognosis and a higher incidence of thrombotic events. So you can also think that in those -- in that situation, even in a patient who is receiving hydroxyurea, their combination therapy with 300 could eliminate those frequent phlebotomies and further improve the treatment regimen for these patients.

I think the most important part that you'll see about this drug are the real high-quality aspect of it is that we see these patients, let's say, a 3- or 4-month intervals. At that 3- or 4-month interval, we see that they have an elevated amount of hematocrit and that triggers us to do a phlebotomy. But in reality, we have no way to monitor them during the interval between their visits, and it's likely that for significant periods of time, they have an elevated hematocrit that's only detected at the time of their visit to our clinic. So as you'll see, the really cool part about PTG-300 is that there's a sustained hematocrit control, which we've really never been able to achieve with any of the other agents or but -- or with phlebotomy alone.

Let's go now on to Slide #10, which is PTG-300 and non-cytoreductive hepcidin hormone mimetic, its mechanism of action. So how does this drug really work? Well, hepcidin hormone, has been established recently in the last couple of decades, is playing a primary role in promoting the sequestration of iron and macrophages and decreasing iron availability for the production of red blood cells. So macrophages are a type of white blood cell, and they are present not only in the bone marrow, but they're also present in all other body tissues. But the macrophages in the marrow are termed nursing cells because their activity is essentially to feed iron to red blood cells in the marrow and to alter -- to allow them to produce additional red cells. This process is disregulated by the JAK2 mutation leading to erythrocytosis. So PTG-300 is believed to limit the excess production red cells in polycythemia vera by essentially allowing that iron to remain in the macrophages. Therefore, preventing its transfer into the erythroid precursors. In addition, it blocks the iron that's present in the macrophages in the tissues outside of the marrow. And therefore, we believe alleviates many of the systemic symptoms that are associated with polycythemia vera.

Let's now go on to Slide 11, which is the Phase II study design. This is a really interesting manner in which this study has been constructed. You can see there are 3 phases. Part one is the dose-finding period, which is over 28 days. And there are 2 components to that. I believe a dose -- effective dose-finding phase, where we essentially dose-escalate patients to meet the inadequate requirements. Then a 12- to 14-week period where we essentially have efficacy evaluation that is to maintain the patient's hematocrit below 45%. And then there's part 2 as a blinded withdrawal where the patients are randomized to receive either the fixed active dose or placebo dose for up to 12 weeks. And then I'm sure the patients will be happy about that, those that go on placebo, they will then allow them -- we will be allowed to put them on to an open-label extension phase up to 52 weeks where they will again be able to receive 300. If the patient's hematocrits exceed 45%, they get supplemental phlebotomies.

Let's go on to Slide #12. This is essentially the responses that we've seen in the 7 patients that have been described, that have been evaluated. The red triangles indicate the phlebotomies, and you can see a lot of them to the left of the solid line. And that's the 32 weeks prior to treatment. And you can see that each of these patients, and these were entry criteria, had at least 3 phlebotomies during that period. And then you can see this dotted line, and that's the time at which the doses -- the drug was started. And the first thing that strikes you is that there are a lot of red triangles to the left and only one red triangle to the right, and that's one of our patients who missed one dose due to the -- unfortunately, due to the pandemic. And the numbers indicate the doses that were administered over that period of time. So for instance, you can see in patient 150201, there was a dose escalation and then de-escalation, which I'll discuss on the subsequent slide. So this really -- this slide really summarizes and probably is our most important slide. And it basically shows that with the administration of this drug and careful titration that phlebotomy is almost virtually eliminated.

Next slide. Let's focus on 2 patients. One is the top patient, which is the blue line. And you can see that this patient -- this is the individual who missed the dose because of the COVID infection. And you can see that he was started at 10 milligrams, then went up to 20 milligrams. And on 20 milligrams, he had a hematocrit 47.5, he was unable to come in at that time because of the COVID infection. So we increased his dose to 40 milligrams, his hematocrit dropped, but it was still above 45. He came in, we phlebotomized him, and we've kept him now on 40 milligrams, and you would have seen on Wednesday, and he did not require a phlebotomy and his hematocrit was below 45.

If you look at the bottom patient who is in bright red, you can see that, that patient started at time 0 on 10, then was increased to 20 and then on week 7 was -- got 40 milligrams and then on week 12 got 80 milligrams. And you can see that, that led to a hematocrit dropping to 37.5. We cut our dose to 40 milligrams, and you can see that over that period of time, she has remained phlebotomy-free. We saw her on Wednesday, and she again remains below hematocrit of 45. So there's a dose adjustment that you can easily do. The drugs are being administered at home by the patients, giving them a lot of freedom and also empowering them to control their own disease.

If we go to Slide 14. This addresses how do we know that PTG-300 is really hitting its target. And what we're measuring here is serum ferritin. And if you can recall, ferritin is a molecule that reflects storage iron. And you can see these numbers in the vertical column, and if you're below 25, that indicates that one is iron-deficient. And you can see it with the administration of the drug at subsequent doses over time, the ferritin doses, the ferritin levels increased in each of these patients except the bottom line where a patient received an extremely hematocrit control with an extremely low dose of 300. So these data indicate that the drug is acting on target.

What about the adverse defense? Because this is a chronic disease, one must anticipate that patients will be treated over decades. This is a small sample set but you can see that we had no serious adverse events and the adverse events that were recorded were essentially just irritations, essentially at the injection site that slowly resolved and one of the patients had a bruise at a 10-milligram dose.

Let's go on now to Page 16, which is our summary. So just to start this off. I think phlebotomy is used -- has probably been used for almost 100 years. And for at least, since I've been in this field, which is from the 70s, there's been great debate about what is the optimal myelosuppressive agent. There's great concern about chemotherapy being used in these patients, perhaps increasing the incidence of evolution to acute myeloid leukemia. We never really anticipated that a hormone therapy might be used for this type of disease. So I think this really represents -- this trial really represents a paradigm shift and it has great importance for patients with polycythemia vera. So I think we can easily conclude that the additional data demonstrates the potential of this drug to almost entirely avoid the need for bottoming the treatment of polycythemia vera. All dose compliant patients were phlebotomy-free. Persistent control of hematocrit levels, I think that's really one of the most important issues is that the patients are -- have a sustained control of their hematocrit, which we anticipate will lead to sustained alleviation of their systemic symptoms and elimination of thrombotic episodes. And again, as I tried to indicate to you these elevated hematocrit levels are associated with significant cardiovascular events such as heart attack and stroke. This drug also offers the possibility of weekly administration without the up and down excursions inherent in phlebotomy therapy or any of the toxicities associated with phlebotomy therapy that I discussed with you.

Also, this reduction in phlebotomy may allow sufficient iron to be available systemically to avoid symptoms that we know that are related to iron deficiency. So PTG-300 has the potential as the first non-cytoreductive therapy for PV. This drug is well tolerated and has a safety profile similar with results in prior studies. So as you can see from my presentation, I'm extremely enthusiastic about this drug and its future. Thank you for your time.

[Dinesh Patel, executive]

Thank you, Dr. Hoffman. I would like to note that the results we have discussed today address the study data as of May 1, and the study continues to enroll. And our plan will be to submit to present additional data at upcoming medical meetings. So at Protagonist, we are now working on 4 clinical programs with our 3 candidates, all discovered through our technology platform.

Our priorities are: one, advancing PTG-300 in polycythemia vera as well as in hereditary hemochromatosis; two, advancing PN-943 to a Phase II study in ulcerative colitis; and three, working closely with our partner, Janssen, to continue Phase II development of PTG-200 in Crohn's disease. As a result of our ability to limit our focus with 300 to PV and HH, we have organized our efforts to extend our cash runway for an additional 6 months. We have taken steps to manage and lower our operating costs and align our resources around our current studies. As a consequence, we now have adequate financial resources to fund planned operating and capital expenditures through the middle of 2022.

Finally, we are mindful of the impact that the current coronavirus outbreak may have on our local operations and global activities. As we disclosed in our financial results released today, we are suspending guidance for PN-943 Phase II initiation and PTG-200 Phase II data, and we are actively working to minimize impact on timelines and move as quickly as conditions would permit. Our priority is maintaining the health and safety of our employees and those who are participating in our studies. We will continue to monitor changing conditions carefully and provide updates as appropriate.

With that, we would like to now open up the call for questions. Operator?

[Operator]

[Operator Instructions] Our first question comes from the line of Chris from Nomura.

[Christopher Marai, analyst]

This is Chris Marai from Nomura Instinet. Maybe the first one is for the physician on the line. Thank you so much for the overview of PV. I was curious how you look at a therapeutic like PTG-300 in terms of clinical practice on sort of an everyday basis as you see PV patients? And how do you think it may fit, assuming this profile remains consistent in sort of the treatment lines of PV, how you may see its usage, in particular relative to drugs like Jakafi?

[Ronald Hoffman;Mount Sinai Hospital]

Okay. I think that's a really terrific question. I think its use would be quite wise -- wide. I think virtually all patients with PV would be candidates for this drug. We've -- as you can see, we have treated young patients and also older patients with this drug. So it's been well tolerated. I think the advantage, again, is that, especially with young patients, those individuals, we do not want to give life-long myelosuppressive therapy or interferon or Jakafi because of unanticipated -- potential for unanticipated adverse effects. So if they have an increased phlebotomy requirement, this would be an ideal treatment for those folks because basically, it would free them up from returning to the clinic as frequently as they do and requiring repeated phlebotomies. When we risk-stratify these patients, those patients that go on the 3 treatments that I've discussed before, frequently, they still require phlebotomies, and it's been shown by European investigators, if you have additional phlebotomies during your administration of these drugs, that you are an increased risk of thrombosis. So in that setting, this drug could be an adjunctive agent that would eliminate the needs for phlebotomy.

Alternatively, and I could see this developing quite quickly, patients are frequently unwilling to take any of these agents, especially hydroxyurea and interferon because of the potential of hydroxyurea and the concern about interferon essentially having systemic symptoms, problems with individuals about immune disease and also its effect to exacerbate depression in patients. So in those individuals, I could see and even in those high-risk patients, if we can control their hematocrits with this drug, which I think we can easily do, and we've demonstrated that. That this drug would be a real competitor for any of those agents. So I think it could be essentially utilized potentially for the broad swath of patients with polycythemia vera. So I think -- and for long periods of time, that's the issue that I'd like to really emphasize to you. For instance, like young females who have Budd-Chiari syndrome, and we usually put those young females on myelosuppressive therapy and interferon for life-long periods of time, and they can live several decades. They would far prefer being on a non-chemotherapy, non-biologic agent like interferon, it would really liberate them, especially from the adverse effects.

[Christopher Marai, analyst]

Okay. That's very helpful. And then I was wondering if we could touch upon the data for a minute. Dr. Hoffman, could you elaborate on some of the effects of spleen size that you may have observed in the trial, if any? What you would hope to see there on an endpoint like that in a patient population like this?

[Ronald Hoffman;Mount Sinai Hospital]

Yes. So in this situation, what you have to understand is this is not myelofibrosis. So in reality, most patients with -- or virtually all patients -- I'll say most, the overwhelming majority of patients with patients with polycythemia that don't have symptomatic splenomegaly. So the endpoints that have been used in the past, let's say, for Jakafi for reduction of spleen size are of minimal importance. So these patients, even though some of them have high-risk disease, really didn't have -- they had minimal splenomegaly at all, only 40% of patients with polycythemia vera have splenomegaly and only for our advanced disease it's symptomatic. So the sample size is too small. In animal models, when hepcidin mimetics were given, those are polycythemia vera animal models, the administration of a different hepcidin mimetic did lead to reduction in splenomegaly but we really were not able to assess this because none of these patients really had significant splenomegaly. So we await treating patients like that to see if the data in the mice is recapitulated in humans as it relates to spleen size.

[Christopher Marai, analyst]

Very helpful.

[Operator]

Our next question comes from the line of George Farmer of BMO.

[Gobind Singh, analyst]

Hi, everyone. This is Gobind Singh on for George. Congrats on making a decision and moving forward with those 2 indications. I guess we had 2 buckets of questions. The first 2, maybe for Dinesh. I know you guys were thinking about once-weekly dosing and possibly twice-weekly dosing in beta-thal. I was wondering if maybe going forward, at least with PV, do you think you might be looking at twice-weekly dosing at all. And I was wondering since we are moving past beta-thal and MDS, if you'd be willing to comment at all as to what kind of data we're seeing in those indications? And I'll have a follow-up for Dr. Hoffman, if that's okay.

[Dinesh Patel, executive]

Yes. Gobind, thanks for the question. And I will have Sam Saks, our CMO, answer the first question.

[Samuel Saks, executive]

Sure. So with respect to the use of 300, we think that it's going to be used widely. You were asking me...

[Dinesh Patel, executive]

About the once-weekly.

[Samuel Saks, executive]

The once-weekly in beta-thal, we don't anticipate that we'll need to go to twice-weekly based on this data. The patients are having a robust response to once-weekly therapy. We can always consider that in patients who max out with respect to the effect. But at least so far, once-weekly dosing in the range that we're studying has been adequate, which is why we're confident about moving for into a pivotal study, because it looks like we're in the active range and we understand how to titrate the drug.

[Dinesh Patel, executive]

Gobind, you may recall that in the beta-thal data, the transfusion-dependent data, the TSAT levels are at 100% near saturation. So that was our toughest population that demanded high doses and twice-weekly dosing to get the TSAT levels into the normal ranges. In comparison to that, diseases like HH, and especially PV, the TSAT burden is incredibly lower, right? So we had always hypothesized that then logically, one would assume that for all these other indications, you may note lower doses and lower frequency of dosing. So all the data that you have seen today, that is once-weekly dosing. And you can see, we are oscillating anywhere between 20 to 40 milligrams over here. And sorry, Gobind, can you repeat your -- the second question for Dr. Hoffman?

[Gobind Singh, analyst]

Sure. Yes. I didn't say it, but it would be great if Dr. Hoffman. I know you mentioned that the spleen sizes is not something you guys typically look at. I believe in the protocol, you guys are looking at a PV-specific kind of symptom score. I was wondering if maybe you'd be willing to comment to how maybe the trend is looking in the patients that you've seen so far. And then I guess the second part of that question was, especially since there's a blinded phase -- that a blinded component to this trial, how are you guys using hydroxyurea or Jakafi and whether it's past history or in combination? Or what's the protocol for how people can give these other medications in addition to PTG-300?

[Ronald Hoffman;Mount Sinai Hospital]

Okay. I can speak to these questions. One is, let's take the second question, and then I'll probably ask you to repeat the first one. But in the second question, let's say, for instance, we have one patient in the protocol. And then I think this guy is emblematic. The -- many of -- this fellow is on maximal doses of hydroxyurea, if we put him on higher doses of hydroxyurea, we'd make him thrombocytopenic and put him at a risk of having a bleeding event. So what we've done with him is we've kept him on a fixed-dose of hydroxyurea and to that fixed-dose of hydroxyurea, we've added 300, and that's eliminated the phlebotomy requirement. Many of the patients who are on the clinical trial have been reluctant to go on myelosuppressive therapy. So a lot of patients are not that interested in going on myelosuppressive therapy because of the toxicities associated with myelosuppressive therapy or interferon. There's also a concern with some of the patients about Jakafi, about secondary malignancies, also increased incidents of shingles that is associated with that drug. And so that's the context that we've been administering the drug. We have not had somebody who have -- we have concurrently treated with interferon. We've only had a patient who have been treated concurrently in a small sample with hydroxyurea.

[Don Kalkofen, executive]

This is part of our goal in expanding the study is to open it up to accrue additional patients with a wide variety of approaches that are used in these patients. But it's too early for the symptom score -- just to comment on the symptom score.

[Ronald Hoffman;Mount Sinai Hospital]

Go ahead.

[Don Kalkofen, executive]

The system score is really well established. It's been used in the registration of Jakafi. It's really well accepted by the field. We're using the standard scoring system and we'll be able to report that out later when we have more data.

[Ronald Hoffman;Mount Sinai Hospital]

Yes. Let me comment on the symptom score. I mean the symptom score is of value. In the patients with polycythemia vera, we've done -- I have a large program project ramped from the NCI. We've used that symptom score, for instance, to assess the efficacy of interferon and also hydroxyurea, and it is useful, but it's not as robust as it is in myelofibrosis. Anecdotally, I can tell you that they're one of the patients in our cohort had intractable pruritus, which was eliminated by the use of this drug. And that was very satisfactory. But again, that's one anecdotal indication. The patients do experience a sense of well-being, but that's really just a global assessment. And I think to really get a good feeling of the results of the symptom score would require a much more -- a much greater group of patients being studied with that tool, quality life tool.

[Gobind Singh, analyst]

That's perfect. That's really helpful. And sorry, Dinesh, I might have missed this. Is there -- can you -- are you guys -- can you comment at all about any data that you've seen with PTG-300? And I think it was an IST with myelodysplastic syndrome.

[Don Kalkofen, executive]

So that study has been discontinued. We decided not to begin that study with a focus on PV. We've had such a strong reaction to the positive data in PV, our feeling was that we wanted to focus our efforts where we saw such great results.

[Operator]

Our next question comes from the line of Mr. Joe Schwartz.

[Don Kalkofen, executive]

Joe, we can't hear you if you're on.

[Dinesh Patel, executive]

Maybe operator, we go to the next question on the interim.

[Joseph Schwartz, analyst]

Hello?

[Dinesh Patel, executive]

Yes.

[Joseph Schwartz, analyst]

Can you hear...

[Don Kalkofen, executive]

Hello?

[Dinesh Patel, executive]

Joe, you are breaking up. There are technical difficulties. Well, why don't we...

[Operator]

We now have the line of Mr. Joe Schwartz of Leerink. We are having some technical difficulties.

[Joseph Schwartz, analyst]

Yes. Are you guys able to hear me?

[Don Kalkofen, executive]

Yes.

[Dinesh Patel, executive]

Yes.

[Joseph Schwartz, analyst]

Okay. Great. I'm not sure what happened there. So I was just wondering if you could talk at all about any of the other blood compartment components like leukocytes, reticulocytes, whether there were any notable changes there and whether you can tie any of that to the targeted mechanism of action?

[Ronald Hoffman;Mount Sinai Hospital]

Okay. If we go back to the -- go ahead.

[Samuel Saks, executive]

Go ahead, Dr. Hoffman.

[Ronald Hoffman;Mount Sinai Hospital]

Yes. I mean we have some appendix slides, which if you can go to slide -- the appendix slide starts on Slide 18. And the next slide basically, which I guess is Slide 19 is essentially the platelets and you can see that there they've been essentially steady in response to the -- in those patients receiving the drug. So the platelet count has not gone dramatically up. But I'd like to emphasize to you that although many clinicians have used platelet numbers as a trigger to treat patients with polycythemia, I think the literature well justifies that it basically -- it does not -- the platelet numbers does not correlate with the thrombotic risk. Hematocrit makes the biggest difference. So we -- if those people are sort of treating patients with polycythemia vera essentially don't go after the platelet count. And we've not had people who have had platelet counts over 1.5 million where you develop a Von Willebrand disease. So as you can see, they remain level.

If you go to the next slide, which is reticulocytes, that's not what you're interested in. You're interested in the next slide, which shows the leukocytes. And you can see that those levels have also remained steady during the treatment period. I should also emphasize to you that none of the patients that received the drug had any thrombotic episodes during the administration of the drug or any evidence of evolution of the disease to myelofibrosis or to acute leukemia. And that's -- the reason I'm mentioning that to you is because frequently, patients have elevated leukocyte counts when that occurs. So the other lineages have remained stable during the period of administration.

[Joseph Schwartz, analyst]

Great. That's helpful. And then for the company, what are the next updates we should look for from this trial? And how quickly do you think you can get a pivotal trial ongoing? And what would be design and an endpoint analysis that you'd target there look like?

[Dinesh Patel, executive]

So thanks for that question. And I will have Sam Saks elaborate on the answer to the question.

[Samuel Saks, executive]

Sure. So we're currently in the process of working with thought leaders to design pivotal studies. So we can't say much more about that until we get that design. We're going to move that forward and discuss it with FDA as soon as we finalize that. The current study is going to continue and expand. We expect the first part of it is, of course, open-label, so we'll be aware of the data as it evolves. The randomized portion will be starting. And we expect that there'll be further data updates in the last half of the year at the various medical meetings in this field that occur that people are well aware of.

[Dinesh Patel, executive]

And what I would like to add is that clearly, even in these difficult times, we are very satisfied rate of enrollment. Today, we showed you data on 7 patients. We also mentioned that now there are 8 patients that are enrolled and the data speaks for itself. So we believe the enrollment will strengthen in the coming weeks and months, and it will be our intent to share the data and share as much information as we gather from this expanded study.

[Samuel Saks, executive]

One of the things that Dr. Hoffman mentioned is these patients have to be phlebotomized. So they have to seek medical care. They can't just stay in their house and hunker down. So that's one of the things that's advantaged us is we actually give them the possibility of administering at home. So that's working in our favor. These patients can't just avoid care altogether. They run the risk of thrombotic events.

[Dinesh Patel, executive]

And then, Sam, as you mentioned during the call, obviously, the next steps are getting together with the thought leaders, with the KOLs and then collect more data and have a good dialogue with the FDA to finalize the next pivotal study.

[Operator]

[Operator Instructions] Our next question comes from the line of Douglas Tsao of HCW.

[Chris Bialas;H.C. Wainwright;Analyst, analyst]

Chris Bialas on for Doug Tsao. Congrats on the data. And I was just wondering if you guys could give a little more color about what you saw in the beta-thalassemia trial that made you decide to discontinue?

[Dinesh Patel, executive]

So all along, our guidance has been that, look, we are doing multiple open-label proof-of-concept studies with the intent of picking a winner. Today, we have picked a winner by a huge margin, and that is what we are able to share. As far as beta-thal is concerned, obviously, we got incredible safety data in 50-plus patients with 1,000-plus injections. We got excellent pharmacodynamic data, as you recall, that we shared during our last December call. And we, of course, cannot share any more information right now because we are under embargo. And -- but we will be presenting beta-thal at an upcoming medical conference in this quarter.

[Samuel Saks, executive]

But I want to incorrect your impression. This is not a matter of us reacting to thal. This is a matter of us reacting to the fact that PV is so outstanding. We really want to emphasize that, as Dinesh said, we were investing in these 4 things in parallel that are open label. We get to see the data all the time. When we saw this data, there was no question in our mind that this needed to be the focus of the company. So I just wanted to make sure you understood that we were really reacting to the positive here.

[Operator]

I'm showing no further questions at this time. I would like to turn the conference back to Dinesh.

[Dinesh Patel, executive]

Great. So in summary, we are pleased to have delivered on our promise to select an indication for the initial pivotal development of PTG-300, which was a major objective for this year. In addition, we would like to thank Protagonist shareholders, the patients who participated in our studies and the investigators who support these studies. In these difficult times, I want to specifically emphasize how thankful and proud I am of the Protagonist employees that have brought us to where we are today. Thank you all for joining us.

[Operator]

Ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.