Study Result

Jun 11, 2021

Good morning. My name is Sarah, and I will be your conference operator today. At this time, I would like to welcome everyone to the Protagonist Therapeutics Investor Conference Call. I would now like to turn the call over to Ms. Jamie Taylor, Protagonist's Vice President of Corporate Affairs. Thank you, Sarah, and thank you all for joining us on today's conference call to discuss the updated Phase 2 rosvertide clinical study results as presented today at the European Hematology Association 2021 Virtual Annual Congress. I am joined today by Samuel Sacks, MD Senior Clinical Advisor Ronald Hoffman, MD, Director of the Myeloproliferative Disorders Research Program at Mount Sinai Hospital and a Lead Investigator for the Phase 2 study Sunil Gupta, PhD, Chief Development Officer Tracy Woody, Executive Vice President, Commercial Strategy and Dinesh Patel, Ph. D, President and CEO. We are also joined today by Don Kalkofen, Chief Financial Officer David Liu, PhD, Chief Scientific Officer and Paula O'Connor, Senior Vice President, Clinical Development. On the call today, Sam Sachs will review the Phase 2 study design and other details. Our distinguished guest and polycythemia vera expert, Doctor. Ron Hoffman, will then review the updated Phase 2 results as presented today at EHAV. Following Ron's remarks, Sunil Gupta will provide an overview of the Phase 3 trial design and next steps. Tracey Woody will then provide a brief overview of the market opportunity and preliminary launch plans. Dinesh Patel will then provide some closing remarks and we will open the call for questions for which David Liu, Paula O'Connor and Don Kalkofen will also be available. Please note that slides on today's webcast are viewer advanced. Earlier today, we issued a press release detailing the updated Phase 2 study results in patients with polycythemidevera as presented at EHA 2021. This release as well as live and archived versions of this webcast presentation are available in the Investor and News section on our website atprotagonistinc.com. Before we begin our formal comments and for those following along in the slide presentation, please turn to Slide 3. I would like to remind you that various remarks we will make today constitute forward looking statements for purposes of federal securities laws. They include statements about our plans and expectations regarding our Resveratide program among others. Actual results may differ materially from those indicated by our forward looking statements. So we encourage you to review the Risk Factors section of our most recent periodic report filed with the SEC. Please now turn to Slide 4. And I will turn the call over to Sam Sacks. Sam? Thanks, Jamie. The ongoing Phase 2 study is shown on Slide 5 is designed to monitor the safety profile and obtain evidence of efficacy in patients requiring phlebotomies that would be at least 3 phlebotomies in the prior 6 months. The study design consists of 3 stages: a 16 week open label stage with weekly subcutaneous doses from 10 to 80 milligrams and dose escalation or reduction in maintenance therapy as necessary, which is monitored every 4 weeks. A 12 week maintenance period at doses of effective desired hematocrit levels and then a randomized blinded withdrawal stage, that's a 1 to 1 assignment between treatment and placebo for up to 12 weeks. The study also has an open label extension for up to 3 years to monitor long term safety and other effects. The primary endpoint is the control of hematocrit below 45% during the blinded randomized withdrawal period. Moving to Slide 6. I want to emphasize 3 key new learnings from the updated Phase 2 data presented this morning. First, the durability of effect is extremely impressive, especially considering the substantially higher number of patients versus what was presented at ASH last December and considering the diverse patient profiles presented across this group. It positions us well as we move into Phase III and we continue to prepare for a commercial launch. 2nd, symptom improvement as reported by patients sets Russ Vertide apart as an important new therapy for PV patients. Finally, it is important to note that this clinical data contributed to the FDA's recent decision to grant breakthrough therapy designation to Russertide in polycythemia vera, which we announced on June 3. Speaking of contributions, please turn to Slide 7. We're proud to have as part of this Phase 2 study a group of leading experts in polycythemia vera. Doctor. Ron Hoffman is 1 of the leading experts in hematology and he knows the textbook because he wrote it. With that, I'll advance to Slide 8 and introduce Doctor. Hoffman, who is a lead investigator in the Phase 2 study and 1 of the world's foremost experts in PV. In particular, Doctor. Hoffman understands the patient experience with this disease as he's been treating patients himself. We are pleased to be able to collaborate with him on this important study. Ron? Thanks for the opportunity to participate in this conference and to relay to you the exciting results that we have for this new novel treatment for patients with polycythemia vera. So on the next slide, which is Slide number 9, I'd like to introduce you to what polycythemia vera is. Polycythemia vera is a form of blood cancer, which is classified as a chronic myeloproliferative neoplasm. Holocythemaviras is characterized by increased numbers of red blood cells, which is manifested as high hematocrit and hemoglobin and frequently patients have high white blood cell count and platelet counts. Their clinical course is chronic. This disorder can last over decades and there are probably over about 100 in the United States who currently carry a diagnosis of polycythemia vera. Treatment for polycythemia vera at best is modestly successful. Its goal is totally directed toward reducing the number of thrombotic episodes, which is the major cause of morbidity and mortality of patients with polycythemia vera. In addition, in those patients who have a high risk or propensity to develop additional thrombotic episodes as judged as due to having an age over 60 and a history of a prior thrombotic agent, cytoreductive therapy can be used. And the most common agents that are used are hydroxyurea, an ancient form of chemotherapy, an oral agent, a parenteral agent, interferon, which is administered in a pegylated form, so it can be administered weekly and also a JAK2 inhibitor called JAKFI or roxolitamib. It's been shown by numerous investigators over the years that the greatest predictor of additional thrombotic episodes is having a hematocrit level greater than 45%. And this was best documented by in a paper in the New England Journal of Medicine in 2013 by Roberto Marcioli and his colleagues at in Italy, but was known for many decades prior to that. 1 of the challenges of polycythemia vera is that those patients who at diagnosis, not only at diagnosis, but with repeated phlebotomies become more and more severely iron deficient. And that iron deficiency can lead to numerous symptoms, including increasing fatigue, pica, which is a symptom where patients eat unusual substances such as starch, decreased ability to form high intellectual functions, also mouth sores, woundings of the nails and generalized feeling of poor health. We have hypothesized that this iron deficiency and the increased red blood cell production in polycythemia vera lead to suppression of hepcidin and that hepcidin suppression enhances iron ability availability for red blood cell production in polycythemia vera. Next slide, please. So on this slide, what we're trying to discuss with you is essentially the mechanism of action of this new drug that is now called Russferatide, but I'll refer to it as PDG-three hundred. So hepcidin is a naturally occurring substance in humans that's involved in regulating accessibility of iron to the body. And not only do the red cells or the erythropic is in the marrow require iron to make additional red blood cells, but virtually all of our tissues in the body have enzymes or substances that require iron. And I think that really explains some of the effects that you'll see with this drug that lead to an improvement in quality of life. So on the left panel, you can see that there's the hypothesis of why polycythemia vera and then hepcidin play a role in the manifestation of this disease. So hepcidin essentially leads to the degradation of this exporter called ferroportin. And you can see here that iron is trapped in a variety of tissues in a group of cells that lead called that are called macrophages. Those are myeloid cells. In addition, hepcidin levels increased hepcidin levels also allow greater transport of iron from the gut. So therefore, during polycythemia vera, you essentially get increased absorption of iron to feed the fuel of allowing red blood cells to be produced in excess. And essentially, you lead to the depletion of the body stores of iron that likely lead to many of the systemic symptoms that are associated with the systemic symptoms that complicate patients' lives with polycycling Nudero. Here on the right panel, you can see that Russferatide reduces erythrocytosis by essentially blocking the absorption of iron from the gut theoretically and also allowing iron to remain within tissue macrophages. And our thoughts are that this retention of iron within the cells within this various tissues throughout the body leads to a dramatic improvement in the symptoms of patients with this particular disease. On Slide number 11, the baseline characteristics of the study that was presented at EHA by my colleague, Doctor. Kremeskaya are provided. And let's just go over those characteristics. I think they're very emblematic of what would 1 would anticipate in a heterogeneous population of patients with polycythemavir. The average, we've accrued 62 patients. You can see that the mean age is 56.3 years. There was a predominance of males in this study. And if you recall, you can look at the risk assessments of these patients. And again, risk is defined as a high risk of developing additional thrombotic episodes. And again, those patients who have high risk have are older than 60 or had a prior thrombotic history and low risk people that don't meet that criteria, you can see basically it's about fifty-fifty. And also you can see the duration since PV diagnosis. You can see there's a broad diversity of time before the diagnosis, and that reflects the long term chronicity of this disease. Also, you can look at the current therapies. You can see the mainstay of therapy, which is bloodletting or phlebotomy, was present in about 46.8% of the patients. But you can see also that over half of the patients were receiving another agent. And those are the agents that I mentioned, basically hydroxyurea, a form of alpha interferon and the JAK2 inhibitor, ruxolitinibin. And some patients had so many phlebotomies that control of their disease required a use of combination agents of these agents, which is called multiple. In the next column, in the next category on the right, you can see the number of phlebotomies in the prior 6 months. And you can see that they range to 3 to over 6. And in the bottom category on the right, that's the amount of the mutation that leads to polycythemia bureaus that's called JAK2B617F. And you can see that 68% of the patients had less than 60% and 32% had greater than 60%, which is a high oatmeal burden. Let's go to the next slide, which I think really tells it all. And this is the number of therapeutic phlebotomies prior to and while the patients were receiving PTT-three hundred. Here you can see the individual patients and each dot indicates a phlebotomy. And you can see to the left, that's the 6 month period prior to administration of this agent. And you can quickly notice that there are an awful lot of dots. Then you can see the number of dots progressively decrease over time after the first dose is administered. And 1 must realize that there was some dose adjustment during that period of time. Then there was a randomization period and then this extension period, you can see that we've accrued accrual has really picked up. So the number of patients that are in this extension phase are less. But you can see, if you look at the individual patients, the number of phlebotomies dramatically decreased. And the majority of patients remain glovotomy free, allowing them to maintain their hematocrit below 45%. This is graphically represented on the figure on the right, which shows the rate of phlebotomies, shows the effect of the drug on reducing the phlebotomy numbers with an impressive p value of less than 0.0 1, which indicates that this is an extremely effective clean drug. Let's go to the next slide. This is a really important slide. It's important for a physician who takes care of patients for patients with polycythemia vera because as you can see in the left panel and also in the right panel, these are parameters of the number of red blood cells that are present in this particular patient. And just let's remember, keeping the hematocrit below 45% reduces the incidence of thrombotic episodes. And as you can see, there's chronicity to this effect. These patients taking this medication on a weekly basis are always virtually always under 45%. That's very different than what occurs now when we see patients intermittently and they come in frequently with high hematocrit levels and they probably had those high hematocrit levels for long periods of time, exposing them to a higher risk of thrombosis. In the panel on the right, you can see the red blood cell count is also maintained within a normal range. Next slide. And this is for those watching or following Slide number 14. 1 also wonders what would happen to the number of platelets in white blood cells. Obviously, platelets are the cells in the blood that predispose patients to normally clot and also white blood cells are cells that fight infection. And as you can see, the white blood cell count and platelet count essentially remained quite stable during the treatment period. Now intuitively, since platelets are important for treating patients with for causing clotting patients in normal individuals, let's say, when we cut ourselves, that's our first line of defense, 1 would think that platelet numbers might be a predictor of thrombosis. And what's been shown in numerous retrospective and prospective studies is that essentially platelet numbers don't play an important role in predicting the onset of additional thrombotic events in patients with polycythemia vera and the best means of reducing the incidence of thrombotic events, additional thrombotic events is tight control of the amatocrit, which I showed you on the last slide, is effectively achieved with the use of this drug. Can we now go to Slide number 15, which shows that PDG-three hundred normalizes iron stores. And for those, uninitiated, serum ferritin levels essentially is a blood test that reflects the amount of iron that's present in one's body. And you can see at baseline, virtually all of the patients were severely iron deficient. And you can see that with the continued administration of this compound on a weekly basis, there was a rise in serum iron stores. Now let's remember that we're limiting that we're restricting the amount of iron to be used for red blood cells, but we're trapping iron within the tissues, other tissues in the body that we anticipate is going to lead to a better performance status of these patients. And that's demonstrated on Slide 16, which shows the improvement in the MPN total symptom scores following PDG-three hundred. I think it's really this is an unexpected finding for us, and I think really, really important. And you can see the symptom score, which is given a numerical value at baseline and then by week 28. And you can see that there's a dramatic reduction in symptom scores. And let's go to the right of this figure. You can see that patients had a reduction in their sense of fatigue. And most importantly, we have many patients here at Sinai, for instance, who have high functioning jobs and because of their iron deficiency, have difficulty with concentration, you can see that many of the patients spontaneously told us that they were able to lead a more fruitful career basically due to improvement in their mental acuity. 1 of the most distressing symptoms associated with polycythemia vera is severe pruritus that's exposed to when 1 exposes oneself to water and that's called aquagenic pruritus. And iron deficiency is least been theoretically implicated in this. And we were happy to see that these patients also experienced a reduction in pruritus. So this symptom improvement in symptoms is something that we are extremely excited about and feel great happiness about. Let's go to Slide number 17. This is another way of a sense of essentially showing the improvement of symptoms. It's a global impression of change compared to prior treatment after 2 months of treatment with PDG-three hundred. Here you can see that the overwhelming majority of patients feel much improved or very much improved. And that's consistent with the prior slide, which essentially talked about the total symptom score. This is a drug. So on Slide 18, we have to look at adverse events in the ongoing subjects in this PDG-three hundred trial. This is an extremely clean drug. And when we look at it, and that's 1 of the remarkable things about this drug, you can see that of the 62 patients, only 50% of these patients had any kind of adverse event. The number of subjects with adverse events related to the administration was 48.4. And if you run down the list of adverse events, you can see the majority of them are related to injections, the local injections. There were only 2 related. And both patients, 1 patient had vomiting and continued on this drug and resolved. Another patient had a popliteal aneurysm in the leg, bled into that area of the buttock, but also has continued on that drug with no subsequent adverse events. Remarkably, there were no Grade 4 events. As I mentioned to you, injection site reactions were the most common and were associated with 28.1% of the injections. And frequently, as the patients got more facile with their ability to administer this drug, these injection site reactions resolved. There were no drug related SAEs. 1 subject dropped out due to an adverse event, was essentially thrombocytosis and no antibody drug antibody responses were noted in any of the patients. So this did not serve as an immunogen. On the next slide, I'm going to conclude the results of the study again that were presented at the meeting at EHUB and my colleague, Doctor. Kremenskaya at Mount Sinai. Again, therapeutic phlebotomies were essentially eliminated and a targeted hematocrit of less than 45% was maintained for the vast majority of patients treated with russpartide or PDG-three hundred. And to me, this is really a remarkable finding. This drug demonstrated long term control of omadocrit as well as durability of effects based on patients treated up to 18 months. So the effect is persistent. Patients could be treated without long term having to come into the clinic that would save resources. Also, patients don't have to undergo the trauma of coming into the clinic and worrying about getting a phlebotomy. And these phlebotomies are not innocuous. Many of our patients have developed phobias to these phlebotomies and also have syncable episodes. Remarkably, treatment with this drug leads to reversal of iron deficiency as evidenced by increasing serumferidin, increases in the mean corpuscular volume and mean corpuscular hemoglobin values. This drug demonstrated similar efficacy in all patients independent of their risk for developing subsequent thrombosis or even in those patients who were on interferon, ruxolitimid or hydroxyurea who continue to have increasing numbers of phlebotomies. And what that means is those people who are on those drugs, who had amatocrits over 45%, even though they were on these medications, were at an increased risk of developing an additional thrombotic event. Remarkably, patients also noted improved outcomes as assessed by the 2 scores that I discussed with you. And remarkably, patients noted major improvement in symptoms, including fatigue and concentration, consistent with improvement in iron deficiency. This drug is extremely well tolerated and the most common adverse events observed were transient injection site reactions, which we attribute really to a learning process on the part of the patients to learn how to administer this drug, which has been very well accomplished by increasing sophistication and facility of the patients. Thank you for the time to allow me to present the results from this exciting study. Thank you, Doctor. Hoffman. I'd like to turn to the next Slide 20. May I have the next slide, please, Slide 21. We are very pleased with the updated results from the Phase 2 study. I'd now like to describe our planned Phase 3 study, which we expect to commence in the early 2022. The Phase III ACE trial will be a randomized placebo controlled study, which is expected to enroll about 250 adult participants, including both high risk and low risk patients who require frequent phlebotomy treatment with or without cytoreductive treatments. The primary endpoint will be the proportion of patients achieving a response, response being defined as the absence of phlebotomy based on the hematocult control between weeks 20 through 32. There will be a durability of response for between week 32 52 weeks of this trial, after which the participants will be offered an open label treatment for evaluating long term effect and safety. Frequency of fibrotinib as well as symptom control as measured by NPN TSS, AGIC will be among the key secondary endpoints. Our Phase 2 study was conducted with a prefilled syringe liquid formulation. As we move forward with an eye to global distribution, we are switching to a solid live life form, which can be dissolved and injected by the patients. The solid LifeLife product is based on a commonly used and well established technology across injectable drug products. Finally, I would like to note that we have been working closely with the FDA to keep them apprised of our plans, secure their input on all key decisions, look forward to increased interaction now that we have secured breakthrough designation To provide more insight into our commercial preparation, launch plans, I will now turn to next slide and turn over to Tracey Moody. Thanks, Sunil. I'm pleased to offer just a brief overview this morning of our commercial readiness efforts for Russ Vertide in polycythemia vera. As you may recall, last year, we provide our assessment of the significant unmet need based on data from a large real world claims database about 28, 000 patients. And now with more certainty based on the Phase 2 data that Doctor. Hoffman just covered and regulatory guidance on the Phase 3 study that Sunil just discussed, my goal today is just to give you a snapshot of the key activities all aimed at successfully introducing resveratide to the market once FDA approved. Our strong clinical data that was just presented has provided us with the basis of building our commercial strategy today, which is early in preparation for a future FDA approval. I first want to say that we're very aware at Protagonist that market access is complex, dynamic and constantly evolving. And so given the importance of this, a strong market access strategy, we are highly focused in this area. We've kicked off our market access work by initiating our U. S. Payer discussions with major U. S. Payers and we're holding a payer advisory board this summer. It's important to remember there's only been 1 branded product approved in PB space in 7 years. So it will be critical for us to educate payers on the impact of this disease and discuss our value proposition and of course seek their feedback. We've also engaged our expert from outside the U. S. To assist us in better understanding the reimbursement landscape in Europe as well as in China and Japan. Health Economics and Outcomes Research is closely aligned with market access efforts and it's critical that we take a step today to demonstrate the economic burden of PV, define the impact of respiratory and health outcomes and demonstrate the economic and cost benefit. Doing this work early and ensuring that it's published well in advance approval is the ultimate goal here. Regarding our positioning strategy, we are heavily engaged in patient and physician research and our approach is to really understand the needs of prescribers and patients as we build the value proposition for for Tide for patients, which is ultimately what every stakeholder cares about. In terms of distribution channels, we are we've kicked off this work stream and exploring the options to best ensure patients can have access to Resveratide once approved. This work stream also includes patient support programs, again, all aimed at eliminating barriers to patient access in reimbursement. Finally, I will mention prescriber education. Physician education around TB and the unmet need will be important part of our scientific and medical affairs group over the next 2 years. And my colleagues are well on their way to getting this work stream started as well. I'll just wrap up by saying that we have a very clear vision at Protagonist and that's to become leaders in the treatment of polycythemia vera. And we're taking those steps early today to position ourselves as a leader for the future. And with that, I will turn to Dinesh for closing remarks. Thank you, Tracy. And if you can now turn to Slide number 24. Before we open the call for Q and A, I will present a brief update across our different programs and our impressive clinical pipeline. We have a significant number of catalysts all across our pipeline over the next 12 to 18 months as outlined here on Slide number 25. For rasputide in PV, we look forward to presenting further updated Phase 2 data during the second half of 20 21 at a major medical conference. Beyond polycythemiavera, rasbordide is also being evaluated in a Phase 2 proof of concept study in hereditary hemochromatosis or HH. We recently completed the 16 patient enrollment and we expect to share our findings from this 6 month clinical proof of concept study during the second half of this year. In addition, guided by the fundamental signs that rasbortide as a mimetic of the natural hormone hepcidin that can modulate excessive erythrocytosis and iron overload, we plan to announce a third indication in the second half of this year, the details of which are being finalized through extensive discussions with KOLs and investigators. Looking ahead, we also plan to advance an oral hepcidin mimetic based development candidate by the end of this year with the intent of broadening our hepcidin mimetic franchise. Moving beyond us for tag and hepcidin mimetics, let's briefly talk about the other assets in our pipeline that have been discovered through our innovative peptide technology platform. Our collaboration with Janssen has been a very fruitful partnership for more than 3 years now. We have discovered 3 assets that are now in different stages of clinical development and a major objective of this multi asset approach with the oral IL-twenty 3 receptor antagonist is to extend and strengthen the Stelara franchise and to facilitate its timely transition from injectable to oral targeted therapy in both IBD and non IBD indications. We plan to complete our current Phase 1 studies with PN235 and PN232 by the end of this year or early next year. And we also expect to provide further clarity on the progression of these assets into Phase 2 studies at that time. Last, but by no means the least, I'm very pleased to share an exciting new development and this is in the context of our fully owned oral gut restricted alpha-four beta-seven integrant blocker PN-nine 43. The enrollment in our 150 patient Phase 2 study of PN-nine 43 in ulcerative colitis is advancing at a very impressive rate. Today, as we close this presentation, I'm delighted to offer revised guidance on this study. And it is that we now anticipate the study completion and data readout in the Q2 of 2022. With that, we can now open the line for questions. Operator? Thank you. We will now begin the question and answer Our first question comes from Yasmeen Rahimi with Piper Sandler. Please go ahead. Good morning, team. Wab, Giddesh, thank you for the guidance on 943. Congrats. Great, great news. All right. I have 3 questions for you on PDG-three hundred. The first 1 would be, can you maybe comment on remaining phlebotomy free or hematocrit control below 45% within the subgroups? So if we look at low risk versus high risk back on therapies and phlebotomy greater than 6. The second question is, can you comment on how many total discontinuations you have had in the study and what the reasons were for it? And then I have a third follow-up question. Thanks, Yasmin, for the wonderful questions. I think in terms of the hematocrit control or the phlebotomies, we can make a broad stroke statement that we are extending sustained consistent hematocrit control across all patient populations. And at a practical level, it's fair to say that we are essentially eliminating phlebotomies in all subpopulations. In terms of the discontinuations, let me deflect that question to our Clinical Development Officer, Sunil Gupta. Thanks, Dinesh. So we had total 4 discontinuations so far. 3 of the discontinuation out of 4 were patient decision to discontinue because of personal reasons. 1, a patient discontinued very early on after literally being 2 weeks into their trial because had a different reaction. 1 patient had so that's the summary of the 4 discontinuation. Fair to say, it's nothing in particular that keeps us awake at night. Got it. Maybe a third question to Sunil would be, can you comment on what percentage of patients required dose titration, if any, by the end of the 28 weeks? And maybe what would be reasons for dose titrating down? So practically as the study design dictates, every patient dose titrated up because we started patients everybody at a very low dose and a 20 milligram. Majority of the patients actually stabilize around 40 to 60 milligram and some people do go down. And as you might imagine, some of the patients are also taking concomitant meds like interferon, HU and rux. And they also have their pattern of response. So sometimes you need to adjust to go up and down, but never resulted into an SAE or anemia or otherwise. So people continued on the treatment and Thank you. And I'll jump into the queue. Is Doctor. Hoffman available for questions during this call? Absolutely. Okay. I'll jump into the queue and ask questions. Okay, operator, next question. Thank you. Our next question comes from Anupam Rami with JPMorgan. Please go ahead. Hey guys. Thanks for taking the question and congrats on the update. 2 quick ones from me. 1 is what portion of the phlebotomies with Russbutide PTG-three hundred would you say were due to say dose adjustments versus say COVID related misses or otherwise? And then maybe a question for Doctor. Hoffman, the KOL on the line. Based on the totality of data presented here today, where do you see PTG-three hundred fitting into your treatment paradigm? Thanks so much guys. So in terms of the phlebotomies, I just want to point out that there was a small number of phlebotomies and the majority of them occurred early during the titration period. So remember the Phase 3 design, it's not unexpected that during titration we might have a phlebotomy here or there. But what we're really studying and what we expect is that once patients are adequately titrated that in the long term follow-up that they remain phlebotomy free and that's the endpoint in our Phase 3 study. Yes. And just to add some statistics, I think we counted this a few days ago. There were 8 patients that required phlebotomase and 6 out of the 8 were during the dose titration phase. So once again, Anupam, we believe our drug is keeping the patients at a practical level essentially phlebotomy free. And now we'll have Ron Hoffman answer to your second question. Doctor. Humphrey, can you please? Yes, sure. Can you repeat the question, please? Yes, please. Anupam, would you like to repeat the question? Yes, sure. Of course, I can repeat the question. Based on the totality of the data here today, where do you see PTG-three hundred fitting into your current I think the drug I mean, I've been in this field a long time. I think it's a game changer. Basically, this drug without any significant adverse effects essentially allows these patients to have steady control of their hematocrit long term. So it essentially frees them up, reduces their thrombotic risk and improves their quality of life. The other drugs are all associated with a variety of toxicities. This drug appears at least with the limited follow-up that we presently have to be limited only to toxicity associated with the local injection. I think the important thing really to mention here is and I didn't really mention this during the presentation because I think the follow-up is limited. Again, this is a disease that lasts for decades. But during this pursuit of this study, we really didn't see additional thrombotic episodes, except for that single patient that had the popliteal aneurysm, which is a congenital abnormality. So we didn't see patients develop strokes or heart attacks. We saw patients feel better. We saw people with smiles on their face when they didn't have smiles. And I think that's a fantastically rewarding occurrence for somebody like me who's been in this field for many decades. So I think it's a drug that's going to be used alone. And in those people that feel that it's necessary to use 1 of the other drugs, for whatever that reason, it's going to be an add on drug and be a very effective add on drug because it doesn't have any additional toxicity. So I see it as a really key member of a new armamentarium of compounds. This is the new compound that's going to be used to treat polycythemia bureaus patients. Our next question comes from Chris Howerton with Jefferies. Please go ahead. Great. Thanks so much for taking the questions and congratulations on the consistently good data here. So for the I guess a few questions from me. 1 is on the lyophilized formulation. I guess I didn't quite catch if all the bridging work was done at this point or if any additional work might need to be done in terms of comparability between the prior formulation in which you're planning on using in the Phase 3 is 1 question. And then the second question that I had was maybe just an exploration of the comment that Doctor. Hoffman made with respect to injection site reactions and something around the learning curve for patients. So I guess I just would like to understand that maybe a little bit better. And then the third question would be just maybe this is a bit early to ask something like this, but perhaps for Dinesh, what does the oral hepcidin mimetic bring you? Is it for the current kind of indications, more convenience or potentially open the borders for other opportunities as well? Thank you very much. Thank you, Chris. Much appreciated. So we will have Sunil Gupta provide some more information about our transition to the lyophilized drug. We will have Sam Sacks talk about the ISR. And then we will have David Lu, our CSO comment on the oral hepcidin mimetic. Sunil, you go ahead first. Thanks, Chris for the question. So Life Life's product or technology has been around for at least 3 or 4 decades and use predominantly stabilized unstable molecules for XYZ reasons, could be small molecules, could be proteins, could be monoclonal antibodies, all of the above. So the technology has been very stable around. So and in our case, it's relatively straightforward because as you know, we have a synthetic peptide, we make it and we do pharmacokinetic, pharmacodynamic comparison in healthy people and we compare to show similarity and FDA has very standard guidelines how to compare those things and that's what we are doing right now. Yes. So Chris to reemphasize, we have done the Phase 1 bridging studies. Sam, go ahead for the ISRs. So in terms of the ISRs, part of the learning curve is we believe that the ISRs are mediated by histamine. We've not seen any reaction generalized or become systemic. We haven't seen previous injection sites light up that sort of thing. It's really a local contiguous reaction. And again, we believe it's histaminic. The effector cells for the skin are at the border between the epidermis and the dermis. We see that by really injecting the drug straight into the more fatty areas, we get the drug below the dermis and we think we see less injection site reactions in those patients who perform that type of technique. We're obviously designing education materials and trying to make sure in the Phase 3 study people use the optimal technique. That being said, because we do believe it's histaminic related, it's being treated and prevented with over the counter antihistamines such as ZYRTEC. We have data that shows preclinically that that works and clinically it's being used in the study to good end. So we think we know what it's mediated by. It's not a generalized reaction. It doesn't take people off the study or discontinue the drug They can be treated easily or prevented with over the counter antihistamine nonciting antihistamines. I don't know if Paul O'Connor is on the phone wants to say anything about our medical affairs programs or how we'll handle ISRs in the future. Paula, you want to make a comment? Hi, good morning, everyone. So certainly, Sam has already mentioned that our primary activity as we move forward will be making sure that we develop educational materials for patients participating in our study and ultimately, when we get ready to go to the market. We're beginning to build our team here in the medical affairs department to ensure that we have wide reaching capabilities to reach investigators and patients throughout the country and eventually throughout the world. And we are working very closely with advocacy groups once again to utilize or to provide information to them that they can distribute through their channels in the future. And I'll stop there. And David, we can talk about the different utility we see for the oral peptide. Yes, absolutely. I think I mentioned in December of last year in ASH that our intent of discovering and developing an oral hepcidin would be complementary to resveratide as a sub q drug. And I think harking back to what Ron Hoffman was saying in terms of the armamentarium that is available to physicians to treat PV, I think we also think about the Phase 2 patient population of PV, but also those that might have the high hematocrits and are phlebotomy naive. We also think about hemochromatosis and what might be best available for patients that are undergoing induction therapy or under maintenance therapy. And as you'll find out later this year, when we announce our 3rd indication for hepcidinimetic, again, having the most flexibility and choices for the physician and for the patients, I think adds the most value. That makes sense. I'd say 1 thing we've seen in our studies across different diseases, including normal volunteers, is that the dosing regimens that are needed for individual diseases may vary depending on the underlying iron status and the nature of the disease. So given that the oral product might be more useful in certain situations with different dosing paradigms. I think that's a great point. And so Chris, we can envision situations where there may be very specific benefit of low daily doses of hepcidin mimetic. Thank you. Yes. Okay. Well, thanks again for all the color everybody and congratulations on the case. So you have a good day. Thanks. Our next question comes from Govind Singh with JMP. Please go ahead. Hi, thanks for taking our questions. Congrats on the data everyone. I guess I had a few questions for Doctor. Hoffman and then for the team if possible. For Doctor. Hoffman, it would be great if we could hear a little bit more about those 3 patients that were on rux and phlebotomy and what their history was and what was the effect when you added Russ Verti to those patients? And then when I look at the PV symptom improvement, it almost feels like a misnomer with the NPN scale because it seems like we're improving a lot of the iron deficiency symptoms. So I'm just trying to tease out what is actually a PD symptom versus perhaps a truly iron deficient symptom. And then I wanted to hear your thoughts on my last question is assuming beta thal is a more difficult disease to treat and to control iron levels than PV, where would you put hereditary hemochromatosis relative to those 2 diseases? And I'll ask the follow-up for the company after, if I may. Okay. Well, I'll go with the symptom question first. I think you've hit a critical point. Many of the symptoms that we have attributed to the underlying myeloproliferative disorder were indeed symptoms that were a consequence of the iron deficiency, which was associated with polycythemia vera. So it's somewhat of a misnomer as you point out that the symptoms were PV related. There are other symptoms perhaps that could be specific to the disease. But what we proved here with this trial is that many of the symptoms that the patients bitterly complain of, especially the concentration issues are relieved by this drug. So and we didn't really have anything patients call it mental fogginess, which I know is a term that is now used for those long haulers with COVID, but our patients were using this term for decades. Those patients that received other agents such as interferon, hydroxyurea or Jakafi, when the agent was added, those phlebotomy requirements were markedly reduced or totally eliminated. And you have to remember that these patients remain on a fixed dose as per protocol of those other agents. In reality, in practice, a lot of those patients probably would have been weaned off of those other drugs and maintained solely with PDG-three hundred. So it's sort of the artificial world that we live in within clinical trials where we had to keep the patients on a fixed dose. Many of the patients, for instance, request that they go off their other agents, which we're not allowed to do. And hopefully when the drug is approved, many patients will go through that kind of scenario. As it relates to the size of the market or the use with an hemochromatosis, I really don't feel that I have the knowledge base really to answer that question. So I'd really defer to 1 of the folks from the company I'd like to keep within my area of expertise. Yes. And what we can say, Govind, is if you remember in beta thal, those are the patients with the highest level of serum iron or TCEP levels and our drug was able to very nicely bring those levels down to what you would see in normal healthy individuals. And in HH, I would say it's lower than the T set and iron serum levels are lower than what you see in beta-twelve, but it is still above what you see in healthy volunteers. So that gives you some spectrum of the overload on a relative basis. Great. And anything we could learn from those 3 patients that were on rux and what the impact was in the unisexper type? Nothing in particular that comes to mind. And again, our broad stroke comment is that essentially we are keeping all these patients of phlebotomy free at a practical level. Great. And I guess the last 1 I think there's 1 this is Doctor. Hoffman. I mean, I think there's 1 thing that you really have to look at. When you look at the ruxolitimod trial for polycythemia vera, there was a reduction in phlebotomy, so many of the patients continued to receive phlebotomy. The drug was not totally effective. So this effect is very different than that was observed in ruxolitimab and that you have in the majority of the patients virtual elimination of phlebotomy. And I don't know, I mean, you'd have to do a face head to head trial, but at least based upon the experiences and we've participated in some of those trials, this drug essentially corrects that parameter. Ruxolitimib improved the parameter. It's a difference of quantity really. Our next question comes from Joseph Schwartz with SVB Leerink. Please go ahead. Thank you and congrats on all the strong results and hard work behind them. I was wondering if you can talk some more about the kinds of patients you'll be enrolling in the Phase 3. Can you provide any insight into the cutoffs for hematocrit, phlebotomy or other features? Sunil, do you want to address that? Yes. So like I said in my statement, we're enrolling all patients who have all risk groups of the patients are all concomitant meds, cytoreductive, phlebotomy combinations thereof. And the requirement we had is the same as what we have for the current Phase II study. In this 1, we have slightly looser criteria, but pretty similar. So we for the phlebotomy alone group, we are recommending 5 phlebotomies per year, which is about 3 per 6 months in the Phase II, roughly speaking. And then we go to with the cytoreductives, we go to even a little lower, about 5 phlebotomist per year with the cytoreductive. So we're broadening the group. As an inclusion criteria. Based on the Phase 2, most of the people are coming in around 4 or 5 phlebotomist independent of cytoreductives or non cytoreductives. That's our people are just coming and enrolling. So that's what we think. So Joe, I think at a practical level, it's fair to say that the enrollment criteria will have all comers like we had in Phase 2, with or without cyto that require frequent subaramase. And of course, in comparison to the Phase 2, which was open label study, here we have 1 to 1 randomization. But best case, as you know, our regulatory dialogue has been incredibly productive and favorable. If you look at the primary and secondary endpoints, it's fair to say that these are the same endpoints where we are scoring an A plus I would say, based on the results from the Phase 2 study. So we felt incredibly confident and excited about initiating this Phase 3 study. Right. Yes, that seems like a fair statement. And based on the natural history for these kinds of patients, what is the thrombotic event rate that you'd expect to see if they were treated with the same standard of care that was used in the current trial? Yes, maybe Doctor. Hoffman can comment on that. So again, it depends upon the risk of the patients. So the biggest risk factor is really prior thrombosis. So the incidence of prior thrombosis predicts that 1 is going to have additional thromboses. And it's several per 100, 000 patient years. And it's not an enormous number, but 1 would have anticipated in this patient's setting that we would have seen something and we really haven't. So it's not these are chronically treated patients. Eventually, each of these patients will probably have additional thrombotic agents, but events, but it's going to require further follow-up. I just want to point out that, it's well known and Doctor. Hough described it earlier that hematocrit control is essential to preventing thrombotic events. So obviously, thrombotic events are higher in patients who are poorly controlled. As we presented at ASH in December, we find in the real world that the vast majority of patients are not being treated to guidelines and are not adequately controlled. So you can't sort of ask the question of how many phlebotomies unless you have the counter question of how well controlled you were. Our next question comes from Tim Chiang with Northland. Please go ahead. Hi, thanks. I have just 2 questions. Dinesh, obviously, you have very good data here in more than 60 patients now. Could you just talk a little bit about how many of the 60 patients are basically at a stable dose with Russertide? How many of them have actually do they still require dose escalation even once you get into the 52 weeks and beyond with this product? Sunil, you want to comment on that? Yes. So I think if we look at beyond 28 weeks or 20 4 weeks, most of the patients are relatively stable dose. We don't change their dose that often. They don't require escalation. Sometimes they even adjust go a little down, up and down a little bit, but very infrequently. So majority of the changes, as you can see, are We We call it a stability dose and coming in when we have more data, we'll be happy to present some dose distribution and stability of data further down. So I think it's fair to say that once a sort of a stable dose range is established during this 16 week of dose range finding, after that, there is a narrow range or a stable dose at which the patient can perform well. I also want to mention and reinforce what Doctor. Hoffman said earlier that the way these patients will be monitored is different. Now they come into the office and they get their hematocrits drawn because they fear that they might have a phlebotomy and so there's all that office time and contact with the patient. Here, we envision that patients will get hematocrits checked at their local labs and the doctor will look at it and tell them whether they need a dose adjustment without all the need for the effect to the office and the interacting with the physician. I see. No, that's really helpful. And maybe just 1 follow-up question for Doctor. Hoffman. Doctor. Hoffman, you mentioned that this product could potentially be a game changer and that it might be used as a monotherapy. I mean, how comfortable do you think the physician community would feel about this product just given what you've seen with the side effect profile so far? Well, I think the side effect profile is very favorable for the drug. I think the issue that you're referring to is the question of what are the what we're basically doing is essentially treating blood counts in order to reduce the incidence of subsequent thrombosis. So there's a big conflict or there's a big I wouldn't say conflict. There's a big discussion whether normalization of the white blood cell count and normalization of the platelet count will essentially be required to further reduce the incidence of robotic episodes beyond normalization of hematocrit, which we've been able to accomplish with this drug, I think in a really remarkable way. There's a variety of studies that retrospective studies, some positive, some negative that have suggested that high white counts and high platelet counts also contribute to the thrombotic tendency. What they've never shown is that normalization of the white blood cell count or normalization of the platelet count will reduce the incidence of thrombosis. So based upon this study, at least the way I look at this disease has changed somewhat. And what I see is the cardinal player or the pivotal player in the risk of thrombosis is really a matter of crit. And the chronicity of control of the matter of that we're that we don't have to deal with peaks and valleys is really an important parameter that is going to improve outcomes in this particular patient population. So there's going to be a group of people that are going to say, oh, no, you can't use this drug because it's not going to reduce the white count or the platelet count. And that we're going to have to use hydroxyurea, we're going to have to use interferon and we're going to have to use Jakafi. At present, I don't feel that way. I really feel honestly that the inadequate is the major player. And each of those other drugs have a much inferior toxicity profile than the drug that we're discussing and that this drug offers it's safer and more effective and more and leads to greater chronicity of long term hematocrit control without those peaks and valleys, as Sam pointed out, that predisposed these patients to thrombosis. I didn't mention studies that were done in Europe by Spanish investigators, because this again remains increased incidence of thrombosis, increased numbers of phlebotomies with the institution of myelosuppressive therapy, those are patients that have increased incidence of thrombotic episodes. So this drug at least so far, and again, I would like to emphasize to you with full honesty that this is a chronic disease. We have follow-up that's limited, appears to be extremely effective in changing the natural history of thrombosis in these particular patients. We had no idea, for instance, whether it will change the natural history of evolution to myelofibrosis or evolution to what we call MPN blast phase. But again, the major cause of morbidity and mortality in this patient population is thrombosis. And in that particular instance to date, this is an extremely effective drug with minimal toxicity. I also want to point out that we expect that there could be some real patient demand for this drug. You noticed that in our Phase 2 study right near the end, we had a burst of accrual. And I believe to some extent that's associated with some of the symptom improvements that we're seeing and interest in physicians and patients in getting on this drug. I've been in this business for a long time. In fact, 1 of the first studies I ever did in the 1980s was in NMPN CML patients with alpha interferon. And in my entire career, I don't think I've ever done anything in hemonc that actually made patients feel better, where patients could perceive that they felt better and would act on It's again, it needs to be confirmed in Phase III studies, so I don't want to overstate it, but 1 cannot trivialize the importance of patients feeling better and them demanding the drug. And 1 thing I would add is like, I know you asked also asked us about the potential for monotherapy. So while our laser like focus is on wrapping up the current Phase II study and kicking off the Phase III pivotal study next year, I want to point out that we are doing additional Phase 2 studies, 1 of the study being where the criteria is patients have abnormally high hematocrit level, above 48%. And at a practical level, these are treatment naive patients. They don't want a phlebotomy, they don't like cytoreductives, that sort of a thing. And that is where essentially then at a practical level, our drug is being used as a monotherapy. We expect to share some initial findings from this study sometime this year. Our next question comes from Douglas Tsao with H. C. Wainwright. Please go ahead. Hi, good morning. Thanks for taking the question. Just in terms of the open label extension phase of the study, were patients did they need to be re titrated after the blind withdrawal, I mean, all patients? No. So typically in the Phase 2 trial, we know we give them the same dose we were giving them before the 28 week period. Okay. And so remind me, we have extended the open level extension from 1 year to 3 years now? No. Yes, that's true. Yes. So we want to be data rich and let the data do the talking. Yes. And more importantly, gives us a durability of response. Doctor. Hoffman mentioned this is a disease of decades. We will be providing data for multi years. Okay. And then also, Dinesh, I know you sort of addressed the question of sort of treating as monotherapy. Is there been any consideration of sort of looking at a design to look at patients who go on to PTG-three hundred with other agents and then have those agents withdrawn over time? Thank you. Yes. We're not ready to detail additional studies beyond the pivotal study at this point, but suffice it to say that we'll have a robust development program that Paula will be running that will include studies looking at things like hydroxyurea and ruxedoses and whether those can be decreased, looking at other aspects of the drug. So we're going to have a full development program, not just a pivotal study and a lot of the questions that you'd like to get answered for the market or would want to think about informing treaters so they know how to use the drug, those will be done in parallel. Thank you for your questions. I'll now turn the call back over to Dinesh Patel for closing remarks. Thank you. Let us go to Slide number 26. So I would like to close by extending my thanks to all those who made today's corporate update possible, including the investigators and patients participating in the respotide program. Doctor. Ron Hoffman, thank you for your support of this work and for being here today. Thanks also to our excellent, excellent employees, partners and investigators for their vital contributions to our programs and mission. Future for Protagonist is extremely bright and we look forward to providing more data reroutes and continue to share exciting announcements in the months ahead. Thank you all. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.