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

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. [Operator Instructions] Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Ms. Jami 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 II rusfertide clinical study results as presented today at the European Hematology Association 2021 Virtual Annual Congress. I am joined today by Samuel Saks, MD, Senior Clinical Adviser; Ronald Hoffman, MD, Director of the Myeloproliferative Disorders Research Program at Mount Sinai Hospital and a lead investigator for the Phase II study; Suneel Gupta, PhD, Chief Development Officer; Tracy Woody, Executive Vice President, Commercial Strategy; and Dinesh Patel, PhD, 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 Saks will review the Phase II study design and other details. Our distinguished guests and polycythemia vera expert, Dr. Ron Hoffman, will then review the updated Phase II results as presented today at EHA. Following Ron's remarks, Suneel Gupta will provide an overview of the Phase III trial design and next steps. Tracy 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 II study results in patients with polycythemia vera as presented at EHA 2021. This release, as well as live and archived versions of this webcast presentation, are available in the Investor News section on our website at www.protagonist-inc.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 rusfertide 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 Saks. Sam?

Thanks, Jami. The ongoing Phase II study, as 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 and reduction in maintenance therapy as necessary, which is monitored every 4 weeks; a 12-week maintenance period at doses that effect the desired hematocrit levels; and then a randomized, blinded withdrawal stage that's a 1:1 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 end point 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 II data presented this morning. First, the durability of effect is extremely impressive, especially considering a 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. Second, symptom improvement as reported by patients sets rusfertide 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 rusfertide 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 II study a group of leading experts in polycythemia vera. Dr. Ron Hoffman is one 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 Dr. Hoffman, who is the lead investigator in the Phase II study and one of the world's foremost experts in PV. In particular, Dr. 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 #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. Polycythemia vera is characterized by increased numbers of red blood cells, which is manifested as a 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 100,000 patients 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 have -- 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 parental agent interferon, which is administered in a pegylated form, so it could be administered weekly; and also a JAK2 inhibitor called Jakafi or ruxolitinib. 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 Marchioli and his colleagues at -- in Italy, but was known for many decades prior to that. One 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; spooning of the nails, in general, largely 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 rusfertide, but I'll refer to it as PTG-300. 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 erythroid precursors 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 hepcidin and 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 -- 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 would 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 associate -- that are associated with the systemic symptoms that complicate patients' lives with polycythemia vera. Here on the right panel, you can see that rusfertide 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 these various tissues throughout the body, leads to a dramatic improvement in the symptoms of patients with this particular disease. On Slide #11, the baseline characteristics of the study at -- that was presented at EHA by my colleague, Dr. Kremyanskaya, are provided. And let's just go over those characteristics. I think they're very emblematic of what would -- one would anticipate in a heterogeneous population of patients with polycythemia vera. 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 are people that don't meet that criteria. You can see basically, it's about 50-50. And also, you can see the duration since PV diagnosis. You can see there's a broad diversity of times 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 blood letting 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, ruxolitinib. And some patients have so many phlebotomies that controlling 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 from 3 to over 6. And in the bottom category on the right, that's the amount of the mutation that leads to polycythemia vera that's called JAK2 V617F. And you could see that 68% of the patients had less than 60% and 32% had greater than 60%, which is a high allele 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 PTG-300. 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 one might realize that there was some dose adjustments 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. Then you can see -- if you look at the individual patients, the number of phlebotomies dramatically decreased. The majority of patients remain phlebotomy-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 0.001 (sic) [ 0.0001 ], 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 this was, remember, keeping 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 #14. One also wonders what would happen to the number of platelets and 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. An as you can see, the white blood cell count and platelet count essentially remain quite stable during the treatment period. Now intuitively, since platelets are important for treating patients with -- are causing clotting agents, in normal individuals, let's say, when we cut ourselves, that's our first line of defense. One 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 hematocrit, which I showed you on the last slide, is effectively achieved with the use of this drug. Can we now go to Slide #15, which shows that PTG-300 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 stored. 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 PTG-300. 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 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. One of the most distressing symptoms associated with polycythemia vera is severe pruritus that's exposed to -- when one exposes oneself to water, and that's called aquagenic pruritus. And iron deficiency, at 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 with that. Let's go to Slide #17. This is another way of essentially showing the improvement of symptoms. It's a global impression of change as compared to prior treatment after 2 months of treatment with PTG-300. 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 talks 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 PTG-300 trial. This is an extremely clean drug. And when we look at this -- and that's one 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 grade 3 adverse events, and they were evaluated as not being related. And both patients -- one patient had vomiting and continued on the 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 -- of 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. One subject dropped out due to an adverse event, which 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 EHA by my colleague, Dr. Kremyanskaya 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 rusfertide or PTG-300, and to me, this is really a remarkable finding. This drug demonstrated long-term control of hematocrit 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. These phlebotomies are not innocuous. Many of our patients have developed phobias to these phlebotomies and also have syncopal episodes. Remarkably, treatment with this drug leads to reversal of iron deficiency, as evidenced by increasing serum ferritin; 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, ruxolitinib or hydroxyurea, who continued to have increasing numbers of phlebotomies. And what that means is those people who were on those drugs, who had hematocrit 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 to the patients. Thank you for the time to allow me to present the results from this exciting study.

Thank you, Dr. Hoffman. I'd like to turn to the next slide, 20. Can we -- may we have the next slide, please, Slide 21? We are very pleased with the updated results from the Phase II study. I now like to describe our planned Phase III study, which we expect to commence in the early 2022. The Phase III 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 end point will be the proportion of patients achieving a response, response being defined as the absence of phlebotomy based on the hematic control between weeks 20 to 32. There will be a durability of response for between week 32 and 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 phlebotomies as well as symptom control, as measured by MPN-TSS, PGI-C, will be among the key secondary end points. Our Phase II 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 lyophilized form, which can be dissolved and injected by the patients. The solid lyophilized 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. We 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 Tracy Woody.

Thanks, Suneel. I'm pleased to offer just a brief overview this morning of our commercial readiness efforts for rusfertide in polycythemia vera. As you may recall, last year, we provided our assessment of the significant unmet need based on the data from a large real-world claims database of about 28,000 patients. And now with more certainty based on the Phase II data that Dr. Hoffman just covered and regulatory guidance on the Phase III study that Suneel just discussed, my goal today is just to give you a snapshot of the key activities, all aimed at successfully introducing rusfertide 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, of 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 PV 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 firm 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 the steps today to demonstrate the economic burden of PV, define the impact of rusfertide on health outcomes and demonstrate the economic and cost benefit. Doing this work early and ensuring that it's published well in advance of 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 rusfertide 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 rusfertide once approved. This work stream also includes patient support programs, again, all aimed at eliminating barriers to patient access and reimbursement. Finally, I will mention prescriber education. Physician education around PV and the unmet need will be important part of our scientific and medical affairs group efforts 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 that leader for the future. And with that, I will turn to Dinesh for closing remarks.

Thank you, Tracy. And if we can now turn to Slide #24. Before we open the call for Q&A, I'll 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 #25. For rusfertide in PV, we look forward to presenting further updated Phase II data during the second half of 2021 at a major medical conference. Beyond polycythemia vera, rusfertide is also being evaluated in a Phase II 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 rusfertide, as a mimetic of the natural hormone hepcidin, that can modulate excess 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 for this development candidate by the end of this year with the intent of broadening our hepcidin mimetic franchise. Moving beyond rusfertide 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-23 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 I studies with PN-235 and PN-232 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 II 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-4-beta-7 integrin blocker, PN-943. The enrollment in our 150-patient Phase II study of PN-943 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 second quarter of 2022. With that, we can now open the line for questions. Operator?

[Operator Instructions] Our first question comes from Yasmeen Rahimi with Piper Sandler.

Wow, Dinesh. Thank you for the guidance on 943. Congrats. Great, great news. All right. I have 3 questions for you on PTG-300. The first one 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, Yasmeen, 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, Suneel Gupta.

Thanks, Dinesh. So we had total of 4 discontinuations so far. Three of the discontinuation out of 4 were patient decision to discontinue because of personal reasons. One patient discontinued very early on, after literally being 2 weeks into the trial, because had a different reaction. One patient had -- so that's a 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 Suneel 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, on 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 responses. So sometimes you need to just go up and down, but never resulted into an SAE or anemia or otherwise. So people continued on the treatment and...

And I'll jump into the queue. Is Dr. Hoffman available for questions during this call?

Absolutely.

Our next question comes from Anupam Rama with JPMorgan.

Congrats on the update. Two quick ones from me. One is, what portion of the phlebomoties with rusfertide PTG-300 would you say were due to, say, dose adjustments versus say COVID-related misses or otherwise? And then maybe a question for Dr. Hoffman, the KOL on the line. Based on the totality of data presented here today, where do you see PTG-300 fitting into your treatment paradigm?

Go ahead, Sam.

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 III 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 in the long-term follow-up that they remain phlebotomy-free, and that's the end point in our Phase III study.

Yes. And just to add some statistics, I think we counted this a few days ago. There were 8 patients that required phlebotomies, 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 your second question.

Dr. Hoffman. Can you please -- yes, sure.

Can you repeat the question, please?

Yes, please.

Anupam, would you like to repeat the question?

Yes. Yes. Sure. Of course, I can repeat the question. Just based on the totality of the data here today, where do you see PTG-300 fitting into your treatment paradigm?

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 as a drug that's going to be used alone. And in those people that feel that it's necessary to use one 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 vera patients.

Our next question comes from Chris Howerton with Jefferies.

Great. And congratulations on the consistently good data here. So for the -- I guess, a few questions for me. One 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 and what you're planning on using in the Phase III, is one question. And then the second question that I had was maybe just an exploration of the comment that Dr. Hoffman made with respect to injection site reactions and something around the learning curve for the patients. 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, Chris. Much appreciated. So we will have Suneel Gupta provide some more information about our transition to the lyophilized drug. We will have Sam Saks talk about the ISR. And then we will have David Liu, our CSO, comment on the oral hepcidin mimetic. Suneel, you go ahead first.

Thanks, Chris, for the question. So lyophilized product or technology has been around for at least 3 or 4 decades and used predominantly to stabilize unstable molecules for X, Y, Z reasons. Could be small molecules, could be proteins, could be monoclonal antibodies, all of the above. So the technology has been very stable and around. So -- and in our case, it's relatively straightforward because, as you know, we are -- 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 I bridging studies. Sam, go ahead, for the ISR.

Yes. 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 III 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. And it can be treated easily or prevented with over-the-counter antihistamine -- non-sedating antihistamines. I don't know if Paula O'Connor, who's 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?

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 hepcidin.

Yes, absolutely. I think I mentioned in December of last year in ASH, our intent of discovering and developing an oral hepcidin would be complementary to rusfertide as a subcu 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 II patient population PV, but also those that might have the high hematocrits and are phlebotomy-naives. 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 third indication for a hepcidin mimetic, again, having the most flexibility and choices for the physician and for the patients, I think, adds the most value.

Go ahead, Sam.

I'd say one 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 a hepcidin mimetic.

Our next question comes from Gobind Singh with JMP.

Congrats on the data, everyone. I guess I had a few questions for Dr. Hoffman and then for the team if possible. For Dr. 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 rusfertide to those patients? And then when I look at the PV symptom improvement, it almost feels like a misnomer with this MPN 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 PV symptom versus perhaps the truly iron-deficient symptom? And then I wanted to hear your thoughts -- and 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 this, if I may.

Okay. Well, I'll deal 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. They were -- 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 barely complain of, especially the concentration issues, are relieved by this drug. So -- and we didn't really have anything -- patient's goal was mental fogginess, which I know is a term that is now used for the 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 and practice, a lot of those patients probably would have been weaned off of those other drugs and maintained solely with PTG-300. 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 hemochromatosis, I really don't feel that I have the knowledge base really to answer that question. So I'd really defer to one of the folks from the company. I'd like to keep within my area of expertise.

Yes. And what we can say, Gobind, is if you remember, in beta thal, those are the patients with the highest level of serum iron or TSAT 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 TSAT and iron -- serum iron levels are lower than what you see in beta thal, but it is still above what you see in healthy volunteers. So that gives you some spectrum of the iron overload on a relative basis.

Great. And anything we could learn from those 3 patients that were on rux? And what the impact was when you added rusfertide?

Nothing in particular that comes to mind. And again, our broad-stroke comment is that, essentially, we are keeping all these patients phlebotomy-free at a practical level.

I think there's one -- this is Dr. Hoffman. I mean I think there's one thing that you really have to look at. When you look at the ruxolitinib trial for polycythemia vera, there was a reduction in phlebotomy. So many of the patients continued to receive phlebotomies. The drug was not totally effective. So this effect is very different than that what is observed in ruxolitinib, in that you have in the majority of the patients, virtual elimination of phlebotomy. And I don't -- I mean, you'd have to do a phase -- 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. Ruxolitinib improved the parameter. It's a difference of quantity, really.

Our next question comes from Joseph Schwartz with SVB Leerink.

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 III. Can you provide any insight into the cutoffs for hematocrit, phlebotomy or other features?

Suneel, do you want to address that?

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 one, 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 3 phlebotomies per year with the cytoreductive. So we're broadening the group and as inclusion criteria. And based on the Phase II, most of the people are coming at around 4 or 5 phlebotomies, independent of cytoreductives or not cytoreductives. Actual 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 II, with or without cyto that requires frequent phlebotomies. And of course, in comparison to the Phase II, which was open-label study, here we have 1:1 randomization. But the beauty is that -- and as you know, our regulatory dialogue has been incredibly productive and favorable. If you look at the primary and secondary end points, it's fair to say that these are the same end points where we are scoring an A plus, I would say, based on the results from the Phase II study. So we felt incredibly confident and excited about initiating this Phase III 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 Dr. 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 one is going to have additional thromboses. And it's several per hundred thousand patient years. And it's not an enormous number, but one 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 Dr. Hoffman 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.

So I have just 2 questions. Dinesh, obviously, you have really good data here in more than 60 patients now. Could you talk -- just talk a little bit about how many of the 60 patients are basically at a stable dose with rusfertide? 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?

Suneel, you want to comment on that?

Yes. So I think if you look at beyond 28 weeks or 24 weeks, most of the patients are on a relatively stable dose. We don't change their dose that often. They don't require escalation. Sometimes they even -- and just go a little down -- up or down a little bit, but very infrequently. So majority of the changes, as you can see, are actually happening in the first part. But after that, they're very stable. We don't adjust their doses at all. We call it a stimulated dose. And coming -- 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 Dr. 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 to 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 -- back to the office and the interaction with the physician.

I see. No, that's really helpful. And maybe just one follow-up question for Dr. Hoffman. Dr. 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 was 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 thromboses. 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 thrombotic 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 thromboses. So based upon this study, at least the way I look at this disease, has changed somewhat. And what I see is, is that the cardinal player or the pivotal player in the risk of thrombosis is really hematocrit. And the chronicity of control of hematocrit that were -- 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 hematocrit 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 predispose these patients to thrombosis. I didn't mention studies that were done in Europe by Spanish investigators because this, again, remains controversial. But there is data out there, and you can look at it in the literature, that those patients that have increased incidents of -- 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 that with all 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 have 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 notice that in our Phase II 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, one of the first studies I ever did in the 1980s was an MPN CML patients with alpha interferon. And in my entire career, I don't think I've ever done anything in hem-onc that actually made patients feel better, where patients could perceive that they felt better and would act on that. It's -- again, it needs to be confirmed in a Phase III study, so I don't want to overstate it. But one cannot trivialize the importance of patients feeling better and then demanding the drug.

And one 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 II studies. One 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 cytoreductive, that sort of a thing. And that is where essentially that, at a practical level, our drug is being used as a "monotherapy." We expect to share some initial findings from this study some time this year.

Our next question comes from Douglas Tsao with H.C. Wainwright.

Just in terms of the open-label extension phase of the study, will patients -- do they need to be retitrated after the blind withdrawal, I mean, all patients?

No. So typically, in the Phase II trial, we know -- we give them the same dose we were giving them before the 28-week period. So...

Just remind me, we have extended the open-label 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 the durability of response. Dr. Hoffman mentioned, this is a disease of decades. So 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. Has there been any consideration of sort of looking at a design to look at patients who go onto PTG-300 with other agents, and then have those agents withdrawn over time?

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 rux doses 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 we'd 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 #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 rusfertide program. Dr. 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 readouts 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.