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

Good day, and welcome to the Protagonist Therapeutics March 3 Conference Call. [Operator Instructions] As a reminder, this call is being recorded today, March 3, Monday, 2025. I will now turn the call over to Mr. Corey Davis of LifeSci Advisors. Please go ahead, sir.

Thanks, Chuck. Hello, everyone, and thanks for joining us on our call today. Joining me from Protagonist are Dr. Dinesh Patel, President and Chief Executive Officer; Dr. Arturo Molina, Chief Medical Officer; Asif Ali, Chief Financial Officer; and Dr. Samuel Saks, Clinical Development Adviser. Earlier today, Protagonist and Takeda issued a joint press release announcing that the Phase III VERIFY study of rusfertide successfully met its primary and key secondary endpoints. A copy of this press release is available on the company's website, along with a copy of the slides we'll be using for today's call. As can be seen in the first slide, please note that we will be making forward-looking statements on this call. These may include statements relating to the safety and efficacy and the therapeutic and commercial potential of our investigational product candidates as well as the benefits of our collaboration with Takeda. For further information relating to the risks and uncertainties related to our business, please see the periodic reports we have filed with the Securities and Exchange Commission. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, March 3, 2025. Protagonist undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities law. With that, I'll now turn it over to Dinesh Patel. Go ahead, Dinesh.

Thank you, Corey. Good morning, and welcome, everyone. It's a very proud moment for all of us at Protagonist today as we share the outstanding top line results from the Phase III VERIFY study of rusfertide in polycythemia vera or PV. As you know, our company is focused exclusively on the discovery and development of peptide therapeutics. This has been a slow, but steady journey for over 16 years that has resulted in a thriving R&D pipeline with 2 very promising assets in late stages of clinical development, namely icotrokinra and rusfertide. Icotrokinra or ICO, is a first-in-class IL-23 receptor antagonist with the potential for being a best-in-class oral targeted therapy for psoriasis. And it is the outcome of our partnership program with Johnson & Johnson that began in 2017. With positive Phase III results from the psoriasis study that we reported in November of last year, and there is a lot more data coming in the first half of this year, it is fair to conclude that ICO is well on its way towards NDA filing. Our second asset is rusfertide, and we are excited to focus on its clinical progress as the exclusive topic of discussion on today's conference call. Rusfertide is being evaluated as a potential therapy for polycythemia vera, and protagonist entered into a co-development and co-commercialization partnership for rusfertide with Takeda Pharmaceuticals last year, and they have indeed been wonderful partners. We are joining today on this conference call to share top line results from the Phase III VERIFY study of rusfertide in PV. So let's move to Slide #4. PV is a rare disease characterized by excessive red blood cell production. And the primary treatment goal is to keep hematocrit levels below 45%. With rusfertide, by virtue of it being a mimetic of the natural hormone hepcidin, which in turn is the master regulator of iron homeostasis in our body, we saw a unique opportunity to provide the first-ever RBC-specific treatment option to patients. To date, we have conducted numerous clinical studies with rusfertide in PV, and these are summarized on this table. We have previously reported on the positive outcome of the Phase II patient study that was centered around patients with high hematocrit levels at baseline. The positive results of the Phase II REVIVE study, which involved a blinded and randomized withdrawal phase, was published in The New England Journal of Medicine last year. And today, we are ready to share the highly positive top line results from the Phase III double-blinded placebo-controlled VERIFY study. All of these studies collectively form a robust regulatory data package for rusfertide, which also has Orphan Drug designation and Fast Track status for PV. So now moving to Slide #5. And you may have seen in the press release from earlier this morning that the VERIFY Phase III study of rusfertide in PV met its primary and all 4 key secondary endpoints centered around efficacy or clinical response and symptom improvements based on patient-reported outcomes. In addition, we are also very pleased with the safety results that were consistent with previous studies with no new safety signals. We realize that there has been some sensitivity around the incidences of cancer in the previous studies, but we have emphasized that PV is a disease that has an inherent increased risk of cancer and even more so with cytoreductive therapies in comparison to similar population without PV. We are glad to report that in this first double-blinded study, wherein we have almost equal number of patients in the treatment versus placebo arm, these are no evidence of increased risk of cancer in rusfertide-treated patients compared to placebo. Taken together, this is the best possible outcome we could have hoped for, and we are thrilled that the Phase III data have confirmed the efficacy, safety and symptom improvement trends observed in previous trials. These results, in our opinion, are truly transformative and reaffirm rusfertide's potential as a first-in-class erythrocytosis specific agent that could alter the existing treatment paradigm in PV, and that both the physicians and patients will see the value and potential utility of this agent at each step of the treatment journey. With these great results in hand, the next step is to continue to work diligently with our partners at Takeda towards regulatory filings. And now, to share the VERIFY Phase III top line results in more detail, I will turn it over to Arturo Molina, our Chief Medical Officer.

Thanks very much, Dinesh. In Slide 6, you will see a trial map. VERIFY is a global Phase III study in patients with polycythemia vera, designed to investigate whether rusfertide plus standard of care is better than standard of care alone. 293 patients with PV from 19 countries were randomized on a 1:1 basis to rusfertide or placebo at the outset with or without cytoreductive therapy. On Slide 7, you will see the inclusion criteria and trial design. The inclusion criteria for VERIFY were quite similar to the REVIVE Phase II study and required that patients be phlebotomy-dependent, which we define as having received at least 3 phlebotomies over the previous 28 weeks or 5 phlebotomies over the previous year. This requirement for frequent phlebotomy indicates that their PV and hematocrit levels are not being adequately controlled with standard of care treatment, which included stable doses of cytoreductive agents. The first 2 weeks of the study following randomization was a dose titration period, followed by the main efficacy evaluation period from week 20 to week 32. This is the 12-week period during which the primary endpoint was evaluated. After week 32, all patients transitioned to open-label treatment with rusfertide. The primary endpoint is clinical response, which I will define in more detail in the following slide. The 4 key secondary endpoints are a combination of efficacy assessments and patient-reported outcomes, also referred to as PROs. These include: one, phlebotomy rate, which is also the primary endpoint for European regulatory agencies; hematocrit control, meaning that all hematocrit levels measured during Part Ia have to be less than 45% at every time point measured; the third key secondary endpoint is a PRO that used the PROMIS Fatigue questionnaire; and the fourth key secondary endpoint is also a PRO that used the MFSAF total symptom score. Before discussing the results, it is important to highlight that all endpoints investigated in this study and the statistical analysis plan were reviewed by the FDA before we unblinded and conducted our analyses. I also want to remind you that the VERIFY study is still ongoing, and patients are continuing on Part Ib where placebo patients have been crossed over to rusfertide treatment followed by a 2-year open-label extension of the study. In Slide 8, I will now provide the results of the primary endpoint of the study, which was the proportion of patients in each arm demonstrating a clinical response. 3 criteria were required to meet the definition of clinical response. One is the absence of phlebotomy eligibility during week 20 to week 32. Phlebotomy eligibility is determined by an established algorithm based on hematocrit levels. Two, is no treatment with phlebotomy during week 20 to 32. And three, the patient must complete all 32 weeks of treatment during Part Ia of the study. The primary endpoint of the study was met, showing that 77% of rusfertide-treated patients qualified as clinical responders compared to 33% of the placebo patients, which is about a 44% difference in response rate. The p-value for this outcome was highly statistically significant at less than 0.0001. These competitive results are demonstrated on the bar graph on this slide. I would like to briefly comment on the 33% response rate in the placebo group, which is noticeably higher than the placebo response rate observed in the Phase II REVIVE study. To some extent, this is the typical shift you see from a smaller U.S.-centric Phase II study to a broader, larger Phase III global study. Based on differences in sites and geography, we would expect a more heterogeneous patient population in the Phase III VERIFY study, including patients earlier in the disease journey. The good news here is that we do not view this as a limitation, since the delta of clinical response between the treatment and placebo arms is very robust at 44%. And this might actually suggest that rusfertide is a potential early treatment option for patients with less advanced disease. Now let's move to the first key secondary endpoints on Slide 9, which is a comparison of phlebotomy rate or a mean number of phlebotomies over the entire 32-week period between rusfertide and placebo. The secondary endpoint is particularly important because it is the prespecified endpoint required for European regulatory filings. This key secondary endpoint was also met with a highly statistically significant p-value of less than 0.0001, with a mean of 0.5 versus 1.8 phlebotomies per patient in the rusfertide versus placebo arm during the entire 32-week period. Additionally, although not a formal endpoint, we were particularly impressed to see that 73% of patients in the rusfertide arm received 0 phlebotomies over the entire 32-week treatment period compared to only 22% in the placebo arm. This demonstrates that rusfertide can be quickly titrated to an effective dose that can control hematocrit less than 45% and obviates the need for a phlebotomy. This rapid onset of action has also been observed in our [indiscernible] rusfertide studies in healthy volunteers in patients with PV. We will now move to Slide 10. Having met the primary endpoint for the U.S. FDA and the primary endpoint for the European regulatory agencies, we were thrilled to see that the other 3 prespecified secondary endpoints were achieved with statistical significance as well. These additional key secondary endpoints include: hematocrit control, or the proportion of patients with a hematocrit below 45% during week 0 to week 32; patient reported outcomes measuring mean change from baseline to week 32 using the PROMIS Fatigue questionnaire that measures patient-reported symptoms of fatigue and their impact on how a patient feels and functions; and the myelofibrosis symptom assessment score, also known as MFSAF. The MFSAF's a questionnaire that measures patient reporting of 7 key symptoms related to myelofibrosis, many of which are common among PV patients. The symptoms assessed by the MFSAF include itching, fatigue, night sweats and pain, among others. It's important to note that our selection of these PRO questionnaires and our overall PRO strategy was discussed and vetted with the FDA. We could not be happier that we have met every single one of the 4 key secondary endpoints. We will move on to Slide 11, the safety slide. On the safety side, we are extremely pleased with the overall profile observed in this study. Rusfertide was generally well tolerated in the Phase III VERIFY trial, and safety was in line with what has been reported in other rusfertide clinical studies. The majority of rusfertide-related adverse events were grade 1 or 2 injection site reactions. No new safety findings were observed in this study. No serious adverse events, or SAEs, were attributed to rusfertide. But most importantly, there was no evidence of increased risk of cancer in rusfertide-treated patients compared to those on placebo. Stay tuned as we have made important observations during the baseline dermatologic screening of patients before they were randomized. And we look forward to discussing this in the future. I will now move on to Slide 12, my concluding slide. So in conclusion, VERIFY is a positive study that met statistical significance on its primary endpoint and all 4 key secondary endpoints. In phlebotomy-dependent PV patients receiving standard of care treatment, the addition of rusfertide reduced the mean number of phlebotomies, improved hematocrit control and improved symptoms compared to placebo. We believe rusfertide is the first therapeutic to prospectively demonstrate a statistically significant improvement in PROs in patients with polycythemia vera. Moreover, rusfertide had a safety and tolerability profile consistent with prior studies and that were no new safety signals. Overall, we believe this is the best possible outcome for the Phase III VERIFY trial. We are very pleased that rusfertide continues to produce data supporting its first-in-class nature and its potential to fulfill unmet needs for patients with PV, who are already received standard of care treatment and yet not achieving adequate hematocrit control. Finally, we are enthusiastically looking forward to sharing the full data set for presentation at upcoming medical conferences this year. So stay tuned. These are very exciting results. With that, I will turn it back to Dinesh.

Thank you, Arturo. So we can go to Slide 13, right? Today's positive Phase III results marked a critical inflection point in Protagonist's decade-long journey in the hepcidin program, further validating our platform and expertise in discovering and developing highly differentiated peptide-based medicines to address unmet medical needs. It is not that common in our biotech and pharmaceutical sector to see a new chemical entity discovered in a de novo fashion progress successfully through all the hurdles of discovery and development over the course of a decade and end up with a highly successful Phase III clinical study outcome. And for that, I would like to congratulate and sincerely thank our extremely talented and dedicated pool of employees, advisers and consultants, our pharmaceutical partner and all the patients, investigators, nurses and caregivers involved in all of our PV trials for their continued support. We look forward to working together with our co-development and co-commercialization partner, Takeda, on the next step for regulatory submissions. I should also note that this positive study results qualify us for a $25 million milestone payment from our partner. And now finally, let me conclude by saying that what excites all of us the most, and I'm speaking on behalf of the entire Protagonist team, is the rare opportunity to potentially offer rusfertide as a highly selective and transformative medicine to many patients whose medical needs remain unaddressed today with current treatment choices. And with that, I will now ask the operator to begin our Q&A session.

[Operator Instructions] And the first question will come from Brian Cheng with JPMorgan.

Congrats on the data. Maybe just first, can you give us a sense of the background characteristics of these patients, specifically around the background therapy at entry? I recall that there is a certification based on the type of cytoreductive therapy. Was there any difference in the response based on the type of cytoreductive therapy background? And I have a follow-up.

Sure. Brian, thanks for the question. As much as possible, we have tried to imitate what we had in the Phase II study in terms of the inclusion criteria. Of course, as Arturo mentioned, now there is more heterogeneity because this is a global study, those sort of things. But all in all, we have stayed close to what was in the Phase II study. So there is a mix of patients that are on phlebotomy-alone versus those on cytoreductive and with this amazing p-value you are saying. And of course, we are saving all these details for presentation at medical conferences. It's fair to say that the data emerges as positive, whichever where you slice it.

Okay. Maybe just one quick follow-up. I guess just going back to thinking about the marketplace for rusfertide in the future. How does this result fit into the peak sales guidance that you and your partner have talked about? And if you can talk about just the market opportunity, that will be very helpful?

Yes. Again, so we and our partner, we have some work cut out for us and, of course, these results are extremely positive. But will work together with Takeda and see what implications it may have and how we may want to share it in terms of the potential market share. I can almost guarantee you that certainly, there will be no downward guidance or revision. That is for sure.

The next question will come from Roger Song with Jefferies.

And my congratulations for these transformational results for PV patients. I have two questions here. One is maybe just give us a reminder for this Phase III complete -- for the clinical response endpoint? How many of those patients actually completed the whole 32-week because that's one of the criteria for the response? And then the second one is regarding the NDA filing second half, understanding you will conduct the open-label extension through 52 weeks, do we have any regulatory arch for that period for the durability in order to file for NDA?

Yes. Thanks, Roger. And before we answer your questions, we hope we met that 44% criteria for the bull case in your excellent report. With that, in terms of the clinical response for the 32-week, Arturo did you recall what the question was?

No. The question has to do with how many patients did not complete the 32 weeks. We have not shared that information yet, and we'll be presenting that at upcoming medical meetings.

But I would remind you that patients who don't complete the study count against us. So if there were a substantive number of patients who were not completing, it would have messed up the outstanding p-value that you see there.

That's a good point.

Just to clarify, I'd add to what Sam said, basically, it is a requirement for the patient to complete all 32 weeks of treatment. And if they don't, they are nonresponders.

Roger, did we answer the question?

Yes. That's my first question. And maybe just second one, in terms of the open-label extension through 52-week durability? What's the regulatory bar for the NDA filing? By the way, this is close to my bull case.

Thank you. We can end the call right now. No. So yes, it's a good question. The durability of response is an important component of the filing. But see, you can imagine we are just grasping this outstanding data, and we will work with our partner and see what are the immediate regulatory steps that could act in our favor. But Arturo, go ahead.

Yes. But to give you a sense of our track record with persistence on treatment and durability of response, please recall that about 80% of patients randomized in the REVIVE Phase II study went on to continue on treatment and subsequently, even on THRIVE. So I think we already have really good data and durability of response from the REVIVE, and we hope to corroborate that data with the VERIFY study.

We do need the 52-week data to submit the NDA, but as Arturo said, there's no particular bar, but one of the things that gives us confidence is the fact that almost 3/4 of the patients remain phlebotomy free for the entire 32 weeks. So we think that bodes well for durability. But again, we will need durability to submit the NDA.

Yes. And I was taking Roger's question from a different angle. So there are mechanisms such as rolling NDAs and things like that. So our communication with the agency will start sooner rather than later. We don't have to wait for the 52-week completion.

And we do have a Fast Track designation.

Exactly.

Great. Congrats again.

Your next question will come from Douglas Tsao with H.C. Wainwright.

Congratulations on the data. Just -- I'm just curious in terms of some of the secondary endpoints. I'm just curious if there were any particular domains, especially the focus on symptom improvement in particular, where rusfertide performed particularly well and sort of will get advancement in terms of treatment for PV patients?

Doug, good question. I think those are the kind of details we want to hang on to for presentation at medical conferences. Sam, do you want to add?

I would just say one thing is, remember, from our PV Day what we've said generally about the disease, that fatigue is the most common symptom. And our first endpoint, the PROMIS fatigue scale is aimed directly at not only do you have fatigue, but how it affects your daily life. And so inherently, you can understand that fatigue is very important in this disease.

And just to add to what Sam said, as you recall from PV Day, we also showed that compared to baseline, and then throughout the duration of participation on the REVIVE study, at every time point that we measured PROs, we saw that the benefit was sustained over a prolonged period of time. So we're also very encouraged by that, the results from REVIVE and how they have translated into positive results in VERIFY.

And I guess also, I know -- or I don't think this was a specific point to the analysis, but if you had any perspective on how quickly patients started to see improvement both on sort of the primary endpoint as well as even some of the secondary endpoints?

Yes. I think, again, we look forward to sharing details of all the wonderful observations that have been made in the conduct of this study. And while we are on this topic, as far as I can recall, this is probably the first therapeutic agent that is showing formally statistical significance in patient-reported outcomes. So -- and of course, the treatment choices are also dictated by improvements in quality of life to a major extent. So I think we have won both ways over here by exercising a 24/7-like hematocrit control, which frees up patients from the phlebotomy burden and also demonstrating it in a statistically significant way that our drug could impact the quality of life through symptom improvements in a positive way.

I'd also say that remember that the context of this call that we have just recently have blinded this data and coming to The Street as rapidly as we can after that fact. So we absolutely have a lot of data mining to do. We think it's going to be very productive given these top line results. So again, we look forward to all the details at the medical meetings, including the kind of dissection of these PROs which are very interesting to the medical community. Medical community has been looking, especially oncology community, for drugs that affect PROs like this, and there's going to be a lot of interest in that particular aspect of the study.

Next question will come from Kaveri Pohlman with Clear Street.

Congratulations on the results. I guess my first question is a follow-up on durability. After 52 weeks, do you plan to end this trial or keep patients on? What factors will be considered to keep patients on treatment after 52 weeks? And do you expect physicians to refer to the Phase II trial results to make decisions? Or just kind of like some color there, and I have one more.

Yes. This is Arturo Molina. The protocol allows for 2 additional years open-label extension and it's open to every patient who completes Part Ib. And like I mentioned before, in REVIVE, for example, about 80% of patients who were randomized went on to our THRIVE study, which gives them another 2 years of rusfertide. Patients want to stay on this medication. That's what we hear from the PIs.

Any updated thoughts on your decision for opt-in or opt out? I know you mentioned it a lot before it will be based on NPV. And now when the data is out, how convincing it is for you to stay opted in? Are there any other factors you would be taking into consideration to make your decision?

Yes. I think as you may recall, we have until the middle of next year to make this decision. So we'll be using the time between now and then wisely and working closely with our partner, and Takeda has been a wonderful partner, to arrive at the right type of win-win situation kind of decision. But of course, today's outstanding Phase III results sort of checks one of the important box and now the next steps, as you can imagine, will be to [indiscernible] that and do another set of marketing research studies, demand studies, that sort of thing to get to an accurate assessment of like what is the market potential of this drug. Before this study, and this was in one of the previous questions, right, the market potential is $1 billion to $2 billion as projected by us and our partner. Now we just have to see where we will end up. And like I said, we have up to middle of next year to make the decision.

We look forward to seeing the reaction of the medical community as we present this data in all its details in the coming months.

Your next question will come from Jon Wolleben with Citizens.

Congrats. Wondering, I think you guys are discussing a placebo response more in the 10% to 20% range. So I wonder if you'd discuss that being a little bit higher than expectations, any learnings there. And then also the difference -- the slight difference between the primary endpoint you guys present and then the European endpoint. Can you discuss a little bit why some patients who seem to have met the phlebotomy criteria didn't get phlebotomies or is there something else going on behind those charts that you guys provided this morning?

Yes. Maybe, Arturo, you should take this question. I know that you had briefly explained the slightly higher placebo rate that was observed.

Yes. So it's important to remember that the primary endpoint is assessed only for 12 weeks. And the secondary endpoint counts every phlebotomy from the time of randomization. And so it's -- first of all, this is a larger study, more heterogeneity in patient populations. It is possible that patients had a lot of phlebotomies and then the disease stabilized a little bit, and they might have been phlebotomized during week 0 to 20. But since they didn't get phlebotomized in week 20 to 32, they're not going to count as a treatment failure; it will be a response that could have happened. But I think the 2 endpoints complement each other, because the key secondary endpoint #2 shows clearly that many, many more patients on rusfertide require 0 phlebotomies compared to a much smaller number in the placebo group.

And I think the beauty over here is like the p-values are so amazingly powerful that whichever way you slice the data, it just comes out as very positive. And of course, at upcoming medical conferences, we are going to slice and dice the data in many different ways, as you can imagine, right? Phlebotomy alone versus phlebotomy and cytoreductive, low risk and high risk, whichever way you can think of it, it's like the data is standing tall.

And have you guys -- did you guys enroll a substantial number of patients who are also on ruxolitinib at baseline?

Well, again, those are the details we will share at upcoming conferences.

I would remind you that in the Phase II, we effectively got the current marketplace of that time in terms of 1/2 on phlebotomy alone, 1/3 on hydrea and such, so we're accessing as Arturo said, a broad patient group, so the Phase II is somewhat of a guidance that you -- the group -- people who need frequent phlebotomies mirror the group as a whole.

And I just want to remind you that ruxolitinib, as you know, is approved for PV patients when they're no longer having an adequate response to hydrea or they are intolerant. So those patients tend to be more advanced.

You can see that in some of our studies. Dinesh?

Yes. I mean we had a few [ up-start ] patients in Phase II. We know we have declared that.

Yes.

Yes.

The next question will come from Julian Harrison with BTIG.

This is [ Ray ] on for Julian. Just one for us. And congrats on the data. Based on the results today, where in the treatment paradigm do you expect rusfertide have the strongest use case with payers?

Yes. I think this is a drug that is working at the very more mechanistic level of the whole excessive erythrocytosis mechanism. So we truly believe that this is a treatment choice that could be -- that would find utility at all stages of the treatment paradigm. So we are the first ones to admit that in the early onset of disease, if the patient is getting by with 1 or 2 phlebotomies a year and they are okay with the phlebotomies, and they should do that or at the very extreme end of the disease, when the patients are moving towards myelofibrosis or [indiscernible] would be the treatment choice, but on an average, these patients, the journey spans for about 15, 16 years. So we would say that rusfertide should find utility at all stages of the disease progression because it kind of works at the core mechanistic level of modulating excessive RBC synthesis.

And to Dinesh's point, these patients are often suffering from profound iron deficiency because since they have the success of erythrocytosis, they're already using up their inherent iron stores, and then what we do is of course, they're required to have frequent phlebotomy. And so -- and that's an iron-dependent mechanism. So perhaps that's some of the reason we saw the PROs that we did is because we don't require the removal of iron from the body to be effective. And as a matter of fact, the serum ferritin rises in our Phase II study, which we think is a marker of iron availability for the body. So there's a clear mechanistic reason why this treatment is different than the standard of care.

Yes. I mean, the moving iron through phlebotomy, that could make the patient anemic, that could lead to some of the symptoms that they get burdened with, whereas rusfertide's job is to just redistribute iron in the body in the proper way, right? And obviously, it seems to be having a positive impact on the symptoms. Arturo, go ahead.

Yes. The other point to make is from the REVIVE study. We have shown that rusfertide can combine well with everything that's out there. So if you have patients on interferon or hydrea even ruxolitinib, if they need frequent phlebotomies and they have that iron deficiency that Sam mentioned, this would be a solution.

The next question will come from Yun Zhong with Wedbush Securities.

Congratulations on the positive data. The first question is just to follow up on what Sam just said on the iron deficiency correction. You didn't share the data, but I just wanted to confirm that, for example, all the biomarkers are moving in the same direction as Phase II. Is that correct, please?

Well, again, it's something that we will share in more detail at medical conferences that you have to appreciate the fact that data is only a few days old in our hands as well. So there is a lot of data churning and data mining that lies ahead of us. But so far, whatever we saw in Phase II seems to be being replicated in the Phase III in a very nice way.

I see. And the second question on the oral hepcidin program, I believe you guided for candidate selection in fourth quarter of 2025. Is that program part of the Takeda agreement or partnership? And how is the data going to be affecting your decision maybe out of the Takeda agreement, please?

Yes. Once again, Takeda just has been a wonderful partner, and it will be our intent to work very closely and cooperatively with them. Contractually speaking, they have the right of first negotiation, but oral hepcidin is exclusively Protagonist's internal program.

Next question will come from Richard Law with Goldman Sachs.

Congrats on the data. Couple of questions for me. How many patients were on hydroxyurea and also interferon at the same time? And then do you have a more difficult-to-treat sort of patient group in mind? And how did rusfertide perform in those patients? And then I have a follow-up, too.

Yes. So again, the slicing and dicing of the subpopulations on different cytoreductives and all that, I would say like we encourage everybody to participate at conferences like EHA and ASCO where those kind of details will be shared. And sorry, Richard, what was the other part of the question?

Do you have a more difficult-to-treat group in mind and how did rusfertide perform in those patients?

So again, this population, there was a lot of heterogeneity of patients with different degrees of severity of the disease. But you may recall that we did a Phase II PACIFIC study, a small study previously, where right from the baseline, these were the patients with very high hematocrit levels. My recollection is like the average baseline number was around 52%.

That's correct.

And over there, what we saw is rapid hematocrit control. So I think rusfertide, I mean, through many different studies, what we are witnessing is like this is a rapidly acting agent, and it could be titrated to effect in the patients with different levels of severity of the disease.

One thing I would remind you is, we've said this publicly before, that this study was stratified for cytoreductive use. So you will get a relatively similar number kind of on active in placebo in the cytoreductive group, and we're anxious to show you that data as Dinesh said, in the context of the medical meeting.

I see. Got it. And then just a follow-up for me. I want to continue the discussion on the secondary symptomatic endpoint. Will be great if you can discuss how clinically meaningful is the difference across these endpoints that you observe? And how do you think patients will improve on a daily basis?

Yes. I think -- I mean, as you know, PROs are a difficult base to capture in a clinical study with statistical significance. And as I mentioned before, this is probably the only agent which achieved statistical significance in the PROs. But our general observations from interacting with the investigators and getting anecdotes from patients is like the drug does have a very positive influence and effect and patients feel that difference. And one example of that is like 80% of the patients continued in our Phase II study moving from the Phase II REVIVE study to then the THRIVE open-label extension study. Sorry, Arturo, go ahead.

No. And I also want to remind you that the data in REVIVE that we showed you was focused on patients with moderate or severe symptoms primarily, but the analysis from the VERIFY study includes all patients, those who have no symptoms, mild symptoms, moderate symptoms and severe symptoms. So the fact that we're able to show statistically significant result between both groups and having patients who have symptoms or very few symptoms in addition to others who are more symptomatic is, I think, very compelling.

I'd also point out that both of the secondary symptom PROs that we used are so-called clinically validated, which means that they've been proven and accepted by the FDA as showing clinical value if you win. And so remember that we've said publicly that we discussed with the FDA and some of these endpoints were actually suggested by them to us or were altered by them for us prospectively before we unblinded. And again, when you use validated endpoints, the assumption from a regulatory standpoint is if you win, it's clinically meaningful.

Just one more comment. Again, we have had several interactions with the -- ongoing interactions with the FDA discussing the PRO strategy. And we have even more analyses that we have not discussed yet, but we'll present in the future. We'll probably have a separate presentation in the future, just focused on the overall PRO strategy, which is very comprehensive and goes beyond what we have already shared today.

Got it. Very helpful. And congrats again.

Thanks.

There are no further questions. I would now like to turn the call over to Dr. Patel for his closing remarks. Please go ahead, Dr. Patel.

Thank you. Thank you again, everybody, for joining us on the call. We look forward to providing regular updates on our upcoming catalysts as they emerge and we truly appreciate your continued support for Protagonist. Thanks.

Ladies and gentlemen, this concludes today's presentation. Thank you once again for your participation. You may now disconnect.