Welcome to the Protagonist Therapeutics June 2nd Conference Call. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a brief question-and-answer session. As a reminder, this call is being recorded today, Monday, June 2nd, 2025. I will now turn the call over to Dr. Corey Davis of LifeSci Advisors. Please go ahead.
Thanks, Betsy. Hello, everyone. 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; and Dr. Samuel Saks, Clinical Development Advisor. Yesterday, Protagonist and Takeda issued a joint press release announcing details of the data that were presented during a Plenary Session at the ASCO 2025 annual meeting, highlighting the full 32-week results from VERIFY, a phase III randomized double-blind placebo-controlled study of rusfertide showing reductions in phlebotomy and improved hematocrit control in polycythemia vera. 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 on this first slide, please note that we'll be making forward-looking statements on the 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 risks, please see the periodic reports we have filed with the SEC. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, June 2nd, 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 security law. With that, I'll now turn the call over to Dinesh Patel. Go ahead, Dinesh.
Thank you, Corey. Good morning and welcome, everyone. As you all know, Protagonist is focused exclusively on the discovery and development of peptide therapeutics. This has been a slow but steady and very progressive journey for us over the past 16 years, and it has resulted in a thriving R&D pipeline with two very promising assets in late stages of clinical development, namely rusfertide and icotrokinra, both of which are eyeing an NDA filing this year. The exclusive topic of discussion today is obviously rusfertide, which is being evaluated as a potential therapy for polycythemia vera, or PV. Protagonist entered into a co-development and co-commercialization partnership for rusfertide with Takeda last year, and they have been excellent partners.
It is a very proud moment for all of us at Protagonist today as we share the full results from the phase III VERIFY study, which were presented yesterday as one of the top five groundbreaking studies highlighted in this year's ASCO Plenary Session. With this, I would now like to turn the call over to Arturo Molina, our Chief Medical Officer, who will share the key findings from the phase III study. Arturo.
Thank you, Dinesh. Let's move to slide four. VERIFY is a global randomized double-blind placebo-controlled phase III study investigating rusfertide versus placebo as an add-on therapy to current standard of care, which is also referred to as best available therapy in patients with PV. The key takeaways from the study are that VERIFY met the pre-specified primary and all four key secondary endpoints centered around efficacy or clinical response and symptom improvements based on patient-reported outcome measures. In addition, we confirmed that rusfertide was generally well tolerated and that safety results were consistent with previous studies, with no new safety signals identified. With respect to patient-reported outcomes, also referred to as PROs, rusfertide led to statistically significant improvements in PRO measures, specifically the PROMIS Fatigue and MFSAF questionnaires.
These outstanding results support our planned regulatory filing in the U.S. in the fourth quarter of this year with our corporate partner, Takeda. Next slide is the trial design. 293 patients with phlebotomy-dependent PV were enrolled across 19 countries and were randomized on a one-to-one basis to receive once-weekly self-administered rusfertide or placebo at the outset, with or without a stable dose of cytoreductive therapy. The criteria for VERIFY were quite similar to the REVIVE phase II study, which required that either low or high-risk PV patients be phlebotomy-dependent over the previous 28 weeks. We define phlebotomy-dependent as having received at least three phlebotomies over the previous 28 weeks or five phlebotomies over the previous year. This requirement for frequent phlebotomy indicates that their PV and hematocrit levels were not adequately controlled with current standard of treatments, which could include stable doses of cytoreductive agents.
All patients were required to undergo phlebotomy to have a hematocrit less than 45% before randomization to establish a uniform baseline hematocrit to facilitate comparison between the rusfertide and placebo arms. Patients were stratified by cytoreductive therapy. In the first 20 weeks of the study, following randomization was a dose titration period, followed by the main efficacy evaluation period from week 20 to week 32, the 12-week period during which the primary endpoint for USFDA approval was evaluated. After week 32, all patients were eligible to receive open-label treatment with rusfertide plus the current standard of care in part 1B, weeks 32 to 52. Patients who completed part 1B were eligible to continue receiving rusfertide in part 2 for two additional years, and as such, this study is ongoing. In the next slide, we examine the baseline demographics.
As seen here, demographics and baseline disease characteristics were well balanced between the two treatment groups in VERIFY. The median age was 57 years, with 46.4% of patients having high-risk disease defined either as age greater than or equal to 60 and/or prior thromboembolic event. With respect to phlebotomy history, the mean number of prior phlebotomies in the 28 weeks prior to study treatment was 4 and similar in both treatment arms. The rusfertide plus current standard of care arm had double the number of patients requiring at least seven therapeutic phlebotomies in the 28 weeks prior to study treatment. The rusfertide treated arm may have had more patients with difficult-to-treat PV. Rigorous pre-screening of potential trial participants identified unknown cancers and ensured patients were on a stable therapeutic regimen prior to enrollment. At baseline, 130 patients, or 44.4%, were receiving phlebotomy alone without concurrent cytoreductive therapy.
When we look at the patients receiving concurrent cytoreductive therapies, we see similar rates of hydroxyurea, interferon, JAK inhibitor in both treatment groups. These rates of usage are in line with the overall PV population and speak to the generalizable or real-world nature of the VERIFY trial outcomes. Next slide, we will discuss the primary endpoint. The primary endpoint of the study was a proportion of patients in each arm demonstrating a clinical response. Three criteria were required to meet the definition of clinical response. The first criterion is the absence of phlebotomy eligibility during week 20-32. Phlebotomy eligibility is determined by an established algorithm based on hematocrit levels, which has been used in other trials in PV.
The second criterion is no phlebotomy treatment during weeks 20-32, and the third criterion is that patients must complete all 32 weeks of treatment during part 1A of the study. The primary endpoint of the study was met, showing that 77% of rusfertide plus current standard of care patients qualified as clinical responders compared to only 33% of the placebo plus current standard of care patients. The P-value for this outcome was highly statistically significant at less than 0.0001. These compelling results are demonstrated on the bar graph on this slide. I would like to briefly comment on the 33% placebo response rate, which is noticeably higher than the placebo rates observed in the phase III REVIVE study. To some extent, this is the typical shift you may see from a small U.S.-centric phase II study to a broader, larger phase III global study.
Based on differences in size and geography, we would expect a more heterogeneous patient population in the phase III VERIFY study, including patients earlier in the disease journey where some were heavily dependent on phlebotomy and required many phlebotomies to reach a hematocrit less than 45%. However, once a hematocrit less than 45% was reached, the rate of subsequent treatments may not need to be as frequent. Additionally, patients enrolled in VERIFY were required to complete all of part 1A prior to transitioning to open-label rusfertide. In contrast, in REVIVE, patients discontinued treatment during the randomization period, become a non-responder, and still go on to open-label rusfertide. This difference in trial design could also have contributed to a lower rate of non-responders in VERIFY.
However, what is important to highlight is the magnitude of treatment effect between rusfertide and placebo is very similar in REVIVE and VERIFY studies, confirming rusfertide efficacy. The difference in response rate between the two arms is robust, 44%. It might actually suggest that rusfertide is a potential early treatment option for patients with less advanced disease. As a reminder, the VERIFY study remains ongoing, and patients are continuing on part 1B, where placebo patients are crossed over to rusfertide treatment, followed by a two-year open-label extension of the study. In the next slide, you will see a forest plot that contains very important information.
When we look at the magnitude of treatment effect across key subgroups, we found that the strong, statistically significant benefit with rusfertide plus the current standard of care in the primary outcome is also preserved across subgroups, including PV low and high-risk groups, geographic region, and the use of concurrent cytoreductive therapy. On this slide, the benefit of rusfertide plus current standard of care is identified as the horizontal bars to the right of the vertical divider line. All subgroups analyzed show a significant improvement in the primary endpoint, the proportion of responders in favor of the rusfertide treated arm. Next slide. VERIFY has four key secondary endpoints that are a combination of efficacy assessment and patient-reported outcomes. Let's move to the first key secondary endpoint, which is a comparison of the mean number of phlebotomies over the entire 32-week period between the two arms of the study.
The secondary endpoint is particularly important because it is the pre-specified endpoint required for European regulatory finance. 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 plus current standard of care group versus placebo plus current standard of care arm during the entire 32-week period. This reduction in therapeutic phlebotomies is similar to that found in the phase II REVIVE study. Additionally, although not a formal endpoint, we are particularly impressed to see that 73% of patients in the rusfertide arm received zero phlebotomies over the entire 32-week treatment period compared to only 22% of patients in the placebo arm.
In the next slide, when we look at the different or the risk differential across key secondary subgroups, we find that the strong statistically significant benefit around rusfertide with the current standard of care in the first key secondary endpoint is also preserved across subgroups, including PV risk category, geographic region, and the use of cytoreductive therapy. Next slide. The next key secondary endpoint we will discuss is hematocrit control, or the proportion of patients with a hematocrit below 45% during week 0 to week 32. Rusfertide plus best available current standard of care was highly effective in controlling hematocrit with a high statistically significant P-value of less than 0.0001. As seen on this graph, rusfertide consistently controls hematocrit from baseline to week 32.
This dynamic is also specifically highlighted after week 32, when the placebo plus current standard of group transitions to rusfertide with the added benefit of phlebotomy at 32 weeks. Overall, data demonstrates that rusfertide can be quickly titrated to an effective dose that controls hematocrit below the threshold of 45% and eliminates the need for phlebotomy. The rapid onset of action has also been observed in the earlier rusfertide studies in healthy volunteers and patients with PV. In the next slide, we will move on to patient-reported outcomes. Initially, we focused primarily on hematocrit and phlebotomy-based outcomes, but now we will focus on patient-reported outcomes, or PROs, that assess patient symptomatology and give insight into the improvement in quality of life, which is, in our opinion, just as important as the clinical outcomes.
Two key secondary outcomes looking at PRO in the study incorporated two validated assessments: the PROMIS Fatigue questionnaire that measures patient-reported symptoms of fatigue and their impact on how a patient feels and functions, and secondly, the Myelofibrosis Symptom Assessment Form, also known as MFSAF. The MFSAF is a questionnaire that measures patient reporting of seven key symptoms related to myelofibrosis, some of which are common among PV patients. The symptoms assessed by the MFSAF include itching, fatigue, night sweats, and pain, among others, as seen on this slide. It is important to note that our selection of these PRO questionnaires and other overall PRO strategy was discussed embedded with the FDA prior to trial initiation. In the next slide, now we are looking at the first PRO secondary measure, a change in fatigue as assessed by the PROMIS Fatigue Short Form 8A.
There was a statistically significant difference that reflected an improvement in fatigue with rusfertide plus best available current standard of care versus placebo plus best available current standard of care in VERIFY with a P-value of 0.03 in this PRO by week 32, using a least squared means difference analysis, which involved modeling of covariates to ensure balance of treatment across potential imbalances. It was part of the pre-specified statistical analysis plan. The next slide provides a little bit more detail. This fatigue questionnaire contains eight questions asking about the effect of a specific treatment on differential aspects of fatigue. Individual questions first report the level of fatigue and the impact it has had on various activities and quality of life and range between 1, which is nonexperienced, and 5, which means always experienced, used to generate a raw score, which is then converted to a T-score.
We look forward to presenting additional data on this PRO at future medical meetings, including additional exploratory endpoints. Next, we will review the second PRO secondary outcome, improvement in symptoms as reported by a change in the MFSAF TSS-7 questionnaire. We found a statistically significant difference using the MFSAF that reflected an improvement in symptomatology with rusfertide plus the current standard of care versus placebo plus current standard of care in VERIFY with a P-value of 0.24 at week 32, again using a least squared means difference analysis, which involved modeling covariates and baseline adjustments. These MFSAF results confirm the data from the open-label phase II results from REVIVE, where the MFSAF was used to assess symptomatology. Next slide provides more details.
This MFSAF contains questions about seven individual symptoms common in myelofibrosis, including fatigue, night sweats, itching, abdominal discomfort, pain under ribs on the left side, early satiety, and bone pain. Each question about the symptoms scored between 0, which means absent, or 10, which means worst imaginable, for each individual symptom with a total score out of 70. Unlike the PROMIS Fatigue instrument, raw data are used to score the MFSAF, and to our knowledge, no other randomized phase III trial in PV has shown a statistical improvement in symptomatology using these PRO instruments. As with the PROMIS Fatigue results, we look forward to presenting more detailed information at an upcoming medical meeting. On the next slide, we will discuss safety. On the safety side, we're extremely pleased with the overall profile observed in this study.
As you can see on this slide, rusfertide was generally well tolerated in the phase III VERIFY study, and safety was in line with what has been reported in other rusfertide clinical studies. A majority of rusfertide-related adverse events were grade 1 or 2 injection site reactions. Grade 1 to 2 anemia is known to be associated with rusfertide mechanism of action due to the reduction in the production of red blood cells. No new safety findings were observed in the study. No serious adverse events or SAEs were attributed to rusfertide. Next slide. As we have previously discussed in the VERIFY top-line conference call in March, non-PV cancers are observed in patients with PV, including skin malignancies, at a higher rate than in the general population. It is not clear whether this risk is due to the PV itself or prior therapies such as hydroxyurea.
Given this risk, we instituted screening exams and identified 10 skin malignancies, including one malignant melanoma prior to randomization. We also identified multiple premalignant lesions such as actinic keratosis and dysplastic nevi. During the first 32 weeks of VERIFY, eight other cancers were identified, with seven being in the placebo plus current standard of care arm and only one in the rusfertide plus current standard of care arm, indicating that there is no evidence of an increased risk of cancer in rusfertide treated patients compared to those on placebo during this 32-week period. However, the rate of serious—moreover, the rate of serious adverse events in the first 32 weeks of VERIFY showed 3.4% in the rusfertide plus current standard of care and 4.8% in the placebo plus current standard of care.
Overall, we found a non-statistically significant imbalance in favor of the rusfertide treatment arm for both secondary cancers and SAEs. Next slide. In conclusion, VERIFY is a strongly positive study that met statistical significance in its primary endpoint and all four key secondary endpoints. In phlebotomy-dependent PV patients receiving the best available current standard of care treatment, the addition of rusfertide reduced the mean number of phlebotomies, improved hematocrit control, and improved symptoms compared to placebo plus best available current standard of care. We believe rusfertide is the first therapeutic to prospectively demonstrate a statistically significant improvement in PROs using PROMIS Fatigue and MFSAF questionnaires in patients with PV. Moreover, rusfertide had a safety and tolerability profile consistent with prior studies, and there were no new safety signals. Overall, we believe this is the best possible outcome for the phase III VERIFY trial. We are thrilled with this outstanding result.
Rusfertide continues to produce data supporting its first-in-class nature. Because its efficacy is rapid, consistent, and durable, rusfertide has the potential to fulfill unmet needs for patients with PV who are already receiving best available standard of care and yet are not achieving adequate hematocrit or symptom control. With that, I will pass it back to Dinesh.
Thanks, Arturo, for sharing that wonderful and positive data all across the board. Based on the phase III data that Arturo just shared on this call, we are concluding that rusfertide has the potential to become a new standard of care in PV treatment. To lift some of the concluding remarks that were made yesterday by the discussant Dr. Walsh during yesterday's Plenary Session, this phase III study outcome is practice-changing, and rusfertide should become part of the standard of care for these PV patients. I would also point out that our pharma partner, Takeda Pharmaceuticals has guided towards $1 billion-$2 billion peak revenue potential for rusfertide in PV.
Now, let me quickly summarize here the key treatment goals we had in mind at the answer of this study along three distinct categories, namely efficacy, symptom improvement, and safety, and recap how rusfertide has scored positively in all of these three categories. Let's start with keeping hematocrit control below 45%, which is the primary treatment goal in PV as per NCCN guidelines. As we know, uncontrolled hematocrit above 45% has serious consequences and is associated with a four-times higher rate of death from cardiovascular and from heart events. Despite the criticality of this treatment goal, real-world patient data suggests that about 78% of the patients treated with currently available therapies, that is, on current standard of care, do not consistently achieve or maintain hematocrit below 45%.
To that end, rusfertide, by virtue of being an RBC or erythrocytosis-specific agent, achieved remarkable absolute hematocrit control in the phase III VERIFY study. 63% of patients in the rusfertide arm maintained hematocrit below 45%, versus only 14% in the placebo arm that has the standard of care therapy. Today, we also shared a lot of new data that provides context around all types of subgroup analysis from the phase III study, and it is indeed gratifying to observe that rusfertide scores positively in all of these subgroup analyses, highlighting that this is a very effective therapy for the broad PV population, irrespective of their risk category or current standard of care treatment options. Phlebotomy is a commonly used treatment in PV, but it has many limitations and results in iron deficiencies, which just amplifies the related symptom burden in these patients.
One of the important goals was to reduce phlebotomy burden or to make the patients essentially achieve freedom from phlebotomies. In that context, the current study showed that 77% of the patients in the rusfertide arm did not need a phlebotomy during this 20 to 32-week primary endpoint related treatment period. If you look at the entire 32-week period, we have more than threefold higher number of patients achieving freedom from phlebotomy in the rusfertide arm versus the placebo standard of care arm. Now, let's move towards the goal of symptom improvement in PV. As you know, the current treatment options are suboptimal at best. Phlebotomies, in particular, are often burdensome as they can exacerbate symptoms by inducing iron deficiency, which causes fatigue, brain fog, and weakness, thereby significantly impacting their quality of life and ability to perform daily activities.
As Arturo showed, we met both patient-reported outcomes-based symptom improvement endpoints in the study, namely the PROMIS Fatigue and the MFSAF TSS-7 scores. Having scored efficacy and symptom improvement, let us now turn towards safety. As you know, in PV, patients have higher incidences of cancer compared to similar normal population without PV, and the cancer rates are even higher for patients who are on cytoreductive therapies. The phase III VERIFY study is the first study where we could evaluate such incidences in the placebo standard of care treatment arm versus rusfertide plus standard of care treatment arm. Based on the comparison of the safety data between these two arms, we can confidently conclude that rusfertide has a generally well-tolerated safety profile with a majority of treatment emergent adverse events being of mild to moderate nature.
Given that all these treatment goals in the categories of efficacy, symptom improvement, and safety are achieved and uniquely aligned with rusfertide's profile of rapid, consistent, and durable hematocrit control, we believe that rusfertide could be adapted for all categories of PV patients who have uncontrolled hematocrit above 45%, something that can occur at any point in the patient journey with this disease, which averages about 20 years. We at Protagonist are very proud to be part of this unique opportunity of being able to potentially offer a highly effective and transformative medicine to the majority of PV patients whose medical needs otherwise remain unaddressed today with current treatment choices.
Now that we have created an exceptional chemical peptidic entity in respiratory, executed an incredibly well-designed phase III program, and delivered the best possible data outcome we could have hoped for, we are ready to gradually transfer the next set of responsibilities to our excellent partner, Takeda. The differentiated product profile defined by the data fits perfectly with the strengths of Takeda, who continue to impress us with their dedication to the program, their marketing investment, and all of their commercial readiness. They are the perfect partner to launch respiratory to ensure that the maximal value is created in the shortest period of time. They did a great job of articulating all of this on their call yesterday evening. If you missed it, I would encourage all of you to listen to the replay.
Takeda is a well-established global team oncology franchise with an experienced leadership team that has respiratory as one of their top priorities. In parallel to all of the extensive commercial preparations that have been ongoing for months now, we will also be handing off the NDA filing responsibilities to the senior regulatory team and working very closely with them towards NDA filing. We are confident that it will be a seamless transition, and the timelines are still very much on track for an NDA submission to the FDA in the fourth quarter of this year. As a reminder on the terms and as summarized in this table, we still have a number of large milestones that will be coming our way, regardless of our decision on the opt-in or opt-out scenario.
While we have not disclosed the revenue rate points associated with the royalty rate tiers, we want to assure you that these are achievable thresholds, which would get us to the high end of this 14%-29% royalty range in a reasonable timeframe following launch. Finally, remember that we have until up to seven months following the NDA filing to make that decision to stay opted in or to opt out, which will be sometime in mid-2026. Next slide. This slide summarizes our respiratory clinic development program in its entirety and highlights that we have delivered on every single one of our respiratory-related milestones over the previous four years, with the next one being the NDA filing in Q4. I could not be more impressed with our internal team's dedication on this program over the years.
This is a great opportunity for me to congratulate the entire Protagonist team on the amazing success with the rusfertide program and a great moment for everybody to be very proud of this great accomplishment. Next slide. This slide summarizes all the critical R&D programs of Protagonist and highlights all of our other accomplishments besides rusfertide over the last 18 months and the upcoming milestones, which includes the NDA filings of the two major drugs in our pipeline, namely rusfertide and icotrokinra. Both of these drugs grew out of our peptide technology platform. Now, as you can imagine, our attention is rightfully increasingly shifting to our discovery pipeline. Thanks to our lucrative pharma partnerships around rusfertide and icotrokinra, we have the financial strength to move each of these programs on our own time up to clinical proof of concept stage.
You already know about PN-881, our oral peptide anti-IL-17 development candidate that is basically approaching phase I studies in Q4. Next up will be announcements about our oral development candidate for obesity and our oral peptide candidate, both of which are on track for Q2 and Q4 of this year. In closing, I would like to congratulate and sincerely thank our extremely talented and dedicated pool of employees, advisors, and consultants, our pharmaceutical partners, and all the patients, investigators, nurses, and caregivers involved in all of our PV trials for their continued support. With that, I will now ask the operator to begin our Q&A session. Operator.
We will now begin the question and answer session. To ask a question, you may press star, then one on your touch-tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star, then two. At this time, we will pause momentarily to assemble our roster. The first question today comes from Brian Cheng with JP Morgan. Please go ahead.
Hey, guys. Congrats on the data, and really thanks for taking our questions this morning. Maybe first, can you talk about how you think about respiratory use when this drug becomes commercialized in a sense of potentially combining with other agents? Because it seems that in the trial itself, in the trial experience, there's a bit of a combination used in the background too. How do you think about the usage there? Also, just the trajectory of adoption, especially in the space that's been historically dominated by cytoreductive? We have a quick follow-up. Thank you.
Yeah, Brian, thank you for the excellent question. I'll make some general comments. Then, of course, Arturo and Sam will chime in. I would say what we have done as of today has created an excellent base for rusfertide. It's like the core data is just amazing. I think this is, in a way, the beginning phase of truly understanding rusfertide's potential. Things like how it would be used in real life and with what combinations or even eliminate, we are clearly showing that we could eliminate phlebotomy, right? The next question is, can you eliminate or lower the cytoreductive, things like that? Those are the things that I think will become more clear over the past with more experiences or maybe even more studies. Arturo, go ahead.
Brian, one thing to note is that historically, most patients have been managed with phlebotomy and single cytoreductive therapy when it's needed. I think the study shows that rusfertide can combine with all the best available therapies that are out there, phlebotomy, interferon, even RUX, and hydroxyurea. What I've heard in recent networks is that the doctors now need to think of maybe we should treat PV with combination treatments because we have more options now. I think that's one new paradigm that we have introduced with this type of study that's like a real-world patient population that included the types of patients you will see across the world.
Remember, Brian, we've always said that if patients were well treated with a small number of phlebotomies and cytoreductive therapies, that they wouldn't be candidates for rusfertide. We found in our real-world studies that that's only about 25% of the patients. We published that previously in ASH. Net-net, if your cytoreductive therapy controls your disease, then you're not a candidate. For the vast majority, who still have a significant phlebotomy burden and therefore everything that comes with it, we show that we're definitely a great choice. To Arturo's point and to Dinesh's point, the future will tell whether we could lower these cytoreductive doses.
Exactly.
Because they're toxic agents. The toxicity of all the cytoreductive drug agents is dose-related, meaning if you can lower the dose even a little bit, you can have more tolerability for the patient. That remains to be seen in future studies.
And the other distinction that you could make between rusfertide versus all available treatment options is that rusfertide specifically goes after RBCs, right? It's an RBC-specific agent. Whereas if you look at phlebotomy or other cytoreductive therapies, it's like, for lack of a better word, it's almost like a pan-therapy. It's going to affect not just RBCs, but also WBCs and platelets. PV, in a way, is a very RBC-centric disease. We'll just have to see. As Sam and I and Arturo said, this is sort of like the launching pad. We are off to a great start. We will try to create more data and more evidence around what is the best practical use of rusfertide as a solo agent or from time to time in combination with other modalities.
I think you saw an ASCO yesterday that discussed and presented some examples of patients who would benefit.
Maybe just one last one.
No.
Oh, sorry. Go ahead.
Go ahead, Brian.
Oh, I just want to see also I think it's also interesting in the data set, in the baseline characteristics, there's also a slight imbalance between the treatment and the placebo arm where the treatment arm actually had more sicker patients when you look at more than or equal to 7 TP in the 20 weeks prior. I mean, one, was that a surprise to you? Can you kind of talk through how that might be a positive to physician? Do you think that physician will understand that?
Yeah, I think it's a good observation, but we just don't want to blow it out of proportion.
Yeah, it's a small percentage of patients. I think what we show in the subgroup analysis is that rusfertide works for all these different demographics and subgroups. One thing I just wanted to, I think that our study is bringing to light is that symptoms in these patients are underappreciated. As you heard from the discussion and from Dr. Kuykendall, an agent like this has potential to not only control the hematocrit, because sometimes the hematocrit can be controlled, but the patient's still symptomatic. We believe that rusfertide, by its unique mechanism of action, where we prevent the iron deficiency and might even improve the iron deficiency, will result in a patient experience modification, which is, I think, a unique term that was brought up by Dr. Kuykendall. I think it's something that we want to expand on because that is just as important.
Modifying the patient experience, we believe, is just as important as anything else that you want to modify in PV.
That small subgroup difference you mentioned is just due to chance alone with a small group. If anything, it goes against us. I think doctors will see that it just confirms the value of rusfertide even in difficult-to-treat patients.
The next question comes from Roger Song with Jefferies. Please go ahead.
Great. Congrats for the data at the ASCO Plenary Session. My question is really focusing on the PRO, the symptom improvement. Given you are the first phase III showing the static on the symptom improvement, multiple questions. First of all, what would be considered clinically meaningful effect size based on the feedback from your investigator and the advisor? How do you believe those data will be incorporated into potential label based on the FDA feedback? Last part is, how do you think this endpoint and the result will support the future clinical use? Thank you.
Yeah. I mean, again, excellent observation, right? And just to rephrase again what Arturo narrated or borrowed the quote from Dr. Andrew Kuykendall, the improvement in the PROs is what allows us to make statements like, "Hey, this could be disease experience or patient experience modifying kind of treatment." These are early days, but this is a remarkable observation and outcome. In terms of what goes into the label, it's like, as you know, we just have to say, "Wait and see," and see how it shakes out with the regulatory agency.
One other thing to remember, Roger, all the nice data from REVIVE that we presented, it was open label and focused only on patients with moderate or severe. Here, we achieved the statistical significance in the entire population, in the intent-to-treat population. We are planning additional analyses looking at the moderate or severe patients, even patients with mild symptoms to specifically more precisely answer the question that you asked. It is very encouraging that even though some patients did not have symptoms, we were still able to show this statistically significant improvement in the entire intent-to-treat population.
I want to point out that we've said before, these endpoints were discussed with the FDA before we began the trial. To your point about clinical relevance, these are so-called validated tools. That's why we use them, and we worked with the FDA to do that. When you use a validated tool, it means that the tool has been shown that if you get a statistically significant result, it has clinical relevance. In your trial, you have to show the details of that and confirm the robustness of that. We look forward to showing you all the details of that in the future. The bottom line is, these are validated tools. That's why we chose them.
Great. Thank you. And congrats again.
Thanks, Roger.
The next question comes from Tara Bancroft with TD Cowen. Please go ahead.
Hi, good morning. I was hoping maybe you could tell us more about your level of confidence in the peak market opportunity and whether you view it as closer to maybe the lower or the high end of the $1 billion-$2 billion range, or if you think now that there is any potential for a larger opportunity given just how positive the discussants' comments were yesterday and how that could inform your decision to opt in or opt out. Thank you so much.
Yeah. Tara, that's an excellent and a tricky question. Congratulations on asking a tricky question. Having said that, yeah, look, Takeda is a pharmaceutical company. By nature, they have to be conservative. We agree with their assessment of the $1 billion-$2 billion market potential. If you ask Protagonist, if you ask specifically me, I would say we feel confident that we could be at the higher end of that range rather than at the lower end. I think I did share a little bit new information in my narration today that we believe that especially under the opt-out scenario, there is a 17%-29% revenue range. We feel comfortable in stating in general terms that we could be kind of having our position at the higher end of that range rather than at the lower end of 17%-29%.
One thing I would point out to your point is, look, we just had the biggest platform in the world, an ASCO Plenary Session with the entire medical audience in this community seeing the results for the first time in detail. Again, we'll have a lot more details on the PROs coming in the future. We have until months after the NDA filing to make our decision. Let's see when all this good information gets out into the medical community, starting with yesterday's presentation, how the view of the molecule and the opportunity changes in the minds of physicians who maybe haven't directly administered themselves.
I mean, Protagonist is going to have two critical activities, right? At one end, both Protagonist and Takeda. I mean, there will be the regulatory filing. All eyes on that. On the other hand, the one-word description of our next big activity is increasing awareness about rusfertide, about PV, the effectiveness of rusfertide in PV. We are off to a great start, right? It's like with the ASCO Plenary Session, right? Roughly around 10,000 pair of eyes watching the live presentation, and the total attendance is around 40,000+ people. Clearly, the word is spreading around, and the data is outstanding. We, Protagonist, will have about a year to watch on the progress, and we will make the right decision at the right time.
Okay. Great. Thank you. I appreciate you navigating such a tricky question.
Of course.
The next question comes from Evan Seigerman with BMO Capital Markets. Please go ahead.
Hi. [Mark Mauffin] on for Evan. Thanks for taking our question and congrats on the data. I wanted to ask about how the strength of this data may influence conversations with payers going forward that you may have to date or expect to have in the future. What aspects of the VERIFY data do you think will be most impactful in ensuring rusfertide is covered broadly for polycythemia vera? Appreciate it. Thanks.
Yeah. Again, it's a great question. It's kind of like trying to reflect upon the future. I think this is where I will be saying less and will be relying more on our partner, Takeda, to kind of point to some clues in that category down the road.
Yeah. One thing I would say, our goal has always been the drug's administered once weekly at home. As was said in the Plenary Session by the doctors, we've always thought that this could get PV to being more of this thing where the patient was tied to the office and their latest hematocrit result, where they needed to sit in a chair for four hours on a particular day, something you could manage at home and really control yourself in the way that people control diabetes and their blood sugar. That paradigm shift, I think, is going to resonate for payers, especially with something that has the PRO benefits.
Because payers, especially in Europe, but also in the U.S. and Canada, they want to know that, "Okay, you're reducing this hematocrit, but the patients are actually living better." We've had powerful anecdotes that you can hear from previous presentations about people going back to work and running marathons and all kinds of things. That is inherent in the kinds of data we showed here.
Even at a fundamental level, let's put symptom improvement aside for a while. The fact is that this is a rare disease. As you know, in the payers category, rare disease-related drugs are approached in a different way. They fall in a different category. That's number one. Number two is, this is a study where we are attending to patients who do not control their hematocrit with the standard of care, right? If you think about it at a practical level, currently, these patients have no choice like rusfertide that is available. When rusfertide does become available, that's where their unaddressed need could be addressed. I'm sure that the payer component is going to be in our favor because we are addressing an unmet need with a very erythrocytosis-specific agent.
Yeah. When you go to a payer and say, "This is for people where their current therapy isn't working," that resonates well.
One thing just I want to add is that the majority of patients from the REVIVE study, when the study completed, asked to continue on treatment. The reason is that they feel better while they're on treatment. By the time we file, we are going to have data on patients who have been on treatment for five plus years. Again, a testament to its durability of effect and consistency of the effect. This new concept of changing how patients live with this disease or patient experience modification, I think, will be very important in looking at the reimbursement as well.
Appreciate it. Thanks for the call, guys.
The next question comes from Kripa Devarakonda with Truist Securities. Please go ahead.
Hi. This is Alex on for Kripa. Given the favorable safety profile that we've seen for rusfertide, especially with respect to the cancer events observed, do you think cancer screening could still be a prerequirement for prior to instigate rusfertide treatment? If it is a requirement, would this be burdensome and could it curtail abuse in a real-world setting?
I think that our data showing that even before randomization, we detected a very high number of cancers and premalignant lesions. We've had discussions with NCCN members, and I think there's a strong move by the NCCN to require at least yearly derm exams to any patient in PV, particularly if they've had hydroxyurea. We think that they should have this, not because they're going to get rusfertide, because it's good medicine for them. They are at very high risk, especially like those two patients with melanoma that we detected. What if they had not been screened and entered the study? What would have happened to them? I think the question of the derm exams is a broader question, and it shouldn't be because the patients need to come on rusfertide.
You may ask why that's the case that we could find these when the patients were seeing doctors regularly. That's because a real thorough derm exam, I'll say, dermatologist is more skilled than hematologist. It also involves getting completely undressed and really thoroughly examine all aspects of the skin. That's not commonly done in the hematology office on a regular basis. Again, to Aristotle's point, this just shows that these patients have these lesions at enough frequency without respiratory that they should be surveilled in a clear and consistent way.
Thank you.
The next question comes from Douglas Tsao with H.C. Wainwright. Please go ahead.
Hi. Good morning. Thanks for taking the questions and congrats on the data. I'm just curious because I think it was Arturo you referenced the fact that you're certainly not initially targeting and weren't enrolled in the trial patients who have relatively low phlebotomy burden on cytoreductive therapy. I'm just curious if you have thoughts on sort of the severity of fatigue and other symptoms that those patients might have. Ultimately, would they benefit from treatment with rusfertide just given the fact that we've seen such dramatic symptomatic improvement in those patients? Thank you.
Yes. The improvement in symptoms is something that once we get more data out, I think there is an interest by the treating physicians to focus more on addressing that part. We hear from some of the doctors that patients complain that they don't believe our symptoms. Our families don't believe our symptoms because or our primary doctors don't believe our symptoms because they look good on paper, so to speak, but they have all these symptoms that we believe are related to uncontrolled hematocrit, uncontrolled PV.
The iron deficiency.
The iron deficiency. I was just going to go there. One thing that we have shown before is that we seem to impact the health of the red blood cells. Patients with iron deficiency are microcytic. They have smaller red blood cells. When patients have been on rusfertide, the red blood cells that were small become normal in size, therefore having better oxygen carrying capacity. There is more to the story that we plan to continue to publish and get out into the public domain and, of course, discuss with the FDA.
The other thing I would say about the low phlebotomy burden cytoreductive patients is you're inferring and talking about the ability of rusfertide to affect the iron regulation, those symptoms. On people on cytoreductives, these cytoreductives are toxic, as I said, and the toxicity is dose related. Even if you're having a low phlebotomy burden and that's not the patients we treated in the study, you might benefit from reduction of your cytoreductive if that's possible with rusfertide because you may have tolerability issues. One only needs to look at those drugs.
As a follow-up, that's all really helpful. I'm just curious, when we think about development and additional studies down the road, is that something that's been transferred over and all development decisions will be made by Takeda, or do you have an opportunity to sort of develop to influence the future clinical work that might be done? Thank you.
Yeah. Once again, our partnership with Takeda is an excellent one. Those are the details that can be sorted out down the road. As you can imagine, both companies feel that we have our hands on an excellent paradigm-shifting, game-changer kind of drug. We are not going to nickel and dime too much and do what is necessary to put rusfertide in the best forum possible.
We have been having advisory boards together jointly. We had them before we joined Takeda. We have shared the information with them. We have some thoughts already on future studies.
The next question comes from Jon Wolleben with Citizens. Please go ahead.
Hey. Congrats on the updates, and thanks for taking the questions. Dinesh, wondering if you could talk a little bit about how you're thinking about opting in and opting out today and what could change between now and mid-2026, kind of what factors into your framework on what the path forward looks like for you guys in respiratory?
Yeah. Look, this is an important question where I can start out by stating that we have a year to make that decision. Having said that, though, what I would also add, though, is currently, we are at a stage where either of those scenarios should be a wonderful choice. Maybe that's how I should be putting it. As we also alluded to, maybe the ASCO Plenary Session is the first big step forward in terms of increasing the awareness of the drug. We'll have a year to watch what the increased awareness does to the drug's potential market opportunity. Then, based on all those kind of information and data, we'll make the right decision.
The next question comes from Kaveri Pohlman with Clear Street. Please go ahead.
Good morning. Thanks for taking my question and congrats on the positive data. This is Christian on for Kaveri today. I would just like to know if you can provide any insight on the comparable fatigue rates observed in the AE profile of both rusfertide and the placebo arm. Why would you see similar rates when the secondary endpoints show improvement in fatigue with rusfertide treatment?
One thing to keep in mind is that the fatigue reported is what the physician asks, whereas the patient-reported outcome is recorded at many more time points, and it is what the patient feels, what they are reporting. I think that is, in our sense, more reliable for the patient experience when it comes from the patient themselves.
Remember, there's one really key difference, which is when you report adverse events, if the patient ever has fatigue anytime during the study, they're reported as having fatigue. The PRO measures, did your fatigue get better? You're right. Similar rates of fatigue in the AE table, but the PROs are asking the question, "Hey, looking back, are you better?
Thanks. That is absolutely a difference. Yeah.
The next question comes from Yun Zhong with Wedbush. Please go ahead.
Hi. Good morning. Thank you very much for taking the questions and congratulations on the positive data. On the baseline characteristics, I see that roughly 50% of the patients were receiving phlebotomy alone despite that their hematocrit was not sufficiently controlled. Is the concern about safety related to cytoreductive therapy the main reason for a patient not to get cytoreductive therapy? Have you ever seen a patient, maybe anecdotally, being able to discontinue or reduce their cytoreductive therapy after rusfertide treatment?
Two different questions. I think the 50/50 split that we have in our study of phlebotomy, excessive phlebotomies alone versus site-plus excessive phlebotomies, I would say that's the general representation of the overall demographics and patient population that you see in PV in general. What was the second question?
I was just pointing out that cytoreductives tend to be reserved for high-risk patients in the guidelines. Recently, interferons are being used in low-risk patients on a small basis, as you see in the study. Generally speaking, the historical guidelines say add cytoreductives when you're not controlled, but also if you have high risk based on age.
The other thing about whether we can reduce the dose, make it dose-sparing, that kind of thing, that is a very attractive scenario down the road. We just have to see how we can address that. The real-world situation is that, unfortunately, as of now, if at all anything, the patient and the practicing physician, they are forced with the unfortunate choice of increasing the dose of cytoreductives in a lot of situations in an attempt to control the disease and hopefully. Nobody likes that. Hopefully, with this drug, and again, this is something we have to prove down the road. It is like if rusfertide can become dose-sparing, that would be wonderful.
That is a question that we did not ask in the VERIFY study, but it is one of the questions we would like to explore in a subsequent study. Having said that, we are looking at the doses of the cytoreductive therapy to see if indeed there were some reductions either for toxicity or because they were not needed. That work is ongoing.
I would say anecdotally in our long-term extensions, we allow modification of the cytoreductive dose. We're getting some anecdotal uncontrolled data on that information that we'll have more to say about later. As Aristotle said, you'd have to do a controlled study to really get definitive information.
The next question comes from Richard Law with Goldman Sachs. Please go ahead.
Hey, guys. This is Paxton on for Richard. Just a quick follow-up on some of the PRO outcomes data. I recall from the KOL Day that you mentioned that you would also be prespecifying these endpoints for patients with moderate to severe symptoms at baseline. Could you discuss trends within this patient population and maybe why these results were presented today?
Yeah. That's the kind of subgroup analysis that continues. Hopefully, at the next major medical conference, we could be sharing.
These are the endpoints that are specified specifically by the FDA in the entire population. Anything we do with subgroup analyses are considered exploratory, and we are planning to do that. We also have the MFSAF that asked questions about concentration, problem concentration. Those are also exploratory endpoints, but we're including the totality of this data in our NDA. Now we focused only on prespecified endpoints, but we'll have a comprehensive abstract in the future detailing all the PRO work because we have a lot more than what we were able to present yesterday. We were limited in the number of slides that we could present.
Remember, FDA has asked us to win in the group as a whole.
To your point about moderate to severe, what it means is the result is so robust that it carries the day for the number of patients who do not have that symptom. Remember, any symptom, only a certain number of patients have that symptom. We are showing we work as a group of the whole, even with patients who do not have that symptom, who arguably can improve. That is the robustness of the data.
This concludes our question-and-answer session. I would like to turn the conference back over to Dr. Patel for any closing remarks.
Thank you again, everyone, for joining us on the call this morning. We look forward to providing regular updates on our upcoming catalysts as they emerge. We truly appreciate your continued support of Protagonist. Thanks.
Thank you.
The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.