Welcome to the Protagonist Therapeutics conference call. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a brief Q&A session. As a reminder, this call is being recorded today, Monday, August 31st, 2026. I'll now turn the call over to Dr. Corey Davis of LifeSci Advisors. Please go ahead. Thank you, Rob. Hello, everyone, and thanks for joining us on our call today. Joining me from Protagonist are Dr. Dinesh Patel, President and CEO, Asif Ali, CFO, Dr. Arturo Molina, CMO, Dr. Ashok Bhandari, Chief Discovery Officer, and Dr. Samuel Saks, Clinical Development Advisor. On Friday, Protagonist issued a press release announcing the FDA approval of rusfertide, now known as MIMRYLO, for the treatment of erythrocytosis in adults with polycythemia vera, or PV. A copy of the release and the slides being used for this call are available on the company's website. As can be seen on this slide, 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. For further information relating to 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, August 31st, 2026. 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 Dr. Dinesh Patel. Go ahead, Dinesh. Thank you, Corey, and good morning, everyone. Earlier this year, on March 18th, we had announced the U.S. FDA approval for our first drug, the first-in-class IL-23 receptor blocker oral peptide ICOTYDE, in partnership with Johnson & Johnson. Today, a few months later, marks the second major drug approval milestone for Protagonist. We are very pleased to announce that MIMRYLO, which is the new brand name for rusfertide, has received FDA approval for the treatment of erythrocytosis in adults with polycythemia vera, or PV. This is a first-in-class medicine that targets the biology-driving red blood cell, or RBC, overproduction in PV. I would like to congratulate both the Protagonist team and our partner, Takeda Pharmaceutical, on this very successful outcome. As most of you know, PV is a rare blood cancer, wherein the fundamental treatment goal for patients, as per NCCN guidelines, is to lower hematocrit, which is the ratio of red blood cell volume to total blood volume, and to maintain this hematocrit level below 45%. While PV is an erythrocytosis-driven blood disease, there has been no erythrocytosis-specific therapy available as a treatment. It is this unmet need that drove us on the path of discovering and developing MIMRYLO. How does MIMRYLO work, and what is its mechanism of action? It is a peptide mimetic of the natural human hormone hepcidin. Hepcidin is the master regulator of iron homeostasis that controls the absorption, storage, and distribution of iron in the body. MIMRYLO mimics the action of endogenous hepcidin to regulate iron availability and thereby help normalize RBC production and maintain hematocrit levels below 45%. This erythrocytosis-specific mechanism is a very different and a more elegant therapeutic strategy compared with the current standards of care, which rely on phlebotomy and cytoreductive therapies to control the consequences of erythrocytosis. These treatments can be associated with treatment burden and adverse effects and do not specifically target the underlying iron dysregulation that fuels erythrocytosis. MIMRYLO is a first-in-class drug of its kind for PV, a first-in-class medicine marking a potential shift in the treatment paradigm for PV. We have high confidence in the long-term commercial potential of MIMRYLO and know that our partner, Takeda, is exceptionally well-positioned to maximize the global opportunity for the product. As a reminder, following our recent opt-out election, Takeda is now solely responsible for all aspects of commercialization and ongoing clinical development, and they are the ones best positioned to provide more specific details on these topics. Before getting into the clinical studies that form the basis of the approval and the broad prescription label, let me first walk you through the discovery and development journey of MIMRYLO, since it speaks volumes about the scientific expertise of Protagonist with peptides, the in-house peptide-centric drug development acumen we have accumulated, and the future strategic vision for the rest of our peptide-dominant research and development pipeline. Going to slide four, let's start with the historical perspective on MIMRYLO journey from concept to FDA approval and commercialization. MIMRYLO, or PTG-300, as it was known during drug discovery and early development, originated from our hepcidin mimetic program more than a decade ago. Its successful approval provides important validation for Protagonist on at least two levels. First, it is a testament to our scientific team's innovative expertise in originating the hypothesis that a hepcidin mimetic could lead to a first-in-class medicine for iron dysregulation-related diseases such as PV. Second, it provides powerful validation of our peptide technology platform and our exceptional expertise in the emerging field of peptide therapeutics. Looking at hepcidin through the lens of a medicinal chemist, we recognized early on that the natural hormone hepcidin presented a unique challenge. It is synthetically complex, unstable, poorly soluble, and only moderately potent, making it unsuitable as a drug in its own right. There was a clear need and opportunity for creating a synthetic peptide with superior pharmacokinetic and pharmacodynamic properties in comparison to the natural hormone. We were able to utilize our peptide chemistry expertise and our proprietary platform on this project. In particular, we applied the technique of scaffold hopping from our platform, which led to the identification of a PTG-300 scaffold, which after further optimization, led to the specific peptide PTG-300, now called MIMRYLO. As a side remark, the peptide platform is now very broad from what it was in those days, encompassing a full range of tools, including, but not limited to, computational matrix libraries, phage libraries, medicinal and peptidomimetic chemistry, formulations, and artificial intelligence. These tools are being judiciously utilized in our new discovery and development programs, which will be highlighted later on in this call. Getting back to MIMRYLO, the discovery of 300 was followed through with our phase II REVIVE clinical proof of concept study, the Takeda partnership, its successful pivotal phase III VERIFY readout, the NDA submission last year in December, and finally, U.S. FDA approval last week on Friday. Along the way, rusfertide received orphan drug designation, fast track designation, breakthrough therapy designation, and priority review. The program also achieved broader clinical and scientific validation, including publication of the phase II REVIVE results in The New England Journal of Medicine and presentation of the phase III VERIFY results at the 2025 ASCO Plenary Session. It has been an incredible journey, and this successful outcome is deeply satisfying for the entire company, especially knowing that PV patients will now have a new treatment option attending to their unmet need of maintaining hematocrit levels and controlling erythrocytosis in a consistent manner. Let me now turn it over to our Chief Medical Officer, Dr. Arturo Molina, who will review the phase III VERIFY results and the approved label and the unmet need in PV. Arturo? Thanks, Dinesh. Let's go to slide five. The phase III VERIFY study was a 32-week double-blind, placebo-controlled study which enrolled patients receiving current standard of care but requiring excessive phlebotomies because of uncontrolled hematocrit. In the placebo arm, participants continued with their ongoing therapy, whereas in the investigational treatment arm, rusfertide was added to the ongoing therapy. The primary endpoint was clinical response in the rusfertide treatment arm versus the placebo arm during weeks 20- 32. The study met not only its primary endpoint of clinical response, but also all the four key secondary endpoints, including the patient-reported outcomes assessing fatigue and overall symptom burden, specifically the PROMIS fatigue score and the MPN-SAF symptom score. Importantly, improvement in fatigue, as measured by the PROMIS Fatigue Short Form 8a, is also incorporated into the FDA-approved label. MIMRYLO had a generally well-tolerated safety profile in the study, with the most common adverse events being injection site reactions and anemia. This efficacy and safety data from the VERIFY study served as the basis for FDA approval of MIMRYLO. As mentioned earlier, the phase III VERIFY studies were presented at the plenary session at ASCO last year. Following the presentation by Dr. Andrew Kuykendall, Dr. Kathryn Walsh from Vanderbilt provided her view as a formal independent discussant. She described the study results as practice-changing and suggested that rusfertide should become part of standard of care for PV patients. Now let me share some of the highlights from the prescribing information from the approved label on the next slide. We're very pleased with the broadened label received from the FDA approval of MIMRYLO. The label accurately reflects the excellent safety and efficacy results submitted in the rusfertide NDA. In terms of efficacy, MIMRYLO achieved a high response rate of 76.9% during weeks 20- 32 and maintained hematocrit control and reduced phlebotomy. Importantly, MIMRYLO improved fatigue in patients with PV, as measured by the PROMIS Fatigue Short Form 8a. This is a very important endpoint as it reflects the patient experience with polycythemia vera. Demonstrating an improvement in symptoms in prospective randomized trials of PV has been elusive to date. For the first time, an improvement in fatigue has been demonstrated and included in the label as a key efficacy outcome in a phase III trial in polycythemia vera. We are also very pleased with the safety profile observed in the MIMRYLO clinical development program. First and foremost, there is no black box warning in the prescription label. Secondly, there are no carcinogenicity signals in the six-month transgenic mouse study and the two-year rat carcinogenicity study. Moreover, in the VERIFY study, there were more cancers observed in the placebo arm compared to the rusfertide arm. Thirdly, the warnings and precautions section includes new or worsening thrombocytosis and injection site reactions. Thrombocytosis was reported in 8% of patients in the MIMRYLO arm. All of these were Grade 1 or 2. Injection site reactions were reported in 56% of patients, the vast majority being Grade 1 or 2, with only 0.7% being Grade 3. Discontinuations related to adverse events were low. Adverse reactions which resulted in discontinuation of MIMRYLO, including injection site reactions in 0.7%, or two patients, thrombocytosis in 0.7%, or two patients, and anemia in 0.4%, or one patient. In summary, MIMRYLO has impressive efficacy and safety in a broad and clean label with no black box warning, and we couldn't have asked for a better FDA approval outcome. Let me now talk about the current treatment landscape and the unmet needs and the potential commercial opportunity for MIMRYLO. Let's go to the next slide. PV affects approximately 155,000 patients in the United States, of whom roughly 78,000 are currently on some form of treatment, with a comparable number of patients in Europe. Current options include phlebotomy, hydroxyurea, BESREMi, an interferon, and Jakafi, a JAK2 inhibitor. A very consistent observation is that the vast majority of this population, approximately 78%, experience elevated hematocrit despite current standard of care treatment, and this is seen across all different stages of treatment. This is worth stressing again. This lack of hematocrit control is observed across all patients throughout the current treatment choices, and these are the types of patients in which the VERIFY study showed a very clear benefit from MIMRYLO. Undisputably, this is clearly a large unmet need for a RBC-specific agent like MIMRYLO, and herein lies the strong differentiation and the commercial appeal of MIMRYLO. The FDA-approved label for MIMRYLO is very broad and allows it to be used as a monotherapy or in combination with any other therapy for PV. MIMRYLO can be expected to be used at each step of the treatment journey. Lastly, I would like to mention that PV is a very slow-growing and progressing disease with a median survival of 14 years. Following diagnosis, patients often require lifelong chronic therapy. The data from our long-term phase II REVIVE and THRIVE clinical studies have shown excellent persistence. A total of 46 patients who completed the randomized portion of the REVIVE study transitioned to the open label extension or THRIVE study. Among these, 96%, or 44 out of 46 patients, were still on MIMRYLO at three years, and 89%, or 41 out of 46 patients, were still on MIMRYLO at four years. This speaks to the longer-term patient choice to remain on therapy and how we expect MIMRYLO to be used as a chronic long-term therapy. In summary, the FDA-approved label for MIMRYLO is very broad, and MIMRYLO can be expected to be used at each step of the treatment journey, both as a monotherapy or in combination with any other therapy for PV. Now, we will have our CFO, Asif Ali, cover the partnership economics and the financials. Thank you, Arturo. Let me start with our strategic partnerships as they are an increasingly important part of how we fund and build the business. Historically, we have relied on a balanced mix of equity raises and partnerships. Today, however, the strength of our partnership model has reached an entirely new level. To date, we have earned approximately $1.2 billion in upfront milestones and op-type payments. We have also substantial future economics arising from each strategic partnership, as noted here. Starting with MIMRYLO, we are eligible for up to $875 million in future milestones and retain a tiered royalty of 14%-29% on worldwide net sales. Takeda has publicly guided to peak sales potential of $1 billion-$2 billion for MIMRYLO. For ICOTYDE, we have another $580 million in potential milestones. We retain 6%-10% in royalties, with HSBC estimating a peak sales potential of greater than $10 billion, with analyst consensus also in a similar range. Across these partnerships, we retain substantial participation in the commercial success of both MIMRYLO and ICOTYDE. Now, with that as the backdrop, the next slide highlights our current cash position as well as the additional payments triggered by the approval of MIMRYLO and the significant milestone opportunities that we just discussed. As for specifics, we reported cash equivalents, and marketable securities of approximately $850 million as of June 30. Approval of MIMRYLO triggered additional payments totaling $275 million, which further strengthens our balance sheet. Beyond that, we remain eligible for up to an additional $1.5 billion in combined milestones from the two products, as well as the royalties we mentioned in the previous slide. To sum up, our strong financial position, together with the potential future cash flows from our partnered assets, leads to three important outcomes. First, it gives us the ability to invest aggressively in the next generation of our R&D pipeline assets, which remains our top priority in terms of capital allocation. Second, this financial strength should provide substantial support for our planned R&D funding requirements, and we do not anticipate the need for an equity-based financing in the foreseeable future. And third, based on our current estimates for future cash flow, we will have the flexibility to consider potential capital returns to shareholders in the form of share buybacks over time. With that, let me turn the call over to Dinesh for some further perspective on our strategic position. Dinesh? Thanks, Asif, and let's go to the next slide. The successful approval of two first-in-class peptide drugs, MIMRYLO and ICOTYDE, coupled with two successful pharma partnerships, have created a unique combination of ample validation of Protagonist's emerging leadership in the field of peptide pharmaceuticals, and it has also created a strong financial base to support our future R&D pipeline. In a way, we have had a very successful past in the form of approval of ICOTYDE in partnership with J&J, a very secure present with the approval of MIMRYLO in partnership with Takeda, and amazing prospects of a much stronger future with a wholly owned pipeline addressing commercial markets valued at over $100 billion. At this stage, let me invite our Chief Discovery Officer, Dr. Ashok Bhandari, to give an overview of our thriving R&D pipeline. Ashok? Thank you, Dinesh. Unlike MIMRYLO, where we embarked on a totally new hypothesis, our current R&D pipeline is exclusively based on clinically validated biological pathways, thereby de-risking our programs and offering higher probability of success compared to the industry norms. Also, most of our projects are peptide-centric, where we have proven expertise and established proprietary platform. Our pipeline is focused in the area of inflammation and immunology, obesity, and hematology. The I&I space is currently dominated by major blockbuster category injectable antibody drugs. Our long-term vision here is to revolutionize the whole sector by offering an oral peptide therapeutic option, one that is similar in the efficacy and safety to the injectable antibodies, but strongly differentiates itself by offering a convenience of a daily oral pill. Our first target in the I&I space was IL-23 pathway, and ICOTYDE is now already leading the race as a first-in-class oral peptide therapy for psoriasis with multiple other potential indications underway. Our next target is IL-17. Injectable IL-17 antibodies like BIMZELX and COSENTYX have a strong foothold in multiple indications like psoriasis, psoriatic arthritis, hidradenitis suppurativa, and spondyloarthritis. PN-881, our oral IL-17A and IL-17F antagonist, recently completed a phase I clinical study, and the encouraging results informed our decision to pursue a comprehensive phase II psoriasis study, which we expect to initiate in the first quarter of 2027. Our third target is in the IL-4 pathway, where we have similar aspirations to offer an oral pill for chronic indications like eczema and asthma, where the current treatment options are dominated by injectable antibodies like DUPIXENT. In the obesity space, the peptides tirzepatide and semaglutide are the clear dominant players. Although oral Wegovy and oral small molecule Mounjaro have started creating oral optionality for patients. PN-477, our GLP-1, GIP, and glucagon triple agonist program, is advancing in phase I with a subcutaneous formulation with oral phase I development plan in the first half of 2027. Injectable triple agonists like retatrutide offer the strongest weight loss observed to date. The hope here would be that PN-477 could be a once-a-day oral pill that could provide maximum weight loss. PN-458, our oral GLP-1/GIP dual agonist, is currently in IND-enabling studies, and we are also advancing amylin mono and polyagonist assets through lead optimization. The field of anti-obesity agents is rapidly evolving, and our strategy is to have a broad portfolio of oral incretin and non-incretin agents against well-validated targets that could offer strong differentiation and improvements over current treatment options. Now moving away from more prevalent indications to our efforts in the rare diseases. PN-8047, our oral hepcidin mimetic, is expected to enter phase I in the first quarter of 2027. Building on the deep expertise in the hepcidin pathway that ultimately led us to MIMRYLO. With that, now I will hand it over to Dinesh. Thanks, Ashok, for that excellent overview of our amazing R&D pipeline. A common and critical feature about most of the R&D programs that Ashok described is that a phase I clinical study in itself could provide an early clinical POC, thereby providing a steady stream of data readouts early on and allowing us to prioritize these programs in a very time and cost-efficient manner. Both the I&I and anti-obesity disease areas belong to mega-blockbuster category drugs that are best commercialized, in our opinion, by large pharmaceutical companies. Protagonist will have a clear preference to structure strong partnerships at the right time and with the right economic terms for these assets and programs. But unlike where we were a few years ago, we now have the financial resources and in-house development expertise to take our assets much further in development and thereby generate significantly higher value in potential partnerships. On the other hand, in the rare disease category, we may be inclined to consider maintaining an independent path all the way through development and NDA filing. To conclude then, in summary, today's approval of MIMRYLO represents another defining milestone for Protagonist, our people, and our platform. For the second time this year, an FDA approval has further validated the strength of our platform and our ability to generate differentiated, first-in-class medicines addressing unmet needs and with meaningful therapeutic and commercial potential. We believe this is just the beginning and not the culmination of a new phase of innovation and value creation for Protagonist as a biopharmaceutical company with expertise in peptide therapeutics. I would once again like to congratulate the Protagonist and Takeda teams, whose dedication, commitment, and collaboration made this important milestone possible. I want to recognize the investigators, study teams, site staff, caregivers, and most importantly, the patients who participated in the MIMRYLO clinical development program. Their contributions were very essential in bringing this important new treatment option to patients with polycythemia vera. With that, I will now ask the operator to begin our Q&A session. Operator? Thank you. We will now be conducting our Q&A session. To ask a question at this time, you may press star one from your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star two if you would like to withdraw your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Thank you. Our first question is from the line of Alex Hammond with Wolfe Research. Please proceed with your questions. Thanks for taking my question and congratulations on the approval. I guess given what appears to be a pretty broad label for patients, how are you thinking about prescriber willingness to adopt this therapy in the frontline setting, likely on top of phlebotomy? I guess what are you and Takeda's expectations for adoption in treatment-naive patients as well? Thank you. Thanks, Alex. Yes, indeed, it has been a great outcome, and we are thrilled that it is a very broad label and a clean label. We expect MIMRYLO to be used all across the PV patient population. It is a drug for all comers because the key criteria is erythrocytosis. As our real-world patient data suggests, this is a kind of condition that is prevalent during all stages of treatment and through all levels of progression of the disease. I will also have Arturo, our Chief Medical Officer, weigh in and make some comments. Yeah. Thanks, Dinesh. As Dinesh mentioned, there is real-world data that shows that with the currently available treatments, about 78% of patients do not have hematocrits below 45 at any given time that you assess them during the course of their treatment. There is where the unmet need really lies. One very important aspect about our study is that it allowed the principal investigators to employ whatever they thought was the best standard of care for their particular patient. Despite using the standard of care, these patients were requiring very frequent phlebotomies, which are associated with adverse events and iron deficiency. To answer your question, we believe that MIMRYLO is an add-on treatment, and it can be combined safely with cytoreductive therapy and particularly with phlebotomy as needed. One of the things I would say is, this is a novel, unprecedented therapy, so there is always a curve of getting adoption of something that is novel and game-changing like this. That being said, one of the things we have going in our favor vis-a-vis adoption is the fact that people feel better. When you are a practicing physician, it does not take too many patients being treated who say, "Oh, this really made me feel better. My fatigue, my ability to function, et cetera," for you to want to prescribe it to more patients. I think that is going to really help the commercial aspect of adoption and having that in the label really aids in helping us with that message. As you know, one of the fatigue measurements has made it into the label in the efficacy part of the label. This is the first time that it has ever happened for a drug related to PV treatment. We believe that is a big win and at the end of the day, quality of life matters the most, and this drug clearly has an impact over that. I just want to second that. Right now, the experience with rusfertide is limited to the principal investigators across the world. But when you talk to them and they share the specific stories of their patients, some of whom were unable to work before starting treatment on rusfertide, and then go on to not only feel better, but go back to work. These doctors are waiting for the approval so they can put other patients that they have who did not make it into the study. I think as physicians get experience with the use of MIMRYLO and they see that not only does it achieve the goal of controlling hematocrit below 45%, literally 24/7, but also improving how the patient feels and functions with their polycythemia vera, we anticipate that physicians will want to offer this as part of the standard of care and one of the treatment options that they can jointly decide with the patient on how best to treat their PV. The next question is in the line of Evan Seigerman with BMO Capital Markets. Please proceed with your question. Hi, this is Conor McKay on for Evan. Thanks for taking our question, and I will offer our congrats on the approval as well. Maybe as a quick follow-up to the last question, appreciating that Takeda is in the driver's seat commercially, we were just wondering if maybe you can speak to your view of the potential uptake trajectory for MIMRYLO. What do you see as the biggest potential frictions and synergies versus currently approved agents? Are there any low-hanging fruits here, or is it really all about broad adoption? Thank you. Yeah, I think as you know, Takeda has provided formal guidance in the range of $1 billion-$2 billion peak annual sales for the drug. What I would quickly add is this is the guidance that was of course provided even before we had the phase III study results, and those results were outstanding. And before we got this amazingly broad and clean label. So time will tell. I would also point out that this is not competitive with other drugs or therapies. The study that was done was standard of care, plus or minus rusfertide, as it was called at the time. This drug can be used in any patient who has erythrocytosis. As we know in the literature and from our own work, the vast majority of patients who are on drugs or phlebotomy alone do not have control of their hematocrit. We do not see this as competitive. In fact, some of these drugs that were used in our phase III study have their own toxicities. Doctors may be interested in thinking about other types of combinations in the future. In a way, this is a first-in-class medicine of its type, right? Until now, there has been no erythrocytosis-specific agent for this disease, which is very erythrocytosis centric. This condition of uncontrolled hematocrit is there in about 78% of the patients. It is a major unmet medical need that MIMRYLO could be addressing. I would not be surprised if the early adoption and eventually the peak potential exceeds our expectations. I just wanted to add that the other cytoreductive treatments, because they affect the white blood cells and platelets, have potential to cause leukocytopenia, like low white blood cells and low platelet counts. If the main problem for a patient is erythrocytosis, now we have a solution that can address the erythrocytosis. Good. Thank you. The next question's from the line of Tara Bancroft with TD Cowen. Please proceed with your question. Hi, good morning. I also want to offer my congratulations on this really remarkable accomplishment. I guess the one thing that would be really helpful in clarifying with you guys is on the blood count monitoring. Maybe from a patient perspective, how much time is typically required at these visits in order to do that? What proportion of patients do you think will require two versus four weeks of monitoring? And how long do you think the monitoring period could possibly take? And I ask that because of the eight weeks or so stability that you observed in the clinic. Maybe just some more details in general on that would be really helpful. Thank you. Yeah. The way I would answer it is it's very much within the norms of whatever requirements are there currently for other agents used for treatment of PV. But maybe Arturo, you can elaborate a bit further. Yeah. As you mentioned, the monitoring every two to four weeks is primarily during the titration period. But what we saw in the study is that patients achieve stable counts within eight weeks, and then as the patient is being followed through a longer period of time, the frequency of monitoring becomes less and less. So in our THRIVE study and REVIVE study, where patients have been on treatment two, three years, their blood counts are only monitored every 12 weeks. This is no different than the way blood counts are monitored for any of the other treatments that are available for polycythemia vera. It fits right with what is the standard of care for these patients. The other thing that limits us in that regard is this drug has a very quick pharmacodynamic effect, so that when you change the dose up or down, you see the effect of that change very quickly. You don't have to wait weeks and weeks to see what happened. You know at week one and week two after making a change directionally, whether you've made the right change and if it is now for too much, etc. That's what limits the titration period is getting to the right dose is relatively straightforward because the time to see the effect of a dose change is very limited. Okay. Thank you very much. The next question is in the line of Richard Law with Goldman Sachs. Please proceed with your questions. Hey, guys. Congrats on the approval from me as well. Given that monitoring and titration period that you require that you guys mentioned, do you anticipate the need to do this through the buy and bill process initially for some time before that can get shifted to patients to do the at home administration? If so, how long do you anticipate that could last? That is really between a patient and their doctor. Some patients, if you are in a rural area, etc, the CBC is the oldest blood test in the world, and it includes both the platelet count, the white count, and the hematocrit. So in one simple blood test, which again is probably one of the most common tests known to the laboratory world, you can get all three things. So how it is done is between a patient and there is no requirement that it be in the office, let us put it that way. In the vast majority of patients on the clinical trials, it was self-administered, especially once the patient had been on it for a couple of months. Yeah. Richard, it is a good point. Eventually, the idea here is the convenience of a self-administered drug at home. Great. Thank you. The next question is from the line of Roger Song with Jefferies. Please proceed with your questions. Great. Congrats for the dual approval within a year, both of which has a very clean, great label. Maybe we will be curious to hear about the feedback about the, particularly for the dosing regimen, as we already discussed a little bit on the titration period and then weekly dosing, and then some adjustment required for those kind of studies back. How should we think about the durability and then also the compliance for the MIMRYLO in real world versus a clinical trial, understanding very low discontinuation during the trial? Thank you. Yeah. MIMRYLO has garnered a wide range of experience through the phase II, REVIVE and THRIVE, and the phase III VERIFY studies, right? What we can say in broad strokes is that for most of the patients, either a 20 mg or a 40 mg dose will do the trick. Of course, there will be situations where someone may require a very low dose, or somebody may require a high dose. In the beginning, those things, it takes maybe a few weeks, few months to settle down. But after that, things are pretty predictable. What we do not want to do is overdose because that would make a patient anemic, just based on the consequence of excessive pharmacologic, right? That sort of thing. But Arturo- Yeah. Roger, as a reminder, when we finished up the REVIVE study and patients and the PIs were informed that the study was coming to an end, we were asked if we could find a way to continue treating patients, and that is why we developed the THRIVE study because there was very high demand from the patients who had already been on treatment for 2+ years who wanted to continue on treatment. I think that speaks volumes. Remember, Roger, part of that is perhaps because people are feeling better. Both Arturo and I are trained as hematologist oncologists, and we do not get to give drugs very often to patients that actually make them feel better. If in fact you look at some of the patient reported outcomes we saw, perhaps that is part of the explanation for the persistence of this drug. Real world is never as good as clinical trials, as you point out. But this has a lot of reason to believe that it is going to have good persistence relative to other treatments that are used in this disorder. The next question is from the line of Brian Cheng with JPMorgan. Please proceed with your questions. Hey, guys. Thanks for taking our question this morning, and truly congrats on the approval here. I am curious if you can just walk us through how you think about the MIMRYLO's trajectory, in your anticipation. I understand that the end game is really about product adoption. But how should we think about the early wave of adoption? Is that coming from those patients who have tried ruxolitinib or falling off Interferon? Just curious how we can think through that early part of the dynamic. Then, second is really about pricing. Have you disclosed the pricing? I do not know if I missed that, and also the gross net for this asset. Thanks for taking our questions. Thanks, Brian. I will answer the second question first. In terms of pricing, that is something that Takeda will share at the right time. In terms of your first question, I think, at some level, it is going to be dictated by the doctor and the patient. But, we take great comfort in the fact that the label is very broad and it is very clean. So it should be a drug for all comers. As you well know, erythrocytosis is a very strong common undercurrent in all patients who are going through all sort of treatment regimens, right? Whether it is a Jakafi or BESREMi or hydroxyurea or phlebotomy alone. So I think, where it pops up first and that sort of thing, I think it should all play out over a period of few quarters, in my opinion. Brian, the trials are coming to an end. The REVIVE study, we expect for all patients to complete treatment in January of next year. Then in VERIFY, as patients continue to make it through that final part of the study, what I hear from the PIs is that then they will go to commercial supply. Also, as the data was presented at ASCO, we started to get quite a bit of requests for expanded access. Although we did not have an expanded access program, I think the doctors are now learning more and more. Even as of from Friday, I have received emails and notes on LinkedIn from doctors who want to know more about MIMRYLO. I would say two things, Brian. One is, we would never speak for Takeda in terms of trying to predict what the trajectory is going to be that is really in their hands. I would make a couple of relevant points. One is, it is a highly targeted audience. This is, every launch has its A, B and C doctors, but this MPN treaters are a very targeted audience at the very top of the pyramid. The second point I would make is because this population of patients are typically diagnosed in their 50s, they are extremely active on the internet, and I am sure you will find plenty of stuff, after we launch here, about patient experience on the internet. Great. Maybe just one quick one, too, on the just the finance side. You guys talked about the potential, well, actually reiterating the potential to return capital to shareholders. Do you have a better sense of the trigger point and, also whether, what the allocation is, dedicated to the return capital to shareholders? Thank you. Yeah. We have always maintained that first things first. One of the first thing was let rusfertide or MIMRYLO get approved. That has happened as of last Friday. The second thing was our top priority is R&D funding. As you know, Ashok gave an overview. You can see it is an amazing pipeline. That is our topmost priority. But, yeah, we do believe that with the revenues that we expect to flow into the company from two partnerships around these two products, there should be an opportunity for proper capital allocation, including share buybacks. But, Asif, you want to make any further comments? Yeah, only to add to what you just said. I mean, we continue to review the size of the buybacks and considering the investment requirements, which is the key capital allocation requirement for us internally. We have disclosed previously that a potential announcement by year-end, so that by year-end timing, is still in my mind the likely timeline for an announcement. Yeah. But in the same breath, we should also add that Protagonist should really be viewed as an R&D story rather than a share buyback story, because it's really the strength and the success and the validation through these two drugs. Now going for repeat performance and betting on the R&D pipeline, that's where the emphasis should be. The share buyback, I don't want to downplay it, but that's almost like a sideshow. Great. Thank you, Dinesh. The next question is in the line of Kripa Devarakonda with Truist Securities. Please just use your questions. Hi, this is Alex on for Kripa, and congrats on the approval on the broad label. Questions from us, are you able to comment on the specific sales thresholds that drive the movement to the royalty tiers? Should we think of the royalty tiers as being the same across global sales? Also for the $275 million approval related milestones triggered by the approval, how much is expected to be recognized or received in the third quarter versus later periods? Yeah, thanks for the question. I mean, as for the, we've not disclosed the specific tiers, but we have disclosed that it is a 21% weighted average royalty at $1.5 billion and 29% for annual sales that exceed $1.5 billion. That should give you a reasonable metric for modeling this out. I'm sorry, what was the second part of your question? On the approval-related milestones of the $275 million, when will it be recognized? In the third quarter or spread across later periods? Yeah, that's something, as you can imagine, is always an interesting, complicated accounting answer. So we'll look into that. We do expect to recognize at least a significant proportion of that in Q4 or Q3, sorry. Okay, thanks. The next question's from the line of- I mean, $200 million is the opt-out fee, so that's straightforward. But the $75 million is the milestone, so yeah. The next questions are from the line of Geoff Meacham with Citi. Please proceed with your questions. Hey, guys. This is Nishant on for Geoff. Let me add to the congratulations as well. On launch, maybe can you talk about the top three or four kind of launch indicators investors should kind of watch over the next six months that will tell us commercialization is kind of tracking ahead or in line with expectations? How prepared do you think are the payers and treatment centers today relative to where they were at the time of NDA submission? Thank you. Yeah, no, I think, look, if you look at our first drug, ICOTYDE, and the details that our partner J&J is sharing, it is fair to conclude that it will take about 6-12 months from launch to get into some sort of a rhythm or a steady state. So similar thing can be expected over here. As we have mentioned before, those are the specifics that our partners will be sharing down the road. We will be, of course, collecting the checks, but kind of exclusively focusing on our emerging R&D pipeline. We are very fortunate that Takeda Pharmaceutical has been very disclosive about this program. They labeled this as one of their three most important launches for the future of their company. Just like J&J with ICOTYDE, we expect for them to do the talking and be wanting to be disclosive, given the importance that they have mapped out for this to the success of their pipeline. Yeah, then maybe about the payer question on their readiness. We think Takeda's doing a great job and is fully ready to launch this thing immediately. This is a novel agent. There's nothing else like it. There's a tremendous unmedical need that makes people feel better. We do not think there'll be tremendous pushback with payers in the rare disease category like this. Yeah, I mean, as you know, PV is a rare disease by definition. So that in itself commands some concessions in the review process. We had priority review, it demands. It is typical to lean towards premium pricing. That's the whole incentive-based system that is set up for attending to rare diseases. So we believe there should be no exception. If you look at the pricing of the recent drugs that have been launched in this area, that can give you some rough guidance. But once again, one has to wait for Takeda to share that kind of information. I would add that with the label being so clean, no black box warning, for the first time, having a key secondary endpoint demonstrating improvement in fatigue and improving how the patient feels and functions, this is a very differentiated compound, definitely differentiated from the other cytoreductive therapies. Great. Thank you, sir. Next questions are from the line of Thomas Smith with Leerink Partners. Please proceed with your questions. Hi, this is Nat Charoensook with answer Tom Smith. Congrats on the approval. Just one question from our end is on dosing. What percentage of patients do you expect to get doses above 82 mg that will require administration across two days? That is extremely unlikely. The vast majority of patients are all in the middle range, and we saw that in REVIVE and in VERIFY. So it is a very small number, less than 1% or 2%, that require more than once a week administration. That is what makes it so easy to titrate, is that the patients cluster so largely in a very narrow range that is not that much higher than the starting dose. Got it. Very helpful. Thank you. The next question is from the line of Douglas Tsao with H.C. Wainwright. Please proceed with your question. Hi, good morning, and congratulations. Dinesh, it's been a great journey. Two questions from me. First, for MIMRYLO, I'm just curious, do you expect that the availability of this to treat erythrocytosis in PV will allow clinicians to broadly optimize treatment with other agents, and that will be a real motivation in addition to patients feeling better, just broadly, clinicians will see an opportunity to better treat PV patients? It's a great question, and I would say at the end of the day, the physician is going to be the best judge over here in terms of what is in the best interest of the patient. We would like to point out, though, that the approval is for treating erythrocytosis in all type of PV patients, irrespective of their stage of disease. Clearly, this drug's job is to control RBC synthesis only. If there are instances, especially in the later stages of the disease, where it's important to manage the WBC and platelet counts, then that is where other treatments become equally important. Yeah, I would like to add that the most commonly used cytoreductive therapy in the VERIFY study and in REVIVE and THRIVE is hydroxyurea. So these patients were being managed with hydroxyurea, and the hematocrits were poorly controlled. Why was that? Probably because if the patients were given more Hydrea, then they could develop neutropenia or anemia or thrombocytopenia, but more likely neutropenia. So now you have a situation where MIMRYLO can control the erythrocytosis, and if there is a need to treat leukocytosis, then that would be a rationale for adding another cytoreductive therapy. But it is hard to manage these patients with Hydrea if it is causing neutropenia, for example. We would not be in the business of trying to convince doctors to change anything about what they are doing with the existing therapies. But that being said, doctors and patients are well aware that the existing therapies have dose-related toxicities, so that could be a motivation for seeking— And just— —an alteration in that dose. But we are not going to be talking about that or promoting that in any way. What I see potential for, remember when we mentioned the real-world data shows that about 78% of patients will have elevated hematocrits through the course of their treatment. Wouldn't it be great from the patient perspective if those numbers went down a lot? That's where I think the unmet need is. The other way to state it is, look, if the core problem is erythrocytosis, you don't need to use a cytoreductive to control that. You can use an erythrocytosis-specific agent, which is MIMRYLO. We believe that is the most common and dominant aspect of polycythemia vera as a rare blood cancer disease. Okay, great. That's very helpful. Dinesh, obviously, as a company, you've now had success with two strategies in terms of drug development. With ICOTYDE, you were able to take a proven mechanism and convert it to an oral peptide. Rusfertide obviously was a novel mechanism. I guess when we look at your pipeline, PN-881, the IL-4, as well as potentially some in the obesity assets, you leaned into the improving the delivery of proven mechanisms approach. I'm just curious, is that where most of the focus is going to be, or do you see an opportunity, either as an independent company or potentially partnering with others to target novel or innovative mechanisms as well? Thank you. That's a great question, Doug. What I would say is Protagonist still has the mentality of a biotech startup. We are bubbling with new ideas, new aspirations. I think it's going to be a combination of both. In today's R&D pipeline, you're right. It is dominated by the true and proven biological pathways, but these are the low-hanging fruits, but with a blockbuster kind of potential, right? Our aim really is to revolutionize the whole treatment landscape of all sort of chronic diseases. A chronic disease means patients have to take a drug for a long period of time. If you look at it, almost all chronic indications are dominated largely by injectables. So, what we are offering, a new peptide as an oral pill, the efficacy and safety of the injectable antibodies and the convenience of an oral pill. That is going to be huge, highly differentiated, and highly desirable for these patients suffering from chronic diseases. Having said that, of course, we are scientific creatures. We have a lot of new ideas, and so that is also something that is brewing in our R&D engine. Over the course of time, we will be able to share more information around that kind of novel targets and approaches as well. Fortunately, we have the financial bandwidth to cover all of those kinds of approaches and targets. Absolutely. Congrats again, Dinesh. Thanks, Doug. Appreciate it. Our next questions are from the line of Catherine Okoukoni with Citizens. Please proceed with your questions. Hi, this is Catherine on for John. Thanks for taking our question. Just a question about sort of the initial target market. I know that you guys have said that this is both kind of an add-on therapy, potentially monotherapy. But as far as the $1 billion-$2 billion peak sales estimate, does that include monotherapy and kind of what portion of naive patients are included? I would assume it includes all type of patients, polycythemia vera patients. But what I can also point out is this is a market projection by a pharma company, Takeda. This is a projection that was made before the outstanding phase III results were obtained, and this is a prediction that was made before such a broad and clean label, with no black box warning, no carcinogenicity components was issued. So I think we couldn't have asked for a better outcome, and we will just have to see how things progress in real practice. And one more thing to add is that we have done analysis looking at all the different subgroups, low risk versus high risk, older versus younger, gender, and every subgroup benefits from treatment with MIMRYLO. And again, with the clean label, an absence of a black box warning, I think this will be a very attractive agent for patients who do not want cytoreductive therapy. If you look at our phase III study, the VERIFY study, you'll see that the demographics of who's on cytoreductives and which cytoreductives they are on exactly mirrors what you would see from the overall marketplace, indicating, A, that both cytoreductive with non-cytoreductive patients still have a problem with erythrocytosis in big numbers, but two, that with amongst the different drugs, again, we get the exact same use patterns you do from the overall market. Perfect, thanks. The next question is in the line of Yun Zhong with Wedbush. Please proceed with your question. Hi. Good morning. Thank you very much for taking the questions. I wanted to ask about your oral candidate, PN-8047, potentially for the same indication of PV. If phase I data do support phase II initiation for PV, can you talk about, I know it is early, but can you talk about maybe a potential patient or target patient population study design? Is there any possibility that you can leverage your experience or data from rusfertide to expedite the pathway? In terms of strategic thinking, does Takeda have the first to negotiate right for the oral compound, please? Thank you. Yeah, I am glad you noticed the oral hepcidin. MIMRYLO is already approved. The oral hepcidin PN-8047, that is at a preclinical stage. MIMRYLO is a first-in-class drug of its type, so it is going to have exclusivity in terms of the market for a good number of years, whether it is our drug or something else. We like that spread out. But in the spirit of what could come next, as you know, through our other programs, we are big believers of oral peptide drugs. Here we have an oral hepcidin functional mimetic. You are right, the phase I will give us a good clue about how the drug is performing by just observing the effect on serum iron levels in healthy volunteers. Then that should get us going towards exploring polycythemia vera as a major indication in a phase II study. We certainly would leverage our learnings from rusfertide. I think that we have a large safety database targeting ferroportin with rusfertide, and given that our MOA would be very similar, except this would be an oral agent, the whole target already has validation, not just of efficacy, but safety. We think we would be able to leverage that in our discussions with the FDA. You are right, Takeda does have the right of first negotiation, but of course, that is only if we choose to partner it. If we choose to partner it, then of course, with that right, we will be certain that we get the market price since they will have to negotiate against others, if you will. Great. Thank you very much. The next question is from the line of Kaveri Pohlman with Clear Street. Please just use your question. Yes, good morning. Congrats on the approval, and thanks for taking my questions. The approved formulation allows for self-administration, but are there still plans to bring an auto-injector presentation to the market? How much additional development work would be required to support that newer formulation, and any timeline on that? The second question is about the VERIFY. You have additional open-label data from VERIFY. Is there any timeline for that as well that you plan to report? Are there, besides this open label, any phase IV study you plan to conduct, or Takeda plans to conduct for rusfertide to collect real-world efficacy and safety data that could also potentially help support the development of PN-8047? Thank you. Yeah. So thanks, Kaveri. Those are a number of excellent questions. I may ask you to remind us of the questions. But I think the first question, in terms of that, what we believe that the next thing that could come down the pipe is an auto-injector for administering the drug, but that is something that Takeda can share in more depth at the appropriate time. As far as publication, yeah, the results from VERIFY are under review. Stay tuned. Yeah. Yeah. Last but not least, long-term data collection and those sort of things, those are the things that would be good to have and that kind of thing. But I would like to state that that is no formal requirement from the FDA for conducting a phase IV study. Right, Arturo? That is correct. Yeah. There will be more details on that. But again, the label is very clean, and the post-marketing requirements are all contained within what we are already doing. But whether or not Takeda chooses to do additional studies for their own purposes, that is up to them. Yeah. We will also be publishing the final results of the REVIVE study that gives you some of that long-term follow-up that I mentioned. Thank you. At this time, there are no further questions, and I will now turn the call over to Dr. Patel for his closing remarks. Great. Thank you all again for joining us this morning. The approval of MIMRYLO is a proud and historic moment for Protagonist and an important validation of the science, the proprietary platform, and the amazing team that helped each other bringing this medicine from discovery to patients. With two FDA-approved partnered medicines, a strong financial foundation, and a wholly owned pipeline advancing across inflammation and immunology, metabolic and hematological diseases, we believe Protagonist is entering an exciting new phase of growth and value creation. Thank you again for your continued interest in and support of Protagonist. Have a nice day. Ladies and gentlemen, this concludes today's presentation. 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