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

Welcome to the Protagonist Therapeutics conference call. [Operator Instructions]. As a reminder, this call is being recorded today, Monday, August 31, 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; and Dr. Arturo Molina, CMO; Dr. Ashok Bandari, Chief Discovery Officer and Dr. Samuel Saks, Clinical Development Adviser. 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 31, 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 18, 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 Polytemavera or PV. This is a first-in-class medicine that targets the biology driving red blood cell or RBC over production in PV. I would like to congratulate both the Protagonist team and our partner, Takeda Pharmaceuticals, on this very successful outcome. As most of you know, PV is a rare blood cancer when in the fundamental treatment goal for patients as per NCCN guidelines is to lower hematocrit, which is a ratio of red blood cell volume to total blood volume and to maintain the hematocrit level below 45%. While PV is an erythrocytosis driven broad disease, there has been no erythrocytosis specific therapy available as a treatment. So it is this unmet need that drove us on the path of discovering and developing embryo. So how does Merino 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 endogenohepcidin 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 standard 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 disregulation 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 level, 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. So going to Slide 4, let's start with the historical perspective on Mimrylo journey from concept through 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 2 levels. First, it is a testament to our scientific team's innovative expertise in originating the hypothesis that hepcidin mimetic could lead to a first-in-class medicine for disregulation 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, overly soluble and only moderately portal, 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 PeP platform is now very broad from what it was in those days, encompassing a full range of tools, including but not limited to competitional tricsliberies, page libraries, medicinal and peptidomimetic chemistry, formulations and artificial intelligence. And 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 revised clinical proof-of-concept study, the Takeda partnership it 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 revised results in the New England Journal of Medicine and presentation of the Phase III VERIFY results at the 2025 coplanary 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 TV. Arturo?

Thanks, Dinesh. Let's go to Slide 5. 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 to 32. This study met not only its primary endpoint of clinical response, but also all the 4 key secondary endpoints, including the patient-reported outcomes assessing fatigue and overall symptom burden, specifically the promised fatigue score and the MFSF symptom score. Importantly, the improvement in fatigue was measured by the promised fatigue Short Form AA 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. These 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 Kirkendall, Dr. Catherine Walsh from Vanderbilt provided her view as a formal independent discussion. She described the study results as practices 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 broad label received from the FDA approval of Mimrylo. The label accurately reflects the excellent safety and efficacy results submitted in the respite NDA. In terms of efficacy, Mimrylo achieved a high response rate of 76.9% during weeks 20 to 32 and maintain hematicrit control and reduced phlebotomy. Importantly, Mimrylo improved fatigue in patients with PV as measured by the promised 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. And for the first time, an improvement of fatigue has been demonstrated and included in the label as a key efficacy outcome in a Phase III trial in polycythemia vera. We're also very pleased with the safety profile observed in the Mimrylo clinical development programs. First and foremost, there is no black box warning in the prescription label. Secondly, there are no carcinogenicity signals in the 6-month transgenic mouse study in the 2-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 precaution 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 and 0.7% and or 2 patients, trogocytosis, in 0.7% or 2 patients and anemia in 0.4% or 1 patient. So 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 need and the potential commercial opportunity for Mimrylo. Let's go to the next slide. TV 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, Bez Remy and interfere and Jakafi a JAK2 inhibitor. A very consistent observation is that the vast majority of this population, approximately 78% experienced 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 hematic 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 an RPC-specific agent like Mimrylo and herein lies the strong differentiation in the commercial appeal of embryo. The FDA approved label for Mimrylo is very broad and allows it to be used to some 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. And 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 patients were still on Mimrylo at 3 years, and 89% or 41 out of 46 patients were still in Mimrylo at 40 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 opt-out 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% to 29% on worldwide net sales. Takeda has publicly guided to peak sales potential of $1 billion to $2 billion for Mimrylo. For ICOTYDE, we have another $580 million in potential milestones, we retained 6% to 10% in royalties with HSBC estimating a peak sales potential of greater than $10 billion with analyst consensus also in a similar range. So across these partnerships, we retained 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, cash equivalents and marketable securities of approximately $850 million as of June 30, and 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 2 products as well as the royalties we mentioned in the previous slide. So to sum up our strong financial position, together with the potential future cash flows from our partnered assets leads to 3 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 2 first-in-class peptide drugs, Mimrylo and ICOTYDE, coupled with 2 successful pharma partnerships have created a unique combination of ample validation of tags 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 secured 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. So unlike Mimrylo, where we embarked on a totally new hypothesis, our current R&D pipeline is exclusively based on clinically validated biological pathways, thereby derisking our programs and offering highest probability of success compared to the industry norms. Also, most of our projects are Epticentic, where we have proven expertise and established proprietary platform. Our pipeline is focused in the area of inflammation and immunology, obesity and hematology. The INI space is currently dominated by a major blockbuster category injectable antibody attacks. 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 pay. 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 with injectable IL-17 antibodies like Vemzelix and Cosentyx have a strong foothold in multiple indications like psoriasis, psoriatic arthritis, hidradenitis supparativa and spondyloarthritis. PN-881, our oral IL-17A and N7 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 a 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 peptide tirzepatide and semaglutide are the clear dominant players. Although oral WIGOVY and oral small molecule Fundao have started creating oral optionality for patients. 477, our GLP-1 GIP and glucagon triple agonist program is advancing in Phase I with the subcutaneous formulation with the oral Phase I development plan, in the first half of 2027. Injectable triple agonist like retetutide offer the strongest weight loss observed to date. So the hope here would be that P-77 could be a once a daily oral bill that could provide maximum rate loss. PN458, our oral GLP-1 GIP dual agonist is currently in IND-enabling studies and we are also advancing Amlin 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. And now moving away from more prevalent indications to our efforts in the rare diseases. PN8047, 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 memorize. 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 Ashokay 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 cash-efficient manner. Both I&I and anti-obesity disease areas belong to make up blockbuster category drugs that are best commercialized in our opinion by large pharmaceutical companies. So obviously, 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 significant 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. So 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, and 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 mini therapeutic and commercial potential. We believe this is just the beginning and not the cumulation 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 team 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. And with that, I will now ask the operator to begin our Q&A session. Operator?

[Operator Instructions]. And our first question is from the line of Alex Hammond with Wolfe Research.

Congratulations on the approval. So 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 lobotomy. And I guess what are you antics expectations for adoption in treatment-naive patients as well.

Thanks, Alex. Yes, indeed, it has been a great outcome. And we are thrilled that it's a very broad label and a clean label. And we expect this to be Mimrylo to be used all across the PV patient population, it's addressed for all-comers because the key criteria is erythrocytosis and as our whole world real patient data suggest this is a kind of condition that is prevalent during all stages of treatment and through all levels of progression of the disease. But I will also have Arturo, our Chief Medical Officer, weigh in and make some comments.

Yes. Thanks, Dinesh. As Dinesh mentioned, there's 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. And there is where the unmet need is 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. And despite using the standard of care, these patients were requiring very frequent phlebotomies, which are associated with adverse events and iron deficiency. So to answer your question, we believe that Mimrylio is an add-on treatment, and it can be combined safely with side reductive therapy and particularly with lobotomy as needed.

One of the things I would say is this is a novel unprecedented therapy. So there's always curve of getting adoption of something that's novel and the game changing like this. But that being said, one of the things we have going in our favor vis-a-vis adoption is the fact that people feel better. And when you're a practicing physician, it doesn't 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. So I think that's going to really help the commercial aspect of adoption and having that in the label really aids and helping us with that message.

I mean -- as you know, one of the fatigue measurements has made it into the label in the efficacy part of the label. And this is the first time that has ever been -- that it has never 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.

So 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 of rusfertide and then go on to not only feel better but go back to work. These patients -- the doctors are waiting for the approval, so they can put other patients that they have, who didn't make it into the study. I think as physicians get experience with the use of Mimrylo and they see that not only they 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 from the line of Evan Seekerman with BMO Capital Markets.

This is Conor McKay on for Evan. And I'll 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 Milo. 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?

Yes, I think, I mean, as you know, Takeda has provided formal guidance in the range of $1 billion to $2 billion peak annual sales for the drug, what I would quickly add is like 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, time can tell.

I'd also point out that this is not competitive with other drugs or therapies. The studies that was done were standard of care plus or minus rusfertide as it was called it for time. So this drug can be used in any patient who has erythrocytosis. And as we know in the literature and from our own work, that the vast majority of patients who are on drugs or phlebotomy alone not have control of the hematocrit. So we don't see this as competitive. In fact, some of these drugs that were used in our Phase III study have their own toxicities. So doctors may be interested in thinking about other types of combinations in the future.

I mean -- in a way well, 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, and this condition of uncontrolled hematocrit is there in about 78% of the patients. So it's a major unmet medical need that Mimrylo could be addressing. So I wouldn't be surprised if the early adoption and eventually the peak potential exits of 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 leukocyte cytopenia, like low white blood cells and low platelet counts. And with -- if the main problem for a patient is erythrocytosis, now we have a solution that can address the erythrocytosis.

The next question is from the line of Tara Bancroft with TD Cowen.

I also want to offer my congratulations on this really remarkable accomplishment. So I guess the 1 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. how many -- like what proportion of patients do you think will require like 2 versus 4 weeks of monitoring? And how long do you think the monitoring period could possibly take. And I ask that because of the 8 weeks or so stability that you observed in the clinic. So maybe just some more details in general on that would be really helpful.

Yes. The way I would answer it is like 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.

Yes. As what you mentioned the monitoring of every 2 to 4 weeks is primarily during the titration period. But what we saw in the study is that patients achieved stable accounts within 8 weeks. And then as the basin 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 2, 3 years there accounts are only monitored every 12 weeks. And so this is no different than the way blood counts are monitored for any of the other treatments that are available for polysycthemia 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 effects so that when you change the dose up or down, you see the effect of that change very quickly. So you don't have to wait weeks and weeks to see what happened. You know at week 1 and week 2 after making a change directionally, whether you've made the right change and not offer too much, et cetera. So 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.

The next question is from the line of Richard Law with Goldman Sachs.

Congrats on the approval from me as well. So given that monitoring and titration period that you acquired that you guys mentioned, do you anticipate the need to be -- to do this through the buy-and-bill process initially for some time before that can get shifted to the -- to patients to do the at-home administration? And if so, like how long do you anticipate that that could last?

That's really between a patient and their doctor. Some patients, if you're in the rural area, et cetera, the CBC is the oldest blood test in the world. And and it includes both the platelet count, the white count and the hematocrit. So in one simple blood test, which again is probably 1 of the most common tests known to the laboratory world. you can get all 3 things. So how it's done is between a patient and there's no requirement that it'd be in the office, let's put it that one.

And 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.

Yes. And Richard, it's a good point, like eventually, the idea here is the convenience of a sell-side minister drug at home.

The next question is from the line of Roger Song with Jefferies.

Great. Congrats for the dual approval within a year, most of which has a very clean grade label. So maybe just we'll be curious hear about the feedback about the -- part 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, so how should we think about the durability and then sort of compliance for the Mimrylo in real world versus the clinical trial, understanding a very low discontinuation during the trial.

Yes. I mean, Mimrylo has garnered a wide range of experience through the Phase II triband the Phase III VERIFY studies, right? And what we can say in broad strokes is that for most of the patients, either a 20 meg or a 40 mg dose, will do the trick. And of course, there will be situations where someone may require a very low dose or somebody may require a high dose. So in the beginning, those things it takes maybe a few weeks, a few months to settle down. But after that, things are pretty predictable. What we don't want to do is over dose because that would make a patient dynamic, just based on the consequence of excessive pharmacology, right, that sort of thing.

Yes. And Roger, as a reminder, when we finished up the REVIVE study in patients in the PIs were informed that the study was coming to an end. We were asked that we could find a way to continue treating patients, and that's why we developed the THRIVE study because there was very high demand from the patients who are bit on treatment for 2-plus years who wanted to continue on treatment. I mean I think that speaks volumes.

And remember, Roger, part of that is because as because people are feeling better. I mean, both Arturo and I are trained as hematologists, oncologists and we don't get to give drugs very often to patients that actually make them feel better. And so if, in fact, you look at some of the patient-reported outcomes we saw, perhaps that's 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's going to be -- have a good persistence relative to other treatments that are used in this disorder.

The next question is from the line of Brian Chang with JPMorgan.

Truly congrats on the approval here. I'm curious if you can just kind of walk us through how you think about the Mimrylo trajectory in your anticipation. I understand that the aim 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 rux or falling off interferon. Just curious how we can think through that early part of the dynamic. And then second is really about pricing. Have you disclosed the pricing, I don't know if I missed that and also the growth on for this asset.

Thanks, Brian. I'll answer the second question first. In terms of pricing, that's something that Takeda will share at the right time. And in terms of your first question, I think at some level, it's 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. And as you well know, erythrocytosis is a very strong common under current and all patients who are going through all sort of treatment regimens, right, whether it's a Jakafi or [ Besam ] 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 a few quarters, in my opinion.

And also, Brian, the trials are coming to an end. And so the THRIVE study, we expect for our patients to complete treatment in January of next year and 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. But also as the data was presented at ASCO, we started to get quite a bit of requests for expanded exits. And so although we didn't have an expanded access program, I think the doctors are now learning more and more. And even as from Friday, I've received e-mails notes and LinkedIn from doctors who want to know more about Mimrylo.

I would say 2 things, Brian. One is we would never speak for Takeda in terms of trying to predict what the trajectory is going to be that's really in their hands. But I would make a couple of relevant points. One is it's a highly targeted audience. So this is -- every launch has its A, B and C doctors. But this the MPN treaters are a very targeted audience at the very top of the pyramid. And the second point I would make is because this population of patients are typically diagnosed in their they're extremely active on the Internet. And I'm sure you'll find plenty of stuff after we launch here about patient experience on theater.

Great. Maybe just one quick one on just the finance side. You guys talked about the potential we're 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 to capital to shareholders.

Yes. We have always maintained that first things first. So one of the first thing was letraspetide or Mimrylo got approved. So that has happened as of last Friday. The second thing was like our top priority is R&D funding. And as Ashok gave an overview, you can see it's an amazing pipeline. So that's our top most priority. But yes, we do believe that with the revenues that we expect to flow into the company from 2 partnerships around these 2 products, there should be an opportunity for proper capital allocation, including share buybacks. But Asif if you want to make any further comments.

Yes, 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. And we have disclosed previously that a potential announcement by year-end. So that by year-end timing is still in my mind, the likely time line for an announcement.

Yes. 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 2 drugs and 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 side show.

The next question is from the line of Kripa Devarakonda with Truist Securities.

This is Alex on for Kripa, and congrats on the approval and the broad label. Questions from us. Are you able to comment on the specific sales thresholds that drive the movement to the royalty tiers? And should we think of the royalty tiers as being the same across global sales? And 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?

Yes. 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 gives you -- should give you a reasonable metric for modeling this out -- and sorry, what was the second part of your question?