Agios Pharmaceuticals, Inc.

Good morning and welcome to AGO's second quarter 2025 conference call. At this time all participants are in a listen-only mode. There will be a question and answer session at the end. Please be advised that this call is being recorded at AGO's request. I would now like to turn the call over to AGO. Please go ahead.

Thank you, operator. Good morning, everyone. I'm Morgan Sanford, vice president of Investor at AGO. Thank you for joining us to discuss AGO's pharmaceuticals second quarter 2025 financial results and business highlights. You can access the slides for today's call by going to the investor section of our website, AGO.com. Please move to the next slide. Today we'll be making certain forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements. Because of various risks, uncertainties, and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. Next slide, please. On the call with me today from AGO are Brian Goff, chief executive officer, Cecilia Jones, chief financial officer, Sveta Milanova, chief commercial officer, and Dr. Sarah Hewens, chief medical officer and head of research and development. Following prepared remarks, we will open the call for questions. With that, please move to the next slide and I am pleased to turn the call over to Brian.

Thanks, Morgan. Good morning, everyone, and thank you for joining us on today's call. Next slide, please. 2025 is shaping up to be a breakout year for AGOs and we believe we have a clear path to deliver sustainable growth and unlock long-term shareholder value. First, we have a TK activator, Pyrokin. Second, momentum is building as we approach multiple near-term high-value catalysts. We hope to add thalassemia as the second approved indication for Pyrokin in the U.S. pending FDA approval and we are now less than 40 days from our September 7th PDUFA goal date. We expect to read out the Rise Up Phase 3 trial for Pyrokin in sickle cell disease before the end of the year and early next year anticipate Phase 2b data for Tebapibed, our more potent PK activator in patients with anemia due to lower risk myelodysplastic syndromes. And third, we are well capitalized to develop and launch Pyrokin in thalassemia and sickle cell disease and to continue to advance our existing development programs as well as look opportunistically to expand our pipeline through internal efforts and business development activities. Please move to the next slide. In the second quarter, we reported $12.5 million in net revenue reflecting the strong value proposition of Pyrokin. We entered into an agreement with Avancinite Bioscience to commercialize and distribute Pyrokin in Europe. This is a capital efficient deal allowing us to focus our investment on commercial launches in the U.S. We exited the second quarter with approximately $1.3 billion in cash, cash equivalents, and marketable securities and intend to be disciplined in our investment behind the commercial buildout of Pyrokin and advancement of our pipeline. In the second quarter, we dosed the first patient in the phase two trial of Teva-Pivot and sickle cell disease and received IND clearance for AG236, our siRNA targeting Tempor6, intended for the treatment of polycythemia vira. We are at an important turning point in our growth story. Near term, we have the potential to transform the treatment of thalassemia and sickle cell disease with Pyrokin. And beyond, we have the opportunity to deliver additional medicines to rare disease patients waiting and in urgent need of innovative treatment options. Please move to the next slide and I'll turn the call over to Cecilia to provide additional commentary on our second quarter performance and the future trajectory for Pyrokin.

Thank you, Brian. Next slide, please. Our second quarter 2025 financial results can be found in the press release issued earlier this morning. And additional details can be found in our 10 queue, which will be filed later today. Let me now take a moment to provide some context and highlight a few key points. Second quarter net Pyrokin revenue was $12.5 million, an increase of 45% compared to $8.6 million in the second quarter of 2024, and an increase of 44% compared to $8.7 million in the first quarter of 2025. Sequential net revenue growth reflects continued commercial execution in PKD, as well as an extra week of ordering in the second quarter and an increase in the number of units processed directly by the specialty pharmacy. In the second half of the year, we expect continued quarter on quarter variability in net revenues due to ordering patterns. Pending approval for Thalassemia in the US, we expect softer PKD demand as a sales force transitions promotional focus to Thalassemia. We still anticipate the fourth quarter to reflect partial demand for Thalassemia given timing of a PDUFA goal date due to the expected time to convert patient enrollment forms to treatment initiation. Taken together on a full year basis across indications, we expect net revenues in 2025 to show modest growth compared to 2024. Cost of sales for the quarter was $1.7 million. R&D expenses were $91.9 million, an increase of $14.5 million compared to the second quarter of 2024. This increase was primarily driven by a $1.7 million milestone payment to our partner Anilam related to the development of AG236. STNA expenses were $45.9 million in the second quarter, an increase of $10.4 million compared to the prior year, driven by continued investment ahead of the potential commercial launch of Pyrokind for the treatment of Thalassemia. We ended the second quarter with cash, cash equivalents, marketable securities of approximately $1.3 billion. Next slide, please. Our strong balance sheet supports our focused capital allocation strategy, allowing us to invest in our next wave of growth and pipeline delivery. First, we have executed a capital efficient commercial buildout, prioritizing investment in potential US launches, which presents the largest commercial opportunity. Last year, we announced our partnership with Newbridge Pharmaceuticals to commercialize Pyrokind in the GCC, and last month we entered into an agreement with Avanza Bioscience to commercialize and distribute Pyrokind in Europe. Both agreements are structured as revenue sharing arrangements that favor AGIUS over the long term. We will record our share of ex-US sales as net revenues. Second, we are strategically investing in our pipeline to advance our early and mid-stage clinical programs. Third, we will opportunistically look for ways to expand our pipeline through internal efforts or externally sourced assets. In closing, I am confident that our balance sheet will enable us to continue to execute from a position of strength. Please advance to the next slide, and I will turn the call over to Sveta to share commercial highlights for the quarter.

Thank you, Cecilia. Next slide, please. Net revenue growth in the second quarter reflects strong execution by our commercial team. However, we continue to anticipate -on-quarter variability due to ordering and inventory dynamics typical for rare disease medicines. As of the second quarter, 248 patients completed prescription enrollment forms, up 6% from the first quarter of 2025. 142 patients are now on active Pyrokind treatment, an increase of 4% on a sequential basis. Please move to the next slide. With less than 40 days to our PDUFA Go date, our commercial team is fully prepared for a launch in thalassemia, pending FDA approval. We believe in Pyrokind's strong clinical profile shown across two phase-3 studies, Energize in -transfusion-dependent patients and Energize-T in transfusion-dependent patients. As shown on this slide, data generated across this robust clinical program means upon potential approval, we are set to deliver a series of firsts in the treatment of thalassemia in the U.S., all of which are profoundly meaningful to thalassemia patients. Next slide, please. We are confident in our ability to deliver on the U.S. Thalassemia is well-diagnosed due to widespread prevalence of newborn patient screening in the U.S. In addition, given the availability of claims data and ICD-10 codes, these patients have an established record of engagement with health care services. Second, the burden of disease is high, meaning symptomatic patients are actively managed and the associated cost of care is significant. Despite this, treatment options are limited, especially for patients with -transfusion-dependent disease, and most patients still rely on supportive therapy. Third, this is a community with a high level of engagement across key thought leaders and robust patient advocacy representation. Just this month, we attended the first Thalassemia International Federation Pan-American Conference where we engaged in meaningful conversations with patients and physicians that reinforced our understanding of their needs. Lastly, robust preparedness supports our ability to deliver a successful launch. Our disease state education is tailored to address the diverse multicultural aspects of thalassemia, and we have leveraged our connections with thought leaders to provide additional disease education for community-based physicians. Last year, we doubled our sales force to approximately 40 employees and have focused our launch planning on non-treatment centers. Initial conversations with payers have been encouraging, reinforced by the compelling benefits-risk profile of viral kinds. Please move to the next slide. We have focused our capital investment on the U.S., which represents the largest commercial opportunity globally with 6,000 diagnosed adult thalassemia patients. Our initial launch is focused on the 4,000 patients that are actively managed due to their eczema. This patient segment includes both transfusions and non-transfusion dependent patients who experience complications and are living with debilitating fatigue. Our agreement with Avantinib Bioscience and New Bridge Pharmaceuticals allows us to provide sustainable tailored access to viral kinds outside of the U.S. We anticipate the first potential regulatory approval in the GCC in the coming months, and I will share additional detail on the commercial launch dynamics in the region shortly. In Europe, we anticipate a potential regulatory decision early next year. Here, we will work with our partner Avantinib on a focused -by-country launch strategy aligned with the Thalassemia disease prevalence. Please move to the next slide. I would like to take a few minutes to double click on the opportunity in the GCC. There are an estimated 70,000 adult and pediatric Thalassemia patients in the GCC, regardless of genotype and phenotype, and the majority of this estimated prevalence is concentrated in Saudi Arabia. However, due to the lack of national registry data, we have been working with our partner New Bridge to refine our launch strategy. Since accessing the region is fragmented, we are focused on targeting all patients actively managed at an institution, and this target launch population represents a smaller proportion of the 70,000 estimated prevalence. Importantly, we see potential to expand access by securing national procurement agreements, which can take roughly two years from approval, during which time access is granted on a -by-patient basis. Once procurement agreements are secured, we expect to further expand access agreements at an institutional level. We're thrilled to partner with New Bridge, a company with extensive experience commercializing medicines in the GCC, to potentially transform the treatment of Thalassemia in Saudi Arabia and the United Arab Emirates. Please move to the next slide. And with that, I will hand the call over to Farah to cover key R&D highlights from the quarter.

Thank you, Farah. Next slide, please. Pyrokinth, our -in-class PK activator, has demonstrated consistent, meaningful clinical data across multiple hemolytic anemias, reinforcing the strength of its differentiated mechanism of action as an allosteric activator of both PKR and PKM2 and the broad applicability of this unique mechanism. In pyruvate kinase deficiency, our first approved indication, treatment with Pyrokinth, resulted in statistically significant improvements across multiple endpoints, highlighting improved hemoglobin levels, reduced hemolysis, and improved patient-reported outcomes. At the end of last year, we submitted a supplemental NDA for Pyrokinth for the treatment of alpha- or beta-Thalassemia, regardless of transfusion burden. In our phase three Energize and Energize-T studies, we showed statistically significant improvements on measures of anemia, including hemoglobin levels, transfusion reduction, and reduction in fatigue. We continue to partner with global health authorities on our regulatory filings and work towards our PDUFA goal dates in the US. In sickle cell disease, we have reported compelling phase two data from the operationally seamless Rise Up Phase 2-3 trial in 2023 and are on track to deliver top-line results from the phase three trial by the end of the year. Please move to the next slide. Last month, at the European Hematology Association Congress, we had a combined 14 abstracts that led to multiple oral presentations, posters, and publications focused mostly on Pyrokinth and Cebapivac. These data add to the robust body of efficacy and safety data, reinforcing the promise of PK activation and the therapeutic potential of Mitapevat and Cebapivac across a range of devastating rare diseases, including Pyruvate kinase deficiency, Phthalostemia, sickle cell disease, and myelodysplastic syndrome. Please move to the next slide. Our Rise Up Phase 2 data reinforce our confidence in the potential to deliver a statistically significant improvement in hemoglobin response and reduction in analyzed rate of sickle cell pain crisis, which are the dual primary endpoints for our phase three trial. As the occurrence and severity of sickle cell pain crisis carry variability, we kept consistency across our phase two and phase three trials by using the same inclusion and exclusion criteria, same definition of pain crises, same adjudication committee and methodology, and by including sites from the phase two and the phase three trials. We hope to deliver data that can speak to the positive impact Pyrokinth can show on the totality of the disease, for example, hemolytic anemia and vaso-occlusion. Additionally, as fatigue is important to patients, we will look at the improvement in the from a fatigue scale as one of our key secondary endpoints. We believe our robust trial design provides multiple pathways to deliver clinically meaningful data and a differentiated profile with Pyrokinth. Next slide, please. We continue to advance our pipeline and are now investigating our potential -in-class PK activator franchise comprised of Pyrokinth and Cebap Divab across four rare diseases. We are also excited to progress the ascending dose phase one trial for AG1H1 intended for the treatment of fendylketonuria and the single ascending dose phase one trial for AG2H3 intended for the treatment of polystitemia zera. As Brian mentioned, in the second quarter, we delivered on the two planned corporate objectives for mid-year with Cebap Divab and AG2H3. These achievements reinforce our consistent strong track record of delivering on our pipeline milestones. I look forward to bringing you additional updates on our pipeline as we look to develop a robust portfolio of medicines to transform the treatment of rare disease. With that, please move to the next slide and I will hand the call back to Brian for closing remarks.

Thank you, Sarah. Next slide, please. In the second quarter, we made strong progress against our 2025 priorities. We achieved important milestones to advance Cebapivet and AG236, two assets with potential to expand our reach into new rare disease indications. We believe 2025 will be a breakout year for Agios as we make strides towards the potential launch of Pyrokinth and thalassemia in the U.S., phase three rise up readout in sickle cell disease, and continued advancement of our mid and early stage pipeline. Please move to the next slide. In closing, Agios has the necessary ingredients to deliver innovative medicines to rare disease patients in need, driving sustainable growth and unlocking long-term shareholder value. At our core, we are fueled by our connections with the rare disease communities we serve, enabling us to deliver clinical benefits that matter to patients with tailored commercial model to best meet patients where they are. Importantly, we are on our way to building a diversified rare disease portfolio. We are rapidly advancing a best in class PK activator franchise with potential across four indications, and we look forward to providing future updates on our early stage pipeline with the opportunity to accelerate our growth outside of hematology. Before we move to Q&A, I'd like to extend my appreciation to the investigators and patients whose participation, partnership, and trust have been invaluable to our development work, and of course, the Agios team who continue to inspire me every day. We look forward to what's ahead as we strive to redefine the future of rare diseases. With that, I'd like to open the call for operator, please open the line.

Thank you. To ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. We ask that you please limit yourself to two questions. One moment while we compile our Q&A roster. And our first question is going to come from the line of Eric Schmidt with Canter.

Your question is for Brian. Good morning, everyone. This is Imogen. I think in the past you've said that you would update investors on any change to Metapivac safety profile, including in cases of liver toxicity outside of phallusemia. Is there anything new that you have to report there?

Morning, Imogen. It's Brian. Thanks a lot for the question. I'll have Sarah comment on that first one with respect to any updates in the safety profile.

So good morning. So no updates to the safety profile. That's it, really.

Okay, great. Thank you. And then one quick follow-up. On the GCC approval dates, is there any more colleagues could share on that? Are you expecting it maybe just after the U.S. approval?

Well, I will say just reflecting on what we had announced in December of last year, I'm really proud of the fact that the team has submitted, this was a first for Agio, submitted simultaneously across four different regions. And all we can share at this point is that we're actively in discussions across all four regions, and we look forward to having the opportunity to give updates on the status of those reviews. And I will also say that Steta and her team are certainly ready from a commercialization standpoint.

Okay, great. Thanks very much.

You're welcome.

Thank you. In one moment, as we move on to our next question. Our next question is going to come from the line of Mark Fram with TD Cowan. Your line is open. Please go ahead.

Thanks for taking my questions. Maybe just with the SAL review ongoing, are you able to comment on, you know, if you're maybe in labeling discussions yet? And obviously, safety information is going to need to be at least somewhat updated just to account for the fact that salicemia is now, well, hopefully going to become an approved indication. So, which is really a thought on how you're anticipating that part of the label to read. And then I'll probably have a follow up question. Yeah, thanks, Mark. So, Sarah can start.

Sure. Thanks, Mark. So, well, maybe just a recap, but as you know, we've submitted to, as Brian just mentioned, four different regions for the indication of salicemia based on our two well-controlled trials that met the primary and key secondary endpoints in both. So, that's the benefit part. You mentioned on the risk side, we have, of course, the hepatocellular injury, which you can already see reflected in the PKD label that was based on the salicemia observation. And so, we do at minimum anticipate there the updates in the PKD label to reflect the indication statement and the dose to be changed to, you know, the, to salicemia and 100 milligrams PIT. But the process and the review are, of course, ongoing and the FDA only provides you an end date of the complete review. So, the final label, that's what we will know at the producing date.

Okay, that's helpful. And then, this is more for Sveta and Celia. Just the SG&A spend has been ticking up, obviously, as you build out and prepare for that salicemia launch. Should we view this as fully built out now and this is kind of the run rate or are there still meaningful step-ups that we should be expecting going forward as the launch actually starts?

Yeah, maybe Cecilia can start on the financial aspects and then Sveta always loves the opportunity to be able to talk about how well prepared her team is for potential launches ahead.

Thanks, Mark. Yeah, from a financial perspective, we do expect to see a little bit more growth on the SG&A side for salicemia. You're right, we built the bulk of the infrastructure with the sales teams and customer-facing teams starting last year after the trials read out. But we do have some launch-related expenses that would obviously only happen, you know, upon approval. So, we do see some coming potentially after that.

Yeah, absolutely. And the team, I can tell you, the team is ready for a potential launch in the salicemia. As Cecilia mentioned, we've deployed the field-based facing organization late last year and that includes about 40 people in the sales organization but also a cross-functional team that is going to interact with different customers. We are excited about having the potential to provide viral counts in the salicemia, of course, pending FDA approval in the U.S. and we're looking forward to give a base when possible.

Great, thank you. Sveta?

Thank you. One moment for our next question. Our next question comes from the line of Selveen Richter with Goldman Sachs. Your line is open. Please go ahead.

Good morning. Thanks for taking my question. As you look to the upcoming PDUFA here for ZAL and focus on the launch, could you just help us understand the initial target patient population that you'll be addressing or just be targeting here initially?

Yeah, thanks a lot, Selveen. And again, I'll turn that one over to Sveta.

Absolutely. So, from a commercial perspective, salicemia is really an attractive indication for us to potentially launch next. And the reason for that is that the patients with salicemia are actually diagnosed and well known to the health care system in the U.S. There is a great data based on the ICD-10 code in the U.S. which we have been able to validate through our interactions with health care professionals. And that gave us a lot clarity not only where patients are currently being managed but also what the patients potentially we should prioritize and focus at launch. When you think about which patients are really the most appropriate for our initial launch target, these are about 4,000 patients out of the 6,000 diagnosed adult patients in the U.S. And the way we prioritize these patients is based on their symptomology, the fact that they are engaged with the health care system and they potentially will require additional management and treatment. And in this group of patients, you see both transfusion dependent patients who might be looking to reduce their transfusion burden as well as non-transfusion dependent patients who are symptomatic, they're experiencing fatigue and other complications of the disease. And both the patient and the physician might be looking for additional management and treatment. As I said, the team is very well prepared for the launch. And we have the opportunity to actually engage with these accounts in advance of the launch. Very importantly for us, it's important to remember and recognize that thalassemia is a disease with high unmet needs. About two thirds of the patients have no available treatment in the U.S. And that unmet need was really reinforced through our interactions with both patients and physicians earlier in the month where we had the opportunity to actually attend the Semi-Internet Regional Physicians Pan American Conference, which gave us a lot of energy and excitement about the potential launch in the future.

Yeah, that's great. And Salvin, just to go back to the numbers for a second, Sveta made the point that a lot of times we get asked about how solid are numbers, the 4,000 patients. It is a pretty important point that these ICD-10 codes have been in place for quite a long time in thalassemia. So there's a lot of rigor around those numbers. And I'll just point out that's in contrast to PKD, where literally the codes were established right before launch. So it's a very different dynamic. And maybe I'll just ask Cecilia to a look ahead from a revenue perspective with a potential launch, what fourth quarter could look like.

Yeah, thanks, Brian. So given the expected goal of PDUFA in September and the time it takes between a PEP and patient initiating treatment from a revenue perspective for this year 2025, we don't expect thalassemia revenues to be material.

Yeah, thanks.

Thank you. And one moment as we move on to our next question. Our next question comes from the line of Emily Bodner with HCWainwright. Your line is open. Please go ahead.

Hi, good morning. Thanks for taking the questions. I guess for the first one, maybe if you could talk about the pediatric opportunity for thalassemia and if you have any timing for potential FDA filing there. And then just maybe if you could confirm that you haven't had any changes to either access or I guess tone of speaking to the FDA in recent weeks given some of the news going on there. Thanks.

Sure. Thanks, Emily. How about Sveto can start on pediatric from a commercial perspective and then Sarah can reflect on the trials and the pathway ahead?

Absolutely. So there are about 8,000 thalassemia patients in the US. As we said, about 6,000 of those are down. So the remaining 2,000 are pediatric patients. Of course, it is a genetic disease where the patients are diagnosed at birth. There is an availability of newborn screening. So there is a high diagnosis rate in that disease. And there is always a high and met need and an opportunity for us to provide value in pediatric patients. But with that, I'll hand it over to Sarah.

The way we are approaching pediatric development is we wait for the benefit risk profile in adults, which we now have. And so the plan for thalassemia indication is doing exactly the same what we have done for the pyruvate kinase deficiency indication with an expansion by running the trials in the pediatric patient population. And then once that data is available, indeed, deliver that to regulators for review.

And I think, if I heard the second part of your question, it was about FDA interactions. Of course, we're not going to talk about specifics, but anything you want to add, Sarah, about our engagement?

No, we always spread ourselves on collaborative engagements and relationships with all of the regulators that we interact with. So I know the disruption in the news. And we have not experienced major disruptions in our team engagements with the FDA and the remains like a collaborative engagement.

All right, thank you.

You're welcome.

Thank you. And one moment for our next question. Our next question comes from the line of Alex Shanahan with Bank of America. Your line is open. Please go ahead.

Hey, guys, this is Matthew on for Alex. Thanks for taking our question. Maybe first from us. I know the initial focus of the launch is on higher frequency visit patients. Curious for those outside the initial focus, what the key points of education are to drive uptake and whether that differs US versus ex US. And then maybe second question on the early stage pipeline. Curious if there has been any change to your development plan in PKU after the approval of PTC's second.

OK, so thanks, Matthew. So I can start on the question about beyond the initial higher frequency clinical touch points, what does segmentation look like?

Absolutely. So as we said, our priority segments are patients that are transfusion dependent or non transfusion dependent patients that require additional management because of their symptoms of the disease. When we look beyond that patient segments, we'll continue to expand into the transfusion dependent patients who might be experiencing symptoms but might not be ready to initiate therapy immediately. It's also important for us to remember that as patients age, the burden of their disease increases, so they might be actually developing complications of the disease as well. The key educational elements there will continue to remain the same. We know unmet need in thalassemia is well characterized, but it is also an evolving field and additional data on the unmet need, especially in the non transfusion dependent patients is emerging. So a lot of our educational efforts are actually disseminating that additional information and continue to engage both with patients and physicians. We're also stressing the importance of continuous monitoring for those patients given the long term disease complications and physiology of the disease, which is an important element for us. So once we are ready to expand, we'll have more engaged both patients and physician community on that front. There will be consistent in the US and ex-US of course, our priority and segmentation across the globe will remain quite consistent. However, ex-US will need to deal with different market access dynamics and patient access, which we'll address with our partners appropriately. On a country by country basis.

And just as a point of emphasis to Spetta's point about ex-US, we're really clear on the geographic priorities. US clearly is our number one priority and that's why Spetta and the team have designed for direct commercialization and we're really proud of the partnerships that we have already established and updated in fact this morning with Europe, with the Vanzanite Biosciences as well as Newbridge in GCC. And that's a, as I noted, that's a very capital efficient approach, but it also leans on localized expertise in those geographies accordingly. And then to the second question about PKU, maybe I'll have Sarah pick up on that.

Yes. So we have not made any changes based on the recent approval. We are very excited about that approval to be able to monitor what happens and of course learn from them as well as they progress. But fundamentally, the same principles around our program remain intact because we have a drug of phenylalanine hydroxylated stabilizer basically, which is completely a novel mechanism of action or all therapy with the potential to really deliver another therapy to patients who still have a dire need even with this recent approval, there will remain a dire need for other options because these patients, they can be in the position that they don't respond to the therapies or they have, you know, if you think about Palimpsik, there may be anaphylaxis or things like that. So there will remain a big, big gap there to address. And you even see that reflected in the current label that they received on the new drug because the stopping criteria when there is no treatment response observed means that there effectively will be people who are not responding to this therapy and will need other options.

And PKU is right in the sweet spot for Agios as a company that takes a lot of pride in innovation to address diseases with high unmet needs. So just like across thalassemia, sickle cell, PKD, any of our diseases that we're pursuing, any innovation is important. And, you know, we like to read that news that you referred to. And we're very excited about the progress that we're making with our own pH hydroxylase stabilizer with 1A1. So thanks a lot.

Thank you. One more moment as we move on to the next question. Our next question is going to come from the line of Andrew Burns with Lurink Partners. Your line is open. Please go ahead.

Hi. Thanks. And congrats on all the progress. This is a follow-up to Mark's earlier question. Has anything changed in the sickle cell trial protocols since you identified risks and liver injury of ASH 2024? Interested in whether the consent forms and the monitoring requirements have changed? And then I have one on TebaPIVET. We noticed that the TebaPIVET trial is using markedly lower doses than the MDF phase IIB trials being conducted. Can you discuss the dosing protocol in this trial and the rationale for lowering the sickle cell trial? Are there data at the relevant doses in MDF

and sickle cell that you can share with us? Hello? Yes. Okay. So in regards

to the sickle cell disease protocol, we've announced in the past that once we identified this risk in the thalassemia program that we had aligned all of our protocols to have monthly monitoring for the first six months. So including our open label extension trials. So for the sickle cell disease protocol, we aligned the open label extension study to match what happens in the first part of the randomized control trial because obviously placebo patients get exposed for the first time in the open label extension study. So we made sure that they have the same type of monitoring. And so that is effectively reflected in the protocols. And we did update those informed consent as well, obviously. And in regards to your next question around the dosing differences between the sickle cell disease phase II and the MDF phase IIB, you are right. We are exploring a lower doses within the sickle cell disease phase II, and that is because the sickle cell disease patients, their metabolism matches the healthy volunteer metabolism that was observed in the phase I. Reminder that we have sickle cell disease patients included in that trial as well. So we have that, but then in the MDF trial in the IIA, we observed that the MDF patients metabolize the drug faster. So we adapted to the doses appropriately. And so that's what you'll see that we are exploring. That's why we are exploring different doses between sickle cell disease and MDF.

Thank you.

Thank you. Thank you. And one moment for our next question. Our next question is going to come from the line of Tess Romero with JB Morgan. Your line is open. Please go ahead.

Good morning, Brian and team. Thanks for taking our question. So to double click back on a few of the earlier questions on the call, is it still reasonable to assume that the potential risk of hepatocellular injury will sit in the warnings and precautions sections of the label, as is currently reflected today? And relatedly, when do you expect to present your open label extension data that you have collected in this population that may be of interest to physicians and institutions as they begin to prescribe in thalassemia? Thank you.

Sure. Thanks, Tess. Sarah can take both of those. I'll just say on the open label extension, we're also interested in the data, of course, but we're going to do things sequentially.

Yes. Or maybe I can start actually with that one. Like on the open label extension, you'll see published data of the open label extensions like we always do, just like what we've done for PKP. Obviously, right now, we're very focused on our ongoing reviews and prioritizing time of the themes there versus trying to get more publications out on extension data. But that's coming for sure. We share that interest, obviously. And you're right, like everybody will continue to be interested in that. So more to come. And then in regards to your question around HCI and where it is in the label, Brian mentioned it earlier. Obviously, we continue to engage with the agency as it goes. Like the benefit-risk review is still ongoing with the agency. I think right now, what you see, what is reflected in the PKP label to date is what we have observed in our program, right? Which is you can see that language in another condition and at a higher dose is in the warning and precaution section of the PKP label. That language has to be updated at some point when we get to the final label for Thalassina. In regards to where it would end up or what would change, we don't comment on ongoing review processes with the agency. But as you know, our FDUFA day is September 7th, at which point the procedure should be completed. And then we will all have the final labeling and can talk more about that.

Thank you.

Thank you. And our final question is going to come from the line of Greg Harrison with Kosha Bank. Your line is open. Please go ahead.

Good morning. This is Teresa. I answer Greg. Thanks for taking our question. I just wanted to see ahead of the launch, potential launch in Thalassina, if you could provide any additional color on the prescriber base for your initial launch focus and how you're planning to address any variability in care between academic centers and community hematologists.

Yeah, thanks, Teresa. I said I can reiterate a few of the points we talked about earlier in terms of in the US, the 4,000 patients that are in our addressable target and add a little bit more on community versus academic.

Absolutely. So Teresa, as I mentioned, in the US, we really benefit from the fact that Thalassina patients are diagnosed and they are well established ICD-10 codes. So we have a lot of clarity of where these patients are currently being treated and managed. In addition to that, the team has been really focused on a very robust launch preparations where we had the opportunity to connect with the prescriber base and profile the accounts and really prioritize them appropriately based on the patients that they have and their potential willingness to manage these patients further. Of course, majority of the transfusion-dependent patients are actually within the academic centers where you would see a little bit more penetration in the transfusion-dependent setting. However, there is a very high unmet need in the -transfusion-dependent patients and that need is very well characterized and understood, even though if some of these patients are managed in the community, we've been able to actually engage with those prescribers, identify where these patients are managed, provide disease education and prioritize those accounts so we can pull them through launch as well at the beginning of the launch.

Thank you and I would like to hand the conference back over to Brian Goff-Fritney for the remarks.

Okay, thanks Michelle and thank you very much everyone for participating in today's call. As you know, we're halfway through yet another busy year. It's a very exciting time at AGIOS and we truly believe that we are poised to deliver transformative new therapies for patients and to create significant long-term value to shareholders. So thanks again and we look forward to speaking with you again soon.

This concludes today's conference call. Thank you for participating and you may now disconnect. Everyone have a great day.