Agios Pharmaceuticals, Inc. (AGIO) Q2 2025 Earnings Report, Transcript and Summary

Good morning, and welcome to Agios' Second Quarter 2025 Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Agios's request. I would now like to turn the call over to Agio. Please go ahead.

Thank you, operator. Good morning, everyone. I'm Morgan Sanford, Vice President of Investor Relations at Agios. Thank you for joining us to discuss Agios Pharmaceuticals Second Quarter 2025 Financial Results and Business Highlights. You can access the slides for today's call by going to the Investors section of our website, agios.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 Agios are Brian Goff, Chief Executive Officer; Cecilia Jones, Chief Financial Officer; Tsveta Milanova, Chief Commercial Officer; and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development. Following prepared remarks, we will open the call for question. 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 Agios, and we believe we have a clear path to deliver sustainable growth and unlock long-term shareholder value. First, we have a derisked multibillion-dollar opportunity with our first-in-class PK activator, PYRUKYND. Second, momentum is building as we approach multiple near-term high-value catalyst. We hope to add thalassemia as the second approved indication for PYRUKYND in the U.S., pending FDA approval, and we are now less than 40 days from our September 7 PDUFA goal date. We expect to read out the RISE UP Phase III trial for PYRUKYND in sickle cell disease before the end of the year and early next year, anticipate Phase IIb data for tebapivat, 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 PYRUKYND 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 PYRUKYND. We entered into an agreement with Avanzanite Bioscience to commercialize and distribute PYRUKYND 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 build-out of PYRUKYND and advancement of our pipeline. In the second quarter, we dosed the first patient in the Phase II trial of tebapivat in sickle cell disease and received IND clearance for AG-236, our siRNA targeting TEMPRSS6 intended for the treatment of polycythemia vera. 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 PYRUKYND. 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 PYRUKYND.

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-Q, 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 PYRUKYND 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 U.S., we expect softer PKD demand as the 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 initiations. 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 $10 million milestone payment to our partner, Alnylam, related to the development of AG-236. SG&A 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 PYRUKYND for the treatment of thalassemia. We ended the second quarter with cash, cash equivalents and 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 build-out, prioritizing investment in potential U.S. launches, which present the largest commercial opportunity. Last year, we announced our partnership with NewBridge Pharmaceuticals to commercialize PYRUKYND in the GCC. And last month, we entered into an agreement with Avanzanite Bioscience to commercialize and distribute PYRUKYND in Europe. Both agreements are structured as revenue-sharing arrangements that favor Agios over the long term. We will record our share of ex-U.S. 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 Tsveta 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 quarter-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 PYRUKYND treatment, an increase of 4% on a sequential basis. Please move to the next slide. With less than 40 days to our PDUFA goal date, our commercial team is fully prepared for a launch in thalassemia, pending FDA approval. We believe in PYRUKYND's strong clinical profile shown across 2 Phase III studies, ENERGIZE in non-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 first 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. launch of PYRUKYND in thalassemia, pending FDA approval for several reasons. First, 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 non-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 reinforce 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 known treatment centers. Initial conversations with payers have been encouraging, reinforced by the compelling benefit risk profile of PYRUKYND. Please move to the next slide. We have focused our capital investments 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 symptomology. This patient segment includes both transfusion and non-transfusion-dependent patients who experience complications and/or are living with debilitating fatigue. Next slide, please. Our agreement with Avanzanite Bioscience and NewBridge Pharmaceuticals allow us to provide sustainable tailored access to PYRUKYND 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, Avanzanite, on a focused country-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, NewBridge to refine our launch strategy. Since access in 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 2 years from approval, during which time access is granted on a patient-by-patient basis. Once procurement agreements are secured, we expect to further expand access agreement at an institutional level. We're thrilled to partner with NewBridge, 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 Sarah to cover key R&D highlights from the quarter.

Thank you, Tsveta. Next slide, please. PYRUKYND, our first-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 PYRUKYND 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 PYRUKYND for the treatment of alpha or beta thalassemia regardless of transfusion burden. In our Phase III 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 date in the U.S. In sickle cell disease, we have reported compelling Phase II data from the operationally seamless RISE UP Phase II/III trial in 2023 and are on track to deliver top line results from the Phase III 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 PYRUKYND and tebapivat. These data add to the robust body of efficacy and safety data, reinforcing the promise of PK activation and the therapeutic potential of mitapivat and tebapivat across a range of devastating rare diseases, including pyruvate kinase deficiency, thalassemia, sickle cell disease and myelodysplastic syndromes. Please move to the next slide. Our RISE UP Phase II 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 III trial. As the occurrence and severity of sickle cell pain crisis carry variability, we kept consistency across our Phase II and Phase III trials by using the same inclusion and exclusion criteria, same definition of pain crisis, same adjudication committee and methodology and by including sites from the Phase II in the Phase III trial. We hope to deliver data that can speak to the positive impact PYRUKYND 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 thrombocytic 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 PYRUKYND. Next slide, please. We continue to advance our pipeline and are now investigating our potential best-in-class PK activator franchise comprised of PYRUKYND and tebapivat across 4 rare diseases. We are also excited to progress the multiple ascending dose Phase I trial for AG-181, intended for the treatment of phenylketonuria and the single ascending dose Phase I trial for AG-236 intended for the treatment of polycythemia vera. As Brian mentioned, in the second quarter, we delivered on the 2 planned corporate objectives for midyear with tebapivat and AG-236. 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 diseases. 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 tebapivat and AG-236, 2 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 PYRUKYND in thalassemia in the U.S., Phase III 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 a tailored commercial model to best meet patients where they are. Importantly, we're on our way to building a diversified rare disease portfolio. We are rapidly advancing a best-in-class PK activator franchise, with potential across 4 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 questions. Operator, please open the line.

And our first question is going to come from the line of Eric Schmidt with Cantor.

This is [ Imogen ] on for Eric. I think in the past, you've said that you would update investors on any change to mitapivat safety profile, including any cases of liver toxicity outside of thalassemia. Is there anything new that you have to report there?

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 no updates to the safety profile. That's it really.

Okay. Great. And then one quick follow-up. On the GCC approval date, is there any more color you 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 the first for Agio submitted simultaneously across 4 different regions. And all we can share at this point is that we're actively in discussions across all 4 regions, and we look forward to having the opportunity to give updates on the status of those reviews. And I will also say that Tsveta and her team are certainly ready from a commercialization standpoint.

Our next question is going to come from the line of Marc Frahm with TD Cowen.

Maybe just with the thal review ongoing, are you able to comment on 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 thalassemia is now hopefully going to become an approved indication. So, what's the latest thoughts on kind of how you're anticipating that part of the label to read? And then I'll probably have a follow-up question.

Yes. Thanks, Marc. So, Sarah can start.

Sure. Thanks, Marc. So well, maybe just to recap. But as you know, we've submitted to, as Brian just mentioned, 4 different regions for the indication of thalassemia based on our 2 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 thalassemia observations. And so, we do, at minimum, anticipate there the update in the PKD label to reflect the indication statement and the dose to be changed to thalassemia and 100 milligrams BID. 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 PDUFA date.

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

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

Thanks, Mike. Yes, from a financial perspective, we do expect to see a little bit more growth on the SG&A side for thalassemia. 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 upon approval. So, we do see some more coming potentially after that.

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

Our next question comes from the line of Salveen Richter with Goldman Sachs.

As you look to the upcoming PDUFA here for thal 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?

Yes. Thanks a lot, Salveen. And again, I'll turn that one over to Tsveta.

Absolutely. So, from a commercial perspective, thalassemia is really an attractive indication for us to potentially launch next. And the reason for that is that the patients with thalassemia 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 of 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 in 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 that to remember and recognize that thalassemia is a disease with high unmet need. About 2/3 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 Thalassemia International Federation Pan American conference, which gave us a lot of energy and excitement about the potential launch in the future.

Yes, that's great. And Salveen, just to go back to the numbers for a second, Tsveta made a point that a lot of times we get asked about how solid are those 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 comment on the look ahead for -- from a revenue perspective with a potential launch, what fourth quarter could look like.

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

Our next question comes from the line of Emily Bodnar with H.C. Wainwright.

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 kind of recent weeks given some of the news going on there.

Sure. Thanks, Emily. How about -- Tsveta 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 U.S. 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 availability of newborn screening. So, we're -- there is a high diagnosis rate in that disease, and there is always a high unmet 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 would -- 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, Emily, if I heard the second part of your question 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 pride our self on collaborative engagements and relationships with all of our -- all of the regulators that we interact with. So, I know the disruption in the news, and we have not experienced like major disruptions in our team engagements with the FDA and it remains like a collaborative engagement.

Our next question comes from the line of Alec Stranahan with Bank of America.

This is Matthew on for Alec. Maybe first from us. I know the initial focus of the launch is on higher frequency of visit patients. Curious for those outside the initial focus, what the key points of education are to drive uptake and whether that differs U.S. versus ex U.S.? And then maybe a second question on the early-stage pipeline. Curious if there's been any change to your development plans in PKU after the approval of PTCs second.

Okay. So, thanks, Matthew. So Tsveta 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 segment, we'll continue to expand into the non-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 that the unmet need in thalassemia is well characterized. But it is also an evolving field and additional data on 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 are also stressing the importance of continuous monitoring for those patients given the long-term disease complications and the pathophysiology 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. They will be consistent in the U.S. and ex U.S., of course. Our priority and segmentation across the globe will remain quite consistent. However, ex U.S. 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 Tsveta's point about ex U.S., we're really clear on the geographic priorities. U.S. clearly is our #1 priority, and that's why Tsveta 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 Avanzanite Biosciences, as well as NewBridge in GCC. And that's -- 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, our -- the same principles around our program remain intact because we have a drug of phenylalanine hydroxylase stabilizer, basically, which is completely a novel mechanism of action, oral 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 -- 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 -- if you think about Palynziq, 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 need. So just like across thalassemia, sickle cell, PKD, any of our diseases that we're pursuing, any innovation is important, and 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 PAH hydroxylase stabilizer with 181. So, thanks a lot.

Our next question is going to come from the line of Andrew Berens with Leerink Partners.

Congrats on all the progress. This is a follow-up to Marc's earlier question. Has anything changed in the sickle cell trial protocol since you identified risks in liver injury at ASH 2024. Interested in whether the consent forms and the monitoring requirements have changed. And then I have one on tebapivat. We noticed that the tebapivat trial is using markedly lower doses than the MDS Phase IIb trials being conducted. Can you discuss the dosing protocol in this trial and the rationale for going lower in the sickle cell trial? Are there data at the relevant doses in MDS 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 when we identified this risk in the thalassemia program that we had aligned all of our protocols to have monthly monitoring for the first 6 months, so including our open-label extension trial. 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 controlled 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 consents as well, obviously. And in regards to your next question around the dosing differences between the sickle cell disease Phase II and the MDS Phase IIb. You are right, we are exploring 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. A reminder that we have sickle cell disease patients included in that trial as well. So, we have that. But then in the MDS trial in the IIa, we observed that the MDS patients metabolize the drug faster. So, we adapted 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 MDS.

Our next question is going to come from the line of Tess Romero with JPMorgan.

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 section 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?

Sure. Thanks. 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. But go ahead.

Yes. Or maybe I can start actually with that one, like on the open-label extension, you'll see us publish data of the open-label extensions like we always do, just like what we've done for PKD. Obviously, right now, we're very focused on our ongoing reviews and prioritize the time of the teams there versus trying to get more publications out on the 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 sits 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 the -- what is reflected in the PKD 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 precautions section of the PKD label. That language has to be updated at some point when we get to the final label for thalassemia. 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 PDUFA date is September 7, at which point the procedure should be completed. And then you -- again, we will all have the final label and can talk more about that.

And our final question is going to come from the line of Greg Harrison with Scotiabank.

This is Theresa on for Greg. Just wanted to see ahead of the launch -- potential launch in thalassemia, 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.

Yes. Thanks, Theresa. Sarah can reiterate a few of the points we talked about earlier in terms of in the U.S., the 4,000 patients that are in our addressable target and add a little bit more on community versus academic.

Absolutely. So, Theresa, as I mentioned, in the U.S., we really benefit from the fact that the thalassemia 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 will see a little bit more penetration in the transfusion-dependent setting. However, there is a very high unmet need in the non-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 for any further 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.