Agios Pharmaceuticals - Earnings Call - Q2 2025

Executive Summary

• Q2 2025 net product revenue was $12.46M, up 45% y/y and 44% q/q, and above Wall Street consensus of $9.52M; diluted EPS was -$1.93 vs consensus -$1.79, reflecting higher R&D (incl. a $10M milestone) and SG&A ahead of thalassemia launch. CFO cited an extra ordering week and more specialty pharmacy units as drivers of the revenue strength. Bold: revenue beat; EPS miss. Estimates marked with asterisk; values retrieved from S&P Global.
• Management reiterated near‑term catalysts: PYRUKYND sNDA for thalassemia (PDUFA Sep 7, 2025) and RISE UP Phase 3 sickle cell topline by year‑end 2025; Avanzanite partnership expands European commercialization.
• Operating expenses elevated: R&D $91.94M (incl. $10M regulatory milestone to Alnylam) and SG&A $45.87M; cash, cash equivalents and marketable securities at $1.339B (June 30) vs $1.425B (March 31) and $1.532B (Dec 31).
• Commercial KPIs strengthened: 248 unique patient enrollment forms (+6% q/q) and 142 patients on therapy (+4% q/q), positioning for thalassemia launch preparedness.

What Went Well and What Went Wrong

What Went Well

• PYRUKYND revenue grew to $12.46M, +45% y/y and +44% q/q, with management attributing strength to ordering dynamics and specialty pharmacy processing volume.
• Thalassemia launch preparedness: CEO emphasized “2025 is shaping up to be a breakout year” and that the team is “less than 40 days” from PDUFA, with robust KOL and advocacy engagement; CCO detailed focus on ~4,000 actively managed adult patients in the U.S..
• Ex‑U.S. leverage: Agios signed an exclusive pan‑European commercialization pact with Avanzanite to distribute PYRUKYND across the EEA, UK, and Switzerland, enabling capital‑efficient expansion.

What Went Wrong

• EPS missed consensus: diluted EPS was -$1.93 vs -$1.79*; net loss widened q/q to $112.02M as R&D rose on a $10M milestone and SG&A scaled ahead of thalassemia launch.
• Near‑term product demand caution: CFO expects q/q variability in PYRUKYND net revenues and “softer PKD demand” during U.S. field transition to thalassemia, limiting 2025 revenue uplift (only “modest growth” vs 2024).
• Safety monitoring burden persists: monthly LFTs for six months across protocols following hepatocellular injury observations in thalassemia; risk language will be updated in final label, maintaining a warning/precautions posture.

Transcript

Operator (participant)

Good morning and welcome to Agios Pharmaceuticals 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 Agios Pharmaceuticals request. I would now like to turn the call over to Agios. Please go ahead.

Morgan Sanford (VP of Investor Relations)

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 statement 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 Pharmaceuticals 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 questions. With that, please move to the next slide, and I am pleased to turn the call over to Brian.

Brian Goff (CEO)

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 de-risked multibillion dollar opportunity with our first-in-class PK activator, PYRUKYND. Second, momentum is building as we approach multiple near-term high-value catalysts. We hope to add thalassemia as the second approved indication for PYRUKYND in the U.S., pending FDA approval. We are now less than 40 days from our September 7 PDUFA goal date.

We expect to read out the RISE UP Phase 3 trial for PYRUKYND in sickle cell disease before the end of the year and early next year. We anticipate Phase 2b data for tebapivat, our more potent PK activator, in patients with anemia due to lower-risk myelodysplastic syndromes. 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 buildout of PYRUKYND and advancement of our pipeline. In the second quarter, we dosed the first patient in the Phase 2 trial of tebapivat in sickle cell disease and received IND clearance for AG-236, our siRNA targeting TMPR6, 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.

Cecilia Jones (CFO)

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 salesforce 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 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 buildout, 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 region, 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.

Tsveta Milanova (Chief Commercial Officer)

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 two Phase 3 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 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. 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's 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 non-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 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 symptomology. This patient segment includes both transfusion and non-transfusion dependent patients who experience complications.

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 region 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 region. There are an estimated 70,000 adult and pediatric thalassemia patients in the GCC region 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 two 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 agreements at an institutional level. We are thrilled to partner with NewBridge, a company with extensive experience commercializing medicines in the GCC region, 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.

Sarah Gheuens (Chief Medical Officer and Head of R&D)

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. Treatments 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 the supplemental NDA for PYRUKYND for the treatment of alpha or beta thalassemia, regardless of transfusion burden. In our Phase 3 ENERGIZE and ENERGIZE-T studies, we showed statistically significant improvements on measures of anemia, including hemoglobin level, 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 2 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 3 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, poster, and publication presentations 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 2 data reinforced our confidence in the potential to deliver a statistically significant improvement in hemoglobin response and reduction in annualized rate of sickle cell pain crises, which are the dual primary endpoints for our Phase 3 trial. As the occurrence and severity of sickle cell pain crisis carry variability, we kept consistency across our Phase 2 and Phase 3 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 2 in the Phase 3 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 PROMIS 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 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 four rare diseases. We are also excited to progress the multiple ascending dose Phase 1 trial for AG-181 intended for the treatment of phenylketonuria and the single ascending dose Phase 1 trial for AG-236 intended for the treatment of polycythemia vera. As Brian mentioned, in the second quarter we delivered on the two planned corporate objectives for mid-year 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.

Brian Goff (CEO)

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, 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 PYRUKYND in thalassemia in the U.S., Phase 3 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 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 questions. Operator, please open the line.

Operator (participant)

Thank you. To ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11. Again, we ask that you please limit yourself to two questions. One moment while we compile our Q&A roster. Our first question is going to come from the line of Eric Schmidt with Cantor. Your line is open. Please go ahead.

Imogen Mansfield (VP of Biotech Equity Research)

Hi, good morning everyone. 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?

Brian Goff (CEO)

Good 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.

Sarah Gheuens (Chief Medical Officer and Head of R&D)

Good morning. No updates to the safety profile? That's it? Really?

Imogen Mansfield (VP of Biotech Equity Research)

Okay, great.

Thank you.

One quick follow up on.

The GCC approval dates. Is there any more, Carly, you could share on that? Are you expecting it to maybe just after the U.S. approval?

Brian Goff (CEO)

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 Agios, submitted simultaneously across four different regions. 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. I will also say that Tsveta and her team are certainly ready from a commercialization standpoint.

Imogen Mansfield (VP of Biotech Equity Research)

Okay, great. Thanks very much.

Brian Goff (CEO)

You're welcome.

Operator (participant)

Thank you.

One moment as we move on to our next question. Our next question is going to come from the line of Marc Frahm with TD Cowen. Your line is open.

Please go ahead.

Marc Frahm (Stock Analyst)

Thanks for taking my questions. Maybe just with the SAL review ongoing, are you able to comment on if you're maybe in labeling discussions yet? 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. What's the latest thoughts on how you're anticipating that part of the label to read? I'll probably have a follow up question.

Brian Goff (CEO)

Yeah, thanks, Marc. Sarah can start.

Sarah Gheuens (Chief Medical Officer and Head of R&D)

Sure. Thanks, Marc.

Maybe just a recap, but as you know, we've submitted to, as Brian just mentioned, four different regions for the indication of thalassemia based on our two well-controlled trials that met the primary and key secondary endpoints in both. 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. We do at minimum anticipate there the updates in the PKD label to reflect the indication statement and the dose to be changed to thalassemia and 100 mg PID. The process and the review are of course ongoing, and the FDA only provides you an end date of the complete review. The final label, that's what we will know at the PDUFA date.

Marc Frahm (Stock Analyst)

Okay, that's helpful. 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 run rate, or are there still kind of meaningful step ups that we should be expecting going forward as the launch actually starts?

Brian Goff (CEO)

Yeah, 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.

Cecilia Jones (CFO)

Thanks, Marc.

Yeah.

From a financials perspective, we do expect to see a little bit more growth on the STNA 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. We do have some launch related expenses that would obviously only happen upon approval. We do see some more coming potentially after that.

Tsveta Milanova (Chief Commercial Officer)

Absolutely. 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 about 40 people in the sales organization, but also a cross-functional team that interacts with different customers. We are excited about having the potential to provide PYRUKYND in thalassemia, corresponding to FDA approval in the U.S., and we're looking forward to give updates when possible.

Marc Frahm (Stock Analyst)

Great, thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Goldman Sachs. Your line is open.

Please go ahead.

Salveen Richter (Managing Director)

Good morning.

Thanks for taking my question. As you look to the upcoming PDUFA goal date here for PYRUKYND 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?

Brian Goff (CEO)

Yeah, thanks a lot Salveen. I'll turn that one over to Tsveta.

Tsveta Milanova (Chief Commercial Officer)

Absolutely. From a commercial perspective, thalassemia is really an attractive indication for us to potentially launch next. The reason for that is that the patients with thalassemia are actually diagnosed and well known to the healthcare system in the U.S. There is great data based on the ICD-10 codes in the U.S., which we have been able to validate throughout our interactions with healthcare professionals. That gave us a lot of clarity not only on where patients are currently being managed, but also which patients potentially we should prioritize and focus on 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're engaged with the healthcare system, and they potentially will require additional management and treatment. 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 need.

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 SIMI Internet Pan American Conference, which gave us a lot of energy and excitement about the potential launch in the future.

Brian Goff (CEO)

Yeah, that's great. And Salveen, 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 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. There's a lot of rigor around those numbers. I'll just point out that's in contrast to pyruvate kinase deficiency, where literally the codes were established right before launch. It's a very different dynamic. Maybe I'll just ask Cecilia to comment on a look ahead from a revenue perspective with a potential launch, what fourth quarter could look like.

Cecilia Jones (CFO)

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

Brian Goff (CEO)

Thanks.

Operator (participant)

Thank you. One moment as we move on to our next question. Our next question comes from the line of Emily Bodnar with H.C. Wainwright. Your line is open.

Please go ahead.

Emily Bodnar (Biotech Equity Research Analyst)

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.

Maybe if you could.

Morgan Sanford (VP of Investor Relations)

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.

Brian Goff (CEO)

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.

Tsveta Milanova (Chief Commercial Officer)

Absolutely. There are about 8,000 thalassemia patients in the U.S. as we said, about 6,000 of those are adult. 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 there is a high diagnosis rate in that disease. There is always a high unmet need and an opportunity for us to provide value in pediatric patients. With that, I'll hand it over to Sarah.

Sarah Gheuens (Chief Medical Officer and Head of R&D)

The way we are approaching pediatric development is we wait for the benefit risk profile in adults, which we now have. 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 once that data is available, indeed deliver that to regulators for review.

Brian Goff (CEO)

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?

Sarah Gheuens (Chief Medical Officer and Head of R&D)

No. We always pride ourselves on collaborative engagements and relationships with all of the regulators that we interact with. I know the disruption in the news, and we have not experienced major disruptions in our team engagements with the FDA. At home, it remains a collaborative engagement.

Morgan Sanford (VP of Investor Relations)

All right, thank you.

Brian Goff (CEO)

You're welcome.

Operator (participant)

Thank you. 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 Alec. Thanks for taking our question. 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. Maybe second question on the early stage pipeline, curious if there has been any change to your development plans in PKU after the approval of PTCs.

Brian Goff (CEO)

Okay, thanks, Matthew. Tsveta can start on the question about beyond the initial higher frequency clinical touch points, what does segmentation look like?

Tsveta Milanova (Chief Commercial Officer)

Absolutely. 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 actually be developing complications of the disease as well. The key educational elements there will continue to remain the same. We know that the unmet need 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. A lot of our educational efforts are actually disseminating that additional information and continuing 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 the pathophysiology of the disease, which is an important element for us. Once we are ready to expand, we will have more engaged both patients and physician community on that front. That 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 will address with our partners appropriately on a country-by-country basis.

Brian Goff (CEO)

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 number one priority and that's why Tsveta and the team have designed for direct commercialization. We're really proud of the partnerships that we have already established and updated, in fact this morning, with Europe with Avanzanite Bioscience as well as NewBridge in the GCC region. As I noted, that's a very capital efficient approach, but it also leans on localized expertise in those geographies accordingly. To the second question about PKU, maybe I'll have Sarah pick up on that.

Sarah Gheuens (Chief Medical Officer and Head of R&D)

Yes.

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. Fundamentally, 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 specialize, 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 Balanziq, there may be anaphylaxis or things like that. There will remain a big, big gap there to address.

You even see that reflected in the current label that they received on the new drug. 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.

Brian Goff (CEO)

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. Just like across thalassemia, sickle cell disease, pyruvate kinase deficiency, any of our diseases that we're pursuing, any innovation is important and we like to read that news that you referred to. We are very excited about the progress that we're making with our own PAH hydroxylase stabilizer with 1A1. Thanks a lot.

Operator (participant)

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 Scott Berens with Leerink Partners. Your line is open. Please go ahead.

Andrew Berens (Senior Research Analyst)

Hi. Thanks. Congrats on all the progress. This is a follow-up to Mark's earlier question. Has anything changed in the sickle cell trial protocol since you identified risks and liver injury at ASH 2024? I'm interested in whether the consent forms and the monitoring requirements have changed. I have one on tebapivat. We noticed that the tebapivat trial is using markedly lower doses than the MDS Phase 2b 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?

Brian Goff (CEO)

Hello?

Morgan Sanford (VP of Investor Relations)

Yeah.

Sarah Gheuens (Chief Medical Officer and Head of R&D)

Okay.

In regards to the sickle cell disease protocol, we've announced in the past that when we identified this risk in the thalassemia program, we had aligned all of our protocols to have monthly monitoring for the first six months, including our open label extension trial. For the sickle cell disease protocol, we aligned the open label extension study to match what happened 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. We made sure that they had the same type of monitoring. That is effectively reflected in the protocols. We did update those informed consents as well, obviously. In regards to your next question around the dosing differences between the sickle cell disease phase 2 and the MDS phase 2, you are right.

We are exploring lower doses within the sickle cell disease phase 2. That is because the sickle cell disease patients, their metabolism matches the healthy volunteer metabolism that was observed in the phase 1. Reminder that we had sickle cell disease patients included in that trial as well. We have that. In the MDS trial, in the 2a, we observed that MDS patients metabolize the drug faster. We adapted the dose appropriately. That's what you'll see that we are exploring. That's why we are exploring different doses between sickle cell disease and MDS.

Brian Goff (CEO)

Thanks.

Andrew Berens (Senior Research Analyst)

Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question is going to come from the line of Tessa Romero with J.P. Morgan. Your line is open.

Please go ahead.

Tessa Thomas Romero (Biotechnology Equity Analyst)

Good morning, Brian and team. Thanks for taking our question. 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? 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.

Brian Goff (CEO)

Sure. Thanks, Tessa. 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.

Sarah Gheuens (Chief Medical Officer and Head of R&D)

Yes, maybe I can start actually with that one. 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 prioritize the time of the teams there versus trying to get more publications out on extension data. That's coming for sure. We share that interest, obviously, and you're right, everybody will continue to be interested in that.

More to come.

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. The benefit risk review is still ongoing with the agency. I think right now what you see, what is reflected in the PKD label to date, is what we have observed in our program. You can see that language in another condition and at a higher dose is in the warning and precaution 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 do not comment on ongoing review processes with the agency. As you know, our PDUFA date is September 7, at which point the procedure should be completed.

Then we will all have the final label and can talk more about that.

Tessa Thomas Romero (Biotechnology Equity Analyst)

Thank you.

Operator (participant)

Thank you. Our final question is going to come from the line of Greg Harrison, Wiscosia Bank. Your line is open.

Please go ahead.

Good morning, this is Teresa Onsur. Greg, thanks for taking our question. 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 and how you're planning to address any variability in care between academic centers and community hematologists.

Brian Goff (CEO)

Yeah, thanks. Teresa 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.

Tsveta Milanova (Chief Commercial Officer)

Absolutely. Teresa, as I mentioned, in the U.S. we really benefit from the fact that thalassemia patients are diagnosed and they are well established ICD-10 code. 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 very robust launch preparations where we had the opportunity to connect with the prescriber base and profile the account 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 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 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.

Operator (participant)

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

Brian Goff (CEO)

Okay, thanks Michelle. 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 Pharmaceuticals and we truly believe that we are poised to deliver transformative therapies for patients and to create significant long term value to shareholders. Thanks again and we look forward to speaking with you again soon.

Operator (participant)

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