Good morning, and welcome to Agios Pharmaceuticals Third Quarter 2025 Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at Agios. Please go ahead, ma'am.

Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals third 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. Next slide, please. Please note we'll be making certain forward-looking statements today. 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. Our third quarter earnings call agenda is shown on the next slide. Joining me on today's call 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.

Thanks, Morgan. Good morning, everyone, and thank you for joining us on today's call to discuss our third quarter highlights beginning on the next slide. With steady progress and a focused strategy, we have a clear path to unlock long-term shareholder value. First, we have multiple high-value catalysts in the coming months that position PYRUKYND, our foundational PK activator to achieve its multibillion-dollar potential across PK deficiency, thalassemia and sickle cell disease. Following the FDA's recent request for a REMS program, our PDUFA date for PYRUKYND thalassemia supplemental NDA has been extended to December 7. We are actively engaged with the FDA and are leveraging this additional time to strengthen our engagement with the thalassemia community and further refine our launch planning. Additionally, we look forward to sharing top line results from the RISE UP Phase III trial of PYRUKYND in sickle cell disease by year-end. Meanwhile, we continue to advance our early and mid-stage pipeline, which includes our other PK activator, Tebapivat, for lower-risk myelodysplastic syndromes, or MDS and sickle cell disease, AG-181 for phenylketonuria and AG-236 for polycythemia vera. Importantly, our strong balance sheet with approximately $1.3 billion in cash and investments positions us to invest in a disciplined manner to both support our potential U.S. launches and advance our rare disease pipeline. Our third quarter highlights are summarized on the next slide. In the third quarter, we reported $12.9 million in net revenue, underscoring the strong value proposition of PYRUKYND. In August, we announced approval for PYRUKYND in adults with thalassemia in Saudi Arabia, our first global regulatory approval for this indication. And earlier this month, we also received a positive CHMP opinion recommending PYRUKYND for marketing authorization in Europe for the treatment of adults with thalassemia. And lastly, we achieved a key R&D priority by completing enrollment in the Phase IIb trial of Tebapivat in lower-risk MDS and we anticipate top line data early next year. With continued momentum across our commercial portfolio and pipeline, our team has demonstrated strong execution and agility, keeping us firmly focused on our mission to deliver transformative medicines for patients. That agility is a competitive advantage as we work to transform the treatment landscape for thalassemia and sickle cell disease. Feedback from these communities through our recent global engagements reinforces the critical need for treatment innovation. Please move to the next slide and I'll turn the call over to Cecilia to provide commentary on our third quarter performance and full year outlook. Cecilia?

Thank you, Brian. Next slide, please. Our third quarter 2025 financial results can be found in the press release issued 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. Third quarter net PYRUKYND revenue was $12.9 million, an increase of 44% compared to $9 million in the third quarter of 2024 and an increase of 3% compared to $12.5 million in the second quarter of 2025. Third quarter net revenue growth reflects continued commercial execution in PKD ahead of potential U.S. approval for thalassemia. Looking ahead, fourth quarter performance will benefit from an additional ordering week compared to the third quarter and we anticipate PYRUKYND net revenue will continue to reflect continued focus on PK deficiency ahead of potential approval for thalassemia in the U.S. On a full year basis, given the strong execution of our sales force to date, we anticipate net revenues in 2025 to show robust growth compared to 2024, although we recognize this growth is on a relatively small revenue base. Cost of sales for the quarter was $1.7 million. R&D expenses were $86.8 million, an increase of $14.3 million compared to the third quarter of 2024. This increase was primarily driven by increased clinical trial costs associated with our PK activation franchise. SG&A expenses were $41.3 million in the third quarter, an increase of $2.7 million compared to the prior year, driven by disciplined investments ahead of the potential commercial launch of PYRUKYND in thalassemia. We ended the third quarter with cash, cash equivalents and marketable securities of approximately $1.3 billion. Next slide, please. Our capital allocation strategy backed by a strong balance sheet enables strategic investment in future growth and delivery of our ongoing pipeline programs. First, we have built a capital-efficient global commercial model, prioritizing our investment in potential U.S. launches, which represents the largest commercial opportunities. We have executed partnerships with NewBridge Pharmaceuticals in the GCC and Avanzanite Bioscience in Europe, both of which are structured as revenue sharing arrangements that favor Agios over the long term. We will record our share of sales as net revenues. Second, we will continue to invest in our ongoing early and mid-stage clinical programs. And third, we are opportunistically looking for ways to expand and diversify 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. In the third quarter, we delivered $12.9 million in PYRUKYND net revenues, up 3% sequentially, once again reflecting strong execution by our commercial team. To date, 262 patients have completed prescription enrollment forms, including 14 in the third quarter, representing a 6% increase sequentially. This has translated into 149 patients currently on therapy, up 5% from the second quarter. These results underscore the strength of our commercial model and the foundation we are building for future growth. We are well positioned to deliver on potential U.S. launches for thalassemia and sickle cell disease. Please move to the next slide. Let's turn to thalassemia and our global commercialization strategy for PYRUKYND. Following the 3-month extension of our PDUFA goal date to December 7, we remain confident in our ability to deliver a successful launch, pending regulatory approval. This confidence is further reinforced by our recent engagement with physicians, patients and advocacy groups, which I will touch on shortly. Outside of the U.S., we have implemented a capital-efficient global commercialization strategy through partnerships with NewBridge Pharmaceuticals in the GCC and Avanzanite Bioscience in Europe. These partnerships allow us to retain full rights to PYRUKYND while preserving our capital investment for U.S. launches. In August, we announced SFDA approval of PYRUKYND for the treatment of adult thalassemia patients in Saudi Arabia, marking our first global approval for thalassemia. Launch activities are underway in Saudi. Our partner, NewBridge, is providing early patient access on case-by-case basis with the potential to expand access after securing national procurement agreements over the next couple of years. In Europe, we anticipate a European Commission regulatory decision in early 2026, following the positive recommendation from the CHMP and we are actively working with our partner Avanzanite Bioscience to refine our launch strategy. Please…

Thank you, Tsveta. Next slide, please. In the third quarter, we continued to make strong progress across our pipeline. In early August, we announced PYRUKYND approval for adults with thalassemia in Saudi Arabia. And earlier this month, we received a positive CHMP opinion recommending PYRUKYND for marketing authorization in adults for the treatment of anemia associated with transfusion-dependent and non-transfusion-dependent alpha or beta thalassemia in Europe and we look forward to a final regulatory decision by early next year. Finally, our reviews remain ongoing in the United Arab Emirates and in the U.S., where we continue to progress towards our new PDUFA goal date of December 7. Beyond PYRUKYND, we were pleased to announce enrollment completion in the Phase IIb trial of Tebapivat for the treatment of lower-risk MDS. Tebapivat, our more potent PK activator has the potential to be the first oral therapy to address anemia due to ineffective erythropoiesis in patients with lower-risk MDS. I will share more on this potential opportunity shortly. Please move to the next slide. As we approach the anticipated top line results for the Phase III RISE UP trial, I wanted to take a moment to highlight the significant need in this community as well as our potential to deliver a disease-modifying novel treatment with PYRUKYND. There are approximately 100,000 diagnosed adult and pediatric patients with sickle cell disease in the United States and a significantly larger number worldwide. Sickle cell disease remains profoundly underserved. The lack of suitable treatment options contributes to a high mortality rate that has, in fact, worsened with U.S. life expectancy in the late 30s, underscoring a significant opportunity for therapeutic innovation. PYRUKYND is a potential first-in-class oral therapy for sickle cell disease, targeting both hemolysis and vasal occlusion through a unique PK activation mechanism of action, activating…

Thank you, Sarah. Next slide, please. In the third quarter, we delivered meaningful progress across our 2025 R&D priorities, once again showcasing our ability to execute swiftly and effectively. Looking ahead, the fourth quarter holds exciting milestones. We are sharpening our launch planning in anticipation of the new December 7 PDUFA goal date for PYRUKYND in thalassemia and we expect to report top line results from the Phase III RISE UP trial of PYRUKYND in sickle cell disease by year-end. Please move to the next slide. Our fundamentals remain strong, backed by a seasoned leadership team with a proven track record. We continue to advance our pipeline and deliver meaningful impact for the rare disease communities we serve, communities whose insights guide us and are vital to our success. We are operating from a position of strength, backed by a balance sheet that not only supports our potential U.S. launches and advancement of existing clinical programs, but also enables us to pursue strategic business development opportunities to further expand and diversify our pipeline and ensure we can create long-term shareholder value. Before we move to Q&A, I want to take a moment to recognize the continued dedication of our employees whose relentless focus and commitment continue to drive meaningful impact for patients with rare diseases. Their work, together with the voices of the communities we serve is foundational to our mission. As we look ahead, we remain resolute in our pursuit of transformative medicines, advancing innovation with the aim of delivering long-term value for both patients and shareholders. With that, I'd like to open the call for questions. Operator, please open the line.

[Operator Instructions] Our first question comes from the line of Eric Schmidt with Cantor.

Maybe first, just on the thalassemia review process. It's been almost 2 months now since you've got the PDUFA extension. Do you have a better sense of what type of a REMS program the FDA is interested in here? I know there's a spectrum of maybe more or less onerous REMS programs. And then just a second follow-up question. I think both Cecilia and Brian mentioned actively looking for external assets. What type of BD makes sense for the company at this stage? And would you wait until the sickle cell readout to transact?

I'll have Sarah take the first one and then I can pick up with the external pursuit question. And Sarah, let me turn it over to you.

Yes. So in regards to REMS and label, as you know, the review is ongoing with our extended PDUFA date of December 7. We per process don't comment on the details of REMS in the label. However, indeed, to your point, there are many different forms of REMS. And as you know, the REMS is requested because of hepatocellular injury. So you can anticipate that it will include monitoring and some form of education.

And Eric, on your second question in terms of continuing to expand our pipeline, our pursuit really is not timed to anything in particular. I'm really proud of the work that the team does to cast the net wide and continue to look at a number of different opportunities. And this goes externally, but it's also organically internally to see if there are other indications, for example, that we should pursue. But again, that's not timed to anything per se. In general, I mean, our sweet spot, of course, is rare diseases. We look for therapies that have transformative potential for patients, early derisking opportunities, if we're talking about earlier [indiscernible] assets. And then I would say another opportunity would be if we find something that doesn't have to be first-in-class, but we always set the bar for best-in-class, which we feel very proud of with our current organic pipeline. So that work continues ongoing. And like I said, I'm really proud of the capabilities that our team has, both with internal opportunities as well as external.

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

Just a couple from us. It's been interesting to see how the different geographies have approached the risk of liver injury for mitapivat in thalassemia. Maybe could you just remind us what sort of liver monitoring requirements are so far being required in Saudi and potentially in EU if it's approved as well? And do you think this could change depending on the U.S. label? And then maybe second, as a follow-up, curious how this monitoring requirement is changing maybe your commercial approach in these different areas.

Yes. Again, Sarah can start with the labeling so far. And I'll just preempt by saying the label we have right now, of course, at this point, only exists in Saudi Arabia and Sarah can comment on that. And then we're still in process with FDA. And in Europe, it's a CHMP positive opinion, but we're still awaiting the conclusion of that review in the coming couple of months and expect that by early next year. And then I'll have Tsveta comment in terms of the impact of some of these scenarios. Sarah, do you want to start?

Sure. So in regards to the label, yes, indeed, for Saudi, it's in line with our proposal of once-a-month monitoring for the first 6 months and that label is now available. For the European Union, we indeed are very pleased that we received a positive CHMP opinion, which from their perspective, confirms the benefit risk profile that we saw. We are -- obviously, the label will only be final when you have the EC decision. So the details will become available at that point in time. And to Brian, Brian already mentioned it, but the U.S. -- the review is still ongoing.

And then Tsveta comments on potential impact of REMS.

Absolutely. So as we all know and there are very few treatment options for the thalassemia patients across the board and with regards to non-transfusion-dependent, transfusion-dependent patients. We remain very convicted behind the strong benefit risk profile of PYRUKYND for these patients and that has been reiterated and confirmed by all of our stakeholders, including all the clinicians that interacted with recently in the field after the announcement of REMS for the potential U.S. label. I can tell you the team is prepared for the launch. We are taking advantage of the additional time to continue the engagement with the community and do disease education. And when it comes to REMS in the U.S., we don't anticipate that to be a barrier to prescribing or have an impact on our commercial opportunity because we know that both the academic as well as the community hematology, oncology practices, they have an experience with REMS. And when I connected both with academics and the community prescribers, they confirmed that to me and the team is confirming that in the field on a daily basis.

[Operator Instructions] Our next question will come from the line of Emily Bodnar with H.C. Wainwright & Co.

This is [ Joey ] on for Emily. Congrats for a great quarter. Shifting focus to Tebapivat. How are you guys looking at what be considered positive data in LRMDS given the data for luspatercept and imetelstat? And then a follow-up, could you also remind us of the Avanzanite strategy for the European thalassemia launch and how the cadence could look like for that?

Yes. I think we're going to follow the same order of entry here. So Sarah can get started on Tebapivat and how we think about the potential in low-risk MDS, which is a very high unmet need area with -- is classic across all of our diseases that we're pursuing very limited treatment options. And then Tsveta can comment on Avanzanite and also probably tuck in some comments about NewBridge too. We have 2 very valued partners outside the U.S. Sarah, do you want to start?

Sure. So in regards to the positive data for lower-risk MDS. So we are very pleased that we were able to announce enrollment of our Phase IIb trial today. So more data will come at the beginning of next year for our program. Obviously, we are going to take the ecosystem around us into account when we look at the data that this program will generate. But what is important, I think, is what Brian just mentioned, there is a huge unmet need for this patient population, specifically as the goal for this population tends to be really also now more and more focused on quality of life. And as you know, like for PK activators, quality of life has been an important component of their benefit profile. So that is something that we were definitely hoping to deliver to.

And, Tsveta, pivoting then to Avanzanite. And since you've also spent some time outside the U.S. recently in Saudi Arabia, maybe you can comment on NewBridge as well and the preparation of our partners.

Absolutely. So starting with Avanzanite, first of all, we are very [Technical Difficulty] about the potential EC decision and approval of PYRUKYND for thalassemia in Europe coming early next year. We're working very closely with Avanzanite team to refine our strategy for Europe. It's important to remember that in Europe, after a regulatory decision and approval, each of the countries needs to undergo a pricing and reimbursement process. So at the moment, we are going with Avanzanite, assessing the market opportunities, prioritizing market where to submit for pricing and reimbursement first. But the pricing and reimbursement process in the European countries can take 12 to 18 months. So just keep in mind that we wouldn't see kind of the immediate impact of an approval on the commercial opportunity in Europe after a EC decision is announced. But we prioritize Avanzanite as our selected partner because they have a very strong rare disease capabilities and expertise as well as the pricing and market access capabilities and we look forward to continue to work with them to provide access to patients in Europe. As Brian mentioned, I actually had the opportunity to spend some time with the team in Saudi towards the FDA approval in August. And again, very senior team here in Saudi Arabia. We consistently hear the high unmet need for thalassemia patients, the strong excitement about the benefit risk profile of PYRUKYND and the value it can bring to that community. But as a reminder, again, in Saudi Arabia, the process after approval starts with one-on-one requests from physicians for individual patients for PYRUKYND early and patient access and market access. And it's going to take about a couple of years until we get to the stage of a national procurement agreement, which will open access more broadly and see the commercial opportunity there.

Our next question will come from the line of Marc Frahm with TD Cowen.

Just back on the liver events. Can you maybe just as you've continued to dose people and follow them for longer and longer, just kind of comment on if any additional events have been observed kind of across the PKR trials? And to the extent any have, have they continued to conform to the kind of description before of occurring within 6 months and importantly, the patient returning to baseline whenever they do stop mitapivat as a result? And then maybe on the commercial side, if you -- I recognize it will take quite a while to work through case-by-case access and actually get to revenue for any of those patients, let alone the reimbursement negotiations. But maybe can you comment on just any level of demand you're already seeing kind of in the Gulf to kind of start that process?

Sure. Sarah, maybe you could just start then with the question Marc has around the hepatocellular injury and have there been additional cases that have met the pattern that we observed in thalassemia. And then Tsveta again can talk about the green shoots, I could say, of demand so far.

Sure. So in regards to the observations that we had in the thalassemia program that allowed us to determine the hepatocellular injury risk for thalassemia specifically, so nothing has changed the way we have assessed the risk. So safety profile remains exactly the same as when we declared this hepatocellular injury risk and we have not observed anything across the program that warrants us to update the safety profile the way we currently understand it.

Tsveta?

So yes, I actually had the opportunity to meet with some key customers in Saudi Arabia this week in some of the biggest hospitals. And as I said, we definitely hear the interest in PYRUKYND profile, the desire to try it in individual patients and gain experience with the product. At the very beginning in the country, it's a very burdensome process, which actually takes months from an individual patient prescription and a request until approval at the hospital level and securing the budget. So we expect that to be the slow process, slow and steady as the individual patient requests get approved, the experience gets stronger and stronger. But definitely, the interest from the community is there and it's high. It's just the process in the country takes time.

And Marc, what I would add is what's unique about Saudi Arabia is, of course, the prevalence is quite different from what we see in the U.S. on a per capita basis, it's about 8 to 9x more common. So on the less rare side, for sure, most people -- most clinicians certainly have a good working knowledge of thalassemia. However, the common denominator that we see across all geographies really is a function of the limited treatment options available is the need for us to continue to educate, particularly the burden that non-transfusion-dependent thalassemia patients face on a daily basis because they're subjected to chronic hemolysis and all the downstream consequences that come from that, we're doing our part to make sure that clinicians have that top of mind as they think about the potential that mitapivat, PYRUKYND could offer. So that's one thing that's not unique to geography. It's across all markets in the world.

[Operator Instructions] Our next question comes from the line of Tessa Romero with JPMorgan.

So for the Phase III portion of RISE UP, has the last patient exited the trial yet? And what are any considerations in terms of the steps and timing to get to your top line? And then I have a follow-up.

Okay. Well, I will allow Sarah to comment. I will just remind that we will not be more refined on our timing guidance for the RISE UP data that we're also eagerly awaiting, we'll be more refined by saying that we're on track for that data by year-end. And Sarah, I'm not sure if you want to say anything additional about where we are on that process.

No, I think you summarized it, Brian. So indeed, like we're not commenting on individual patient status, but we are indeed on track to deliver the top line data by year-end. And since we are very -- like we have delivered several Phase III clinical trials per our milestone. So we are a well-oiled machine at this point in time to get from database locks to top line results.

And I'll just say -- I mean, Tess, if I can just add, I am really pleased with the continued excellence in operations from the team because, of course, we have a lot of moving parts underway simultaneously. We have launch preparation. You've heard from Tsveta. We've got Sarah's team working on labeling for our PDUFA date that's approaching for thalassemia, December 7 and then, of course, getting ready for a data readout for RISE UP. So we're -- this team is really delivering and I'm really pleased with the operational excellence.

Okay. So you can't tell us if your top line will be before or after your PDUFA date?

What an excellent follow-up question and I'm going to stick to it by year-end.

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

This is [ Lydia ] on for Salveen. Maybe just another one on the REMS program. Do you anticipate the requirements to apply kind of across the label to PKD and sickle cell as well? And have you received any physician feedback on how this might impact uptake, particularly with sickle cell where some of these treatment centers might not see PKD and thalassemia patients as well?

Yes. I think, Lydia, I might just start on this one to say, first of all, the REMS request has been specific to thalassemia. So that's an important point. And with respect to any potential outcome or impact rather in sickle cell disease, the most important step is what we literally just had discussed is getting to the point of the RISE UP Phase III data. That's the most important next step. And then from there, we'll be better guided around the benefit risk profile.

And I'm showing no further questions at this time. And I would like to hand the conference back over to Brian Goff for closing remarks.

# Well, thanks, Michelle, and thank you very much, everyone, for joining us on this morning's call. As you've seen, and as I just mentioned, we've delivered on many of our milestones this year. So we have 2 of our most anticipated inflection points approaching by year-end. As you can imagine, this is a very exciting time at Agios and we truly believe that we are poised to deliver transformative new therapies for patients and create significant long-term value for 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.