Agios Pharmaceuticals - Earnings Call - Q4 2024

Executive Summary

• Q4 2024 product revenue was $10.7M, up 20% sequentially on year-end stocking and reserve adjustments, and up ~51% YoY; net loss was $96.5M; cash and marketable securities ended at $1.5B.
• FDA accepted the thalassemia sNDA with a PDUFA goal date of September 7, 2025; Phase 3 RISE UP in sickle cell completed enrollment; ACTIVATE-Kids in pediatric PK deficiency met its primary endpoint.
• Management guided that 2025 PK deficiency revenues will be “relatively flat” vs. 2024 and that SG&A and R&D will grow YoY as the company prepares for thalassemia launch; initial thalassemia ramp is expected to be a partial quarter in Q4 2025 and not a large bolus due to payer/formulary timing.
• Stock-relevant catalysts include the thalassemia PDUFA decision (Sep 2025), RISE UP topline by late 2025, and continued commercial build; Q4 revenue quality factors (stocking/reserve) are non-recurring per management, implying a likely softer Q1 2025 print absent similar tailwinds.

What Went Well and What Went Wrong

What Went Well

• Thalassemia regulatory progress: FDA accepted sNDA; PDUFA date set (Sep 7, 2025). CEO: “Agios had a transformative year in 2024… poised for multi-billion-dollar potential”.
• Clinical execution: RISE UP Phase 3 enrollment completed (>200 patients); ACTIVATE-Kids achieved primary endpoint; robust data flow at ASH and sustained momentum across pipeline.
• Balance sheet strength: Cash and marketable securities of $1.5B at year-end 2024, supported by $1.1B milestone/royalty monetization tied to vorasidenib; CFO emphasized financial independence to fund launches and pipeline.

What Went Wrong

• Persistent operating losses: Q4 net loss of $96.5M; R&D of $82.8M and SG&A of $51.7M increased YoY as commercialization ramped, pressuring near-term P&L.
• Revenue quality caution: ~$1.6M of Q4 revenue uplift from stocking and reserve adjustments; management does not expect these items to repeat in Q1 2025, tempering near-term revenue trajectory.
• Safety monitoring scrutiny: Following hepatocellular injury observations at higher dosing in another condition, protocols were tightened to monthly liver tests for first six months across programs; PKD label updated with warnings/precautions, raising regulatory/labeling focus ahead of thalassemia review.

Transcript

Operator (participant)

Good morning and welcome to Agios' fourth quarter 2024 conference call. At this time, all participants are in 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' request. I would now like to turn the call over to Chris Taylor, VP Investor Relations and Corporate Communications for Agios.

Chris Taylor (VP of Investor Relations and Corporate Communications)

Thank you, Operator. Good morning, everyone, and welcome to Agios' conference call and webcast to discuss our fourth quarter and full year 2024 financial results and recent business highlights. You can access the slides for today's call by going to the Investors section of our website, agios.com. On today's call, I'm joined by our Chief Executive Officer, Brian Goff, Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development, Tsveta Milanova, Chief Commercial Officer, and Cecilia Jones, Chief Financial Officer.

Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result 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, and with that, I'm pleased to turn the call over to Brian.

Brian Goff (CEO)

Thanks, Chris. Good morning, everyone, and thank you for joining us. Our mission at Agios is to develop and deliver transformative medicines that elevate and extend the lives of patients living with rare diseases. We are especially focused on rare diseases that result in the dysfunction and destruction of red blood cells, including pyruvate kinase deficiency, thalassemia, sickle cell disease, and lower-risk myelodysplastic syndromes, or MDS. Our lead product, Pyrukynd, a pyruvate kinase activator, has a novel mechanism of action that improves red blood cell metabolism and increases the amount of energy, or ATP, available to support red blood cell health. Today, we are pleased to share with you our results from the fourth quarter, as well as reflect on accomplishments throughout 2024 and our expectations for the exciting new year ahead.

Our rare blueprint for success uniquely positions us to drive significant growth and shareholder value creation over both the near and the long term. First, we have the exciting prospect of two additional commercial launches to support what we consider to be a multi-billion-dollar growth opportunity for our lead product, Pyrukynd. We are planning for a potential approval and launch in thalassemia in September of this year, followed by sickle cell disease in 2026. Second, our early and mid-stage pipeline is robust and poised for clinical advancement, offering a strong foundation for innovation and growth. And finally, supporting it all is our highly experienced team with a proven track record of executional excellence and our strong balance sheet, which puts us in the enviable position of being able to independently grow the company and execute on these exciting opportunities.

2024 was an exceptional year of executional and scientific excellence at Agios, as shown on this slide, with checkmarks for each of the key milestones we projected one year ago. We meaningfully advanced each of our key programs, including filing for regulatory approval in thalassemia across four markets and completing enrollment in phase III RISE UP study for sickle cell disease, and we continue to progress our early pipeline, building the foundation for sustainable long-term growth. After a transformative 2024, we believe 2025 is a breakout year for Agios. Over the next 12 months, we will focus on three key priorities. Number one, maximizing the potential of the Pyrukynd franchise. Number two, advancing and diversifying our key pipeline programs, and number three, strategically focusing our capital deployments to sustain and drive our growth.

Building on all that was accomplished in 2024, we have another year ahead with compelling commercial, regulatory, and clinical milestones. Today, we announced top-line results from the ACTIVATE-Kids phase III trial of mitapivat in pediatric patients with PK deficiency who are not regularly transfused. This is Agios' first pediatric clinical program for mitapivat in a rare hemolytic anemia, and we are excited for Sarah to share with you the positive top-line data from this study in just a moment. We also anticipate some exciting developments for our mid- and early-stage pipeline programs. For tebapivat, our novel PK activator, formerly known as AG-946, we expect to complete enrollment in the ongoing phase IIb study in lower-risk MDS by year-end and initiate a phase II study in sickle cell disease by mid-2025.

Additionally, we expect to file an Investigational New Drug Application for AG-236, our siRNA targeting TMPRSS6 inhibition intended for the treatment of polycythemia vera in mid-2025. And the most significant expected events for 2025 include the September 7th PDUFA goal date for our sNDA filing of Pyrukynd in thalassemia, and the phase III readout of the RISE UP study of mitapivat in sickle cell disease by year-end. As you can see, this year promises to be exciting with multiple catalysts across our pipeline that hold significant value for shareholders and have transformative potential for patients. With those introductory comments, let me now hand it off to Sarah to review our exciting progress in R&D.

Sarah Gheuens (CMO and Head of Research and Development)

Thanks, Brian. Our pipeline includes a well-rounded mix of late-stage programs nearing market entry and promising mid and early-stage opportunities that showcase our therapeutic depth and breadth. We prioritize opportunities where our expertise and resources can make a measurable impact and create significant value. As you may have seen, this morning we announced top-line results from our second phase III pediatric study, ACTIVATE-Kids, which evaluated mitapivat in pediatric patients with PK deficiency who are not regularly transfused. This complements the phase III ACTIVATE-KidsT study of mitapivat in children with PK deficiency who are regularly transfused, which read out top-line data in August of last year. Turning to the results of the ACTIVATE-Kids study, a total of 30 patients aged 1 to less than 18 years old were enrolled with 19 randomized to mitapivat twice daily and 11 randomized to matched placebo.

All patients in both arms completed the 20-week double-blind period. The primary endpoint of the study was hemoglobin response, defined as a greater than or equal to 1.5 g/dL increase in hemoglobin concentration from baseline that is sustained at two or more scheduled assessments at weeks 12, 16, and 20 during the double-blind period. The primary endpoint of the study was met. There were 31.6% or six of 19 patients in the mitapivat arm achieving a hemoglobin response compared to 0% or zero of 11 patients in the placebo arm. In addition, improvements in changes from baseline for markers of hemolysis were observed in the mitapivat arm compared to the placebo arm. In the 20-week double-blind period, a similar proportion of patients had adverse events in the mitapivat and placebo arms, and there were no discontinuations of study treatment due to adverse events for any reason.

The safety results were consistent with the safety profile for mitapivat previously observed for adult patients with PK deficiency who are not regularly transfused. With data now available from the randomized placebo-controlled double-blind period of both phase III pediatric PK deficiency studies, we look forward to sharing more detailed findings with the community and interacting with regulators. The ACTIVATE-Kids and ACTIVATE-KidsT phase III studies mark Agios' first pediatric clinical program for a rare hemolytic anemia, providing valuable insights that will help shape the company's future clinical programs evaluating mitapivat in pediatric patients with thalassemia and sickle cell disease. Now turning to thalassemia. This is a rare lifelong inherited blood disorder that causes chronic anemia, and patients with thalassemia often experience a range of debilitating complications such as organ damage, stroke, and other serious health issues.

Common management strategies for thalassemia, such as blood transfusions and iron chelation therapy, can also lead to significant secondary effects compounding the health challenges patients face. Today, patients have limited or no effective treatment options, with 67% of diagnosed patients in the U.S. having no approved therapies. In 2024, we announced positive results from the ENERGIZE and ENERGIZE-T phase III trials evaluating mitapivat versus placebo in adults with non-transfusion-dependent and transfusion-dependent alpha or beta thalassemia, respectively. A top-line summary of the results across these two studies is shown on the left-hand side of this slide. Based on the favorable benefit-risk profile observed in both the ENERGIZE and ENERGIZE-T phase III studies, we believe mitapivat has the potential to become a foundational and convenient oral medication for thalassemia patients, regardless of their genotype or transfusion needs.

In December, we announced the simultaneous filing for regulatory approval of Pyrukynd for this indication in the U.S., the European Union, Kingdom of Saudi Arabia, and the United Arab Emirates, and last month, we announced that the FDA accepted our Supplemental New Drug Application with a PDUFA goal date of September 7th, 2025. Moving on to sickle cell disease. This inherited lifelong blood disorder is estimated to affect approximately 120,000-135,000 individuals across the U.S. and EU-5, with a global prevalence exceeding 3 million. Clinical features of sickle cell disease are chronic hemolytic anemia and vaso-occlusion, which can lead to pain, poor quality of life, organ damage, and early mortality. There is an urgent need for novel therapeutic options to elevate the standard of care for patients suffering from this debilitating and life-threatening disease.

Based on the positive results from phase II RISE UP study, along with encouraging data from other hemolytic anemias with a shared pathophysiology, we see significant potential with mitapivat in sickle cell disease as well. The phase III RISE UP study completed enrollment in October 2024, with over 200 patients enrolled globally, achieving this milestone just over a year after recruitment began. In this study, we have two independent primary endpoints: hemoglobin response and annualized rate of sickle cell pain crises. Attaining either primary endpoint allows us to apply alpha to the trial's secondary endpoints. With our secondary endpoints, we are using a variety of measures to assess mitapivat's potential in improving how patients feel and function. We expect to report top-line results from this phase III study in late 2025, with a regulatory filing and potential U.S. approval in 2026.

We believe mitapivat has the potential to emerge as a best-in-class therapy aimed at addressing the high unmet needs in this disease by improving anemia, reducing sickle cell pain crises, and making patients feel better. Next, I'd like to give a brief update on tebapivat, which is currently being explored as a potential treatment option for low-risk MDS and sickle cell disease. With lower-risk MDS, we aim to deliver the first oral therapy that addresses anemia due to ineffective erythropoiesis in the disease. This disease affects approximately 75,000-80,000 patients in the U.S. and EU-5, with lower-risk MDS accounting for approximately 70% of all MDS cases. Last year, we initiated a phase II-B study of tebapivat in MDS, featuring three cohorts at dosages of 10, 15, and 20 mg, all of which are higher than the 5 mg dose in the phase II-A study.

Enrollment is proceeding well, and we are on track to complete enrollment later this year. Additionally, last September, the FDA granted orphan drug designation to tebapivat in this indication, underscoring the importance of bringing an oral treatment option to patients suffering from this rare disease. In sickle cell disease, given the significant medical need and the heterogeneity of the disease, treating physicians emphasize the importance of having multiple treatment options available. In 2024, we presented phase I results of tebapivat in sickle cell disease at the ASH annual meeting. Based on these findings, we will advance this clinical program to phase II development, with patient enrollment expected to begin in mid-2025. With that, I will now turn the call over to Tsveta.

Tsveta Milanova (Chief Commercial Officer)

Thanks, Sarah. By 2026, we have the potential to expand Pyrukynd indications to include thalassemia and sickle cell disease, addressing the needs of these two very underserved patient populations. With our anticipated launch in thalassemia later this year, we are aiming to deliver the first therapy indicated to treat all subtypes of the disease. And with sickle cell disease, our goal is to deliver a novel oral therapy that improves anemia, reduces vaso-occlusive crises, or VOCs, and improves fatigue. By expanding Pyrukynd into these two larger patient populations, we aim to transform the treatment landscape for patients living with these diseases, thereby creating a multi-billion-dollar opportunity for our company and our shareholders. Our team is working diligently to prepare for a potential near-term launch in thalassemia with three key areas of focus.

First, we are executing a robust disease state education campaign that highlights the disease pathophysiology, the long-term complications of the disease, and current standards of care, and the importance of frequent monitoring and management. Second, we are right-sizing our cross-functional field team to ensure a successful launch in this larger, yet still rare market. For example, for PK deficiency, our sales team was staffed at 18-20 professionals. For thalassemia, we have strategically grown the sales organization to approximately twice that size. And third, we are actively engaging and educating payers on thalassemia to facilitate disease understanding and support patient access. There are approximately 6,000 adults diagnosed with thalassemia in the U.S., with most patients diagnosed before adulthood. With the availability of claims data, we can identify where these patients are managed within the healthcare system, offering valuable clarity for our launch preparations.

Within that population, we estimate that Pyrukynd's initial launch focus will address approximately 65% of the adult thalassemia patient population. We expect patients with more frequent contact with the healthcare system due to their disease symptoms to be considered for therapy first. These patients include those who are transfusion-dependent, as well as those that are non-transfusion-dependent, already experiencing complications or debilitating fatigue. Our team is actively engaged in the field, continuously deepening our understanding of these diverse patient segments and the multicultural dimensions of the disease. As we move toward increasingly larger launch opportunities, we are anchoring on the transformative profile of Pyrukynd in thalassemia, characterized by a number of firsts.

This is potentially the first therapy for both alpha and beta thalassemia patients, the first oral therapy for the disease, the first treatment to demonstrate quality-of-life improvements for non-transfusion-dependent patients, and the first treatment to demonstrate 36-week durability of effect in reducing transfusion burden. This is what motivates us to deliver Pyrukynd to people suffering from thalassemia as quickly as possible. Finally, let me provide a brief update on the current launch of Pyrukynd in PK deficiency. In the fourth quarter of 2024, we generated $10.7 million in net Pyrukynd revenue, compared to $9 million in the third quarter of 2024. In the U.S., a total of 223 patients have completed a prescription enrollment form, including 12 in the fourth quarter of 2024, a 6% increase versus the prior quarter. This has translated into 130 net patients on therapy for this ultra-rare disease.

We believe the capabilities we continue to strengthen through the current launch will provide a firm foundation from which to maximize potential future U.S. launches of Pyrukynd in thalassemia in 2025 and in sickle cell disease in 2026. Looking at the month ahead, our team will continue to sharpen its focus on the preparation for launch, with thalassemia as our main priority. We are excited about the commercial potential of thalassemia. This is driven by the following three factors: patients are diagnosed and known to the healthcare system, the burden of disease is well characterized, and there are well-established KOLs and patient advocacy groups. We are confident that all these elements, together with our robust preparation, will pave the way for a successful launch. In closing, we are inspired and energized by the potential to bring a new therapy to these underserved patient populations around the world. With that, I'll turn the call over to Cecilia.

Cecilia Jones (CFO)

Thanks, Tsveta. Our fourth quarter 2024 financial results can be found in the press release we issued this morning, and more detail will be included in our 10-K, which will be filed later today. Let me now take a moment to provide some context and highlight a few key points. Fourth quarter 2024 net Pyrukynd revenue was $10.7 million, an increase of 51% compared to $7.1 million in the fourth quarter of 2023. We note that revenue in Q4 of 2024 was higher, primarily driven by year-end stocking and adjustments to certain revenue reserves. These account for approximately $1.6 million in Q4, and we do not expect these items to repeat in the first quarter of 2025.

While lower in the fourth quarter of 2024, gross-to-net has generally been and is expected to be in the 10%-20% range on an annual basis, consistent with other rare disease launches, and will experience quarter-to-quarter variability. Cost of sales for the quarter was $1.3 million. R&D expenses were $82.8 million for the fourth quarter, an increase of $5.3 million compared to the fourth quarter of 2023. This was primarily driven by workforce-related expenses. SG&A expenses were $51.7 million for the fourth quarter, an increase of $16.4 million compared to the prior year quarter. This was primarily driven by an increase in commercial-related activities as we prepare for the potential approval of Pyrukynd in thalassemia in 2025. It is worth noting that we received a total of $1.1 billion in milestone payments following the FDA approval of vorasidenib, which were recorded in the third quarter.

These payments included a $905 million payment from Royalty Pharma in connection with the vorasidenib royalty purchase agreement Agios announced in May 2024, as well as a $200 million payment from Servier in connection with Agios' divestiture of its oncology business in 2021. As a reminder, Agios will retain a 3% royalty on annual U.S. net sales of vorasidenib greater than $1 billion. Taking all this into account, we ended the fourth quarter with cash, cash equivalents, and marketable securities of approximately $1.5 billion. We expect that this balance, together with anticipated product revenue and interest income, will provide the financial independence to prepare for potential Pyrukynd launches in thalassemia and sickle cell disease, advance existing programs, and opportunistically expand our pipeline through both internally and externally discovered assets.

Going forward, and with our PDUFA data in sight, we are shifting our focus to preparing for the potential launch in thalassemia, and we expect 2025 revenues for PK deficiency to be relatively flat compared to 2024. Regarding thalassemia, it is worth reminding everyone that it can be several weeks, particularly at launch, between prescription enrollment form and a patient initiating therapy. Combined with the expected time to set up payer access, we're looking at more of a partial quarter in Q4, which should be factored into modeling revenue expectations for 2025. Obviously, we are eager for the September 7th PDUFA date to arrive, and the team is well prepared for it. Looking into 2026 and beyond, we're optimistic about the team's ability to translate the favorable market dynamics Tsveta described earlier into a significant revenue trajectory for thalassemia.

In closing, we remain focused on creating shareholder value, including by proactively managing our cost base and deploying a disciplined cash allocation approach as we prepare to support potential future launches of Pyrukynd. As we move toward additional potential value-creating milestones in the near term, I am confident that our balance sheet will continue to enable us to execute from a position of strength. I will now turn the call back over to Brian.

Brian Goff (CEO)

Thanks, Cecilia. Before we conclude, I'd like to highlight one more piece of news from our press release this morning. Dr. David Schenkein has informed us that he will step down from our board of directors effective February 28, 2025, to devote more time to his other commitments. He will continue to serve as a strategic advisor to Agios' leadership team, concentrating on advancing the company's clinical development programs. David has been with Agios for 15 years, serving as the company's CEO for 10 years and throughout as a member of the board of directors. On a personal level, I'd like to thank David for his friendship, mentorship, and guidance throughout my years leading Agios. He has played an instrumental role in shaping our company into what it is today. On behalf of the entire organization, I also want to express our deep appreciation for his invaluable contributions.

We are truly grateful and look forward to continuing our collaboration with him in his new advisory role. 2024 was marked by exceptional progress at Agios, and as you've heard, we have exciting regulatory and clinical milestones ahead in 2025. We believe 2025 will be a breakout year for the company based on anticipated approval and launch of Pyrukynd in thalassemia, a critical phase III readout in sickle cell disease, and important anticipated progress across our mid and early-stage pipeline. In closing, I'd like to briefly reinforce Cecilia's comments. We have a very strong balance sheet, which provides us with the ability to independently execute across our key priorities, which include maximizing the potential Pyrukynd launches in thalassemia and sickle cell disease, advancing our existing early and mid-stage clinical programs, and expanding our pipeline with both internal and external opportunities.

We remain committed to disciplined cash allocation, ensuring our strong balance sheet supports the achievement of key milestones and positions us for continued value creation. We look forward to the future as we strive to change the trajectory of these rare diseases. With that, I'd like to open the call for questions. Operator, please open the line.

Operator (participant)

Thank you. If you'd like to ask a question, please press star one one. If your question has been answered and you'd like to remove yourself from the queue, please press star one one again. We ask that you please limit yourself to one question and a follow-up. Our first question comes from Eric Schmidt with Cantor. Your line is open.

Eric Schmidt (Senior Biotech Analyst)

Thanks for taking my question and follow-up, and congrats on all the progress. Looking forward to another remarkable year in 2025. Maybe first for Sarah, what's the company's plan or strategy for updating the investment community on the safety profile of mitapivat? Should there be any further cases of hepatocellular injury or any signals whatsoever there? And then for Brian, now for probably the past year or so, I think you've been talking about the multi-billion-dollar potential of mitapivat in these additional indications. How do you think about peak sales potential in either thalassemia or sickle cell disease as you construct that multi-billion-dollar estimate? Thank you.

Brian Goff (CEO)

Sure. Thanks, Eric. Sarah, you want to start on the first question?

Sarah Gheuens (CMO and Head of Research and Development)

Sure. So thanks, Eric, for the question. So as we have done when we were aware of this new safety information for thalassemia, we have updated the investor community at the time that we were able to make that call that there was a change in the safety profile of the drug. So if anything would change to the safety profile of the drug as we currently understand it and we make that call, then we would update you guys as well.

Brian Goff (CEO)

And on the second question, Eric, on the multi-billion dollar potential that we see for Pyrukynd, I'll say that we're very excited for the position that we have right now with all the momentum, the backdrop of the clinical data, as well as now the PDUFA date for thalassemia that we talked about. And just to characterize why we have such conviction in the long-term potential in thalassemia, as we said on multiple calls, two-thirds of the patient population in the U.S. have no approved therapy option, which presents a profound opportunity in terms of unmet need for those patients. And we look at the combined opportunity of both the ENERGIZE and the ENERGIZE-T data, and it's a really compelling profile. So that'll be obviously the first step on that multi-billion dollar pathway.

The second, with sickle cell disease, I think it's been really obvious to the whole community that the unmet need in sickle cell disease has always been very high, and it has actually increased in the past few months given some of the challenges and limitations in available therapeutic options. So that's an important step for us too. And of course, we'll be in a position to give more guidance as we move through these approval pathways, the launch phases. And in the case of sickle cell disease, it's getting to the point of the data readout at the end of this year for the RISE UP phase III studies. So a lot of conviction. That's all with Pyrukynd. And of course, we're building out a PK activation franchise beyond that with the benefit of tebapivat. As we've noted, we're pursuing a phase II study in sickle cell disease, as well as we're already enrolling in our phase IIb for low-risk MDS. So a lot of opportunity ahead.

Operator (participant)

Thank you. Our next question comes from Divya Rao with TD Cowen. Your line is open.

Divya Rao (Equity Analyst)

Hi, team. This is Divya on for Mark. Congrats on all the progress, and thanks for taking my question. Just two. One on sickle cell. So after the liver tox disclosure in thal last year, can you provide any details on changes to the sickle cell trial protocol? Is it mostly in the OLE portion, or were there any changes to the core portion of the trial? And then I have a follow-up.

Sarah Gheuens (CMO and Head of Research and Development)

Thanks, Divya, for the question. So in the core period, so after we had made that call, we took a look at the monitoring across all of the trials, and we were already monitoring in our core period for liver test enzymes along the way in each of our trials in the blinded period, which is very in line with how people start therapies in the real world and monitor drugs in the beginning when they start patients on drugs. In the open label, we had to make a tweak to align the monitoring frequency, so once a month, to what we were doing into the core period of the sickle cell disease trial. So now everybody is being monitored across all of our programs once a month for the first six months of exposure.

Divya Rao (Equity Analyst)

That's helpful. And then with tebapivat being explored in sickle cell, how should we think about the development path there? Is this more of a proof of concept before moving into other diseases? Or if the trial's successful, do you actually plan to move forward into pivotal development in sickle cell with this program?

Brian Goff (CEO)

Yes. Thanks, Divya. I think I'm going to have Tsveta comment on that from a longer-term commercial perspective because, again, it's a real benefit to have not one, but two opportunities in this very complex, very high unmet disease.

Tsveta Milanova (Chief Commercial Officer)

Absolutely, so Divya, when we think about sickle cell disease, Brian mentioned it, there is such a high unmet need in the patient community, and we hear it loud and clear from clinicians that there is a need for more than one treatment option with the need for more than one PK activators, so as we currently stand with tebapivat, we are looking for an opportunity to build a sickle cell disease franchise across both Pyrukynd and tebapivat. In terms of specific co-positioning of the two products and how we're going to develop tebapivat, well, we'll be guided by the data. As always, we'll need to see the RISE UP data. We'll need to see the tebapivat phase II data. We'll be looking at the competitive environment at that point in time. Sarah and I work very closely together to develop a clinical development plan, which will not only meet the needs of regulators, but will be commercially viable for us as well.

Brian Goff (CEO)

As we get closer to the mid-year start, we'll, of course, get more clarity on the trial design and exactly what that looks like.

Divya Rao (Equity Analyst)

That's helpful. Thank you.

Brian Goff (CEO)

Sure.

Operator (participant)

Thank you. Our next question comes from Gregory Renza with RBC Capital Markets. Your line is open.

Gregory Renza (Senior Biotechnology Research Analyst)

Great. Good morning, Brian and team. Congrats on the progress in the year. And thanks for taking my question. Brian, maybe just dipping into the pipeline and as you get your handle on the PK activation portfolio, I just wanted to ask about just your enthusiasm or how you're characterizing your level of enthusiasm with respect to AG-181, the PAH stabilizer. Maybe just remind us of that specific mechanism, how it stabilizes PAH, and perhaps why it should work well with patients who don't respond to the cofactor treatment. Thank you.

Brian Goff (CEO)

Sure. The first thing I'll just say, Greg, is I do not pick favorites among children within our pipeline. We're really proud of all of the across the pipeline is my first comment. The second is we're in a really good position of strength from a diversification within the pipeline in both type of asset, disease, as well as stage of development. With respect to AG-181, which is a phenylalanine hydroxylase stabilizer, in a way, it's similar to pyruvate kinase activation where it stabilizes the enzyme that's needed for the conversion of phenylalanine to tyrosine. We're in phase I now. And of course, we look forward to giving continued updates as we make progress on the development opportunity. But this is a very high unmet need population.

We're talking about 35,000-40,000 patients and a very small subset of those who are actually actively treated, and they have, frankly, very limited treatment options. So it's another mark of excellence that this came out of the Agios discovery and development. And again, it's right in the sweet spot of what we do best at Agios, which is address high unmet need rare diseases. And we definitely look forward to giving you more updates.

Gregory Renza (Senior Biotechnology Research Analyst)

That's helpful, and maybe just a broader question, taking a step back, as you look at your potential cash deployment internally and, of course, externally, how are you seeing the market for external assets, especially in light of what is a rather active market, not just domestically, but also globally?

Brian Goff (CEO)

Yeah. Great question. First of all, to reinforce what you just said, we're clearly, as one of our key ingredients, as a compelling rare disease company with a very bright future ahead, we're pleased with the, I'll call it, enviable strength of our balance sheet, and that enables us to, as a first priority, as I noted in my comments, to make sure that we maximize these launch opportunities. We have thalassemia with the PDUFA date this year. We have sickle cell disease potentially next year following the RISE UP readout, so that's job one. Job two is, as you just asked me, we have other mid and early-stage products in our pipeline. We want to make sure that we continue to deliver on those value-creating inflection points, and then to your question, we have actually scaled up our business development capabilities, particularly from a search and evaluation standpoint.

I think it's important, as any healthy company will do, to be very disciplined in that approach. But we're very clear on what would match well with the Agios rare disease capabilities, which continue to increase, particularly on the commercial side. And we look domestically, and we also have global line of sight as well. But we'll be very thoughtful and disciplined in where we believe we can add significant value creation.

Gregory Renza (Senior Biotechnology Research Analyst)

Great. Thanks, Brian.

Brian Goff (CEO)

You bet. Thanks, Greg.

Operator (participant)

Thank you. Our next question comes from Greg Harrison with Scotiabank. Your line is open.

Greg Harrison (Director of Biotechnology)

Hey, good morning. Congrats on the progress, and thanks for taking the question. Thinking about how you think investors should be modeling the launch trajectory in mitapivat and thalassemia in maybe 2026, understanding there will be some time to get access and lag time before initiating therapy in Q4, but would you expect there to be pent-up demand or an initial bolus in some of these patient groups that you discussed as the initial launch focus?

Brian Goff (CEO)

Yeah. Thanks, Greg. I'm going to start by just saying I'm really proud of Tsveta and her entire commercial organization that has been so dedicated to particularly disease state education for thalassemia, which is very much needed in this arena. And we're really well-positioned and prepared for now the PDUFA date in September. And Tsveta, you want to comment on what those dynamics look like towards the end of the year?

Tsveta Milanova (Chief Commercial Officer)

Absolutely. So thanks for the question. The team is working very diligently to prepare for launch, and we are super excited by the opportunity to provide these treatment options to patients in the U.S. As you mentioned, we've given guidance on our initial launch focus, which covered about 65% of all of the thalassemia patients in the U.S., which is 6,000 in total. From a long-term perspective, we are definitely educating to increase the urgency to act to monitor and treat these patients, having said that we don't expect to have an initial bolus in patients. Patients come to their doctors on a frequent visit, depending on their transfusion, depending on non-transfusion status and complications. So we will expect to capture these patients as they come.

Of course, we'll continue with the disease education to ensure that the right conversations are happening for them to make the appropriate choice for the best treatment for patients moving forward.

Brian Goff (CEO)

Yeah. And I mean, this is smart triaging too. When we say 65% targeting, it doesn't, of course, mean we don't eventually target the other 35%, but we're making thoughtful choices to make sure that we get off to a solid start in terms of that launch ramp. And the team, as Tsveta had noted earlier, has already been so-called right-sized for this opportunity. And now the intensive focus between now and the launch is disease state education. And then once we get clarity on the label and we have that launch opportunity, we're going to be in a great position.

Greg Harrison (Director of Biotechnology)

Thanks. That's helpful. I also wanted to ask about the Gulf region and the launch there. Are you getting a better handle on the commercial potential in the region, and how should investors be thinking about that opportunity?

Tsveta Milanova (Chief Commercial Officer)

Yeah. We are seeing the Gulf region. Obviously, the U.S. is our number one commercial priorities and organization. Then when we look ex-U.S., the Gulf is the second commercial opportunity for us. Within the Gulf, Saudi Arabia is the biggest market. As we've noted, we have a breakthrough designation in that region, and we're working very closely with the NewBridge team to go through the regulatory process in Saudi Arabia. When we think about launch ramp in that region, the way I'll think about it is more closely related and similar to the European market dynamics. It's a national healthcare system when there is a national decision on approval and price.

However, within the different segments within Saudi Arabia in the healthcare system, for example, the private sector, the Ministry of Health, as well as academic institutions, will need to work with those segments in the healthcare system to ensure that there is a formulary access, which can take time to ramp up over time. But there is a big commercial opportunity from patient numbers, and we will navigate that with NewBridge accordingly.

Greg Harrison (Director of Biotechnology)

Great. Thanks so much.

Brian Goff (CEO)

Thank you.

Operator (participant)

Thank you. Our next question comes from Chris Raymond with Piper Sandler. Your line is open.

Chris Raymond (Managing Director)

Yeah. Thanks for taking the question. Two questions. First, I guess, on the PED studies in PKD, I think you've characterized ACTIVATE-Kids and ACTIVATE-KidsT as giving insights into future pediatric work in thal and sickle cell. Can you maybe elaborate a little bit on this benefit? Would you expect some, perhaps, short-circuiting, I guess, of a pediatric program there, or would there potentially be labeling benefits sort of out of the gate just from this work? And then the second question, I know you've had this question a number of times, but just on the PDUFA and a potential panel, just with all this focus on liver injury, our companies rarely hope for a panel, but it would seem that with all this attention that's on this, this actually might be beneficial just to sort of put some light on this. Any thoughts there on your desire there on a panel or not? Thank you.

Brian Goff (CEO)

Thanks, Chris. Sarah, you want to start on both or start with pediatric?

Sarah Gheuens (CMO and Head of Research and Development)

Yeah. I'll start with the pediatric. So while we're saying that this is really helpful, pediatric development is very hard, right? And so transfusion trials are also very hard to run. So we have worked through a lot of logistical things that we needed to consider for those pediatric trials and have now experienced implementing these pediatric trials and bringing them to a successful completion. All of those lessons learned along the way will apply to any other future pediatric trial we run. So there is a huge benefit from actually having that hands-on experience, and that will impact things like feasibility, startup, and clinical trial logistics on any of those programs. So we're very happy with that.

And then, of course, because we're following a very similar path across the hemolytic anemia in the adult development, we went from PKD to thalassemia to sickle cell disease, had benefit-risk in the PKD adults and now in the thal adults. There are a lot of lessons that can be applied from adults to PEDs as well. So we're just, in general, very excited about expanding the patient population there. And then that, of course, any label negotiation you go through helps with the next label negotiation as well. So multiple benefits along the way. In regards to the PDUFA date and the potential for a panel, so we are very happy that the PDUFA date has been announced. So for September 7th, we have not heard that we would be having a panel at this point in time.

So indeed, panels are a lot of work, both for us and for the FDA. So I'm not sure if I can fully agree with the assessment that we may be hoping for a panel. I would just, I don't know. I think either way, we will be ready if it would happen. That being said, I do think you already shed light on what actually happened because we had the PKD label update with the warning and precaution, which truly highlights what we have observed in the thalassemia patient population. And that assessment has been agreed upon with the FDA for the label update in PKD. So I think we're good with the current data.

Chris Raymond (Managing Director)

Thank you.

Brian Goff (CEO)

Thanks, Chris.

Operator (participant)

Thank you. Our next question comes from Alec Stranahan with Bank of America. Your line is open.

Alec Stranahan (VP and Senior Analyst in Equity Research)

Hey, guys. Thanks for taking our questions, and congrats on the updates from us as well, and look forward to a busy 2025 ahead. Just two from us. Thinking about the process of scaling your sales force for thal, given the ENERGIZE studies have both been presented at major medical meetings, what is your sense of the level of awareness among physicians as well as patient advocacy groups? Is this kind of tracking with your hopes, or is there maybe more work to do there? And has this fed into the number of reps you've hired for commercialization or not really?

Brian Goff (CEO)

Yes, Tsveta, do you want to get started?

Tsveta Milanova (Chief Commercial Officer)

Yeah. Absolutely. So first of all, in a very disciplined way, once we had the data from the ENERGIZE study, we made the decision to actually press the button and start right-sizing the customer-facing organization for launch. The way we approach the launch as any rare disease launch is a very comprehensive way, focusing on the patients, physicians, and payers, and ensuring we have the right organization. We have already right-sized the sales force in particular. As we've said, we had about 18-20 hemolytic anemia specialists covering PK deficiency for thalassemia. Given the fact that we have very well-established ICD-10 codes, it allowed us to actually right-size the organization appropriately. So the totality is about double that size.

From an awareness perspective, the team has been in the field in the U.S., connecting both with the KOL community, but also with the prescriber base, majority of which is community hematologists. And I can tell you, aligned with expectations, there is a high awareness not only of the disease, but of the potential for new therapeutic options for these patients and a Pyrukynd's profile. We are continuing our efforts on disease state educations with both patients and physicians, as well as we are very well connected as an organization with the patient communities and the patient advocacy groups. Sarah and I actually had the opportunity to meet with TIF recently, and I can tell you that the excitement that comes from those groups is very, very high for the potential of Pyrukynd. So we are working hard to prepare. I can tell you we are ready for launch, and the team now is actually going deeper and deeper to make sure that we execute very successfully from the beginning on the opportunity ahead of us.

Brian Goff (CEO)

Yeah. And of course, before we got the PDUFA date, we didn't know when the date would be set. And so the team, as any great pre-launch team does, we've been prepared for a range of scenarios. The fact that we now know it's September, Tsveta and the team are maximizing this opportunity in terms of disease state awareness between now and then. And every month, we see continued progress with the KOL community as well as the in-the-community treating physicians. They're doing a great job.

Alec Stranahan (VP and Senior Analyst in Equity Research)

Thanks. And then just a quick one on pediatric PKD. Curious, just to put a finer point, if you intend to seek approval in both transfusion populations, the regularly and not so regularly transfused, and whether you think approval across the patient groups could be warranted, maybe given the totality of the data across the two studies. Thank you.

Brian Goff (CEO)

Yeah. That's an emphatic yes.

Sarah Gheuens (CMO and Head of Research and Development)

That's an emphatic yes. When you asked the question, I actually nodded yes, so the data across the two trials is really supportive of benefits, of a positive benefit-risk profile across the patient population. In the regularly transfused trial, we have patients, and we still have patients who are completely transfusion-free, so that is an enormous clinically meaningful benefit, and then here on this trial, we clearly have positive results across the board, statistically significant across using both methodologies, Bayesian methodology and a frequentist approach, so we're very pleased with that as well, and we're looking forward to and hopefully obtain that broader label for patients with PKD.

Brian Goff (CEO)

Yeah. I mean, I know this is an investor call, but from what fuels us as an organization is the stories that we hear from patients. In PKD in general, of course, Pyrukynd is the only approved therapy for adult patients. These parents have had kids who some have been splenectomized, and others are awaiting and might have that as a potential. To have this promising data clinically relevant in the ACTIVATE-Kids trial of transfusion-dependent pediatric patients, and now with today's data, this is really compelling. We will certainly do our best to move that along with the regulators at the right time to make this available for patients.

Alec Stranahan (VP and Senior Analyst in Equity Research)

Thank you.

Brian Goff (CEO)

Thank you.

Operator (participant)

Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.

Hi, good morning. This is Lydia on for Salveen. Thanks so much for taking our question and congrats on all the progress. Maybe just a follow-up to the previous question on pediatric PKD, could you just discuss how expanding into the pediatric population could potentially impact the total opportunity in PKD? Thanks so much.

Tsveta Milanova (Chief Commercial Officer)

Yeah. Absolutely. So the pediatrics is about 20% of the PKD opportunity. As we know, PKD is an ultra-rare disease. When we look at the pediatrics trial, as Sarah mentioned, for us, it's a good opportunity to provide a treatment option for patients in need that currently have no treatment options. But very importantly, it's a starting point for us to continue with the pediatric development across all of the other indications and apply all the learnings there to thalassemia and potentially sickle cell disease in the future.

Brian Goff (CEO)

Yeah. And maybe just to reinforce the point that Cecilia made earlier too in PKD revenue, this is about 20% of the population, but this is an ultra-rare population. So again, the way we look at PKD this year, particularly in light of the preparation and focus we have for thalassemias, we're expecting flat revenues over 2024. But again, for pediatrics, it's an important addition when we get to that point for treatment optionality for these patients.

Thanks so much.

Thank you.

Operator (participant)

Thank you. Our next question comes from Tessa Romero with JPMorgan. Your line is open.

Tessa Romero (Biotechnology Equity Analyst)

Hey, guys. Thanks so much for taking our questions. So just a brief financial question from us to start. Cecilia, in terms of your OpEx, what is the right way to think about the evolution of your SG&A expenses and the cadence of a ramp-up there over 2025 and into 2026? And on the R&D side, any additional color you can give us there? And then I have one follow-up.

Tsveta Milanova (Chief Commercial Officer)

Sure. Thanks for the question. So as we mentioned, we continue to proactively manage our cost basis as part of our disciplined capital allocation approach. That being said, as Brian described earlier, we have three buckets or three priorities on that. The first one is preparing to maximize the Pyrukynd opportunity with the potential to have back-to-back launches and also advancing the pipeline. So for both SG&A and R&D, we expect to see growth year over year in the coming couple of years. You will see some quarter-over-quarter variability. Not everything always is straight line, but we do anticipate to see growth on both items.

Tessa Romero (Biotechnology Equity Analyst)

Okay, and can you quantify what growth means?

Tsveta Milanova (Chief Commercial Officer)

We haven't given specific guidance on growth, but like I said, we're being very disciplined on how we approach this. Like Sarah mentioned, we waited to see the thalassemia data to kick off the bigger ramp on thalassemia. We're doing a similar approach on sickle cell. We want to try to be prepared so we don't want to find ourselves in a positive scenario where we didn't prepare for that, but we're doing it in a very disciplined approach.

Tessa Romero (Biotechnology Equity Analyst)

Okay. And then within that, from a timeline perspective, can you lay out for regions beyond the U.S. how you're thinking about timing of approval? So I'm thinking about the EU, Saudi Arabia, and the UAE.

Brian Goff (CEO)

Yeah. I think, Sarah, you want to comment there and Tsveta can touch on commercialization approach.

Sarah Gheuens (CMO and Head of Research and Development)

Yeah. The timing of approval, so the PDUFA date for the FDA, that's September 7th that is announced and everything. The others, they don't give proactively a date by which they will approve. So it depends on how the process goes and the amount of questions you get along the way. But we're very excited about the progress that is currently being made and are on track to deliver.

Tsveta Milanova (Chief Commercial Officer)

Yeah. And from a commercialization perspective, as I commented earlier, in the Gulf region with the biggest opportunity, Saudi Arabia, after you have an approval, we'll need to go through the access and formulary discussions with the different parts of the country. So the actual ramp is going to take some time, but very similar to how the European healthcare systems work. For Europe, from a commercialization perspective, we're looking for a potential partnership there as well.

So as soon as we have EMA approval, we'll be able to actually navigate the European healthcare systems as well. As you know very well, in Europe, it's a country-by-country pricing and reimbursement decision. So again, there'll be a time lag between approval and actual commercialization in Europe too.

Tessa Romero (Biotechnology Equity Analyst)

Okay. Thanks so much.

Brian Goff (CEO)

Thanks, Tess.

Operator (participant)

Thank you. I'm sure no further questions. I'd like to turn the call back over to Brian for closing remarks.

Brian Goff (CEO)

All right. Thanks a lot, Michelle. Well, thank you very much, everybody, for participating in today's call. We are a month and a half into the start of what promises to be a very busy and exciting year. It's an exciting time in Agios. We really believe that we're poised to deliver transformative new therapies for patients and create significant long-term value to shareholders. So thanks again, and we look forward to speaking with you again soon.

Operator (participant)

Thank you for your participation. This does conclude the program, and you may now disconnect. Everyone, have a great day.