Hey everyone, thanks for joining this session with Agios Pharmaceuticals, and welcome to the first session of day two of the 2025 Bank of America Healthcare Conference. My name is Alex Stranahan. I'm a Senior Biotech Analyst covering Agios at Bank of America, and I'm pleased to be joined today by Brian Goff, Chief Executive Officer, and Sarah Gheuens, Chief Medical Officer of Agios. Thanks for being here, guys. Thanks a lot, Alex. It's great to be back with you again. I can't believe it's just been a year. I know. It feels like we've had a year's worth of news in four months already. Yes. It'll be interesting to see what the second half has in store. You know, Brian, maybe just we can start off, you know, Agios, what's going on at the company? What are the main focus areas for you guys, and what's sort of the, you know, the second half outlook in terms of things to be? Yeah, happy to. Again, thanks for hosting us, and thanks a lot to everybody who has joined us to hear the Agios story. It's a really exciting time. If you're new to Agios, I'll just start by saying our mission is to develop and deliver medicines that have transformative potential for patients who are living with rare diseases. The real focus of that effort are rare diseases that involve the destruction or the dysfunction of red blood cells, namely pyruvate kinase deficiency, or PKD, thalassemia, sickle cell disease, and low-risk MDS. The real highlight of our pipeline is a product called PYRUKYND, or mitapivat. Mitapivat involves a very novel mechanism of action targeted towards improving the metabolism of red blood cells, which ultimately leads to more energy available and a healthier cell. PYRUKYND is currently commercialized for PKD, or again, pyruvate kinase deficiency, but we are pursuing indications in thalassemia and sickle cell disease, and I'm sure we'll have a great discussion about those pursuits today. We had a really transformative year in 2024, and that's why I can't imagine how fast this year has gone by and how much we've accomplished. Last year, we were delighted to announce the results of two pivotal phase III studies for thalassemia. They're known as ENERGIZE and ENERGIZE-T. We delivered statistical significance on all of the primary and all key secondary endpoints. That put us in a great position where December of last year, we announced that we had simultaneously filed for regulatory approval in four different markets: in the U.S., in Europe, and in the Gulf, in both Saudi Arabia and the United Arab Emirates. We had a great start to this year where we announced in January that the FDA had accepted our application and granted a PDUFA goal date of September 7th of this year, which, as a side note, is less than four months away now. We are very excited about that opportunity. Our commercial team has really geared up, and I would say at this point is fully ready for this exciting launch opportunity of PYRUKYND in thalassemia. The other big event from last year focuses on sickle cell disease. In October, we were really pleased to announce that we had fully enrolled our RISE UP phase III study in sickle cell disease. It is a 52-week study. Fast forward, that is another really important catalyst for us later this year. We expect to read out that data by year-end. The other thing I'll just mention that happened last year is we significantly strengthened our balance sheet, and we're in a great position, particularly in this macroeconomic environment. We ended the first quarter of this year with approximately $1.4 billion on the balance sheet. It's been a great year. Sarah and I would be delighted to talk about all of that progress and more. The last two things I'll just say is, again, on the balance sheet perspective, in this environment, we really think we're in a position of strength, and we see the strength of our balance sheet as an opportunity for us to remain disciplined in capital allocation, but really create significant value for shareholders, most important of which is our journey to build a multi-billion dollar franchise with PYRUKYND. One point of pride for the organization is we talk a lot internally about being fueled by connections. That really means that we stay very close to the patient communities. We're very passionate about the work that we're doing. I think, frankly, that's contributed to our performance, and it also certainly fuels the culture internally at Agios. Plenty more to say, but I'll stop there and would welcome your questions. Okay. Fantastic. So definitely several irons in the fire. Maybe first we can talk about thalassemia. Sure. PDUFA date, September 7th, like you said. Everything's still on track here, or any feedback from the agency you received on timing? Yeah, I'll let Sarah start on that one. It's been so far a good journey. So far, so good. It feels like a very normal procedure for us with questions coming in and us providing the answers. Our PDUFA date is September 7th, so we're very anchored to that date and very excited about that getting closer. Maybe I'll just add too that one of the updates that we offered on our earnings call is the first quarter of the year, our messaging was that the FDA has been silent. We haven't heard anything with respect to an advisory committee. The update we provided a couple of weeks ago is the FDA has now communicated that at this time, they're not planning an advisory committee, but of course, the review is ongoing for thalassemia. I guess, given that this would be maybe potentially the first broad approval across thalassemia subtypes, was an AdCom maybe expected, or was that kind of factored into your review thought process? We did not expect an AdCom or had a wish for an AdCom, obviously. I think the story and Brian highlighted it. Yes, it's the first indication for a broad population of thalassemia that was submitted, but the clinical trial data is clear, right? We have on the efficacy side a very clear and clean story with statistical significance on all primary and key secondary endpoints across the two trials. The subgroup analyses highlight that everybody stands to potentially respond to the drug. From that side, it's a pretty straightforward story. On the safety side as well, we have a clear safety profile. As you know, we've updated our safety profile with hepatocellular injury, but that as well is an event that you can monitor for, and then it's manageable because you can discontinue the drug. The labeling language that we've proposed around that is also clear. The benefit-risk profile, therefore, in the overall thalassemia population is, from our perspective, favorable. In that context, I think an AdCom, I don't know, it seems like a lot. Yeah. Especially having the approval in PKD certainly helps. Yeah, I mean, this is an sNDA, and we have now, even commercialization-wise, three years-plus of experience with PYRUKYND in pyruvate kinase deficiency and multiple late-stage trials across multiple hemolytic anemias. So we really feel like we're in a position of strength. Okay. Very good. I appreciate this is dynamic and in flux almost daily, but any high-level thoughts on FDA staffing, ability to meet approval deadlines? We have not seen too many misses, maybe one or two, but those could be one-offs. I know that Makary has reiterated that they feel that they are fully staffed. I do not think they have let any of the reviewers really go in this transition. Any changes or color from your recent interaction that you can share? No, not that we have noticed. I think this really, from our perspective, feels like a normal procedure with back and forth across the whole spectrum of the filing. There is not a topic that seems to be forgotten or neglected. From our perspective, it feels really like a business as usual. Therefore, we are continuing with that same mindset and are very much looking forward to September 7th. Yeah. Maybe I'll just add, we're talking about FDA right now, understandably, but again, we filed in four markets simultaneously, and you could add the same sentence to all of those regulatory engagements. They've all continued at pace and as expected. Again, we're just really excited about having the chance for not just one, having approval for one segment of thalassemia, but this is a high unmet need population with very limited choices. What we're pursuing is alpha thalassemia as well as beta thalassemia and both non-transfusion dependent and transfusion dependent, all subtypes. That is across all the geography. Correct. Yeah. Maybe on that point, Brian, just remind us of your plans for the ex-U.S. launch, when these approvals could come, how you're balancing driving successful launches, international expansion, retaining economics. Yeah, it's a little tough to say when the approvals will come, but as I say, we're at pace and very encouraged by the progress that we're making. With respect to different geographies around the world, we're really clear on the priorities, particularly for thalassemia. U.S. is our number one priority. Then outside the U.S., the clear number two is Saudi Arabia, and you could even say the Gulf region proper. Last year, we announced a partnership that we put in place with, you could think of a full-service distributor by the name of NewBridge to help with the commercialization in the Gulf. The reason we did that is this goes back to capital allocation efficiency. It would take quite an effort for us, Agios, to scale up to capture the potential that exists. We sought out in a very competitive process a partner who knows the region very well, is already scaled up and ready to go, and we have that in place. Looking beyond the Middle East, then Europe as an example, we expect to pursue the same option where we're not planning on going direct. We would look for and are having engaged discussions now on partnerships, again, to make sure that we protect our priorities of direct in the US, partnership ex-U.S. Yeah. That's probably the right balance, right, in terms of if he were to go alone, you would be maybe sacrificing the volume side. You'd have to build out the capabilities. It's a big investment. You maybe come out ahead through that kind of. It's very clear to us that for quite a distance, next dollar invested will have a better return in the U.S. through direct investment versus the partnerships outside the U.S. Very good. I guess for the FCC countries, is expansion or, I guess, approval here dependent on getting that U.S. approval? Is there any linking between these different geographies? Sarah can speak to that. One thing I'll just say is that we did get, and it's very new, but we got breakthrough designation in Saudi Arabia. That is part of the backdrop, but. Yeah, exactly. It is because of that that we are able to file as a new entity there directly to the SFDA. This was a new procedure. We are going through that new procedure, but it feels also very much like it is almost like an in-between the European and the U.S. procedures. That is what it feels like for the team. We are getting questions, answering them, deadlines, pre-specified deadlines, and everything is just moving along there as well. We have not talked about so far, but just to put some numbers on this, in the U.S. for thalassemia, we are talking about 6,000 adult patients. In Saudi Arabia, in the Middle East, we are talking about 70,000. On a per capita basis, the prevalence is roughly 8x-9x greater than the U.S. There is a lot of focus by the regulators, by the Minister of Health on this particular disease, which we are quite proud to be a part of. Makes sense. We touched on briefly kind of the overlap with having the approval already in hand for PKD. You have a Salesforce for PKD. There's also been some label updates to that PKD label. Maybe walk us through sort of where you stand on the Salesforce, if you could leverage that also for a thalassemia launch, and then whether you think all sort of the known profile of mitapivat is kind of reflected on the label today. Yeah, I'll speak first about how we've set up our commercialization model, and then Sarah can comment on the label update, which was really important, and we were quite pleased to have early this year. As you noted, we launched in PKD in February of 2022, and it was a rather small team. This is an ultra-rare disease. For sales folks, there are about 20. There's more than that because what's important about rare disease commercialization is not just frontline salespeople, but patient services, clinical nurse educators. There's a whole support team. To dimensionalize it, about 20 for PKD. For thalassemia, and we waited until we saw this great data last year to make this change, we scaled up to about 40 for thalassemia salespeople. That is fully recruited, fully trained, and what the team is focused on right now are really two different things in preparation for launch. First, very importantly, is disease state education. This is a disease where there have been very limited choices. What tends to happen classically in a rare disease like that is the sense of urgency is more diminished. We are really putting emphasis on the fact that non-transfusion dependent thalassemia patients, for example, are not less at risk. They might be more at risk because they are undertreated and they are suffering from chronic daily hemolysis where the patient may pay a price down the road. Disease state education is one part, and the other is account profiling. We have a really good map through claims database analysis and interaction with these different sites of care to know where we want to prioritize our efforts. We are fully ready to go. Again, right now, we're just waiting for the PDUFA date. From a label perspective, maybe Sarah can talk about that update. Yeah. The hepatocellular injury that we observed in thalassemia, that warning and precaution language that we have proposed is in the PKD label. It describes what we have seen in thalassemia. It says in patients with another condition being thalassemia because it's not a labeled condition to date for PYRUKYND. It basically describes the events that we've observed and then what physicians should be on the lookout for, very straightforward language there. From our perspective, when that was implemented in the PKD label, or maybe we should actually speak to that, we see continued demand for pyruvate kinase deficiency patients, basically. Yeah. We talked to a lot of investors who have done their own market checks and have talked to clinicians who have treated either PKD patients or thalassemia or sickle cell disease. The general consensus that we certainly see this ourselves is that testing on a monthly basis when you're onboarding a patient to a new treatment for a hemolytic anemia is standard of care. It has been a kind of non-event. In our labeling recommendations, our recommendation to the FDA, which they align with, is test everybody. Don't try to be too fancy about certain subsegments because that's, again, the normal course of treatment. In this last earnings update, we were really pleased to be able to show that PKD continues to be a very slow ramp because it is ultra, ultra rare, but we actually had increase in patient demand with the backdrop of this label change. We felt very comfortable in that regard that both patients and clinicians have certainly accepted this just fine. Okay. Okay. Makes sense. Maybe shifting gears now to sickle cell. You've got data update in 4Q. Maybe walk us through the trial design, sort of the powering assumptions on the two primary endpoints, which it sounds like if either one is met, that could maybe be a path forward for submission for approval. Maybe just walk us through sort of the design and thought process there. Sure. It is the RISE UP trial. It is an ongoing phase III placebo-controlled randomized trial for patients with sickle cell disease. What we are trying to do with this trial is highlight that mitapivat can potentially provide benefit for the totality of the disease because sickle cell disease is a very complex disease, but its really tough features are hemolytic anemia on one end and then vaso-occlusion on the other end. The trial is designed in such a way that we can speak to both of those components of the disease. We have two primary endpoints. The one primary endpoint, hemoglobin response, is tackling that hemolytic anemia component. Analyzed rate of sickle cell pain crises is tackling the vaso-occlusion component of the disease. There is an alpha split on those two endpoints. That allows us then, if one or both are positive, to transfer alpha to secondary endpoint testing, which has other ways of looking at how patients feel, which is important from a regulatory perspective that you demonstrate that people feel and or function or survive better. That is actually then in that bucket, we're looking at how patients feel via fatigue. With this drug, just like what we've done for thalassemia and pyruvate kinase deficiency, trying to highlight that when you have that improvement in hemoglobin, improvement in hemolytic anemia, people also feel better, feel less fatigued. That fatigue component, I mean, people are very focused on vaso-occlusion in the context of sickle cell disease because it's a dramatic event, right? It's horrific. It's painful. People can die in the context of having an episode like that. When you talk to patients, they highlight that the fatigue is extremely devastating for them as part of their disease and that there's not really anything they can do about it. That's what we are trying to highlight with this trial design, that we can tackle all of these components of the disease. Of course, on the hemolytic anemia side, we are building upon the evidence that we have generated for thalassemia and for pyruvate kinase deficiency, vaso-occlusion. That's purely in sickle cell disease, a component that is important. That evidence, or why we think we have a possibility to actually highlight benefit there, is built upon, mechanistically, on a lot of preclinical work, but then also on some of our investigator-sponsored trials in which we have followed sickle cell disease patients. But then most importantly, our own phase II, which was another blinded randomized control trial in which we were able to select the dose for phase III, but also saw when we were testing 50 mg BID and 100 mg BID against placebo, that there was this trend on improvement on vaso-occlusion, which was 70% in the 100 mg BID dose reduction. Therefore, we're excited about our phase III. We're very much looking forward to the end of the year, and we're hoping that the cards will turn favorably. I'd like, if I could, just to add one point to a big picture about sickle cell disease is that sometimes what gets lost in these discussions is this is a lethal disease. This is where the lifespan of someone with sickle cell disease is in the 40s, which is shocking to say out loud and shocking to hear. What it tells us is, one, all of these endpoints matter. We feel really good about the careful and thoughtful design that we've put into our RISE UP trial. Two is there is room for and a need for multiple different types of drugs and treatment options. Frankly, that's one of the motivators that we've had with having mitapivat, where we're talking right now about the RISE UP trial. We also announced recently that we'll be starting mid this year with our other PK activator, tebapivat, a RISE UP phase II like trial for sickle cell disease. The reason is we want patients to have optionality. We're looking to build a lasting franchise, but we know there's no one drug that everybody responds to. That's really the backdrop of our strategy. It's also a mindset of how to think about, quote, competition in this space. There is room for plenty. Yeah. Okay. Maybe we can double-click on that point, Brian. How do you see tebapivat? We've gotten questions like, why start the study when we haven't seen the mitapivat data? I mean, the timing component is whatever. It's like whenever it's ready to go, let's get it to patients. How do you see these maybe coexisting? Is there any mechanistic rationale why one would work better in a certain patient than the other? There are plenty of examples, I mean, really compelling examples across the industry, particularly in rare diseases where there are multiple drugs, even more than two, within the same therapeutic application, same disease. To answer your question, what we're doing is putting our foot forward now on phase II for tebapivat. We know we will learn a lot as we go forward. By year-end, we'll get the readout of the RISE UP mitapivat phase III data. At a point, we will learn the results of the tebapivat phase II data. Of course, there's another PK activator, teba pivat, in development as well that we expect at a certain point to learn what that profile looks like and other modalities. We'll make smart, efficient decisions about how to allocate our capital and how to further develop tebapivat accordingly. Again, there's a lot on the table. There is so much unmet need, and we have enough runway in front of us to be able to design the trial post phase II for tebapivat according to what the highest needs are. Okay. Maybe we can talk about how you guys are thinking about the competitive landscape. We've had some withdrawals. We've got cell therapy, gene therapy options coming up the pipe or recently approved. How do you see mitapivat and maybe tebapivat sort of slotting into the evolving treatment paradigm? This is oral therapy as a starting point, which makes it very accessible for ideally a broad population and also ideally beyond the borders of the U.S. as we have geographic expansion. I think to have gene therapy available, if you're a patient, that is really exciting hope. From a pragmatic perspective, it is on a whole different side of the spectrum in terms of availability and ease of onboarding and the conditioning that comes with it and so on. I think it creates a really important inspiration. From our view too, the more different types of companies that are investing in sickle cell disease, the better because everybody will invest in education around the world on the unmet need, how patients need to be given different therapeutic options. I think we're just exceptionally well-positioned pending our data, not just for PYRUKYND, but again, also to build this real lasting franchise. Okay. Makes sense. You guys put out a press release this morning highlighting your EHA presentations next month. Maybe walk us through sort of the scope of what we should expect there. I think there was maybe a couple on sickle cell as well. Sure. Agios has, again, a really great presence at a conference. The team has done an amazing job. We're very pleased because we have a couple of oral presentations that are either our collaborators or ourselves that have data that will be presented. We're very proud of our pediatric PKD data. We had a data announcement on the regularly transfused pediatric pyruvate kinase deficiency patients a while ago. I'm blanking out on the timing. We were able to submit that to EHA, and it's going to be presented there. What we have there is a couple of children became transfusion-free, which, of course, is very meaningful for those specific patients to be when you're dependent on transfusions and then you don't need them anymore. That's very clinically meaningful. We're very, very happy that that data will get a spotlight. One of the investigator-sponsored trials that I mentioned earlier for sickle cell disease will be presenting data as well, estimates. That is a trial that is run in the Netherlands by Dr. Van Beers. That data will be presented. We also have some preclinical work in MDS patients highlighting that PKM2 is reduced in MDS, which, of course, is important for our mechanism of action. We have a very nice spread of early mechanistic work to clinical data and pivotal trials that is going to be presented. We cannot wait to be there. This is like EHA and ASH. These are our Super Bowls. We are really pleased to have 14 different abstracts at EHA and a lot to share across our entire pipeline. Yeah. Milan's a little bit better than Orlando. Sure. Brian, maybe circling back just in the last minute or two that we have, $1.4 billion in cash is a great position to work from. Is there a scenario where you get approval and, you know, the launch is going well, sickle cell looks like it could be approvable as well, that this cash balance could actually carry you through to profitability? What's sort of the runway here and how are you thinking about capital allocation over the next few years? I love that scenario. If we're going to close down here, that's a good way to start. Yeah, I think, first of all, $1.4 billion, we know that that is a very unique position to be in in this macroeconomic environment. We don't take that lightly. We're very serious about efficient capital allocation, very disciplined. Our priorities are clear. You mentioned the first one, which is get the launches right, create maximum value. Our ambition is a multi-billion dollar potential for this PYRUKYND franchise. Number two is we do have a kind of middle part of our pipeline. We talked about tebapivat a little bit that we're looking to advance as well. That would be our second priority. Third is expand the pipeline. That can come in two different directions. Internal organic opportunities, which we constantly pursue. Sarah's team does a great job from a translational perspective and research. We also are, of course, looking externally. In fact, we recently added a key member of our team, Krishnan Vishwanathan, who's tasked with business development, corporate strategy, just to make sure that we're constantly assessing the landscape externally. That just positions us really well as a company to be sustainable and continue to grow and deliver value for shareholders. Fantastic. With that, I think we're right at time. Please join me in thanking Brian and Sarah for the great conversation. Thanks for being here at the conference. Thanks a lot, Alex. Thanks, everyone. Thank you.