Great. Good morning, everyone, and thank you so much for joining us. We're really pleased to kick off the Goldman Sachs Healthcare Conference with the Agios team. With us, we have Brian Goff, Chief Executive Officer, and Sarah Gheuens, Chief Medical Officer and Head of R&D, and Salveen Richter. I cover the biotechnology sector. With that, Brian, let me turn it over to you to start with any opening comments.
Sure. Thanks a lot, Salveen. Thank you very much for hosting us. Thanks, everybody, for joining in to hear the Agios story. It's a really exciting year for us. Second half of 2025, we have at Agios two very significant catalysts. The first one is we're actually less now than 90 days away from our PDUFA date. This is for Pyrukynd, our novel PK activator, oral activator for thalassemia. We're really excited about this opportunity in front of us. This will be a significant launch opportunity. I'm sure we'll talk about that. Secondly, by the end of the year, we're anticipating the readout of our sickle cell disease RISE UP phase III trial. If we're successful, that means that we have a very unusual and enviable position of having two potential back-to-back launches: thalassemia this year, followed by sickle cell disease next year.
That really helps us build upon our growing foundation in classical hematology and puts us well on our way towards building a multi-blockbuster franchise with Pyrukynd. The U.S. is clearly our most important opportunity in front of us. With that in mind, as we think about access around the world for patients, last year, we were really pleased to announce an agreement with a full-service distributor, NewBridge. This is focused on patients who have thalassemia or sickle cell disease in the Middle East. Actually, right now, we're really pleased to announce that we have signed an agreement with a European full-service distributor known as Evansenite. They have great experience with rare disease products. This would give them full rights to Pyrukynd in Europe, as well as in Switzerland and the U.K. It is a really exciting period.
That's, from our perspective, a very capital-efficient way of us maintaining focus on the U.S. and making sure that we get those launches right, that we continue to advance our pipeline, but also, again, making sure that patients have access in other parts of the world. The last thing I'll just say is we also have, beyond Pyrukynd, a mid and early-stage pipeline. We have another PK activator, AG-946, which is a more potent oral PK activator that we're pursuing in phase II studies for both sickle cell disease as well as low-risk MDS. The low-risk MDS phase II trial is already in enrollment now and should be fully enrolled by year-end. The sickle cell phase II study is starting mid-year. Lastly, earlier in the pipeline, we have a PAH stabilizer, phenylalanine hydroxylase, for phenylketonuria. This is known as AG-181.
We were really pleased to announce a couple of months ago that we're now advancing into MAD dosing in healthy volunteers. We have, lastly, AG-236, which we are pursuing for polycythemia vera. Mid this year, we're submitting an IND. We have a lot going on. Second half of the year is a really important time for us. We're really excited about what that could mean for Agios and for patients.
Before we jump into the pipeline, perhaps we can just go a little deeper into this European partnership.
Sure.
Can you help us understand why you chose this partner and maybe their infrastructural capabilities with regard to owning that European landscape?
Yeah. The key phrase is full-service distributor. We always have choices about do we deploy our capital to build up infrastructure outside the U.S., or do we go with a partner who already has that infrastructure? We chose the latter, again, because the U.S. is such a key priority for us, as well as advancing our pipeline. Evansenite, as I mentioned, already has experience with rare disease products. This is a company that is growing. They're, I must say, quite hungry and enthusiastic for the opportunity with Agios and with Pyrukynd. It is very analogous, as I said, to the setup that we have with Newbridge in the Middle East.
The economics with regard to this transaction?
Yeah. It's a revenue share agreement. In the early stages with Evansenite, it skewed more in favor of Evansenite up to a threshold, and beyond that, then it skews in favor of Agios. It's a very economically friendly deal from our perspective.
Starting with Pyrukynd and thalassemia, as you noted, September 7, PDUFA here. Can you discuss the outlook for the label and pricing and early launch dynamics?
Yeah. I'll start, and maybe Sarah, as we get into a discussion about the clinical trials, could add on here. I think the highlight for thalassemia in our pursuit with Pyrukynd is last year, we were so pleased and proud to read out two statistically significant phase III trials in two very different populations in thalassemia, where we achieved significance on all primary and all key secondary endpoints. What that means is we have a potential to establish a series of firsts in thalassemia. Pyrukynd has the potential to be the first oral therapy approved. This is an opportunity where it's the first data set that includes quality of life fatigue specifically, with statistical significance for the non-transfusion-dependent patients. The first to not only have great data for beta thalassemia patients, but also alpha thalassemia patients.
When we looked at the transfusion-dependent study, Energize-T, this is the first that establishes up to 36 weeks of duration and counting for transfusion independence for these patients. It is a very unique and compelling opportunity. From a pricing perspective, I think the best way to think about it is this is still rare. We are in the neighborhood of what we already have in terms of pricing with pyruvate kinase deficiency with our current commercialization with Pyrukynd.
Can you discuss the key areas of launch preparation and where they stand today?
Sure. We're very well prepared. In fact, you always want to be ready in case an approval would come early. As I mentioned, the PDUFA date is September 7, 2025. We have already established our commercial infrastructure. We essentially built on what we already had in place for PKD, where Pyrukynd has been approved since 2022. In broad numbers, we roughly doubled the size of the sales force to about 40. They're all in place. They're all trained. Right now, we're focused on three key things. One is disease state education to make sure that clinicians well understand the pathophysiology of thalassemia, the complications that can come with this disease, and the fact that these patients need to be actively monitored and managed, transfusion-dependent or non-transfusion-dependent.
Secondly, as I said, the commercial teams are in place, and they're now very active on what we call account profiling, just making sure that we've got a really good network and connections with the key treaters who have thalassemia patients. Third, we've already begun the journey of engagements with payers. This is a well-diagnosed, well-established disease, about 6,000 adult patients in the U.S. We know how to deploy. We know the payer composition. As I said, the team is very well prepared.
You've spoken to targeting about 65% of patients with the most physician interactions to start. Can you discuss the clinical profile of these patients and how often they interact with physicians?
Yeah. Generally, within the 6,000, as you noted, our initial targeting is about two-thirds of those patients. The point of delineation is these are patients who are generally hemoglobin of less than 10. It'll be a mix of transfusion-dependent patients as well as non-transfusion-dependent patients who have complications. Remember, non-transfusion dependence is a gradient. It might be that right now they're not dependent on transfusions, but they actually are susceptible to the disease and the complications and might be heading in that direction. I think in the early days, from a pragmatic perspective, these patients tend to have higher frequency of visits with their clinicians. That gives us an access point to educate both the clinician and have the clinician offer, upon approval, a new treatment alternative with Pyrukynd. We think that'll be more of the early-going opportunity with launch.
One thing I'll just mention, though, Salveen, is that when we first start, there is always a gap between the prescription enrollment form initiation and when the patient actually starts on therapy. That can take a few weeks. We've guided that with the PDUFA date in September, when we think about the fourth quarter of this year, it'll tend to be, practically speaking, a kind of partial quarter until we get to revenue generation.
Non-transfusion dependent is a gradient, as you mentioned, with physicians in some cases thinking that they're less severe and thus don't require as much interaction with the physicians. Help us understand how you're going to educate in this population and kind of what needs to be done to really kind of have this group emerge as a viable treatment.
Yeah. Maybe I'll look at Sarah and just to comment on hemolysis and how devastating thalassemia can be. One thing I'll just say as a lead-in is that part of our education is the phrase non-transfusion dependent, in a way, works against the psyche of what the patient is facing. We're going to work really hard to make sure that that's well understood.
Yes, indeed. I think, and more and more, the physicians are aware that non-transfusion dependent thalassemia is really bad. That is also because more and more, we know from natural cohort data that hemolysis is deadly in the long run. An ongoing hemolytic anemia ultimately leads to iron overload in different organs, a lot of comorbidities, and ultimately early mortality in these patients. That is now more and more understood, to the point that actually some physicians are now thinking that they really did a disservice to patients by labeling them non-transfusion dependent thalassemia because they actually see that in the long run, they have a worse outcome. The field is evolving. The literature is evolving. I think this is also where patient advocacy organizations do play a role. For thalassemia, they are pretty well established.
This will, I mean, obviously, this is a kind of classic dynamic in chronic rare diseases where there have been very limited treatment options. We have a lot of experience at Agios across many rare diseases. This is our moment in many ways to make sure that we get clinicians to rethink what the journey for the patient can be, what the devastation can be cumulatively over time. It is a great opportunity to have potentially a label that covers all patients so the doctor does not have to think too hard about which subsegment. Our goal is, based on the data that we have, that Pyrukynd can be appropriate for all thalassemia patients.
At last year's American Society of Hematology meeting, you disclosed new cases of hepatocellular injury, which has since been added to the label here. Just help us understand if there's been any impact to commercial uptake and overall clinical profile and the viewpoint of physicians.
I think largely it's been a non-event locally when you think about prescribing clinicians. And we always encourage investors, do your market checks. You're going to hear the same thing, which is when a patient is onboarded for the treatment of a hemolytic anemia, naturally, they would go through regular testing. And we're talking here about monthly testing. In the case of our pyruvate kinase deficiency label for Pyrukynd, it's monthly testing for the first six months. The reality is clinicians typically continue well beyond that anyway. So it's been a non-event. And I think the best indicator we have in that regard is we just reported the first quarter results, which included continued growth, lower growth for PKD, but continued demand generation, which shows that this has been something that's well in the treatment pattern of how clinicians onboard patients.
I think from the clinical trial perspective also, the clinical trials just continued. We did not have a dropout or things like that occur post this announcement. From a higher-level labeling perspective, this is an event that we, to Brian's point, are able to pick up on very routine lab tests that you can get in any lab. You do not even have to go to the clinic for that, that all physicians are able to interpret, especially in the context of this disease where there is end-organ damage, which includes the liver, and monitorable and manageable in the sense that you can stop the drug. What was very pleasing is that all the patients that had an event actually returned back to their baseline.
Let's pivot to Pyrukynd in sickle cell disease, where we're expecting pivotal data late this year. Can you provide a brief overview of the study design and the powering aspects of these trials?
Sure, Sarah.
Yeah.
As Brian mentioned, what we are hoping to deliver for patients living with sickle cell disease is a drug that can treat the totality of sickle cell disease. You have two big components to this disease, hemolytic anemia and vasoocclusion. The trial is designed in such a way that we can deliver endpoints that talk to those two components of the disease. One of the primary endpoints is a hemoglobin response. The other primary endpoint is an analyzed rate of sickle cell pain crises. The hemoglobin response is to talk to the anemia, and the sickle cell pain crisis is to talk to vasoocclusion, which are both very important aspects of the disease.
What we have in our key secondary endpoints is a quality of life measure, looking specifically for fatigue, because we do know from patients with sickle cell disease that they find the fatigue a very important debilitating symptom of their disease, and they really do not have anything that can tackle that component of their disease. The trial is really designed in such a way to be able to speak to all of those aspects. There is an alpha split on those two primary endpoints to be able to transfer dependent on if one or both primary endpoints hit, we can transfer that associated alpha to the secondary endpoints. The powering assumption, so the trial is well powered with, for each endpoint, we have more than 90% power to be able to deliver to that. 198 patients followed for 52 weeks.
I'll just take the opportunity to say with pride to speak to the capabilities of Sarah and her team and frankly the product profile that this RISE UP phase three trial was enrolled start to finish. It's a one-year trial in a year, which if it's not a record in sickle cell disease, it's a really high bar. I think that speaks to the excellence of how closely we have continued to work with the community on the design of this study, the enrollment of the study. Frankly, we're already thinking about how we appropriately commercialize with success. It also speaks to how appealing this potential profile is in the eyes of both investigators and patients.
In the phase two trial here, you did show a significant improvement on hemoglobin response. How does that translate to vasoocclusive or pain crises here as we look to the translation in the phase three?
We do not think necessarily that one endpoint is dependent on the other. The hemoglobin response, the read-through from that endpoint is related to the read-through in the phase three. We did also, of course, look at sickle cell pain crisis in the phase two. There we saw those dependent reduction in sickle cell pain crises for 100 milligrams b.i.d. against placebo and then 50 milligrams b.i.d. against placebo over that short duration. That together with data from other ongoing investigator-sponsored trials further supports us exploring this endpoint in the phase three.
Speak to your confidence based on the trial design and your prior data and hitting both endpoints.
The prior data is very, very supportive of our phase three trial design. We are very much looking forward to the end of the year. In addition, I think for sickle cell disease, it's really important to think about the logistics of the trial. We have tried to, based on lessons learned from other sickle cell disease programs, keep a lot of consistency between how we ran the phase two and how we ran the phase three, which goes into using exactly the same definitions, exactly the same inclusion-exclusion criteria. The patient population is not all of a sudden a different type of patient population. Up to the adjudication committee, the same people are assessing the endpoint, things like that. We try to keep that as consistent and stable as possible.
If the study hits on hemoglobin response but not on vasoocclusive crises, walk us through what this means from both a regulatory standpoint, but a commercial standpoint, more importantly.
This is because the vasoocclusion endpoint for any program is a little bit more risky endpoint than a hemoglobin response, especially because this is our third program specifically looking at hemoglobin. This is why we build in a fatigue endpoint, because fatigue can speak to how patients feel. That is, from a regulatory endpoint definition, really important that you have an endpoint that can speak to how a patient feels and/or functions and/or survives. On top of that, as we mentioned earlier, fatigue is really important for the patient population itself.
That is why we do also believe that when you have a drug that can actually make people feel better because they feel less fatigued and you have a trend on vasoocclusion in the context of a landscape where there is really nothing for sickle cell disease patients, that that would be a very viable and good option.
Yeah. I think oftentimes in venues like this, what gets lost is we get into the details of the trial. Sarah just nicely outlined that there are multiple pathways. It's a really thoughtful, well-designed trial. What gets lost, though, is this is a fatal disease. When you spend time in this community, you realize just how desperate they are for new treatment options. The average life expectancy is into the early 40s, which, as you hear it, is pretty shocking and sometimes gets lost in the nuances of sickle cell. We are really excited about—we're not that far away, but we're really excited about the potential to finally get the data read out. We've always strived for a so-called hemoglobin plus profile, and we have more than one pathway to get there.
Moving to the earlier stage pipeline, so Tebapivat, your next generation PK activator. Can you speak to how the profile is differentiated from Pyrukynd, but then also the data that's been presented to date and when we can expect that phase two B data?
Yeah, I'll let Sarah speak to the data itself. First, at a strategic level, what an advantage from our perspective to have not one, but two pyruvate kinase activators. For us, the ambition in the case of sickle cell disease is to build a lasting and growing franchise. We just talked about how devastating this disease is, how many different therapeutic options are ultimately needed. Here we have a great opportunity to do just that. In the case of low-risk MDS, really pleased with the fact that we're already actively recruiting and will be fully recruited by the end of the year for our phase two B study. This is a rapidly growing market with, again, very few treatment alternatives, in fact, none that are oral therapy. We've got two different pathways that are very exciting for Tebapivat.
Maybe, Sarah, you can just talk about high level the profile differences.
Sure. It is a more potent PK activator. We need to give fewer milligrams to actually get to similar pharmacodynamic effects. In addition, Mitapivat has weak in vitro aromatase inhibition that was dialed out of the 946 or Tebapivat compound. Because of the increased potency, we also can give it once a day instead of twice a day. Those are really the big differences. In regards to the data for sickle cell disease, we have generated phase one data that does show a good hemoglobin response. Based on what I just outlined earlier, that it is truly a devastating disease, this is really a PK activator worth exploring for sickle cell disease. That is exactly what we are doing now in the phase two to learn more about the molecule there.
For MDS, because that is a little bit of a different type of anemia, we had to bridge it to thalassemia, which also has a big ineffective erythropoiesis component. We decided to go very carefully with a very rapid, but a small phase two A study in which we tested just one dose to really understand what the drug could do. We learned there that for MDS, there is a more fast metabolism of the drug in MDS patients. We were able to adapt our phase two B to explore different doses. That is exactly what we are doing now. We are very eager also, again, to get to the end of the year because that is when we are targeting full enrollment for that study.
When you look at the sickle cell programs here with Mitapivat, but your second generation, can you just overlay the data sets that you've seen to date at the same period of time just to help us understand what's playing out clinically?
For Mitapivat, we have data sets in pyruvate kinase deficiency, thalassemia, sickle cell disease, and then investigator-sponsored trials in hereditary spherocytosis. All of those are hemolytic anemias in which we've seen consistently a good hemoglobin response and actually people really feeling better. We have that for PKD in the label. For thalassemia, we have now the phase three also highlighting that we can statistically significantly improve fatigue. There is going to be data presented at EHA from our investigators on the other hereditary spherocytosis trial. It's just a lot of data, a lot of exposure. It's just at a very different phase of development. Tebapivat is earlier in its development phase. We're in a phase two both for MDS and for sickle cell disease.
For sickle cell disease, it's where you can compare the data, much smaller data set, but we do see a good, real good hemoglobin response in the phase one that allows us to see if we can learn more about that drug. Again, it's just a different phase of development. So Tebapivat just needs to work a little bit more to get to the same type of exposure so we can do that overlay better.
Just maybe two other points I'll make in terms of strategic advantages of having two different PK activators. You refer to it, Salveen, as second generation. We don't necessarily call it that. It's another PK activator that we can develop differently. First, when you think about from in the U.S., from an IRA perspective, these are both oral therapies, it positions us really well. We've essentially saturated the pursuits indication-wise with Pyrukynd. We feel really good about the opportunities in front of it. Now we can continue to develop Tebapivat as well independently. The second comment I'll make is from a patent perspective. You can think of the life cycle of Mitapivat, Pyrukynd into the mid-2030s. In the case of Tebapivat, carries into the early 2040s.
There's a number of advantages with the setup on our way to building this multi-billion dollar franchise.
Highlight for us when you look at your pipeline outside of the PKD drugs, what you're strategically kind of most excited about, both from a data standpoint, but also just as you see your vision of becoming this multimodal rare disease company, how you're going to prioritize.
Yeah. First, I'll say we're really proud of the foundation that we're building in classical hematology. We've already discussed three different hemolytic anemias. We're continuing to look at other areas that we could continue to expand, whether it's with our PK activation franchise or other opportunities. Beyond that, as I mentioned, we have two other earlier stage compounds in our pipeline. One is outside of classical hematology, which is AG-181 for phenylketonuria. This is yet another, this comes from our cellular metabolism roots, but it's another disease that is desperate for innovation, very limited treatment options for these patients. As I mentioned, we're in MAD dosing in healthy volunteers. Over time, we look forward to finding the results of AG-181 in PKU patients. Back in classical hematology, another area that we're excited about is polycythemia vera. This is with our AG-236.
This is the asset that we licensed a couple of years ago from Alnylam. It's a Tebapivat 6 inhibitor. As I mentioned, we are filing an IND mid this year. That's going to put us on a journey into a potentially much larger patient population, which, again, needs new therapeutic options.
To close here, could you just speak to your balance sheet capacity and interest in doing business development to grow the portfolio?
Sure. Happy to. We're positioned very well. As of the end of the first quarter of this year, we reported approximately $1.4 billion on the balance sheet. We're really clear on our capital allocation priorities. The first, as I mentioned, is getting the launches right, particularly in the U.S. That's why we've done these partnerships outside the U.S. Secondly, advancing the pipeline that we just spent time discussing, which we think can create a lot of value for our shareholders. Third is continue to expand and diversify the pipeline. From a business development criteria, the way we look at it is, first, we want assets that have transformative potential for patients. We love the concept of de-risking early. If it's got a low entry point, that's appealing for us.
We have a great example of that with AG-236, as I mentioned, that a couple of years ago we licensed from Alnylam. Anything that has a well-established regulatory pathway, though, I will say we're not intimidated by our creativity in Sarah's organization with rare diseases on shaping what that regulatory pathway could look like. I think in this environment, like everybody, we'll continue to be very disciplined about what we bring into the organization and when. We do see opportunities that could very well fit into the Agios foundation that we're building as well as our exciting capabilities.
Great. With that, thank you so much for your time.
Thank you very much, Salveen. Thanks everyone.