The forty-sixth Annual TD Cowen Healthcare Conference. Marc Frahm from the biotech team here at TD Cowen. next up, we're really pleased to have with us from the team at Agios, we have Brian Goff, CEO, and Tsveta Milanova, the Chief Commercial Officer. maybe to start off with, Brian, you want to just kind of give a level set for people who maybe aren't.
Yeah.
super in the weeds and just kind of what the next kind of key value-creating milestones that you see over the next kind of 12 to 18 months or so.
Sure. Well, first off, Marc, thanks a lot for hosting us, and thanks everybody for listening in to the Agios story. This is a really exciting year, 2026 for us, building on a lot of events that we had and a lot of progress made in 2025. I think the highlight of 2025 was more towards the end of the year when we were really pleased to have the approval of PYRUKYND, which is mitapivat, for the treatment of thalassemia. That launch is underway. I know Tsveta will be delighted to share more about the dynamics there. We also, of course, are pursuing expansion of our PK activation or pyruvate kinase activation franchise with mitapivat, first and foremost. Last year, we also read out data from our RISE UP Phase 2/3 study.
We read out the Phase 3 portion of that study for sickle cell disease. We've talked about in this quarter is our planned meeting with the FDA for an sNDA, pre-sNDA discussion of the path forward for sickle cell disease. We've guided that upon receipt of those, the minutes from that meeting, we will give disclosure of our regulatory path forward. We also have another PK activator, a more potent PK activator known as tebapivat. There we have two simultaneous studies that we're pursuing, Phase 2 studies, one also in sickle cell disease. The guidance there is that in the second half of this year, we'll look forward to the top line results of that study. We have a Phase 2b study in lower risk myelodysplastic syndrome or MDS that is fully enrolled.
In fact, both of these studies are fully enrolled. For MDS, we're looking forward to that data readout in the first half of this year. We also, as I'm sure we can talk about, have other pursuits even earlier in our pipeline, one in Polycythemia Vera, which is in phase 1, and another for phenylketonuria, PKU. We have a lot going on. There are a lot of catalysts to come in 2026, and it certainly is an exciting time for us.
Okay. Maybe we'll start with sickle cell just 'cause I think that update's probably next. You want to maybe review the phase 3 dataset and what, you know, 'cause obviously it hit on 1 primary endpoint, not on the other, as well as 1 of the kind of more key secondaries. Just what is the kind of value proposition you're going to the FDA with as to why it should be approved and are there any kind of regulatory examples you would point to as a kind of that resemble that in a dataset that have supported approval?
Always hard to align on an exact example.
Yeah.
of any situation in the biotech industry. Just to take a step back in terms of the data that we saw, as you noted, we had 2 primary endpoints. One was focused on hemoglobin improvement, and the other was focused on vaso-occlusive crisis reduction. We were successful on the first for hemoglobin improvement, and I would characterize it to say we had a very strong anti-hemolytic finding in the phase 3 portion of the RISE UP study, such that 41% of the patients studied actually had a gram or better of hemoglobin improvement. We also had statistical significance in other markers of hemolysis. A good example of that is indirect bilirubin reduction, as well as average hemoglobin concentration increase.
What is interesting about this, and I should mention for the vaso-occlusive crisis, we did not hit statistical significance on that side of the study. What's interesting about the RISE UP study is that if you take the responders, the 41%, and go back to our pre-specified analysis of hemoglobin concentration and what happened, what we have found is those patients have a pathway towards additional clinical benefits. In fact, the average hemoglobin increase was 1.6 grams per deciliter, which you really don't find in the wild, so to speak. That only really comes through transfusions. We were very compelled by that finding, and what we found is for those responders, they had a pathway to subsequent clinical benefits, such as further reduction in their sickle cell pain crises, as well as improvements in fatigue.
That's a really important crux of the approach with the regulators is it's a responder analysis. This study also showed us that from a safety perspective, very favorable safety profile. One key component of that is we did not see incidents of the hepatocellular injury events following the same pattern that we observed in thalassemia, which led to our REMS that we have now with AQVESME and thalassemia. I think the general approach, and what we certainly have heard from thought leaders in the community is this is very likely a kind of try first scenario because the safety profile is so compelling.
The data from a hemolytic anemia standpoint is, so compelling as well, and if you're a responder, you have a pathway towards additional benefits. You can try as patients do already with mitapivat in pyruvate kinase deficiency, and if it works, great, and if it doesn't at a certain time point, you can simply stop. The reality in sickle cell disease, though, is there isn't a lot else to try, and that's a point that we've heard emphatically from the community is this is a therapeutic desert. We've yet to hear anybody who has said to us, you know, we really want new therapeutic options, and we like what we see from the data and let us know how we can help.
Okay. You mentioned you're having the pre-sNDA meeting with the FDA. I guess how much kind of review risk is Agios willing to accept? You know, do you need to have very clear feedback that this is very likely to support approval to ultimately go forward with a filing or, you know, if you get much more in the gray area of this is a review decision that you're willing to, you know, push forward and see what that decision is?
Yeah. When you have a pre-sNDA or a pre-NDA meeting, what you will not get is an agency leaning in saying, "Yes, we see this as approvable or not." What you get are there's three key components that go into these meetings. One is review of the data itself, which is, you know, a key step, obviously. Secondly is FDA leans on the sponsor to propose what a pathway could look like and any other aspects that are needed in that regard. The third is there's always a discussion about any review issues that need to be sorted out. That is our approach, and again, that's why it's really important that we await the meeting's minutes from that meeting, and then that will guide our disclosure to the Street in terms of our strategic pathway towards next steps.
We're just waiting on the minutes at this point or and the meeting's happened or the meeting has not happened yet?
I will say that we have guided towards the meeting occurring in the first quarter, and as I just noted, Marc, what's really important as a next step is when we get the minutes, that will be our opportunity to create transparency with those who are following the Agios story to know what we believe are the next steps.
Okay. Is that update going to be in the first quarter or it's not clear?
I'm gonna go back to a rinse and repeat here.
Okay. Okay.
Let me say this. In terms of the meeting minutes, typically, but not exclusively, it's about a 30-day window to receive the minutes post the meeting.
Okay. Okay. I mean, you kind of started to develop that idea of, you know, kinda try it out if it's ultimately approved to try it out. I guess what does that model look like from a commercial perspective? How is the market opportunity maybe a little different, if at all, under, you know, this data package than, you know, maybe the dream that had been there a year ago if they'd hit on VOCs overall?
This is where it's great to have our Commercial Leader right up here with me.
We had an opportunity to discuss the data package with a lot of our customers around ASH and following up the disclosure of the data. I think Brian mentioned that there is a lot of excitement about the potential of having an anti-hemolytic agent for this hemolytic anemia and a lot of excitement about the data as well. If you think about it from a commercial perspective, what we heard from clinicians is saying, "Look, we'll be willing to try the product. The only thing that is actionable and measurable for us, irrespective if we had hit on VOCs or not, is hemoglobin levels and hemolytic parameters." The real utilization, assuming we have a label, would be the clinicians are gonna try it for their patients. They're gonna follow up on hemoglobin levels, on the hemolytic parameters.
They'll have the discussion with the patients, how they feel, and make a decision on benefit on who to continue based on these parameters. They'll always, of course, track VOCs, but what we heard from physicians is they are not gonna be using that as a metric for benefit from the product fundamentally. We see a very strong commercial opportunity with mitapivat in the sickle cell disease space, especially given the fact that this community really does not have treatment options there. Our study was designed in a way where we basically tested mitapivat in our inclusion criteria also on the top of hydroxyurea and could show a benefit there as well.
you know, since the primary drive on that will be that anemia, you know.
The anemia parameter.
...the hemoglobin benefit. What % of patients do you think are anemic enough at baseline that they would have a real chance of showing an improvement that has to kind of go through that route versus the broad?
It's a hemolytic anemia. We haven't kind of disclosed the specific numbers, but the majority of the patients have an element of hemolysis, and we believe that they will be eligible to potentially benefit from mitapivat. That in combination with the tolerability profile, that it is an oral option, and fundamentally, you tend to see benefit relatively quickly in the treatment journey. We believe that strongly supports that try first approach and only continue the patient that benefit. This is very similar, if not exactly the same of what we experience with PK deficiency and thalassemia. The clinicians take exactly the same approach.
They'll try the patients, they'll follow them up for a meaningful period of time, and if they see a benefit, which is defined more broadly than just 1 gram per deciliter improvement in hemoglobin, they'll look at the totality of the hemolytic parameters and how patients feel they'll continue on therapy after that.
Okay. I think we're expecting phase 3 data shortly from a competitor molecule in the same pathway, etavopivat. How is Agios gonna be evaluating that data and how, if at all, might that data kinda impact your willingness to push forward with the filing?
Well, I'll take the last part of your question first, which is it doesn't have impact on our pursuits. As I said, we feel that we have very well-established clinical benefits now from the RISE UP Phase 3 portion of the study. Again, we have two studies because this was an operationally seamless Phase 2/3 study, meaning the Phase 2 portion was dose finding, but it also had a unique set of patients, was placebo-controlled, randomized. As you noted, yes, there is another company, Novo Nordisk has a pyruvate kinase activator as well. We'll have to see how that data reads out. They've guided that this will be coming in the second quarter of the year, but it has no impact on our approach.
Okay. What's the early response to the label been from physicians, but I think at least as importantly right now is payers as well?
Very positive across all of the stakeholders. I'll start with patients and physicians. As we reported at the end of January, which is the first four to five weeks of the launch, we had already 44 prescriptions from REMS-certified physicians on the product. We are very pleased with the initial start of the launch. The both clinicians and patients have been very enthusiastic about the fact that we have a broad label. I actually was in interactions with one of our KOLs, and they said, "I still cannot believe that I have a treatment option for transfusion-dependent, non-transfusion dependent alpha and beta thalassemia patients," and that has been fantastic.
When we move to the payer perspective, we are in the initial stages in the launch, so at the beginning, you actually need to go through medical exceptions until payers put the product on formularies, which is gonna take about six to nine months. Again, a very kind of positive reception there. We have a very experienced team, and we see no hurdles to basically patients initiating therapies. We expect that to continue. We have a very strong label supported by good data. Also, thalassemia is a rare disease from a payer perspective, so we don't expect the category to be managed. You know, as I said, the team is very strong, so we'll continue to navigate that very well.
I'll just say, Marc, too, we've looked forward to this launch for a long time. It was one of the key reasons why I joined Agios, was this opportunity in thalassemia. One of the key reasons why I recruited Tsveta, we worked together at Alexion, who really knows what she's doing and has a great team, you know, supporting this launch. We also are aware that PKD for Agios was not really a needle mover in terms of revenue, but it's been a great opportunity to position how well mitapivat works in the real world, and it also has been a fabulous platform to build commercial capabilities in rare for Agios. Here we are. We know it's a show me story, but as Tsveta said, you know, healthy start to the launch.
Early days, but good start and no surprises from our perspective.
Yep.
We get a lot of skepticism from some investors of really how meaningful the thalassemia market is from a commercial perspective. What do you think people are missing?
I think people generally will, as I just said, over-index a little bit in part on PKD, which was very hard to dimensionalize how big that opportunity is. Very different dynamics than what we see in thalassemia. I'll let Tsveta speak to the triangulation that she and the team have done to characterize. We do know how many patients there are. We have a really good sense account by account of the dynamics.
Yeah, absolutely. I think it's partly to what Brian mentioned is after PKD deficiency, can you do it with thalassemia? We have a very different launch dynamics in thalassemia. Patients are diagnosed and known to the healthcare system, we've been able to validate these numbers through account profiling and prioritize the accounts, so we can actually have a meaningful start for the launch. The other thing is, the non-transfusion-dependent thalassemia, it's very hard to benchmark because there were no therapeutic options there was probably a little bit more over-indexing on the initial start of REBLOZYL in thalassemia. We have a very different label and a very different product profile, which positions us to basically establish AQVESME as the standard of care for thalassemia.
Initial start of the launch, but Brian Goff mentioned very good signals in terms of the potential there. We see prescriptions coming from the community heme/onc , which is the majority of our prescriber base across the country. We don't have a concentration in this initial prescriber, just couple of KOLs starting and potentially handicapping the opportunity of the launch there. We also see patients that we expected to initiate therapy first to be the first movers, and they are a combination of transfusion-dependent patients who have more frequent interactions with the healthcare system, but also non-transfusion-dependent patients who are actively engaged with the healthcare systems, symptomatic and looking to benefit from therapy.
Okay. You mentioned, it touched on some of this, the REMS certifications with the REMS program here. Obviously you had to work through that in January to get that program up and running. Should we expect the kind of the pace of certification to accelerate throughout kind of Q1 into Q2, or was there kind of a bolus of docs ready to get, you know, who you got certified quickly, and then it's a maybe slower ramp after that? Just how should we think of that trajectory?
From a launch trajectory perspective, there are a couple of elements. The first one is we don't expect a massive bolus of patients that captures the majority of the addressable patient population in the first few quarters of the launch. The reason for that is that thalassemia is not an imminently life-threatening disease, so we would expect more gradual trajectory and steady growth of the launch over time. The other thing is what we are benefiting from is in a way you have two subset of patients based on their frequency of interactions with the healthcare system. Initially, you will see, and we expect to see, and this what we are seeing is more prescriptions from the transfusion-dependent patients just because they see their physicians, they go out for a transfusion, see their physicians in every three to four weeks.
Over time, however, the launch is gonna scale up through the bigger opportunity, which is the non-transfusion-dependent patients who have less frequency of interactions with the healthcare system as well. From a REMS certification perspective and the physicians, what happens is in the big centers, of course, the physicians get certified and you'll see some depth of prescribing. Our REMS, the way it's structured, it's first very simple, and the majority of the physicians will actually REMS certify as they are ready to prescribe. It's a very fast process. It happens once for the physician certifications and once they are certified, the patients needs to go through the process of liver testing, but it's just not gonna be either a hurdle or accelerator of the launch trajectory.
You mentioned that kind of patient mix should shift over time that, you know, it'll be heavily transfusion-dependent early on because they're coming to the doctors very frequently. What's that mix look like, you know, three, four, or five years down the road in your, in your head?
As we mentioned, the out of the 6,000 adults in the U.S. that are diagnosed thalassemia patients, two-thirds of them are non-transfusion-dependent patients. We'll see the scale-up of the launch over time being driven by the non-transfusion-dependent patient segment.
I mean, long term, you think revenue is 2/3 the transfusion non-dependent or non-transfusion-dependent patients, or is it a lower penetration in that population, so it'll be some lower number?
You can look at it in couple of ways and fundamentally, if you look at it in the initial addressable launch segment, 50% of which is 4,000, 50% are transfusion-dependent, 50% are non-transfusion dependent population. We expect to penetrate both of the segments equally. From that perspective, I wouldn't expect a lower penetration in our addressable patient population by segment.
Yeah, that's the key. I mean, we have a broad label. You said in several years from now, we would look to match the prevalence distribution of the population.
Yeah.
Okay.
Yeah.
Maybe another mixed one, but looking ex-U.S., just what does that over time kind of frame the opportunities outside the U.S.? We're used to many franchises these days.
Yeah.
-are 60%, 70% US revenue, right? What does it look like for, PYRUKYND?
For a mitapivat, what we have guided towards is a $1 billion commercial opportunity for PK deficiency and thalassemia globally. If you have to break it down, the majority of that is gonna be thalassemia, and the majority of that is gonna be in the US. Other regions such as the Gulf countries, they have higher prevalence, but especially in the initial years, given the market access dynamics in that region, we'll see lower penetration and lower revenues. Europe, of course, is another segment that is always of interest. The prevalence of thalassemia is very sporadic in that region, and also it takes time for the countries to get the products reimbursed. The majority of the driver for revenues in the short and the long term is gonna be thalassemia US.
Okay. What's the approval right now is in adults and teenagers, right? What is the plan to kind of broaden that? I mean, you mentioned everybody is getting diagnosed, at least in the U.S.
Yep.
with essentially newborn screening. You know, obviously, it's...
Yep.
always easiest to get somebody right when they're being diagnosed. What's the plan to get to lower ages?
Actually in both thalassemia as well as in sickle cell disease, which we talked about earlier, our ambition is to extend the age of approval to move from adults into pediatrics. We haven't talked about the specifics, of course, yet, but that definitely is in our sights.
Okay.
Do you need to get an answer on sickle cell before you kind of start that work, or is the thalassemia pediatric plan kind of completely independent?
Well, thalassemia is approved. We know that there's a pediatric population that'll be important going back to your phrasing, over the coming years. In the case of sickle cell disease, what is interesting is we would already be looking to pursue a pediatric trial. This goes back to potential, you know, regulatory pathways. Obviously, our ambition right now from the RISE UP data would be full approval because we really believe strongly in the clinical data that we have. The FDA's commented as recently as ASH in December of last year about hemoglobin as a surrogate endpoint. They've talked about an accelerated pathway. This goes back to optionality from our perspective. One of those options may be a pediatric trial that could fulfill whatever the endpoint objectives are at the finish line. That's as one scenario.
Okay. Maybe on tebapivat, just that's the next kind of.
Yep.
Mm-hmm
... pipeline update is in MDS. Just what does an attractive drug profile look like when we see that data? You know, there are some approvals in low-risk MDS anemia.
Mm-hmm.
Some launches have gone well, others have not. What's the target profile look like?
When we look at the data, the first thing is it's a Phase 2b study, and it's a dose finding study, so that's gonna be an important insight that we're gonna get from that study. When we think about, where we can commercially position the product, we'll be looking at the data through the lens of three variables. The first one, of course, is efficacy. The second one is tolerability, which we know is very important in the MDS patient population because it's an elderly patient population, as well as, our potential differentiation on route of administration. What we hear from physicians is that we don't have to match the efficacy of any of the existing products if we can actually show a benefit on tolerability as well as route of administration.
For that patient population, their primary objective is to keep them untethered from the clinic and stay at home as much as possible. The current treatment options they have are IV treatment options or physician-administered subcutaneous product, which is REBLOZYL. Even if they get them to transfusion independence, patients needs to go to the clinic on a frequent basis to receive their therapies. A product that is orally administered with a good tolerability profile that can actually keep them out of the clinic is gonna be very attractive.
Sounded like you had something to say. No? The maybe with tebapivat also, there will be sickle cell data later in the year. Is the importance of that data very how dependent or is it entirely dependent on the regulatory update for mitapivat? Or is there a path where if you have a, you know, poor outcome with the FDA discussion on mitapivat, that tebapivat still has paths forward in sickle cell?
Yeah, I'll say it this way. We're excited with the potential we see in tebapivat for sickle cell disease. This is, again, a landscape, it's a therapeutic desert. There are very, very few options for these patients. We believe in pyruvate kinase activation as a mechanism. The key ingredients that'll go into what we do next in terms of tebapivat beyond phase 2 will depend on, number one, the phase 2 data itself, number two, the regulatory pathway and the result of that with mitapivat. Of course, contextually, we're gonna look at the competitive environment as well. That'll guide us as to what to do as the next step. This is, again, can't emphasize enough, an area where patients need new options, and I think this presents a very exciting opportunity.
Okay. Other pipeline asset that you did touch on earlier was the TMPRSS6, siRNA. You know, there are some other TMPRSS6 assets that have been in the clinic.
Yep.
I guess what has already been established with that target? What are still the big unknowns, unanswered questions with the target? We can get into the molecule itself.
Yeah. I mean, this is something that we in-licensed from Mount Sinai back in 2023. This is AG-236. TMPRSS6 is really at the center of iron homeostasis in the body and endogenous regulation of hepcidin, which is critically important. The target here is polycythemia vera patients, which need new options beyond phlebotomy. Part of our inspiration here is we've seen through rusfertide and their development, which is exogenous introduction of hepcidin, that in fact hematocrit levels come down. Patients can avoid phlebotomy. What we see with ours is the opportunity to have that as a very durable effect with tight hematocrit control and optimally very long intervals of therapy for the patients.
Mm-hmm.
Is it really the interval that's the differentiation for some of the other TMPRSS6 assets that are, you know, kind of in phase 1, 2 development, they're antibodies and such.
I think it's-
Do you think it's a more effective drug?
Yeah, I think more the latter. I mean, of course, interval will be a key component, but the effectiveness and, again, that tight control and avoidance of peaks and troughs, all of that fits together, for a therapeutic area that really needs disruption. One thing I'll just mention is what we're looking towards here is the phase 1 healthy volunteer data, the readout to guide us on next steps, and that'll come in 2026.
Yeah, and how much are we gonna be able to tell about that kind of tight control, any impacts on hematocrit in a healthy volunteer study versus how much do we have to wait for 2027 and beyond for actual PV patients?
There will, of course, be steps beyond-
Yeah.
We believe we'll be able to see enough to validate the mechanism, the GalNAc conjugated siRNA approach that we're taking in the case of AG-236 to guide us for next steps.
Mm-hmm.
Okay. Unfortunately, we're actually over time, we're gonna have to cut it off there. Thanks a lot for joining Brian and Tsveta.
Thank you very much.
Thank you.
Everybody in the room.
Exciting year for us. Thanks a lot.