Thanks. Hello, everybody. Luca Issi, senior biotech analyst here at RBC Capital Markets. Today it's our great privilege to have Agios as part of our 2026 RBC Capital Markets Global Healthcare Conference. Representing the company here, we have the whole team here. Brian Goff, Chief Executive Officer, Sarah Gheuens, Chief Medical Officer, as well as Tsveta Milanova, Chief Commercial Officer. Thanks again, guys, for joining. How are you doing?
Very well. Thanks a lot for hosting us.
Good. We have a long list of questions here, but maybe before we go into specifics and ask about, you know, FDA correspondence and conversations and whatnot, maybe Brian, it would be fantastic if you can start a little bit big picture, talk about what progress has the organization made over the last few months, and maybe most importantly, what's ahead here for Agios.
Yeah, happy to. Thanks a lot. Thanks, everyone, for tuning in and listening to the exciting Agios story. It has been, you know, a really great start to 2026 for us with, as you just noted, a lot to talk about. We've been very focused on discipline execution across the board. I'm very proud of the progress that we've made. We've also continued to sharpen our focus, particularly in rare hematology, which is very exciting. We started the year with our launch of AQVESME, mitapivat, for thalassemia, and I know Tsveta will be excited to share more about that. I would characterize it as a very strong first quarter of launch, which we just disclosed in our first quarter results. Early days, but a very good start, very meaningful for the thalassemia patients who benefit.
Secondly, just last week, we announced that we have progressed or advanced towards an sNDA. We filed with the U.S. FDA mitapivat for the treatment of sickle cell disease. We've submitted that sNDA. We also announced last week that in pursuit of an accelerated approval pathway, we gave some details on the affiliated confirmatory study. There will be more details about that and the totality of the RISE UP data that supports the sNDA at the upcoming EHA meeting next month in Stockholm, Sweden. Very good progress for us. We're also advancing our broader pipeline, and the focus there is to really make sure that we're targeting where the biology is more proven and where there is a clear path to value for patients.
We're very proud of the fact that we've got a nice series of catalysts that will continue to play out in 2026. I think, Luca, the big picture is we're positioning Agios for long-term success. Very proud and excited about the rare disease focus in hematology with a very strong foundation. Of course, the ultimate objective is to have durable value creation for the long term.
Sure. Sure. That's a great overview. Maybe, Sarah, if I can pivot to you. Again, congrats on the sNDA for sickle. Again, we look forward to all the, you know, exciting data obviously at EHA. Can you just maybe talk high level about your level of conviction that the FDA will ultimately approve this drug on an accelerated approval basis? Again, you know, the trial obviously had two primary endpoint. The trial obviously hit one or two primary endpoint, and then I think one of the key secondary endpoint was actually fatigue. That, you know, the P value there for fatigue was maybe not hit. Walk us through why you have high conviction that ultimately you can get accelerated approval from the FDA.
Well, as you know, we've had a pre-sNDA meeting with the agency to discuss the data of the RISE UP trial, which was our sickle cell disease trial with two primary endpoints, as you point out. Because of the hemoglobin primary endpoint, we were able to have the discussion with the agency, and especially because there was a lot of other clinical meaningful data within the trial, confirming the strong anti-hemolytic profile of the drug, but also showing within hemoglobin responders additional benefit. That allowed us to discuss the accelerated approval pathway and get to an agreement on that pathway, which of course requires a confirmatory trial. Last week we also spoke about that.
We highlighted that we submitted the sNDA for their review, and we also highlighted that we were able to get to agreement on that confirmatory trial . The confirmatory trial is a streamlined trial focused on transfusion independence. And that is based on data of the RISE UP trial, so it's informed by that, and we'll speak more about that at EHA as well. The other thing that is important to highlight, it's 159 patients, one year long, but it's very streamlined and a simple trial to participate in. Another important feature is that we are lowering the age range to 12 years of age to help with pediatric development as well.
Gotcha. Gotcha. That's actually super helpful. Obviously the clock is now ticking in term of the 60 days, obviously to get, you know, the filing accepted. Are you anticipating a priority review or standard review, again, in the context of the unmet medical need of sickle cell disease more broadly? Have you guys commented on that side?
Well, there is obviously a huge unmet need in the context of sickle cell disease, and I think the agency and us have worked with speed on the confirmatory trial together. Standard review, priority review is ultimately their decision to make, and we will, you know more when we have a PDUFA date. Needless to say, I think everybody understands that sickle cell disease is in need of different treatment options and that there is an urgency.
Gotcha. Gotcha, that's helpful. If I can ask, obviously you had multiple interactions with the regulators. I guess, you know, how recent were those interactions with the regulators? Have you had conversations with the FDA before or after the Novo data? Does that data changes the conversations in any capacity or is that maybe not the right way to think about it?
The short answer is I do not think their data impacts our data package, nor the pathway we are on. As we've mentioned last week, we were able to announce our submission under the accelerated approval pathway. That, of course, means you've had interactions with the agency along the way to get to this point, because you do need alignment on your confirmatory trial as well. We feel confident in our data package, and now it's under review.
Can I just.
Please.
Another point too, which is as a reminder, because sometimes this is missed by the investor community. This is an sNDA, as we said. In terms of interactions with the FDA, certainly we've had multiple interactions for the sickle cell sNDA, but more broadly across hemolytic anemias, many interactions over multiple years with Sarah Gheuens and her team. To the credit of the FDA, in many cases, you know, a very similar review team. There's a lot of sponsor-FDA familiarity that we've gone through passing from our first approval for mitapivat and PKD back in early 2022, as we noted most recently, thalassemia, which received approval at the end of last year, now of course, the sNDA approach with sickle cell disease.
Gotcha. Gotcha. That's super helpful. Maybe talk a little bit I mean, obviously, we're all waiting for the data at EHA, but maybe just talk about maybe some of the powering assumptions around the trial. 159 patients you already mentioned. We're gonna probably see a reduction in transfusion burden at EHA. Do you wanna maybe kind of set expectations for how we should think about that data set? Maybe just kind of clarification question, is the reduction in transfusion burden that we're gonna see at EHA pre-specified, or was that a post-hoc analysis?
Yeah, no. The data was prospectively and systematically collected in the RISE UP trial, so it, I mean, it wasn't a fishing expedition.
We are, we will show that data that underpins the current trial at EHA. That will hopefully help people understand the powering assumptions, the sample size, and the simplicity of the trial, really. I think the beauty of the trial is transfusions. We have run several transfusion trials before, so I think the team has great comfort with running a trial like this. I think the simplicity of it is really also a strength of this trial in the sense that physicians really like the simplicity of it. Yeah, more to come at EHA.
Gotcha. Gotcha, that's helpful. Maybe remind us what proportion of the patients in RISE UP actually received transfusion, and is there a I guess, how should we think about the patients that were enrolled in RISE UP versus the patient that will be enrolled in the confirmatory trial? Would it be fair for us to assume the new confirmatory trial even enroll more patients that are dependent on transfusions to help the powering or, yeah.
Yes. In the Rise Up trial, we did not have a requirement for having had transfusions in the past. We did not allow chronically transfused patients in Rise Up because in the context of sickle cell disease, that's typically done for stroke prevention. We're intending to enroll a very similar patient population in this confirmatory trial as the Rise Up trial, with the only difference is indeed that there is a transfusion requirement as it relates to that inclusion criterion.
Gotcha. Why the difference in age, 12 and older versus 16 and older?
We have now, of course, efficacy and safety data in 16 and up, which supports further development into the pediatric patient population. We're taking this opportunity to further lower the age range.
Gotcha. Gotcha, that's helpful. Maybe a couple more here. Again, I know we have to wait for data at EHA. A lot of these questions are maybe a little forward-looking here. How should we think about how you're going to plan to capture the baseline characteristics in the phase III trial? Are you going to have a long kind of run-in period whe re you are going to measure how many transfusion these patients receive, or are you going to rely on medical record? If you are relying on medical record, is the FDA okay with that approach, or how should we think about that?
There's a regular screening period. It's not like we're going to have a long run-in period, but we're relying on the investigators to identify the patients properly using our inclusion and exclusion criteria, just like in any other trial.
Okay, that's helpful. Maybe if I can go back to the the Novo data. Again, we only have the top line. I'm glad, Brian, you highlighted, you know, some of the differentiations around safety and the fact that this molecule has been around for a long period of time versus obviously the Novo molecules are maybe a little bit more kind of newer. Well, I guess, what's the best way to kind of rationalize the 27% reduction in crisis that they have shown versus maybe your, you know, your benefit was a little bit more modest? Is there some pharmacological differences between the molecule that can rationalize that, or it's just maybe they've run, you know, a trial that enrolled kind of a better patient populations? How should we think about all that?
Right now we are missing so much information as it relates to the actual patient population enrolled that it is hard to fully interpret the numbers that have been released. We're looking forward to hearing more about the patient population, including their where they enrolled, which countries they enrolled. The baseline VOC rate that those patients had in that overall trial. Patient population hydroxyurea use, all of those different things may matter. The way the statistics are done matter too. There's a lot of information we need to actually put an interpretation on that number. So far, what we are taking away from the data is that PK activation works in sickle cell disease, so that is, you know, a positive.
Focusing on our data, I think we have, again, strong conviction on our data set because we have consistently shown hemoglobin response, anti-hemolytic effect, which is really important in the context of sickle cell disease. That translates into all this other additional clinical benefit, which we'll show at EHA. The transfusion reduction that we also saw within the RISE UP clinical trial data set, and then of course our safety data as well.
True. Gotcha. That's helpful. How should we think about the label at this point? I mean, you obviously have two labels now for the same molecule, however, obviously for sickle you're dosing 100 milligrams, right? How should we think about where the label will fit? I mean, this is obviously a question related to the main difference between the two labels today is that one obviously has the REMS program versus the other one doesn't have the REMS program. Should it be the base case scenario that you will get the REMS program, or like what's y eah?
We have optionality here, right? AQVESME, to your point, has the REMS, is the 100 milligram dose, currently for thalassemia, approved for thalassemia, we have PYRUKYND without a REMS, which is currently approved for pyruvate kinase deficiency. We have that optionality. Either way, I think Tsveta's team has shown that they can, you know, execute on a launch in a rare disease with a REMS. That being said, as we've discussed before, the profile, the safety profile is favorable in sickle cell disease, this may not warrant a REMS. This will be a matter of negotiation as well.
Yeah, sure. A conversation with the regulators there. Tsveta, maybe pivoting to you, but still sticking on kind of sickle cell disease, how should we think about pricing? I mean, obviously two. Not only there's two different labels, but there are also two different price points. How should we think about on a relative basis where your drug will be priced in sickle versus where it is today on for the two other indications?
Absolutely. As Sarah mentioned, commercially we'll be ready to execute irrespective of the brand name and the label, and we see a very meaningful commercial opportunity with sickle cell disease. We'll comment more on pricing once we are at the time of approval because we'll need to take into account the actual label at the time as well as the evolution of the competitive environment, but we are in a strong position to execute irrespective of that.
Okay. Can you have a price that is different than thalassemia and PKD, or will it have to be one versus the other, or is maybe too early to comment on it?
It is too early to comment, because of course there is the WAC price, and then there is a gross to net variability which needs to be factored. One simple factor is even if we don't change the price at all, the WAC or, you know, or anything else, the fact that the sickle cell disease patient population has a higher Medicaid payer coverage, that automatically will increase our gross to net, because of the 23% mandatory rebate that's in that space. There are kind of some differences between the diseases which will impact in a way kind of your net price. The final pricing strategy will depend on the label and how the competition and the market evolves over time.
What proportion of patients with sickle cell disease are Medicaid versus the other two? I don't know.
In thalassemia and PKD, majority of the patients are commercial. With sickle cell disease, you know, the data varies and it's also age dependent, but it can be about 50% of the patient population. Of course, when we look at our priority launch segments, and the way we're gonna approach the launch, you know, it will probably skew it a little bit more towards the commercial payer segment, but these are still elements for us to consider as we continue with launch preparation.
Gotcha. Gotcha, that's helpful. I think both Brian and Sarah highlighted that the team did a fantastic job launching. The drug again for only Q1. 242 scripts for thalassemia. Can you just maybe talk about the trajectory of the launch, and can you just maybe give us a sense of what proportion of the 242 was transfusion dependent versus independent? What proportion was alpha versus beta? Like that'll be helpful.
Absolutely. We are very encouraged by the initial stages of the launch and the reception of the community for the product profile of AQVESME. As we said, 242 prescription in the first quarter from REMS certified physicians. It was a very kind of healthy start of the launch, being the prescriptions are coming from majority of the clinicians that are in the community, which is what we expected from across the country, so they're not concentrated within certain prescribers. We see a very healthy breadth of patient subtypes, being transfusion-dependent, non-transfusion-dependent, alpha and beta thalassemia patients. As expected, however, the majority of the prescriptions or a large proportion of the prescriptions were from the transfusion-dependent patients.
That's primarily driven by the frequency of interactions with the healthcare system that these patients have, as well as a kind of a meaningful healthy start in the NTDT segment from the most engaged NTD patients. The launch is basically going exactly as we expected it to go. Over time, we'll move into penetrating deeper into the NTDT segment, which is 2/3 of the opportunity and is really our opportunity to continue to scale and deliver a sustainable launch through thalassemia. Given that the fact that they have a less frequent interaction with the healthcare system, we'll continue to see kind of sustained demand, which we'll expect to moderate over time as it happens with any other rare disease launch.
You used the word moderation. How should we think about the moderation in terms of, like, scripts going forward? You know, in every launch there's a little bit of a pent-up demand, if you will, and you guys highlighted, you know, the 40 up until the end of January versus the 242 at the end of March, and I think you're cautioning us about thinking about a 242 for the whole quarter 200 two months, I guess. Like, how should we think about the moderations from here? Maybe related to it, are you committed to continue to share those scripts with us? At some point you'll stop and have revenue speak for itself, and if so, when would that be?
We haven't said exactly when we're going to sunset prescriptions. As expected, we'll do so as the launch progresses further, and we'll provide additional information on the launch dynamics to help you assess how the launch is going. When we said about moderation, as I said, you know, we need to look at the quarter as a consistent demand generation. In the first quarter for 242 prescriptions. You know, in the initial stages of the launch you get the fast movers from a clinician perspective as well as the most engaged patients. We have a 4,000 patients target patient population in the U.S., we have a long way to go. You know, we'll look to maintain the demand generation as sustainable as possible over time.
You know, as you move into less engaged patient segments, you know, by definition that is gonna the actual demand growth is gonna slow down. The important thing for thalassemia is it's a disease with higher med need. This launch is very, very meaningful for that community because this is the first product that actually covers the totality of the thalassemia community. It's not really competitive. There is no competition along the way, with the way things are going and the reception we hear from the community, as we stand today, we're comfortable with the $1 billion peak sales guidance that we gave for PKD and thalassemia globally with the majority of that being driven by thalassemia in the U.S.
Gotcha. That's helpful. I'm sure I'm pushing my luck here, but are you committed to actually share the scripts for Q2?
You know, I think that that's a very fair assumption given that we're, you know, that early in the launch and that will be a meaningful kind of lead indicator.
Yeah, we I mean, I would add we always follow the pathway on trying to give the investor community clarity around how we're doing, the trajectory. There is a point where, as noted. You know, it won't make sense, and it's really gonna be more about the revenues. We're still very much in the early days of launch.
Gotcha. Gotcha. That's very helpful. Maybe one last one, Tsveta, if I may. You mentioned 10 to 12 weeks from script to treatment initiations.
Yep.
How can we do better?
In kind of We guided initially to the 10 to 12 weeks. What happened in the first quarter, because of that kind of initial highly engaged prescriber and patient uptake, we saw that time being shorter because these are the patients, either they are transfusion dependent, they get their liver test done quickly, or the physicians, you know, they call the insurance companies, get the prior authorization through. Over time, we expect that time kind of to move closer to the 10 to 12 weeks. We'll always work to shorten that time. There are two drivers that kind of stand behind the 10 to 12 weeks. One of them is very standard for any specialty rare disease product, which is the insurance prior authorization process.
We'll look to shorten that. The team is already working with payers to get, you know, the policies being written and that could speed up the process. The second one is actually doing the liver test, which is a requirement before initiating therapy as part of the REMS. Now when we have more transfusion-dependent patients, they get their liver testing done with every single transfusion, so that's not kind of additional time commitment. As the launch moves more towards the NTDT patient segments, it might take longer for these patients to get actually their liver test done on time and the insurance verification and that's why the 10- to 12-week timeframe. I can tell you the team is working to make that as short as possible.
Gotcha. Gotcha. That's helpful. I know we're almost out of time. Maybe for the next generation, tebapivat, I think you guys have described that upcoming catalyst for PV as high risk, high reward.
MDS
Sorry, for MDS. Can you maybe expand on it? Why it's high risk, high reward?
High risk because it's the first non-hemolytic anemia in which we're studying PK activation, so really focused on the ineffective erythropoiesis component, making bridges to thalassemia there. high reward b ecause, you know, dependent on the data we know that MDS is a really big market, that their patients are outliving their current therapy options. A PK activator with, you know, an oral with a good safety profile can definitely provide some meaningful advancement there.
Gotcha. That's super helpful. Maybe Brian, if I can close it up with you, when you kind of step back and think kind of big picture about Agios and the story, what do you think is the most kind of underappreciated aspects of the story at this point?
Oh, good question. I think fundamentally it's what we just talked about, the sickle cell disease dynamic. I'd make three points. One is this is an area that is super high unmet need, number one. Number two is the strength of our data RISE UP, as we talked about, and now we're quite proud of the fact that we have an sNDA filed and an accelerated approval pathway we're pursuing. The third is you just heard from two exceptional leaders that really know what they're doing, whether we're talking about the regulatory development pathway or the commercial prowess that we have built up at Agios. We feel very well prepared for sickle cell disease, and I think that's fundamentally underappreciated still to date.
Gotcha. With that, I have 3,000 more questions, but we're tight. Appreciate you guys joining us, everyone, for joining us at the RBC conference, we'll talk soon. Thanks again.
Thank you. We appreciate it.
Thank you.