Welcome back to the 45th Annual TD Cowen Healthcare Conference. Next session, we're really happy to have with us the team from Agios. We're with Brian Goff, CEO, and Sarah Gheuens, the CMO and head of R&D. Maybe to start off with, Brian, you want to just kind of give a high-level kind of status update for the company, and then we'll dive into some of the Q&A, and also, for anybody in the audience, we certainly welcome your participation as well if you have burning questions as well.
Sure, I'd be happy to. And thanks a lot, Mark, for hosting us. Good morning, everybody. Thank you very much for listening in to the Agios story. Just as a background, our mission at Agios is to develop and deliver transformative therapies that have the potential to elevate and extend the lives of patients who are living with rare diseases. And the core focus, in terms of the diseases that we really spend a lot of time on, are those that result in the dysfunction or destruction of red blood cells, namely pyruvate kinase deficiency, thalassemia, Sickle Cell, and as well as low-risk myelodysplastic syndromes. Our lead asset is a product called PYRUKYND, chemically known as mitapivat.
And this has a very unique mechanism of action that ultimately improves the metabolism of the red blood cell, which leads to better hydration, better longevity, and a higher level of energy for the cell. And as I said, we're already commercialized, in fact, with PYRUKYND in the U.S. for adult patients who have pyruvate kinase deficiency. We're very focused on extending that indication list, moving into potentially thalassemia as well as sickle cell disease. Now, last year, 2024, was an exceptional year for Agios. We had a number of corporate milestones that we put forward. The majority of those were focused on advancing our mid and late-stage pipeline. And in fact, across the board, with every single one of those milestones, we delivered on or ahead of schedule. One of the highlights was with thalassemia in 2024.
We actually announced results for two phase III pivotal studies known as ENERGIZE and ENERGIZE-T, which we'd be happy to talk about this morning as well. Based on the fact that all of the primary endpoints and all key secondary endpoints were statistically significant, we announced late last year that simultaneously we filed with four different regions for regulatory approval: the U.S., EMA, as well as the United Arab Emirates, and the Kingdom of Saudi Arabia. Fast forward to the beginning of this year, we were delighted that the FDA has now issued a PDUFA goal date for thalassemia of September 7th of this year. We're very much looking forward to that.
Our commercial team spent the better part of last year scaling up appropriately for a launch of the magnitude of thalassemia, still a rare disease, but certainly larger potential than we had experienced with PKD. And the team is taking advantage of every moment between now and that PDUFA date to go deeper on account profiling as well as disease state education, really leading to a higher sense of urgency to treat the thalassemia population. The other big event was in October of last year, we announced that we had fully enrolled our RISE UP phase III pivotal study for sickle cell disease. And a big milestone for this year is by year-end, we'll look towards the data readout in sickle cell disease. And that, of course, with success, would give us potential for another launch in 2026. So back-to-back opportunities. thalassemia this year, sickle cell disease next year.
Sitting to my left is Sarah Gheuens, our Head of R&D and Chief Medical Officer. Sarah, I'm sure this morning too, will share updates on our other PK activator known as tebapivat. This is formally known as AG-946. There we're pursuing, starting at the middle point of this year, a phase II study as well in sickle cell disease as we look to build out a franchise. We already have well underway a phase II-B study in low-risk MDS. The goal is to have that fully enrolled by year-end. The last comment I'll make, Mark, is that our balance sheet as well is in a real position of strength. Last year, at the middle point of the year, we monetized vorasidenib royalty from the transaction that we did back in 2021 with Servier.
And that put us in a really good opportunity for disciplined capital deployment with really two key priorities. One is get the launches right, because again, thalassemia will be starting with success with the FDA later this year, and the other is continue to expand our pipeline. And we look to do that internally with continued expansion of organic opportunities as well as externally. And with that in mind, and this is like what Steve Jobs would say, is just one more thing, Mark, is I'm really pleased to announce this morning that we have a new member joining our leadership team. His name is Dr. Krishnan Viswanadhan, and he will be the Chief Corporate Development and Strategy Officer. So his task is, first of all, long-term strategy initiatives that will lead to growth, business development, and of course, continuing to help us advance the portfolio as well.
And I'm really excited about having Krishnan join us. Most recently, he was at Be Biopharma as their President and Chief Operating Officer, deep set of experiences in the industry, and he'll be a really nice addition to the team. So the moral of that story is we've started the year strong, and this is a big year ahead for Agios, and we look forward to your questions.
All right. Thanks for that overview, Brian. Maybe to start off, we'll start in thalassemia since that is the next, well, hopefully the next launch. Sarah, you want to put some of that data that was presented back at ASH just in context, the fatigue benefit that was seen in the non-transfusion dependent patients, but then also with the transfusion benefit in the transfusion dependent patients. Just what type of impact does that actually have on a patient's life, the fatigue benefit that you were able to show? What are the types of things that they may be able to do now if they take mitapivat versus they couldn't before?
Sure, so our thalassemia program has two clinical trials: ENERGIZE-T, which is the transfusion-dependent patient population, and then ENERGIZE, which is the non-transfusion-dependent patient population that was able to participate, and in that trial specifically, we were looking for a hemoglobin endpoint, but we're able to support that with a key secondary endpoint looking at fatigue, because we do strongly believe across our different development programs that it is important to be able to speak to what we call hemoglobin plus, and that plus comes typically from fatigue benefit, like a benefit on fatigue here. We were able to show statistically that we were able to improve fatigue. That's the first program that ever has occurred in thalassemia, and of course, that's a clinical trial endpoint.
But when we talk to patients, it comes down to they have very tangible benefits that we would never even think about in our real life. They can go to a supermarket and go buy food with no interruption. So they can actually complete a normal supermarket run, which they were never able to do. They are able to complete a shower in one setting without having to actually take a break, sit down, that they're too tired to lift their arms to wash their hair, things that we would never even consider as having an impact on our lives, but they just can't do, or not having to take naps during the afternoon, which means that they actually can hold jobs, full-time jobs, things like that, people who are able to go back to school, that they had to give up school.
There's a lot of tangible things, real-life things that improve their lives that we can't even start measuring in a clinical trial.
Mark, maybe I'll just add one other item. You asked it in the framing of thalassemia, but as Sarah said, this is a common thread across all of the diseases that we're pursuing. Fatigue itself is a misnomer in a way, because it's not how a layperson would think about fatigue. You can't sleep it off. This is a function of the chronic hemolysis that occurs and lowering of hemoglobin. For example, when you talk to sickle cell disease patients, as bad as vaso-occlusive crises can be, there are mechanisms that patients can do to accommodate and cope with it. There's nothing for fatigue. You hear oftentimes when you talk to a patient with sickle cell disease, that is very high on the list of attributes that they're looking for new therapeutic options.
Okay. So you touched on, sorry, you touched on the ENERGIZE, the fatigue benefit, but maybe ENERGIZE-T, that transfusion burden reduction that you were able to show. Can you put that in the context of Reblozyl and kind of the value proposition there from an efficacy perspective?
Right. So on the transfusion reduction side, so we've looked at different ways, the endpoint of measuring transfusion reduction. We did it slightly differently than with luspatercept. Our primary endpoint was a 50% reduction in any 12 week rolling interval, because of course, for a patient, the time ongoing is important. It's not like just a fixed time that matters, right? And we were able to show statistical significance there with an oral therapy. So this is something that if we can actually remove transfusions from a patient via an oral pill, it's not substituted by another clinic visit or another hospital visit to get treatment administered. So that's a huge value proposition on time gained for patients.
I think transfusion reduction by itself is really accepted as a clinical endpoint, but it goes again above and beyond that, because the fact that patients can then, with the time gained, do something else is very meaningful for people.
Okay. And then at ASH, in those presentations, you also disclosed a couple of cases of liver injury, maybe continued follow-up, as you've said at many other venues. Safety is an always evolving thing for any drug, even once it's marketed. Just maybe context of kind of what's been observed since and how the changes that you have made around liver monitoring are working in your ongoing trials.
Sure. So what Mark is referencing to is that at ASH, we had announced that we had observed a new event of hepatocellular injury in thalassemia patients. And we proactively proposed that as a warning and precaution for label. And it comes down to what we observed was within the first six months of treatment, transaminase rises, that when the drug was discontinued, patients returned back to normal. So our monitoring guidance that we are proposing in the label is indeed like monitor for transaminase increases or liver function abnormalities once a month for the first six months, because that was a time frame in which we observed this event. And then if you see an ALT increase of five times upper limit of normal or more, then just discontinue the drug and do your workup.
So that has been in guidance, that's been the guidance across our different programs as well. And so far, we haven't observed a change or like anything new. So we feel confident about the way we've described this event and the data. I think this also was already updated in the PKD label. So based on the thalassemia observation, we have made an update to the pyruvate kinase deficiency label and made a warning there based on what we observed on thalassemia.
And in that FDA, the review that the FDA did to ultimately lead to issuing that new label, can you maybe speak to what level of data they were looking at when they did that? Were they just looking at the Energize data? Did they go back to the PKD data to reanalyze that? Were they also provided with RISE UP data, which is obviously evolving?
Right. So the RISE UP study is the sickle cell disease phase III study, which is still blinded. The phase II component though is unblinded. So what we've submitted to the agency is all of our safety data as it is available. To your point, we continue to accrue more and more exposure with our ongoing programs. But right now, what we've submitted at the time is still relevant for today.
But yeah.
To be specific, was blinded data from RISE UP included in the submission for the label update?
You want to repeat it if you want.
The question is, is blinded data submitted into the review of safety information? Blinded data gets submitted in specific forms and specific reports that we are required to submit to global agencies across the board with the caveat that we are all blinded. There is part that can be reviewed in a blinded fashion.
Okay. And then maybe with that recommendation of liver monitoring that is now in the label for PKD and kind of what you're seeking to have in the label for thalassemia, just put that into the context of standard clinical care of a thalassemia patient and how it may or may not adjust what a physician actually would be doing.
So we were already monitoring on a monthly basis in our ongoing clinical trials. So we didn't change anything like that. The thing that we did do in our open label trials was align the monitoring frequency to once a month for the first six months. From a physician perspective, what we hear when we talk to physicians is that this is something independent of guidance that we would be giving, that that is something they would do no matter what, especially in the context of hemolytic anemia, starting new drugs. They are looking at the liver and kidney function along the way. So there was no concern from a physician's perspective on implementing this type of monitoring.
And so certainly for the clinical trial investigators, and if I could just mirror image, our commercial team, of course, has done appropriate research with people who ultimately, if given the opportunity, would be prescribing PYRUKYND for thalassemia. And the same is true that if they're onboarding a patient for a new treatment, you certainly in normal course of treatment, you would be checking regularly for hemoglobin changes, typical CBC lab values, and so on. And so we found that this is, I think what's reflected in the PKD label, monthly testing for the first six months is absolutely in the course of business that would be done. And again, that's true in thalassemia. That would be true as well in sickle cell disease.
Okay, and in that filing for thalassemia, what is the indication statement that you're kind of seeking?
So based on the clinical trial data that we have generated in which we were able to demonstrate benefits across the whole thalassemia patient population, independent of genotype or transfusion need, that's the indication statement we are seeking. So basically an indication that covers the whole thalassemia patient population.
Okay. And some investors that I've spoken with expressed a concern that maybe the FDA might only be willing to accept these liver injury events or potential liver injury events in the most severe thalassemia patients. And in their view, that might mean a restriction of the label to just kind of transfusion dependent patients. Obviously, that's not what you're seeking. What are your thoughts on that idea? And why do you think that would be an inappropriate review of the data?
So a couple of things. I think from a thalassemia perspective, this is a very bad disease with a lot of comorbidities. And so to carve out a more severe population versus a non-severe population will be tough to do because there is a lot of hidden, smoldering, ongoing comorbidities that people may not even be aware of that they have, or people who had it are better managed and it's like under control.
So there is like the whole spectrum of medical care here that is in interplay, which is why from our perspective, we have taken an approach to just warn the whole patient population, not focusing on specific risk factors of potential liver disease that are sometimes spoken about in the context of drug-induced liver injuries, but rather be holistic and monitor the whole patient population, which I think is the right thing to do, especially because patients who would not be treated in the context of their thalassemia, they will continue to develop comorbidities. They will ultimately get more and more organ damage, including liver disease over time because of untreated disease.
Commercially, this is probably more a Brian question, just how should investors think about pricing? Obviously, there's a price that's out there for PKD. There is Reblozyl for at least a portion of the population. Just how should you think about thalassemia pricing for people who get sickle cell?
I think in summary, we're really well positioned. I mean, we're going to have clarity once we get to the point of just building on the question you just asked, what does the ultimate label look like? And so we'll know the ultimate value. But the current price in PKD is $335,000 WAC per year. That's an ultra-rare disease. thalassemia is in the same neighborhood of rarity, although larger as an opportunity for us. And so we believe ultimately we're really well positioned. One other point I would just add is that in PKD, payers do not manage the category at all, and we would expect the same in thalassemia.
Okay. It will move to Sickle Cell. Sarah, you want to start out Sickle Cell discussion, just kind of reviewing what you think the highlights are of the data that you've produced, but maybe also speak more broadly of the PKR field within sickle cell disease.
Sure. We completed the phase II portion of the RISE UP study, which is our sickle cell disease clinical trial. In that trial, we were able to highlight that the two doses that we tested, which was 50 mg B.I.D . and 100 mg B .I.D. against placebo, were both positive, statistically significantly positive for a hemoglobin response. And then in the secondary endpoints, we were able to observe hemolytic parameters improvements, which was stronger in the 100 mg dose, which was part of why we chose the 100 mg dose. And we also observed the sickle cell pain crisis trend, which was a reduction in VOCs compared to placebo in both doses, but again, stronger on the 100 mg B .I.D. And the safety profile that we had observed was very, the drug was well tolerated. We had a huge patient number rolling over into their open label extension study.
So that was why we were able to select the 100 mg dose that we are now testing in phase III, which is the blinded trial. There we have two primary endpoints. One is a hemoglobin response again, which we're measuring from month six to 12, an average hemoglobin response. And that is important because that average will allow us to speak to the durability of the response. And then the second primary endpoint is a reduction in sickle cell pain crisis, which is an accepted clinical endpoint. But as we spoke about earlier, people are also highlighting how important fatigue is to them. So that is what we have in our secondary endpoints as well, so that we can, if we hit on one or both primary endpoints, we can move on to secondary endpoint testing.
And within that bucket, we have other ways of looking at how patients feel and function. Our goal is to deliver on all of those components because that would really then deliver for the first time a treatment for the totality of sickle cell d isease. Patients are really in dire need with everything that has happened in the recent months in the sickle cell disease field to hopefully have a good option.
And I'll just add, because you also asked, within the class, so if we look at PK activation and our positioning of PYRUKYND, mitapivat, and the data that we all had a chance to see from Tebapivat at ASH, the phase II data, these are of course different drugs, different studies, but I would say that we still have a lot of conviction with our best in class, first in class potential with PYRUKYND.
Sarah, you started to touch on kind of the statistical plan there that you can win on either primary endpoint and then go to the secondary. Just talk about the kind of alpha split. I mean, if you want to disclose the exact numbers, that would be great. But also just the broader kind of philosophical approach to how you've split that across the various ways to analyze the data.
So the two primary endpoints, so the hemoglobin response and the sickle cell pain crisis, we've created an alpha split on those, so 0.02, 0.03, in which if we hit on only one, then that associated alpha goes on to secondary endpoint testing. If we hit on both, it's 0.05 that moves on to secondary endpoint testing. We did that for multiple reasons. Like if you look at the sickle cell disease development landscape, it's tough development. So when you look at sickle cell pain crisis specifically, we wanted to make sure that we have an opportunity to go on to secondary endpoint testing if we would only show a trend on VOCs to be able to still speak to feel and function. We've taken a lot of logistical considerations into the trial as well to protect that endpoint as best as we can based on lessons learned from previous development.
Is FACIT-Fatigue the first of the secondary?
There's a bucket that is going to be tested as a secondary endpoint, of which PROMIS SF13a is the way we are going to look at fatigue, which is like FACIT-Fatigue. It's just opposite scoring.
Okay. And then when we get to that data, just how do you, so obviously ideally you'll show a statistical benefit on VOC and then the path forward is very, very clear. But if that isn't the case, if it is a trend, just how do you approach that kind of totality of the data across VOC, maybe a trend, maybe you've hit on fatigue, just what is a meaningful outcome in that scenario?
So there are many meaningful scenarios that I could potentially think of. So it will depend on the totality of the data, but ultimately we always have to put something in a framework of an unmet need, the benefit observed, risks observed, and other therapies available. So for sickle cell disease, I think there's a huge unmet need. I mean, this is a disease that kills people. Like each time somebody has a sickle cell pain crisis, they can die. And if they don't die, the life expectancy overall is still much younger than for any of us, just because of the comorbidities that they acquire in the context of the disease. So it's a horrible, horrible disease. The unmet need is huge.
On the benefit side, if we can speak to a drug that delivers on that field function in our survival the way a regulatory endpoint is defined, then there is really nothing else to compete against, right? If you look at the category of what else is available, well, the Oxbryta it got withdrawn from the market. Crizanlizumab only has shown benefit in one trial on sickle cell pain crisis specifically. So there's a huge part of the disease that is left with no treatment, the hemolytic anemia component, and hydroxyurea that is standard of care. Our drug is actually, it's possible to use it with or without hydroxyurea. Hydroxyurea has huge tolerability effects over time as well, plus a bunch of other issues. So there are, I can see many ways we can actually talk to data when it's there.
Okay. Another topic that comes up in my investor conversations about your story is a concern around the risk that there may be if people miss doses or when they come off, either within your trials in a formal way or needing to come off for other reasons commercially. There may be a VOC risk in that kind of immediate follow-up period. Just how is that captured in your trials and how do you expect the FDA to kind of approach this formal VOC endpoint within the kind of on-drug period versus maybe a short period afterwards where maybe if that theory is correct, there are some VOC events happening?
So within a clinical trial specifically, once a patient comes off drug, there is a safety follow-up period. Now in the phase two, the vast majority of people actually chose to continue in the clinical trials. So we don't have a huge data set, but from the data that we have, we have not observed that. We have not observed what we call the withdrawal VOCs, which is one of the terms that has been thrown out by people. If you think about a disease like this, you have to think about it like other diseases that have flares of things occurring to them. If you take a treatment, those flares will be reduced. If you stop taking it, at some point those flares are going to come back.
sickle cell disease is complex because those flares can come in the context of multiple triggers that a person may or may not do. So we are anticipating if a person stops taking the drug, that at some point the disease will manifest itself again because it's not a curative therapy. The data, like I said, the data so far has not suggested that if a VOC occurs, it's worse or more severe or different than a pattern that the patient previously experienced.
Okay. This is back to Brian, back to pricing. You talked about it in thalassemia, but maybe in sickle cell, if you're able to show this profile we were just talking about of hemoglobin plus, just how should we think about pricing relative to maybe the PKD and Thal?
I mean, let's smile when we talk about that scenario. That would be a real win for patients if we had the profile that Sarah just described that's hemoglobin plus and gives different pathways for value for them. Obviously, this is a larger volume patient category, and so it gives us optionality in terms of pricing. But how and exactly what that looks like, again, we're going to need to see the data. And then of course, at the moment of pricing decision, you also look contextually as to what else is available in the treatment milieu for the patient. And if anything, it's become more limited over the past few months. So again, I think we're in a real position of strength there as well.
Okay. And we're running up on time, but maybe quickly on tebapivat . So obviously there is the MDS trial that is going to complete enrollment hopefully by the end of the year, but you're also opening up now a sickle cell trial. Sarah, you want to talk to just how does this fit into sickle cell longer term relative to mitapivat?
Yeah, I can start and then I can build on. Yeah, go ahead.
This is a phase II that we're running in sickle cell disease and looking basically for hemoglobin again and like other parameters in that context of that disease. From our perspective, we always work very closely with commercial to deliver towards trial designs that can deliver to target product profiles that are considered meaningful into the patient population. Again, this is a disease that has room for many, many, many, many drugs.
Yeah, I think the ultimate way to think about this is we're looking to build a franchise, a meaningful franchise in sickle cell disease. And it's clear that multiple products is a winning formula, even within same class, that's the case. And our objective is to continue to expand the addressable market that's available for one of our PK activators.
Okay. And then I know we're really up on time, but you did discuss at the beginning the hire this morning, or that was publicly announced this morning at least. Just you want to talk through the BD strategy that's kind of behind that hire?
Yeah, I mean, for us, again, it's internal opportunities, organic as well as external. And last year, we actually bolstered the capability of our search and evaluation team because ultimately we want to make sure that we have a chance to look at everything that might fit in the Agios sweet spot. And here we've actually now added a new leader in that regard with Krishnan Viswanathan. So our sweet spot is now that we have a very strong rare disease spine of capabilities, assets that are rare for sure, have validated targets, clarity in regulatory pathway. We're very good, of course, at hemolytic anemias, but we're not tied to that as the only therapeutic option. Rare is really the umbrella that we cast in that regard. And anything that we do will, of course, come with a lot of assessment, diligence, scrubbing, and discipline.
But fairly early stage discovery like you did before with 10% or do you think there is a place in the pipeline for more things that are already maybe have some clinical data?
We don't constrain ourselves to a stage of development. I would say pragmatically, there's probably more that we get a chance to look at that's a little bit earlier stage where there might be a value creating opportunity, but we don't bound ourselves in that regard.
Okay. Unfortunately, it's all the time, so we're going to have to cut it off there.
Thanks a lot.
Thanks a lot.
Thank you very much, Mark. Thank you, everyone.