Agios Pharmaceuticals, Inc. (AGIO) Earnings Call Transcript & Summary

Everyone, thanks for joining the session with Agios Pharmaceuticals, and welcome to the first session of Day 2 of the 2025 Bank of America Healthcare Conference. My name is Alex Stranahan. I'm senior biotech analyst covering Agios at Bank of America. I'm pleased to be joined today by Brian Goff, Chief Executive Officer; and Sarah Gheuens, Chief Medical Officer at Agios. Thanks for being here, guys.

Thanks a lot. It's great to be back with you again. I can't believe it's just been a year.

I know. It feels like we've had a year's worth of news and 4 months already.

Yes.

So it will be interesting to see what the second half has in store. But Brian, maybe just we can start off Agios, what's going on at the company, what are the main focus areas for you guys? And what's sort of the second half outlook in terms of things to be...

Yes, happy to. And again, thanks for hosting us, and thanks a lot to everybody who has joined us to hear the Agios story. It's a really exciting time. And if you're new to Agios, I'll just start by saying our mission is to develop and deliver medicines that have transformative potential for patients who are living with rare diseases. And the real focus of that effort are rare diseases that involve the destruction or the dysfunction of red blood cells, namely pyruvate kinase deficiency or PKD, thalassemia, sickle cell disease and low-risk MDS. And the real highlight of our pipeline is a product called PYRUKYND or mitapivat. And mitapivat involves a very novel mechanism of action, targeted towards improving the metabolism of red blood cells, which ultimately leads to more energy available and a healthier cell. And PYRUKYND is currently commercialized for PKD, there again, pyruvate kinase deficiency, but we are pursuing indications in thalassemia and sickle cell disease. And I'm sure we'll have a great discussion about those pursuits today. We had a really transformative year in 2024. And that's why I can imagine how fast this year has gone by, and how much we've accomplished. Last year, we were delighted to announce the results of 2 pivotal Phase III studies for thalassemia. They're known as ENERGIZE and ENERGIZE-T, and we delivered statistical significance on all of the primary and all key secondary endpoints. That put us in a great position where, December of last year, we announced that we had simultaneously filed for regulatory approval in 4 different markets in the U.S., in Europe and in the Gulf, in both Saudi Arabia and United Arab Emirates. And then we had a great start to this year, where we announced in January that the FDA had accepted our application and granted a PDUFA goal date of September 7 of this year, which, as a side note, is less than 4 months away now. So we're very excited about that opportunity. Our commercial team has really geared up, and I would say at this point, is fully ready for this exciting launch opportunity of PYRUKYND thalassemia. And then the other big event from last year is focuses on sickle cell disease. And in October, we were really pleased to announce that we had fully enrolled our RISE UP Phase III study in sickle cell disease. It's a 52-week study. So fast forward, that's another really important catalyst for us. Later this year, we expect to read out that data by year-end. The other thing I'll just mention that happened last year is we significantly strengthened our balance sheet. And we're in a great position, particularly in this macroeconomic environment. We ended the first quarter of this year with approximately $1.4 billion on the balance sheet. So it's been a great year. And Sarah and I would be delighted to talk about all of that progress and more. The last 2 things I'll just say is, again, on the balance sheet perspective, in this environment, we really think we're in a position of strength, and we see the strength of our balance sheet as an opportunity for us to remain disciplined in capital allocation but really create significant value for shareholders, most important of which is our journey to build a multibillion-dollar franchise with PYRUKYND. And then 1 point of pride for the organization is we talk a lot internally about being fueled by connections. That really means that we stay very close to the patient communities. We're very passionate about the work that we're doing. And I think, frankly, that's contributed to our performance, and it also certainly fuels the culture internally at Agios. So plenty more to say, but I'll stop there and would welcome your questions.

Okay. Fantastic. So definitely several irons in the fire. Maybe first, we can talk about thalassemia.

Sure.

PDUFA date, September 7, like you said, everything is still on track here, or any feedback from the agency you received on timing?

Yes. I'll let Sarah start on that one. It's been so far a good journey.

So far so good. It feels like a very normal procedure for us with questions coming in and us providing the answers. Yes, our PDUFA date is September 7, so we're very anchored to that date and very excited about that getting closer.

And we -- maybe I'll just add, too, that 1 of the updates that we offered on our earnings call is the first quarter of the year, our messaging was that the FDA has been silent. We haven't heard anything with respect to an advisory committee. The update we provided a couple of weeks ago is the FDA has now communicated that at this time, they're not planning an advisory committee, but of course, the review is ongoing for thalassemia.

I guess given that this would be maybe potentially the first broad approval across thalassemia subtypes, was an ADCOM maybe expected, or was that kind of factored into your view thought process?

We did not expect an ADCOM or had a wish for ADCOM, honestly. I think the story, and Brian highlighted it, yes, it's the first indication for a broad population of thalassemia that was submitted. But the clinical trial data is clear, right? We have on the efficacy side, a very clear and clean story with statistical significance on all primary and key secondary endpoints across the 2 trials, the subgroup analysis highlighted that everybody stands to potentially respond to the drug. So from that side, it's a pretty straightforward story. And then on the safety side as well, we have a clear safety profile as you know we've updated our safety profile with hepatocellular injury. But that as well is an event that you can monitor for, and then it's manageable because you discontinue the drug. So the labeling language that we've proposed around that is also clear and the benefit risk profile, therefore, in the overall thalassemia population is, from our perspective, favorable. So in that context, I think in ADCOM, I don't know, it seems like a lot.

Yes. And especially having the approval in PKD certainly helps.

Yes. I mean this is an sNDA, and we have now even commercialization-wise, 3 years plus of experience with PYRUKYND in pyruvate kinase deficiency and multiple late-stage trials across multiple hemolytic anemias. So we really feel like we're in a position of strength.

Okay. Very good. And I appreciate this is dynamic and flux almost daily, but any high-level thoughts on FDA staffing, ability to meet approval deadlines. We haven't seen too many miss. It maybe 1 or 2, but those could be one-offs. And I know that [indiscernible] had rated that. They feel that they're fully staffed. I don't think they've let any of the reviewers really go in the transition. But any changes or color on your recent interactions you can share?

No, not that we have noticed. I think really from our perspective, feels like a normal procedure with back and forth across the whole spectrum of the filing. So there is not a topic that seems to be forgotten or neglected. So from our perspective, it feels really like a business as usual. And so therefore, we are continuing with that same mindset and are very much looking forward to September 7.

Yes. And maybe I'll just add, we're talking about FDA right now, understandably. But again, we filed in 4 markets simultaneously. And you could add the same sentence to all of those regulatory engagements. They've all continued at pace and as expected. And again, we're just really excited about having the chance for not just 1 -- having approval for 1 segment of thalassemia, but this is a high unmet need population with very limited choices. And so what we're pursuing is alpha thalassemia as well as beta-thalassemia and both nontransfusion-dependent and transfusion-dependent, all subtypes.

And that's across all the geography?

Yes.

Yes

Maybe on that point, Brian, just remind us of your plans for the ex-U.S. launch when these approvals could come? How you're balancing, driving successful launches, international expansion, retaining economics?

Yes, it's a little tough to say when the approvals will come. But as I say, we're at pace and very encouraged by the progress that we're making. With respect to different geographies around the world, we're really clear on the priorities, particularly for thalassemia. It's -- U.S. is our #1 priority. And then outside the U.S., the clear #2 is Saudi Arabia, and you could even say the Gulf region proper. And last year, we announced a partnership that we put in place with you could think of a full-service distributor by the name of New Bridge to help with the commercialization in the Gulf. And the reason we did that is this goes back to capital allocation efficiency. It would take quite an effort for us, Agios, to scale up to capture the potential that exists. So we sought out in a very competitive process, a partner who knows the region very well, is already scaled up and ready to go, and we have that in place. Looking beyond the Middle East, then Europe as an example, we expect to pursue with the same option where we're not planning on going direct. We would look for and are having engaged discussions now on partnerships again to make sure that we protect our priorities of direct to U.S. partnership ex-U.S.

Yes. And that's probably the right balance, right, in terms of, if he were to go alone, you would be maybe sacrificing the volume side, you'd have to build out the capabilities. It's a big investment. So you maybe come out ahead through that kind...

It's very clear to us that for quite a distance, next dollar invested will have a better return in the U.S. through direct investment than versus the partnerships outside the U.S.

Very good. And I guess for the FCC countries, is expansion or, I guess, approval here dependent on getting that U.S. approval? Is there any linking between these different geographies.

Sarah can speak to that. One thing I'll just say is that we did get -- and it's very new, but we got breakthrough designation in Saudi Arabia. So that's part of the backdrop, but...

Yes, exactly. So it's because of that, that we are able to file like as a new entity there directly to the SFDA. So this was a new procedure. And so we are going through that new procedure, but it feels also very much like -- it's almost like in between the European and the U.S. procedures. That's what it feels like for the team. So we're getting questions answering them deadlines, prespecified deadlines and everything is just moving along there as well.

And we haven't talked about so far, but just to put some numbers on this, in the U.S. for thalassemia, we're talking about 6,000 adult patients in Saudi Arabia and the Middle East. We're talking about 70,000. And on a per capita basis, the prevalence is roughly 8 to 9x greater than the U.S. So there is a lot of focus by the regulators, by the Ministry of Health on this particular disease, which we're proud to be a part of.

Makes sense. We touched on briefly kind of the overlap with having the approval already in for PKD. You have a sales force for PKD. There's always been some label updates to that PKD label. Maybe walk us through sort of where you stand on the sales force, if you could leverage that also for a thalassemia launch? And then whether you think all sort of the the known profile of mitapivat is kind of reflected on the label today?

Yes, I'll let -- I'll speak first about how we've set up our commercialization model, and then Sarah can comment on the label update, which is really important, and we were quite pleased to have early this year. As you noted -- so we launched in PKD in February of 2022, and it was a rather small team. This is an ultrarare disease. So for sales folks, they are about 20. And there's more than that because what's important about rare disease commercialization is not just frontline salespeople, but patient services, clinical nurse educators, there's a whole support team, but to dimensionalize it, about 20 for PKD and for thalassemia, and we waited until we saw this great data last year to make this change, but we scaled up to about 40 for thalassemia, salespeople. That is fully recruited, fully trained and what the team is focused on right now are really 2 different things in preparation for launch. First, very importantly, is disease state education. This is a disease where there have been very limited choices, and what tends to happen classically in a rare disease like that is the sense of urgency is more diminished. So we're really putting emphasis on the fact that non-transfusion-dependent thalassemia patients, for example, are not less at risk. They might be more at risk because they're undertreated, and they're suffering from chronic daily hemolysis, where the patient may pay a price down the road. So disease state education is 1 part, and the other is account profiling. So we have a really good map through a claims database analysis and interaction with these different sites of care to know where we want to prioritize our efforts. So we are fully ready to go. And again, right now, we're just waiting for the PDUFA date. But from a label perspective, maybe Sarah can talk about that update.

Yes. So the hepatocellular injury that we observed in thalassemia, we -- that warning and precaution language that we have proposed is in the PKD label. So it describes what we have seen in thalassemia. So it says in patients with other condition being thalassemia because it's not a labeled condition to date for PYRUKYND. And then it basically describes the events that we've observed and then what physicians should be on the lookout for, a very straightforward language there. And from our perspective, when that was implemented in the PKD label or maybe you should actually speak to that about the -- we see continued demand for pyruvate kinase deficiency patients basically.

Yes. We -- I've really talked to a lot of investors who have done their own market checks and have talked to clinicians who have treated either PKD patients or thalassemia or sickle cell disease. And the general consensus that we certainly see this ourselves is that testing on a monthly basis when you're onboarding a patient to a new treatment for a hemolytic anemia is standard of care. And so it's been a kind of non-event and in our labeling recommendations, our recommendation to the FDA, which they align with is test everybody. Don't try to be too fancy about certain subsegments because that's, again, the normal course of treatment. And in this last earnings update, we were really pleased to be able to show that PKD continues to be a very slow ramp because it's ultra ultra rare, but we actually had increase in patient demand with the backdrop of this label change. So we felt very comfortable in that regard that both patients and clinicians have certainly accepted this just fine.

Okay, okay. Makes sense. Maybe shifting gears now to sickle cell. You've got data update in 4Q. Maybe walk us through the trial design, sort of the powering assumptions on the 2 primary endpoints, which it sounds like if either one is met, that could maybe be a path forward for submission for approval. But maybe just walk us through sort of the design and thought process there.

Sure. So it's the RISE UP trial. It's an ongoing Phase III placebo-controlled randomized trial for patients with sickle cell disease. And what we're trying to do with this trial is highlight that mitapivat can potentially provide benefit for the totality of the disease because sickle cell disease is a very complex disease, but is really -- the features are hemolytic anemia on one end and then vaso-occlusion on the other end. So the trial is designed in such a way that we could speak to both of those components of the disease. So we have 2 primary endpoints. So the 1 primary endpoint, hemoglobin response is tackling that hemolytic anemia component and then analyzed rate of sickle cell pain crises is tackling the vaso-occlusion component of the disease. And so there is an alpha split on those 2 end points. And that allows us then, if 1 or both are positive to transfer alpha to secondary endpoint testing, which has other ways of looking at how patients feel, which is important from a regulatory perspective that you demonstrate that people feel and/or function or survive better. So that is actually then in that bucket, we're looking at how patients feel via fatigue. So we're with this drug, just like what we've done for thalassemia and pyruvate kinase deficiency, trying to highlight that when you have that improvement in hemoglobin, improvement in hemolytic anemia, people also feel better, feel less fatigue. That less -- that fatigue component, I mean, people are very focused on vaso-occlusion in the context of sickle cell disease because it's a dramatic event, right? It's very -- it's horrific, it's painful, people can die in the context of having an episode like that. But what patients -- when you talk to patients, when they highlight that the fatigue is extremely devastating for them as part of their disease and that there's not really anything they can do about it. So that's what we are trying to highlight with this trial design that we can tackle all of these components of the disease. Of course, on the hemolytic anemia side, we are building upon the evidence that we have generated for thalassemia and for pyruvate kinase deficiency, vaso-occlusion, that's purely in sickle cell disease, a component that is important. And that will build that evidence or why we think we have a possibility to actually highlight benefit there is build upon our -- mechanistically on a lot of preclinical work, but then also on some of our investigator-sponsored trials in which we have followed sickle cell disease patients. But then most importantly, our own Phase II, which was another blind randomized controlled trial in which we were able to select the dose for Phase III, but also saw when we were testing 50 milligrams BID and 100 milligrams BID against placebo that there was this trend on improvement on vaso-occlusion, which was 70% in the 100-milligram BID dose reduction. So therefore, we are excited about our Phase III. We're very much looking forward to the end of the year, and we're hoping that the cards will turn favorably.

I'd like -- if I could, just to add 1 point to a big picture about sickle cell disease is that sometimes what gets lost in these discussions is, this is a lethal disease. This is where the lifespan of someone with sickle cell disease is in the 40s, which is shocking to say out loud and shocking to hear, but what it tells us is, one, all of these endpoints matter, and we feel really good about the careful and thoughtful design that we've put into our RISE UP trial. Two is, there is room for and the need for multiple different types of drugs and treatment options. And frankly, that's 1 of the motivators that we've had with having mitapivat, where we're talking right now about the RISE UP trial, but we also announced recently that we'll be starting mid this year with our other PK activator Tebapivat, a RISE UP Phase II like trial for sickle cell disease. And the reason is, we want patients to have optionality. And we're looking to build a lasting franchise, but we know there's no 1 drug that everybody responds to. And so that's really the backdrop of our strategy. But it's also a mindset of how to think about quote competition in this space. There is room for plenty.

Yes. Okay. Maybe we can double-click on that point, Brian. How do you see Tebapivat. We've gotten questions like why start the study when we haven't seen the mitapivat data like -- I mean, the timing component is whatever, it's like when it's ready to go, like let's get it to patients, but how do you see these as maybe coexisting? And is there any mechanistic rationale why one would work better in a certain patient and...

Well, there are plenty of examples. I mean, really compelling examples across the industry, particularly in rare diseases, where there are multiple drugs even more than 2 within the same therapeutic application, same disease. And so to answer your question, what we're doing is putting our foot forward now on Phase II for Tebapivat, but we know we will learn a lot as we go forward. By year-end, we'll get the readout of the RISE UP Tebapivat Phase III data. At a point, we will learn the results of the Tebapivat Phase II data. And of course, there are other -- there's another PK activator Tebapivat in development as well, that we expected a certain point to learn what that profile looks like and other modalities, and we'll make smart efficient decisions about how to allocate our capital, and how to further develop Tebapivat accordingly. But again, there's a lot on the table. There is so much unmet need, and we have enough runway in front of us to be able to design the trial post Phase II for Tebapivat according to what the highest needs are.

Okay. Maybe we can talk about how you guys are thinking about the competitive landscape. We've had some withdrawals. We've got cell therapy, gene therapy, options coming up the pipe more recently approved. How do you see mitapivat and maybe sort of slotting into the evolving treatment paradigm?

This is oral therapy as a starting point, which makes it very accessible for ideally a broad population. And also ideally beyond the borders of the U.S. as we have geographic expansion. I think to have gene therapy available, if you're a patient that is really exciting hope, but from a pragmatic perspective is on a whole different side of the spectrum in terms of availability and ease of onboarding and the conditioning that comes with it and so on. But I think it creates a really important inspiration. And from our view, too, the more different types of companies that are investing in sickle cell disease, the better because everybody will educate -- invest in education around the world on the unmet need, how patients need to be given different therapeutic options. And I think we're just exceptionally well positioned pending our data, not just for PYRUKYND, but again, also to build this real lasting franchise.

Okay. Makes sense. And you guys put out a press release this morning highlighting our EHA presentations next month. Maybe walk us through sort of the scope of what we should expect. I think there was maybe a couple on sickle cell as well.

[indiscernible] again a really great presence at a conference. So the team has done an amazing job, and we're very pleased because we have a couple of oral presentations that are -- either our collaborators are ourselves that have data that will be presented. We're very proud of our pediatric PKD data. So we had a data announcement on the regularly transfused pediatric pyruvate kinase deficiency patients a while ago [indiscernible]. But we were able to submit that to EHA, and it's going to be presented there. What we have there is -- and a couple of children became transfusion free, which, of course, is very meaningful for those specific patients to be -- when you're dependent on transfusions and then you don't need them anymore. That's very clinically meaningful. So we're very, very happy that, that data will get a spotlight. And then we have one of the investigator-sponsored trials that I mentioned earlier for sickle cell disease, we'll be presenting data as well estimate. So that's a trial that is run in the Netherlands by Dr. [ Hamber, ] so that data will be presented. And then we have also some work -- preclinical work in MDS patients, highlighting that PKM2 is reduced in MDS, which, of course, is important for our mechanism of action. So we have a very nice spread of early mechanistic work to clinical data and pivotal trials that is going to be presented, so we can't wait to be there.

And this is like EHA and ASH. These are our Super Bowls. And so we're really pleased to have 14 different abstracts at EHA and a lot to share across our entire pipeline.

Wuhan is a little bit better than Orlando.

Sure.

Brian, maybe circling back just in the last minute or 2 that we have $1.4 billion in cash is a great position to work from. Is there a scenario where you get approval on [indiscernible], the launch is going well. Sickle cell looks like it could be approvable as well, that this cash balance could actually carry you through to profitability. Like what's sort of the runway here? And how are you thinking about capital allocation over the next few months?

Well, I love that scenario. If we're going to close down here, that's a good way to start. Yes, I think, first of all, $1.4 billion, we know that, that is a very unique position to be in, in this macroeconomic environment. We don't take that lightly. We're very serious about efficient capital allocation, very disciplined our priorities are clear. And you mentioned the first one, which is get the launches right, create maximum value. Our ambition is a multibillion-dollar potential for this PYRUKYND franchise. Number 2 is, we do have a kind of middle part of our pipeline. We talked about Tebapivat little bit that we're looking to advance as well, and that would be our second priority. And third is expand the pipeline, and that can come in 2 different directions, internal organic opportunities, which we constantly pursue. Sarah's team does a great job from a translational perspective and research. We also are, of course, looking externally -- and in fact, we recently added a key member of our team, [ Krishan Viswanadan, ] who's tasked with business development, corporate strategy, just to make sure that we're constantly assessing the landscape externally. And that just positions us really well as a company to be sustainable and continue to grow and deliver value for shareholders.

Fantastic. Well, with that, I think we're right at time. So please join me in thanking Brian and Sarah for the great conversation. And thanks for being here at the conference.

Thanks a lot, Alec. Thanks, everyone.