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

Great. Good morning, everybody. Thanks for joining us for Day 2. I'm Matthew Harrison in Investment Banking at Morgan Stanley. Very pleased to have Agios with us for the next session. Just quickly before we get started, I have to read disclosure statement. Please note that important research disclosures can be found at morganstanley.com/researchdisclosures. Really pleased to have Brian and Sarah with us this morning. Brian, let you introduce yourselves, and then we can jump into it.

Sure. Thanks a lot, Matthew, and thanks, everybody, for listening in. I'm Brian Goff, I'm the CEO of Agios and I joined in the middle of last year, 2022.

Hi, everyone. I'm Sarah Gheuens. I'm the Head of R&D and Chief Medical Officer, and I joined Agios in the end of 2019.

Super. So Brian, maybe I thought we could just start off with -- you've been here about a year. Company's made a lot of progress. Maybe you could just reflect on how it's gone and what you're looking forward to?

Yes, sure. Thanks a lot. Well, it has been a great year for us. I would say that Agios on all fronts, all facets of the company has really executed beautifully and I'm very proud of what the team has accomplished. We have meaningfully advanced our late-stage pipeline, and I'm sure we'll have a chance to talk about that this morning. We also continue to make progress with our launch of PYRUKYND for adult patients with PKD, pyruvate kinase deficiency. And also, over the past year, we have generated very consistent data across all of the diseases that we're pursuing and I would say, looking ahead, that gives us even more conviction about the probability of success that we have across a number of different diseases. We also have continued to expand our pipeline. In fact, on our last quarterly call, we announced that we've added just a gem of an asset that we acquired through licensure from Alnylam, and this is to target a rare blood condition called polycythemia vera. And it's early stage, but we're really excited about that potential as well. So when I think about the year, I think we're just building momentum and very set up for delivering on our continued commitment to generate long-term value creation. So while I'm proud of what we've accomplished, I'm even more excited about what's to come.

And then just given the recent deal with Alnylam, can you comment a little bit on how you see the breadth of the pipeline? Do you think there's more work to be done from the BD side or you feel like you have a full pipeline and now you just want to execute on what you've got?

That's a good one. We definitely have a lot going on. We have already a diverse pipeline covering PYRUKYND, our flagship, PK activator. We have another PK activator, AG-946, which we're pursuing for low-risk MDS. As I noted, we've added the Alnylam asset now for polycythemia vera. And we have another Agios-generated product or compound, which we're pursuing for PKU, phenylketonuria, where our goal is to have IND for that by the end of the year. So we have a lot going on. But I would say as a healthy biopharmaceutical company, our foot is never off the gas in terms of looking at how we can continue to build and diversify the pipeline, but we will obviously do that in a very disciplined way.

And then just one other question before we maybe move into sickle cells, just around capital allocation more broadly. I think a lot of people they see you have a very large cash balance. Obviously, given all of the pipeline priorities, right, you need to fund those, but how should people think about cash balance and capital allocation?

Yes. I mean the facts behind where we stand now is as of the second quarter, we reported about $950 million on our balance sheet. So we see that as a clear position of strength, certainly in this arena. That said, we're very, very disciplined about how we utilize that cash. We have a number of Phase III programs. I noted that we have a late-stage pipeline. So we have 5 different Phase III programs underway right now, 2 for PKD pediatrics. We have 2 for thalassemia. And now we're very pleased to be advancing into Phase III for sickle cell disease. So no shortage of internal investments to be made from a capital allocation standpoint. But as I said, we're always working very carefully and in a disciplined way for BD as long as it creates value for the long term.

Okay. Super, super. Why don't we start in sickle cell because I think that's the most recent update. I guess maybe before we go into the data, I think it would be helpful to just get your view. Obviously, there's been a lot of advancement of different kinds of mechanisms in sickle cell disease. So could you just sort of outline for everybody how you view the market and where you think their unmet needs or how you're trying to position your assets?

Yes. I mean this is an area that is just right for therapeutic disruption. And frankly, as you say, there are a number of different modalities that are being pursued. We, as a company, entirely focused on rare diseases and very passionate about the patient journeys that people go through each year for everyone. We think that this is an area where multiple modalities will be the answer key, not a single approach. So that said, what we have with PK activation is, we believe, a very different way of addressing the needs of the red cell in the sickle cell disease patients. And we're talking about in the U.S. about 100,000 patients. But of course, globally, it's a much, much larger population than that. If we're successful, we often use the phrase hemoglobin plus as the end goal for us. So what we're looking to achieve is not just improvements in hemoglobin and markers of hemolysis, but also vaso-occlusive crises and ideally feel and function through a PRO measure, how patients feel. So it's really a totality approach. And again, I think where sickle cell disease is right now, having this option if we're successful as a small molecule, an oral pill will be really advantageous for patients if we can deliver on that.

Okay. Super. Sarah, maybe let's just talk through -- remind people sort of the headline from the data and when we might see the full presentation for all the details.

Sure. So the RISE UP study is an operationally seamless design. So we've completed the Phase II right now, unblinded, and those patients are continuing to an open-label extension. And in that study, we were able to highlight that there was an improved hemoglobin response in both mitapivat's dose arms against placebo. And in addition, improvement in hemolysis and erythropoiesis. And then we also were very pleased to see a reduction in sickle cell pain crisis in that population. So if you compare the dose to placebo in the 100 milligram, we saw about a 70% reduction in sickle cell pain crises. And so we, of course, have submitted that data to a big medical conference to ASH. We are waiting to hear from them, and then we will present all of the full details on that aspect. We're very excited because what Brian was speaking to around sickle cell disease where we're trying to really target 2 components of the disease, vaso-occlusion and hemolytic anemia. The Stage 2 data package really supports that, that is a possibility. And supports us moving forward into Phase III.

And obviously, Phase II wasn't powered on vaso-occlusive crisis. Can you just remind people, a, your view on the regulatory endpoint for Phase III for approval and then how you're powered on vaso-occlusive crisis?

Right. So the endpoint of sickle cell pain crisis is considered a clinically meaningful endpoint. So from an FDA perspective, endpoints that are targeting how patients feel and function and or survive are the bar that you need to meet. So there's no question that, that is one of those endpoints that meets one of those categories. And so in regards to the power assumptions we have made, we were targeting to reduce by one sickle cell pain crisis in the course of the overall program. And the Phase II data actually supports that, that is something that we can observe and move forward to Phase III. And so that is where we have not made any changes to our Phase III program based on the Phase II data observed.

Okay. Okay. Great. And maybe just to talk a little bit more about the various aspects. So obviously, there are cell therapies. There are other -- there are CRISPR programs, et cetera, which are probably targeted at one end of the spectrum of patients. There have been recently some oral drugs launched. They've had, I think, probably most investors would call it moderate success in the marketplace. So maybe you could just talk about why you think they've had some moderate success in the marketplace and what you think your profile can deliver in terms of maybe actually being able to realize the large potential patient population?

Yes. Maybe I'll start, and then Sarah can fill in here, too. The -- it's very clear that the patient community needs different options. And again, when we think about the opportunity for an oral small molecule that addresses all the dimensions that Sarah discussed and for feel and function and for safety profile, if it's the type of treatment, which we believe we have, where the patients can continue taking the product long term that's potentially a game changer. I think sometimes the investor community is a little too tough on the previous launches, Oxbryta as an example because when we look at the Oxbryta launch, this happened during the COVID era, and they were adding a meaningful number of patients every quarter. The issue is that tolerability has been a challenge for some of those patients. And so you don't get the same continuity quarter-over-quarter with a growing population. We think what we have with PYRUKYND, mitapivat could be a very different situation. And again, if we can deliver on hemoglobin and the fatigue elements that come with that -- and by the way, as a side note, when we talk to patient communities, what they often say is vaso-occlusive crisis are horrible. However, there are treatments. There are things that can be done. They can be managed through that. Hopefully, fatigue is something the patient can never actually overcome. You can't adjust to live life with fatigue. So with that as 1 key dimension, and then, again, adding a benefit in vaso-occlusive crises and feel and function that together, we think, against any other modality will be highly differentiated.

And maybe just to clarify, right, I mean, it sounds like duration of therapy you think is what could lead to sort of that stacking approach you haven't seen. Is that what you're trying to say?

Yes. And I'll bridge to the launch that we have underway right now with PYRUKYND for adult patients with pyruvate kinase deficiency. A different disease in the sense that this is on the ultra-rare side of the equation. And so we're -- we started that launch journey early last year, and we're making progress. One of the most encouraging things that we see is that the persistency of patients on PYRUKYND has really been a delight. It's been, if anything, better than what we would have expected from the clinical trials. And we use that as potentially a proxy or how patients in the case of sickle cell might respond and stay with therapy and even nearer term, our pursuits in thalassemia, which is potentially our first launch coming next in 2025.

So why don't we come back to that because I think there's some questions we can ask about the launch, but you talked about thalassemia and how you think it's not talked about enough. So why don't we start on thalassemia. Obviously, you're going after beta but also alpha. Maybe just talk to people a little bit about the program, I think people are familiar with beta more than they are with alpha.

Do you want to take that one, Sarah, sir?

Yes, indeed. So we have alpha thalassemia in our program as well, which is unique because other drugs have been developed for beta thalassemia. Alpha thalassemia, however, is also hemolytic anemia with severe comorbidities and early mortality just as non-transfusion dependent beta thalassemia was underestimated how severe this disease was. And so now it's much more appreciated that there is a lot of end organ damage in those diseases still leading to shorter life. And that is because even if you don't get transfusion, there is a dis-regulation iron metabolism across the board, and that leads to iron overload in different organs. And then the fact that you have chronic hemolysis adds to the damage as well. And so we -- because of the mechanism of action and really we talked about focusing on that last step of the glycolytic pathway, there is an opportunity to target that across those different genotypes. And so that is what we are currently studying in our programs. And so we have 2 trials, 1 that is focused on nonregularly transfused patients and another one that is focused on regularly transfused patients, so that we can look at the improvement on hemolytic anemia across the spectrum of the disease. So across the spectrum of the disease, meaning all transfusion burden and all genotypes.

And just from a study standpoint and a regulatory standpoint, do you have to split out the alpha and beta patients? Or is it -- or are you considering that all as one group from a study?

So from the primary end point, we look at it as one group. But of course, this is a prespecified subgroup analysis.

And then maybe just remind people in terms of the market sizes, how to think about alpha versus beta and especially U.S. versus non-U.S.

Yes, it's an interesting question. This thalassemia itself is pretty fascinating in the global distribution. So if we define the traditional markets, U.S., EU5, we're talking about 18,000 to 23,000 patients. But the interesting part is for beta thalassemia, in particular, the Mediterranean belt is disproportionately prevalent. In fact, we often talk about the Gulf countries GCC, where the total population is 70,000 roughly. And so that's on a per capita basis 50x more common, more prevalent than in the U.S. In fact, so much so that it's not even thought of as a rare disease. So as we look at how we want to commercialize, we've been very public about the fact that we're carefully assessing potential partners who could help us supplement the footprint beyond what we believe we can focus on it should be the U.S. and in particular, the Gulf. And then if we look at Asia, where alpha-thalassemia is quite prevalent, that's another opportunity as well. It's a very unique globally distributed disease, at least relative to the experience that I've had in the past.

And how should people think about -- because I think one of the things people always think is, okay, well, small number -- or relative to the total size of population, a small number of patients in the U.S., pricing outside the U.S. is lower. So therefore, the market opportunity is modest. Can you help people dimensionalize market opportunity?

Yes. I think the -- so the scale of this disease globally means that we will have an opportunity to stratify pricing and all the economic dynamics alike. The overall opportunity we talked about PKD plus thalassemia is more than $1 billion. And then in terms of the specifics of that, of course, once we see the data, which is coming soon, I'll just note that these Phase III trials, we're expecting readouts for the nontransfusion-dependent patients first half of next year, transfusion-depended patients second half of next year. Once we get clarity on that data, of course, that will guide us on pricing dynamics.

Yes. And thanks for mentioning the time line. I think one of the other questions people always want to have some sense of is what's the bar for success in these studies, whether it's regulatory success or commercial success, maybe are the same or different?

Well, I think it's always all of those because they're sequential. But we'll say regulatory, I think Sarah and the team has done a fabulous job with deep expertise in what we do well, which is diseases focused on the red blood cell, designing a study that we believe is well positioned to not only achieve regulatory success, but be meaningful for patients. Then of course, there's the commercial dynamics. Ultimately, the way we think about it is we're not successful unless patients have access. And so that's where one of the other, I'll call it additions to the team that was made early this year was Tsveta Milanova, who I worked with at Alexion, where she was the Head of the U.S. She's joined us as our Chief Commercial Officer. And one of the major areas of focus for Sarah will be making sure that we have line of sight to access across all of our diseases.

Great. Great. And then maybe just lastly before we move on to PKD. There are obviously other PKR activators. Novo probably is the one most people know about. Can you just talk a little bit about how you view potential differences or differentiation between your drug and some of the competition?

We've seen fairly limited data, in fact, very limited up until the point of acquisition by Novo of Forma. And so since then, it's been quite muted. So I would say that what we feel great about is that we're -- we've seen consistency in data with mitapivat PYRUKYND across all the diseases that we're studying. And so far, you could add up now PKD, pyruvate kinase deficiency. We've talked about thalassemia, where last year our Phase II program was published in Lancet. We're now imminently getting our Phase III data and sickle cell, as Sarah noted, I think, to the delight of everyone who's paying attention to what we've done. That was a very compelling readout, the Phase II study. So if nothing else, the consistency of data that we have is, we think, a very important differentiator. Beyond that, we really have to see what their data looks like. It is a similar mechanism but we think that our pursuits therapeutically in a very wide array will be differentiating enough. I will also note that as I said, upfront with our pipeline, not only do we have PYRUKYND-mitapivat, we have another PK activator known as AG-946, and that's the one that we're pursuing for low-risk MDS. Anything you want to add, Sarah?

Well, I think you highlighted it. It's -- our PK activator has now been studied in 3 hemolytic anemias and for a long period of time. So the amount of safety exposure that has been built up across the board with this compound is significant, and we're very proud to have the first placebo-controlled randomized data set in sickle cell disease.

Great. Great. Brian, you touched a little bit on PKD. Maybe just talk to people a little bit about how the launch has been going, how people should think about metrics with the launch? And what your -- how you're thinking about success in terms of the launch?

Yes. I think -- well, I'll take your last question first. Success to us is continue to make progress with this launch. It will be slow and steady. It is for sure on the ultra-rare side of the equation. Again, for the U.S. and EU5, we talk about 4,000 to 8,000 patients, but that's an estimate because we are the first ever in the 60 years that PKD has been known as a disease to actually offer the first ever therapeutic offering that's approved that is also disease modifying. So we are carving that path and slow and steady progress, we would see a success, but also building capabilities that prepare us for these meaningfully larger launches to come like thalassemia and sickle cell disease. Where we are right now in the launch is we reported in the second quarter that we have 99 net patients on therapy. And again, this is since the first part of last year. We have 147 so-called PEFs, which are prescription enrollment forms. And this is the starting point before a patient actually moves on the therapy. And an interesting point is of that, there are 130 unique prescribers that have actually prescribed PYRUKYND. So if you just take that -- those 2 numbers, that shows you that this is a classic example of inch deep, mile wide in terms of the prescriber base and that's why we see this as a slow and steady launch. You're not going to find CKD treatment centers and the like. But what this is doing is it's showing people the benefit of a PK activator or a disease that has impaired glycolytic pathway, the need for energy [ ATP ] production for the red cell, and we think that's translatable for these other diseases like thalassemia and sickle cell disease, which have commonality in the underlying pathophysiology. So it's early days. We will look to continue to make progress with the adult population. We also, as I noted, have a pediatric Phase III program underway and with success that allows us in the 2026 time frame potentially to expand into the pediatric population as well.

Okay. Great. And then I guess on ped specifically, can you talk about what portion of the opportunity there are just so people have some sense.

Think of it as 80-20, roughly. And again, these are approximations because we're learning more and more each quarter about the population, but roughly in 80-20.

Okay. Super, super. Can you talk a little bit about 946, maybe we should spend a little bit of time there. So I guess, first, I think people are familiar with MDS, but maybe talk about what's the difference between low risk and high risk and why you think that's the right population to go after.

So we are indeed focused on the lower-risk MDS. There is a multitude of reasons is important there. So people can have anemia in that context and never actually evolve through malignancies. So -- but still have a huge impact on their quality of life and the way they experience life with lower-risk MDS. So we believe there is an opportunity there to help patients who actually are really suffering from that. The oral compound that we have 946 is currently being studied in the Phase IIa in lower-risk MDS, and we're specifically focused right now on nontransfusion burden or low transfusion burden population because they are subdivided in different categories depending on the amount of transfusions to look really for that hint of efficacy and for safety to then move forward into a Phase IIb in which will do dose finding and expand the patient population to include a higher transfusion burden as well. Yes. So the trial actually enrolled fast, so we moved forward our goals. And so we've added actually a corporate milestone of readout by the end of this year.

And in terms of differentiation versus your lead compound, are you expecting -- I mean, I guess, obviously, you're going on a different indication, but maybe just talk about the differences in the compound as well.

Sure. So if you think about our 2 PK activators, so the PYRUKYND one, it's twice daily dosing versus this one has once daily dosing. It's a more potent PK activator. PYRUKYND had weak in vitro aromatase inhibition, which this one does not have. However, we studied PYRUKYND for an extremely long time. So we have -- we now have not observed that translate into any clinical effect like adverse events associated with that. So -- and 946 is still building its safety exposure. And it gives us an opportunity to study another PK activator in another indication, which is -- maybe you want to speak about that.

Yes. Well, we also have -- you're referring to sickle cell disease?

No, on the IRA.

Oh, yes. Well, what I was going to say, too, is we also have a Phase I effort for 946 in sickle cell disease, which gives us optionality there. Yes, and you alluded to it, Matthew, but the advantage that we have with having another PK activator is really twofold. One is, from a pricing standpoint, of course, this is a different economic swimming lane. So that helps. And then secondly, and this is serendipitous. We didn't plan for it because we started well before the event. But in a world of IRA, it's particularly advantageous to not have to continue to stack more indications with PYRUKYND and now have a different asset that we can pursue.

And then I guess 2 last questions maybe in the last couple of minutes. Can you just talk about -- you obviously got royalties on a portfolio of oncology assets. What's the outlook there? And do you see that as a meaningful contributor in terms of cash flow to the company?

Yes. A couple of comments. One, we're super proud of the fact that vorasidenib resin which is now owned by Servier following their acquisition of our oncology assets in April of 2021. That came out of Agios research. And this is one of the special things about Agios is -- our track record is, frankly, just unbelievable in the products that we have discovered, developed and commercialized. We have a track record like very few others. And vorasidenib at ASCO this year was 1 of 4 products selected or data sets rather selected for a plenary session, and this has had more than 5,000 abstracts. So it's being pursued for patients with recurrent or residual IDH mutated low-grade glioma. So obviously, an area of huge unmet need and the data showed that they hit on both primary and secondary endpoints. The reason, in addition to the benefits for patients that, that is important for Agios from an economic perspective is we have a $200 million milestone that will be paid upon U.S. approval. And secondly, we retain the rights to a 15% royalty on U.S. net sales. Now we -- it's Servier's product, so we can't comment on exact time lines, but we were delighted when we listened to their interviews at the time of ASCO, noting that they're anticipating approval in the second half of next year. So that's a relatively near-term event. It's important for us economically. But again, it's just a great mark of excellence for the science that's come out of Agios.

And then finally, we didn't get to talk about the Alnylam program that you in-licensed, but maybe in the last minute here, we could build that, touch on your excitement and why you think it's a good fit in the portfolio?

It checks all the boxes that we have in our very disciplined BD filter. So first and foremost, it's rare, and I talked about a patient population of 100,000 in the U.S. Secondly, it's transformative in potential. There's no disease-modifying therapies available for patients with polycythemia vera. And third, we're just thrilled with the fact that we could access this particular asset early so that we can derisk it or is derisked from a regulatory standpoint. The pathway [indiscernible] inhibition is very well documented. And so just checked all of those boxes. And our goal right now is to initiate IND-enabling studies, and then we'll be excited to report out on that progress.

Great. Brian, Sarah, thanks for being here. I appreciate the time.

Thanks, Matthew.

Thank you.

Thanks, everyone, for listening and your interest in Agios. Thanks a lot.