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

Welcome, everyone, to the 43rd Annual JP Morgan Healthcare Conference. My name is Tess Romero, and I'm one of the Senior Biotech Analysts here at JP Morgan. Our next presenting company is Agios Pharmaceuticals, and presenting on behalf of the company, we have CEO, Brian Goff. Brian?

All right. Thank you very much, Tess, and good morning, early. Good morning, everybody. It's a real pleasure to be here. And I'm excited to share the updates on our outstanding progress and more importantly, our exciting future ahead. Before I get started, I just want to remind everybody that I will be making some forward-looking statements. These are based on our current expectations and beliefs, and I would refer you to our SEC filings for more details. So I want to start here this Fueled By Connection title and just reiterate the fact that, this is a mantra that Agios believes deeply in. And the reason for that is we have a fundamental belief that for us to really make a difference for patients with rare diseases, we really need to engage the community. We need to work deeply to understand their needs and work collaboratively to develop transformative medicines that can benefit patients in need. The harsh reality is that there are more than 7,000 rare diseases that have few or no treatment options, and that's our passion. We're working very hard to change that. A little history lesson on Agios over the past two decades. The best way to describe this is to think of Agios in terms of three distinct chapters. We began, as I said, about two decades ago with deep expertise in cellular metabolism, and out of that work came three oncology products that each were first-in-class in their category. And additionally, that's the time when we really started building our foundation in rare diseases, which we continue to leverage to this day. The second chapter began just a few years ago in 2021 when we made a bold decision to focus entirely on rare diseases. And the core of that is red blood cell health. This is also the time period where we introduced successfully PYRUKYND, our first-in-class pyruvate kinase activator. And -- we also, during that period -- or since that period have consistently executed on our clinical trials and we've generated a string of very consistent late-stage clinical data. And we're going to talk about a lot of that data this morning. And now here we are in the third chapter, this is all about expanding and accelerating growth and leveraging this very deep foundation that we've built across multiple capabilities. And I'm excited to share with you the progress that we've made as well as, again, what's to come as we evolve our pipeline. Looking back for a moment on 2024. This was marked by exceptional progress at Agios. We're very proud of this. And once again, you can see the checkmarks across the slide, we delivered on or ahead of schedule on every single one of our key objectives. And ultimately, what this means is we have advanced our value-creating catalysts for the organization, and this sets up PYRUKYND, especially for a multibillion-dollar potential. Now looking ahead to 2025 and beyond, we believe we have a rare, pun intended, rare and distinct blueprint for success. The key ingredients, you can see here, we have four pillars. The first is that, as I mentioned, we are building a multibillion-dollar market opportunity for PYRUKYND. This is based on two potential near-term launches. Thalassemia, this year, 2025, as well as Sickle Cell Disease based on the data we'll report out later this year with potential launch in 2026. Secondly, we have an early and mid-stage emerging and diversifying pipeline, which I'll talk about again this morning. Third is standing in front of me are members of our fabulous team who continue to execute with excellence, a deeply experienced team in rare diseases, and I'm really proud of all that they continue to accomplish. And then lastly, and this is very unique in this era. We're in a very strong financial position with our balance sheet. I'll share more about that in just a little bit. But the setup for all of this is it positions us for momentum and to deliver on these exciting opportunities ahead. Now our pipeline at a glance, you can see is very well rounded and has a mix of late-stage opportunities, which we'll talk about more with PYRUKYND as well as early and mid-stage opportunities. And we really focus on prioritizing our pipeline based on our capabilities and very careful resource allocation, which we believe can create maximum value creation for our stakeholders. So after a transformative 2024, we've categorized 2025 as a breakout year for Agios. And over the next 12 months, as you can see on this slide on the right-hand side, we have three key priorities. First, is to continue to maximize the potential of the pyruvate -- or PYRUKYND franchise; secondly, progress and advance our emerging mid- and early-stage pipeline. And lastly, very careful, thoughtful, disciplined capital deployment to make sure that we create value and ultimately, sustain growth. What I want to do now is walk through the specifics of each of those three priorities, and I'm going to start with maximizing the potential of the PYRUKYND franchise. By 2026, as I've mentioned, we have the potential to expand on our pyruvate kinase deficiency indication with two potential indications over the next year plus. The first is thalassemia. The second is sickle cell disease. And I just want to emphasize, these are populations that are in desperate need of new therapeutic options, and we're very motivated to have the opportunity to deliver on behalf of these patients. The goal with thalassemia is to deliver the first therapy that addresses all subtypes of thalassemia and will be regardless of transfusion need. In the case of sickle cell disease, what we're looking to do is deliver the first novel oral therapy, that addresses a combination of both hemolytic anemia as well as the vaso-occlusive crisis. And by delivering on these two opportunities, what we're trying to do simultaneously are two things. One is deliver on a multibillion-dollar opportunity for our shareholders. And secondly, and again this is what really fuels us at the patient level is to establish and deliver new treatment options for these patients living with both sickle cell disease and thalassemia who are in desperate need of new options. Now if we focus a little more deeply on thalassemia. This is a rare lifelong blood disorder -- inherited blood disorder that causes chronic anemia. And the challenge for these patients is they can suffer from debilitating health effects really from two different sides. First is the underlying pathophysiology of thalassemia itself. And this can cause organ damage, stroke, quality of life issues and a number of other serious life complications, health issues. The second comes from the treatment management strategies themselves, whether it's blood transfusions or iron chelation. And the reality is that these treatments themselves can have a compounded health effect for these patients. And you can imagine just how challenging that is day in and day out. And that's why the focus on having a very novel therapy that supersedes some of these challenges and gives patients a different level of hope ahead is very exciting for us. The reality is that most thalassemia patients have limited or no treatment options. And to put a finer point on that, as you can see on this slide, 2/3 of the patients in the United States have no approved therapy. So in 2024, we were really proud to announce the results of two highly successful pivotal Phase III studies. This is the ENERGIZE study and ENERGIZE-T. Collectively, these studies were addressing patients who are non-transfusion dependent as well as transfusion-dependent with thalassemia and then both genotypes alpha and beta thalassemia. You can see a top line summary of the results on the left-hand side of this slide. And based on the very favorable results, we believe that PYRUKYND can represent a novel oral convenient therapy for these patients that is effective for all facets of thalassemia, again, regardless of transfusion need and regardless of genotype. As we announced last December, we -- we're very proud of the fact that we've now simultaneously filed in four different geographies in the U.S., in Europe, as well as in the Middle East in both the Kingdom of Saudi Arabia as well as United Arab Emirates. And it's been a busy start to 2025. Just last week, we announced that the FDA has accepted our sNDA file for thalassemia. The file classification is a standard review, and we're really pleased to now have a PDUFA date of September 7 of this year, 2025. So as you can imagine, we are actively preparing for a potential launch of PYRUKYND for thalassemia this September. To give a little bit of characterization as to what the opportunity looks like. There are approximately 6,000 diagnosed adult patients in the U.S. What is important and what is markedly different from where we started on our PYRUKYND rare disease commercialization journey with PKD is that nearly all of these patients are diagnosed and in fact, they're diagnosed well before adulthood, thanks to the ubiquity of newborn screening. The other advantage is that there are well-established ICD-10 codes for thalassemia, which enables us to do robust claims database analysis. And what that does is helps us really target in a refined way clinicians who are high potential to have thalassemia patients. It also enables us to have the type of segmentation detail that you can see on this slide. So our focus initially is about 65% of the thalassemia population in the U.S. This is largely focused on patients who have a higher level of interaction with their health care practitioners. And that's based on transfusion status. It's also based on non-transfusion-dependent patients who themselves have medical complications requiring clinical intervention. Our team is very actively engaged in the field. And what's interesting about this particular opportunity is that it's multiculturally very diverse. And so we're working very hard to understand all of those insights and nuances and make sure that our deployment and our educational activities are aligned accordingly. So from a commercial standpoint, there are three key pillars of focus. The first, as I just mentioned, is a very robust disease state education program. We actually began this last year, as a consequence of the very positive top line data readouts that we saw by midyear. And there's three parts to this focus. The first is to make sure that clinicians understand the underlying pathophysiology of thalassemia. Secondly, and very importantly, the long-term complications that all patients with thalassemia face, and third is the importance of frequent monitoring and management of these patients. Secondly, in terms of our commercial customer-facing team deployment. We were very thoughtful and disciplined in how we did that. We gated expansion until we saw the disposition of the energized data at the start of last year. And we have now thoughtfully rightsized our deployment, which is larger than for PKD, but still appropriately sized for a rare disease opportunity. And then lastly and really importantly, we're already on the journey of engaging with and educating payers to make sure that ultimately, when we get to the point of launch and commercialization, the challenges of thalassemia as well as the value proposition of PYRUKYND are very well understood. So moving on to sickle cell disease, our second near-term potential launch opportunity. While this is still rare, this affects -- sickle cell disease affects a much larger patient population. And the numbers you can see on the left-hand side of the slide really represent that across the U.S. and the EU5, we're talking about 120,000 to 135,000 patients. And if you open that aperture to a worldwide basis, it's actually more than 3 million. This is an inherited lifelong blood disorder, which is ultimately caused by a mutation in hemoglobin. The consequence of that mutation is that the red blood cells are more likely to sickle. And when they sickle, they impede blood flow throughout the body, which creates a cadre of really devastating clinical consequences for the patients. And that obviously includes hemolytic anemia, but moreover, pain, impairment in quality of life, debilitating fatigue and the really sharp reality is early mortality for these patients. So again, we are really motivated to have an opportunity to make a difference. This is a population that frankly needs multiple new therapeutic options, and we're really delighted to be on the cusp of being able to move forward in that direction starting in 2026. So based on the positive Phase II RISE UP study results that we reported 1.5 years ago, actually, last year, we began enrollment in our RISE UP Phase III program. And I'm really proud of the fact that we announced last October that we have completed enrollment in this study. This is a global study that included more than 200 patients with sickle cell disease. And if I can pause for just a moment and brag about the incredible capabilities of our team, as I noted, that enrollment started shortly after we reported the top line results of our RISE UP Phase II study. And in just over a year, we completed that enrollment in the Phase III portion, and that is truly amazing for this population. We have two primary endpoints in the RISE UP Phase III study, and I'll just highlight two primary endpoints, not co-primary endpoints. One is measuring hemoglobin response and the other is an annualized reduction is the goal of sickle cell pain crises. We also have a suite of secondary end points. And the common theme across those is really different measures to look at benefits in terms of quality of life. The most important of which is how patients feel and function. And fatigue is one of the things that we hear about very often when we interact with the community, there are -- there's no coping mechanism currently for patients to manage the fatigue that comes day in and day out with sickle cell disease. So our target here is to report the top line data of this RISE UP Phase III sickle cell disease study later this year. And then as I mentioned, with the potential launch in 2026. Our ultimate belief is that PYRUKYND has the potential to be not just best-in-class, but also first-in-class and a real novel new therapy in the mix for these patients. So now moving on to our second priority. This is about progressing and advancing and diversifying our early and mid-stage pipeline. And what I want to do here is begin with our second PK activator. This is now known as Tebapivat. It's -- for those of you who know the Agios story, this is formerly AG-946. You can think of this as a novel PK activator -- we're really proud to have this to give us optionality about how we further expand this franchise ahead. And currently, we're pursuing clinical trials with Tebapivat in two different areas. One is low-risk MDS or myelodysplastic syndrome. And the other is also in sickle cell disease as we have an ambition to continue to build a franchise ahead. If I just start with low-risk MDS, the aim here is to deliver the first oral therapy that addresses hemolytic anemia caused by ineffective erythropoiesis. And just as we have with all areas that we're pursuing, low-risk MDS is also in significant need of new therapeutic options, and there are no currently approved oral therapies available for these patients. The numbers are -- this affects 75,000 to 80,000 patients across the U.S. and the EU5. And about 70% of the MDS patients would be categorized as low risk. So last year, we initiated our Phase IIb study with Tebapivat in low-risk MDS. And again, as a corporate goal, our ambition is to have that fully enrolled by the end of this year. I'll just also highlight that last September, the FDA granted orphan drug designation for Tebapivat to that for low-risk MDS. And I think that just puts a finer point on the fact that there's a recognition of how urgently we need new therapeutic options for this area. Looking at sickle cell disease, as I noted, sickle cell disease patients need multiple modalities. They need multiple therapeutic options, and we're really proud to have the opportunity to have not one but two PK activators that we're developing for sickle cell disease. The ultimate ambition is to open up a wider range of patients that would have a potential to benefit from one or potentially both of our PK activators along their journey. In 2024, we presented the Phase I results for Tebapivat in sickle cell disease. And we have announced that we will now be moving into Phase II. The corporate goal for that Phase II study is to begin enrollment in the middle part of this year. And now I want to move on to our earlier stage programs. We have two to highlight here. One is AG-181. This is a PAH stabilizer or phenylalanine hydroxylase, really targeted towards PKU, phenylketonuria, which is a metabolic disease where it ultimately results in the buildup of an amino acid known as phenylalanine, and as that accumulates in the body, as you can see on this slide, for medical need, these patients really suffer from severe medical consequences. So we initiated a Phase I study in healthy volunteers last year, and this study is ongoing. Secondly, we have AG-236, and this is an siRNA targeted towards TMPRSS6 inhibition. And this is really focused on polycythemia vera, which is a myeloproliferative neoplasm, ultimately overproduction of red blood cells. And the unfortunate reality for these patients is that current standard of care is phlebotomy, which we see as entirely unacceptable in this era. And that's our ambition, is to advance both of these products to give these patients who also need new therapeutic options, a real novel approach ahead. Lastly, our third priority, again, focused and disciplined capital deployment. And I just want to highlight that we have a very strong balance sheet, which as of the end of September of 2024, we had approximately $1.7 billion in cash, cash equivalents and marketable securities on our balance sheet. And I think everybody listening in knows that's a very unique position to be in for a company of our size. And so this cash balance, combined with anticipated product revenue, interest income really gives us the opportunity to deliver on the three priorities that you see here, maximizing our PYRUKYND franchise towards that multibillion-dollar opportunity; secondly, advancing our early and mid-stage pipeline; and lastly, continuing to look organically at how we can further our development of our pipeline as well as in a very disciplined way, seek external potential BD opportunities as well. So these are our expected milestones for 2025. I've talked about each of these. I think just like 2024, you can imagine for Agios, this will be yet another exciting and breathless year ahead. We're excited about what this means. And again, it's a two-parter. It means an opportunity to deliver significant value creation for our shareholders and really that transformative potential for patients who count on us. We're really excited. And I'll just highlight that, again, the summary of this whole discussion is that, number one, our goal is to continue to develop the PYRUKYND franchise towards that million dollar -- multibillion-dollar opportunity, advance this early and mid-stage robust pipeline that we have and then deploy our capital to deliver on all the opportunities ahead. So with that, I'm going to stop there and turn it over to Tessa for Q&A. And I'll just take one moment while we're making the transition to introduce the team that's joined me, this fabulous team that I talked about upfront. So here with me today, we have Sarah Gheuens, who is our Chief Medical Officer and Head of R&D. We have Tsveta Milanova, who is our Chief Commercial Officer; and Cecilia Jones, our Chief Financial Officer. Thank you very much, and Tess, I'll turn it back to you.

Great. Brian, thank you for the presentation, and welcome, everyone. So I thought I would start the conversation in thalassemia. Can you walk us through the framework for how you're thinking about the cadence for potential regulatory filing acceptances and approvals and time lines to launch? I know we had an acceptance of your filing in the U.S. But can you just walk us through that?

Sure. Maybe this is a great opportunity for Sarah to get started. And since she's up here on stage, I just want to say, again, I'm really proud of what Sarah and her team have done, not just in executing on these clinical trials that played out so beautifully last year, but also, again, as you just noted, four simultaneous filings. So Sarah, you want to get started?

Sure. Thank you. So yes, we're very proud that we were able to submit into four different regions at the same time. So those filings are now progressing, and those different regulators have started their procedures. The U.S. has accepted the filing and has the target PDUFA date of September 7. So now we are in that process towards working together towards that date. And then for the European agency, so the EMA, they also have a very standard sort of process with different time lines. It will be after the FDA normal procedure that you would hear back on that. For the Gulf, so we've also filed in Saudi and in the United Arab Emirates. That is new. We were able to file without having first approval in the U.S. or in Europe, which is a new process for them as well. So -- and that was possible because we obtained breakthrough medicine designation for the product, and that allowed us to actually file earlier than you would normally be able to do so. So that is a new process. We are going through those motions altogether. But so far, it's been a great experience.

I will maybe just add for a second that we did not highlight this on the slide or I didn't talk about it, but the reason the Gulf is so important is because I mentioned that in the U.S., there are 6,000 adult diagnosed patients with thalassemia; in the Gulf, there are 70,000. And on a per capita basis, that's -- the prevalence is about 8 to 9x greater than we see in the U.S. So you can imagine in that region, there's also an ambition to have new therapeutic options, particularly for thalassemia.

When you think about the use of the product in VAL, what are the key opportunities and potential challenges as they relate to uptake?

That's a great question for Tsveta Milanova, who is very excited about launch preparation.

Absolutely. So we're super excited about getting ready for launch. By far, in the U.S., we see as the biggest commercial opportunity. So I'll touch on the opportunities in the U.S. As Brian mentioned, when we look at the thalassemia population, there is 6,000 adults diagnosed with thalassemia in the U.S. So having the patient population diagnosed and the availability of claims data gives us a lot of clarity of how to approach the launch and prioritize our launch efforts. And that's fundamentally very important for launch. There are three patient segments that we prioritize our efforts and our initial launch focus for us. These are the patients who are transfusion dependent. They have a very regular interactions with the health care system, and we expect for them to be the first probably potential to hear about the product and see adoption there. The other two segments are within the non-transfusion-dependent space, either they have developed disease complications and require additional monitoring and therapy or they live with very debilitating fatigue, low hemoglobin levels, and we see a great opportunity for uptake early on in that patient population as well. When it comes into challenges, it's something that we actually think about and address already prelaunch is probably the misperception that non-transfusion-dependent patients are at less risk or "less severe" and that's why all of our disease education efforts ahead of launch, focusing on both patients and physicians are actually focused on highlighting the disease, morbidities, complications and potential mortality, especially in the non-transfusion-dependent patients. And we really look forward to actually engage and energize that community to continue to look for better options for them.

We have fielded a number of questions since the ASH conference in December about whether hepatocellular injury as a potential risk will or will not hold back use in patients with thalassemia. What have you heard in the early days here from the physician community on the risk-benefit trade-off?

Maybe Sarah could start in terms of the overall picture, particularly from a regulatory standpoint. And then Tsveta Milanova can comment again on what we've heard from clinicians and in some cases, even from the patient communities themselves.

Sure. That would be great. So what this is referring to is that we have updated based on the totality of the data we had for thalassemia. We have updated the safety profile to include hepatocellular injury as an important potential risk. So we have proposed a warning and precaution language around that based on the occurrence of 5 cases across the program. One was in each blinded randomized controlled trial, and 3 were in the extension studies when they were first exposed to mitapivat. All the patients improved upon discontinuation. And so we have guided towards monitoring for potential liver injury in the first 6 months. So you draw liver tests on a monthly basis for the first 6 months. And if you would see an ALT increase or specific transaminase increase of 5x or more of the upper limit of normal then just discontinue the product, which is a very straightforward clear language that is easy to use in the context of lab draws that are often obtained in this patient population. So that label language is now already reflected in the existing label for pyruvate kinase deficiency. So based on those cases in thalassemia, the USPI was updated for pyruvate kinase deficiency to include that -- exactly the language that I just explained. So which is important because that means that we've already agreed around these concepts for the label in the context of PKD with the FDA based on those thalassemia cases. In regards to where does that leave us for thalassemia. So we are very excited about the overall benefit risk profile in this condition. If we start with the risk, this is something that is monitorable via something that does not increase the burden for this patient population and which is actionable by just stopping product. And then on the positive side, the benefit part of the equation is positive across both trials. So we hit on statistical significance on all primary, all key secondary endpoints in two well-designed randomized controlled trials. So we feel very -- we're very pleased with the benefit part of the equation as well. And so -- and then put that into the context Tsveta already highlighted it, but it is a horrible disease with basically no treatment options for the vast majority of the patient population. So putting that all together really gives a strong favorable benefit risk profile, which allowed us, of course, to file in those four different regions. In regards to what have we heard on the clinical trial side, really not much this -- because this is part of something that physicians are very used to doing, especially in this condition and also with other products that they have -- that they are using like iron chelation therapy, which has also a warning for liver injury.