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

Welcome, everyone, to the 42nd Annual JPMorgan Healthcare Conference. My name is Tessa Romero, and I'm one of the biotech senior analyst here at JPMorgan. Our next presenting company is Agios, and speaking on behalf of the company, we have CEO, Brian Goff. Brian, over to you.

All right. Well, thank you very much, Tess, and good morning, everybody. Really delighted to be here. I'm going to start with introductions on who is with me. We have Cecilia Jones, our CFO; Sarah Gheuens, who is our CMO and Chief Medical -- sorry, Chief Medical Officer and Head of R&D; and also Tsveta Milanova, who is our Chief Commercial Officer. So before I get started, I just want to remind everybody that I will be making forward-looking statements that include our expectations and beliefs going forward. And so I would refer you to our SEC filings. Now Agios is entirely dedicated to developing and delivering transformative therapies for patients who are living with rare diseases, and I am particularly excited to share with you our strategy for significant growth and value creation, particularly over this catalyst-rich period of the next 12 to 24 months. So to get started, Agios is well positioned to deliver multiple clinical and regulatory catalysts. And these are gearing up to position us to enter into multibillion-dollar categories, namely thalassemia and sickle cell disease. And we're very proud of the fact that we are the pioneers of this core mechanism of pyruvate kinase activation. We also are experts in cellular metabolism. And this has led us to PYRUKYND or mitapivat, which is the first and only approved therapy for patients with pyruvate kinase disease, and this is a disease-modifying therapy or deficiency, I should say. Now the mechanism is playing out to be particularly unique because I think many understand that there are benefits from -- with hemoglobin that come from pyruvate kinase activation. But increasingly, what we're learning is the benefits for patients go well beyond hemoglobin alone. And with each step forward that we make on delivering data based on this mechanism, we're increasing significantly the probability of success for our programs going forward. And we were particularly delighted just last week to announce the very positive results from our pivotal Phase III study known as ENERGIZE, which was targeting non-transfusion-dependent thalassemia patients, and I'll share more about that in a little bit, but that certainly creates more momentum again for these catalysts going forward. The last thing I'll say is that we are well capitalized, and we continue to grow our pipeline. We've done this in 2 different ways. One is with our internally organically developed programs. A good example of that is our PAH stabilizer that is really a great feature of the expertise in cellular metabolism from Agios. With this, we are targeting phenylketonuria or PKU. And another example is from externally in-licensed products. And a great example of that last year was our in-licensing of an siRNA from Alnylam that inhibits [ temper 6 ], and this is targeting polycythemia vera or PV. Now as we prepare for these launches to come, we have a wonderful backdrop of already having PYRUKYND, again, is the first and only disease-modifying therapy approved for an ultra-rare condition known as PKD. And the commercial capabilities that we've built over the last couple of years to deliver on this launch, we will be leveraging for sure, into our potential future launches in thalassemia and sickle cell disease. But these opportunities actually have some very interesting and compelling features that are actually quite different from PKD. The most obvious of which is these are significantly more prevalent diseases on a global basis. But more importantly, both thalassemia and sickle cell disease are readily diagnosed. And that's thanks to the ubiquity, particularly in the U.S. of newborn patient screening. The other feature is that on a global basis, both of these diseases have very well-recognized burden of disease at the patient level, and that certainly helps with the motivation to adopt a novel treatment therapy. Now the mechanism of pyruvate kinase activation is very unique. And at the core, this is all about addressing the imbalance of energy that cells under metabolic press have. So in essence, there is an imbalance of both the supply and the demand and by increasing or activating pyruvate kinase, the last step in the glycolytic pathway, we're looking to normalize that balance and increase the level of energy for the cell. The benefits, as I mentioned that we see are not just hemoglobin improvements, but also ineffective erythropoiesis improvement, markers of hemolysis and increasingly, what we're starting to see are the benefits directly to the patient in terms of in the case of sickle cell disease, improvement in vaso-occlusive crises, also feel and function, and we saw this again just last week with the readout of our ENERGIZE data showing improvements in fatigue at the patient level. On the left-hand side of the slide, though, you can see another unique feature of the pyruvate kinase activation mechanism unique to our franchise, mitapivat and our other PK activator, AG-946, specifically not only do -- does this mechanism activate PKR, which essentially controls energy at the red blood cell level, but also another ISO enzyme known as PKM2, and this is important because it regulates cellular energy at the tissue level, and we believe that this could be important for downstream organ damage. And our intent to bring that to life is to study renal impairment in sickle cell disease patients. So you can see at the bottom the growing stack of late-phase trials that we've reported out. And the most important thing is that this data has continued to be consistent and compelling across these hemolytic anemias. Now if I take a step back just a couple of years ago in 2021, Agios made the decision to divest our oncology business, which was really the way the company started, and we made a complete pivot to a focus on rare diseases. And I think what's striking is to just reflect on what our pipeline looked like in rare disease and PK activation at that point in time, we had a total of 3 programs underway. And if you advance to today, you can see the dramatic enhancement and depth of our pipeline. In fact, with just our PK activation franchise alone, we have nearly tripled the number of programs that we had at that time and you can note at the bottom, not only have we advanced the pipeline, but we've expanded and diversified again, noting our PAH stabilizer that we're advancing for phenylketonuria as well as the asset that we in-licensed from Alnylam, where we're focusing another very high unmet need in polycythemia vera. 2023 on every dimension was a tremendous year for Agios. We put forward a very ambitious list of goals, which was largely geared towards advancing our pipeline. And you can easily see just across the board a bunch of checkmarks which we're very proud of. We delivered on every goal that we put forward. And to name a few, looking again at thalassemia and the opportunity we have in front of us. We fully enrolled earlier last year, both of our ENERGIZE and ENERGIZE-T Phase III pivotal studies. We actually did that ahead of schedule. And that obviously positions us very well for the readout that we announced just last week, the very positive readout of our ENERGIZE Phase III study targeting non-transfusion-dependent patients. Additionally, in sickle cell disease, at the midpoint of the year, we were delighted again to read out a very positive Phase II study. This is part 1 of the operationally seamless Phase II/III design. And what we're very proud of is just 3 months after we read out that data, we were already enrolling our pivotal Phase III portion of the RISE up study for sickle cell disease. I'll also note that our other PK activator, AG-946. We have been advancing in low-risk MDS. This is a disease that is very much about ineffective orthosis, and we enrolled that Phase IIa proof-of-concept study, again, well ahead of schedule. And then we were delighted in the fourth quarter of last year to announce positive results of our prespecified proof-of-concept endpoint of transfusion independence. We achieved 40%. The last thing I'll just say again is we're really excited about improving the early, or advancing the earlier stage of our pipeline, namely the PAH stabilizer for PKU as well as the in-licensing agreement from Alnylam. Now the first potential launch in front of us is thalassemia. And this is a very profound and severe disease for patients around the world who suffer from the chronic hemolysis that comes with this genetic mutation affecting both the alpha and beta globin genes. And what you can see on this slide is, on the left-hand side, there are really 2 segments of thalassemia. And I'll note our intent is to deliver for all forms of thalassemia. But nearly 70% of the patients, as noted in orange are non-transfusion-dependent thalassemia patients. And this was the focus of the ENERGIZE study that we just reported out last week. Unfortunately, for these patients, they have no currently approved therapeutic options in the U.S. And then the other blue section of this pie chart is the remaining patients, and these are so-called transfusion-dependent patients. This is the depiction in the U.S. These transfusion-dependent patients are the focus of the other pivotal Phase III study known as ENERGIZE-T. And now that we have the positive readout of ENERGIZE as we just reported, we are delighted to have very soon at the midpoint of this year, the expected readout of the ENERGIZE-T study. So again, the intent of our pivotal Phase III design is to encompass all subtypes of thalassemia transfusion-dependent patients, non-transfusion-dependent patients and also as well the subtypes, including both alpha and beta thalassemia. To go a little bit deeper on the unique nature of thalassemia, it is uniquely geographically concentrated, very large population worldwide, 18,000 to 23,000 patients in the U.S. and EU5. And on the previous slide, I should have noted, approximately 6,000 patients in the U.S. alone are already diagnosed and active in the system. But if we go outside of the U.S. One geography in particular, GCC or the Gulf region has a shockingly high prevalence of thalassemia. And in fact, about 70,000 patients, which is roughly 8 to 9x the size of the U.S. alone. So when you look at the disease impact at the patient level on the right-hand side of this slide, there is a disconnect in a way in that these patients are subdivided, as I noted in non-transfusion-dependent thalassemia as well as transfusion-dependent thalassemia. And unfortunately, non-transfusion-dependent thalassemia patients have historically been thought to be less severe, less at risk for all these disease impacts. And increasingly, what we're learning is that they are subjected to hemolysis every day and hemolysis is deadly because free heme in the body is toxic. And so in many ways, they're even more undertreated and even more vulnerable, and that's why we're delighted to have this ENERGIZE data to directly address what these patients are so in need of. The data itself that we reported is just amazing on many levels. First of all, we were highly statistically significant with our primary endpoint of hemoglobin improvement. And in fact, the p-value was less than 0.0001. But as I noted, the benefits for this mechanism of pyruvate kinase activation were really showcased in this study because beyond hemoglobin, we also hit statistical significance in both of our key secondary end points One is average hemoglobin concentration improvement. And the other, which is I think the one that was a real pleasant surprise to many is that the average facet fatigue score and fatigue is a very profound element of unmet need for these patients also met statistical significance. Again, reinforcing these benefits that go broadly beyond hemoglobin alone. The safety profile demonstrated that the adverse events were very balanced between both mitapivat as well as the placebo group. Four patients in the mitapivat arm led to -- had AEs that led to discontinuation, there were none in the placebo group. And the last point I just want to make is at the very bottom, which is that all of our prespecified end points favored the mitapivat arm. And so another way to think about that is there were no subgroups that skewed the results one way or the other, a very balanced profile, which again fits beautifully with our target of addressing all dimensions and all subtypes of patients with thalassemia. So the next steps, as you can see on the right is our tradition is we top line the data and then we look ahead to a major medical meeting to feature the totality of the results, and we look forward to doing that. As I noted, we're delighted that ENERGIZE-T is not that far away. So we'll look forward to those top line results at the midpoint of the year. This data then will be packaged as one submission as an sNDA to the FDA. And that will be by the end of this year and then pointing towards a potential launch in 2025, which we are very excited about. The commercial aspects of thalassemia are also very different and very appealing, but quite different from PKD where we've currently been commercializing. Just to name a few of these features for one, the diagnostic intensity is very different. There are already, as I noted, in the U.S. alone, 6,000 adult patients who are already diagnosed with thalassemia. We've already talked about the fact that 70% of these patients approximately have no therapeutic options. And then the providers themselves and where these patients are treated is much more concentrated than we have faced with PKD. And the example here is that about 50% of these patients are actually being treated in approximately 150 hemon treatment groups across the U.S. which is a very favorable situation for us. And then even the advocacy groups are much more established. So this is more of a patient connected community, and Coles anemia is one example and TIF is another. And then again, looking outside the U.S., in just the Gulf region alone, you have 8 to 9x the prevalence that we have in the U.S. So the summary is we're targeting an all-inclusive design for PYRUKYND. We already have now the backdrop of very positive ENERGIZE results. We're looking ahead to the ENERGIZE-T readout. We submit all this data, have an opportunity for best-in-class and ultimately foundational therapy for these patients and a launch next year. Now if I move to the other key significant near-term launch opportunities, sickle cell disease, I think this is very well known certainly in the U.S. and around the world, another devastating hemolytic anemia with very high unmet need. These patients really suffer from anemia, from the risk of stroke, renal impairment and ultimately shortened lifespan, perhaps the most striking stat on this slide is the fact that the average lifespan for a sickle cell disease patient today is approximately 45 years. So we are delighted to have a very advanced program to address this significant opportunity. I just want to reflect back to the data that we were so thrilled to present at ASH just last month. And this is the full data set for our Phase II portion of the operationally seamless Phase II/III RISE UP study. The first point is statistically significant improvement in hemoglobin against both of our doses tested 50 milligrams as well as 100 milligrams. And secondly, again, moving towards benefits beyond hemoglobin, 4 out of 4 of the markers of erythropoiesis as well as hemolysis also met statistical significance -- or sorry, improvements. And then, again, a very surprising and very exciting feature was that with both doses, we also saw a positive trend in the devastating vaso-occlusive crises that patients are literally tortured with having this disease, and we were very proud of that result. So looking ahead now, this was a very efficient study operationally. We made no changes to the Phase III design with the exception that we picked our dose, and that is the 100-milligram dose. And I'm very proud of the fact that Sarah Gheuens and her entire research team focused on this program within 3 months, we're already actively enrolling patients for this study. So for PYRUKYND, the setup here is again an opportunity to become foundational best-in-class, potentially first-in-class therapy and what we're targeting is not just anemia, but the totality of symptoms and needs for these patients, which go into sickle cell pain crises and again, fatigue where if you talk to patients with sickle cell disease. They have management techniques for pain. They cannot adjust life for fatigue. And so having this entire profile is very special, and we look forward to that opportunity as well. We will deliver full enrollment is our target of this study by the end of this year, data coming in 2025, and that puts us on a course for a potential launch in 2026 just a year after our thalassemia launch. Moving to the rest of our pipeline. We're in a very advantageous position to have not just 1, but 2 PK activators. So our second novel PK activator known as AG-946, we're currently pursuing in low-risk MDS in a Phase II study. We read out, as I noted, the Phase IIa portion in the fourth quarter of last year, and we were very pleased that we met our prespecified end point 40% of the patients achieved transfusion independence, and that gives us the fortitude to advance thoughtfully with the Phase IIb program at the midpoint of the year. We also have already submitted an IND late last year for our PAH stabilizer for phenylketonuria. This is a very high unmet need category that fits in beautifully with our expertise in cellular metabolism, and we're looking to commence a Phase I study this year with this PH stabilizer. And then the asset that we in-licensed from Alnylam for polycythemia vera 10,000 patients in the U.S., frankly, they're subjected to what we think of as medieval therapy. This is phlebotomy and we're looking to revolutionize the way these patients are treated with this very novel mechanism of [ temper 6 ] inhibition. So 2024, the setup for this year, we've already checked one very important box where we had targeted positive readout of our ENERGIZE thalassemia program for non-transfusion-dependent patients. I mentioned we're also starting our Phase I for PKU. The midyear point, that's the important readout for ENERGIZE-T, which we very much look forward to. We are completing enrollment in the one remaining Phase III program in pediatric PK deficiency. I noted we're looking to begin our Phase IIb study of low-risk MDS with our AG-946 asset. And then at year-end, we will be submitting the package for approval for thalassemia for PYRUKYND. Sickle cell disease, a RISE UP Phase III study, we're looking to have fully enrolled. And then we will read out actually the first of our 2 pivotal Phase III PKD pediatric programs. And that is a setup for -- when I stood here a year ago, I said we are about to enter a catalyst-rich period. We are squarely right in the middle of that. So that's a setup for 2025. Here, we're looking for the readout of the sickle cell disease Phase III data. We will be looking towards a potential launch in 2025 with thalassemia. And then the second of our pediatric PKD programs will be reading out. In 2026, we have remarkably the potential for 2 launches, one in sickle cell disease and the other in pediatric PK deficiency. We are ultimately -- I hope the takeaway here is extremely well positioned to prepare for these meaningful growth opportunities. We have a very special and remarkable mechanism of action with PK activation. We're the world's leader with that franchise. It is advancing beautifully. This mechanism we're learning goes well beyond what people have traditionally thought, which is beyond hemoglobin. And as I said, we continue to just stack up data readout after data readout, which only increases the probability of success of our franchise. And we will continue in a disciplined way to look towards how we can advance and grow and diversify our pipeline. So with that, thank you very much. And Tess, I'm going to turn it over to you for questions.

Great. Thank you, Brian, for the presentation. Please come on up. So I thought I would start the discussion here on the ENERGIZE study results, which Brian, thank you for articulating those right now for us. I did want to just ask about helping to contextualize that hemoglobin response rate that was observed. And mechanistically, why might a patient not respond?

Yes. Well, first of all, I just want to reinforce that the results were as good as we could have imagined. The fact that we were highly statistically significant with the hemoglobin finding at the 100-milligram dose and as well that we now have demonstrated once again that the benefits go well beyond hemoglobin. But I'll let Sarah comment on the second part of your question about hemoglobin response in general.

Yes. So thanks, Tess. I think it's also very important what you just last mentioned the hemoglobins of making people feel better is critically important in the context of hemolytic anemia, where people are really suffering from fatigue. So we're very pleased with that because that also adds to the consistency of our data that builds on the pyruvate kinase efficiency observations in which we had a very similar package coming out of the Phase III trial and now we see that again in thalassemia. In regards to so-called nonresponders. It really depends. So right now, we have given you an insight in the intent-to-treat analysis, hemoglobin response defined as 1 gram per deciliter over a period of time within the trial between week 12 and week 24 on average. We do know, though, that there are also people who are maybe not necessarily reaching a clinical trial bar but can still have some benefit on hemolysis and on patient-reported outcomes. So this is something that we will be talking about more with -- once we get through the first part of the data presentation. But this is a very important thing that there is more than just the hemoglobin component to feeling to demonstrating improvement. So mechanistically, why there may be some people that are truly nonresponders, we don't know. We have analyzed that extensively in our PKD trial, of which there for some people, there is a logical reason in the sense that they don't have enough enzyme left be able to respond from a wild-type perspective, we don't have that full insight yet.

And this actually segue ways really nicely into my next question, which is, what should we specifically look for in terms of what we may see in that fuller medical meeting presentation. Of course, not with the data itself is, but the types of analyses that we might expect right.

So very consistent with how we have done this before. We always present our intent to treat analysis. So it will be our primary and secondary -- primary key secondary endpoints and other secondary endpoints, which are focused on hemolysis. And then, of course, the details around safety as well. And then from there, we typically do further analysis digging in more into responder analyses, but that will come at a later time.

And how should we think about the level of read-through between ENERGIZE and ENERGIZE-T?

So indeed, it's a different patient population in the sense it's that they need transfusions, ENERGIZE-T, which in ENERGIZE, they need an occasional transfusion, but it's to a different level. Now the fact is that you can postpone transfusions if your hemoglobin stays up we do see a read-through there in the context that when you improve hemolytic anemia by an improvement of hemoglobin that should pull through to a trial in which you are studying transfusion independence or transfusion reduction. And we have seen that in our pyruvate kinase deficiency trial. So now we are very much looking forward to a media readout of ENERGIZE-T.

Yes. And maybe I'll just underscore that too because, again, if you look at the totality of all of the data that we've read out thus far with mitapivat, if you go back to PKD, ACTIVATE, ACTIVATE-T, I mentioned RISE UP, the Phase II program, and now we have ENERGIZE and thalassemia. The data has been consistent. It has been compelling, and it's continued to show that there are these benefits beyond hemoglobin. So to the question about read-through and probability of success, I think I reinforced that a couple of times in my prior comments, we have increased conviction with every study, that this is a very significant mechanism, very novel and is showing broad benefits for patients.

I should have said, please wave your hand if you do have a question, I don't think my iPad is working. So can we talk a little bit about ENERGIZE-T in a little more detail here, particularly what you're looking to see around the primary endpoint, which is a 40-week read on transfusion reduction, what response rate are you looking for there?

So the primary endpoint in ENERGIZE-T is defined as a 50% reduction in any 12-week rolling period between week 12 to week 48. So basically, any consecutive 12 weeks that a patient has a 50% reduction in transfusions, then that means that, that patient is a responder. So we're very much looking forward to that data. I think that is really a clinical meaningful way to look at data because we basically give patients multiple chances to have that type of reduction, we can highlight how a patient can be dynamic in the course of a period of time like this, and that is clinically very relevant.

Okay. And you are enrolling a broader population here of both alpha and beta thalassemia patients. So how do you think about the relevant clinical thresholds here to benchmark your results to -- and perhaps it might make sense to orient folks in the room on what is currently available for TDPT, but not alpha thalassemia.