Good morning, and welcome to day three of the 2024 Bank of America Healthcare Conference. Thanks for joining this session with Agios. My name is Alec Stranahan. I'm Vice President and Senior Biotech Analyst covering Agios here at BofA. And I'm pleased to be joined by Brian Goff, Chief Executive Officer of Agios, and Sarah Gheuens, Chief Medical Officer and Head of R&D. Thanks for being here, guys. Happy to be here, Alec. Thanks very much for the invite, and good morning, everyone. Perfect. I believe Brian's going to run through some prepared remarks to start, and then we'll jump into Q&A. So with that, Brian, over to you. Yeah, thanks a lot. I mean, this is really good timing to have a discussion like this. It's a really exciting time at Agios. We have a lot of momentum, and for those who are new to our story, as a snapshot, Agios is a company that is really focused exclusively on rare diseases, and at the core of that focus is red blood cell health. And that really points towards our industry-leading mechanism of PK activation, pyruvate kinase activation. And our flagship product, mitapivat, which is known commercially as PYRUKYND. We were really pleased to have launched PYRUKYND back in early 2022 for an ultra-rare indication called PKD or pyruvate kinase deficiency. And that has served as a wonderful platform for us to build up commercial capabilities in rare, but secondly, also to see how PYRUKYND performs in the rare space in the real world. And that's a great setup for the next indications that we're working on, where we're late stage in development right now, and that's thalassemia and sickle cell disease. 2023 was a fabulous year for us. We delivered on all of our corporate objectives to advance our clinical pipeline, and we started 2024 on a real high note. In January, we reported out our ENERGIZE pivotal phase III study, and ENERGIZE is focused on the non-transfusion-dependent thalassemia patients. And why that's important is because in the U.S., that's about two-thirds of the population. So we start from a real position of strength. We were very pleased that we hit on the primary endpoint, statistical significance, that's hemoglobin improvement. But I think what surprised a lot of folks was both key secondary endpoints were also significant, and the most important of which was, fatigue, FACIT-F atigue, a patient PRO measure. And that is, essential because that's one of the devastating symptoms of thalassemia. It also is across the board for hemolytic anemia, is a, you know, a real challenge for patients. I will note as a quick advertisement that two days ago, when the EHA abstracts were announced, we were really proud with the fact that ENERGIZE will be featured as a plenary session. So for the folks listening in, we encourage you to take note of that, and you'll have a chance to see, you know, the full data set. The next study, the second study in the thalassemia program, is what we call ENERGIZE-T, and the only difference there is that's focused on transfusion reductions in the transfusion-dependent population, so the other third of the population. We announced earlier this month that we're expecting that top-line data set, actually Q2, the quarter that we're in right now. Lots of momentum. Last year also was a great year for us with sickle cell disease. We announced the top-line results of RISE UP, phase II data for sickle cell. We hit with both doses tested, statistical significance in hemoglobin improvement. Again, there was a real aha coming out of that study, which is a positive trend in sickle cell pain crisis reduction. So I must say, in looking to my left here, Sarah Gheuens and her team did a fabulous job of moving very quickly from that data into the start of enrollment in our phase III RISE UP study. I'll just note that our goal for that is to be fully enrolled by the end of this year. We have a great setup where thalassemia will get data this year for the second of the two studies. Our intent is to package those up together, file by the end of this year. That gives us a potential launch in 2025. Sickle cell, fully enrolled, is the target for this year, data next year, and a back-to-back launch scenario in 2026 with sickle. All in all, it's just a super exciting time. The last thing I'll just note is from a balance sheet perspective, and again, a real position of strength, we ended the first quarter with approximately $714 million on the balance sheet. And that includes a $200 million milestone that we will receive upon approval of vorasidenib, which is now owned by Servier. That was part of the divestiture that we did in 2021. What's not included in our cash runway, very importantly, is a 15% royalty on vorasidenib U.S. net sales. So that gives us, obviously, a lot of optionality. So all in all, great momentum. We have opportunities for first-in-class, best-in-class launches, and we're working on building a multi-billion dollar franchise. Fantastic. Well, definitely a lot going on, and I hope we can drill down into each of those areas. So now we'll jump into the Q&A. I've got a few here, but I welcome those in the audience. If you do have a question, just raise your hand, and someone will be around with a microphone. But, you know, Brian, maybe just to start at a high level, mitapivat is looking like it could be sort of a pipeline and a drug, so to speak. Could you maybe talk at a high level, and you did touch on this, but you know, how you're thinking about developing this asset?... not just in PK, but also already approved, where it's already approved, but also thalassemia and sickle cell. What is sort of the the grand vision for this asset? Yeah, a couple points. One, we actually like the phrase, "pipeline and a product," but it's a little cliché, so we, you know, we try to avoid it and talk more in grand terms. So two aspects. One is that I noted that we're the industry leaders with pyruvate kinase activation, and that is, of course, with mitapivat and the great progress we're making in PKD, in thalassemia, as I talked about, and in sickle cell disease. And I should note, we have four pivotal phase 3 studies that we'll be reading out by the end of next year. So great momentum there, but we also have another PK activator. And the main difference there is it's more potent, and we refer to this as AG-946. And we have two different pathways that are underway right now. One, which is the most advanced, is in low-risk MDS. Late last year, we reported positive data, positive proof-of-concept data in low-risk MDS in a phase 2a study. We got a lot of learnings out of that study, and I'm sure Sarah would be happy to talk about that. And now we're preparing for commencement of a phase 2b mid this year in MDS. And that's another growing market, high unmet need. So we're looking to extend PK activation as far as we can take it. The other area where we're doing research with 946 is in phase 1 in sickle cell disease, and the main point there is to obtain data in a hemolytic anemia with our other PK activator. Fantastic. You know, congrats on the plenary for ENERGIZE at EHA. I think that's a huge win for the program, and it will definitely elevate it, at least within the physician community. What can we expect, you know, from the talk? This is your non-transfusion-dependent study. Well, I know Sarah would be proud to talk about it. Yeah, we're very happy that ENERGIZE was selected for a plenary at EHA. As you can expect from, you know, in line with what we have previously done, our first big presentation is always our intent-to-treat analysis, so the primary endpoint, secondary endpoint, safety. But we're also very happy that there is an additional poster presentation the day before that goes into more detail about our patient-reported outcomes and also performance measures. Mm-hmm. So we'll be highlighting an improvement in facet fatigue there, but also in 6-minute walk tests, adding to that, you know, totality of the data and feel and function for patients. Mm. So EHA, we're very excited to go and can't wait to get there. Yeah. Great. And maybe we can actually drill down further into beta thalassemia. So the next update beyond EHA is gonna be ENERGIZE-T, which I think everyone is eagerly looking forward to. I think you've got it to middle of this year. Could you maybe walk us through the expectations for this readout? It's a slightly different patient population. So, you know, how would you define success from this study? Well, obviously, we're hoping to, you know, hit on the primary endpoint, and that would be the statistical significance piece. That being said, we look at these two trials together, and the unique component of our development program is that this is truly for all of thalassemia. So alpha and beta thalassemia, non-regularly transfused and regularly transfused, with the hopes to be able to deliver a label that, you know, no matter where you fall as a thalassemia patient, you can benefit potentially from this treatment. Mm-hmm. In regards to the ENERGIZE population, so the two-thirds of the thalassemia population where we now have data, we are very pleased with those results because it does cover the biggest part of the population, and we've also highlighted already that based on our pre-specified subgroup analysis, there is not a single group that is driving the overall efficacy, meaning we see efficacy in all of the genotypes. Mm-hmm. In regards to ENERGIZE-T, so where we're blinded, and we don't know yet, it's also an all-comers population. The difference is there that these people participating are regularly transfused, and therefore, we're measuring hemolytic anemia improvement via a transfusion reduction response. Success on a clinical trial basis would be the statistical significance, of course, but there is a lot of data there that can support clinical meaningfulness because what we hear from... for the real world, in the context of this product profile and the way it is used, that any transfusion reduction can be meaningful for an individual patient. Okay. Yeah, and can I just add, Alec, too, that it's these two studies together, for people who are just learning about thalassemia, this is a historic period because the, in the case of, the U.S. population, out of the 6,000 patients, as I noted, two-thirds of those are non-transfusion dependent. They have no approved treatment option in the U.S., none. And there's another dimension to alpha and beta thalassemia. Sarah has alluded to alpha thalassemia patients have largely been ignored- Mm-hmm. - from pharmaceutical development, and they have no approved treatment options. So you can imagine if you're in the thalassemia community, and you hear about the data that we reported in January, and now we're gonna feature in a plenary session at EHA with ENERGIZE, that's a breakthrough. This is oral therapy, which makes it- Mm. - that much more convenient for patients. And now to have the kind of sister study of ENERGIZE-T, and we don't know the data, of course, but we're excited to see what that looks like because that package is a breakthrough historically for... or has the potential to be a breakthrough historically for these patients. Yeah. Great, and definitely having a broad, you know, regardless of transfusion dependency, that would be a first of its kind, right? That's right. That's right. Particularly also as an oral therapy. Yeah. How does ACTIVATE-T, this is your transfusion-dependent PKD study, how does this provide potential read-through to ENERGIZE-T? So, I think it's the overall program that we compare to the thalassemia program because we took a very similar development approach. Basically, having those two trials, one non-regularly transfused and one regularly transfused trial, complement each other and highlight that we can improve hemolytic anemia as measured via a hemoglobin response in people who are not regularly transfused, but then a transfusion reduction response in people who are regularly transfused. Because hemoglobin, you can't reliably measure because of the transfusions. And so we, we took that exact same approach now for thalassemia. And of course, now we have the first part of the puzzle, as, as Brian mentioned. The second part of the puzzle, we are still blinded to, but it's the same principle. Mm-hmm. Examining the disease as a whole, as one disease, independent of transfusion burden. The drug, the mechanism of action, is really focused on that red blood cell health, which is also independent of the, of the transfusion. Okay. And I think I know the answer to this next question, since you mentioned that, you know, you saw same responses across genetic subtypes, and it's an oral therapy. But I guess, what patients with thalassemia would be best suited for mitapivat? I guess, where do you see this fitting into the current treatment paradigm? Well, we're always obviously subject to the data and how it specifically reads out. But if I sort of invert it a little bit and talk about what is our goal, our goal is that all patients with thalassemia would have an opportunity to be on mitapivat. And again, if you just break it down, the fact that it's oral therapy makes it very convenient for the patients. We're already in a position of strength because of the ENERGIZE data, which covers two-thirds of the population. And this is a population, by the way, where they and their clinicians, they will need to be educated because they've never had a therapeutic option, so we need to help them understand what the potential looks like. Likewise, for investigators or for clinicians rather, there is a misnomer that non-transfusion dependent patients are somehow less at risk than the transfusion-dependent patients. It may be the inverse, because the ones with transfusions are actually, you know, they're in treatment, they're getting active transfusions, but all patients are undergoing ongoing chronic hemolysis, and that's the part that, in the long term, can be deadly for these patients. So it's really all types, and that is the beauty of the ENERGIZE program, is all dimensions we've designed to be covered in our clinical program. Okay. Okay, great. And Brian, you mentioned the US market as being roughly 6,000 patients. Could you maybe talk about what the global opportunity could look like and, you know, how you would approach commercialization ex-US? Yeah, we're very focused on two specific regions which have a very significant opportunity. The U.S., for sure, with the 6,000 patients, and again, 4,000 of those are non-transfusion dependent. The other big geography where we have a lot of focus is the Gulf or GCC region. And what is interesting and creates a tremendous opportunity is, on a per capita basis, the prevalence of thalassemia is a significant multiple of the U.S. There are approximately 70,000 patients in the Gulf region who have thalassemia, and the setup is the same. They have very limited treatment options. It's generally well known, particularly in the Gulf, that this is a more ubiquitous disease than we see even in the U.S. And so that's why our commercialization efforts are such that we're actively pursuing partners. You can imagine when the ENERGIZE data read out, we got a lot of attention from people who are interested in partnering for this opportunity, and that's where we are right now. Mm-hmm. is preparing for that. Beyond that could take, you know, beyond those regions, could also take the form of other partnerships as well. Right. Especially being an oral therapy, it could be easier to break into these other geographies. Yeah, and you know, what's great right now in thalassemia and sickle cell disease is we're seeing a lot of different modality approaches. And so the gene therapies, of course, have ex vivo, have made really good progress. That's beneficial because that is also educating these markets about the opportunity. But we're on the opposite end of the spectrum, as you note. Mm-hmm. To have an oral therapy married up with other potential options is really healthy for a biopharmaceutical ecosystem. I think there also our clinical trials are present in the region, so there is local experience with the product and engagement from key opinion leaders there as well. I think that is definitely an important attribute to the programs. Oh, that's a good point. And maybe along the lines of, you know, the regulatory path from here, I think obviously we'll see what ENERGIZE-T looks like, but, I think you've guided to a filing expected by the end of this year. Could you maybe walk us through your discussions with regulators or your regulatory strategy? We engage with different regulatory authorities along the program at typical milestones. We have engaged properly across the programs. I think right now our goal is really to submit the two trials together so they can enhance each other and have one review for the overall thalassemia, and that would be the approach we would like to take globally. Okay. Okay, great. Maybe moving on to PKD. So this is your approved indication. So maybe walk us through how PYRUKYND, the launch is going in this indication. Yeah, I'll take that one. I mean, it's really been a great opportunity for us because, as I noted earlier, when we pivoted as an organization at Agios to divest our oncology business to Servier, which has continued to be very successful, and really focus on rare diseases, starting with PKD, it's a challenging launch, but it's been a great proving ground for us, again, for building commercial capabilities and seeing how PYRUKYND performs in the real world. Mm-hmm. So, this launch we always describe as slow and steady growth. And Tsveta Milanova, who is our Chief Commercial Officer, and I worked at Alexion in prior life, and we dealt with launches just like this, where you just continue to make progress, and in the end, it never really stops. They just continue to grow. But you don't see inflections, you don't see a bolus. The challenge with this launch is it's very diagnostically intense. PYRUKYND was the first ever approved drug for PKD in the more than 60 years that PKD has been known as a disease. So you can imagine the educational lift involved in that. And so we've made great progress since early 2022. We reported in our last quarter earnings call for Q1 that we now have 120 so-called net patients on therapy. Those are patients who are the end result of having started and some who have discontinued. Mm-hmm. That was 10% sequential growth over the prior quarter. It just emphasizes that slow and steady growth. Okay. Maybe just talk a little bit about treatment duration and if there's, like, a stacking effect that you see. Yeah, and that's been one of the real bright spots, is, you never really know when you see the clinical trial results, how it will play out in the real world. Well, and we haven't been specific on the numbers, but I can say qualitatively, we've been very pleasantly surprised with the patient persistency that we see. Those who discontinue, a lot of that reason is because they simply haven't responded, because not every patient, you know, has a response to PYRUKYND. But for those who do, one of the beauties of this product is not only does it work on hemoglobin and red blood cell health, but the patients feel good. Mm-hmm. That's a very real differentiating feature, it certainly in PKD, but it also has a read-through to thalassemia, which we've already seen the fatigue data from ENERGIZE, and we certainly think that potential exists in sickle cell disease as well. Great. Yeah. And we'll see that totality of, you know, not just the efficacy metrics for the clinical study, but also the totality of the, you know, quality of life at EHA. At EHA. Yeah. That's our second advertisement in this... Go to EHA. One point to highlight there is that because we're talking about PKD, this is now the second hemolytic anemia in which we see that same pattern. Mm-hmm. So, the consistency of the data across the hemolytic anemias has been, has been great. Right. Right, right. So you do have a sales force for PKD. Is there any synergies that you could leverage here for a launch in thalassemia as well? Or we have to sort of build out, you know, a bespoke sales force? Well, the answer is both. Again, that's why the sequence is just perfect for us as an organization. So we began to build up our commercial capabilities and presence with PKD. There is overlap between hemolytic anemia prescribers, though it's not 100%. So we build from PKD as we move into thalassemia. And, you know, credit to the disciplined OpEx approach that we've taken, guided by our CFO, Cecilia Jones. We waited until we had the ENERGIZE results early this year to gate building up further commercially, and we're doing that in a very controlled fashion. But we essentially ultimately want to be in a good position to maximize the value of the thalassemia launch. And it goes beyond that, too, by the way. We can always leverage the core of commercial, and then as we continue to make progress with our clinical trials and move in, for example, into sickle cell disease, we can continue to further expand appropriately. Okay, that's actually a perfect transition. Let's talk about sickle cell. Could you maybe walk us through, you know, the ongoing program? I think we're expecting data next year. And how would you sort of frame, you know, phase three enrollment, completion, timing, and then, you know, what the data readout could entail? Yeah, Sara. Yes, sure. So our phase three, we are very happy with how it is going. We have guided towards a full enrollment by the end of this year, which would indeed put us in a position for data next year and a potential launch the year after. In regards to the data, the way the trial is designed is really trying to deliver data for the totality of sickle cell disease. So we have two primary endpoints. One is hemoglobin, and the other one is sickle cell pain crisis reduction. So those are two very important components in sickle cell disease because people truly suffer from the hemolytic anemia component, which makes them very fatigued. And we know from patients that that is very, very important to them to have a drug that actually tackles that aspect. Sickle cell pain crisis is just an absolute devastating event that can be deadly, right? Each sickle cell pain crisis can actually potentially kill you. So that's why those are the two primary endpoints. We have an alpha split on those two primary endpoints to be able to go on to secondary endpoint testing, which gives us other measures of looking at how patients feel, function, and are doing on sickle cell pain crises. So the data package that the RISE UP phase 3 will generate will hopefully deliver towards the, the product profile of a one-stop shop type therapy that can tackle sickle cell disease. Can I just ask, do you want to do a third advertisement for EHA and talk about the renal study that will be featured? Yes, I do, actually. At EHA, we have our two trials highlighted. So we've just spoken about RISE UP, which is a trial in progress poster at EHA, but we are also embarking on another clinical trial for sickle cell disease focused on kidney health. Mm. Because lots of patients with sickle cell disease suffer from sickle cell disease nephropathy. And with the mechanism of action of our drug, we believe there may be potential benefit on proteinuria. So that's what we're going to measure in this other trial. So details will be presented at EHA. Okay, and maybe just quickly on the competitive landscape in sickle cell. You know, it sounds like you're approaching the disease through a few different arms with your different studies. How will this feed into, you know, a competitive, clinical profile, in sickle cell? Well, we're already starting from a position of strength. Even if you just look across all of our studies, and again, it goes back to the red blood cell health component, as well as how patients actually feel, which is critically important in any chronic rare disease, where you are dependent on not just patients starting, but patient persistency as well. And so the data that we got last year, the RISE UP phase II data, was very inspiring because of the hemoglobin improvement that we saw in both doses, and of course, we picked to go forward the higher of the two doses. But also, you know, markers of hemolysis is a major component that is unique to the data that we've seen consistently to mitapivat and the mechanism of pyruvate kinase activation. And then the fact that we saw in sickle cell disease, we weren't powered for this, but seeing the positive trend in these sickle cell pain crises is very encouraging, and we'll have to wait to see the data. But if we are successful on even a combination of these measures, that is a very competitive profile in sickle. Okay. Okay, great. And we've touched on, you know, PKD, beta-thal, sickle cell. Those are the main, I think, focus points for investors today. But you also have an earlier pipeline. You mentioned AG946. This is your second PK activator. You know, how are last year's phase IIa results informing design of the phase IIb in LRMDS patients? So our phase IIa was really our first endeavor in an anemia that is slightly different than the other ones that we had studied before. And so we chose to go with a small phase IIa open label to really get learnings in this specific disease. One thing that we learned from that study was that the dose was not high enough. So one of the changes we are making for phase IIb is actually increasing our doses. And then some other changes will be made, too. So we've guided towards starting that phase IIb mid-year, and so are on track to do so. Looking forward to really then also talk more about the full details of the phase IIb trial. Okay, great. And, Brian, in your prepared remarks, you mentioned your strong cash position. Maybe we can just turn to that, and you know. I guess first, how are you thinking about monetizing the anticipated revenue stream? Or how should we be thinking about that 50% royalty on vorasidenib? Yeah. So I would say that investors should think about that as a really strong option for us, because we could retain it, we could monetize all of it, we could monetize part of it, and actually, we have history doing this, fairly recently with Tibsovo. Mm-hmm. Where we did monetize remaining royalty post the divestiture to Servier. So I think the net takeaway of that is, this gives us you know, really good balance sheet strength to build upon what we already have. We will be disciplined on how we deploy our capital, but we also have no shortage of just great opportunities to invest in, whether it's the late-stage studies or preparing for the launches or even possibly selective BD to continue to build out our franchises. So all in all, it just reinforces the momentum that we have and the position of strength. Okay, fantastic. I think we're just about up on time, but you know, looking forward to your analyst event around EHA, on- So are we. On Sunday at 10:00 A.M. I think it'll be good. Yep. So looking forward to that, but, you know, I think we'll have to leave it there. But thanks so much for joining the conference. Alec, thank you very much, and for everyone who tuned in, thanks so much for your interest in Agios. It's a really exciting time. Great. Thank you. Thank you.