We'll go ahead and get started. Good morning, everybody. Welcome to the 2024 RBC Global Healthcare conference. My name is Greg Renza, one of the biotechnology equity research analysts here at RBC, and for our first fireside chat this morning, we're pleased to be joined by Agios Pharmaceuticals. And joining us from the company is the CEO, Brian Goff, and the Chief Medical Officer, Head of R&D, Sarah Gheuens. Guys, it's great to see you. You too, Greg. Thanks very much for hosting us, and good morning, everyone. Well, it's a rather interesting time for Agios, a great deal going on. Brian, maybe for opening remarks, we'll just have you kick it off with some color on mitapivat and Agios for those who are less familiar with the company. Yeah, happy to. Agios is a company that is exclusively focused on rare diseases, and the core of that focus is around red blood cell health. And we have a very unique mechanism that delivers that, which is pyruvate kinase activation, and we're the industry leader in PK activation. We have a flagship product, as you noted, called mitapivat. It's commercialized as PYRUKYND in the U.S. And we were really pleased to have the first approval for mitapivat back in early 2022 for an ultra-rare condition called pyruvate kinase deficiency. But what is exciting right now, in particular, is that we're rapidly advancing our late-stage studies into significantly larger potential indications, namely thalassemia and sickle cell disease. 2023 was just a great year for Agios. We made progress against all of our corporate goals of advancing our pipeline. I must say, we were delighted to start this year, 2024, on a really fast start with the announcement of our top line results for ENERGIZE, which is a pivotal phase III study for non-transfusion-dependent patients with thalassemia. What's important about that is that this represents approximately 2/3 of the thalassemia population in the U.S. And the results of that study at a high level was very strong statistical significance on the primary endpoint of hemoglobin improvement. And what I think pleasantly surprised a lot of folks was also both key secondary endpoints of fatigue through the FACIT-Fatigue scale, as well as hemoglobin concentration, also were statistically significant. So that's a really nice setup for a potential launch in thalassemia next year in 2025. Moving ahead, earlier this month, we announced that the other of our two thalassemia pivotal phase III studies, this one's known as ENERGIZE-T, for transfusion-dependent thalassemia patients, will be toplining those results this quarter, and we're really excited about that opportunity as well. The plan is to combine both of those studies in a single file, which we will submit by the end of this year. And again, that sets us up for a launch in 2025 in thalassemia. Particularly unique is this covers all thalassemia subtypes, alpha and beta thalassemia. And again, in the U.S., about 2/3 of the population have no approved treatment options. But I noted we're moving into sickle cell disease as well. Last year, one of the most exciting events was the report of our top line results from the RISE UP phase II study in sickle cell disease. What was interesting was both of our tested doses had statistical significance, again, of hemoglobin improvement, and the wow factor on top of that was that there was a positive trend in improvement in sickle cell pain crises, which are just devastating for sickle cell disease patients. Now, to my right, Sarah Gheuens and her team did a fabulous job moving very quickly from that RISE UP phase II result to starting enrollment in the RISE UP phase III study, which we're currently enrolling, and the goal there is to be fully enrolled by the end of this year. That would set us up for data in 2025, and then here we have a situation of back-to-back potential launches, thalassemia 2025 and sickle cell in 2026. And then the last thing I'll just note is, earlier in the pipeline, we also have two other very important assets. We have AG-181, which we're pursuing for phenylketonuria or PKU, and we started phase I studies the beginning of this year. And we also have another more potent PK activator known as AG-946. And, we read out last year our phase II-A result for low-risk MDS, and we're planning to start the phase II-B portion the middle of this year. So it's a great story. We're in a really strong cash position. We ended the first quarter with $714 million. We have a near-term potential milestone of $200 million payment from Servier based on the approval of U.S. approval of vorasidenib. Their PDUFA date is now announced as August 20th of this year. All of that is included in our runway guidance. What's not included is, very importantly, a 15% royalty on U.S. net sales, and we, we have the option to monetize some or all of that. And again, the PDUFA date is very soon, so it puts us in a really strong position. So we have momentum, we've got an opportunity for first-in-class launches, and we're preparing to build a multi-billion-dollar franchise. ... So there's a great deal going on, Brian. There is a lot. And maybe sticking with the here and the now, and the present, maybe just weaving in Sarah as well, with respect to the top line that's coming, as you mentioned, this quarter, ENERGIZE-T transfusion dependence. Maybe speak to the confidence you have from seeing certainly the prior ENERGIZE data, but just in general, how the trial is set up for potential success, what is your confidence there? Well, a couple of things here. I think the way we think about thalassemia is it's a hemolytic anemia, and, you know, the fact that you get transfusions or not is just a matter of care in a way, the disease remains the same. And so that's the principle, the underpinning principle of the program, that one, the disease is the same, and the mechanism of action of the drug is not dependent on transfusions either. So you can look at this as two supporting trials that are measuring an improvement of hemolytic anemia via a different endpoint, meaning a hemoglobin response, which we now already have the data on, or a transfusion reduction response, which we are still blinded to. It's the same principle set up as what we had for pyruvate kinase deficiency, in which we did a very similar approach. We generated data in a phase II in a non-transfusion-dependent population, then expanded that in a phase III, set up exactly the same way, and there we were able to highlight that principle of, that the drug improves hemolytic anemia as measured by those two endpoints. So like I said, we now have the endpoint that covers 2/3 of the population already with the non-transfusion-dependent trial, and now we're waiting for that other third of the patient population. As Brian said, we guided, we updated our guidance towards Q2, so very exciting times. Great. Maybe just cover a bit, we initially had a mid-year guidance for- Yes ... for the readout, but there are some factors, pushes, and pulls. Yes. How do you speak to just the ability to narrow that to the second quarter, especially when we think about patients who are currently in the trial or maybe sticking with rolling over? Right. And that's the unique thing about our trials, because the drug does have a taper, mechanism. Like, you have to taper if you want to come off drug. Mm-hmm. That means that dependent on the choices of the last patients, there is a two-month window about that creates a difference there. So we weren't able to pinpoint guidance more specifically until we actually knew the decisions of the last couple of patients, what they would decide to do. And so now we know, and so we have updated our guidance to be, you know, much more in tune with, with what we expect. Great. Great. And you touched a bit, Sarah, on the primary endpoint. We all love to compare across trials and across programs and agents. Maybe touch a bit on ENERGIZE-T's primary endpoint, maybe the differences with respect to luspatercept and the BELIEVE trial. What are those implications? Sure. So our primary endpoint is indeed a different endpoint than the primary endpoint that luspatercept used for their trial in transfusion-dependent thalassemia patients, and their trial was focused on beta thalassemia. Right. So that's already a big difference because the patient population between the two trials is different in the sense that we allow for all thalassemia to participate across our program. The primary endpoint, the definition is also different. So they had a 33% reduction in a fixed 12-week period interval within their trial. We are looking for a 50% reduction in any 12-week rolling window across the duration of the trial. And why we chose that endpoint is because it's a much more dynamic assessment of a thalassemia patient, because there are fluctuations in care, and this gives us multiple shots on goal- Mm-hmm ... because we assess each 12-week period interval. We also know that this is an endpoint that the regulators use to assess benefit, and so therefore, we decided to actually go for that endpoint as well. Maybe to add one finer point, because we know you're gonna do cross-study comparisons- Right ... that in addition to the points that Sarah makes about the endpoint measure that we have, which is in fact a bit different from the luspatercept trial, is also the fact that mitapivat is an oral therapy. So frankly, any reduction in transfusions is important at the patient level. But secondly, one of the confounds with luspatercept is it's a sub-Q given every three weeks. Mm-hmm. And so if, if you're a patient who is transfusion dependent, you need to go through the calculus of can you get in sync your treatment with your infusion schedule? And mitapivat has a very different situation, of course, for the patients. Oral therapy is obviously very convenient, and that, we assume, will not be the key feature because we think the data is really compelling, but it's an added element- Mm-hmm ... that means we don't have to even match numerically luspatercept. To be clear, we don't know the data, but we really feel like we're in a position of strength competitively. Method of administration with an oral is worth appreciating when it comes to looking at the endpoints and the rationale, and the clinical utility. I think it's especially important for once it hits the real world, because the clinical trial is the clinical trial. You have to have a bar, like a preset bar. Mm-hmm ... that you put there. But in the context of how mitapivat is used, you can imagine that for patients who otherwise spend a lot of time in clinic just getting a transfusion, if even one can be removed, that gives a lot of time back to people. Mm-hmm. So this goes where there may be a benefit in the real world, may be assessed differently than within a clinical trial. Yeah. And maybe to that, do we have a sense of the proportion of transfusion-dependent patients who maybe have a more modest response but still can benefit from, from mitapivat, still could receive treatment in the real world? Well, we're blinded to the data, so I don't—we don't know yet where our population will fall. Mm-hmm. You can imagine that, like, for people not having to come to clinic, and actually have now all of a sudden two days, basically, because you need to get your blood drawn- Mm-hmm. To get cross-matched, then you need to come to get the blood transfusion. So it's a lot of time that people spend in clinic. That, that can be very meaningful, even if you go from three weeks to four weeks schedule. Mm-hmm. Okay. And we're certainly hearing the, the, the regulatory strategy, the readiness for, for a launch in, in, in 2025, a broad, a broad label. Maybe, Brian, just speak to that, that market opportunity in the U.S., in the EU, when you come in hand with both ENERGIZE and, and ENERGIZE-T as the potential base case. Yeah, it's a really compelling opportunity. And if I just focus on the U.S. for a moment, there are approximately 6,000 adult patients across all subtypes of thalassemia. And I'll just note, and this is clearly different from our PKD launch, these are readily diagnosed situation where there's been an ICD-10 code for quite a long time. This is a well-recognized disease, though there's educational aspects that we'll need to do to awaken the community to the unmet need of the non-transfusion-dependent population. Of those 6,000, as I noted, about two-thirds of those are non-transfusion-dependent patients, so think of that as 4,000 patients. And then it's about 50/50 in the U.S. between beta- and alpha-thalassemia. And the alpha-thalassemia patients, just like non-transfusion-dependent patients in the U.S., have no approved treatment options. So it's a very high unmet need category. There's never been an oral therapy that has demonstrated efficacy for this population. And then you mentioned Europe, but I just want to pivot to another region that's particularly important, even more so, and that's the Gulf region or GCC. There, it is a multiple of the U.S. population. We're talking on the order of 70,000 patients with thalassemia. So when we think about what are our commercialization approaches, we're really looking for ex-U.S. partners, partner or partners. And you can imagine that based on the very successful data that we reported in January of the ENERGIZE trial, there's a lot of interest. Mm-hmm. So we feel like, again, we're in a real position of strength. The U.S. will really be our core focus for us at Agios, and then through partnerships, ex-U.S. Maybe sticking with the ENERGIZE data set, there should be more forthcoming, middle of this year. We know... We're not saying there's an association, but we know EHA, so some EHA news will come out in a few hours. You mentioned, Brian, that the FACIT score. What additional quality of life indicators could bolster the argument for adoption for the ENERGIZE data set? Yes, Sarah, you want to take that? Well, indeed, like we have more data within the trial. We also have performance measures in the trial, like six-minute walk test. So we have quality of life, just like patient-reported outcomes as it relates to fatigue, but then also performance measures, and six-minute walk test is a well-accepted measure. Mm-hmm. to assess that physical functioning. What also is important in the ENERGIZE data set, which underpins the mechanism of action, really, is the hemolysis improvement. The hemolysis improvement and impact on ineffective erythropoiesis, because that truly feeds into the mechanism of action of mitapivat, improving red blood cell health and making sure that the cells don't hemolyze and die. And that is important for a couple of reasons, because hemolysis is tied into long-term organ damage. Obviously, in a phase III, you can't measure impact on long-term organ damage. That would take multiple years. But the fact that you impact that primary event is very important. So that is definitely something that also helps in messaging towards physicians. Correct. For patients, it is nice because the hemoglobin and the improvement in fatigue, you do something immediately for your, for yourself, but it's kind of like taking cholesterol medications down the line. If you improve hemolysis, the long-term, you know, long-term impacts- And we- -are tackled. We've seen this with PKD. As I, as I noted, this is a much smaller launch. It's ultra-rare, but, that journey began in the beginning of 2022. One of the real interesting aspects with an admittedly smaller scale launch is the fact that this, these fatigue benefits, the how patients feel, the hemolysis improvements, the hemoglobin, that combination has really helped with patient persistency, which is so critically important in all of these chronic hemolytic anemias. That's true in thalassemia, and as we look ahead to sickle cell disease, you know, we're expecting the potential for the same scenario as well. I wanna touch on sickle cell next. Before I do so, I just wanna ask on a world where if the ENERGIZE-T doesn't perhaps meet our expectations and call it an unfavorable or an equivocal outcome, is there an alternate plan? Are we taking mitapivat through just with non-transfusion-dependent for a more narrower label? I think that would depend on the data set- Sure. Right? But, like unfavorable, that, that would be a problem. Mm-hmm. If it's not hitting the primary endpoint, but there is still signs of benefit within the data set, you can leverage that data set as a supporting trial still. So I think our going in position would remain the same. Mm-hmm. Would, of course, be much more discussion and, more analyses during the process, but the goal would still be to have a label for thalassemia. Yeah. And again, this is a pretty unique situation. As I reflect on launches in the rare disease space that I've been a part of, it's, I'm not sure that I've had a scenario where you have two pivotal studies, and the first one's already read out and already addresses two-thirds of the population. Yeah. That's a clear position of strength. And so our plan is we're filing at the end of this year, what the data reveals, which we're gonna learn, you know, this quarter will guide us on, on what the totality of that package looks like. That makes sense. Let's flip to sickle cell, the phase III RISE UP. How's that progressing? We're on track. Well, yeah, I want to brag again about Sarah Gheuens and her clinical operations team. Again, looking back at last year, the trial design itself is very elegant. It was an operationally seamless phase II, III study. And when we read out the very positive data with both the 50 mg dose as well as the 100 mg dose, both BID, and saw that both were statistically significant, and then we had this positive trend on sickle cell pain crisis. The great news is there were zero changes moving from the phase II portion in trial design to the phase III. The only change was we picked the dose. We picked the higher of the two, 100 mg, and almost in record speed, the team had already advanced into recruiting the phase III trial, and we're on track, and I'm very, very proud of what the team continues to deliver in that regard. Despite a traditionally challenging environment? Despite the tradition... Yeah, I guess our team is, the RISE UP team is a very passionate team. Actually, all of the teams are very passionate, I should say. But, they're really going for it. And I think the enrollment goals that we had set were, are ambitious in the context of sickle cell disease, but the team is on track, and we're like, we're looking forward to deliver a full enrollment by the end of this year. Yeah. And then the other thing that is also for sickle cell disease, which we haven't spoken a lot about yet, is because of the mechanism of action, there is an additional component to mitapivat, that it's a pan PK activator, so meaning it also activates PKM2, which may play a role in certain organs. So we're also actually embarking on a renal study to further elucidate the potential benefit on sickle cell disease nephropathy. I'm glad you brought that up because one question when it comes to PK activation is just to have a better understanding of the oral component versus the oral competitors or the oral landscape. And certainly, there's general pushback in the market for oral drugs in sickle cell based on launch experiences, as we know. So how do some of those differentiating points of mitapivat help to maybe enable a clinical experience that could buck those trends? I think what we're trying to do is really deliver a drug that can treat sickle cell disease as a whole, meaning the hemolytic anemia with the fatigue, because I think it is important that patients actually feel better when they're on a drug. And then the improvement on sickle cell pain crisis as another big component of sickle cell disease. But then now also, taking that one step further to look at organ damage, that is important in the context of sickle cell disease with this other trial. Yeah, and sorry, can I just add that I know among the investor community, there's always a temptation to look for analogs. Yeah. And in our situation, whether it's thalassemia, as we talked about, or sickle cell disease, there aren't really analogs for our opportunity in front of us. I think the best aspect you can look at is the efficiency with which we've recruited all of our clinical studies. Oftentimes, that's a good proxy of how the product profile is received, both at the investigator level and the patient level. And sickle cell disease has never had... The community has never had a product that has the potential to have hemoglobin and fatigue and sickle cell pain crisis improvement, and that's what we're going after. That, that's really helpful. And then maybe in thinking about just the PK activator landscape, we have others in this space, namely, mitapivat, looks like they're underway with establishing some of their p hase III timelines, maybe extending to 2027, if I recall. What significance does this lend to mitapivat's potential, maybe as an earlier market entrance in sickle cell? How do you break down the PK activation landscape? Well, I'll just start by, and then Sarah can add to this, by saying that that is why, first of all, we're the industry leader with PK activation. We have not one, but two. Secondly, we have a real opportunity to be both first in class and best in class, and the first in class is a function of some of these updated timelines that you'll talk about. And I think the third thing is, again, it speaks to the excellence across the board with how Agios executes, and a big part of that is the clinical trial execution, but it is reflective of the product profile that patients and investigators see. Anything you want to add? Yeah. No, I think you summarized it perfectly. Great. There's always so much to cover. I want to just acknowledge the pipeline and what else you have going on, Brian. Maybe we can just do that, just asking and closing on AG-946 development, just contextualizing some of that early data, where you are with the current program, and just thinking about the phase II-B studies for MDS. Yeah, stay tuned. We were excited about the proof of concept study for phase II-A that we reported at the end of last year, and our guidance is the phase IIb study will commence in the middle of this year. We also have... We're pursuing in another- ... to get data in the hemolytic anemia sickle cell disease, a phase I study, and we've not guided yet on the results or the top-line results of when we report that. But stay tuned. We're excited about the potential for PK activation across the board. There's a lot coming. Well, Brian, Sarah- There is. We'll leave it there. Thank you so much. Thank you, Greg. Thank you. Thanks, everybody. Therapeutics for a fireside chat as part of our 2024 Global Healthcare conference. Representing the company, we have Sandy Macrae, President and CEO. Sandy, thanks so much for joining us. How are you doing today? I'm doing well, thank you. It's a pleasure to be here. Great. Great, great. So we have a long list of questions here, but maybe before we ask some of the questions into the individual programs, can you just maybe big-picture talk about what progress has the organization made over the last few months, and most importantly, what's ahead here for Sangamo? Yeah, I've literally just come here direct from ASGCT. At ASGCT, we showed our new capsid, which is, without a doubt, we believe, best in class. We showcased the first-ever presentation of our integrase, which allows the recombination of large pieces of DNA. What it does is it reflects Sangamo's belief that being at the front of the science is always important, and it allows us to dedicate our future to neurology. To do that, you need both the cargo, the zinc fingers, or the integrase at one point in the future, but you also need a way to deliver it, and that's one of the key takeaways from ASGCT this year. It's about delivery, and there's a limit to the number of times people will go after the same disease and deliver. What's exciting is new ways to deliver, either with LNPs or with new capsids, as we've shown. That takes real scientific and focus, and that's what Sangamo has chosen to do. We've made some great medicines. The hemophilia product that with Pfizer, they'll show the results of the phase III in the summer, and they're tracking to file a BLA in beginning of next year. And once they do that, we get $220 million worth of milestones, and then 14%-20% royalties. We've got beautiful data on Fabry, and the agency has given us this remarkably thoughtful way forward with the phase III design that they've agreed with us. Allows us to get registration with as few as 25 patients. It really is one of the moments where you realize it's a partnership between the companies and the FDA to bring medicines to patients. And that allows Sangamo, as an entity, to focus on the science and bringing new medicines and new into new frontiers for genomic medicine. That's awesome. That's a great, great review, Sandy, here. Maybe staying big picture, I think some investor may actually argue that zinc finger proteases maybe don't have the same versatility than CRISPR-Cas9, and some of the more novel approaches that the field more broadly was able to develop the last few years. What would be your pushback to that? You know, I've been doing this job for nearly eight years now, and when I started, there was CRISPR, Editas, and Intellia. Now, I count 27 companies, and I'm not sure what each one brings that's different from the other. People still come back and use zinc fingers, and there was an article, an independent article from the Lombardo group recently showing that the zinc finger repressors are better than CRISPR, and that's an independent bake-off. Why do I like zinc fingers? I like them because they're natural. You and I have hundreds of zinc fingers controlling our genes. I like them because they're small. They're an eighth of the size of the CRISPR. They're a quarter the size of the mammoth small CRISPR. They are used in the body, so what they do, the repressors, is they control the expression at the promoter level, so they don't cause double-stranded breaks. And then we can add a whole series of functionalities onto it and choose what it is that we do based on the disease that we're trying to control. For the brain, because the cells don't divide, the repressors and activators are actually very useful tools. The zinc finger repressors is something we've been talking about for some time, and at ASGCT, we showed activators, unique activators, to turn genes back on again. So I'm very happy that I have the zinc fingers, and I'll watch the rest of them squabble over which is the best CRISPR. Gotcha. And then, with the integrase, we showed that we can once again pioneer the field. David Liu, a great, respected scientist, I sat in a panel with him once, and he said, "The dream is recombination at greater than 10% efficiency." And what we showed was 30%-50% efficiency with the recombinase. And what that will do eventually, it will let us put whole genes into the genome and correct for a whole variety of errors, and I think that is where the field is going to go. Got it. Got it. That's actually very helpful. You mentioned your new focus, obviously, on CNS. Can you maybe just talk about that a little bit, and maybe in the context of the route of administration? How are you thinking about prioritizing key or route of administrations? You have three programs. I think for one of your programs, you're actually using intrathecal delivery versus for the other one, you're hoping to use, obviously, IV with your novel approach that crosses the blood-brain barrier. Can you just maybe just expand- Sure. A little bit on how you're thinking about routes of administration here? So we made this decision 3 years-4 years ago, that this is where we're going to go. We made the decision that Fabry was the last liver-targeted gene therapy. We had a long-term plan because that's what you need to do, and we had a long-term plan that we would take Fabry into phase III, and that would finish that, and then the company would focus on neurology. The finances over the past couple of years brought that to a crescendo sooner than we'd expected, and that's why we're going to partner Fabry, and we're making great progress with those conversations. We looked at where the zinc finger repressors particularly work well, and neurology seemed to be the place. We looked at where there was unmet medical need, neurology seems the place. We believed that we could invent or discover a capsid that allows us to cross the blood-brain barrier. But before we did that, I told Amy and her team to find me things that existing capsids would be able to address, and that's where Nav1.7 came. 'Cause Nav1.7 uses an existing capsid. It's given intrathecally. It goes to the dorsal root ganglion, that's where the pain circuitry is controlled, and it turns down or turns off Nav1.7, which is a very well-understood target that everyone's trying to drug for tens of years. And because as a small molecule given systemically, it has cardiac side effects, nobody could make it into a medicine. Now, we've made it, we believe, into a medicine because we can administer it intrathecally and turn off the pain signal in patients with intractable pain. We should have an IND for that. We're literally completing the GMP tox studies at the moment. There should be an IND this year, in the clinic next year, and hopefully, results by the end of next year. Got it. Got it. That's very helpful. Can you just maybe talk about the non-human primates data and what you're seeing there for Nav1.7, particularly the histopathology findings? Is that- It looks good. Okay. And there has been a concern, there has been a discussion about dorsal root ganglion, and I think it usually is when people put a very active promoter, usually GFP and high doses, and they see inflammation in the dorsal root ganglion. We see none of that, 'cause we're using zinc fingers, which are natural, and we're using a sensible promoter, and in all of our histopathology, it's looked absolutely fine, and we've had good conversations with the agency, and they agree with our assessment. Great. Great. Great to hear. Maybe talk about indication selection and indications prioritizations. Why, for Nav1.7, do you think that chronic neuropathic pain is the lowest-hanging fruit, if you will? Why are you prioritizing that as your first indication that you're pursuing for that target? I get asked this usually in the context of Vertex and Nav1. 2. Mm-hmm. And that's a-