Welcome back to the 44th annual TD Cowen health care conference. I'm Marc Frahm from the biotech team. We're really happy to have the next session here with Agios where we have CEO Brian Goff and CMO Head of R&D Sarah Gheuens as well. Maybe Brian you wanna start off with just kind of giving a high-level status update and summary of Agios and and just kind of lay out what you think are the key events over the next year or so.
Sure. Well, first of all, thanks very much for hosting us, Marc. We're very happy to be here. It's a great start of the year for us at Agios. As many folks will undoubtedly know, we're a company that's focused on rare diseases and the core of our focus is on red blood cell health. And we were delighted to start this year with just an excellent readout of the ENERGIZE data set, which is a phase III trial focused on non-transfusion dependent patients with thalassemia. And we would be happy to discuss that even more. But the highlights are that this alone represents about two-thirds of the thalassemia population in the U.S. So now we look ahead to the middle part of this year, is the second of our two phase II trials in thalassemia that's called ENERGIZE-T.
This is focused on transfusion dependent thalassemia patients. Then we will package both of those two studies up together at the end of the year and submit a file and we'll be looking towards hopefully with just successful data along the way an opportunity to launch into thalassemia next year. We also were really pleased the last year to present the RISE UP phase II data in sickle cell disease. That was at the middle of the year. We presented the full data set at ASH and we were delighted there to have both a hemoglobin improvement finding that was statistically significant actually at both doses as well as positive trends in the all-important vaso-occlusive crises or sickle cell pain crises.
Just looking to my right with Sarah and the team just did an amazing job of very quickly going from that data readout phase II to within 3 months the start of enrollment for RISE UP phase III. We're looking to have that trial fully enrolled by the end of this year. We would get a data readout in 2025. That's a setup for then back-to-back potential launches thalassemia 2025 sickle cell disease in 2026. So I think the takeaway for where we are at Agios right now is we have great momentum. We have a very special and unique mechanism of action of pyruvate kinase activation which really supports our flagship product mitapivat or brand name PYRUKYND. It's just a busy time where we're accelerating our pipeline and moving into multi-billion dollar indications.
Maybe this is a little bit for you, Brian, but also for Sarah. Just, you know, I think people in the investment community have historically looked a decent amount at beta thal transfusion dependent patients. But once you go beyond that to the other populations of thalassemia that you're pursuing, there's a lot less experience. Maybe just review kind of the unmet need in those other populations and kind of the relative patient numbers in those four buckets alpha beta thal transfusion dependent transfusion non-dependent.
Maybe I'll do the numbers and then Sarah can take over on the unmet need itself. If we focus on the U.S. there are about 6,000 diagnosed adult patients in the U.S. and this is all of thalassemia. Within that 6,000 it breaks down to almost 50/50 between alpha and beta thalassemia which is a little bit unique. That's due to significant immigration patterns in the U.S. On a worldwide basis it's more like 1/3 alpha thalassemia 2/3 beta thalassemia. 50/50 in the U.S. and then with the dimension of transfusion dependent and non-transfusion dependent as I noted non-transfusion dependent patients are about 2/3 of the total. Here we're talking 4,000 patients in the U.S.
Again as a side note, that's why we were so delighted to have the positive readout of the ENERGIZE data because we feel like that population that currently has no approved therapies in the U.S. is now addressed by the ENERGIZE data. And the other 1/3 are the transfusion-dependent patients. And that again is the data readout that we'll look forward to at the middle part of this year with ENERGIZE-T. Maybe Sarah can say a few words on the clinical needs, the patient needs in the population.
Sure. So for non-transfusion-dependent thalassemia there are no treatments available to date. So the only treatment available in the U.S. is luspatercept for transfusion-dependent beta-thalassemia patients. So our drug hopes to provide the treatment for all thalassemia independent of genotype independent of transfusion needs. And that's how our trials were designed to be able to support efficacy and safety data there. In regards to the unmet needs, so non-transfusion-dependent thalassemia patients still suffer from the same hemolytic anemia. So they have an ongoing anemia with fatigue impact to their performance and general quality of life. But most importantly hemolysis leads to iron overload independent of transfusions, leads to chronic iron accumulation in secondary organs so organ damage there.
So they have huge morbidity and mortality, which before was not much appreciated, but now physicians clearly understand that and clearly want something to treat non-transfusion dependent thalassemia patients. And in regards to, do patients want something if they don't want to don't need transfusions? Definitely we had clearly they are very willing to participate in a clinical trial. We were able to enroll this trial ahead of schedule and actually had more patients wanting to participate, which typically speaks to people wanting to do something about their disease.
Okay. And maybe you wanna review the kind of top line data that you were able to show, and then, you know, when should investors expect to kind of see the full data presentation?
Yeah. So our clinical development program has two trials ENERGIZE and ENERGIZE-T. ENERGIZE is the trial that we read out and that's the trial that covers non-transfusion-dependent thalassemia patients both alpha- and beta-thalassemia patients. And we were very pleased with the results because we were able to highlight statistical significance on our primary endpoint meaning the hemoglobin response was met in 43% of the patients treated with mitapivat versus 1.6% in placebo. But most importantly that was actually accompanied by statistical significance on patient-reported outcome as measured by FACIT-Fatigue. And that's the first time that that was that that has happened in a clinical trial encompassing both subtypes. And then obviously because of the mechanism of action we also are very pleased with the hemolytic parameters and the improvement there.
Another point that I would like to highlight is that from the pre-specified subgroups that we tested, so genotype was a stratification factor in the trial. For instance, all of the pre-specified subgroups favored mitapivat versus placebo, which is very very good as well.
Okay. And maybe that fatigue scale that you were able to show the benefit on it. Can you give some context for the magnitude of the benefit there? What does that mean for a patient, that what you were able to show?
So we have not disclosed the full details on the results yet and hope to do that at an upcoming medical meeting. But the fact that we were able to hit on statistical significance in that clinical trial on a PRO is very meaningful. And it's actually the second program in which we were able to do so because we also had this happen in PKD. In regards to what does this concretely mean for patients if patients feel better then they are more likely to want to stick to a treatment and actually take a treatment. In what does this practically mean that's gonna be defined differently for every patient that is going to go on drug.
But it can go to being able to perform activities that they were never able to do before, like and simple things like completing a shower without getting out of breath or brushing your hair, very simple things like that, to be able to actually get through a day and do normal amount of work in the household or at their jobs without having to take naps, things like that, to just performing better in general. And so we hear patient anecdotes from, you know, from trial participations across the different hemolytic anemias that speak to things that they have been able to accomplish that go above and beyond.
Yeah. I would just add as a company that is deeply focused on rare diseases and the details of the patient journey itself this is where our commercialization approach will really matter. Because in the case of thalassemia especially and you might even say sickle cell disease as well sometimes the words work against the reality for the patient. So fatigue when we just say that word everybody has a kind of mental image of what fatigue is. But for these patients it's devastating fatigue. It's as Sarah says maybe they can't even groom themselves raise a hairbrush can't walk up a flight of stairs without having a rest for an hour. And it's that kind of impact that we think is so special about this mechanism.
I would also say, and we talked about it already, non-transfusion dependent thalassemia that phrase "non-transfusion dependent" works against the reality because a lot of times people think oh that's less severe they're less at risk. What we're seeing increasingly is because all of these patients are subjected to daily hemolysis. Hemolysis free heme in the body is deadly and can accumulate and cause organ damage. That's what we're gonna look to address with this very unique mechanism of action hopefully with the plan in a very broad label for all patients.
Okay. In that trial, one you know concern we've heard from investors is that they look at the data you were able to that you did release on hemoglobin response and they compare it to the Beyond trial of Reblozyl obviously didn't lead to a U.S. approval but it has ex-U.S. and they look at that and say the hemoglobin response doesn't seem quite as good as that. But you did hit on fatigue. How do you how do you reconcile those Sarah?
So this is where we've always highlighted that a hemoglobin plus story is important in this context. So we are able to highlight that the way we improve hemoglobin by impacting hemolysis makes people less fatigued. So we can speak to clinical benefit from improving hemoglobin. I think that is a unique difference in that patient population. And then, in the other way around, also, there was a higher response rate with luspatercept if you just compare percentage-wise. But they were not able to hit on that patient-reported outcome. And so that's where we truly believe that the mechanism of action and the way we improve hemoglobin is very very important.
Okay. And then the other piece on that that I get from investors is how to translate that then over to ENERGIZE-T and the transfusion-dependent where it is really about transfusion burden, you know, reducing transfusion burden. And a lot of that decision to transfuse—it's driven by just a pure hemoglobin count number, right? So like.
Right.
You know, doesn't this imply that you're unlikely to show quite as good of just pure transfusion reduction?
No, because our mechanism of action impacts hemolysis, which is ultimately how the hemoglobin degrades to a point at which a person needs to be transfused again. So the fact that we impact that hemolysis component should be able to lead to a prolonged time frame by which a person gets transfused. You don't need to overstimulate and increase hemoglobin to get there.
Maybe you wanna dive in a little bit more on that, just kind of the difference of the mechanisms of action here when we think about comparing to Reblozyl and you know and how that plays out in a transfusion patient who is getting transfusions.
So the way the patient gets a transfusion in a clinical trial, there is a transfusion threshold that is calculated for each patient. And that is based on the historical transfusions patients receive. And then once they enter into the trial, that threshold is used to determine if the patient needs a transfusion yes or no. And that's what we want to standardize across all of those different trials and bring consistency across the board. And also to make sure that it's not very subjective just by feeling better really or saying that they feel better that it gets postponed. So there is a standard way to do that. And so the point is to try to not get to that transfusion threshold because that's what triggers a transfusion.
Again and again, I hope the takeaway from this discussion 'cause I know there's a lot of folks listening in is this is ultimately a very different mechanism. It's kind of rewiring the way we're thinking about some of the biomarkers and what one could conclude. And it's clear that in the focus on red cell health it's more than just hemoglobin. And that's not to be apologetic about the fact that mitapivat does elevate hemoglobin but it's more than that. And as Sarah said it's hemolysis it's increasing the ATP energy of the cell to handle the oxidative stress that comes with thalassemia. It's better hydrating the cell. And the consequence for the patient is they feel better. And so that's why we're very careful to help people not try to make comparisons across studies because these are across studies with very different mechanisms.
Okay. And in there in your last answer Sarah, you mentioned you know having these thresholds in the trial right that are set based on historical data. But of course I mean based on the other data and other indications mitapivat seems to be making the patients feel better. And that is part of this you know why they had a threshold. So how does that impact kind of real-world use of mitapivat?
And that's of course where the difference between clinical trials and patient care in the real world comes in. Because indeed in the real world it is patients are not necessarily looking for that 50% reduction in any 12-week you know rolling period. But any prolongation in their transfusion schedule may be meaningful because that can give them a full day back which 'cause transfusions do take like a long time in clinic. So any transfusion that they can postpone is gonna be meaningful. And that's what we hear from patients and physicians especially because this is an oral pill that can be taken in the comfort of their home. And it's not adding to their clinic visits which you know for luspatercept you still have to go to clinic every 3 weeks to get a subcutaneous infusion.
When we do see this data, the ENERGIZE-T, I guess how are you gonna evaluate that? That the threshold is a 50% reduction is a response, right? Of
Yeah. That's the end point. Yeah.
Is the endpoint, you know, what's a meaningful difference there, you know, when you read it out? Is it just that sig? Is it some other threshold or some other number?
So now of course we're shooting for to hit on statistical significance for our primary endpoint which again is like that 50% in any 12-week rolling interval. We specifically did that in collaboration with the agency. But that is also because any 12-week rolling period is more meaningful than a fixed period because a patient is dynamic, and that's why we chose that endpoint. We feel confident that we powered our trial properly to meet that primary endpoint and that the sample sizes can accommodate this. But of course we're blinded and we're gonna have to wait until we actually see the data.
Recognizing Brian, I know you're trying to discourage people from cross-trial comparisons. But invariably that's what we do on Wall Street.
Got it.
So there's some subtleties there of the endpoint that are different. You wanna kinda run through how it's different, you know, with luspatercept and how to think about those differences and how transfusion reduction is being measured?
Yes. So the primary endpoint for luspatercept was a 33% reduction in a fixed 12-week period between week 13 and 24 as our primary endpoint. But again that is picking a specific period. When we spoke to the agency, we, you know, collaborated on that. And we know that the 50% reduction in any 12-week rolling period was part of the assessment made on luspatercept. But that was not a pre-specified endpoint for their trial. However it's a pre-specified endpoint for ours because that is what we know is used as a bar to assess efficacy.
Okay. Obviously it'll be informed some by the data. But just how should we think about pricing right? Yeah, there is a price out there for it; it's approved in PKD, that that price is there. You know when this launch hopefully launches in thalassemia in a year and a half or so you know how should we see is that price being able to be maintained? Do you need to reduce it 'cause it is a larger patient population?
Yeah. I think I mean first of all everyone will appreciate the fact that we don't talk specifics on price until we actually have the data and we have clarity on the label. But the good news about the sequence of how we've stacked these indications is that the prevalence continues to increase when we go from PKD ultra-rare to thalassemia rare and sickle cell disease rare but greater prevalence. I would think of it as thalassemia and PKD are still very much in the same neighborhood of general prevalence. We talk in terms of 3,000-4,000 patients for PKD in the U.S. and about as I noted 6,000 patients who are diagnosed adult patients in the U.S. So we believe that the pricing is manageable.
I must say that we hope with the data readouts that we face a situation where we say okay, as we step up from 6,000 diagnosed thalassemia patients in the U.S. to potentially 100,000 patients with sickle cell disease, we hope we have that challenge. We think it's navigable certainly in the U.S. and definitely around the world.
And in terms of building out for those 6,000 thalassemia patients, you know, walk through kinda the incremental commercial build that you need in the U.S. and.
Yeah. We have a rather small commercial footprint right now, understandably, because we're commercializing PKD, which, as I noted, is ultra-rare. This is for adult patients only. We've been very thoughtful to not expand until we had clarity on the disposition of the ENERGIZE data. Now, as I noted, that data played out so positively that we feel very well prepared to address two-thirds of the addressable market in the U.S. So we're now thoughtfully preparing for expansion. I would still think of that as modest. This is still very much a rare disease, and it's not only, you know, sales reps and customer-facing teams. It's more sophisticated than that in the commercial lever that will be executed for this rare disease. But modest investment is what we think is appropriate to capture this opportunity.
And would I mean hopefully ENERGIZE-T is positive. But would you be willing to launch with just ENERGIZE and just that population if ENERGIZE or is that not a.
It's, well, it's an interesting scenario that we're in right now. But thankfully these two trials are very close together. So we have always planned to file this as a package. And secondly we already with the ENERGIZE data we have a very strong package. Supplementing that is what we're gonna be looking for from ENERGIZE-T. That's the other roughly third of the population in the US. And there are many benefits that can come from that trial besides just the primary endpoint. But again the plan is submit that together at year-end.
And I missed one question I meant to ask you Sarah. I just, obviously, the primary endpoint, the transfusion reduction—are there other kinda important secondaries you would point to beyond, you know, like the fatigue score from the, you know, or something else that now gets to that?
It's different ways of measuring transfusion reduction. Quality of life, specifically FACIT-Fatigue, you can't really measure that in a transfusion reduction trial because the moment a person gets transfused they actually feel better typically. There are some other quality of life questionnaires related to transfusion specifically that are being measured there. But the true clinical meaningfulness comes from the different ways of measuring transfusion reduction.
Okay. Unless there's from the audience something in thalassemia that's gonna spend the rest of the time on sickle cell. Okay. So let's move to sickle cell. You did touch on the phase II data. Maybe Sarah you wanna just walk through the activation there of the phase III and kinda where you are in the phase III in terms of getting it going?
Yeah. So we had great phase II data. And this is where the seamless operational design for the phase III really helps. Because of that dataset we were able to proceed with the protocol fast. Didn't have to change anything to our inclusion/exclusion criteria. And we're able to, as Brian mentioned it earlier, get to enrollment fast after a phase II. And so right now the team is very focused on getting the full phase III trial up and running globally. And enrollment is on track. And so we are, you know, we've declared our milestone to have completed enrollment by the end of this year. So looking forward to that.
And is that the next update from that is when you complete enrollment or is there an interim, you know, some companies will release, say, when they've crossed, you know, 50% or, you know, some other threshold?
We don't currently plan on doing that. We don't have an interim analysis obviously.
And.
Stay tuned 'cause we have we have a lot to talk about. This is a very dynamic year for us as was last year.
And in terms of the phase II-A, you know, obviously it did show a trend on VOC.
Yeah.
We definitely get pushback at small dataset. And you know, but what gives you confidence that this small dataset followed for you know just a few months is really predictive of what's gonna happen in the phase III?
A couple of things that give me confidence on that. So first of all, this is actually our third dataset in sickle cell disease. So we had two open-label trials, one at the NIH, one with Dr. Van Beers in the Netherlands. And now our RISE UP dataset that are all pointing in that same direction. And we're very pleased with the placebo-controlled trial dataset of RISE UP because it hit on the hemoglobin, hemolysis, and sickle cell pain crisis reduction. It, so it delivered on that trifecta of data. And why I feel very good about that dataset is because both doses hit against placebo, so 50 mg and 100 mg for hemoglobin response were positive against placebo.
But then when you looked at the hemolysis improvements and the sickle cell pain crisis reduction, there was also that dose trend with the 100 mg being stronger for hemolysis and for sickle cell pain crisis as a trend. So the fact that those hemolysis and sickle cell pain crisis both point in that same direction gives me confidence as well. And so therefore we didn't change anything on our, like I said earlier, to our inclusion and exclusion criteria based on that dataset. Didn't change anything in the design in the powering assumptions. So I feel very confident about our phase III.
The other piece we get pushback on is just the rate even on the placebo arm, the rate of VOC seemed lower to people than what has been seen in competitor phase III programs or even in your baseline characteristics. So, was there maybe walk through kinda why that may have happened and.
Sure. So the baseline characteristics are one way to try to capture a patient population that is having enough sickle cell pain crisis to be able to measure that reduction. This was only a 12-week period of observation that we then extrapolated. And even with that slower lower number you still see that clear pattern within the dataset. So we feel this is exactly the reason why you want placebo-controlled trials to be able to see how there is like a good distribution around the baseline characteristics and then see that play out over those 12 weeks that you observe them.
And then Adakveo was approved, had a confirmatory phase III that, you know.
Yeah.
So it was approved with potentially a VOC benefit. And then confirmatory you know failed to show that. Just any learnings there that you've been able to incorporate into the trial as to kinda how best to conduct a phase III here?
Well, I think we have gone for as much consistency as possible between our phase II and phase III. Meaning, again, we're using the same definitions, same type of patient population. But it even goes to the same adjudication committee, things like that, that I think are important. Plus, our phase II sites are all participating in phase III, so have experience with the trial as well. What I mean, what happened to crizanlizumab is very unfortunate. I don't, I mean, I really feel bad about that 'cause the sickle cell disease community really needs therapies, many therapies. But again, I think our program is set up in a very different way just because of all of those things that I just mentioned.
Brian, is it all about hitting VOCs? Is that the kinda only way you'd wanna file in sickle cell or are there other things that from a maybe medical but also strategic.
Well, I think sickle cell pain crisis is without a doubt an endpoint that is considered clinically meaningful. So from a regulatory perspective if you hit on sickle cell pain crisis that is an easier hurdle to cross. That being said when you talk to patients they feel like they can manage sickle cell pain crisis with opioids. But they are looking for solutions on how they actually feel. So fatigue comes out as a major complaint and something they can't tackle. And this is indeed not to Brian's point earlier fatigue I feel a little bit tired. This is exhaustion to a point that we can't imagine. And that is what they are really looking for a solution.
So we are looking at that as well in our trial because we have that hemoglobin plus story that we always talk about hemolytic anemia impacting that and thereby making people feel better. So we're looking to do a similar thing for sickle cell disease.
Yeah. I just wanna add and that's what I'm very proud of that we do at Agios is we shoot for an ambitious goal on behalf of these patients. And sickle cell disease, for those who have spent time with patients, it tortures patients. And that's why we cheer for everybody who's pursuing advancements in this area. They need multiple options. We're really proud of what this mechanism can offer these patients. But if we could get hemoglobin improvement, yes, vaso-occlusive crisis of course in the mix. And then addressing this devastation of fatigue that's a real win. But hemoglobin plus any of those would be very significant for the patients. And likewise again on thalassemia we're going after a broad label. It's we don't wanna leave anyone behind. That's the way we designed our trials.
That's really the core of what we're so proud of at Agios.
Coming back to the question about commercial build-out, now thinking outside of the U.S., you haven't commercialized PKD outside the U.S. and it is approved but you haven't commercialized it. Is thalassemia enough to build that or do you need to get going or do you need to see the sickle cell data at least maybe not approvals but see the data to kinda know what you have before you make a decision of what the best path for is?
Well, no, for thalassemia I mean it we could treat these independently. For thalassemia it's a very interesting geographic footprint uniquely. The U.S. is clearly our top priority. But coming right after that is the Gulf region GCC. And there you know when I talk about 6,000 diagnosed adult patients in the U.S. in the Gulf we're talking about a population of 70,000 thalassemia patients. So much so that it sometimes is not even described as rare. For that we're looking at partners. And that can take different forms. But I would think of it as a partner that has local strong expertise full service that could seize that opportunity and really create significant value. Other more traditional areas like Europe for example astonishingly it's not as significant for thalassemia.
When we go to sickle cell disease that is a much larger global population here. We're talking about 1 million patients on a global basis potentially.
And then thinking through pricing in sickle cell just ha you know you mentioned you know hopefully you're in this position.
Yep.
Where, I mean, should we look to drugs like Adakveo and Oxbryta as reasonable comps, or the dataset you're hoping to build would justify a very different price? Just how do you think through that?
I would look at it as, again, as I said, the sequence is going the right way for prevalence. That sickle cell is a meaningful step up in prevalence. If we deliver on the label that Sarah has talked about, that is tremendous value at a patient level, at a payer level. And we would price it accordingly. Now, where exactly that is, that probably depends a lot on the geography. And it depends on how we have sequenced the launches around the world. But it's navigable from our perspective. And the way we'd like everyone to really think about this is, this is a significant value-creating opportunity. And these are multiple billion-dollar-plus launch opportunities right in front of us.
And fortunately that's all the time we have. So we're gonna have to cut off the conversation here. But thanks a lot, Brian and Sarah and everyone else for joining.
Thanks, Marc. Thanks, everyone.