Great. Good morning, everyone. Thanks for joining us. I'm Salveen Richter, biotechnology analyst at Goldman Sachs. We're really pleased to have the Agios team with us. We have Brian Goff, CEO, as well as Sarah Gheuens, Chief Medical Officer. Maybe just to start here, Brian, if you joined Agios as CEO last year, can you just discuss any notable changes in strategy in addition to where you stand on your lead, you know, commercial assets as well as the pipeline at this point?
Sure. Thanks a lot. First of all, thanks so much for hosting us. We are thrilled to be here. We have a lot to talk about. It's a very exciting time for Agios. The last year, for me personally and as well for Agios, has been absolutely tremendous. We had many accomplishments, which we're very happy to talk about. We have a lot of milestones coming this year and beyond. Well, first of all, let me just say that Agios is a company that is exclusively focused on developing transformative products for patients that are living with rare diseases. Our focus right now is on building a pyruvate kinase activation franchise.
Looking back on last year, what we were thrilled about is that we had our first launch in this arena, and this is with PYRUKYND or mitapivat, which was approved for adults with pyruvate kinase deficiency. This represents the first approval in the 60 years that PKD has been known about as a disease. This is a disease-modifying therapy, again, for adults with PKD. What we're seeing is not just success on an ongoing basis with the launch, but also continued generation of very consistent data with PYRUKYND, not just in PKD, but across other hemolytic anemias that we're pursuing. That was quite an accomplishment. We also made some changes to the management team, and in the room with me today is Tsveta Milanova, as an example, and Tsveta is our Chief Commercial Officer.
We worked together at Alexion, where she ran the U.S. business. At this moment in time, when we have so much going on and we're preparing for launches even beyond PKD, it's just wonderful to have someone like Sveta with her commercial rare disease launch experience and her significant experience in reimbursement in the U.S. and around the world. That's perfect timing. We have a balance sheet that is enviable, particularly in this particular market. We left off in the first quarter of last year with about $1 billion on our balance sheet.
I'll just make a side note that in addition to that, we had an interesting scenario play out last, 2 weeks ago at the ASCO meeting, where vorasidenib, which came out of the Agios labs, this is a product for low-grade, IDH1 and IDH2 mutated glioma, was one of four products chosen for a plenary session among 5,700 abstracts. The data was phenomenal. This is now owned by Servier, but the reason I bring it up is that we have a $200 million milestone that we retain, such that when vorasidenib is approved in the U.S., we receive that milestone, and we will receive 15% royalties on U.S. net sales. We don't have specifics as to exactly what the launch timing will be. That's determined by Servier.
We were really pleased, number 1, to see the data, because it's so meaningful for patients. Secondly, we read in their press release that they're looking to a potential launch in the second half of next year, if all goes well. That only further strengthens our balance sheet, and we're really happy about that. The last thing I'll just say is in terms of milestones, and I have an update for today's discussion, that we have a program, a study underway for our other PK activator, AG-946, and this is a phase 2a proof of concept study in low intermediate risk MDS for the anemia portion of the disease. I'm really happy to report that as of now, we have completed enrollment for that phase 2a study.
Our original goal was the end of this year, so now we have updated our guidance such that we'll be looking towards a data readout by year-end, and we're really excited about that. This is a high unmet need area that I'm sure we can talk more about, but it's just another piece of evidence of how great the execution has been from Sarah Gheuens and her clinical development team. I'll add that we're equally excited that this year we accomplished conclusion of enrollment for our thalassemia program, and that's ENERGIZE and ENERGIZE-T. That puts us on a path towards a readout for ENERGIZE, the non-transfusion dependent patients in the first half of next year and ENERGIZE-T in the second half of next year.
If that goes well, then we're looking at a launch potential in 2025 for all subtypes of thalassemia. Lastly, we have, of course, our sickle cell disease program underway, and we have guided towards a readout of our Phase 2 program in sickle cell disease at the midpoint of this year. We're looking forward to approaching that date soon. Very excited about that potential, and that will guide us to a pathway with success towards a Phase 3 program, and that may set us up for a potential launch for sickle cell disease in 2026. We have a lot going on.
... Exciting. Maybe let's start with PYRUKYND and sickle cell disease and where you've guided to the top line data disclosure midyear. Can you just remind us of the benchmarks that you're setting up into this readout? You know, how should we think about what the clinical bars here are and what you want to see at this point in the drug development situation?
Sure. I'll just say again, just to brag about Sarah, that her team has done a fabulous job of not just executing on these trials, but also working deeply with the community to make sure that the setup for the trial really captures endpoints that are meaningful ultimately for the patients and their families. Maybe Sarah can describe some of the highlights of the trial design.
Sure. The RISE UP study is an operationally seamless clinical trial, a randomized clinical trial, a phase 2 and a phase 3 in 1 protocol. What we've guided to is indeed phase 2 data, middle of this year. That phase 2 data is a 12-week study, 69 patients randomized 1 - 1 - 1, there's 2 doses being tested against placebo. Within that 12-week time period, the primary endpoint is focused on a hemoglobin response. That hemoglobin response is defined as a 1 gram per deciliter increase or more, compared to baseline, you know, between week 10 and week 12 compared to baseline. The benchmarks we've used are voxelotor to make assumptions around response rates that we potentially can observe within those arms, to be able to measure a hemoglobin increase that can be statistically significant.
We also have our safety data that we're going to be assessing, at the same time, because it's very important to establish benefit and risk, right? That's the top focus, and then that will be supported by other secondary endpoints that are measuring, fatigue, also sickle cell pain crises, which is our first randomized controlled trial data set that is looking at that. That being said, the secondary endpoints, they are limited. We can't really statistically test them the way we would do for a phase 3, because it's a phase 2, smaller sample size, shorter in duration.
To Brian's point, where, the way we're thinking about this drug is really to deliver at the end of phase 3, a drug that can be very meaningful for patients, because it would then hit on a trifecta that is important for sickle cell. Sickle cell pain crises, hemoglobin increase, that then is further supported by measures that patients actually feel better.
Perhaps put this in context of, A, the patient population that you're aiming to target here, but then also with competitive dynamics and what you've seen other drugs show, how you think of that commercial aspect and the bar you have to meet there.
Sure. So in the sense of the population that we're trying to enroll, this is really for a sickle cell disease population that is hemolytic anemic, meaning so we have some boundaries around the decrease in hemoglobin that they need to have at baseline. What is very important is for the VOCs, we actually require them to have at least two VOCs at baseline so that we can effectively measure a reduction. If you know, enroll patients that don't have enough VOC, there's not really anything you can measure. This is really a choice around, you know, endpoint, chances of success for an endpoint. At the same time, we also put a cap for maximum VOCs, also for logistical reasons, because we need people to...
First of all, if you are really having so many VOCs, more than ten, you just have a ton of comorbidities, and it becomes very hard to actually complete the trial, and it becomes hard to actually measure the endpoint. That's where we have to put some, you know, limitations around that. We are allowing for hydroxyurea, now going into the more competitive space. hydroxyurea is standard of care in the U.S., we believe it's very important for the patient population to be allowed to just continue their standard of care. We are taking that into account from the stratification perspective for Phase 3. We are not allowing for any other drugs like crizanlizumab or voxelotor, because we do want to establish the benefit risk for PYRUKYND by itself.
I think in hindsight, with the, you know, the things that are happening to crizanlizumab in Europe, it's also not globally available, those therapies. That's the right thing to do. It definitely makes it easier from, like, a logistical perspective. From a competitive, like, where would we fit? It's a drug that has a completely different mechanism of action than the ones that are currently available. Our goal would be to hit on all of those different components of sickle cell disease, which currently the other drugs, the more novel therapies, have not delivered on. We believe sickle cell disease is such a horrible disease that patients truly need multiple options. This is where we're hoping to be able to provide another therapy.
Vaso-occlusive crises are not a primary endpoint at this point, or just looking at that event rate. How do you think about the need to show a trend over time or a decline in VOCs?
That is where we're truly looking at the totality of the data, both from the Phase 2, but also the data that has been gathered in our investigator-sponsored trials, plus the data that has been gathered on the biomarker side. It's truly looking for an appropriate signal in Phase 2 that can guide us to Phase 3.
Right. Remind us, you're looking at two doses here.
Yeah.
Deciding which dose to move forward, right?
It's a dose finding, study indeed. It's 100 milligrams BID that will be tested against placebo and 50 milligrams BID that will be tested against placebo.
Maybe to put all of this in context, help us understand what you've seen with this drug so far that leads you to believe you will have the target profile you're looking for. you know, in, I guess, what is that target profile when you think of some of these drugs that are out there? I know you mentioned what the competitor bar is, but what commercially are doctors really looking for to kind of change the patient experience here?
This is where the input from patients and physicians has been very important because, yes, Sickle cell pain crisis is important, and to come to what we have observed so far, is we have, you know, observed improvements from point of sickling. We have observed, of course, the pharmacodynamic parameters that we would want to see in the context of our mechanism of action, with an increase of ATP and a reduction of two, three-DPG. The data sets generated by two of our collaborators, Dr. Tan at the NIH and then Dr. van Beers in the Netherlands, in Utrecht.
Both of those data sets actually have followed patients now, and Dr. van Beers recently presented at EHA, an update on his data set, in which he highlighted a trend on improvement of VOCs and a reduction on days in the hospital when a patient had a VOC. All of those pieces that are being gathered continue to remain consistent and continue to support that this mechanism of action of pyruvate kinase activation may be a good thing for sickle cell disease.
I, yeah, I would just add, too, that again, having spent so much time with the patients, their family members, and really listening to how they talk about the struggle with sickle cell disease, I think that's where Sarah and the team have done a really elegant job of not so much just for the phase two program that we're talking about, but with the end goal, if we were to proceed through to phase three at the finish line, any combination of everything that she just discussed, of hemoglobin, of course, but also feel and function, and we'll be measuring that to the PROs and then naturally, the VOCs.
What's interesting is when we've talked to patients, what sometimes we hear is that pain itself, which takes on such a bright spotlight in sickle cell disease and creates so much suffering, the patient can adjust to the pain on some level. There is medications they can take. They can come up with adaptive mechanisms. The fatigue is the thing that's so shocking, that fatigue, the word itself, is a bit of a misnomer to describe how profound that impacts their lives. And fatigue they cannot adjust to. When we think about, to answer your question of, PK activation and what mitapivat may offer for these patients, if we're able to deliver on any combination of those endpoints, that is a big win.
To have it, you know, on top of all that, as an oral therapy, very simple for patients, we have to think longer term about not just addressing the challenges in the U.S., but of course, around the world. That's very exciting for us as an organization.
Perhaps we could just transition over to the asset and its use in beta thalassemia and alpha-thalassemia. You helped to find those opportunities for us and, you know, there's an unmet need, clearly, in alpha-thalassemia. How do you think about beta thalassemia at this point?
Thanks for the question. First of all, we'll just talk about the size of thalassemia as it's classically defined in the U.S. and EU5. We talk in terms of an addressable market of 18,000-23,000 patients. Already, for us, that's a significant step up from the PKD population, where we refer to numbers of 4,000 patients-8,000 patients. The interesting part of thalassemia from a global concentration standpoint is that outside the U.S. and even outside of Europe, in the Gulf region, for example, if we were to compare the prevalence in the Gulf to the U.S., we have 8,000 patients roughly in the U.S., 70,000 in the Gulf region. It's so common, it's often not even described as a rare disease.
Now, when we look at what options these patients have, alpha-thalassemia, to your point, there are no pharmacologic therapeutic options available. That is super high unmet need, and we're really pleased that we've taken an all-comers approach in the design of our ENERGIZE and ENERGIZE-T trials. No genotypes have been excluded. That is a nice setup for alpha-thalassemia. Beta thalassemia, the non-transfusion dependent patients really have no pharmacologic options in the U.S., and the transfusion-dependent patients do have limited therapeutic options. The question is: What is the feel and function effect for those patients? What is the ease of use? What is the sustainability of the effect? We see a setup where there's a significant portion of the thalassemia community that just needs something as a new option.
What we have with tebapivat is the potential for, again, oral therapy to address the underlying pathophysiology that affects the red blood cell, both on the hemolysis side as well as the ineffective erythropoiesis side. Again, our approach will be to have this global an approach for all comers. We're really pleased with the progress that Sarah and the team have made. Again, it's now fully enrolled on both trial sites, and that's a great setup for 2024 data readout. Anything you want to add, Sarah?
Well, I think the trials, both trials are really meant to highlight the improvement of hemolytic anemia. The way the trials are set up is they divide the population in two based on transfusion needs. The totality of the data gathered across those two different trials will indeed address the totality of thalassemia. The way the clinical trials are set up is also they are being run in where the thalassemia patients are. We do have presence in the Gulf region, for instance, or in Asia, because alpha-thalassemia is more present there.
What are the commercial dynamics in the Gulf region? If you know, at the end of the day, if you're commercializing them.
Well, at a very high level, it's an interesting region in the sense that there's more concentration of treatment centers. To be able to address that population in many ways would be more efficient than in the U.S., for example, where treatment of care is more distributed. The way we're looking at approaching this commercially is through partnerships, almost certainly, and we're looking at a wide range of partnership types. I mean, you can go from a larger company who has direct presence in the Gulf region and other regions, for example, and/or distributorships, which is maybe the more classic kind of setup.
We're also very interested in having discussions with the authorities within the Gulf region or within Saudi Arabia, as an example, because for them, thalassemia is so significant, it's a national crisis, and we think there probably are opportunities to approach this in a very different way to ultimately establish access for patients in a sustainable way and broadly.
Remind us here the bars for success, and I'm just curious, when you address different populations in the one trial, are there any differences we should be aware of, you know, be it mutations or other aspects that could result in different outcomes per patient population?
Sure. ENERGIZE, that's the population that is not regularly transfused, so there the bar is an increase of 1 gram per deciliter for hemoglobin. The other trial is a transfusion reduction response because those patients are regularly transfused. In regards to the genotype, both are enrolled. The differences, and this is actually based on the phase 2 clinical trial that was published in The Lancet, in which we enrolled different genotypes and saw responses across the board. To us, it's the genotype is accounted for more in the context that the clinical trial needs to represent the overall thalassemia population and the stratification on that. There is not right now, based on the phase 2, a treatment response that would be more or less present based on that data set.
We're excited, and eagerly awaiting the completion of the trials.
Any thoughts on pricing dynamics in these markets, both sickle cell and beta thalassemia?
Just as a matter of policy, we don't comment on pricing before the data readout. I think it's for, you know, for very understandable reasons, that the data itself dictates the value that's offered by the product. We're excited to see the data readout. At that time, you know, we'll have a look at the geographic distribution, what the data means in terms of value creation. That's when you establish the price.
With PYRUKYND in PKD, the drug was approved about a year and a half ago. Just remind us on the trajectory going forward.
Yeah, I think we're making really important progress. This is a population that, as I mentioned up front, has no other therapeutic option, and we're delighted to take the lead role in not just introducing PYRUKYND for those patients, but even more importantly, taking on the burden of all of the education that the clinicians need, the activation that patients need to understand this is a disease, there is a new treatment available for them. We have just lapsed our first four full quarters on the market. The numbers were reported at the end of the first quarter, was 89 patients on therapy. These are net patients, meaning patients we've added net of discontinuations, which I will note has been very small to date, and that's encouraging. Behind that, we've generated 127 so-called prescription enrollment forms.
Upstream of that, we haven't disclosed the numbers, but we've continued to increase the patients under management, is what we call it, which are identified patients in the population. This is among the most challenging kinds of launches that one could imagine, because it's on the ultra-rare side of the equation. There's never been education or another therapeutic option, so this is the first ever. It's very similar to the world that I, and also Sveta, as I mentioned, our Chief Commercial Officer, came from when we were at Alexion, where in the case of PNH, it's widely distributed across the country. PKD is kind of one doctor, at the most, one patient. The heavy lift is all around the educational component and how can we efficiently find providers who are likely to have a patient with PKD?
That's really, you know, that's kind of the 80/20 rule of our effort. By far, the majority of our efforts are going around, again, education and identifying. The pull through is relatively straightforward for the patients, and it does take some time. What we're finding is once patients are on therapy, they're staying on therapy, and that's encouraging as we think about future launches of thalassemia and sickle cell disease, where rare chronic diseases like this mean persistency is as important as initiation.
In terms of the physician awareness and the need to educate here, recognize these patients are underdiagnosed. Are they also misdiagnosed? If so, what are they diagnosed with?
Patients with PKD I mean, they present with fatigue, is the most profound clinical manifestation. They could be misdiagnosed across a whole range of hemolytic anemias. That's where one of the elements that we're very proud of is the offering of what we call Anemia ID, which is a panel of genetic testing, not just for PKD, but across a number of hemolytic anemias. That has led to some success of identifying these patients. It also, frankly, because it identifies other hemolytic anemias, has helped patients find other diagnoses. I think, in the community, it's given a real recognition of what Agios is trying to do across a number of diseases and how we're trying to work with the community to advance treatment.
It is, you know, this is the case for many ultra-rare diseases. It's a long journey for these patients.
How are the response rates playing out versus the clinical trials in the real world population?
We've seen in terms of response, if anything, it's been very consistent with the clinical trials. As a quick reminder, with the target of 1.5 grams per dL of hemoglobin reduction as the endpoint in the ACTIVATE trials, that was 45%. What we have just released at the EHA, and Sarah could talk about this, too, is data that shows that in the longer phase, an even greater portion of patients can respond. That's one part where it's been very consistent with the clinical trials or better. Again, for persistency, what we found in the real world since the first day of launch, although admittedly low numbers, is that it's been encouraging to see that patients tend to get a relatively quick response if they do respond.
If they do, they tend to stay on therapy, for longer than we would have initially expected. Anything you want to add, Sarah?
No, I think that's exactly it. The beauty of the clinical trials is that the open-label extensions are still ongoing, we have really good data that is coming out of there on maintenance of effect, how people feel, as well as PRO data that remains clinically significant. What we are also very excited about is that we're starting to see signals on iron overload in the long run with the drug. Lots of good data to present at EHA and medical conferences.
Remind us where you stand on ex-U.S. commercialization.
Yeah, we have, for ex-U.S., for PKD in particular, we are not yet commercializing, though we have approval in the EU and in Great Britain. It's on the ultra-rare side of the equation, our, you know, the values of the company is we need to make sure that patients have access. Through the medical affairs team, Sarah's organization, we have developed a program which we call the Global Managed Access Program, for patients with PKD, adult patients, and that allows them to have access to the product. Again, we've not yet commercialized. For commercialization, we're looking mostly towards our data readout in thalassemia, to really guide us on what a larger program could look like commercially, a build-out. We're actively having discussions with partners.
We're very careful in what an ideal partner or partners would look like to commercialize for both PKD, and if we're successful, thalassemia and potentially beyond for sickle cell disease. Meanwhile, we're making sure that patients have access.
You spoke earlier about your next generation PK activator in low-grade MDS, or low risk MDS.
Mm-hmm.
Maybe you could just walk us through how this asset's differentiated and how to think about this MDS opportunity?
Yeah, I'll let Sarah comment. I will just say that strategically for us, we're thrilled to... As I mentioned, we're building a PK activation franchise, so we're thrilled to not have only mitapivat. We have AG-946 as well, and there are many strategic benefits to that. That allows us to pursue multiple therapeutic areas, but separate out different economic swimming lanes, so to speak. The pricing dynamics are more flexible in that regard. From an IP perspective, I'll just note that we have IP composition of matter for mitapivat into the 2030s. We have IP for AG-946 into the 2040s. Then from an IRA perspective, and this was not planned per se, but serendipitously, it's advantageous to have not one, but two products. Maybe you want to comment, Sarah, on the-
The clinical-
What we know about the asset.
Well, I think they're just in a different phase of development, right? Our knowledge on PYRUKYND is just much bigger because of the extensive safety exposure, and AG-946 is working towards building that. The biggest difference, I guess, is the potency. It allows for AG-946 to be given once a day versus PYRUKYND twice a day. AG-946, lower amount of milligrams needed for that same effect, versus AG-348. We're testing doses 50 milligrams-100 milligrams. Right now, the highest dose for MDS is 5 milligrams. AG-946 does not have aromatase inhibition in vitro, which was, there was weak in vitro aromatase inhibition on mitapivat, but that didn't play out clinically into adverse events.
We've monitored that extensively, which is where the safety exposure that we've generated really helps. There's a slight difference in the chemical structure as well, but other than that, it's truly PK activation that we're studying for both of those molecules.
Just maybe as a quick reminder, too, on the current therapeutic pursuits, we have a phase 1 study underway in sickle cell disease, which is really meant not so much for sickle cell disease per se, but to get data in a hemolytic anemia. Then, as we noted up front, and you just referenced, we do have a phase 2a study, proof of concept study underway for low intermediate risk MDS. Again, absolutely thrilled to be able to announce this morning that that's now fully enrolled. That's a 20-patient study, 16 weeks in duration. It's open label, and again, we would be looking for by year end to get a data readout.
Perfect. Bristol has an asset in the same population. I guess, how do you think about differentiation here or the bars that we've seen them, you know, in terms of their data they share in COMMANDS?
Yeah, I'll just comment commercially and Sarah can fill in from a clinical standpoint. MDS is very similar to all of the areas that we're addressing in that there's lots of room for innovation and for new therapeutic options for patients. You know, from an Agios perspective, we think it's absolutely great that a company with the scale and the resources of BMS are continuing to invest in MDS and others to create new therapeutic options for patients. That certainly helps us from a market development standpoint. With AG-946 itself, you know, this is a very different mechanism of action. Again, we're talking about highly potent PKR activation, which we think has a lot of promise in not just the sort of the anemia side of the equation, but even the ineffective erythropoiesis.
To be as an oral therapy, when we think about broad access around the world with different dynamics of distribution, and from a patient experience standpoint, that's very advantageous as well.
I think indeed, that's what we're currently focused on. From a clinical development perspective, we're in the phase 2a. We're really trying to look for proof of efficacy now in this smaller data set. We're looking at people who are not transfused or have a low transfusion burden over 16 weeks with the proper endpoint of either hemoglobin improvement or transfusion reduction. From there, we will open it up to a population that has also more transfusion burden for phase 2b. We have not discussed our phase 3 plans yet, nor the target product profile that we're trying to reach at the end, more to come as we continue to develop.
Maybe one last question here. Recognize your, you know, your focus at this point with regard to all these programs. How are you thinking about future growth with regard to the R&D pipeline?
Yeah, I think, well, first of all, there's another asset that we have earlier in our research that we haven't even talked about, which is a PAH stabilizer that we're looking at towards an IND at the end of this year, and that would be targeted towards phenylketonuria or PKU. That's yet another very high unmet need disease with very limited options. It's early for us, but we're excited about the potential, again, towards an IND, and that'll guide us where we go from there. More broadly, business development is, I believe, for any healthy biotech or biopharma company, particularly like Agios, we're always on the move, looking. We've actually expanded the capacity of our BD team to make sure that we have a sense of what is out there.
It's a very dynamic market and we want to be opportunistic, but always very disciplined to seek out assets that are value creating, fit in very well with our capabilities. We have very distinct filters that we go through when we look at those assets, and we'll see where that takes us. I think we're a company where we don't need to do a deal immediately, so it's not like we have that kind of urgency that some companies face, but we do think that's a part of our equation as we look to diversify and deepen our pipeline for the longer term.
Great. Well, with that, Brian and Sarah, thank you so much.
Thank you, Sarah.
Thank you.
Thanks a lot, everyone.