Good morning, everyone. Thank you so much for joining us. We're really pleased to have with us the Agios team. With us, we have Brian Goff, Chief Executive Officer, as well as Sarah Gheuens, Chief Medical Officer. So to start, Brian, I'm gonna turn it over to you for any opening comments.
Well, thanks a lot, Salveen. Thanks for hosting us, and for those of you who got up pretty early this morning to listen in, thank you very much. It's an exciting time at Agios, and as a snapshot, I think many people know that Agios is focused on rare diseases, and the core of that focus is on red blood cell health. Our lead product, mitapivat, is really the leader in a class called PK activators or pyruvate kinase activation. And I must say, we have just made excellent progress this year. So, our focus therapeutically is PKD, which is pyruvate kinase deficiency, where mitapivat, or commercially known as PYRUKYND, is already indicated and launched in the U.S. But we're also pursuing further indications in thalassemia and in sickle cell disease. And as I noted, the momentum is just great.
In January of this year, we announced top-line results from the first of our two pivotal Phase III trials focused on thalassemia. The first trial is known as ENERGIZE, and that's focused on non-transfusion-dependent thalassemia patients. We were really thrilled with meeting the primary endpoint statistically, not only in hemoglobin improvement, but in the very difficult-to-attain patient PRO finding of fatigue through the FACIT Fatigue Scale. That was in January, and we followed that up just last week. On Monday, we announced the top-line results for the second of those two studies. That's known as ENERGIZE-T, and the T is because the study focuses on the transfusion-dependent thalassemia population. I know Sarah, sitting to my left, will be delighted to talk about the results, but suffice it to say, we achieved statistical significance on the primary endpoint of transfusion reduction.
We also achieved statistical significance on all three of the key secondary endpoints, which largely were focused on duration, of or durability, I should say, of the transfusion reduction. And we also had a really, impressive finding of transfusion independence in almost 10% of the patients. So now we are prepared to combine the results of those two studies and, package up a file with the FDA by the end of this year. And meanwhile, our commercial team is gearing up for a potential launch next year in 2025. So that's just the timing of this discussion for us is just superb. We also are advanced with another indication, as I noted, sickle cell disease.
Last year, about this time, we announced the Phase II results of the RISE-UP trial in sickle cell disease, and we're really pleased to see both statistical significance in hemoglobin improvement, as well as a positive trend in vaso-occlusive crises. We followed that up very quickly with commencement of enrollment of the Phase III portion of that Phase II, III study, and the goal there is to be fully enrolled by the end of this year, get data from the sickle cell study next year, and then the setup for Agios' potential back-to-back launches, thalassemia next year and sickle cell disease in 2026. So a lot of momentum.
The last thing I'll just say from a balance sheet perspective is, our CFO, Cecilia Jones, just did a fabulous job of setting up a very competitive process for monetization of a royalty that we held for vorasidenib approval in the US that's now owned by Servier. We had 15% royalty upon FDA approval of US net sales, and thanks to the competitive dynamic, that resulted in $905 million upon US approval, which will be added to our balance sheet. That is in addition to the other milestone that we still retain, which is $200 million from Servier upon FDA approval. I'll just note, too, that we still retain 3% of annual US sales that are above $1 billion, even after that monetization.
We have had a very positive, breathless, you know, year to date in 2024, and we're just thrilled about the momentum and the opportunity to serve patients in a broadening set of indications.
Really nice to see. So starting with the data sets that we saw, could you help us understand them and talk about how they'd be viewed in the commercial setting? Specifically, in ENERGIZE-T, there was about a 30% reduction in transfusion burden compared to a 12.6% reduction in the placebo arm. Help us understand the rate of reduction in the placebo arm and in the context of that.
Yeah, maybe Sarah can start with why we designed the study as such, and then I can build on the commercial applicability of the findings.
Right. Thanks. So the primary endpoint was a 50% reduction in any rolling 12-week period within the clinical trial. So there was a 48-week observation period, and then if a patient had a 50% reduction in any given 12 weeks, that was considered a responder. So we had modeled for a placebo rate using all of those scatter plot data, looking at all of the confidence intervals around that. So we had taken into account that we could have potentially a higher placebo rate than what was observed before, and that effectively occurred in this trial. So we were very happy that we made the assumptions we have made. But I think the key message here is that even with a high placebo rate, we were able to demonstrate statistical significance on that primary endpoint.
Where I think the true special data comes in is in the key secondary endpoints, because that is where we have longer stretches of duration. The last endpoint is a 50% reduction over a stretch of 36 weeks, between week 13 and week 48, and we were able to hit statistical significance on all of those endpoints as well. Then the transfusion independence, of course, we were very pleased to see that data as well, because being away from clinic for 8 weeks with an oral therapy is really meaningful for patients. So that is where I think the way we have looked at drug effect across the clinical trial can really provide a comprehensive package for people to make calls on the therapy.
And then, you know, commercially, for just this trial alone, this sets a very high bar, for all other therapies that are pursuing thalassemia. And for patients themselves, this is, this is potentially transformational because for one, the transfusion reduction is very meaningful. At 50% reduction, we knew that that was a high bar to set, and we thought that was quite relevant for the population. Two, is in the secondary endpoints, what's so exciting is we've now seen that up to 36 weeks, that effect is maintained, and that's the first ever in a, a pre-specified endpoint in a pivotal, Phase III study in thalassemia. And then transfusion independence, you know, as I noted, it's almost 10% of the population that studied that achieved transfusion independence. But with mitapivat, which is an oral therapy, it's kind of a different level of independence.
One part is the independence of the transfusions themselves, but the other, which is ultimately our goal, is to help the patients become independent of the clinical setting, and that is very compelling for these patients, and I think a really unique attribute that we'll look to leverage in our communications about this during the launch.
In both the ENERGIZE and ENERGIZE-T studies, you included both alpha and beta thalassemia patients and noted that neither subgroup drove the positive responses seen in the trial. Could you provide any further details on the respective efficacy of these two groups? And how confident are you in being able to include both these populations in your label?
Sure. So for the ENERGIZE trial, that's the trial that was focused on non-regularly transfused patients. We had a stratification factor on alpha or beta genotype. And so we have indeed spoken about that there was not a subgroup that drove the overall efficacy results, and the data will be presented at EHA on Saturday. So you can see more there. But we were very pleased with that because it does mean within that trial, that we were able to observe that there is drug effect across those different patient populations. For the ENERGIZE-T trial, we did use another stratification factor because alpha thalassemia patients overall, in the thalassemia patient population, are less commonly transfused than beta thalassemia patients.
So we used a stratification based on non-beta zero, beta zero versus beta zero, beta zero, and then included the alpha- thal patients in the non-beta zero group. And so again, here we are pleased to see that on that stratification factor, there is not a specific subgroup driving the overall efficacy results. And of course, our goal is to present a similar data package like what we are doing now at EHA for ENERGIZE, to have the same type of presentation for ENERGIZE-T at a later upcoming medical meeting.
And again, from a commercial perspective, the beauty of both data sets, ENERGIZE and ENERGIZE-T, is we don't have to get into nuances about. You know, the data for this subpopulation versus the other. The target product profile is that all of thalassemia is covered. And now, thanks to the data from ENERGIZE, which addresses, as Sarah says, both alpha thalassemia and beta thalassemia patients who are non-transfusion dependent, and now ENERGIZE to cover, the other third of the population, which is transfusion dependent, but not having to nuance about subtypes, that's, that's an incredible opportunity for this population.
At EHA, you plan to share additional measures, including, of fatigue, including other physical, functional, and thalassemia symptoms. How meaningful do you think that would be, or additive kind, to kind of the overall data set that we've seen to date?
So that data will be presented on Friday, and it's truly an overview of the patient-reported outcomes and performance measures that we have collected in the ENERGIZE trial, and it shows consistency across the different, different tools that we've used. So I think it's very meaningful because it does speak to how people feel and function, on drug when, you know, when they have thalassemia. So it's a very comprehensive data package with a whole range of efficacy measures that we believe can speak to clinical benefit.
...When we think about non-transfusion-dependent thalassemia, there's a view sometimes that it's not severe or life-threatening, given the lack of a need for transfusions. In that context, how do you think about adoption in this population and the commercialization education efforts really needed to kind of educate and gain kind of momentum?
Trial piece, but the non-transfusion dependent patient population, I think where we can first see that people actually do want a therapy for their disease, is the fact that the trial enrolled and that we had a good enrollment in that clinical trial. Because typically, when people don't want to participate or don't feel like they need something to tackle their disease, you have trouble with your clinical trial on an execution perspective. And so I think that's one of the signs from a patient population, a patient population level, that both physicians and patients have an unmet need, and have an unmet need that makes them want to participate in a clinical trial.
From a medical perspective, there is a lot of data out there right now that non-transfusion-dependent patients actually do develop severe comorbidities and have an increased mortality that can be even worse than people who have been transfused. And so there is definitely, from that content, medical content, an unmet need as well, because these comorbidities, they continue to build up, specifically driven by hemolysis and iron overload, that those patients also deal with, despite not being regularly transfused.
Yeah, and this-- And you're exactly right, Salveen. This is classic rare disease preparation, especially when you address populations that have had limited or no therapeutic options. And in this case, in thalassemia, the non-transfusion-dependent population, if I focus on the U.S., is about two-thirds of the total thalassemia population, and they've had essentially nothing that's been approved for their treatment. So the classic approach is there will be a lot of education that will need to be done. Tsveta Milanova, our Chief Commercial Officer, has already begun to build out her team, which we, we held off doing until we saw the disposition of the ENERGIZE data in January. And given how positive it is and now ENERGIZE-T, you know, we're really preparing first with education, which actually began in earnest on May eighth, which is World Thalassemia Day.
And the focus there, as Sarah noted, is, number one, to make sure that clinicians are increasing their management and monitoring of these patients. And number two, from an educational standpoint, it's the realization that they have a hemolytic anemia, these non-transfusion-dependent patients, and that means that they have ineffective erythropoiesis, as Sarah noted, and every day they suffer from chronic hemolysis, which in the long run, can really affect morbidity and mortality. So that's, that's the crux of our focus. I think what we'll see from a launch perspective is a gradient over time of, as that education, you know, really resonates with the community, as well as patients having an opportunity to try the product. And we believe word of mouth effect will be an important component, you know, and then we'll expand from there.
On the potential to commercialize ex-US, you've noted that you're actively looking for a partner to commercialize globally. Can you provide an update on the efforts here?
Well, the first update is you can imagine if you're a potential partner and you see both of these data sets from ENERGIZE and ENERGIZE-T, that's a very compelling proposition. And so we've had no shortage of, you know, interest around the world. Our core focus outside the US. Number one, US, really number one, and number two for us is the Gulf region, the GCC. And our approach there is most likely a distributor type of approach, and there are many types of distributors. What we'll be looking for is a so-called full service distributor, where we can work very closely to, as we just talked about, be in sync around the educational messages that are required to mobilize the population, make sure that access is very strong. And the Gulf is a remarkable opportunity.
In the U.S., we talk about 6,000 diagnosed adult patients with thalassemia. The Gulf thalassemia population is about 70,000 patients. So that really is our key focus. And then from there, we'll continue to look for what the right approach is, to commercialize, but those are really our top two priorities.
Other competitor programs within the PKR class, such as Novo's asset?
There's really... I guess there's not a lot to be said. We haven't seen any data, and if anything, we have a very meaningful lead now at this point, with two positive Phase III trials. I think beyond just PK activation class, just in total, as I noted, this is a very high bar. We have demonstrated in two different studies, hemoglobin, beyond hemoglobin aspects, real outcomes for the patients. In ENERGIZE, we showed benefit for fatigue, which is critical at the patient level. And now in the ENERGIZE-T study, as we've talked about, we showed very meaningful benefit in transfusion reduction. We've shown durability of response. And ultimately, if you're really trying to be free of the burden of clinical treatment, an oral therapy is quite meaningful.
Great! Transitioning over to PYRUKYND in sickle cell disease... Where do you stand right now with enrollment progression for the Phase III trial?
I will just start by saying I'm very proud of what Sarah does every day, and this is another mark of excellence in the progress we're making.
I'll add to that, that I'm very proud of the whole clinical team that is actually working on this, because it is, you know, it takes a village to get these trials to the finish line. So we had enrolled our first patient relatively fast after we completed our Phase II clinical trial dataset, which we were very excited about because it was, it highlighted that we had a positive hemoglobin response, but then also we saw a trend on hemolytic parameters and on sickle cell pain crises, which is, of course, now the focus of our Phase III clinical trial design, with two primary endpoints, one focused on hemoglobin and one focused on a reduction in sickle cell pain crisis, with a goal to deliver a therapy that can treat the totality of sickle cell disease.
So where we are now with the clinical trial execution, we have guided towards complete enrollment by the end of this year, and we are on track to do so.
In the Phase II RISE UP trial, the drug demonstrated a significant improvement in hemoglobin response rate. Help us understand or contextualize this as we look to the context of readthrough to vaso-occlusive crises for the Phase III.
Right. So, what we saw in the Phase II beyond that statistical significance result on the hemoglobin response, which we actually leveraged to select the dose for Phase III. We also saw a trend in sickle cell pain crisis and a trend in hemolytic parameters. And what was nice to see within that clinical trial data set, it was against placebo, right? So it's a first Phase II placebo-controlled clinical trial data set that showed that both doses had a trend towards improvement on hemolytic parameters and sickle cell pain crisis, but we saw a better trend in the 100 milligram dose. And so that is where you can see that consistency in the data set, which gives us confidence for Phase III.
In addition, we have 2 investigator-sponsored trials that have been ongoing for a while now, 1 at the NIH and then 1 in the Netherlands, that continue to show similar data. So it's the totality of the data and the consistency of the data across the whole program that makes us excited to try to deliver to that goal of completing enrollment in Phase III.
What differentiates the asset from other agents in, you know, the PK activator class or just the overall sickle cell therapeutic class here in your viewpoint?
So I think from from a PK activator against others, as I mentioned in our Phase II, we've this is the first drug that actually delivered on end hemoglobin response and that clear pattern across all of the hemolytic parameters and the sickle cell pain crises at the same time. So that gives us confidence towards our goal of delivering a therapy at the end of Phase III that can truly tackle the totality of sickle cell disease. And that's the differentiator, because right now, people have choices between a drug that focuses on the anemia component of the disease or on the sickle cell pain crisis component of the disease. So our goal is to really try to deliver for the totality of the disease with this therapy. So that would be a major differentiator there.
And then within the PK activator class, we have a pan PK activator. So we activate PKR, which is important in the context of the red blood cell metabolism, but we also activate PKM2, which is expressed in different tissues across the body, which we are now exploring the potential benefits of... from as well in a renal study. So we are actually, in sickle cell disease, there's a lot of organ damage. PKM2 is expressed in renal tissue. We're trying with this study to highlight if we can measure improvement in kidney health in sickle cell disease. And that is important because the kidney is one of the, you know, target organs that get damaged in a lot of patients. So if we can show some improvement there, that would be very meaningful for the patient population.
What are the clinical and commercial bars here for this readout?
So I think the clinical bars, there are multiple ways to think about that, because, of course, our goal would be to and be positive on the hemolytic anemia component and the sickle cell pain crisis component. But what we're trying to deliver to is that hemoglobin plus story, as Brian mentioned before, with hemoglobin, that leads to people actually feeling better. So that would be a very meaningful clinical bar, if we can deliver on that.
Yeah, in many ways, commercially, it's the same dynamic that we just talked about with thalassemia. These are patients who have very limited treatment options, and as Sarah noted, that's it's all about not forcing the patient to have to make a choice and trade off one of the real benefits that they need. And just like in thalassemia, where we've seen hemoglobin plus, benefits, it'll be the same thing in sickle cell disease, and we are eager and, preparing for success. In fact, commercially, as I noted, now we're expanding so that we're prepared for a potential thalassemia launch in 2025, and then that could be back-to-back with sickle cell in 2026.
PYRUKYND in PKD for the treatment of PKD has been on the market for a little over two years. What are your thoughts now as you think of the forward trajectory and maybe what needs to be done to further penetrate this market?
Well, I think with, with PKD, what's been really elegant about this, in preparation for successively larger launches to come, whether it's thalassemia and/or sickle cell disease, is that this has been a great real-world platform for us to see actually how mitapivat PYRUKYND performs in the real world. And as we've talked about in other venues, we continue to be really pleased with the persistency that we see. These patients are admittedly, you know, very challenging to find, to, to have clinicians diagnose and identify them. But once they're on therapy, the persistency in the way the patient feels, is very compelling, and it's given us a good read-through to what it might be like on chronic therapy, whether it's thalassemia or sickle cell disease. The numbers for PKD will continue to be slow and steady.
You can imagine now with optionality of expanding our indication base, we're gonna focus a lot of our efforts on thalassemia, and hopefully, if the data guides us there, on sickle cell disease as well. But for PKD, slow and steady, and using that as a proof point for real, real-world, real-world PYRUKYND use, as well as a platform to build out commercially from there.
You're also developing a next-generation PK activator in low-risk myelodysplastic syndrome. Can you remind us where this program stands and what the next catalysts are?
Do you wanna start?
Sure. So we have completed a Phase IIa, in which we were able to highlight that 40% of the patients reached transfusion independence with AG-946, which is that next PK activator that we are studying. And from there, we had a decision made that we would continue to move forward with a Phase IIb, in which we would be exploring more doses. And so one of the lessons learned from Phase IIa is that we're bringing forward higher doses to IIb, because we didn't reach maximum PD effect in the IIa. So we have guided towards getting that trial up and running by mid-year, and so we are continuing to work on that.
I think that's one of the key reasons why we identify ourselves as the worldwide leader in PK activation. For one, we pioneered the science, but two, it's a real advantage to have not one, but two PK activators, which gives us therapeutic optionality. We also have a Phase I study that we're pursuing in sickle cell disease. So there you can see we have franchise opportunity with AG-946, our other PK activator, and we also have very different opportunities therapeutically in the case of low-risk MDS. And that is a high unmet need arena with apparently very large potential. We've been tracking the growth that we've seen with Reblozyl as they moved into a first-line position, and it's already well over, you know, $1.2 billion, $1.3 billion annualized sales on a reported basis.
That's a great opportunity. It's another place where PK activation can shine, and we may have potential beyond that as well.
Remind us of the features in which it's differentiated from PYRUKYND?
Go ahead.
So it is a higher, has a higher potency, so we need less milligrams to get to similar pharmacodynamic effects. And one of the differentiators between the two molecules was that mitapivat had some weak in vitro aromatase inhibition. This molecule does not. That being said, on mitapivat, that has not translated into any clinical effects, but it is, you know, one of the differentiators.
Then maybe commercially, to state the obvious, it's not a pharmacologic difference, but an opportunistic difference, is because we're in different therapeutic areas, it gives us pricing optionality. It's a different sort of economic swimming lane, which again, is strategically a real advantage for us, for our portfolio.
How are you thinking about positioning of this drug in the low-risk myelodysplastic syndrome population, just in light of Bristol's drug that's on the market there as well?
I think the data will guide us, which is the most important point. But we were pursuing this with the potential, similar to what, you know, we're seeing in or we've seen now in thalassemia, where the patient can have, less dependence on the clinic in the form of transfusion reductions. And again, because it's an oral formulation, that's a whole different level of independence than with the incumbents that are currently in, the treatment options for low-risk MDS.
Great. Just opening up to the audience for any questions. I'll keep going here. You spoke about the Royalty Pharma transaction. Help us understand now with the cash position you have, kind of the asset outlook that you have, you know, where you think this company will be in a year or three years, and how you think about kind of the catalyst path from here?
From a cash position?
Cash and just overall strategy.
Yeah, well, what's so exciting right now at Agios is that we have very advanced late-stage programs. We have multiple launch potential in front of us. We just talked about our other PK activator, AG-946, which we're also looking to advance. And then we haven't even talked about earlier in the pipeline, we have other assets that we're developing. We have a PAH stabilizer known as AG-181, and we were really excited to announce the start of that, clinical pursuit in Phase I in, going after the PKU population. This is, another area of high unmet need, very limited treatment options. And earlier than that, last year, we acquired an asset from Alnylam, which is an siRNA asset for polycythemia vera.
It's a TMPRSS6 inhibitor, and this is a massive population that essentially phlebotomy is the standard of care. So to answer your question, we're looking to advance our late stage, move into launch opportunities, make sure that commercially we're successful with those launches. We wanna make sure that we're progressing our other PK activator and then advancing our already internal earlier stage assets. We have a lot of organic opportunities. Beyond that, as we build up our capabilities commercially, as we grow our pipeline, as we build our leading presence in classical hematology, we're always gonna have our foot on the gas in terms of looking for value-enhancing BD opportunities. But the beauty of Agios is we have so many great things going on right now. It's not like we're in a race, or we have to do something immediately.
I think from an investor perspective, that should give confidence that we will always be seeking, in a disciplined way, whatever is most value enhancing.
Well, with that, thank you so much. Really appreciate you joining today.
Thanks, Salveen.
Thank you.
And thanks, everybody. It's a very exciting time at Agios, and we really appreciate your attention.