Great. Good morning, everyone. We're going to get started, and welcome back to day two of the 2025 RBC Global Healthcare Conference. My name is Greg Renzo, one of the biotech analysts, and we're pleased to be joined today by Agios Pharmaceuticals. Joining us from the company is the Chief Executive Officer, Brian Goff, as well as the Chief Financial Officer, Cecilia Jones. Guys, it's great to have you. Thanks for joining us.
Thank you very much for hosting us, Greg, and thanks a lot, everyone, for joining us.
Brian, we'll just have you get us started with you providing an overview of Agios, where you are, your focus with Pyrukynd or mitapivat, and the variety of inherited rare blood cell diseases. Over to you.
Yeah, sure. Thanks a lot. It's a really exciting period. For the folks who are new to the Agios story, I'll just begin with our mission, which is to develop and deliver medicines that have transformative potential to elevate and extend the lives of patients who are living with rare diseases. Our core focus is on diseases that involve the destruction and dysfunction of red blood cells. Specifically, we're talking about pyruvate kinase deficiency, or PKD, thalassemia, sickle cell disease, and low-risk myelodysplastic syndrome, or MDS. Our flagship product, as you just mentioned, is Pyrukynd, chemically known as mitapivat. Pyrukynd involves a really unique mechanism of action that essentially improves the metabolism of the red blood cell. The result of that is that the red blood cell is healthier, better hydrated, and thrives better in the face of these very challenging diseases.
Now, Pyrukynd, really pleased with the fact that we've cleared our third year of commercialization already, which has given us great experience with Pyrukynd mitapivat in PKD, where it's currently commercialized in the U.S. And we're actively seeking additional indications in both thalassemia and sickle cell disease. I mentioned it's an exciting period. Last year, 2024, was in many ways a transformative year for Agios. The highlight of last year was that we read out two pivotal phase III studies for thalassemia known as Energize and Energize-T. And the strength of that package is that across both studies, we achieved statistical significance on all key primary and all primary and all key secondary endpoints. That put us in a position to, December of last year, we announced that we simultaneously filed for regulatory approval in thalassemia in four different regions.
That is the U.S., Kingdom of Saudi Arabia, United Arab Emirates, and in Europe. We started this year on a strong note in January, announcing that the FDA has accepted our regulatory file for thalassemia and granted a PDUFA goal date of September 7. If you are keeping track, that is only about three and a half months away, which we are really excited about. Meanwhile, our commercial team led by Tsveta Milanova.
We were just talking about this earlier.
Apologies. Led by Tsveta, the team is very well prepared for our potential launch in thalassemia. What's important about this is that thalassemia patients in the U.S. have very limited approved therapeutic options. Two-thirds of the patients have none. That's the non-transfusion dependent patients who have alpha thalassemia or beta thalassemia. We're excited about that. The other big event last year was in sickle cell disease. We were really pleased to announce in October that we fully enrolled our RISE UP phase III pivotal study. It's a 52-week study. If you do the math, that means we'll be fully prepared to read out that data by the end of this year, which is a really important milestone for Agios and even more importantly for patients who very much need new therapeutic options.
Cecilia also, I must say, did a great job last year strengthening our balance sheet through a royalty monetization. We ended the first quarter of the year with approximately $1.4 billion on the balance sheet. All in all, a great year and some important milestones. Again, we're only three and a half months away from our very important PDUFA date for thalassemia. I'll stop there and happy to field your questions.
That's great. It is so important to demonstrate how you're coming into 2025 with such a running start, not just with the accomplishments, the transformations you're talking about in 2024, but also historically with the molecule and your pipeline. We like how you do characterize 2025 as this breakout year. When it comes to having commercial traction in PKD, having regulatory interactions with thalassemia, as well as, frankly, pivotal and important data, those are aspects that just one of them would be coveted by a company in your peer group. Certainly eyes on thalassemia, a great deal of chatter about regulatory friction or not when it comes to transitions there. You've recently provided an update about the supplemental NDA. Just give us a state of where you are with that acceptance in January with respect to having a September action day.
We're sort of in that mid-range now where we should have some sense of advisory committee. You've said no, but you have healthy interactions. Just give us a state of the state, please, on the filing.
Yeah, happy to. You already mentioned one important feature, which is this is an sNDA. So mitapivat is well characterized. As I noted, we've been commercialized with real-world experience with Pyrukynd since the beginning of 2022. With respect to the FDA, we get a lot of questions about, have you felt dynamics in terms of staffing and so forth? The way we refer to it is, if we were not watching the news, I'm not sure that we would notice any difference. The project manager is consistent, has been all the way through our other regulatory files. As you also noted, we reported in our first quarter earnings call that the FDA has communicated to us that at this time, they're not planning an advisory committee. I think that was an important update. Of course, the review is ongoing.
We are just a few months away. We are very well prepared. I think this speaks to the strength of the package that we have submitted.
Sure, sure. Other sponsors are preparing for early approvals. Others are preparing for delays. Maybe just speak to the versatility or the flex that you have in the launch preparedness that you've spent and the team are embarking on.
Again, Tsveta is very much on top of this. Job one as a commercial leader is always be prepared for an early scenario. Frankly, we are ready now. We actually, from an efficiency of capital deployment, waited last year until we had the very positive readout of the first of the two pivotal studies, Energize, beginning of last year. At that point, that's when we scaled up. When I say scaled up, this is still rare, but we appropriately adjusted the sizing of our commercial field teams to make sure that we would be ready. Since essentially the middle of last year, we've had that team in place. They're fully trained, fully ready to go, and very focused on disease state education, but prepared for an early scenario.
Okay, okay. That's helpful. Investors certainly focus on the full profile of mitapivat, but with recent areas of scrutiny on the safety and tolerability side. When we think about the liver findings in thalassemia, you've updated the label, the current marketed label. You've discussed how you're framing that up with respect to thalassemia. Maybe talk a little bit, Brian, about any ability to decipher the underlying mechanism behind the hepatocellular injury, how that's managed, certainly when it comes to discontinuing the drug. You've had some interesting findings there. What is the latest with the views on the liver findings?
Yeah, let's do, we'll do a two-parter. I'll start and talk about the findings themselves, and then Cecilia can talk about what's been so encouraging is the read from clinicians who treat patients with hemolytic anemias, and specifically PKD or thalassemia. First, just as a reminder to everybody, in December of last year, when we were presenting the full results of the Energize-T study at ASH, we also disclosed that we'd identified a risk of hepatocellular injury. The totality of what we disclosed was there were five patients who were identified with this risk. Four of the five had confounding factors. One did not. And there were essentially one each from each of the two pivotal studies and three from the crossover in the open label extensions going from placebo to mitapivat. What's important about that is all those patients were identified.
They had this event in the first six months, and they were all identified through monthly monitoring, which was a standard part of our clinical trial protocols. That in essence, and I should note, they all returned back to their baseline upon drug discontinuation. That in essence already tells us a lot. One is it would be difficult to identify the exact mechanism because we're talking about five patients, four of whom had confounding factors. Secondly, the fact that all those patients returned back to baseline has given clinicians quite a bit of comfort that they would already anyway go through, these patients would go through normal testing starting on a new drug for a hemolytic anemia treatment. Maybe Cecilia can comment on some of the learnings we've had from the clinicians.
Both from the clinical trials and the real world on the commercial side, we have not seen anything as a concern from clinicians like these. Physicians are very used to monitoring patients, especially when they initiate these types of treatments. Monitoring for them was not an issue from a burden perspective. This is a test you can get in a lab kind of near your home. You do not have to even go into the office. We have not seen that. From a numbers perspective, our Q1, we reported 234 prescription enrollment forms to date, which is consistent with the growth we have seen on the prior quarters. That resulted in net 136 patients on therapy. We really have not seen an impact on that. Physicians, like I said, are very comfortable with the monitoring. This is monitorable, manageable. We have not seen that.
That's great. No disruptions based on the commercial metrics you've seen. Do you have a going-in base case about what a label could look like to account for some of these scenarios? What types of warnings would it mimic PKD? How would we frame up, how should we frame up the ethal label and what that could look like?
Right now we have it, we were mentioning before, the PKD label was updated to reflect the thalassemia cases. You see it in another condition at another dose because it's not approved yet, but that means thalassemia at 100 mg. That is in the warning and precautions. It has what was observed and what needs to be done if you observe elevated tests. Right now, we think that is reflective of the cases. We had, like, you know, people ask if it's a black box warning and things like that. Usually, those are more in cases where there's a fatality or a liver transplant or more of a bad outcome. We haven't seen those. Logically, we would expect something similar. Again, labels are part of reviews and discussions. We'll know once we get there.
That's helpful. Brian, you discussed a little bit about the opportunity, the unmet need for the ethal patients across the different types. Maybe talk a little bit about your conviction of this commercial opportunity with you and the team. As we think about the potential white space and upside, maybe just weave in a little bit countering the bear case that just could become another sort of sluggish rare disease launch.
Yeah, you want me to take that?
You can go.
Yeah. Thanks for asking that. It's a question we get quite a bit. I think, first of all, what's been important with the PKD launch is it's admittedly ultra rare. We've really characterized that this will not be a needle mover with respect to revenue, but it's been very important on two fronts. One is to get real-world experience with Pyrukynd. One of the key features that we've seen is the persistency that patients have had with PKD has been very encouraging. I think that's a really strong indicator about the feel and function aspect, the fatigue benefit, for example, that patients experience. Secondly, it's been a really nice platform for us to build up our commercial capabilities, getting ready for meaningfully larger launches to come, namely thalassemia and potentially sickle cell disease as well.
There are some key features that really make thalassemia a very different equation than PKD. One is that we talk about 6,000 adult patients in the U.S. with thalassemia. That is very well characterized because there are well-established ICD-10 codes for thalassemia now. Frankly, even before, for decades, there have been ICD-9 codes established. That number is validated substantially through claims database analysis. Most patients are diagnosed through newborn screening anyway. Number two is it has been a real challenge educating clinicians on the burden of PKD. Most clinicians have not even really heard of it. Thalassemia is a very different situation. Burden is well understood, the burden on the patients. Most doctors know of thalassemia. We certainly, you know, have seen that there is more concentration of patients than we experience with PKD.
The third is that there are well-established thought leaders in this space and mirroring that, well-established patient advocacy groups. A good example is internationally, there's the Thalassemia International Federation or TIF. In the U.S., there's Cooley's Anemia Foundation. Both of those are very important communities that are also supplementing education for both patients and providers.
That's great. That's great. Let's turn to sickle cell disease as you're thinking about the layering of expanding opportunities that you're referencing. You've mentioned the trial enrollment data later this year. Maybe talk to us a little bit about what you'd like to see, what levels up. We'll start on the efficacy side when it comes to the RISE UP study. What does mitapivat need to see to be clinically adoptable in sickle cell, even potentially approvable with the dual endpoints and the success of the prior trials that you're building on? What should we be seeing to be competitive?
I think the first place we should start is the unmet need for this population. It is hard in a venue like this, it is hard to even describe how profound that unmet need is. In the last year, the unmet need has only grown because, as most folks know, one of the therapeutic options, Oxbryta, voxelotor, was actually removed as a treatment option for patients. A very challenging period for the community. The setup that we have in the elegant design for RISE UP phase III is, as you noted, these are not co-primary endpoints. There are two primary endpoints. One is focused on hemoglobin increase of a gram per deciliter or better. The other is focused on sickle cell pain crises or vaso-occlusive crises reduction. Those are the two primary endpoints. We believe very strongly in the powering assumptions that we have put behind those.
We also have set up, they each have their own respective alpha. For secondary testing, one of the really important measures that we'll be looking at is fatigue. Again, fatigue is almost indescribable for somebody who doesn't have sickle cell disease. It's not tiredness. It's fatigue you cannot sleep away. It's one of the biggest impairments on the quality of life for patients. The other complicating dynamic is chronic pain itself only adds to fatigue. We think that that's also a really important measure. The design has been set up as what we call hemoglobin plus. That's the target for us. We're looking for an improvement in hemoglobin, which we've demonstrated now across three different hemolytic anemias. The plus could be vaso-occlusive crises improvement and/or fatigue benefit as well.
Any of those permutations would be a very compelling package for patients.
That's helpful. We talk about PK activators as a class and mitapivat just having several unique qualities. Maybe talk to us a little bit about some of those differentiators between mitapivat and others in this space. Now, granted, you are many years ahead of the competition, namely tebapivat. As you think about not only demonstrating what you need to for the phase III, but also how it compares and fares across the broader class, what are the key differences to point out?
I think one is very consistent data that we've had, again, across multiple hemolytic anemias, which shows the strength of the mechanism itself and the broad applicability of the mechanism. Mechanistically, what we're talking about here, as I noted upfront, is this is about increasing the throughput of the glycolytic pathway, which is the only source of energy for the red blood cell, ultimately increasing ATP, energy available for the cell. In sickle cell disease, there's also a dual benefit, which is lowering, as a consequence of increasing that throughput, lowering 2,3-DPG, which is linked very much towards the sickling of these cells. You know, you could think of that as, well, that's theoretical mechanistic aspects. We saw very strong data in our RISE UP phase II study that read out last year. There we saw, of course, hemoglobin improvement.
Importantly, we saw positive trends with both doses tested in vaso-occlusive crises improvement. The only changes that we made between our phase II and our phase III study is that we picked the higher dose, the 100 milligrams b.i.d. because that was consistently beneficial across hemoglobin, the trend that we saw, the positive trend in vaso-occlusive crises, and all measures of markers of hemolysis. The setup here is really unique and potentially very beneficial for a community that, again, has such limited treatment options.
Yeah. Maybe going to the value proposition with respect to the unmet need and the differentiation, talk a little bit, Brian and Cecilia, just about pricing strategies with Pyrukynd. We certainly have an established place for the ultra rare disease. We know with thalassemia, multiple markets globally, sickle cell as well, larger market, also global. Such chatter about most favored nation pricing, potential policies, maybe some mismatches and solving for disconnects. How is Agios thinking about the value proposition and how pricing works in these layered indicators?
There is a lot in there.
Today, you're right, we have a price of $335,000 annual WAC for pyruvate kinase deficiency. As we think, in general, I'd say pricing for us is something we look at based on the value proposition. We usually won't comment until we know exactly the label and in the case of sickle cell, the data as well. In general, the way we see thalassemia from a payer lens, it's in the neighborhood of PKD. Still a rare disease. We don't expect it to be a managed category. The access team has done a tremendous job on PKD and has already started pre-approval, like information exchanges with payers, and everything has gone really well there. We expect thalassemia to be kind of similar to PKD from a payer perspective on how to think about it. When you go into sickle cell, obviously a much bigger population.
Again, we'll wait to see the data when we see there and go from there. In terms of different countries, we're in a kind of a different place than most companies are because today we only have a price in the U.S. So there isn't any other nations to compare to. It is a little different. The way we're thinking of international expansion as well as today, our focus is the U.S. When we think of thalassemia, that's where we're going. Like we said, we built the team. We have everything. That's the main focus. The second part is on the Gulf countries in the Middle East, where we established a partnership with a company named NewBridge. As Brian said, we've also filed in Kingdom of Saudi Arabia and United Arab Emirates. That is kind of number two. Europe is kind of a third in the tiers there.
We'll probably do a similar partnership as we have for GCC. Even Europe is different because it's certain countries in Europe. It's not your traditional pattern of where patients are located.
It is really clear. U.S., number one priority. The Gulf region and specifically Saudi Arabia, number two. We can be, from an MFN perspective or any other dynamic, very selective and thoughtful about where we go from there. It really is, we are in a unique position relative to nearly every other company.
In the last moments we have, maybe just talking the broader portfolio and just extending to the sickle cell landscape and talking about other PK activators, you have another with tebapivat. So maybe just put that into context, the profile of tebapivat and sickle cell based on the phase profile that you've shared.
Yeah, I mean, we have a lot to learn with tebapivat. Fortunately, we're about to commence on the phase II aspect of that journey middle of this year. The goal here is that we're in an advantageous position of having not one, but two PK activators. Tebapivat, the most prominent feature right now is it's a more potent PK activator. Our target is, again, with this community in need of different therapeutic options, options that have been developed differently to tackle different aspects of the disease, puts us in a position of building a proper franchise for sickle cell disease. We're excited about starting the journey of tebapivat and sickle cell disease in phase II. We're equally excited about what's already underway with tebapivat, which is our pursuit of low-risk MDS.
We have a phase II B study that we're actively enrolling in. The target there is to be fully enrolled by year-end. The main message for everybody is there's a lot coming. It's been an exciting year in 2024, but 2025, as you said upfront, is a real breakout year for Agios.
That's great. We are just on time. We always want to talk more pipeline and business development, but we will leave it there. It is a great place to close. Best of luck with the rest of the year.
Thanks a lot, Greg. Thanks, everybody.