Good morning, everyone. Day two of the Learning Partners Global Healthcare Conference. I'm Andrew Berens , Senior Biotech Analyst at Targeted Oncology. We're really excited to have Agios join us for this session. We have Sarah and Cecilia. Thank you for spending some time with us to walk us through the story. Maybe for those that are not familiar with Agios, you could tell us a little bit about the company before we jump into the Q&A.
Great. Thank you for having us, Andy, and thank you for everybody listening in. For those that are not familiar with the story, Agios is focused on developing therapies that hope to elevate and improve the lives of patients with rare diseases. Our focus today is in diseases that result in the dysfunction or destruction of red blood cells, particularly in pyruvate kinase deficiency, or PKD, thalassemia, sickle cell, and lower-risk MDS. Our lead asset is called PYRUKYND, and its unique mechanism of action is intended to improve the metabolism of the red blood cells, improving hydration, longevity, and overall energy. PYRUKYND today is approved in the U.S. and is commercialized in the U.S. for adults with pyruvate kinase deficiency, or PKD. We are also hoping to expand the indications and potentially launch in thalassemia and sickle cell disease. We had a tremendous year in 2024.
We had a lot of corporate goals set up at the beginning of the year, which we met on or ahead of time, and very excited with the progress we've made with our pipeline. I'd say a particular note was the thalassemia program for us. We had two phase 3 studies that read out last year. The first one is ENERGIZE that was in non-transfusion dependent patients with thalassemia. The second one is ENERGIZE-T with patients with transfusion dependent thalassemia. Together with the data for both studies, we were able to file by the end of the year simultaneously in four regions: the U.S., EMA, Europe, Kingdom of Saudi Arabia, and United Arab Emirates. For the U.S., particularly, we have a PDUFA date set by the FDA for September 7 of this year.
The commercial team is very fully focused on getting ready for that date and that approval as we continue to work on disease education for thalassemia, target profiling for the physicians that may have patients as we gear to kind of a larger indication. We started with PKD, which is ultra rare. Thalassemia is still rare, but a bigger indication. On the sickle cell front, we were also very excited to announce in October of last year that we completed the enrollment of our phase three study called RISE UP. For that one, the next milestone will be towards the end of this year, the readout of the top line for that study. If successful, hopefully have a launch in the U.S. right after thalassemia in 2026. We also made progress with our second PK activator called AG-946 before that.
That one has an ongoing study in lower-risk MDS, which is also a very exciting area with fast growth. We have a phase 2b study currently underway there with enrollment expected to be completed by the end of this year with data coming next year. A second path for AG-946 we are exploring is in sickle cell disease as we plan to start a phase 2 study by mid of this year. That would allow us to build a franchise in sickle cell, which is a disease with very high unmet need. Last but not least, we also have a very strong balance sheet, which we bolstered last year as we monetized the royalty for vorasidenib as part of our transaction with Servier back in 2021. We ended up the year with $1.5 billion in cash and equivalents.
The way we're thinking about that for capital allocation is in three key areas of priorities. One is obviously maximizing these potential launches and creating a multi-billion franchise for PYRUKYND. Second would be advancing the pipeline with tebapivat and some of the earlier stage programs we have. A third bucket would be to expand the pipeline both from internal organic opportunities we're looking at as well as looking externally through business development. A very exciting year ahead of us as well for us at Agios and looking forward to your questions, Andy.
Great. Anybody in the audience that has questions, feel free to let me know. I guess why don't we start with PYRUKYND commercially now? It's done fairly well, but it's obviously a small indication. What have been the takeaways from patients staying on the drug? I mean, what's been the tolerability of the profile of the drug?
Yeah, so for context, PKD is an ultra rare disease. It has very low diagnosis rates and not an urgency to treat. It is a slower launch in a way than we expect than we did for thalassemia. To your point, we've learned a lot of things in terms of how patients feel after taking the drug. We've had very good persistency on the drug. It also allowed us to build foundation in capabilities in things like market access and patient services that we plan to expand in thalassemia. We have not seen any pushback from an access perspective in PKD. As we pivot a little bit to thalassemia, it's a little different because we know that there are 6,000 adult patients. They are diagnosed. They're known to the system. From a launch perspective, we can do target profiling. We can do disease education more dedicated there.
The other thing I'd say we also learned in PKD is mile wide inch deep in a way. It's like one physician will have one patient in their whole career. You don't have a physician have a bolus of patients. That's a little different in thalassemia as well. We have a little bit more depth. Also, the patient community is more organized in thalassemia. Very different launches, but PKD served as a really good foundation for us.
Right. In general, the patients that, I mean, I guess the feedback we got is patients like the drug. It makes them feel better. They stay on the drug. The ones that do come off of treatment for PKD, is it generally for lack of efficacy or it's safety tolerability?
Yeah. For PKD, the underlying, the pathophysiology, it's a different mutation for each patient. There's a ton of different mutations. We can't predict treatment response based on the underlying genotype. The way to go about this is for a patient to try. Then within six months, if they don't have an improvement on hemolytic parameters or hemoglobin or they don't feel better, they just tend to come off. The vast majority of patients though do feel better and do have some improvement on hemoglobin and on their hemolytic parameters. Even if they don't reach a clinical trial bar of 1.5 grams per deciliter, but they reach a hemoglobin improvement of one gram per deciliter, for instance, they choose to stay on the drug.
Okay.
They do really feel better. Like when you talk to patients, it's, and those are things you can't really measure in a clinical trial, but the way they describe the impact on their lives, what they're able to do, like from activities in their life, going back to a full-time job, going to school, being able to complete a shower. I always think back of this one patient who described to us that she was never able in her life to go through one shower without having to take breaks, things that we can't even imagine as like having an impact. Now she's able to lift her arms, wash her hair, finish her shower. Those are things that are really meaningful to people.
Right. I think it's, I mean, the reason I asked the question is I think when we talk about sickle cell, the drugs that were approved and were no longer approved, I think the feedback we got was patients didn't necessarily feel better. Some of them felt worse.
Right. I think this is something that we have seen in PKD and now also in thalassemia that the way we improve hemoglobin actually also makes people feel better. These are the first programs that actually were able to deliver on a statistically significant result for fatigue. We have measured fatigue both on the PKD program and in the thalassemia program. For the thalassemia program, it was actually our key secondary endpoint. We hit statistically on an improvement in fatigue.
Okay. No, I think that's definitely important. Why don't we talk about thalassemia and then we'll go to sickle cell. You do have the PDUFA date in September. There's some speculation about whether or not there'll be an adcom or not. Some people think that could be a good thing. I think you said on your earnings call, you're not welcoming an adcom. I mean, obviously they're unpredictable and a lot of work and expense to prepare for. What are your thoughts now about the potential for an adcom ahead of that September PDUFA date?
The same as our earnings call still, like we are in the process of filing an active engagement with the regulators. To date, we have not been informed that we will have an advisory committee. Of course, if that would change, we would let you all know. To the point of we're not welcoming it, we are. Like if they tell us that we have to have an adcom, we will obviously be fully ready to engage with the regulators that way and then would welcome that opportunity. Needless to say, like from a filing perspective and a workload perspective and indeed the resources, I would prefer that we just progress as is versus actually having one.
Right. Okay. I mean, I think one of the reasons people are questioning the need for an adcom was your disclosure at the ASH meeting about the potential for liver toxicity. I guess what struck me was we have a lot of companies that have small molecules that have LFT elevations, and they usually classify them as transient LFT elevations. I guess you're taking that next step. People are questioning whether that's conservatism on the company or is there something that makes you more concerned than the companies that are seeing these transient LFT elevations?
I think it's all about context of the disease and the risk profile observed, right? Thalassemia patients are patients who have a lot of liver disease as part of their condition. If you don't treat thalassemia, for sure people end up with bad livers over time. Actually, now that people are better managed, one of the big causes of death in thalassemia is liver disease. It makes it very hard to actually examine and look at data because there is a lot of confounders in this patient population. That being said, why we actually called it an important potential risk was because we had observed cases in our program that had a similar pattern. The fact of the matter was that despite confounders or no confounders, they all improved on discontinuing the drug and returned back to their baseline.
While we don't call it just a regular transaminase fluctuation on a drug is because two out of the five patients ended up having a hospitalization, which to me is like that's not just a random lab fluctuation. It's more serious than that. While we feel it's appropriate to actually have a warning and precaution around it to draw extra attention of the physicians to this phenomenon.
Okay. The liver disease in thalassemia, and we'll talk I guess in sickle cell whether it's also seen there. You said even in patients that are not treated, meaning if you didn't give transfusions or chelators or anything, there's like an innate liver disease. It's just from the, is it the hemolytic aspect that causes iron overload?
Yeah. They have a dysregulated iron metabolism and the ongoing hemolysis releases free heme and iron into your system, which basically it does accumulate in your organs even if you're not transfused. Obviously, if you get transfusions on top, typically iron overload is higher and people are on chelation, but not all non-transfusion dependent patients are on chelation.
Okay. Sickle cell is also a hemolytic disease with iron overload and it has also an ischemic aspect to it. Do those patients also have a similar background rate of liver disease?
Liver is one of the target organs, like is one of the organs that really gets damaged in the context of sickle cell disease. To your point, the pathophysiology is a little bit different between thal and sickle. In sickle cell disease, you have this acute ischemic component that adds to it. For both diseases, if you get transfusions, there's always risk of transfusions by itself. If you already have some baseline abnormalities, you tend to respond more severely to whatever insult comes next. There's a multitude of reasons.
Right. I think obviously the benign profile of the drug and PKD and patients staying on the drug and the feedback we got was very positive. It caught a lot of us off guard when you guys had that disclosure at ASH. That was on the heels of the decision of Brox-Brida, which was also another surprise, I guess, that made people question the VOC need in that trial. I think I understand why the market reacted like it did. We'll see how things.
Yeah. I think that's where there is a difference between how the market reacted and how the physicians in our clinical trials and the community has reacted to this. I think when you speak to the providers who take care of thalassemia patients, they are routinely monitoring for liver disease. We just discussed it like from thalassemia, but also iron chelation by itself, you need to watch for liver disease. They are very much in tune with this. For us to propose a monitoring on a monthly basis for the first six months and then when you observe something to actually act upon it was almost for them routine. We did not have that type of reaction speaking to physicians.
Okay. In terms of your next generation Tsveta Milanova, and then I think there was a prior drug that was a PK drug developed in around 2015, 2016. Is there anything about, is it a direct consequence of the mechanism potentially, or is it something with the scaffold or metabolite? Do we know if there's something related to the drugs?
The three drugs are different from the scaffold perspective. The one that you're referring to was something that we stopped developing based on an observation in a healthy volunteer, which was a different type of event than what we've observed in thalassemia. I think if we talk about drug-induced liver injury, it's extremely complex. Typically, almost any drug that gets metabolized in the liver at some point will have a signal for liver injury, being transaminase fluctuations versus more severe events. Sometimes that is linked to the way it gets metabolized. Sometimes that is linked to the dose. Sometimes there may be risk factors within a specific patient population. For us, this is not possible to really determine at this point in time because it's a very few number of patients in the context of a rare disease.
That is a very confounded patient population. For us, we took an approach of just highlighting when you start taking this drug for the first six months, just watch out for these liver enzymes and then take appropriate action as you see fit, which is a very clear and clean guidance, which is typically what you like from a post-marketing perspective to be simple and direct.
Right. Okay. When the patients, I think you said this, when they, if it's identified by the monitoring, it is reversible. Do the patients have to come off the drug permanently or do they just dose reduce and they can go back on it?
It depends because if you see something like this, what we've put in our PKD label is to just discontinue the drug. If you think there is another cause and you want to restart the drug, you can do a rechallenge. That is when you think it's something else causing the event, right? Like typically when you have a pattern like this, physicians tend to do a workup in the context of the individual in front of them. Maybe they have a viral infection or maybe it is the drug. They all will make their independent assessment. If they find another cause, they can restart.
Right. Okay. In terms of the commercial opportunity, what are the plans for the company? A lot of the thalassemia patients are not in the U.S. and the Mediterranean region. Walk us through kind of how you guys see the commercial opportunity if the drug is difficult.
Yeah. Our first focus obviously is the U.S., which we spoke a little earlier, and the team is obviously gearing up for that. For Agios U.S., we're not directly commercializing. What we've decided is to partner with, it's a distributor agreement, but it's a full-service provider. The biggest area outside of the U.S. is the Gulf countries, with Saudi being about 75% of that region. As I mentioned, we filed in Saudi and United Arab Emirates in parallel with the U.S. and Europe. We have breakthrough medicine designation from a regulatory perspective. I can speak to that in a second. From a commercial perspective, GCC is about 70,000 prevalent patients in thalassemia in that region. From a dynamics, it's more similar to a European type of markets, both from a pricing dynamics perspective and in general how it works.
They have Ministry of Health, they have private institutions, they have academic institutions. You go through the regulatory approval and pricing initial discussion at a national level first. Each nation does their own review. You still have to go through formulary access discussion. It takes longer, like different in the U.S. where you get your approval, pricing, and you go. It is a bigger opportunity, of course. It will take longer to get there. There is generally lower pricing than the U.S., but given the volume, obviously there would be a lot of discussions with them in terms of budgetary impact. We are very excited. We partnered with a company named Newbridge. They are very well known in the region. This is a very common model. We have all had experience in prior companies doing this. They work very close together with us.
We still have full strategic control in terms of the decision-making. For me, it's also a very efficient way of doing capital allocation versus having to build total new infrastructure outside of the U.S. That's for GCC. For Europe, we're looking to build a similar model.
Okay. I guess there is an approved drug in this indication. I guess what do we learn about the reimbursement? I mean, I think you suggested that the pricing for thalassemia at least could be maintained at the PKD pricing, but it sounds sickle cell might be tougher. Is this a price-sensitive market?
The way we think about it, we usually don't really discuss pricing until you have full data and a label in general. What we think about, so PKD today is $335,000 annual WAC in the U.S. Like I said before, we haven't seen any pushback. It's not a managed category. It's an ultra-rare disease. Thalassemia is bigger in the context for Agios, but it's still a rare disease. It's still in the neighborhood from a payer perspective. We think we're very well positioned there from a pricing perspective. As you migrate to sickle cell, we're hopeful to be in that position to have that indication as well. It's a much bigger indication. It's 100,000 patients. We will guide our pricing decision based on the data when we see it, as well as a competitive landscape around it as well.
Okay. I mean, some of us have always thought, even before Brian took the helm, that at least it would solve the pricing problem to have a separate drug in sickle cell, but the company has always been committed to mitapivat and PYRUKYND.
Yeah. We're still looking at, Tsveta Milanova, it's something we will explore. Sickle cell is a disease that's going to need many, many therapies. These patients, it's a complex disease. Not everybody responds to drugs. That's why we are excited to see the phase one data we presented last year and entering into a phase two to build a franchise from a commercial perspective to be able to take more of the branded patients on branded drugs. It also gives us a different play also. They have different patent lives. Pricing could be a way to differentiate. We'll be guided, similar thing, would be guided by the data once we have both AG-946 and Tsveta Milanova. We're very excited to have two options for these patients that are in dire need, of course.
Right. Let's talk a little bit about, we have under 10 minutes left. I mean, sickle cell for a lot of investors is the real big opportunity. There's obviously MDS, which is also big that you guys are pursuing, but I think that's considered more of an option. Sickle cell seems most tangible, I guess, especially if you get approved and patients feel better. Now that Oxbrida is no longer on the market, the competition's less. What do you think? I mean, the question I guess is, is a VOC, is a clinically meaningful endpoint going to be important? Is a trend going to be okay? We did see another PK drug actually in a small trial show a VOC benefit.
I guess, do you think, I guess first that the FDA wants to see a definitive VOC benefit or is a trend going to be enough?
I think it always depends on the totality of the data you present. Obviously, we're shooting with a primary endpoint to show improvement on a VOC, but the way we've designed the trial is if we wouldn't only have a trend, so wouldn't reach statistical significance, because we've done an alpha split on the two primary endpoints, the other primary endpoint being hemoglobin, we can move on to secondary endpoint testing, which has other ways to look at how patients feel and function and also other ways to look at VOC. The way the trial is designed gives us a lot of optionality. Obviously, we're hoping to hit on both primary endpoints.
Right. Okay. In terms of the background VOC rates going in, I think that it's sometimes difficult because patients when they enter a trial are monitored more regularly than they are maybe before when they were just being treated by their primary care physician or their hematologist. How does that tend to trend in trials? Is it that once you end up with more severe patients or less severe patients when you use the background rate as entry criteria?
Yeah. I think we look back for one year at the patients that enroll into the trial. One of the requirements is to have had at least two sickle cell pain crises in the year prior. We have a definition that is applied to what is a sickle cell pain crisis. The investigator highlights that they meet or do not meet that criterion. If they meet the criterion, then they can move on into the trial. Each sickle cell pain crisis event that would occur gets captured per that definition, and it goes on to an adjudication committee. That is the difference, right? We have an adjudication committee while the trial is ongoing. We are not adjudicating historical events. Same definition, but we do not make all, I mean, it would not be possible to do everything in a screening period, basically.
You do rely on that. That being said, the way the investigators assessed the events and the way the adjudication committee assessed the events in our phase two was very similar. That is always a good sign. On top of that, our phase two data, the way we have captured it, we had projected that people would have around the baseline sickle cell pain crisis rate of about three. That is exactly what occurred in the phase two. In the phase two, we had a little bit of a lower rate in the patient population once they were in the trial, which speaks to the fluctuation in the patient population, but it still allowed us to measure a dose response on sickle cell pain crises.
We feel very confident with the way we've applied the definition, the way we've set up our inclusion criteria and the adjudication committee, and then the data collected in the trial, that that is a really good setup for phase three. For phase three, we have the same type of assessment, so same inclusion criteria, same type of patient population, which is typically where sickle cell disease, I think, sometimes had some issues that the criteria from phase two changed quite a bit towards the phase three patient population. We're not doing that. Similar patient population, same adjudication committee, a lot of the same sites and investigators that contributed to phase two, they're all still in phase three. We try to make it as protected as possible.
Right. I think one of the KOLs highlighted to us, I think one of the Dacia, which did not demonstrate the VOC on the confirmatory basis, but I guess it is that in the background rate and the baseline rate for the previous year, patients may not go to the hospital. A lot of the definitions of VOC require some sort of definitive intervention, either a hospital visit or a written change in medication or something. In the trial, when you are watching a patient, like they are definitely going to go, like if they have pain, they are told to go. It actually inflates the amount of VOC. It is very hard to demonstrate a VOC benefit in a trial. Is that what has happened with the Dacia?
I don't know. I don't know what exactly happened with Dacia. There were like a couple of differences between the phase two and phase three. I don't know ultimately what drove this, right? That may be part of it, but I think there is potentially additional reasons and maybe all of it compounds. I think from our perspective, though, we are, like I said, we have a lot of safeguards, like operational safeguards along the way, trying to keep things as similar as possible to be able to replicate. The other thing that we do is actually measure, there is a pain diary as well for patients to fill out so that we can capture events that occur that maybe did not trigger the patient to go to the hospital. We have other things in the trial to try to collect all of that data.
Right. Okay. The other, I guess, concern with Oxbrida was the infection rate from malaria, which I guess you're decreasing the sickling. I mean, how are you, I mean, you're going to have patients, I guess, enrolled from those same regions. How have you taken that risk?
Yes. We do have patients enrolled out of regions where malaria is present, which I think is the right thing to do in the sense of that's where sickle cell disease is. Typically, it's a good thing to try to enroll a patient population that is representative of the overall patient population. Also, because people that live in Western Europe or in the U.S., they go back and forth and can come home with malaria. It's good to understand what happens typically in the context of a clinical trial. Hydroxyurea did not have that phenomenon, right? This was something that was observed on Oxbrida. I don't know if that was a random chance versus something really linked to potentially mechanism of action. What we have done is we try to go for really balanced enrollment across all of the different regions in the world.
You could enroll a sickle cell disease trial really much faster if you go to certain regions, but we try to really make sure we have a good representation of the U.S., Western Europe, and the Middle East as well, avoiding some of that.
Okay. Do you get the sense? I mean, it seems like if you guys can succeed in the trial and get it approved, there's a huge need now, especially for a drug that improves hemoglobin, but also makes patients feel better and lessens the amount of time they spend in the hospital. It really is, it's a big opportunity if you can get the drug there.
Yeah. We're very excited, very excited. We're like shooting to have the data by the end of this year.
Okay. Great. Any questions from the audience? Rogios. Okay. Thank you. Appreciate it. Look forward to the updates and all the progress you guys have made.
Thank you.
Thank you for having us, Andy.
Thank you, everyone.