Good afternoon, everyone. My name is Gena Wang. I'm a senior biotech analyst at Barclays. It is my great pleasure to introduce our next presenting company, Agios Pharmaceuticals. Sitting on the stage with me, we have Sarah Gheuens, Chief Medical Officer and Head of R&D. We also have Cecilia Jones, Chief Financial Officer. Before we dive into the questions, maybe I will let you guys give a quick overview about the company, and then we can discuss.
Great. Thanks, Gena, for having us, and thanks, everybody, for listening. For those of you that might not be as familiar with our story, our mission at Agios is to develop transformative treatments for patients living with rare diseases. Our main focus right now is on diseases that result in either dysfunction or destruction of red blood cells. We have programs in pyruvate kinase deficiency, or PKD, thalassemia, sickle cell disease, and lower-risk MDS. Our lead program is called PYRUKYND, or mitapivat, and it has a unique mechanism of action that's called PK activation that allows it to help the metabolism of the red blood cells. It improves their hydration, longevity, and the energy of the cell that then helps these patients.
PYRUKYND is approved today and commercialized today in the U.S. for adults with PK deficiency, and we're hoping to extend into new indications in thalassemia and sickle cell. 2024 was a super exciting year for Agios. We set up the year, the beginning of the year, with a lot of corporate milestones, which we hit on all, either on or ahead of schedule. One of the highlights that we had in 2024 was on our thalassemia program, where we presented the data of our two phase III studies. One was called ENERGIZE, which was for non-transfusion dependent patients, and the second one is ENERGIZE-T for transfusion dependent patients.
Between the two studies, we covered the totality of the patient population in thalassemia, and those results enabled us to file simultaneously by the end of the year in four regions: the U.S., Europe, Kingdom of Saudi Arabia, and United Arab Emirates. For the U.S., particularly, we have a PDUFA goal date set for September 7th of this year. The commercial team is really gearing up to that date. We've been increasing our sales reps and everybody surrounding the launch from PKD, which was ultra rare, into still rare, but much bigger indication for us in thalassemia. We're very excited for that. Another highlight of the year was for the sickle cell part of the program. We have a phase III study called RISE UP. In October of last year, we announced the full enrollment of the study.
It's a 52-week study, so we expect to have top-line data for that study by the end of this year. The next program, or the next molecule we have, is also a PK activator that's called tebapivat, or it used to be AG-946. We have two paths for tebapivat. The first one is in lower-risk MDS. For that one, we're well underway on a phase IIB study, and we expect to complete enrollment for that study by the end of the year. That's a very exciting area with high growth, and we're looking forward to having the data for that study as well. The second part of that will be also to have a second PK activator in sickle cell.
We're planning to initiate a phase II study by midpoint of this year, and that will allow us to eventually, hopefully, have a franchise for sickle cell, which is a disease with very high unmet need. Lastly, I would say we have a very strong balance sheet, which was bolstered last year through the monetization of the vorasidenib royalty that we had kept from the transaction we did with Servier back in 2021. We ended up the year with $1.5 billion in cash and equivalents. The way we think about the priorities for cash allocation or capital allocation is, first and foremost, be able to maximize the launches, hopefully back-to-back launches. If we're successful on sickle cell, we would have thalassemia in 2025, sickle cell in 2026, and we're hoping to build a multi-billion dollar franchise with PYRUKYND.
The second priority is to advance the pipeline. Tebapivat, like I described, and we also have some earlier programs in phenylketonuria, PKU, and polycythemia vera. The third bucket would be to expand our pipeline, and that could be both on internal organic options and opportunities we're looking for, as well as external opportunities through business development. We have a very exciting year ahead of us for 2025, and we look forward to continue to share our progress.
Sounds great. Maybe starting with your PKD program, how has the interaction with the FDA proceeded in recent weeks since your supplementary NDA just was accepted and PDUFA was assigned?
Yes, we are indeed building upon our PKD story now with the thalassemia program. We have a supplemental NDA that was submitted, and as Cecilia mentioned, the PDUFA action goal date is September 7th. Right now, the review is actively ongoing and progressing as expected, and we are very excited about the potential opportunity to deliver this therapy for patients with thalassemia.
Any comments regarding potential outcome?
To date, we have not been informed that there will be an advisory committee, but as we've mentioned in the past, if we would be informed at any time point, then we will, of course, let the community know.
What could be the latest time that you know that there will not be any outcome?
There is not really a specific time point by which you are truly in the clear. However, as we are continuing to progress, the chances of something like that continue to decrease.
Okay. Maybe regarding the label change, what is in the community with the increased monitoring, what is the feedback there?
You are referring to the label change that we have made for pyruvate kinase deficiency. We have added a warning and precaution based on an observation made in the thalassemia program, in which we had observed hepatocellular injury in thalassemia patients. We have updated the label language for pyruvate kinase deficiency to reflect that observation. That warning and precaution has led to a request to monitor on a monthly basis for the first six months of exposure to PYRUKYND, both for PKD and then across all of our clinical programs. In regards to how that has been perceived, it has been perceived as part of normal routine care, really. Patients, when they are started on a new therapy, when they have a hemolytic anemia, are routinely being monitored, both for efficacy, but also for safety.
Physicians are used to actually routinely monitor for liver function, for kidney function in the context of these diseases, especially the liver is an organ that often gets damaged in the context of these hemolytic anemias, or also is in the context of iron chelators, something that needs to be monitored.
Okay. Regarding the potential timing for approvals in thalassemia in the U.S., EU, and other parts of the world.
Those regulators, they do not give you an action date like the U.S. does, but those filings are progressing as normal and as anticipated. We are looking forward to progressing those further.
Okay. For the commercialization, what kind of maybe preparation you have done regarding the sales outreach?
Yeah. Our main focus is the U.S. right now. We are commercializing that directly. We had started, obviously, building an infrastructure with PKD, but because it's ultra rare, it was much smaller. As we move into thalassemia, it's a broader patient population. We are expanding. The nice thing is PKD gave us the opportunity to build the foundation on things like market access, patient services, and now we're leveraging that and enhancing. We had about 18-20 reps when we were just PKD, and we doubled that as we geared to prepare for thalassemia. Sales reps is only one part of the ecosystem, if you want, of the support that we have. In terms of outside of ex-U.S., we're not building direct presence. What we've done is for the Gulf countries where there's a big prevalence.
If you think the U.S. is our first market, the second one or the second group would be the Gulf countries. There are about 70,000 patients with thalassemia in those countries. That is where you see we filed into Saudi Arabia and United Arab Emirates, as well as Europe and U.S. There we signed an agreement with a company called NewBridge, and this is a specialty company that does distribution of products for a lot of different pharmaceutical companies. They are very well known in the region. They understand the region. They basically are your feet on the ground. They carry all the costs and the investment, but we still keep the strategic decisions and the strategic control of the asset, as well as managing with pricing.
Our teams work very closely with them, but we leverage their expertise in the region, and we'll probably do something very similar in Europe.
Okay. Regarding the safety profile, do you think beta thalassemia and the sickle cell have a different threshold that what patients are willing to take?
Each patient has to make their own individual decision, right? We are still working to generate the benefit-risk profile in sickle cell disease because our phase III is still ongoing. Once that is available and if we can deliver to the target product profile that we are looking for, that will always be an individual discussion between patients and physicians.
Okay. I think that's a good transition to sickle cell. Maybe the phase III trial, remind us the primary endpoint and what is your goal for the phase III trial?
As Cecilia mentioned in the beginning, we are indeed studying PYRUKYND in sickle cell disease. We believe that because of the mechanism of action of the drug, this drug has the potential to deliver an improvement both on hemolytic anemia and on vaso-occlusion in the context of sickle cell disease. Both those components are very important for patients living with sickle cell disease. Hemolytic anemia, obviously, has all of the complications of anemia, makes people really feel very, very bad, very fatigued. This is not, "I'm tired." This is like a bone-crushing fatigue that is really limiting what people can do. The hemolysis and the hemolytic anemia ultimately leads to end-organ damage as well. The vaso-occlusion part of the disease is basically acute ischemia that leads to pain and can lead to organ damage as well, and ultimately can also lead to death.
Very horrible disease, big unmet need. Our phase III program is designed in such a way that we're trying to deliver one therapy that can address the totality of sickle cell disease. That means we're looking to improve hemolytic anemia. One primary endpoint is a hemoglobin response, and then we're looking to improve vaso-occlusion. The other primary endpoint is looking at sickle cell pain crisis reduction. We have done an alpha split on those endpoints because we would like to, if one or both are positive, move on to secondary endpoint testing. Within that secondary endpoint bucket, we have other ways to look at how patients feel and function. As I just highlighted, fatigue is very important for patients living with sickle cell disease, so that is also something we are looking to improve.
We have precedent on being able to deliver on that, on an improvement of fatigue, both in our thalassemia program and in our pyruvate kinase deficiency program.
Regarding the primary endpoint, what is the alpha allocation?
It is 0.02 to the hemoglobin response and 0.03 to the sickle cell pain crisis rate.
Okay. What is your assumption for the control arm?
For the sickle cell pain crisis rate, we're looking for the baseline of three sickle cell pain crises in the prior year that then we look to continue in the year that they are on drug, and then the drug is hoping to reduce that from three to a little bit less than two.
Okay. So basically 30% reduction?
Yes.
Okay. For the hemoglobin level, the percentage you define?
For the hemoglobin level, we are looking to improve the average hemoglobin concentration by 1 g per dl between week 24 all the way to the end of the trial. It's important that that is an average hemoglobin, not just a one-time point in that time period, because we're also looking to highlight maintenance of effect by doing this. The trial is 90% powered to look for that improvement of 35% on the hemoglobin response.
Okay. For the VOE also, is 90% power?
Yeah. One is 91% and the other 90%.
Okay. Going to the secondary endpoint, also maybe remind us what you've shown so far and why you designed the study this way.
Yeah. The study is designed this way to really try to deliver to the totality of the disease as highlighted, but we've based that also we have a phase II, obviously, which was a dose-finding study. We tested two doses against placebo with a primary endpoint of a hemoglobin response. We looked at hemolytic parameters as a secondary endpoint and also a trend in sickle cell pain crisis reduction. Across the two doses, we were able to show an improvement when compared to placebo trends because we did not do statistical testing on the secondary endpoints based on the sample size and the shorter duration. We basically have a hemoglobin improvement, a hemolytic parameter reduction, and a trend on sickle cell pain crises as well that allowed us to move on to phase III.
Okay. And then secondary endpoint, is there any hierarchy there or are we just even split of the alpha?
Yeah, we're testing everything together.
Okay. That's very good. Maybe status phase III, like the timing.
Yeah, we're very excited because the team really worked very hard and very collaboratively with all of the different sites, and they were able to enroll the study fast. We announced full enrollment last October, so one-year observation period for this study. One of our corporate milestones this year is delivery of the data of that trial by the end of this year.
Okay. Maybe going back to the primary endpoint, since you have a co-primary endpoint.
Two primary endpoints with the alpha split. Yeah.
I see. As long as you're hitting one, that will be enough for approval?
For approval, that is like you do need the risk profile and all of that too.
Right. If what you define as a positive study, as long as you hit one of the primary endpoints, that would be enough, or if they want you to hit both?
Everything is always dependent on the totality of the data. You need to be able to speak to clinical meaningfulness in your data package. Obviously, sickle cell pain crisis reduction is considered a clinically meaningful endpoint, but when you speak to patients, what they are really looking for as a solution is something that also improves their fatigue. Hence, we have designed that trial to be able to deliver to that. In the context of hemolytic anemia, when you can actually hit on hemoglobin and have a patient report that outcome that is also statistically significant, that is also a clinical meaningful benefit. We have in that secondary endpoint bucket also other ways to look at sickle cell pain crises.
I think, as always, a regulator will always look at the totality of the data, especially in the context of a disease that is horrible and has a huge unmet need with no options. You really have to speak to the totality of the benefit-risk profile.
Okay. Just try to understand. Have you agreed with FDA? Did FDA say anything that one is enough or you wanted?
No. An agency will, I have never heard of an agency committing proactively to what they will approve. Even if you hit on, if you have a positive trial and a positive primary endpoint, you really need to have the totality of it work out, right? There are plenty of precedents of drugs that did hit on a primary endpoint and ultimately did not get approved, and the other way around, drugs that did not hit on a primary endpoint but ultimately got approved because it is really everything that matters.
Right. Okay. That makes sense. Was the study designed based on the feedback from the FDA?
Yeah, of course. We always work with all of the different stakeholders, with the different regulatory authorities across the globe. We work with our patient advocates and advisory boards with patients and, of course, the physicians as well to make sure that we can deliver a drug that is not just going to hit on that you can claim a clinical trial is positive, but you really want to deliver something meaningful to all of those different audiences. We take feedback into account from all of those different stakeholders to come up with what we believe is the best plan forward.
Okay. Quickly on your AG-946, what kind of data will we see later this year?
For 946, it's another PK activator that we're currently studying in MDS and in sickle cell disease. For MDS, we have a corporate milestone of enrolling, full enrollment of a phase II- B in lower-risk MDS. That is not data, but it's actually an important step to be able to deliver data in that program. For sickle cell disease, we have a corporate milestone of having first patient enrolled mid-year.
Okay. Okay. Good. For your PK franchise, you do have several assets there. How do you see this coexist in the marketplace?
Yeah. Like first, sickle cell disease is a complex disease and will require a lot of options for these patients. They do not all respond to the drug, to individual drugs. First things, we cheer for everybody that is trying to get therapies for these patients. For us, like you said, we have two PK activators, PYRUKYND, which Sarah was just talking about, which we expect to have the data readout this year. The second one is tebapivat , which is also a PK activator, but a more potent agent there. Our thinking is to be able to build a franchise to have the ability to address more patients down the road with our franchise. As well, there are also different patent lives on each of our products, so it allows us to have flexibility there. We are very excited to be able to go, but it is earlier, right?
That's entering into phase II.
Okay. Good. Cecilia, you did mention you have $1.5 billion. That's a lot of cash for a biotech company. How do you say, from the BD perspective, how would you use this cash?
Yeah. What we've said for a while, we're very disciplined in how we think about business development, and we establish criteria in terms of we want something within rare. That's kind of our core of what we are. We probably don't want to go ultra rare again as we did with PKD, but still stay within the rare area where we've established very good capabilities on clinical development, and now we're building on commercial transformative drugs that we really don't want to meet to or something that really doesn't address an unmet need. Something that has ideally a way to early de-risk the program as we do kind of smaller bets before we put a lot of capital in it, as well as good clear path to a regulatory approval.
Our team has been amazing at being creative at designing studies, but we have to have an end in sight there. Of course, something that's value creative. In terms of what we're looking at, probably we're agnostic to modalities. I'd say probably not gene therapy. That would be very much outside of our capability there, but we are agnostic otherwise in terms of modalities. In terms of stage of development, probably towards the earlier side where we can, again, apply all our capabilities to clinical development with potential back-to-back launches. We have the commercial team definitely busy there.
Very good. I think we have one minute left. Maybe which are the key topics you wanted to emphasize that you think investors will misunderstand?
Yeah. I think we have a lot going on, so we're very excited. I don't want to pick a favorite child, but for one, I think we have an incredible potential with PYRUKYND as a franchise to build a multi-billion dollar franchise there, hopefully with success in RISE UP. That would mean back-to-back launches in thalassemia and in sickle cell after it. We also have an advancing pipeline with tebapivat, with the two programs. We didn't get to talk a lot about the next ones, but we have another asset in PKU, which is in healthy volunteers right now, and we're expecting to file an IND on the earliest asset, which is AG-236. Like you said, we have a very strong balance sheet, which allows us to move all these programs along.
Thank you very much.
Thank you. Thanks for having us.
Thank you.