All right. Good morning, everyone. Day two from sunny Miami of our global healthcare conference. I'm Andy Berens, senior biotech analyst, and we're really very happy to have Agios Pharmaceuticals. We have Cecilia Jones, the CFO, and Sarah Gheuens, the CMO. Thank you for joining us.
Thank you for having us. Very excited to share everything that's going on at Agios.
Great. Why don't we start with just a brief overview of the company, what you guys are doing, for those in the audience that may not be familiar with Agios?
Great. Yes. For those of you who don't know our story very well, we are a rare disease-focused company, and our core focus is on the red blood cell health. We have a pioneering PK activation franchise, and our lead asset is mitapivat or PYRUKYND, which is currently commercialized in the US for an ultra-rare disease called PKD or pyruvate kinase deficiency. And then we also have late-stage studies in both thalassemia and sickle cell disease. 2023 was a very exciting year for Agios, but we also started 2024 on a great start. We had a positive readout for one of our two phase 3 studies on thalassemia called ENERGIZE, which enrolled patients with alpha- or beta-thalassemia that are considered to be non-transfusion-dependent. And in that study, we showed statistical significance on both hemoglobin improvement as well as secondary endpoints of patient-reported outcomes.
Sarah can speak more about that later. We are now eagerly awaiting for the second trial to readout. It's called ENERGIZE-T and also enrolled patients with alpha- or beta-thalassemia, but in this case, transfusion-dependent patients. We expect that to readout by mid-year. The split roughly in the U.S. is two-thirds of the patients are non-transfusion-dependent, and a third is transfusion-dependent. On the sickle cell side, we have a phase II/III study called RISE UP. The phase II portion of that, we did a topline in June of last year and the full presentation at ASH in December, again also showing statistical significance on hemoglobin improvement and a trend in sickle cell pain crisis, which is a very important metric for sickle cell disease. That one, like I said, we did the readout, and Sarah's team did a phenomenal job.
We started enrolling three months after that, and we expect to be fully enrolled by the end of this year with a readout next year, 2025, and a potential launch in 2026. And I should say, sorry, for the thalassemia, we expect to put the two trials together and file at the end of this year for a potential launch in 2025. So back-to-back potential launches there. We have a second PK activation asset called AG-946, and that is being studied in lower-risk MDS. We had a phase IIa readout at the end of last year, and are expecting to have the second or sorry, the phase IIb portion of that starting to enroll mid-year of this year.
And then on the non-PK activation side, we're very excited today to share that we have initiated dosing on AG-181, which is a molecule that also came out of the Agios lab, and it's for the treatment of phenylketonuria or PKU. And then last but not least, we also have an asset in preclinical, which we acquired through a licensing deal with Alnylam. So very excited about our pipeline and everything going on at Agios. We also have a strong balance sheet with $806 million of cash at the end of 2023. I would be remiss if I'm not referring to this.
Great. Well, thank you for that overview. I'd like to start, I think, with something that I've perceived as misunderstood, and I probably didn't fully appreciate it until we spoke about a month ago about it. But let's talk a little bit about the PKR drugs and, as a class, what they do. And I think the thing that I find interesting is there's a difference between what mitapivat does and the PKR as a class versus what some of the other drugs that are treating the same diseases, like Oxbryta, GBT601, luspatercept. So in terms of how I mean, obviously, in PKD, the drug makes a lot of sense, and you're approved there and selling the drug. But when we start to think about these other opportunities where anemia is a problem, what's unique about the PKR class versus some of those other drugs I just mentioned?
Sure. So I think it really comes down to the mechanism of action. So PK activation is focused on the last step in the glycolytic pathway, and glycolysis is the way the red blood cells get their energy. So it's very important to address that. The diseases that we are studying, they have an imbalance in energy. So by actually focusing on getting more energy to the cell, there is better red blood cell health, which translates into an improvement in hemolysis and an increase in hemoglobin, which now we have shown across multiple indications that that mechanism of action indeed translates into an improvement of hemolysis and an improvement of hemoglobin. But not only that, what is differentiated here is that the way we do that actually leads to people feeling better.
So in PKD, we were able to highlight that via a specifically designed patient-reported outcome tool, that way of raising hemoglobin translated into people feeling less tired, for instance. And now we have the same type of data in thalassemia. So in our non-regularly transfused patient population, we have highlighted that we have shown that the way we improve hemoglobin there also translates into a better outcome as measured by FACIT-Fatigue. So again, improving patients' fatigue, and that was statistically significant. So that's the first time that that actually ever happened in thalassemia. So that's unique about this mechanism of action. If you compare it to luspatercept, for instance, [it] is available for regularly transfused patients but not available for non-regularly transfused patients. And one of the big differences between the two compounds is the patient-reported outcome.
In regards to sickle cell disease, the story becomes a little bit more complex because higher up in the glycolytic pathway, there is another step that is disturbed in the context of sickle cell disease. And patients with sickle cell disease have an elevated 2,3-DPG, which again is one of the steps higher up in the glycolytic pathway. And we know that our drug addresses that as well. And that one is specifically linked to sickling. And so the fact that we were able to highlight that we have anti-sickling effects via certain research studies, but that that also translated into our phase II clinical trial data in which we were able to highlight a trend of improvement in sickle cell pain crisis gives us a lot of hope that we can provide a meaningful therapy for sickle cell disease.
Okay. So just to summarize, you're saying the mitapivat and the PKR drugs, they primarily work by preventing hemolysis, red blood cell destruction. They help the red blood cell be more stable. And some of those other drugs I mentioned actually treat the anemia by increasing production rather than destruction. And I think it's an important distinction because a lot of people compare the hemoglobin increase when they're trying to decide, "Oh, this is not as potent a drug as, say, GBT601, which has 3 grams per deciliter increase." But you guys are actually showing less destruction, which also then, I think, has at least the hypothetical benefit of decreasing inflammation. They have a cytokine pathway, iron depositions, and things like that.
I do get a sense that people don't always appreciate that that's a pretty distinct difference between what you're doing and what these other drugs have shown previously.
No. And I think you're exactly right. And I think the commonality, they are hemolytic anemias. And so the fact that we tackle hemolysis via this pathway is very, very meaningful.
Okay. I know you guys and I think the other drug that was acquired have shown some early data, like flow cytometry and different metrics about the red cell stability and how elastic it is. Do you remember the specifics of all those? I just remember them being pretty compelling, that the red blood cell does seem to be more robust when PKR is on board.
Yeah. It goes into red blood cell membrane stability. That was highlighted, for instance, in sickle cell disease patients on our product, that we improved that. Each of those experiments basically highlights positive outcomes. That's the other thing about our product that is very nice. It's what we call the consistency and the compelling data across the different indications because all of it always points in the same direction so far.
Right. So why don't we talk a little bit about the thalassemias, and then we'll move to some of the other indications? You've already shown in transfusion-independent patients. Can you just summarize the data that we've seen so far?
For thalassemia, non-transfusion-dependent patients, so our primary endpoint was a hemoglobin response in which we hit on that endpoint. So mitapivat was statistically significant. We had 43% of the patients meeting that clinical trial endpoint. But most importantly, in our key secondary endpoints, we have a statistically significant result for FACIT-Fatigue, which never happened before in a thalassemia development program, and that again being supported by an improvement in hemolysis, which of course is very important in the context of the mechanism of action that we just discussed. And so we are very excited and really are looking forward to present that data in more detail at an upcoming medical meeting.
Right. Should we expect to see improvement in some of those parameters we just mentioned, hepcidin, iron, any markers of inflammation?
So no, in the sense that this was a phase 3 with very specific primary endpoint, key secondary endpoint testing. Things that impact iron typically take a longer time to measure. And so this is why we are always very interested in our open-label extension studies as well, because we continue to study patients over time. In regards to impact on iron metabolism, the best data that we have right now comes from our PK deficiency clinical trial program in which we were able to highlight that patients over time do have an improvement in their iron metabolism, and actually some of them used less chelation.
Okay. Luspatercept had some data in the same population. It wasn't actually approved in this indication, and I think they withdrew their application. Sometimes investors compare the magnitude of benefit that they had versus what we saw with mitapivat. Like I said initially, I think it's doing different things. What does luspatercept do in this disease to increase the hemoglobin, and what did they show? Do you remember the endpoint?
So yes. So the hemoglobin response, they had a good hemoglobin response in their clinical trial in non-regularly transfused beta-thalassemia patients. So that's 77%. So percent-wise, that sounds higher than our percentage in our clinical trial. However, the totality of the package, specifically the patient-reported outcomes, they did not hit on that statistical significance, which I think is a key difference in the data package. And then it's always about benefit-risk. So it's always the risk profile of these drugs is important too. They ended up disclosing that they withdrew the application because they were not able to fully address the FDA's questions around benefit-risk. So I think it always comes down to the totality of the package.
Do we know specifics about what the FDA was concerned about?
No. I mean, this is the level of detail that was provided.
I'd heard I don't know from where, but I thought that there was some concern that there were secondary hematopoiesis centers that were being stimulated?
There is extramedullary hematopoiesis described on the product, which you can see in the USPI as part of the safety profile of the drug. Yes.
Okay. And how does that manifest itself? What's the problem with that?
So the problem is that when you start having hematopoiesis to compensate for not enough hematopoiesis in other parts of your body, dependent on where that happens, it can cause other problems. So if it's in your spine, you can have some neurological complications. So there are different things. Dependent on where it happens, there are secondary consequences.
Okay. And again, I think this goes back to that initial concept.
Overall health.
They're driving more production where you guys are preventing destruction. I would assume creating more red blood cells makes the hemoglobin go up, but that also means probably more of them are probably being destroyed in otherwise and causing more inflammation, offsetting maybe any symptomatic benefit.
Yep.
Okay. All right. And then I guess just in terms of the next steps before we start talking about transfusion-dependent patients, what are the next steps for this program? And I guess commercially, how big an opportunity is this?
So this trial, the ENERGIZE trial, the non-regularly transfused patient population, what is also unique, and we didn't touch upon that one yet, is alpha-thalassemia patients were included. So the beauty of this is that the genotype of thalassemia doesn't matter in that context. For next steps for the program, we're waiting for ENERGIZE-T, as Cecilia mentioned earlier, to have that readout come in. And then the goal is to submit both of those trials together to the regulators for review.
That would be a single package?
That will be a single package. There is a multitude of reasons for why to do that, but the trials are reading out relatively close to each other. Our goal is to have an indication for all of thalassemia so the two trials can support hopefully each other. The goal of the two trials is really to highlight an improvement in hemolytic anemia as measured via two endpoints, one being hemoglobin response in people that are not regularly transfused. The other trial is trying to highlight that improvement via a reduction in transfusions.
Okay. These patients currently, what are they treated with? And I guess how many of them do you think that are being treated that are addressable?
So right now, the only part of the patient population in the U.S. that has an option is the regularly transfused beta-thalassemia patient population. That's about 2,000 of the diagnosed thalassemia patient population, overall about 6,000 adult thalassemia patients being diagnosed. That leaves a whole chunk of the patient population that doesn't have any options right now. Our program is really set up to address, to provide hopefully a therapy for that whole population of thalassemia patients.
Okay. How much larger do you think that would increase the addressable market?
Yeah. So I think what we know is there's about 4,000, sorry, 6,000 adult patients diagnosed with thalassemia, roughly 50/50 between alpha and beta, and two-thirds and one-thirds, the division between NTD and TD. They're diagnosed, so they're known to the system. And that's a big difference to our PKD where we have to focus much more on the diagnosis piece. So we're working as well as teams. And our commercial team is working to understand better the market, do more market research to answer those questions.
Okay. And do these patients get iron or anything?
So they have iron overload. Even if they are not transfused, they typically have iron overload because there is a dysregulated iron metabolism. So they're often on chelation therapy right now. The vast majority of patients is managed symptomatically. If you need transfusions, you can get transfusions. Sometimes people end up having a splenectomy. But then because of the iron overload and the ongoing hemolysis, there's a lot of secondary organ damage, which then gets managed dependent on the organ.
Okay. And so hypothetically again, a PKR drug could decrease the hemolysis and help them without that problem that they struggle with?
Which is a very nice concept because in ENERGIZE, the way our data package now reads out for ENERGIZE is from a patient-physician counseling perspective, if you can improve hemoglobin by decreasing the hemolysis, that in theory should have a longer-term benefit, which I know physicians are very interested in. But patients actually invest in it. They feel better fast. So it's almost they're investing right now in themselves, but by doing so, they can also invest in their future selves.
Okay. Is it fair to say that the regulatory authorities may prefer a drug that prevents hemolysis more than one that creates more red blood cells that ultimately could cause more hemolysis?
I don't think that's how regulators will always look at the totality of the data package, so benefits and risk. And the mechanism of actions are what they are, but it's the totality of the package that needs to be looked at. And I think right now from ENERGIZE, we really have a very compelling efficacy data package and a good safety profile. So it's a good story to start with.
Right. Well, I know that the agency is very, very sensitive to changing hemoglobin levels historically, especially in dialysis patients.
Well, and the regulators all consistently across our different programs have highlighted that it needs to be more than hemoglobin alone. So for PKD, same thing. It has to be hemoglobin and something else. So we were able to provide hemoglobin hemolysis improvements and patient-reported outcomes. For ENERGIZE, we have a similar data package, which allows us to give that hemoglobin-plus story on the efficacy side. And that is always put into context of the overall exposure and safety profile.
Okay. Why don't we shift gears to the transfusion-dependent patients? There, luspatercept is approved. So can you just give us an idea of the design of the trial, how heavily transfused are the patients that are going into that trial? And should we compare the data to the luspatercept's data when we see it?
So the trials, the endpoints on the luspatercept trial versus our trial is different. So they had a primary endpoint of a 33% reduction in a fixed 12-week period that they looked at as a bar for measuring clinical benefit. We have chosen after consultation with the regulators to go for a 50% reduction any 12-week rolling period because it's a more dynamic assessment, and you continue to follow patients across the whole length of your trial, which is very in line with how people are being assessed in the real world. It's more dynamic. So that's a key difference. So the numbers from an endpoint perspective will already be different. That being said, we've just discussed the mechanism of action. I don't think this can be apples-to-apples comparison because our mechanism of action is completely different.
We're basically avoiding cells to hemolyze, so avoiding people to go back down to a trigger point for transfusion versus creating more hemoglobin and avoiding transfusions that way. So yeah, we're not going to do or I would suggest not to do clinical trial comparisons like that.
What about the patients that are being enrolled? How do the entry criteria? Are they similar between the two trials?
Yes. Overall, they are similar in the sense that the patient population is regularly transfused, meaning there is a certain threshold of transfusions that they need to have before they can participate so we can reliably measure a potential reduction. The big difference, of course, is genotype. We are all-comers versus their trial is focused on beta-thalassemia again. But other than that, overall, it's a relatively similar population.
Okay. And remind me how many transfusions will these patients have coming into the trial? What's their baseline transfusion?
They have to have at least 6 transfusions, 6 red blood cell units transfused over the 24 week prior to coming into the trial. So it's a.
About one every month?
Then it goes up to even more transfusions. We do cap at some point. It becomes too much to be able to reliably participate in a clinical trial. There's too much burden of the therapy versus burden of the clinical trial as well.
Are the patients that are enrolled, do they have a washout period where they don't get any transfusions just prior to entry, or could they get it the day before they start?
They get transfusions per their schedule. The way we address standardization across the clinical trial is that we calculate a threshold by which each patient should be transfused based on what historically happened to that patient. That's a way to standardize practice across the clinical trial sites.
Okay. The reason I ask is these patients will obviously have transfused red blood cells in their circulation. Just wondering if there's any data to suggest that a PKR inhibitor could actually increase the health of these transfused red cells who may have been frozen for some time and be energy depleted and not that healthy?
Right. And so it's definitely a very interesting question, something we're thinking through as well as how could we tease that apart? However, in a big global phase 3 trial, that's the type of work you can't easily do. It would provide a lot of burden to the sites to try to tease that out and get good quality samples to be able to do further research on that.
Right. Have you guys done any preclinical work to look and see are the transfused red cells more energy deprived and less healthy in general?
Again, it's a question that we're thinking through on how to best address. We'll make sure to provide more updates later.
Okay. Okay. And the guidance now, you moved it up from it was the second half. Now we're going to see.
Mid-year.
Mid-year? Okay. Be a big readout.
A big readout, yes. We want to push forward time.
Right. Okay. Why don't we move to some of the other indications? You mentioned sickle cell, and you guys presented some data recently. When are we going to get the next update from the sickle cell program?
So right now, we're really focused on having the phase 3 completely enrolled. So we've guided towards the last patient by the end of this year. And so that's one of our milestones. So we anticipate to talk about that at some point. And then the next part will be, data will only come at the end of the trial when we have completed the full trial. We're not doing an interim analysis on the phase 3.
We set data readout 2025.
Okay. And so we won't get another update on the 20-some-odd patients we saw?
No.
Okay. Just to remind, I think in the opening remarks, you did comment, but you guys showed a benefit in hemoglobin, but you also had symptomatic improvement, which hasn't really been seen with any of the other sickle cell drugs, correct?
Yeah. The phase two data package was very compelling. It was the first placebo-controlled trial dataset that highlighted an improvement in hemoglobin, a trend in improvement in hemolysis, and sickle cell pain crisis. So the consistency of that was very nice to see. And it was also hemolysis and sickle cell pain crisis, the trend was stronger with the higher dose. So we took the higher dose forward to phase three. And the phase two data package, because it hits on that hemolytic anemia component but also on the sickle cell pain crisis component, really gives us hope for a product profile that we're trying to shoot for, providing a drug that improves hemolytic anemia, improves the pain crises, makes people feel better, and can provide a therapy that can address the totality of what sickle cell disease patients need.
Right. And again, the feedback I always get from investors is, "Oh, GBT-601, 3 grams, so this is not as potent." But what you're describing is also this phenomenon of decreasing destruction versus just increasing the production or maybe the red cells clumping together.
Correct. And that's the thing I think we've now you mentioned it earlier as well. Hemolysis does trigger inflammation in an environment that is prone to sickle cell pain crises. So I think that's the beauty of our mechanism of action, that it hits on these multiple components that are important in the context of sickle cell disease. In regards to 601, we're very excited about their data as well. Sickle cell disease is a horrible disease. So we are really hoping that all of these therapies actually make it to the finish line so patients have choices because they need much more. The thing with their mechanism of action, it's similar to VOX. So they have a higher hemoglobin improvement.
But because voxelotor hasn't been able to really highlight and feel and function benefit or sickle cell pain crisis benefit, that is something that is going to have to be shown for the new molecule.
Okay. Right. And again, I mean, to me, it seems like there could be a rationale for combining the drugs, not just to get a higher hemoglobin increase but to get a higher hemoglobin increase and also prevent destruction simultaneously, right?
It's indeed a different mechanism of action. In theory, there is no competition between the mechanisms of action.
Okay. And just with the few minutes that are left, I wanted to touch on MDS because I know it was an indication I was excited that you guys were trying for and you decided to go forward with it. I think the feedback we got from investors was they just weren't convinced that in low transfusion or patients with low disease burden, you could see a placebo effect of similar. But I know you guys are going higher in the dosing, but.
Yes, indeed. I think this is where we're very happy with the design we chose because this was our first endeavor in an anemia that is different from the other hemolytic anemias that we've been discussing. So we chose to go with a phase 2A in which we tested one dose in a relatively broad lower-risk MDS population. And one of the key learnings there was that we need to dose higher. So the PKPD observations in MDS patients are not the same as in healthy volunteers. And so that's where we've learned a lot from that trial and are going to be testing higher doses in our phase 2B. And we're looking forward to actually have that trial start enrolling mid-year.
Right. And that would be an all-oral drug to treat a disease that only has intravenous and injectable drugs?
Yes. Yes.
When might we get more data on the higher dose?
We haven't spoken yet about when we anticipate providing more data on that trial. We're right now very focused on getting the trial up and running, and that is our current goal.
Okay. What was the dose-limiting toxicity that you saw that could provide a ceiling on the level you can go to?
In healthy volunteers, we saw thrombocytopenia at a higher dose, at a 20-mg dose. We've published those data a while ago. Now, that being said, thrombocytopenia, what we've observed was actually monitorable, manageable, and reversible. Once the drug is stopped, the platelets just return back to normal. In the context of MDS, the physicians are very comfortable managing thrombocytopenia. All the other drugs also have thrombocytopenia. The fact that it is something that can easily be monitored is actually a plus.
What level above where you are now did you start to see thrombocytopenia?
It was 20 milligrams in the healthy volunteers. We tested five milligrams in MDS. We have a lot of room at which we can test higher doses.
Okay. Well, great. That concludes the session. Thank you for joining us, and thanks everyone in the audience for joining us. Look forward to all the progress you guys have made.
Thank you.