Agios Pharmaceuticals, Inc. (AGIO) Earnings Call Transcript & Summary

Hi, everybody. Welcome back to the 40th Annual Canaccord Genuity Growth Conference, which is being held virtually this year. I apologize for a little bit of a delay here for some technical issues. But we're very excited to have Agios with us today, a company that many investors know very well. So we're excited to have the CFO of Agios, Andrew Hirsch; as well as Chief Medical Officer; Dr. Chris Bowden with us today. So Andrew and Chris, welcome.

Great. Thanks, John. Thanks for having us.

Super. Well, if it's okay, I just wanted to start out with a question about your sickle cell program, which has gotten a lot of attention as of late. It's being closely followed. We know that mitapivat has shown some really interesting early data here. You've shown a hemoglobin increase of at least 1 in a number of patients. Just wondering if you could talk a little bit more about the program and what to expect for the remainder of the year and perhaps into next year?

Chris, do you want to...

Andrew, do you want to touch on a couple of those things? Or should I just go ahead?

Why don't you just go ahead at this point, given the time is...

All right. Well, we were very excited to launch this study in conjunction with the sickle cell group at the NIH. And we had a lot of important data at the EHA meeting earlier this summer. We disclosed a full data set on the first data from our studies in thal, a study in thalassemia patients. And at the same time, we issued a press release in sickle cell disease to summarize top level findings from that. And the reason why that was important was because on the basis of that data in those first 9 patients who've been a with sickle cell disease, we declared proof-of-concept and that we would now move forward into designing pivotal trials and getting them reviewed by regulators with the goal to activate the next year. That's kind of the high level of what we did based on what we've been seeing with the initial data. Now in -- here in July -- August, sorry, we're now glad to hear that the NIH clinical center is open and is accruing patients to clinical studies, including ours. So we're -- we can't guide to additional numbers from those 8 patients for whom we presented data on. We're hoping that we'll have more data though to speak to in addition to the 8 patients that we provided the top line press release on at ASH. Another important part of our PKR franchise is the follow-on molecule 946. Mitapivat has years of safety data and efficacy data now across 3 different indications. However, we have been bringing -- talking about a follow-on molecule, AG-946 for some time. And that study in healthy volunteers is now open and dosing. We will be able to publish data on that trial when we complete the accrual, analyze the data, so we can't guide to which meeting, when or where we will be able to do that. But we wanted to let people know that, that was now underway because that was one of our goals for the third quarter of this year. And then the last thing, John, I think, in terms of how we're thinking about sickle cell is somewhat similar to thalassemia, where we've got what we need in terms of understanding proof-of-concept. We have a great molecule with mitapivat. And now we want to move it forward and get feedback on -- from regulatory agencies on our design -- our proposals for pivotal trials to have registrations globally.

Okay. Great. Also wondered if you could talk a little bit about the work that you're doing with mitapivat and beta thalassemia. You've shown us some interesting data already that illustrates that you can increase hemoglobin there. And I just wondered if you could talk about what might be a level of hemoglobin increase that you believe is clinically relevant? Obviously, a little bit of a tough question, but just curious as to how you're thinking about that.

Yes. So the first thing is, I just want to make the point that we're studying the drug in both alpha and beta thalassemia. And in our ASH -- in our EHA presentation, we talked about our accrual of 5 patients with alpha thalassemia, and they appear to also be having a comparable hemoglobin increase with patients with beta thalassemia. Then now you get to the important question of increasing hemoglobin as an endpoint to describe clinical benefit. We don't think that hemoglobin -- an increase of hemoglobin of 1 gram or greater in and of itself is sufficient. And we think what we need to demonstrate are couple of things, and this is more like and ors as opposed to hemoglobin and, and, and. So first, there is aspects of ameliorating the hemolytic anemia through secondary endpoints like erythropoietin, LDH, bilirubin, because not only do they support the mechanism of action and -- reticulocytes are another one, they lend credence to the fact that you're reducing the work that bone marrow is having to do and potentially decreasing some of the inflammation that's associated with chronic hemolysis. So those can be very important supportive data points. So that -- and what's the flip side of that? If you go in with a data set in nontransfusion-dependent patients and show that the mean hemoglobin increases 1.1 grams, and you don't have a lot of other supportive data, then you can -- people can raise questions about how is this drug working? Is it actually working? And how much is it really contributing to this increase? Then there are other aspects that I think are important. And here, I'm talking about nontransfusion-dependent patients. What about their quality of life? That is, do they feel better by virtue of not just the hemoglobin going up, but does the reduction in some of those markets, I just talked about, translate into the -- an improved general feeling of well-being, do they have more energy? Are they able to work more and aspects like that. Some other longer-term endpoints that I think are potentially are important is, do you -- and how do you affect the iron access? So these patients are very iron-avid because of their ongoing hemoglobin. And if you could -- hemolysis, and if you can tame the hemolysis and bring it down, do you also see changes in iron indices or evidence that you're affecting iron metabolism because that could also have a pretty important impact in terms of keeping people off chelators and avoiding the impacts of iron overload over the course of several decades. So we think hemoglobin is a very good primary endpoint. It's very clear. You can measure it. It has clinical relevance, but it's at least a gram and then there has to be other supporting data.

Okay. Great. That actually makes a lot of sense that it sounds like you're saying it's not just about the hemoglobin increase that you look to have data to support the mechanism of action, which makes a lot of sense. Okay. Great. Also maybe wondered if we could ask just 1 or 2 questions about TIBSOVO, which has really started to pick up in the market as of late. So you've guided to $105 million to $115 million in revenues for 2020. It looks like you're well on track to achieving that range. Just curious, in your minds, what is it that you think would really kind of hit the accelerator and drive frontline usage for TIBSOVO? Would it be a couple of specific data readouts that you'd be looking to there? And could you perhaps remind us of the potential timing?

Yes. Sure, John. I'll take that one. So look, as you know, in addition to the relapsed/refractory label, we do have a frontline label for IC-ineligible patients as a monotherapy, and we continue to see uptake across both relapsed/refractory and the frontline setting, and that's really driven some of that performance. And while we can't promote to it, we do see, from our market research, that about half of the use that we're getting in both the frontline and relapsed/refractory patients received TIBSOVO in combination with another therapy, and that's usually in HMA. And so to your point, I think what we really see that growth accelerating when we have combination labels, and we can actually promote to that because the data so far has been really, really, really strong. And so remember, we're running 2 studies in the frontline in combination. One is the AGILE Phase III study that's in combination with azacitidine, and we expect to complete enrollment next year. At this point, just given the COVID-related slowdown in enrollment that we saw, we can't be specific right now in terms of the timing, but we'll give more visibility once we can provide more precise time line for that completion within 2021. And then the HOVON Phase III study that includes both TIBSOVO and IDHIFA in combination with 7 plus 3 that's turning to enroll and what we've guided to is that we expect the label in that indication in 2024.

Okay. Great. And 1 other question on TIBSOVO. We get a lot of questions regarding how TIBSOVO compares to and can compete with venetoclax in AML. It's interesting. It seems like AbbVie has really gone to great lengths to describe how a BCL-2-targeted agent can also cover IDH mutations. Just curious as to how you think the physicians are thinking about this? Are they looking at your agent, which is designed to target IDH mutations in the same way that they might be thinking about how venetoclax could be used here?

Yes. I think it's interesting. When we look at our market research, it continues to suggest that physicians prefer to target the target, that if there's a drug that treats an actionable driver mutation, that's their first choice. And I think that's what we've seen that it tends to be the therapy of choice for IC-ineligible frontline IDH1 AML patients. So that, to me, is what our market research says. We think the data that we have shared has been impressive in terms of the Phase I combo data, right, where we saw a pretty impressive CR/CRh rate of 70% with underlying that a CR rate of 61%. And then these patients, in addition to this response, they're getting these sort of deep molecular responses, which we can no longer detect the clone. And so that can result into a pretty impressive 12-month OS of 82%. I think it's important that when you look at the Phase III study with venetoclax, and certainly, it's an important drug for AML, there are certainly limitations to their data set. They do go through great lengths to break out the IDH subset, as you pointed out. But importantly, they don't really differentiate IDH1 and IDH2. I think they also didn't allow patients who received prior HMA into that study. And then the sample size, of course, is -- comparable to actually are sample size in sort of 23 patients. So I think those are important caveats when you're looking at that subset of data. But again, the feedback we get from the marketplace is that the physicians want to target the target. Chris, I don't know if you want to add anything to that.

I think the big aspect that needs to continue to be developed. And the only other thing I have to add to what Andrew said is how durable will the emissions be on the end. We always look at these data from the perspective of IDH1 versus IDH2, not IDH1 plus IDH2, which is frequently how it's presented. While the target is somewhat similar, there are some important differences in biology. So that's a really important aspect.

Okay. Great. And maybe we could shift back a bit to mitapivat. So just wondering how we should be thinking about looking at the initial data from the ACTIVATE and the ACTIVATE-T studies, which, I believe, you've mentioned, we may see data there either at the end of 2020 or the beginning of 2021. What do you think are the sort of the key things that investors should be looking at there?

Well, the 2 trials are designed to provide a data set that can give us a broad label, adults with pyruvate kinase deficiency. And that's the reason why we have 2 separate trials: one in patients who are not regularly transfused, where the primary endpoint is hemoglobin increase over 1.5 grams compared to placebo; and then the other trial is called ACTIVATE-T, and that's in patients who are regularly transfused. Now that's a single-arm trial. So it doesn't have a control arm. There's just not enough patients out there that do an adequately well-controlled study. So the ACTIVATE study, the randomized trial has a success boundary, right? We have to see a hemoglobin response rate of greater than 35% in order to achieve statistical significance if the response rate in the placebo arm is 5%. So those are our prespecified statistical boundary. So that study meets its -- crosses the boundary or it doesn't. It's declared positive or negative on the basis of that. Now -- so let's just focus on that trial for a minute because it ties in a little bit with what we talked about with thalassemia. So this is a group of patients where they're not regularly transfused. They have to have a hemoglobin less than 10. So they have at least moderate anemia. The majority of them will be symptomatic. And so what will we be looking for, for additional supportive evidence will be those quality of life instruments that are supportive that in patients who respond, that they feel better, they're able to achieve more in their life. And additionally, those secondary endpoints that I spoke about in terms of are you addressing? Is your mechanism of action underlying some of the -- addressing some of the underlying aspects of the biology of the disease? Or were tick counts going down? Is the drive from EPO going down? So that you're clamming down the marrow and the cells are living longer. And of course, what do the safety look like, right? That's just -- and this would be the first time that we're actually seeing a safety readout versus placebo. I think it will be a very important aspect in terms of how you can think about how this drug is active and increases hemoglobin other secondary measures of disease, secondary endpoints, I should say. And what does the safety profile look like against placebo? There's another aspect of that trial that we haven't gotten into the level of detail of how much we would report initially, but there's crossover with placebo patients at the end of the 6-month dosing period. And I think that data has the potential to also be very helpful for us because in patients who have a sensitive genotype category, we would see that -- we would expect to see them respond as well. And I think that would be pretty strong supportive evidence that you're on placebo for 6 months and you flip over to active drug and you see your hemoglobin go up. And that will help, again, against this occasional comment we hear about what's the baseline fluctuation of hemoglobin and if you don't do anything. ACTIVATE-T now is the single-arm open-label study in patients who are regularly transfused. There, the endpoint is the percentage of patients who have a -- the number of percentage of patients who have a 33% or greater reduction in their transfusion burden. And that in and itself is very easily measured. The greater the magnitude of the reduction in transfusion burden that we see per patient will be very important in terms of the weight of evidence of clinical benefit. So this is a group of patients that if you see some percentage of patients who have significant reductions in their transfusion burden beyond that primary endpoint, then I think that will be very important in terms of swinging and convincing regulators that we should have in the broad label. The reason why that is, is because mitapivat is a drug that in pyruvate kinase deficiency is you can give for several weeks. It's very well tolerated, and you can understand if you're having a response pretty rapidly in nontransfusion-dependent patients. And my guess or hunch is that we'll probably see the same thing in transfusion-dependent patients, albeit it will take a little bit longer to start to get some sense that the drug is working.

Okay. Excellent. Well, thank you very much, Chris and Andrew, for joining us today. I apologize again for the technical issues, but really great overview and information on mitapivat and also TIBSOVO. Also, thanks very much to the listeners on the webcast. And I hope everybody has a great rest of the conference.

Thanks, John.

Thanks, everybody.