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

Got it. This is helpful. Maybe so looking at the papers, I think the paper came out sometime last year, at the same time last year when, I think it was when it was published for PKD Phase II trial. And it seems like about half of the patients respond really well with this agent. And so what about the other half of the patients? Is this a fair way to think that it doesn't work in those other half? Or it's just that they're not responders, a different level of responses that are there? And how does the next-generation PK-R activator 946 come in the picture for those patients? Do you think it could be complementary to expand the horizon there? It is more like it would work similarly to mitapivat responders? How do you think about that?

Yes. So there's a couple of things to keep in mind about the Phase II data. And what we now know is that somewhere between 15% and 20% of PKD patients have a double non-missense mutation, and we've excluded those patients from the Phase III trial. So if you take that 15% to 20% that would have been in the Phase II program, now they're not enrolled in Phase III, you can adjust for that. We also know that there are some mutations that don't respond that well to mitapivat. The R510Q mutation is one of those. So the Amish population. So we've we think we understand many of the mutations associated with PKD. I think you'll hear people talk about, including our Chris Bowden, that there's probably over 200 of them. We don't -- we haven't characterized all 200-plus of them, but we think we know enough about this. And with the Phase III trial design where we know that certain patients won't respond, we've excluded those patients because it's better for them not to spend in the trial that the drug won't work, and it improves your chances of success with the trial. So that's how we think about that. We're very optimistic about the readouts on these trials. You mentioned 946. The 946, we know does work in some mutations that mitapivat does not work in, including the R510Q patient population. 946 now has moved into healthy volunteers. We've dosed healthy volunteer patients. And now there was a bit of a pause on healthy volunteer studies, as you know, during the pandemic, and now we're back on track with that. So we look very much forward to getting that healthy volunteer data for 946. And then thinking about what our options are for taking the drug forward, we're riding the mitapivat horse very hard now since it's a drug that we have data on from PKD, thalassemia, both alpha and beta and sickle cell, and we love the drug, we think it can be a blockbuster drug. And we're going to look at the potential portfolio options, life cycle management options with 946. 946 is, at least preclinically, potentially more potent than mitapivat. As I said, it potentially does work in some mutations for PKD that mitapivat doesn't work in. Will -- it has, at least, preclinically no aromatase inhibition, which, by the way, for mitapivat, and we will be taking to mitapivat into pediatric trials as well, we have the regulatory support for that, so the aromatase inhibition as it turns out, I mean, mitapivat has been essentially a lab of value where you see some of that. But the data still stays in the normal range, and we've seen no clinical manifestations of it. So we actually don't think that, that characteristic of mitapivat is going to be a hindrance in in the commercial space, and we're hearing that back from physicians as well. But 946 theoretically has no aromatase inhibition. So there's some characteristics around 946 that may make it helpful to have in the portfolio, but not necessary to have in the portfolio, is the way that I would put it, and maybe gives us some life cycle management opportunities. There's also some other hemolytic anemias that you can think about that we don't have data in yet. There's a broader range of those that would include some of the rare ones like Diamond-Blackfan and others. And so I think we're going to have some choices with how we think about the portfolio around this mechanism.

So it -- just to understand it, the Amish patient population would not be the target initially at least with mitapivat because they don't respond to the drug?

Correct.

Okay. Got it. So that is one question we get a lot because, I mean, the market itself, it will take some time to generate the market, to develop the market for PKD disease. So can you talk a little bit about your efforts there? And I think you've had a registry open, so where is the registry right now? So just your efforts there.

Yes. So we've -- between the peak registry, our ongoing Phase II program, the patient finding efforts that we pursued globally, we have found well over 1,000 of these patients around the world in our estimate for the incidence rates in the U.S. and Europe is 3,000 to 8,000 patients. It's a pretty wide range, but we think it's an underdiagnosed disease. And when you've got treatment options, you're actually going to see better diagnosis. As we talk more and can contribute with the physician community to characterizing the mutations and even just finding them all and documenting them and things like that. I think that's going to be helpful over time as well. And frankly, going into a launch where you've identified more than 1,000 of these patients is going to put us in a great place with respect to how we take the drug forward. With all of these things, I mean, what you find with these underdiagnosed and undertreated diseases is many times, maybe not every time, but often, as soon as you haven't approved therapy and the awareness is raised, you improve diagnosis, you get more interactive or more engaged interactions from patients with their physicians when they know that there's a treatment option out there for them. A lot of these patients, if they know there's no treatment option, they're not actively going to their physicians asking because there's nothing for them to go for, right? So it's also the case with PKD that. Heretofore, there hasn't been a well-organized patient group. We've been starting to work with patients to help them connect, to help physicians connect. And at some point, I think there will be some momentum -- more momentum, we've been part of generating that already now, around patient advocacy for this particular disease as soon as there is a treatment for it. So we feel really good about where we are with that. It's going to be an ongoing effort for us. I think the -- for a company like ourselves to be investing in the disease and taking it seriously and wanting to do something for these patients has been very much appreciated, and we're also listening to them and physicians in terms of what they need, what we can bring to them in terms of value and how to together take this forward. So we're very excited to do something for these patients that are highly underserved. And we're excited about the ongoing label expansion potential for mitapivat because it's great to go into a rare disease. We love it. It's wonderful. From an investor standpoint, I think you'll also like to see us benefit in even more patients. So by doing the right thing for patients, we'll also potentially end up with a blockbuster drug here.

So that's always the case. And I think that is a nice segue into the least talked about program, sickle cell disease program here. So we have seen some interesting early data with sickle cell program. So can you please characterize that -- those data in -- because we have quite a bit of competition here as well in this particular disease area, you have Oxbryta, you have other agents as well. So can you please put that data in context? And then I have follow-ups on that.

Yes. So let me just talk about the program generally and a little bit about the competitive landscape. So if you for those who are following it, there are 2 approved products today. Plus you've also got something that people sometimes, I think, forget a little bit about -- you've got hydroxyurea that is still sort of a staple part of the treatment regimen for a number of sickle cell disease patients. And in the NIH-sponsored trial that we're working with them on patients can be on an area in combination with -- or in conjunction with mitapivat along the way. So I think that's something to keep in mind. But Oxbryta, the Global Blood product is a different mechanism. Adakveo, the Novartis product is a different mechanism. So we would we were the discoverers of PKR activation and the fact that it works both in the mutant PKD as well as activating wild top, which has taken us in the thalassemia and sickle cell disease. And I will just remind the audience that we've been studying mitapivat for almost 6 years in humans and well more than 6 years from the origination and the research program. So we think we know a lot about PKR activation mechanism. So Oxbryta is labeled for hemoglobin increase, Adakveo is labeled for a reduction in vaso-occlusive crises. We -- it's early days with our sickle cell data, but we're very happy about where we are. As you'll remember from the data that we disclosed back in June, we had 9 patients enrolled in the NIH trial up to the point where the virus caused a pause in enrollment. And we had 8 of those that were evaluable with 5 out of 8 meeting the 1 -- at least 1 hemoglobin -- 1 gram per deciliter increase in hemoglobin response rate that was the definition of the primary endpoint there. So 5 out of 8. We actually had 7 out of the 8 patients have hemoglobin increases. It's just that 2 of them did not quite make it to the 1 gram per deciliter, but they did have hemoglobin increases. So we only had 1 of the 8 evaluable patients not respond. So I think that's relevant. And in the meantime, the NIH trial has reopened for enrollment. They started dosing patients again in the sickle cell trial back in the middle of August. We expect that data will be presented at ASH. We will have -- we expect to have a full data set for the 8 evaluable patients that you've already seen the high level data for, so there will be even more details around those patients. And based on enrollment, reopening and with the dosing period associated with the trial, we expect by the time we get to ASH, even though it certainly wouldn't be in the abstract as the abstracts tend to get turned in 3 or 4 weeks ago. But we would expect that there will be an additional number of patients that the investigator will want to talk about from the podium at ASH. 2 of the -- because we've talked some about the dosing schedule and the different dosing levels, as you'll remember, we added 100-milligram dose back at a time when we had already made the proof-of-concept decision to go forward based on the results that we saw with the 50-milligram dose. So we didn't have to do it, but we thought, given some of the experiences that we've seen in thalassemia and the fact that way back from the PKD trials, we knew that we could dose up to 300 milligrams safely with the drug. We decided to add 100-milligram dose in collaboration with the investigator in the sickle cell trial. 2 of the 8 patients that we spoke with you about back in June have received the 100-milligram dose. And all of the patients that are being enrolled starting back in mid-August, and that will finish out the enrollment for the trial, will also receive the 100-milligram dose. So you'll have the 5 20, 50, 100 for all of that next wave of patients, and you have it for 2 of the 8. So we would also expect for the investigator to speak about that 100-milligram data at ASH as well. I think that we've got a chance here, and many of you probably know the Oxbryta data, I think the response rates were around 50%, maybe just slightly greater than that in the label data. So we've still got half of the patients who -- for that response rate associated with hemoglobin increase that don't respond to Oxbryta. So we think there's plenty of opportunity there. But more importantly, I think with mitapivat and its mechanism because it lowers 2, 3-DPG, which then impacts oxygenation, which is a similar effect of Oxbryta, though through different mechanisms, and we increase ATP, we feel like we have a good chance of showing both hemoglobin increase as well as potentially, we're being very thoughtful about the design of our sickle cell pivotal program, and you'll hear more about that over time, we expect to initiate that in 2021, about how we can design that trial to hopefully show both hemoglobin increase as well as potentially a reduction in vaso-occlusive crises because we impact both oxygenation as well as hydration of the and the life span and the red blood cells. So we're coming at those 2 different biomarkers with the mechanism of PKR activation, which we think should give us the potential to have a differential profile in the marketplace. And that's a lot of talking I just did. So maybe I'll stop, so you can ask some supplementary or complementary questions.

Well, this is very helpful. I mean these were the complementary questions. So you kind of addressed them all actually. How -- one question I still have is that how important it is to have a differentiation there? I mean, given that if -- let's just say, if you don't show any benefit on VOC, would that be that an issue? If you just have better response rates, would that be up? I mean, how do you think about that dynamic there?

So we think -- I mean we think that showing both will be a win-win. We think -- and our sort of base case assumption is that hemoglobin increase, given we do have a different mechanism than the existing approved product is enough and that we can be very competitive in the marketplace. So we're actually -- for our base case sort of revenue and regulatory approval, a chance of success and all that assumptions are assuming that we can get there on hemoglobin increase. But we're planning to throw everything that we can at this in terms of intelligent pivotal clinical program designed to generate as much data as we can to potentially have a very robust data set that we we've been highly differentiated, where you could think about really big win-win scenario there as a possibility with some upside potential associated with it versus what we would assume in any kind of base case planning scenario right now. So the mechanism supports coming out the disease from these couple of different impacts, as I said, on 2, 3-DPG and ATP, so mechanistically, we think there's a strong rationale there, and we want to give the drug we every chance to win in the clinical program in that regard.

This is very helpful, actually. I completely understand. Maybe just wanted to touch upon thalassemia, you have alpha and beta thalassemia both in development. What is next for the program? What could we see next from the data point of view? And I think you have a pivotal program in place for 2021. So can you talk a little bit more about that program?

Yes. So we've got a lot going on. There's many reasons we love our story. So I'm including that we've been engaged with regulators on the design of the pivotal program for thalassemia. We are moving it forward. We hope to disclose -- to finalize and then disclose the details of that pivotal plan for all of you by the end of the year. So I guess, ASH is going to be a big time for us, hopefully this year. And it will include both alpha and beta thalassemia patients. As you probably know, we're the only company that's generated clinical data in alpha thalassemia patients, and they represent about 30% or so of the total thalassemia patient population and haven't gotten a lot of attention. I think we have some opportunities to educate on why those patients may need to be treated as well as treating beta thalassemia patients. So our program will include both of those patients, the pivotal, it include transfusion-dependent as well as non-transfusion dependent patients. So we're really trying to go for across a broad spectrum of thalassemia patients, share the details of the pivotal program with you around the end of this year, and then we'll be initiating that trial next year in 2021. And it's probably on a little faster time frame than sickle cell just based on the fact that we had data, the proof-of-concept data a little earlier for thalassemia, 6 months or so compared to sickle cell. But we're excited about both indications, moving full speed ahead with both of them. And the non-dilutive financing that we did in collaboration with Royalty Pharma back in June, has allowed us to start to fund those pivotal programs. So they're now both included in our base case plan. So we're funding those as well as we, at the time, extended our runway of 6 months. So we're able to take those 2 new things on and extend our runway with that financing. So we're very excited about that.

Great. So this was 1 more question I had, so we covered it. The -- so 1 question, I just wanted to understand your thoughts on. So going back to oncology, you have such a great capability in-house and you have developed some molecules in-house. MAT2A seems like it doesn't have monotherapy impact, but it could be a combination agent eventually. A bigger picture question, where is the -- so like now there is so much focus on synthetic lethality as an approach, trying to target cancer. And if I understand it correctly, MAT2A is a synthetic lethal program, basically. That's exactly what it is. So can you talk a little bit about your capabilities in the oncology program, where it stands in terms of your criteria, your priorities because you have quite a lot going on. And is there a partnership opportunity for MAT2A or outside of MAT2A which you could explore further?

Yes. So I think it's been really interesting because we were able to bring the IDH inhibitors out of our scientific platform into oncology as monotherapy agents. And then what you see is that the more significant expansion opportunities for those as you take them forward, in terms of label expansions likely are in combination, then you see the interest in combining with Venclexta and Vyxeos and all of those sorts of things. So -- and we all know that the oncology space is probably largely a combination-driven approach for many, many patients. So we have some cool targets coming along. We still think that MTAP-deleted cancers is an area of opportunity in a time-met medical need. So we like our MAT2A inhibitor concept. The preclinical data shows the potential for combining MAT2A inhibitor with multiple agents, and we saw very strong rationale for that, in combination with taxanes, which is why we expanded the Phase I program to include the 2 trials in pancreatic and lung in combination with taxanes. We know there's other options there as well. So including some combinations that we generated preclinical data on that maybe we haven't talked that much about, and we think there is some mechanistic rationale in combination with PRMT5. So I'll remind everybody that we -- it was only the month of May, and that maybe seems like a long time ago with everything that's been going on for the last 3 months or so, that we completely exited the previous relationship with Bristol that was on both the discovery research side as well as the MAT2A inhibitor development. And as we continue to generate data on AG-270, we think the current combo trials are going to be informative for that much of the preclinical work we've done is informative. And we know we have an active drug from the monotherapy data despite the fact that it was a basket trial and we can talk about the efficacy levels, but we know it's an active drug. So there's some openness that we have, quite a bit of openness, in fact, to potential partnerships. And I've said many times, if AG-270 is successful in the current combinations or if there's a potential other additional combination strategy, we'd be very happy to partner that drug with somebody to optimize its value creation potential for patients and for the company. We have some other interesting targets coming along out of the discovery group. It is a very productive group. And science doesn't come in linear progression. So sometimes there's waves and things like that, but we've got some, we think, cool targets coming along that we'll find the best way to talk about it at the right moment in time and think about our clinical strategy approaches for those as well.

Great. Thank you, Jackie. I think we are 3 minutes over the time. But thank you very much for this candid conversation. Really appreciate, always. And thank you for all the insights.

Thanks, Mohit. Thanks, everybody, out there. Take care.

Thank you, everyone, for joining us today. Hope you have a great day.