Agios Pharmaceuticals Inc (AGIO) 2020 Q2 法說會逐字稿

Good morning and welcome to Agios' Second Quarter 2020 Conference Call. (Operator Instructions) Please be advised that this call is being recorded at Agios' request.

I would now like to turn the call over to Holly Manning, Director of Investor Relations.

Thank you, operator. Good morning, everyone, and welcome to Agios' Second Quarter 2020 Conference Call. You can access slides for today's call by going to the Investors section of our website, agios.com.

With me on the call today with prepared remarks are Dr. Jackie Fouse, our Chief Executive Officer; Dr. Chris Bowden, our Chief Medical Officer; Darrin Miles, our Senior Vice President of U.S. Commercial and Global Marketing; and Andrew Hirsch, our Chief Financial Officer and Head of Corporate Development. Dr. Bruce Car, our Chief Scientific Officer, will join for Q&A.

Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the risk factors section of our most recent Form 10-Q filed with the SEC and any other filings that we may make with the SEC.

With that, I will turn the call over to Jackie.

Thanks, Holly. Good morning, everyone, and thanks for joining our second quarter 2020 results call. The second quarter was an incredibly productive and important time for Agios as we made significant progress across the business and accomplished several of the key objectives that we set for 2020. The steps we took in Q2 solidified our strategic priorities for the remainder of the year and move us closer to achieving our 2025 vision.

Seven years ago, we discovered the first pyruvate kinase R activator, mitapivat. And since then, we've led the science behind this mechanism, advanced the Phase III program in pyruvate kinase deficiency and became the first company to establish that activating wild-type PKR may provide therapeutic benefit in other hemolytic anemias, such as thalassemia and sickle cell disease. Over the past quarter, we further underscored our leadership in the space and shared key updates that support our next phase of development for mitapivat.

To start, we established compelling proof-of-concept for mitapivat in sickle cell disease, demonstrating that PKR activation has the potential to treat chronic hemolytic anemia and markers of sickling in these patients. In addition, at EHA, we presented data for the first time at a medical meeting for mitapivat in thalassemia, showing sustained hemoglobin responses in both beta-thalassemia and alpha-thalassemia patients. In May, the FDA granted us Orphan Drug Designation for this indication.

As we look ahead, we are firmly committed to the rapid advancement of mitapivat across all 3 of these disease areas. The remainder of 2020 will be focused on preparations for top line data from the PK deficiency Phase III studies and the submission of an NDA for mitapivat's first indication and the indication of pivotal programs in both thalassemia and sickle cell disease in 2021. In June, we secured $255 million of nonequity capital through the sale of our IDHIFA royalty and future milestones to Royalty Pharma to help fund these efforts.

In addition to our progress on the rare genetic disease side of the business, we've continued to drive commercial execution for TIBSOVO and advance our malignant hematology and solid tumor clinical programs. At ASCO and EHA, we presented data underscoring the utility of IDH inhibitors in both areas. And in May, we published a manuscript in Lancet Oncology, highlighting data from the ClarIDHy Phase III study of TIBSOVO in cholangiocarcinoma. As a result of the manuscript, the NCCN Guidelines were updated to recommend treatment with TIBSOVO for patients with advanced IDH1 mutant cholangiocarcinoma. We look forward to having overall survival data from the ClarIDHy study in the near future, which will support an expected sNDA submission in the first quarter of 2021.

I'm proud of our team for accomplishing all this great work while continuing to combat the challenges and complexities caused by the ongoing COVID-19 pandemic. The disruption to global health care systems continues to evolve as infection rates fall in some parts of the world while rising in others, including in many states here in the U.S. Our organizational resiliency team and clinical operations response team remain active in assessing COVID-19's impact on every facet of our business on an ongoing basis. While the majority of our employees continue to work from home, all lab employees who need access to our Cambridge research labs have returned to work under a set of operating procedures designed to protect their health and well-being.

In addition, as local regulations and institutions have allowed, some of our field team can interact with their customers in person again. We continue to evaluate additional operating procedures that will allow a broader return to on-site work. I would like to thank each and every Agios employee for continuing to advance our programs for patients while balancing the pandemic's significant impact on their personal and professional lives.

Before I turn the call over to Chris, I think it's important to acknowledge recent events, which have, once again, exposed the realities of racism and racial violence in our country. At Agios, we believe matters of racial injustice should be acknowledged and decried, and we are committed to act in allyship against this destructive force in our communities. All of us at Agios believe in the value of diversity, and we are committed to making Agios a welcoming and diverse workplace where individuals of all backgrounds can thrive and contribute meaningfully to our mission on behalf of patients.

Chris, let me turn it over to you.

Thanks, Jackie. I'll start with mitapivat, our first-in-class PKR activator, currently being evaluated across 3 distinct hemolytic anemias. As Jackie highlighted, we achieved important milestones for this program in the second quarter that support broadened clinical development in both thalassemia and sickle cell disease. Our most advanced program is in PK deficiency where we have 4 years of experience in treating patients and have the potential to provide first disease-modifying therapy.

Earlier this year, we completed enrollment in our 2 Phase III studies, ACTIVATE and ACTIVATE-T. Since the beginning of the COVID-19 outbreak, we have focused on ensuring patients have access to study drug and that we capture all data regardless of a patient's ability to get to their trial center. This includes home visits, telemedicine approaches, the use of local laboratories and courier shipments of drug. As the core period of both studies comes to an end later this year, we are working with our global clinical trial sites to understand the time line to complete necessary steps for database lock. We still anticipate top line data from both ACTIVATE and ACTIVATE-T sometime between the end of 2020 and the middle of 2021. We will narrow this time line based on our ability to confidently predict trial site access in the wake of the ongoing global pandemic. We expect to file for regulatory approval in both the U.S. and EU next year with a potential 2022 commercial launch in PK deficiency in both geographies.

Moving to the Phase II study of mitapivat in thalassemia. We completed enrollment earlier this year with 20 patients. And in June, we presented updated data on 13 efficacy-evaluable patients at the virtual EHA meeting. The data showed the treatment with mitapivat induced a hemoglobin increase of greater than or equal to 1 gram per deciliter in 12 of 13 evaluable patients during weeks 4 through 12, including 4 of 4 alpha-thalassemia patients where there have been no new treatment options in decades. In addition, 7 of 8 beta-thalassemia patients achieved a sustained hemoglobin response during weeks 12 through 24. Our focus now is to advance the development of mitapivat for these patients as quickly and efficiently as possible. By the end of the year, we expect to finalize a robust pivotal development plan that scans both alpha- and beta-thalassemia as well as transfusion-dependent and nontransfusion-dependent patient populations with the goal of initiating a pivotal program in 2021.

Now let's turn to sickle cell disease where we are collaborating with Dr. Swee Lay Thein of the National Institutes of Health on a proof-of-concept study with mitapivat. In June, we announced that clinical proof-of-concept was established based on a preliminary analysis data from this study. The data showed that over a 6- to 8-week dosing period, 7 of 8 patients experienced a hemoglobin increase, with 5 of 8 patients achieving a hemoglobin increase of greater than or equal to 1 gram per deciliter from baseline. Adverse events seen in this study were consistent with previously published data from mitapivat in patients with PK deficiency or expected in the context of sickle cell disease.

Based on these results, we're working quickly to get regulatory and advocacy group input for our pivotal development plan in sickle cell disease, which will put us in position to initiate the study in 2021. Patient enrollment in the Phase I sickle cell study was temporarily halted earlier this year in the wake of the COVID-19 pandemic, and they are actively working to reopen the study this summer. Dr. Thein plans to enroll up to 25 patients in this study, and she will submit data from the trial for presentation at the ASH meeting in December. Due to the earlier pause in enrollment, it's not yet clear how many additional patients will be included in that presentation above the 9 patients that served as the basis for our proof-of-concept evaluation.

I'll now move to our malignant hematology programs where we're focused on geographic and indication expansion for our IDH1 inhibitor, TIBSOVO. To start, in the EU, we have received our day-180 list of outstanding issues for our TIBSOVO filing in relapsed or refractory AML. And at this time, we still anticipate receiving a CHMP opinion by the end of the year. In frontline AML, we are enrolling 2 global Phase III combination studies, AGILE and HOVON 150, which will allow us to further broaden TIBSOVO's frontline label to include combination use with azacitidine and 7 plus 3, respectively. We are also enrolling patients in the reopened myelodysplastic syndrome arm of the TIBSOVO Phase I study with the goal of generating the data necessary to pursue a potential U.S. regulatory filing. We expect to complete the additional enrollment in 2021.

In addition to these registration trials, we continue to explore and generate data with TIBSOVO in novel combinations through our investigator-initiated studies. Data from one such study, the venetoclax plus TIBSOVO, plus or minus azacitidine IST, conducted by Dr. Courtney DiNardo and MD Anderson, were presented earlier this year at ASCO and EHA, showing that the combination was well tolerated and effective with composite complete response in 80% of patients. In May, we shared that site start-up activity had slowed and enrollment interruptions occurred at some trial sites due to the pandemic. Some areas have begun to stabilize, though we continued to track recent surges and the impact on trial sites. At this time, our enrollment guidance remains unchanged for the AML and MDS studies.

I'll now move to solid tumors. Last year, we reported positive PFS data from the ClarIDHy Phase III study of TIBSOVO in previously treated IDH1 mutant cholangiocarcinoma. And this quarter, we expect to have mature overall survival data from the study to support a potential supplemental NDA filing. Based on the anticipated timing of the data, we expect the sNDA submission is now likely to occur in the first quarter of 2021, which has been narrowed from our previous guidance. In addition, we continue to enroll our other solid tumor studies: the INDIGO trial, our Phase III study of vorasidenib, our brain-penetrant IDH inhibitor in low-grade glioma; and the AG-270 Phase I combination arms in non-small cell lung cancer and pancreatic cancer. Like our other ongoing trials, we continue to monitor the pandemic's impact on site start-up and enrollment activities and have no updates to previous guidance at this time.

With that, I'll turn it over to Darrin to discuss our second quarter commercial performance.

Thanks, Chris. I'm pleased to share that our commercial team has continued to deliver strong performance in 2020, recording $27.6 million of net sales of TIBSOVO in the second quarter, a 22% increase from Q1. Access restrictions related to COVID-19 notwithstanding, quarter-over-quarter growth was driven by an increase in both new scripts and refills with the largest increases seen in the relapsed/refractory AML setting. Furthermore, we continue to expand our prescriber base, growing at 15% in both the academic and community setting over Q1.

Market research continues to show that the majority of physicians consider TIBSOVO to be standard of care in IDH1 mutant AML and the leading targeted treatment for newly diagnosed IDH1 mutant AML patients in eligible or intensive therapy. Though not a focus of our promotional efforts, we continue to observe that approximately half of TIBSOVO use in both the relapsed/refractory and frontline settings is in combination and, most frequently, this occurs with a hypomethylating agent.

Our patient assistance program, myAgios, continues to operate uninterrupted in the midst of the COVID-19 pandemic as we support patients through these challenging times.

As Jackie mentioned, in response to the growing concerns related to the pandemic, the majority of our field team has continued to work from home since mid-March, though some have begun to safely interact with their customers in-person again as local guidelines and practices have allowed. We've experienced success continuing to engage customers with tools enabling remote interactions. As a result of performance through the first half of the year, we reiterate our full year 2020 U.S. TIBSOVO net sales guidance of $105 million to $115 million.

I'll now turn it over to Andrew to discuss our second quarter financials.

Thanks, Darrin. Our second quarter results can be found in the press release we issued this morning, which I'll summarize. More details will be included in our 10-Q filing later today.

Total revenue for the second quarter was $37.3 million, which consisted of $27.6 million of net sales of TIBSOVO, $6.4 million of collaboration revenue and $3.3 million of IDHIFA royalty revenue. Compared to the second quarter of 2019, total revenue grew by 42% driven by a 101% increase in TIBSOVO sales, offset by a decrease in collaboration revenue.

As we announced in June, Royalty Pharma purchased our tiered sales-based royalty rights on worldwide net sales of IDHIFA as well as rights to receive up to $55 million in outstanding ex U.S. regulatory milestone payments from BMS for $255 million. This transaction will be accounted for under the debt method, which required us to record a liability on our balance sheet for the purchase price net of issuance costs. We will continue to record the IDHIFA royalty through the life of the arrangement.

In addition, we will record noncash interest expense associated with the liability. The liability will be reduced by the royalty revenue recorded in each period and increased by the noncash interest expense. For the period in which interest expense exceeds royalty, the liability is increased. And for periods in which the royalty revenue exceeds interest expense, the liability is reduced. The liability will be reduced to 0 and were no longer eligible to receive royalties under the 2010 agreement.

TIBSOVO revenue grew by $4.9 million compared to Q1 2020, which was driven by continued strong unit demand and channel inventory levels returning to more normal levels versus where we ended Q1. Gross to net for the quarter was within the expected range, but we have seen increases in Medicaid and PHS utilization over the first half of the year and expect that trend to continue over the balance of the year. Cost of sales for the quarter was $675,000.

Turning to operating expenses. R&D for the second quarter was $90.9 million, a decrease of $16.5 million compared to the second quarter of 2019. The year-over-year decrease in R&D was largely driven by lower collaboration spend related to $6 million in milestone payments for AG-636 and an undisclosed early stage research program in Q2 of 2019, ramp-down of the ClarIDHy Phase III study of TIBSOVO and HOVON startup expenses incurred in Q2 2019 and lower spend across ongoing TIBSOVO clinical studies as a result of slowed enrollment and reduced activities due to the COVID-19 pandemic.

Selling, general and administrative expenses were $36 million for the second quarter, representing a $3.6 million increase over second quarter 2019, driven primarily by the initial gated infrastructure build of our EU operations and offset by reduced travel and industry engagement in our commercial organization given restrictions in place to combat the COVID-19 pandemic.

We ended the quarter with cash, cash equivalents and marketable securities of $794 million, which includes the amount received under the Royalty Pharma agreement. We now expect our Q2 ending cash balance, in addition to expected product revenue but excluding anticipated program-specific milestone statements, will fund our current operating plan, which includes pivotal programs from mitapivat in thalassemia and sickle cell disease, through the end of 2022.

With that, operator, please open the line for questions.

(Operator Instructions) Our first question comes from Alethia Young with Cantor.

Congrats on the progress throughout the quarter. I guess I just wanted to ask maybe about mitapivat in peds and kind of any color you can give us on the timing and plans to move forward there. I know you said you're moving forward but just any color there would be helpful.

Alethia, its Chris. I didn't catch -- you're looking for an update on which program?

Mitapivat in the peds. Can you hear me now?

Okay. Yes, yes, yes. No, I just didn't hear the peds part. Right. So we're looking to initiate a trial in pyruvate kinase deficiency next year. The process of negotiating the study design with both Europe where the crucial part of -- it's a box here to check in order to be able to file in an adult indication and then you make a commitment that you have to strictly commit to, it takes a while, and so we're working through that. But we anticipate opening that trial in 2021. And then our plans in thalassemia and sickle cell that will embark on pediatric development are still coming together.

Sorry, I meant PKR in peds, like...

Yes. So we're going to -- we're targeting opening a trial in children with pyruvate kinase deficiency next year. And then we will also do pediatric development with mitapivat in thalassemia and sickle cell. But those plans remain to be defined at this point.

Our next question comes from Anupam Rama with JPMorgan.

Congrats on all the progress. I had a broader kind of sickle cell question and thinking about mitapivat. One of the most frequent questions that we've gotten post-EHA is, how do you ultimately think about levers for differentiation, whether it's against other PKR activators as well as established players like GBT, for example?

Anupam, it's Chris here. I'll start, and some others may want to jump in. I think that the ability for mitapivat is really looking at 2 factors, and that would be increasing hemoglobin for patients who are experiencing anemia as a basis of their disease and, of course, the occurrence of acute chest syndrome, pain crises and all those things, aspects that really are part of the unmet need. So the best-case scenario for us in our early development data from the NIH study suggest we have the potential to affect both. With regards to competitor PKR activators, it's really going to bullet down to a number of things, is that we've got 4 years' plus of data with mitapivat, and we're getting ready to put a follow-on molecule into the clinic. We know a lot and have been the leaders in defining the biology, the translational science as well as the clinical science. So that's really going to, I think, shake out as additional data emergence. And I think the safety and efficacy profile in the setting when you're getting drug for long periods of time is really important.

I think the other thing that we may see, depending on how many additional drugs come on the market, will be -- targeted therapies could potentially be combination therapy. That's something else in the distance. And then finally, you asked about how does -- how do any of these drugs fit in given the presence of Oxbryta. And that's a drug that has accelerated approval, to date has shown increases in hemoglobin that was sufficient for accelerated approval in about 50% of patients. So if you just step back for a minute then -- and it did not show any improvement, statistically significant improvement, in the reduction of VOCs. So if you just step back for a minute, there's -- and you look at the potential Oxbryta population, you can see that at least half of those patients aren't going to have an adequate response, and that can establish from -- a patient population for you right there.

This is Darrin. Maybe just to add one more point to what Chris laid out, I think he made the most important points. In terms of depreciation in class, I mean, ultimately, it will come down to data. The advantage that we have is going to be the depth and breadth of our patients' experience, right, because we'll have 1, 2 indications, though -- and the product will be very familiar to the treaters before any other potential in-class competition makes it to market. So I think that adds considerably to raising awareness, linearity, comfort with mitapivat relative to other products.

And this is Bruce Car. Just adding to that, important within class differentiation is the uniqueness of the mechanism of actions of the allosteric PKR activators. So while we improve the health of the cells, we improve the ATP content. So the energy of the cells and lowering 2,3-DPG, we directly improve the affinity of the hemoglobin for oxygen. This is complementary to the mechanisms that increase hemoglobin as like hydroxyurea and others. So we believe, ultimately, these mechanisms will be complementary, potentially even synergistic, when combined, to which others have alluded.

Our next question comes from Tyler Van Buren with Piper Sandler.

Had a follow-up related specifically to the mitapivat sickle cell program. You noted that enrollment was halted, but that it should reopen this summer, which I think to mean potentially in a month or so, and that you eventually plan to enroll 25 patients, but it's unclear how many above 9 you'll be able to get before ASH. So can you just talk through that a little bit more? What gives you confidence that it should reopen this summer relatively soon? And then just maybe walk through the time that would be required on study for these patients to get more above that 9 number in time for ASH?

Yes. Tyler, it's Chris here. I think the reason why we think the study will reopen is because of the communications that we're getting from the NIH and from Dr. Thein's group in that they're anticipating that the center should open within the next several weeks. And then I think the second part of your question is, so then what's the data flow look like, and that would depend on how many patients they can consent enroll and are permitted to treat. And that may be a function -- I don't know whether the NIH is going to -- my guess is that they will be doing a staged reopening. And so really, the number of patients that can come in will be -- to be an administrative issue. So overall then, patients come in. They have some baseline testing, and then they're going to get treated for 8 weeks, have to taper and then they go off.

So in terms of how many patients would be added to any ASH presentation will really depend on how early they open, how early in the remainder of the summer do they get open and how many people can they consent to bring in. Add on 8 weeks of treatments and taper time, and then they, of course, need some time to pull things together in order to get it ready for a presentation in December. So early, early days. Now we're encouraged by the fact that they are pretty confident they're going to get opened in the next couple of weeks. And Dr. Thein is working on having patients lined up to come in, and they have some experience now with the drug. So we're keeping our fingers crossed that we'll be able to get a few more patients in. But we know, at a minimum, it will be the details on the 8 patients we talked about at the EHA meeting.

Our next question comes from Peter Lawson with Barclays.

Just on the TIBSOVO revenues and the number of unique subscribers. Is there anything you can talk through as regards to the impact from COVID and anything you can say about off-label use?

Sure. Darrin here. So we haven't been able to detect a significant impact from COVID thus far. We've seen nice growth in new scripts and refills, both of which are continuing to move in the right direction. As we noted, we had a very significant expansion of new prescribers in both the academic and the community setting. But it's -- the fastest growth is actually occurring in the community setting, which is encouraging as well. The -- there are a couple of risks, though, that are associated with COVID, right? So ultimately, we are yet to see it, but there potentially can be an impact in terms of the initial diagnosis of patients with AML. Though it's a treatment-emergent disease, the reluctance of patients to show up could potentially manifest over time. But we haven't seen that significantly as of yet.

The continued work-from-home restrictions on the sales force can potentially add some pressure. But what we've seen also is an increase in Medicaid and 340B utilization as well, and we would expect that to continue, as Andrew indicated earlier. And then in terms of spontaneous adoption, off-label use in other settings as -- because we've shared many times, we've limited insight into utilization in indications outside of AML, but we do have anecdotes of those uses.

Our next question comes from Kennen MacKay with RBC Capital Markets.

Maybe I was just hoping you could discuss a little bit more in sickle cell the real sort of urgent need for tapering, really any medication that is used to sort of bolster the number of red blood cells in circulation, especially if this is acting by shifting the oxygenation curve of red blood cells and oxygen binding curve. That's something that I think is still maybe a little bit underappreciated in that setting.

Kennen, it's Chris here. So you were asking the question of tapering?

I'm sorry, on discontinuation of drug. Yes, just going back to some of the safety events that we saw in sickle cell.

Yes. Well, we established with our -- mitapivat in pyruvate kinase deficiency that the best thing -- the ideal situation if the patient is going to stop drug is to gradually taper. And if you think about it, then you've got a drug that's binding and stabilizing pyruvate kinase in the setting of pyruvate kinase deficiency and then activating it in all these diseases, so abruptly stopping has the potential for a more rapid decline in hemoglobin than if you taper it and a rapid decline then the patient can acclimate as rapidly -- can't acclimate as well as if you do a slow taper. So that's really where that comes from.

Now the aspect of -- one of the things I think that comes up is people are worried about compliance because of the statements and data that indicates that noncompliance may be more of an issue in sickle cell versus other diseases. We don't think that missing a dose here and there is likely to be a problem based on what we know about the pharmacokinetics and the biology of the molecule. But I think that the guidance that in the ideal situation, you want to avoid abruptly stopping the drug and have a taper is likely to be present. I would also say that's true for a lot of drugs, whether they're in the hematologic space or other areas where chronic dosing is something that you do.

And maybe just as it relates to the competitive landscape here, just how to -- in one way, at least one of the mechanisms of mitapivat is a little bit similar to the mechanism of Oxbryta, shifting that oxygen affinity for partial pressure curve. Can you maybe talk a little bit about the theoretical combinability of these agents, whether that's realistic or something that wouldn't make sense? And congrats on the progress during Q2.

Yes. Well, I think the combinability is something that we're interested in not just in sickle cell but in thalassemia as well as new products come on. And I think that is the complementarity of mechanisms of action. So if you're in -- a thalassemia example first. If you have something that enhances terminal erythroid differentiation like luspatercept, is there at least a theoretical interest that by having more cells get to that late stage so that they can be affected by that drug, luspatercept? Then that's certainly of interest. There's been recent publications in the sickle cell literature where people are seeing this -- the number of new drugs coming in as offering some real potential for complementarity. Specifically for mitapivat and Oxbryta, it's an interesting thought, if you can get somebody up 1 gram with Oxbryta or 1.5 grams, will they benefit from another 1.5 grams by adding PKR wild-type activation on mitapivat? And on the one hand, that's appealing. And then on the other hand, you've probably heard from sickle cell docs is that they're a little more careful about how they adjust hemoglobin in these patients.

So yes, it's definitely of interest not just for Oxbryta but potentially for other drugs that come along, whether it's a Novartis P-selectin inhibitor and others. But I think that we -- just based on our data now in sickle cell, the early day that we talked about at ASH -- at EHA, and what we see in thalassemia and our long-term experience with mitapivat in pyruvate kinase deficiency, I think we -- I'm very excited about just looking at this drug as a single agent because I think that we have the opportunity to do both, address both range of components of the disease and reduce that hyperactive bone marrow that's really working hard to keep up with anemia. I think there's a potential that we can demonstrate that patients will feel better as well. So yes to combinations, but I think we have a very strong ground to think that we have a single agent benefit that we'll be able to provide to patients.

And just carrying on from that, Chris, the patient-reported outcomes being favorable -- very favorable anecdotally for our treatments with mitapivat across the indication. That isn't the case with Oxbryta, notwithstanding its approval for increasing hemoglobin. And important is that the covalent finding of Oxbryta to hemoglobin, it prevents the sickling, so that's a very important thing, but it also lowers the ability of hemoglobin to carry oxygen, and that's very important. Now we're able to preserve hemoglobin in healthier red cells such that they carry more oxygen and that there's a higher affinity of the binding for oxygen. So we believe we have actually a superior mechanism than to that of Oxbryta.

Our next question comes from Chris Shibutani with Cowen.

Questions are focused on mitapivat, 3 of them. For mitapivat, you've previously updated on the PEAK registry and patient identification. Any updates there? You've also described narrowing the time lines based on ability to access trial sites to get the ACTIVATE data that was in assessment. You obviously had to meet 3 months ago. I'm just curious to know whether, thus far, your sense is that progress has been quicker perhaps than you thought or more challenging. Any color in terms of an update on how that progress is? I know you gave us the first half as the span. Secondly, for sickle cell disease, you have this collaboration with the NIH. Can you just remind us what optionality you have and any plans that might be in place to do clinical work in this indication independent of the NIH? Or are you tethered to them contractually? Just help us understand since I think a lot of the sharing of data is depending upon decisions jointly made and perhaps if you had options to direct trials and activities on your own, that would be helpful for us to know.

Okay. Chris, it's Chris Bowden here. PEAK is up and running at multiple countries across the world. It's enrolling well. One of our ambitions is to take the natural history study and be able to pull those data with PEAK. It's something we're working on. That database is from the Boston Children's Hospital, so merging that into -- or combining that, pulling it and doing the analysis is something that we're interested in doing and hope to talk more about in the future. So -- and we think that's going to be an important -- an ongoing important data set for us to describe the burden-of-disease outcomes, the variations in treatment approaches. And we're looking forward to starting to be able to publish that and hope to be able to guide to that.

With regards to the challenges and the ups and downs of clinical development in the time of a global pandemic, as I commented on in my remarks, I can't talk about specific places, specific sites. But if you just step back for a minute and you look at how the pandemic has locked down United States as it moves from the East Coast and the West Coast, down to the south and up and around, there's a fair amount of unpredictability there. And depending on how locked down a hospital is and how they're managing clinical trials and their clinical research staff and the fact that when they stop and then start, there's a queue, those are the types of factors that we're looking at in trying to understand how we're going to get in there and pull our data, and that's why we can't provide any more guidance at this point.

But what I can tell you is that we've done a good job in terms of making sure patients stay on drug, capturing data by any of the means that I talked about in my prepared remarks. And we'll just have to see how thing develop before can provide more definitive guidance, which is why we didn't update it on this call. And then with regards to the NIH and issues around how we choose to do development, we don't have any restrictions. I mean that's a CRADA agreement we have with them for a trial. We freely shared the data. We're, in fact, performing a number of the assays that are being done with Bruce's group. So we have freedom to operate, and we're moving forward expeditiously to get a sickle cell trial up and running in 2021. And that's not dependent on any way of an approval from the NIH or -- for that matter. And we have a very good relationship with them in being able to discuss and describe that data and present it to health authorities as needed.

It's Jackie. I just want to jump in for a second, and I think something Chris said is really important to just reiterate. On the ACTIVATE, ACTIVATE-T trials, you have 2 issues that you probably want to think about. One is data integrity, and that is where Chris spoke to how good a job our team has done to make sure that patients stay on drug and that the trial -- they finish their trial experiences smoothly and in line with the protocol. And then the second is timing of being able to release that or have in hand, analyze and then release that top line data. So I think data integrity is extremely important. If we were fast at getting the data out that there was compromises to the data, that would be more serious than ensuring data integrity first and then the timing of when we get that top line data out.

And we're -- as Chris said, we feel good about that -- what the team has done to support data integrity, and we haven't narrowed the timing window just yet because we've got a little ways to go to get into the sites and see that. And then I think also, Chris, part of your -- the first question included the patient-finding efforts. And right now, between our clinical programs and our patient-finding efforts, we're at about 2,000 patients identified. Thanks.

Our next question comes from Mohit Bansal with Citigroup.

This is [James] on for Mohit. I had a question on AG-270. Another company recently announced a collaboration to explore MAT2A with PRMT1, and they published some preclinical data showing greater potency and solubility compared to 270. Have you seen this data? And what are your thoughts on their MAT2A program and possibility for a combo with PRMT1?

This is Bruce Car. I believe you're referring to the [Ideo] molecule. Yes, in terms of the ability of this pathway to lower S-adenosylmethionine, the combination with PRMT1 is an entirely appropriate one, and we believe also PRMT5 could be a potential player in this field.

Our next question comes from Michael Schmidt with Guggenheim.

I had 2 more on sickle cell and one on TIBSOVO. Maybe a little bit of a follow-up to a prior question on the Phase I NIH data. I was just wondering if any additional information might be available on that one patient that experienced a VOC event. I think at the time, it was classified as possibly treatment-related, but obviously, VOCs occur at high frequency in patients in general. I'm just wondering, Chris, if there's been any new information on that specific event that you might be able to share?

Nothing new. The VOC occurred during the taper. We didn't see any events while patients were on active treatment. You're absolutely right that that's an unfortunate component of the disease and one we're trying to address, which is the VOCs. We didn't see any additional ones during the taper over the course of those 8 patients that were able to complete either 6 or 8 weeks of dosing. No -- so no new information, and it's something we'll continue to track. And I think given our overall sense of that data that we've talked about at ASH is that we clearly achieved proof of concept, and we're excited to move forward.

Great. And then I think you mentioned meeting with the FDA and discussing plans for regulatory trials or approval -- pivotal trials. And given some of the possible differentiation that was talked about earlier, just wondering how you think about taking advantage of that in your trial design. For example, what are your thoughts about pursuing an accelerated approval pathway similar to GBT using Hb increase or potentially incorporating clinical outcomes such as VOC reductions? I guess how do you think about those considerations?

Yes, that's the major focus for our team now in terms of putting together a clinical development plan that can lead to approval, accelerated or regular, in the United States but in -- and other geographies outside the U.S. And that the interesting part of mitapivat is that we have the potential to -- we clearly have the potential to address hemoglobin. We demonstrated that early on, and we know now that activating wild-type PKR is an important strategy in chronic hemoglobinopathies overall, if you will, mainly thalassemia and sickle cell we've demonstrated so far. We think that we have the opportunity to reduce VOC. So then -- so what, I'm not saying anything new here. The interesting part is how you combine those as well as potentially patient-reported outcomes into a package that can get you there as rapidly as you can but also have the greatest impact to patients.

So we're working hard on that, and we're looking forward to having those discussions with both agencies as rapidly as possible. The other thing that we want to do is get input from patients and patient advocates because I think that that's going to have an important impact on the type of data that we're -- that will impact patients and really compel them to use the drug. So lot of factors in play. I know that accelerated approval based on the increase in hemoglobin has been demonstrated with Oxbryta. And that's something that we're looking very hard at. But we think there's a lot more for us to be thinking about on the basis of the mechanism of action of mitapivat and the unmet need overall.

Okay. Great. And then a commercial question on TIBSOVO. Just curious if you could share what market share now is in either frontline and also relapsed/refractory AML since it seems like you've seen growth in both. Just curious what market share is at the moment. And then also wondering if you've already been seeing use in cholangio based on the recent NCCN listing.

Sure. So Darrin here. So given the population and our visibility into utilization, I can't -- I don't know exact penetration numbers by line of therapy. What I have are the reflections of physicians through market research and their use by setting. So I can't give you exact penetration number. But what I do see is the change in utilization as stated by physicians over time. And so that's when I make statements about increased adoption in different settings, that's what I'm relying on. And what we've seen is continued adoption and continued improvement -- or increase adoption, I should say, in the frontline setting and a nice spike in the relapse setting as well. And we've seen actually in the last quarter, increased use of the product in combination with HMA as well. And then in terms of utilization in cholangio, yes, we've heard -- we've had anecdotes of utilization in the cholangio setting as well. And given the recent NCCN guidelines, it wouldn't be surprising if we continue to see adoption there as well.

Our next question comes from Mark Breidenbach with Oppenheimer.

Congrats on the forward progress. Maybe just another mitapivat question following up on one of Kennen's questions. It sounded like you're not really worried about the potential for a rebound effect in sickle cell patients who missed dosing for a day or 2. I guess I'm just wondering what's giving you confidence around that statement. And I'm also wondering why a drug taper doesn't appear to be necessary for patients on Oxbryta. Any speculation as to why they can get away without a taper would be very helpful.

The reason -- it's Chris here. The reason why we don't think missing a dose or 2 here or there is based on what we see -- what we know about drug binding to enzyme and sticking, what we know about when you look at effects from our healthy volunteer study, for example, where we looked at 2,3-DPG and ATP levels after patients had stopped dosing, they actually stayed elevated for several days. So I think that's some of the data that gives us confidence that we don't think that's going to be an issue that as you miss a dose and suddenly, you have a -- you get into some sort of withdrawal problem. And then the second part of your -- oh, yes, that's right, why do they not have to taper. Well, they -- Bruce may want to comment on that. But one of the things that is interesting is that when you look at some of their Phase I and II data, you will see that there are VOCs that occurred as patients were coming off drug.

They just haven't attributed to drug, and investigators think it's not drug-related. So that's about all I can say about that. And I think that the main thing for us in terms of differentiating versus Oxbryta is going to be, a, the percentage of patients that have a response to mitapivat versus Oxbryta, if both drugs are available in the marketplace; the overall activity versus VOCs, whether we can demonstrate that or not and whether with longer follow-up, they will be able to; and then there are other aspects of how the patients feel better taking these drugs. And I think from -- as I've commented earlier on, if we can increase hemoglobin and address VOCs with a pill that you're taking twice a day, that -- we think that has a pretty good compelling reason to use.

Yes. And just agreeing with you there, Chris, the very long pharmacodynamic effect of mitapivat is the reason why individual missed doses in the VOC schedule are not going to matter. The mechanisms of action between Oxbryta and mitapivat are quite different. And I mentioned previously, the covalent binding to the valine at the end of the sickle hemoglobin with Oxbryta is a permanent binding. That's what's meant by covalent binding. And it will persist for the entire lifespan of the hemoglobin, which is longer than 30 days in the case of hemoglobin as bound to Oxbryta. That's possibly a reason.

Our next question comes from George Farmer with BMO.

This is Gobind on for George. Just on the same theme as the prior colleagues that were asking. With the VOC patient, if I remember correctly, I think the titration, the taper protocol is 12 days. So perhaps, you might be willing to comment on, was that VOC patient during the latter half perhaps of the 12 days, and that's maybe where you're getting your confidence that missing a single dose is not -- probably really not going to matter? And then if I remember correctly, I think you guys mentioned 2 patients had been dosed on the 100-milligram protocol right before the COVID-19 shutdown happened. I was wondering if you guys have seen any of the hemoglobin responses. If I'm understanding that correctly, in those patients, because it seems like there's a really strong dose-response relationship, then I wouldn't be surprised that the increases are better there.

The patient who experienced VOC did, indeed, have it closer to the end of the taper than at the beginning. And I think that qualitatively, that's in line with what you just heard Bruce and I talked about with regards to the ability to tolerate and not have untoward effects from missing a dose or 2 or several doses of mitapivat. What we talked about at EHA was that we gave data that 7 of the 8 patients treated in that trial had an increase in hemoglobin, and that 5 of 8 had an increase over 1 gram. And that was across all the cohorts. So we didn't provide individual data because we want to save that for the ASH presentation and to give that presentation the most power that it can to get a good slide at the meeting. So your question is a great one, does going from 50 milligrams to 100 milligrams or 200 milligrams, what is there and what is the extent of that dose-response relationship with regards to whether its hemoglobin or impact on oxygen dissociation curves. That's something we'll look at. It would be too early. Like I said, I can't comment on the hundreds versus the patients who only went to 50. And it's a small patient number where we're going to want to see additional patients and as we think about the dose question in sickle cell.

I will remind you that in thalassemia, we -- in that protocol, we went from 50 to 100. And we saw some slight suggestions that we may be seeing a little more bump when you go from 50 to 100, whether that same thing will occur or something different in sickle cell remains to be seen. The thing we know about mitapivat that I think is really -- gets back to the -- why you always hear me talking about the safety of the drug is we understand the safety profile across many years now from dosing an extension in the DRIVE PK study. But we also know that there's a range of doses that are pretty well tolerated and are suitable for development. And I think that the nuances of PKR in the context of the individual diseases are such that there's a possibility. There may be a range of doses that clinicians will want to be thinking about as they balance optimizing efficacy with safety. So it's -- I have a lot of comfort with having worked with this drug now for several years and looking at the safety profile. So it's a very interesting question. And we just need more data, but we know there's a range where we can dose this drug, and it's pretty well tolerated.

I'm not showing any further questions at this time. I would now like to turn the call back over to Jackie Fouse for any closing remarks.

Thank you, operator. Thank you all for joining us on our call this morning. I would like to reiterate that despite the challenges and uncertainties that lay ahead of us all, I remain incredibly excited about the progress we've made at Agios across our focus areas so far this year.

To close, I would like to thank the tremendous employees at Agios for their dedication and passion for making a difference for our patients, particularly during this uncertain time in the world. I also want to thank all the patients, caregivers and physicians who participate in our clinical trials. Without them, we cannot do what we do. Thanks again for joining us today. We look forward to seeing you and hearing you soon. Take care.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.