Agios Pharmaceuticals, Inc.

Good morning and welcome to AGO's first quarter 2020 conference call. At this time, all participants are now listening online mode. There will be a question and answer session at the end. Please be advised that this call is being recorded at AGO's 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' first quarter 2020 conference call. You can access slides for today's call by going to the investor section of our website, agios.com. With me on the call today with prepared remarks are Dr. Jackie Faust, our Chief Executive Officer, Dr. Chris Bowden, our Chief Medical Officer, Darren Miles, our Senior Vice President of U.S. Commercial and Global Marketing, and Andrew Hirsch, our Chief Financial Officer and Head of Corporate Developments. Dr. Bruce Carr, 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 factor section of our most recent Form 10-K filed with the SEC and any other filings that we may make with the FCC. With that, I will turn the call over to Jackie.

Thanks, Holly. Good morning, everyone, and thank you for joining our first quarter 2020 results call. At the beginning of the year, we laid out ambitious plans for 2020. Along with the rest of the world, we couldn't know what challenges would lay ahead related to the impact of the COVID-19 pandemic. The past few weeks have stretched each of us personally and professionally as we adapt to the necessary constraints of physical distancing and realize more than ever how our actions can impact the people around us. We wish continued good physical and emotional health to all of you, our patients, the system's healthcare professionals, our AGEOS team members, and humanity at large. There is no modern playbook for a crisis of this type, but at OGS we quickly realigned our priorities around the health of our employees and their families, our communities, and the patients we serve. To start, in February we activated our organizational resiliency team and clinical operations response team to assess the evolving coronavirus outbreak and put plans in place to address its impact on every facet of our business. On March 10th, we made the decision for most of our employees, including lab and field personnel, to work from home to reduce the likelihood of exposure or transmission of the virus to others, a policy that remains in effect. Our supply chain strategy has ensured uninterrupted supply of our commercial and clinical medicines, and our patient assistance program, MyAGIOS, has been a constant resource to help new and existing TIBSOVO patients remain on therapy. including those that have lost insurance due to unemployment. With the help of our dedicated employees, we have been actively supporting our communities and health care workers, including organizing a donation of AGIOS's personal protective equipment supply to local hospitals, raising more than $22,000 for the Greater Boston Food Bank, and encouraging blood donations. The teamwork and resilience I've witnessed in these last few weeks has truly been remarkable and gives me hope that we will come out of these challenging times even stronger than we were before. Turning to the impact on our business, we've taken a fresh look at our priorities and made important resource allocation decisions to support execution against the most critical objectives for our business. During this period of disruption and uncertainty, we're focused on delivering on our top objectives, including driving TIPSOVO performance, enrolling our late-stage AML and glioma studies, and advancing mid-pivot across multiple disease areas, all while conserving cash and increasing our financial flexibility. As a result of our prioritization efforts, we have extended our forecasted cash runway by six months through June of 2022. Andrew will further discuss the decisions we have made later in the call. As I mentioned earlier, we created a clinical trial task force in February to ensure the safety of patients on our clinical studies and to implement plans to keep as many patients on study as possible. We have been managing this on a patient-by-patient basis, consistent with FDA guidance. Chris will walk you through the impact of each program and trial, as well as the measures our team have taken to address pandemic-related challenges. On the commercial side, we saw strong TIPSOVO performance to start the year and an acceleration of revenues during the month of March into April, which reinforces our confidence in our 2020 product revenue guidance. Darren will discuss the trends we saw in Q1 in more detail. Through these efforts, we remain on track to achieve our AGEOS 2025 strategic vision. Before I wrap up, I want to thank every AGEOS employee for their incredible work over these last few weeks. Your determination in the face of adversity has quite literally saved lives, and I could not be prouder to be on your team. Chris, let me turn it over to you.

Thanks, Jackie. As I go through our clinical update, I will share with you the status of our studies based on our best estimate of the impact we see today from the coronavirus pandemic. As a partner and collaborator on more than a dozen clinical trials, Our focus has been on supporting our sites, investigators, and the patients enrolled in our studies as they all deal with the strain of COVID-19. As Jackie mentioned, our clinical operations response team meets daily to assess the evolving situation and mitigate disruption to the best of our ability on a patient-by-patient basis. I'll start with Medipivac, our lead PKR activator, currently being evaluated in pyruvate kinase deficiencies thalassemia, and sickle cell disease. In the first quarter of this year, we achieved several important milestones for our most advanced program in PK deficiency, where we have the potential to provide the first disease-modifying therapy for this disease. In March, MediPIVAT was issued a positive opinion on its application for orphan drug designation by the CHMP for the treatment of adults with PK deficiencies. HEMA orphan drug designation provides us with a number of benefits, including 10 years of market exclusivity. In addition, we completed enrollment in the ACTIVATE Phase III study admitted to that in PK deficiency patients who are not regularly transfused. In total, we enrolled 80 patients. In the ACTIVATE T study in PK deficiency patients who are regularly transfused, we enrolled 27 patients. For both studies, our focus now is to do everything we can to ensure patients on study have access to study drug and to capture clinical data regardless of a patient's ability to get to their medical center. This includes home visits, telemedicine approaches, the use of local laboratories, and courier shipments of drug. To our knowledge, as a result of these efforts, no patients on these studies have missed study drug to date. As the core period of both studies come to an end later this year, we do anticipate challenges to our ability to access sites for data cleaning, particularly in those areas most affected by the pandemic. Given this, we now anticipate top-line data from both studies sometime between the end of 2020 and the middle of 2021. Based on our current assumptions, potential approval of MnDOT-PIVAC in PK deficiency is now expected to occur in 2022. We hope to further narrow these timelines once we have a better understanding of when participating sites will allow for monitoring visits and how access will affect our ability to achieve database lock once the last patient visit has occurred. Moving to the Phase II study of medipivac and thalassemia, we completed enrollment in the study earlier this year with 20 patients. above our initial target enrollment of 17. As you may recall, we established proof of concept in thalassemia in December based on interim data from this trial, demonstrating that treatment with midipivac induced a hemoglobin response of greater than or equal to one gram per deciliter in seven of eight evaluable patients. Data from 13 efficacy evaluable patients, including those with beta and alpha thalassemia, have been accepted for presentation at the European Hematology Association Congress in June, which is being held using a virtual format this year. As we've disclosed previously, Dr. Suile Chen of the National Institutes of Health submitted the data from the proof of concept study of midipivac and sickle cell disease for presentation at EHA. Although the data were accepted, due to the new virtual format of the meeting, The NIH has decided not to present the data and instead submit it for presentation at the ASH annual meeting in December. We are still on track to make a decision on proof of concept for Meditivac and sickle cell disease by mid-2020. The goal of the study is to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating oral doses of Meditivac. In addition to the 5 mg, 20 mg, and 50 mg BID doses evaluated in the original protocol, Dr. Chan recently amended the study to dose patients up to 100 mg of midipivac twice daily for two weeks. Dr. Chan plans to enroll up to 25 patients in this study, though enrollment is currently paused in light of the COVID-19 pandemic. Beyond midipivac, we have developed a next-generation PKR activator AG 946. In March, we received clearance from the FDA for the AG 946 IMD application, and we expect to initiate a phase one healthy volunteer study in mid-2020. The phase one study will evaluate AG 946 in approximately 32 healthy volunteers in a single ascending dose cohort followed by a multiple ascending dose cohort. The goal is to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of HE946, a potentially therapeutic doser. In addition, we have included the option to enroll a further multi-ascending dose cohort in adults with sickle cell disease if the safety and tolerability profile supports continued dosing. 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 and refractory AML, and at this time, we still anticipate receiving a CHMP opinion by the end of the year. In frontline AML, we are focused on enrolling two global frontline combination phase III studies which will allow us to reach the largest number of AML patients with an IDH1 mutation. The first is the Agile Phase III study of Tibsovo in combination with azacitidine, and the second is the cooperative group HOVON 150 study of Tibsovo and IDFA in combination with standard induction and consolidation chemotherapy. As a well-tolerated oral oncology therapy, physicians continue to refer patients to both studies, and patients have been able to access TIBSOVO, including home shipments, as necessary. However, site startup activity has slowed, and enrollment interruptions have occurred at some sites due to the pandemic. The Agile trial, which we originally projected to complete enrollment by the end of this year, is now expected to complete in 2021 as a result of Q1 delays in site activations in China and enrollment interruptions across the globe. In recent weeks, some Chinese sites have been able to open, and we expect to provide more precise timing on enrollment completion as countries move away from the crisis and return to pre-pandemic work environments. The majority of clinical trial sites for the HOVON 150 study are in Europe, and enrollment at sites in heavily impacted countries has slowed. We're still relatively early in the accrual process, and since it is a fairly long study, we may be able to make up some time along the way. We'll provide an update on expected enrollment completion once all sites are activated and we have a read on accrual rates. Beyond AML, we recently reopened the myelodysplastic syndrome on the phase one study of TIBSOVO with the goal of generating the data necessary to pursue a potential US regulatory filing. Since we are early in the process for reopening this study, psych startup activities have experienced delays, and enrollment completion is now expected in 2021. Finally, I'll turn to AG636, our DHO-DH inhibitor currently being evaluated in a Phase I dose escalation study in advanced lymphoma. At the beginning of the year, we planned to make a go-no-go decision on further development of AG636 by the end of 2020. As a result of the prioritization exercise that Jackie highlighted, and very limited enrollment in the study, a total of 11 patients enrolled over the course of 10 months, we have made the decision to stop in-house development. At this time, we plan to look for a partner to advance the program. I'll now move to solid tumors, where we are advancing pivotal studies of IDH inhibitors in cholangiocarcinoma and low-grade glioma. and evaluating AG270, a MAT2A inhibitor, in combination with taxane in pancreatic and lung cancers. Last year, we reported the positive readout of the CLARITY Phase 3 study of TIBSOVO and previously treated IDH1 mutant cholangiocarcinoma, showing that treatment with TIBSOVO reduced the risk of disease progression or death by 63%. In mid-2020, we expect to have mature overall survival data from this study to support a potential supplemental NDA filing. Based on the current state of the COVID-19 outbreak and the impact it has had on trial site resources, we anticipate challenges in collecting the LS data from site and executing the data cleaning process. Given this, the SNDA submission is now likely to occur sometime between the end of 2020 and the middle of 2021. The INDIGO trial is our Phase III study of voracidinib, our brain-penetrant IDH inhibitor, and low-grade glioma that initiated in December. We are currently experiencing some startup and enrollment delays as a result of the pandemic. Given the early stage of this study and its long timeline, we will likely be able to make up some time along the way. We'll provide an update on expected enrollment completion once all sites have been activated, and we have a better view on accrual rates. In the meantime, we look forward to sharing updated data from the phase one study of boracitinib and non-enhancing low-grade glioma at ASCO in late May. Lastly, enrollment in the AG270 phase one dose escalation combination arms is ongoing, but has slowed at some sites as resources have been shifted due to the COVID-19 pandemic. We still expect to be able to make a go, no-go decision on this program. no later than 2022. To close, I'd like to thank our clinical operations response team, as well as all of our safety, medical, regulatory, and technical operations colleagues for going above and beyond the call of duty these last few months. The implications of this crisis are far from over, and it's with their hard work and leadership that we're able to stay informed, support our clinical trial partners, and make decisions in the best interest of patients. With that, I'll turn it over to Darren to discuss our first quarter commercial performance.

Thanks, Chris. I'm pleased to share that we delivered strong performance during the first quarter, recording $23 million of net sales of Tibsilvo, a 16% increase from the fourth quarter of 2019. Growth was driven largely by increases in new scripts and refills in both the newly diagnosed and relapse and refractory and non-segments. Our market research shows that Tibsilvo-containing regimens are considered standard of care for newly diagnosed IDH1 mutation-positive patients ineligible for more intensive treatment and first relapse or refractory patients. This is further reflected in our measurement of patient share in both the newly diagnosed and first relapse settings. Though not a focus of our promotional efforts, we continue to observe that approximately half of tipsovo use in both settings is in combination most frequently with a hypermethylating agent. Furthermore, This growth was supported by continued expansion of the unique prescriber base by 25% from Q4. While we did see the typical Q1 seasonal increase in patient assistance resulting from changes of benefit design at the start of the year, the magnitude of increase was less than we expected as underlying TIPSOVO demand grew substantially during the quarter. 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, our field team has been working from home since mid-March, and we've experienced success continuing to engage customers with tools enabling remote interactions. The urgency to treat patients with AML is high, and professional oncology guidelines favor effective oral options with well-tolerated safety profiles as healthcare professionals wrestle with the needs of patients with COVID-19. Given these dynamics, Tipsovo's efficacy, safety, and clinical benefit profiles position it well as a preferred option for treating IDH1-positive patients. These factors, coupled with sustained momentum in physician demand through April, give us confidence in our full year of 2020 U.S. Tipsovo net sales guidance of $105 to $115 million. We continue to monitor market trends carefully given the ongoing impacts of the pandemic. I want to thank the exceptional team at AGIOS for rising to the challenges posed by COVID-19. and continuing to deliver for our patients, our customers, and the business. I will now turn to Andrew to discuss our first quarter financials.

Thanks, Darren. Our first quarter results can be found in the press release we issued this morning, which I'll summarize. More detail will be included in our 10-Q filing later today. I'll start by discussing the quarter and then describe some of the cash conservation actions we've taken that have enabled our increased runways. Total revenue for the first quarter was $87 million, which consisted of $23 million of net sales of TIBSOVO, $61 million of collaboration revenue, and $3 million of IDFA royalty revenue. The year-over-year increase in revenue was primarily driven by a $42 million increase in collaboration revenue. As a result of BMS's notification that they would not be extending the 2016 MEO research collaboration, and that they won't be selecting a program for continued development and opt-in rights, we recognize the vast majority of the deferred revenue on the balance sheet during the quarter. Going forward, we will recognize the remainder in the second quarter through the expiration of the research term in mid-May. After that, collaboration revenue will mostly consist of reimbursement for activities we're conducting on BMS's behalf for commercialization and development of IDFA and reimbursements under our Seastone agreements Quarter-over-quarter revenue growth was also driven by an increase of $14 million of net sales of Subsovo that Darren described earlier. Gross-to-net was largely consistent with the first quarter of 2019, but we ended the first quarter with channel inventory levels lower than we did in December, both in absolute units and weeks of demand. Cost of sales for the quarter was $533,000. Turning to operating expenses, R&D for the first quarter was $91 million, a decrease of $4 million compared to the first quarter of 2019. The year-over-year decrease in R&D was largely driven by the recording of milestones for the initiation of the HOVON 150 Phase 3 study in the first quarter of 2019 and winding down of the TIBSOVO Clarity Phase 3 study and the Phase 1 hematologic malignancy study. Selling general and administrative expenses were $39 million for the first quarter, representing a $7 million increase over first quarter 2019, driven by increased headcount to support our U.S. operations and the initial gated infrastructure build in EU. We ended the quarter with cash, cash equivalents, and marketable securities of $613 million. As Jackie laid out at the beginning of the call, we recently made important resource allocation decisions to support the execution of our critical business objectives while conserving cash and increasing our financial flexibility. As part of this exercise, we conducted a critical review of our spend across the business to capture reduced spending levels that will naturally occur due to the impact of the global pandemic, such as travel and clinical trial spend. In addition, we made decisions to delay or reduce spend on lower-priority activities. These include stopping development of AG-636, Parking select research programs, including our program in Friedrich's ataxia, delaying the start of longer-term clinical studies that are required but not time-sensitive for our main clinical programs, limiting hiring except for a select number of roles that will help us build critical capabilities, as well as significantly reducing our contract workforce, and delaying IT and facilities infrastructure projects. It's important to note that we made these decisions given the uncertainty that current global situations injected into the financial markets and not out of any liquidity concern. As a result, we now expect that our Q1 ending cash balance, in addition to expected product revenue and royalties, excluding anticipated program-specific milestone payments, will now fund our current operating plan through June 2022. With that, operator, please open the line for questions.

Thank you. And as a reminder, ladies and gentlemen, if you have a question at this time, just press star then one on your telephone keypad. To withdraw your question, press the pound or hash key. Please stand by while we compile the Q&A roster. And our first question is from Tyler Van Buren with Piper Sandler. Please go ahead.

Hey, guys. Good morning. Great to hear about the increased cash runway. Thanks for taking the question. I guess on mid-appevat in sickle cell, when you state, you know, the decision on proof of concept remains on track for mid-2020, could you, and I understand that the data will be presented at ASH, but will we see any data when you make that decision at mid-year? And if so, what will we see? And specifically, what do you need to see to make a decision in terms of proof of concept or moving forward?

Chris, do you want to take that one?

Sure. Good morning, everybody. It's Chris Bowden here. And what you should anticipate is a top-line data sharing similar to what we did with a thalassemia data at ASH at the end of last year, where we presented some efficacy data on the primary endpoint of that study, which was increasing hemoglobin. and made some high-level statements around safety. Some of you who attended our investor event will also note that we did provide some individual patient data. So I can't tell you precisely what will be in that announcement today because we're going to be looking at the data and pulling all of that together. In terms of what we need to see for proof of concept, that is to move to the next stage of development From an efficacy standpoint, there are two readouts that we're interested in. One of them addresses the issues of the hemolysis and anemia. And the second is related to findings that we would see from the drug that could have an effect on basal occlusive crises. So really looking at oxygen dissociation curves, sickling curves, looking at ATP, 2,3-DPG happening in red cells when patients are on different doses of treatment, and then, of course, looking over the course of their treatment to see what changes we might see in hemoglobin as well as endpoints that would be addressing ineffective erythropoiesis, sort of chronic and ongoing hemolysis. So it's a lot of different data that we'll be looking at. and we're looking forward to being able to provide our view of that data in the middle of the year.

And just as a quick follow-up, can you give any more color on your decision to increase the dose to 100 milligrams, and should we expect to see a meaningful number of patients on the 100-meg dose at year-end with some of the challenges you're experiencing in the near-term enrollments?

Hard to answer part two of your question at this point. Everyone's hoping that with the measures that have been taken to address the pandemic, that they will continue to be effective and that the NIH is hoping that they will be able to begin to enroll patients once they feel like they've got control on all the issues that they think are important for for doing that. With regards to the 100 milligram BID dose, in pyruvate kinase deficiency, we treated those patients starting with 300 milligrams BID, which was the initial dose in our Phase II dry PK study. And in our ACTIVATE trials, now our pivotal studies would go from 5 to 50 milligrams. The thalassemia trial, we have studied two doses, 50 and 100. So the NIH was aware of this from the beginning, and with our initial discussions with them, they chose to study that range of doses, 5 to 50, those three doses, 5, 20, and 50, in order to understand the PK and PD and effects on hemoglobin. And with our continued discussing with them and sharing our data from thalassemia and some other aspects, they've now decided they wanted to study 100 milligrams in the trial, and we're very appreciative of that because that will give us a greater dose-ranging experience in terms of looking at all those other endpoints I was talking about.

Great. That's very helpful. Thanks for taking the questions.

You're welcome.

Operator, is there another question?

Yeah.

Nagios is ready.

Thank you. Our next question is from Anup. Rama with JP Morgan.

Hey, guys. Thanks so much for taking the question. On the finance side and extending the cash runway, so what's the assumption here for sort of enrollment across studies picking up and the infrastructure building continuing? And if the pandemic is prolonged, what are the push-pull levers on the cash runway guidance maybe being extended potentially? Thanks so much.

So it's Jackie. Hi, Ana Palm. And Andrew's probably going to want to jump in on this, but I'll just start at a very high level. And I think Andrew said this in his prepared remarks. There are some expenses that we would expect to, because of the delays, to potentially go down and just stay down, including some T&E and things like that. Many of the other ones are also related to gating based on how the situation unfolds, and so some of those could be gated for an extended period of time. Of course, we're all hoping that from a clinical trial enrollment standpoint that things pick back up and come back to the enrollment curves that we would have forecasted before this, but in any event, that pushes things out by a little bit at a very minimum. So I don't know, Andrew, if you want to Add anything? Yeah.

Sure. Yeah. So, Anupam, I think, you know, the actions that I talked about, you know, in terms of things that we're delaying or pushing off, you know, those are through that runway period. And so, you know, as you're probably well aware, it's a pretty dynamic situation. And so, you know, we're poised to react as the situation changes. And so, you know, I think, you know, there are potentially other levers as we see business developments unfold. you know, throughout the period. But it's just too hard to predict what those are going to be right now. So we felt comfortable that these are the right decisions to make today to buy us that runway through June of 2022. And then, you know, we're closely monitoring the situation and we'll be able to kind of, you know, react if need be.

And just another quick one real quick. So for Activate and Activate T, Chris, I think you said that no patients have missed a dose yet. But what sort of measures and strategies do you have in place to sort of mitigate any potential loss to follow-up data over the course of the next few months? Thanks so much.

Well, we've got our teams now are focused on staying in touch with investigators for not just our PKR program but for all of our trials as much as possible with our CRO partners. in terms of anticipating when patients are coming up to important study visits, when they may need to have a laboratory value. And so what we're doing is following the FDA and the EMA guidance in terms of taking any steps we can to capture all of that data. And then to document it, which I think is going to be one of the key factors. Like any trial, there's always missing data. And so our goal is to really go after key efficacy data, key safety data, and keep getting drug to patients as we've been able to do. I think there will be certainly the potential for us to have to evaluate how we would address missing data depending on how much it is and which data you're talking about, whether you do it through various sensitivity analyses that could be discussed with the authorities, et cetera. But at this point, the overall goal for us, and as best as we can tell, we've been pretty effective at keeping patients on treatment and getting the requisite data that we need to collect. I think one of the biggest impacts you heard from us on our prepared remarks in terms of the pandemic are aspects around accrual and then actually getting into sites to extract data out. So that's about, you know, I think, you know, Andrew's comment, the dynamic situation is constantly evolving. Some places are getting better, and the smoke is starting to clear a little bit, and other places we're still just working on a day-by-day, patient-by-patient, site-by-site basis.

Awesome. Thanks for taking our questions.

Thank you. Our next question comes from Peter Lawson with Barclays.

Hi, thanks for taking my questions. Just on tip server revenues, I wonder if you could provide any more detail around potentially off-label use you're seeing or increased off-label use and whether scripts are being written longer and any changes in inventory. That would be great. Thank you.

Darren? Yep, Darren here. So happy to talk about it. We limited insight into utilization in expanded indication or expanded disease settings. We are aware, though, of anecdotal use beyond AML, like cholangio, glioma, but can't give you an exact number at this point. In turn, I think the other part of your question was about inventory. Is that correct? Yes, that's right. Yes. I think maybe I can ship it to you, Andrew, or I can take it.

Sure. I'm happy to answer it. Yeah, so I think that's really just because of the shipping patterns, right? The quarter ended on, like, a Monday, Tuesday, and that's typically, you know, when we see shipments. And so we don't recognize revenue until units are received. So it's really just related to the vagaries of timing and shipping patterns. Great. Thank you.

And then just on the... Sorry.

I'm sorry. I was just going to say, I think maybe one thing to note is that, because I think it was sort of embedded in your question, is frankly the mix of the scripts hasn't changed very much from Q4 to Q1 in terms of the split between monotherapy as well as combination with azacitidine or hypomethylating agents in in AML. So I think that maybe is worth noting. We haven't seen an impact from the pandemic in terms of the general dynamics of how the drug's being used.

And maybe just to add, just something to note is that the key driver, the driver for growth in the quarter was a significant uptake in AML. That's been the main driver here.

Yeah. Gotcha. Thank you. Thanks for the clarity. And just on the Chinese sites that are reopening, how long did that take to come back online? When do you think that will be back fully online, and is that kind of a good model, do you think, for Europe and the U.S.?

When do we think the Chinese sites will all be coming back online? Well, it looks like that's happening now, and then I think that really one of the key factors for us is to look at screening rates because you've got to screen 100 patients to find 10 potentially eligible AML patients. Remember, they have to be IC ineligible as well. So that's probably the strongest predictor for us to start to get some insight in terms of how this is ramping back up and what the impact is on the overall accrual timeline. I can't emphasize that enough because you just have to think of that number. Approximately 30% of patients are IC ineligible. Then 10% of that 30% has an IDH1 mutation. And then some fraction of those patients are eligible for the trial. So that's why we really pay a lot of attention to the funnel, the number of patients who are being screened. And that's a function of how many patients are getting to the site. And one of the, I think, big impacts for for AML trials is that AML patients are at a relatively higher urgency of treatment in the oncology spectrum where just about everybody is pretty urgent. But if you think about a really busy hospital that is just overwhelmed and swamped with patients with COVID and dealing with that, enrolling a patient on a clinical trial versus giving them standard of care may be a decision you just have to make out of pragmatism.

Great. Thanks so much. Very much appreciate it.

Thank you. Our next question is from Chris Shibutani with Colin. Please go ahead.

Thank you and good morning. With mid-pivot at EHA in the thalassemia opportunity, can you just remind us whether or not we're going to see any information in the mid-May abstracts versus the presentation? And of the 13 patients that you'll have there, How many will be available with all the same markers, in particular for hemoglobin? Just a little bit more insight into what you'll be able to present. Thanks.

Well, we will have some data in the abstract, and that will certainly give you an opportunity to understand a little bit about that. Certainly, we'll have more information in the presentation. And what we plan on doing is presenting data for patients who have safety data, or all patients who've had at least one dose of drug. And then we'll present efficacy data in patients who've made it out to 12 weeks. So when we, at ASH, we spoke to eight patients, and since then we've enrolled a total of 20. And then our data cut will then dictate, and the duration of follow-up is how many patients get in with both alpha and thalassemia. It won't be the complete data set, and so then we'll follow up with that, but we would anticipate that we'd have a sizable portion of those patients that you'll be able to get a good sense of both efficacy and safety.

Got it. And then just to confirm with the sickle cell opportunity, I believe there were plans for 25 patients to be enrolled. Was that actually achieved, even if the NIH group has decided not to do the virtual presentation or the enrollments on target?

So the NIH study, Chris, has the opportunity to accrue up to 25 patients. And I think what they're going to ultimately, their sample size, is likely to be somewhere between probably between 15 and 25. They can evaluate 15 evaluable and stop, or they can go all the way up to 25. I think with the amendment now, up to 100 milligrams BID, they haven't told us what their exact plans are in terms of accrual, and I think the actual numbers are very much dependent on how soon they get open again.

Great. And then lastly, the 946, you're adding a sickle cell cohort. Give us a sense for how many patients that might be and maybe some sense where you tentatively believe we may be able to learn of those kinds of results.

No guidance on when we will be able to provide the results yet because that trial hasn't opened yet. It's being affected by the pandemic. And we're not ready to disclose the sample size. Some of that would depend on what we saw in the healthy volunteer part of the study. Great.

Thank you for all the program updates.

Yeah. Thank you. Our next question comes from Alethea Young with Cantor Fitzgerald.

Hey, guys. Thanks for taking my question, and hope everybody's doing well over there. Maybe a couple for me. One, can you just talk a little bit about, I'm sure it's certainly delayed, but just your conviction and focus on potentially talking to Bristol about IDFA. Another question I had is just, is there any potential opportunity as it relates to, you know, Benetoclax obviously being a little bit more difficult to administer, obviously, than your drugs and your medicines and IDH. Have you seen kind of being shifted in opportunity there? And then the third question is, around these two activate studies. It seems like at least my assumption was that the smaller one maybe was perhaps coming earlier than the bigger one. And I just wondered, is there any kind of sequencing color that you can provide in light of the update guidance today? Thanks.

Hi, Alicia. It's Jackie. So just on the Bristol IDFA question, IDFA continues to be strongly partnered with BMS Celgene under the 2010 and we continue to co-promote IDFA together in the U.S. I think things are going very well with that partnership, as they have for almost a decade. We understand from Bristol that, for now, they wish to retain their rights to lead on IDFA and maintain our relationship as it is. So we will continue to serve IDH2 patients with our partner, BMS.

And I can take up the – sorry, go ahead, Jackie.

Chris or Darren, I don't know who the next question should go to.

I can take up the second question, Jackie. So regarding venetoclax, as I mentioned in my remarks earlier, a number of treatment recommendations have been issued over the last month trying to provide guidance to the community about how to handle the treatment of AML patients. as the institutions and practices wrestle with the impact of COVID-19. Those treatment guidelines favor the use of oral treatments where possible in order to minimize patient visits to the practices, transplants, infusions, all that. So overall, orals are favored in this market for the circulation safety. Ideally, orals that offer significant efficacy and safety. Relative to venetoclax, I can't comment on their overall profile. I think what's important is that the physicians are taking into consideration the ease of administration, but also the ease of being able to manage the safety profile or AEs associated with the treatment as these patients are going to be more remote And I think those things all added together fare well for us in both the newly diagnosed patients as well as in the relapsed refractory patient setting.

I think I have a question.

Yeah. So, Aletheia, it's Chris here. The two trials, while they may have some overlapping sites, they're also being run at some sites independently. Some sites have only activate, some sites have only activate T, and some sites have both. So I can't provide you any guidance around sequencing in terms of how COVID may or may not impact sort of our ability to get in there, get the data out, et cetera. You know, our original guidance was that we would provide top-line data at the end of the year for both trials. And as I stated in my prepared remarks, COVID has impacted that, and we would be looking at when we release top-line data, it would be with both trials. So that hasn't changed. One other thing is, going back to Chris Yubitani from Cowens, In my prepared remarks, you asked a question around thalassemia. We actually, I said in my prepared remarks, we have 13 efficacy of out of the patients that we submitted in the abstract. So you'll see that.

All right, we'll continue. Ladies and gentlemen, As a reminder, in the interest of time, we ask that you please limit your questions to one. Before we proceed, please limit your questions to one. Our next question is from Michael Smith with Guggenheim.

Hey, guys. Thanks for taking my questions. I just had one on AG946. I know this... This backup molecule, so to speak, was designed to have, you know, less aromatase inhibition rather than to emit a pivot. But I was just wondering if there are any other characteristics that might be different, you know, thinking of potency or selectivity or anything that might, you know, I guess, improve characteristics even further for this molecule and how you think about positioning that longer term? both in hemoglobinopathies and also in PKD. And then the other question was really on Tipsovo. We've heard from other companies that there's been a little bit of warehousing in some cases of oral cancer drugs around the COVID-19 crisis early on. I'm just wondering if you've seen anything like that in your case as well. Thank you.

Okay, so... Mike, it's Chris Bowden here for 946. So while aromatase inhibition with mitopevat has not been a problem to date, it's something we continue to follow, and it is not inhibiting its development, and so we're able to take that molecule forward. At the same time, AG946 has several other attributes in addition to it not having off-target effects on aromatase that that could make it a better molecule. We think its pharmacokinetic properties may lend itself to once-daily dosing. It is more potent against wild type compared to midipivac. And in the realm of pyruvate kinase deficiency, it has some activity against some mutants that we've seen as being relatively non-responsive to midipivac. So it has the potential to be a better molecule from an efficacy perspective and convenience perspective across all indications, and it has the potential to have a broader spectrum of activity in pyruvate kinase deficiency. That said, I just want to emphasize that we can, and right now we're doing a lot of pivotal trials, execution with deactivates and PK deficiency, planning in thalassemia with metapivets. We have a lot of confidence in that molecule. I think, Darren, you've got the second part right.

Yes, I'll address the question regarding warehousing. So we've scoured our customers and our distributors to make sure that we've got the right insight on this particular question. And if you recall, we have a fairly narrow distribution channel, so it allows us to have greater oversight or insight into how the drugs logistically are being managed. So to answer your question, no, we don't have evidence of any stockpilings. And to add on to that, we've only heard of one or two instances where peer sought a more than one month fill for patient order. So we feel fairly confident that we don't have inventory stockpiling, either at the practice or institution or with patients.

Great. Thanks for taking my question. It was very helpful.

Thank you. Our next question is from Mohith Dansal with Citigroup. Great.

Thanks for taking my question. I hope everyone is staying safe. A couple of questions, if I may. One is, are you seeing any trends in terms of some doctors choosing TIPSO even over induction regimen, especially during pandemic? Asking from the point of view of elderly patients who may be otherwise eligible for induction. And then the second part of this is more for strategic. Should this DHO-DH deprioritization, should we take this as a signal of company now focusing more on the rare genetic diseases as the core franchise while deprioritizing hematology for the future programs? Thank you.

I was just going to hop in real quick on the strategic question, Darren, and then let you, because I think the strategic one is pretty fast. Sorry to interrupt you, Darren. The answer is no. I mean, I think we had, I don't think, but I know we had already planned to make a decision on next steps related to DHO-DH over the course of this year, and we came to that decision, you know, a little bit earlier than the year maybe than we had previously planned. And the treatment landscape for both normal Hodgkin's lymphoma, where we were studying the drug, as well as AML, have both significantly changed over time. And based on that, as compared to when we started this program, and as we said, just given the lengthy time to enroll patients, we decided that we would move that particular program program, you know, out from the portfolio and try to partner it. I personally think that if that drug ever sees the light of day, it's probably going to be in a combination regimen, and if that's the way forward for it, we'd rather do that potentially with a partner. So that's the latest to that. Darren, sorry.

With regard to your question, If you look at the treatment guidelines that I referred to earlier, both those issued by ASH and institutions that have been handling a disproportionate number of COVID cases, both will indicate that it's reasonable to consider less intensive treatment options for patients who otherwise may have been eligible to receive intensive chemotherapy 7 and 3. So Tepsovo would be one of those reasonable options for those patients, whether alone or in combination, as we're seeing the community do spontaneously. That said, I haven't received any antidotes that indicate that Tepsovo has been initiated in those treatments yet, but it's still somewhat early days.

Very helpful. Thank you.

Thank you. Our next question comes from Mark Breidenbach with Oppenheimer.

Hey, guys. Good morning, and thanks for fitting me in. A quick one probably for Chris on Activate and ActivateT. I'm wondering, since we're looking at a potential maybe six-month delay until top-line data from previous guidance, Are we going to see any difference in the follow-up times for the assessments of the endpoints in these trials versus what's specified in the original protocols? And specifically with regard to activate T, I'm wondering if, you know, this is the one that uses a transfusion dependence endpoint and not a hemoglobin response endpoint. I'm wondering if you can comment on how we'll be able to deconvolute any reductions in transfusions from drug versus patients simply avoiding going to the clinic as a result of the pandemic. Any thoughts you can give on that would be very helpful.

Yeah, okay. The first part is would we expect a delay and follow-up? And Can't say for sure at this point, but our view of this is that there are 27 patients in active AT, and so each one of them is extremely important. And so the one upside, if there is, for lack of a better term, is that you know where each and every patient is as opposed to, you know, a 10,000-patient cardiology trial where you just can't do that. So as best as we can tell, we're trying really hard to stay on top of assessments and patients getting their visits and staying in touch with the investigators. And then your question around did they miss a visit because of COVID, because their outpatient clinic or their clinic, however, their physician or group was prioritized in other directions. we will be able to capture that and then we'll have to see what that looks like and for how many patients were actually affected in terms of analyzing that data.

Okay, that's helpful. Thank you.

The only other thing I would add, and this just goes with some of the higher level things we've been saying, you know, we and other companies now developed case report forms to be able to capture COVID-related events and then documenting is really important. And so when the dust clears from this, that will be a key aspect in terms of describing your results. And if you look at the guidelines from the agencies, they provide a lot of input on how we should be thinking about this. And we are spending a lot of time tracking it. And we're also talking with lots of other companies in terms of how we're doing it. And we, in fact, have had some companies, including us, are having interactions with FDA and IRB. So it's a very active area. I think it's a really important point that you raise.

Thank you. Thank you. Our next question comes from Kenan McKay with RBC Capital Markets.

Hi. Thanks for taking the question, and congrats on the Q1 progress and execution despite the pandemic. My question is on Medipivet. I was wondering why the dosing strategy for sickle cell disease was different from beta thalassemia to begin with, and hoping you could give us some color behind the clinician's decision to escalate the dose in Medipivet SCD, what that was based on. And secondarily on SCD, with all the moving pieces of the new dosing strategy and the pause in enrollment and pulling the presentation from EHA, now you'll be making the go, no-go decision before any of this data is publicly presented at ASH in December. So really hoping that you could help us understand what's needed to be seen to go forward in SCD, if that's similar to Betafil, where 80% to 90% of patients need to achieve a one gram per deciliter hemoglobin response, or if not, really what you're focused on and your level of confidence around achieving that proof of concept. Thanks so much.

Yeah. Hey, Ken, this is Chris. As per one of the earlier questions from Tyler, we had been discussing all of our data with Medipivac in both pyruvate kinase deficiency and and thalassemia in our overall plans as the NIH was putting their trial together. And as they were thinking about how long they wanted to treat patients, their first experience of a PKR activator in patients with sickle cell disease, they landed mostly based, I think, on our dry PK range of dosing that we were studying of 5 to 50 milligrams. And from the get-go, given that this was a trial that they were taking into patients for the first time, I think it was pretty clear. And if you've had any interactions with the NIH, that's a hotbed of clinical research, and they bring a lot of flexibility of thought into their studies. So as we've been going forward in terms of looking at their data and looking at our thalassemia data, they took the decision to escalate, add that amendment to 100 milligrams. They are the sponsor of the trial, so ultimately they make those decisions. And initially they wanted to study three doses and then recently decided to add the 100 milligram dose after the 50 milligram dose. And we're very supportive of that. Much like at ASH, we declared proof of concept on the basis of eight patients' worth of data with a top-line release. And now we're going to show a much more detailed data set for the first time at EHA. So this is operating somewhat in the same way. I think then the issue is that's on everyone's mind is how do you determine proof of concept? And it really comes back to what does the totality of data look like in terms of the two potential endpoints that you can think about in sickle cell disease, addressing the anemia, hemolytic anemia, and hemolysis, and the untoward effects of that, as well as what do you see with 2,3-DPG and sickling curves, and how does that help you think about could you potentially address these occlusive crises. The other really important aspect that we'll need to look at, albeit it will be a relatively small number of patients, is safety. So it's going to be those factors we'll look at, we'll analyze the data, and we're confident that we're going to be able to decide whether we can move forward into the next phases of clinical development by the middle of the year.

Thank you very much. I appreciate it. Just to sort of reiterate some of your last question, I think the other point is that You know, just because, you know, you may not see the data, you know, it's an open-label study and we see the data with the NIH, so we'll be able to make that proof-of-concept decision based on the data.

Thank you so much. Next question is from George Farmer with BMO Capital Markets.

Hi. Good morning. Thanks for taking my questions. Regarding MediPivot, just wondering if you have any experience at this 100-meg dose, if you could remind us what the safety profile looks like. And then also maybe, Darren, could you comment on what you see the impact of the metaclass studies, the phase threes with low-dose IRC and hypomethylating agents? How do you see the results having any impact on KeepSovo? penetration in AML?

The way it's Chris here, the 100 milligram safety or the 100 milligram experience is really derived from several sources. Our first experience with the drug was in healthy volunteers, and we studied a range of doses from 15 milligrams BID up to 700 milligrams BID. out for a total of 14 days of dosing. And that's still an important data set in terms of reference for us. And then in DRIVE-PK, recall that approximately 25 patients were randomized to a starting dose of 300 milligrams. And then over the course of the trial, for various reasons, we deescalated a number of those patients. So we have an experience above 100 milligrams in a group of patients. And then in the salicemia study, patients escalate at six weeks up to 100 milligrams. So we have an ongoing experience there. So overall, from what we've seen so far, we think this is certainly in the range from a tolerability perspective.

So Darren here, I'll address the venetoclax question. So, as you know, the Venn LDAC study was negative. There wasn't a tremendous amount of LDAC use in the newly diagnosed patients in the U.S., so we don't expect too great an impact there. Regarding the Valley study with a combination with HMA, we also think there will be fairly modest impact there. If you remember our then has been available for some time now in the setting. It's established in the patient profiles that physicians think best use. This additional study would perhaps confirm their use there. But remember, our frontline strategy has been focused on those patients who've been previously exposed to an HMA for an antecedent disorder like MDS. And our most recent market research, which is post- the disclosure of the VIOLA study, continues to show that we are the most preferred regimen for IDH1 positive patients in the newly diagnosed setting as well as in the relapse setting. And then we'll look forward to the results of the Agile study, which will be the more exhaustive evaluation of Ivo plus HMA. I'd also just remind us that the About half the use of Tepsilvo in the frontline setting is already in combination with HMA. And same goes, actually, for use in the first relapse setting, also in combination with HMA, though we don't promote to it.

Great. Thanks very much.

Thank you. Our next question is from Andrew Behrens with SBB.

Thanks. Just to follow up on sickle cell, since I know you guys were making the go-no-go decision before we see the data, are there actually going to be any formal quality of life metrics or an impact on basal occlusive crises that will be part of your decision, or is this going to be strictly made based on surrogate biomarkers? And then how should we think about the next-gen PKR drug in this decision, since the gaps between these two assets may be narrowing? And then also just some comments on the profile of the drug, how it should possibly fit into the sickle cell treatment paradigm in regards to the new drugs that have been approved or in development.

Yeah, so we're not collecting quality of life data. It's an open-label, single-arm study across a number of dose ranges. and we are definitely collecting safety data, and if patients have adverse events of any kind, including vaso-occlusive crises, we will capture all of that. The interpretation of that either way has to be looked at from the perspective of you don't have a control, and you might take some conclusions away if If you look at the patient's prior VOC history, depending on how accurate that is. So we'll be looking at that data mostly from a safety perspective, VOCs that is. So the majority of our decision-making, when I say the totality of efficacy data, it's around hemoglobin laboratory data, secondary markers of chronic hemolysis. Are we addressing that? LDH, bilirubin, reticular site counts. Are they going in the right direction? And then the pharmacodynamic data set that would be informative around thinking about are you impacting the shape and the sickling propensity of the red cell. With regards to 946, it's really too early to talk about the positioning of that molecule because we're devoting our energy to thinking about developing mid-PIVAT potentially in sickle cell disease, thalassemia, and other indications. And that drug's got to demonstrate that it's safe and does what we hope it will do. So let's cross that bridge, and then we'll be able to start thinking about where it might fit into the overall armamentarium in terms of PKR activation broadly. And then lastly, how would a drug like Minipivat, if we thought it was a compelling drug development opportunity in sickle cell, where would it fit? And, well, depending on the data that we see from the NIH, we could see it as potentially addressing both aspects of the disease that affect patients. Anemia and raising hemoglobin and hopefully making them feel better and reducing vaso-occlusive crises would also be a win, as well as just reducing the overall inflammation that's associated with chronic hemolysis, which we think could be a very an outcome of the drug that could be associated with clinical benefit. At the same time, at the entry of global blood and the Novartis molecule that reduced VOCs, it's crowded, so we'll have to, or I'd say it's somewhat crowded, so we'll have to think very carefully about the patient populations that we go into, and that's going to be the next order of business if we feel like we have proof of concept from this NIH study.

Great. Thanks for all the color. Appreciate it.

Thank you. And our last question is from John Newman with Canaccord.

Hey, guys. Good morning. Thanks for taking my question. It's a quick one. Just on Tibsovo, I just wondered if you've seen an uptick in prescriptions via mail order, given the drug is oral and should be easier for people to take. Just wondered if you're seeing that on your site.

Darren here. So if you recall our overall distribution strategy, about a third of our of our drug is distributed via specialty pharmacy, two specialty pharmacies in particular. So we know that largely those are going to be mail order. And a fair portion of the balance of our drug is distributed via mail order but through institutions or dispensed via SPs that are owned by fairly large practices. So the orientation of our overall distribution strategy works well in a setting like this where patients may be more reticent to go to the institution pharmacy to obtain their treatment. And we've emphasized for institutions that we have flexibility to help those that aren't able to ship drug through their mail-order pharmacy, that they'll be able to access our specialty pharmacy channels to be able to do so as well. Okay, great. Thank you.

Thank you. And this concludes the Q&A session. I would like to turn the call back to Jackie Faust for her closing remarks.

Thank you, Operator. Thanks again, everybody, for joining us today. I want to just reiterate that despite the challenges and uncertainties that lay before us as the pandemic continues to play out, I remain incredibly excited about the progress we've made across all of our three focus areas so far this year. I'm very proud of the OJOS team. And to close, I just want to thank all of the brave healthcare and essential workers who are on the front lines of the COVID-19 pandemic. We should all think of them every day and what they're doing for all of us. As always, I would also like to thank the tremendous employees at Agios for their dedication and passion in making a difference for our patients. And lastly, I would like to thank all of the patients, caregivers, and physicians who participate in our clinical trials. Without them, we could not do what we do today. and they also are navigating through this difficult moment with a lot of courage and commitment. Thank you again, and we look forward to speaking with you soon. Take care, everybody.

And with that, ladies and gentlemen, we thank you for your participation in today's program, and you may now disconnect. Thank you.