Good morning, and welcome to Agios' Third Quarter 2021 Conference Call. At this time, all participants are in a listen-only mode. There will be a question-and-answer session at the end. Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Holly Manning, Senior Director of Investor Relations.

Thank you, operator. Good morning, everyone, and welcome to Agios' Third Quarter 2021 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. Sarah Gowen, our Chief Medical Officer; Darrin Miles, our Chief Commercial Officer; Jonathan Biller, our Chief Financial Officer and Head of Legal and Corporate Affairs; and Dr. Bruce Car, our Chief Scientific Officer, who 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 our most recent filings with the SEC and any other future filings that we may make with the SEC. With that, I will turn the call over to Jack.

Thanks, Holly. Good morning, everyone, and thanks for joining our third quarter 2021 results call. Strong goal and operational execution continued at Agios. With our NDA and MAA filings on track, our commercial team is focused on launch preparations for mitapivat which has the potential to service the first disease-modifying therapy for pyruvate kinase deficiency. Our patient support infrastructure is in place. Our field team of sales representatives and nurse clinical educators are fully engaged with health care providers and our disease education efforts continue to accelerate. We are also working diligently on start-up activities for three pivotal studies in thalassemia and sickle cell disease, all of which we expect to initiate by the end of 2021. These trials underscore the potential of mitapivat to serve as a pipeline within a single drug and an important new treatment option for people with these underserved, profoundly challenging lifelong hemolytic anemias. Beyond mitapivat, we continue to advance our earlier-stage clinical and R&D efforts to build sustainable future growth potential based on our leading expertise PK activation and cellular metabolism, all within our core focus on genetically-defined diseases. We look forward to this year's American Society of Hematology Annual Meeting, where we will be presenting new data across our clinical programs, including important updates in sickle cell disease, thalassemia and PK deficiency. On November 17, we plan to host an Investor Day to share exciting updates on our research and development pipeline and provide further insights into our commercial launch strategy and expectations for mitapivat in PK deficiency. As we look to the end of the year and 2022, Agios is extremely well positioned to enter our next phase of growth with our first genetically defined disease commercial launch on the horizon, three pivotal adult trials, two pivotal pediatric PK deficiency trials and a robust pipeline filled with optionality and possibility. With that, I will now turn the call over to Sarah to walk through our clinical development programs in more detail. Sarah, welcome to your first quarterly results call as our Agios CFO.

Thanks, Jackie. We are extremely excited about the potential we have to impact the lives of individuals with genetically defined diseases, beginning with mitapivat for PK deficiency and other hemolytic anemias with significant unmet medical need. As I will discuss, we continue the momentum across all of our clinical programs in the third quarter. In PK efficiency, we continue to work with regulators in the U.S. and EU as they conduct their reviews of our regulatory submissions for mitapivat. We are encouraged by the positive engagement. And consistent with the review process, we are currently replying to questions from both the U.S. and EU regulators. As the FDA granted priority review to our new drug application, we remain on track for the February 17 PDUFA date. Based on the dialogue to date, we are currently not expecting an advisory committing. In the EU, as expected for the procedure, we received the questions from the Raptor and the critical assessment of those by the corrector. Our marketing authorization application remains on track for potential approval in the second half of 2022. These filings include data from the ACTIVATE and ACTIVATE-T Phase III studies in non-regularly transfused and regularly transfused adults with PK deficiency which both met their primary endpoints as well as important secondary endpoints and patient-reported outcomes as well as supportive data from the two ongoing extension studies. The data package underscores the potential of mitapivat to serve as the first therapy for the full spectrum of PK deficiency patients. We expect to share a longer-term extension data in PK deficiency at ASH in December and look forward to ASH abstracts going online tomorrow. We also remain on track to initiate the pediatric clinical program in PK deficiency in 2022. Moving to thalassemia, our two global placebo-controlled pivotal trials of…

Thank you, Sarah. With approximately four months to go before our U.S. product approval and launch I'm very pleased with our progress with respect to the pre-approval disease education, patient to physician profiling and overall launch readiness. The third quarter was our first with a full complement of the customer-facing teams in place, including sales representatives, clinical nurse educators and patient support managers. We ramped up personal and digital disease education activities, including live health care provider education programming and patient-focused seminars. Over the quarter, we accelerated physician and patient profiling and validation and continue to narrow down our physician target list to what we anticipate will be about 2,600 physicians. In the process of profiling, the field team has confirmed what we saw in our most recent quantitative market research, which is that the target physicians currently actively manage three to five hemolytic anemia patients of unknown most of whom are likely eligible for genetic testing via in an attempt to help them reach a definitive diagnosis of their hemolytic anemia, including potentially PK deficiency. Among those physicians profiles who were confirmed to currently treat PK deficiency many have one to two confirmed PK deficiency patients diagnosed and under management. Additionally, the recent approval of the new ICD-10 code for PK deficiency, we expect to be able to further refine targeting efforts to find previously diagnosed patients with PK deficiency. Our sales team referred to as hemolytic anemia specialists and clinical nurse educators are also educating practices on the availability of anemia ID and answering questions about the service. In the third quarter, we observed the largest quarter-over-quarter increase in requests for ID since the launch of the program in December. This reflects both the impact of our educational efforts and the community's eagerness to identify their patient's hemolytic…

Thanks, Darrin. Our third quarter 2021 financial results can be found in the press release we issued this morning, which I will summarize. More detail will be included in our 10-Q filing later today. As a reminder, our third quarter financial results discussion only includes our continuing operations on a comparative basis, which excludes results from our divested oncology business. Research and development expenses for the third quarter were $64 million, an increase of approximately $12 million compared to the third quarter of 2020. The year-over-year increase in R&D was driven primarily by start-up costs associated with the Phase III studies of mitapivat, thalassemia and sickle cell disease and our disease education and engagement efforts for mitapivat and PK deficiency, ,thalassemia and sickle cell disease. Selling, general and administrative expenses were $27.2 million for the third quarter compared to $28.3 million in the third quarter of 2020. We also recorded $2 million in TIBSOVO income from royalties in the third quarter of 2021, which is included within the gain on sale of oncology business line item in our income statement. We ended the quarter with cash, cash equivalents and marketable securities of approximately $1.4 billion. With this cash balance, we expect to be able to execute our current operating plan through major catalysts into cash flow positivity without the need to raise additional equity. In Q3, we repurchased approximately 5.3 million shares for $254 million representing an average price per share of $47.94. Since commencing share repurchases through the third quarter, we have completed approximately $783 million or just under 2/3 of the $1.2 billion share repurchases authorized by our Board of Directors. The face of our 10-Q also reflects repurchases from September 30 and to the date of the file 10-Q and shows a total year-to-date share count reduction of more than 16 million shares or just over 23% of our starting share count and a total spend of just over $800 million. Given the substantial progress we have made in the first six months of our repurchase program and the potential for alternative investment opportunities we are seeing, we have paused share repurchases. This strategy will allow us to allocate additional capital to accelerate programs in our pipeline and/or complementary business development opportunities that could arise. We continue to have the optionality to repurchase shares within our remaining authorization. As Jackie and Sarah have mentioned at our Investor Day on November 17, we look forward to updating investors on the progress we have made with our internal pipeline efforts and some new investment opportunities we see with our internally discovered drugs. With that, operator, please open the line for questions.

Our first question is from John Newman with Canaccord Genuity. Your line is open.

Hi, guys. Good morning. Thank you very much for taking my question. The question is on the mitapivat Phase III study in sickle cell disease. I'm just curious, first question is, are the endpoints, co-primary endpoints? And the second question is, are you looking to enroll patients at baseline that have a minimum number of pain crises for that Phase III study.

Thanks for your question. So the answer to -- so this is Sara the new CMO. So for the first question around the Phase III and the endpoints, the primary endpoint, so there are two separate primary endpoints. And that is a very deliberate design with an alpha split over the two primary endpoints that allows us to move on to secondary endpoint testing if we get on one or both primary endpoints. And the endpoints are the hemoglobin response and an analyzed rate of sickle cell pain crises. And then to the second question, yes, so we do the inclusion criteria, there is a requirement for patients to have at least 2 up to 10 pain crisis in the year prior to enrollment.

Our next question comes from Alethia Young with Cantor Fitzgerald. Your line is open.

Hi guys. Thanks for taking my question. I was just curious about kind of the sickle cell pivotal. And are you allowing hydroxyurea in combination? And do you think it would work well mitapivat? Thank you.

Yes, sure. So we do allow hydroxyurea into the trial. We actually have generated data in sickle cell disease patients who have been taking hydroxyurea while being exposed to mitapivat. And so the way we address that is by a stratification on hydroxyurea in the clinical trial.

And did you see any different effect with hydro there versus not?

What the question?

Any difference in the fact when mitapivat was combined versus not?

No. And that is too early to tell, right? So that would be something that we would be looking to look at in a subgroup analysis at the end of Phase III.

Our next question comes from Kennen McKay with RBC Capital Markets. Your line is open.

Hi guys. Thanks very much for taking question. Can you talk maybe to your current thinking on the incidence and prevalence of pyruvate kinase deficiency based on your ongoing patient monitoring and patient identification efforts from the PK deficiency natural history study or your Peak Registry. And maybe for Darrin, as we get closer to launch and these efforts are intensifying. Just wondering how those prevalence estimates have sort of evolved over time or change over time. Thank you.

Sure. It's Darrin. The -- it's still early days, right? So we've guided to a prevalence number between 3,000 to 8,000 between the U.S. and the five EU. So assume somewhere between $1,500 to $4,000 in the U.S. The -- we're still in the early days, obviously, of patient finding, and we know that that'll continue to grow leading to the launch which should accelerate even further once we get through the approval. So right now for our planning purposes, we stay within that range. We assume that we're somewhere around 3,000 is what we do our planning around. But that we'll be able to confirm that as we move forward. Something that's going to be helpful moving forward is the adoption of the newly approved IC-10 for PK deficiency. But that was just recently approved. And so it will take a while before we see that universally employed by the community.

Our next question comes from Anupam Rama with JPMorgan. Your line is open.

Hey, guys. Thanks so much for taking question. I know that the AG-946 Healthy Val data presented at ASH, I think this trial had an optional sickle cell cohort. There have been some additional indications outlined in the slides today. What are next steps for this program? And will we maybe get a better sense of that at R&D Day in a couple of weeks? Thanks so much.

So indeed, you will be seeing more on the AG-946 development programs at the Investor Day on November 17. So right now, it's indeed in a healthy volunteer portion with a second part to the clinical trial that is focused on sickle cell disease. And we're excited about that because it will allow us to generate data in the context of hemolytic anemias. And then we have a lot of optionality based on that, so looking forward to discuss more with you on November 17.

Our next question comes from Ram with Cowen and Company. Your line is open.

Thanks for taking my question. Maybe just a little bit of follow-up on patient prevalence work that Darrin's has been doing. What -- can you give some idea of the NemID test results, are they tracking in line with the experience? So I think in the very early days, you said they were, but it was early. So I'm curious to see if that's being maintained? And then maybe could you also quantify when you say that the volumes of demand for those tests has increased the greatest Q-over-Q in Q3. Can you maybe quantify that versus the first half? I mean did you see as many volume -- as many tests in Q3 as all of the first half or something smaller or something bigger than that?

There's a lot in there, but it's good question, all right. So, as I mentioned in my prepared remarks, we did see a very significant uptick in requests for the tests in Q3, and that's in large part related to looking also growing momentum. But also, so first of all, for that we've had the field, field team in place, right. So they've been helping to educate the practices, the practices, and agencies as well, we like to order the test. So I think we're just shy of about 2000 tests by the end of Q3. In terms of what we're seeing, in terms of the results, I expected it to fluctuate right, particularly as the volume of test results, as requested in the results, our tests are conducted, and then the results are reported. And there is a meaningful material difference between what we the setting in which the Spanish study was conducted, which is a controlled study setting, versus the old comer type experience that we have in the in the U.S., but we're the testing in the U.S., allows physicians to be able to look at the host of potential explanations for the patient's hemolytic anemia. So in the Spanish experience, we saw about 20%. We expected it to be lower, but we didn't know exactly what that would mean. So I would say 20% continues to be the upper end of the range. I think it would be misleading I think to tell you exactly where we are today, because I would love to be able to see this further adopted more uniformly across the country have very strong pockets of utilization, I'd like to be able to see it used more broadly. And I'd like to see us have more confirmed tests come through before we start reporting retail on what we're observing there.

Our next question comes from Mike King with H.C. Wainwright. Your line is open.

Hi guys. Good morning. Thanks for taking question and congrats on the progress. A lot of people have addressed my questions about the market perhaps. So I think I'll maybe shift to understanding reimbursement, Darrin, can you -- Maybe talk about your expectations regarding what proportion of patients you think will be covered by private pay versus either Medicare or Medicaid? And what requirements you guys are going to have to have to attain the reimbursement that you would expect for mitapivat in PKD?

Sure, sure. No, I put all this work is preparing to be able to provide that information to you at the Investor Day later this month, but I'll give you a preview now. So we expect that it's -- that the -- what we'll observe for PKD is reflective of what we would observe for the overall U.S. population. So about 55% or so of patients, we expect 55% to 60% should be commercial, just about even split 15% or so, Medicare, 50% Medicaid and then the balance number of other DOD and cash. The -- what we are -- what we can expect is that is that you're going to have a ramp right so you will have complete formulary coverage for patients, particularly commercial patients. That will, in large part, dependent on when commercial payers are going to hold their P&T committee meetings, which are on the right? So that will take time to be able to get to universal coverage there. Medicaid and Medicare usually lag So that may be a little slower than commercial. In terms of what payers need from us. I think the thing that's been pretty clear. And at this point now, we've had a host of one-on-one discussions with individual payers and a fair amount of research on this at this point. If we're successful in making -- in establishing a firm understanding of the natural history of the disease the long-term morbidities and complications associated with PKD, then the unmet need, the severity of the disease, regardless of transfusion history is pretty well accepted and understood by the community, right? Once we make the story. And so then -- and the clinical data, right? So the safety efficacy data are pretty clear and compelling. So there's a little of convincing you have to do there. You just have to make sure people have a good understanding of it. Once you have that, then we expect a fairly favorable access which you'll have differences based on individual patients in benefit designs. But we would expect pretty good access. The key will come down to what the label looks like at the end of the day and what price we choose, right, to make sure that we're sort of optimizing the business opportunity, but making sure that we're also optimizing the ability for all patients to be able to access the treatment as their physician here is appropriate.

If I might just ask a quick follow-up. Are you guys anticipating a single point of contact for the genetic testing versus genetic testing versus actually getting patients enrolled on to mitapivat therapy? Or what I would hate to see is you've got confusion, either with access to the genetic testing and the transfer over to actually a physician writing a script for that patient? How is that process going to be managed?

Well, the -- so PerkinElmer, right, is the partner that we work with to provide the genetic test, right? And not every patient is going to necessarily get a genetic test, right? So commonly used test will be the enzyme -- with enzyme assay, right? The genetic test is helpful and can be this confirmatory there, right? So they're not limited to using our -- the tool that we support. Now what we are intending to do is to have a mandated hub, right? So for every script that is written the physicians will submit the script to go to myAgios, right, our patient support service, and patients then will opt in to the service accordingly, right? So that will give us the opportunity then to ensure that the appropriate confirmation of the patient diagnosis is in place helping them with supporting their engagement with payers and then be able to engage with the patients and the practices on all the appropriate disease education, connecting them with other patients in the PKD community, things along those lines and provide sort of surround some in terms of adherence support for the patient as well. So the physicians are limited to go back to your central question, the patients -- the physicians are limited only to our -- the genetic tests that we provide -- But we -- but through the prescription and then fulfillment process, right, we're able to provide a seamless service to ensure the patient is able to get on treatment successfully. And it gives us the best line of sight to individual patients

Our next question comes from Mark Breidenbach with Oppenheimer. Your line is open.

Good morning and thanks for taking the question. This is probably a follow-up to Anupam's earlier question. It's probably directed to Sarah regarding AG-946. I was just wondering kind of what factors are leading to the decision to first put 946 into a sickle cell cohort as opposed to some of the other hemolytic anemias? And also, I'm wondering if you're seeing any pharmacodynamic thresholds that 946 needs to clear in healthy volunteers to justify continued development in terms of two, three DPG reduction and maybe ATP increases, things like that. What would you kind of see as a best case scenario from the healthy volunteer data.

Okay. Great. So the current protocol, the way it is set up is it generates -- it's a very typical single ascending dose, multiple ascending dose study in healthy volunteers. And we're, of course, looking for pharmacodynamic engagement within that group and looking to max out and also generate appropriate safety data, which is like very classical Phase I type work. And then the protocol is set up with certain decisions around the pharmacodynamic engagement observed in healthy volunteers to move forward with the proper doses in the 946 sickle cell disease component of the trial. In regards to what why sickle cell, the sickle cell disease, clearly, there is a huge unmet medical need, and we're looking to further advance multiple therapies there for those patients. However, as with any development after any phase of clinical development, there will be go, no-go decisions to decide what is the best path forward for a specific molecule. Regardless -- despite -- it generates data for sickle cell disease, but because we're looking for hemolytic anemia and also what we've observed in the top about across different hemolytic anemias, we are looking at that data as generating optionality for the rest of the decision-making across different indications.

Our next question comes from Salveen Richter, Goldman Sachs. Your line is open.

This is Elizabeth on for Salveen. So as you start thinking about the pediatric population in PKD with the pivotal study set to initiate next year, we wanted to get your thoughts on how patient identification efforts for pediatrics could differ versus the older patients? And are there any particular differences that you would highlight here?

Well, so right now, of course, the patient identification is focused on the feasibility of the clinical trial. So we have taken a very standard approach while engaging with sites to understand how many patients they have, how many patients would fit into the eligibility criteria of the clinical trials for pediatric development. And so that is the phase where we're currently at with our pediatric plan. And so we're very much looking forward to initiate those studies in 2022.

And maybe just at the efforts that we're currently employing to support patient identification or patient profiling in the community is limited to adults, right? So we're also coming across pediatric patients as we engage with the individual practices. And so we're maintaining sort of inventory of that as we collect more market information.

Our next question comes from Andrew Berens with SVB Leerink. Your line is open.

A couple for me. Just want to clarify the planned disposition of the remaining $1.2 billion in cash that was allocated for share repurchases. You've used about 2/3 to date, and it did sound in your prepared comments as if there was some flexibility with the remaining 1/3. Is there a possibility you may allocate that to external BD activities? Or are you committed to repurchasing shares? If it's the latter, just some idea of what the timing will be. Should we expect a similar cadence as what we've seen over the last 12 months. And then just a comment on 946. Since it's going to be tested in sickle cell, are you still planning to advance mitapivat in sickle cell disease and how far behind the 946 if that becomes a lead candidate for sickle cell disease.

Okay. This is Jonathan, and I'll start with the share repurchase question. So what we've decided to, given the progress we've made repurchased now to date, just over 16 million shares, reducing our starting share count by a little over 23% and seeing observing some opportunities in our internal programs to potentially accelerate them as well as just looking at the external BD landscape and seeing valuations coming down fairly significantly over the last -- most of this year, that there could be a possibility for a higher likelihood of finding executable complementary BD opportunities. We've paused share repurchases. So we still retain the optionality. We have a 10b-18 plan in place, so we can repurchase shares. But right now, our priority for capital allocation of that remaining 2/3 would be opportunities to accelerate our pipeline and to do some -- the remaining 1/3 -- I'm sorry, 1/3 of our should repurchase the $400 million. So that's where we are now. There's no set timing on when we may or may not repurchase additional shares and it will be a balancing act of seeing what opportunities we have internally and potentially with BD. And as that plays out, we'll make determinations on to -- with respect to how much, if any, of the additional authorization that we'll execute.

And then to your last question around mitapivat in sickle cell disease development, we're super excited about continuing to progress. We talk about through the proper clinical development

Andy, it's Jackie. -- nobody's asked me a question. Yes, so I'm getting -- I'm not feeling neglected. So I'm going to jump in. So thank you for asking your two questions. I just also want to point out that after we close the oncology divestiture with Serie and then we brought those funds in end of March, we were always flexible in terms of how we were going to think about our capital allocation. But what we knew at the time was that we were in a unique situation given our -- where we were in terms of the Agios life cycle and having undertaken was a relatively large transaction for a company of our size. And given the amount of capital that we had raised over our history, our initial priority, and that's where we had the $1.2 million share authorization was to kind of what I call reset our capital structure by giving some of that back to our shareholders, which we now have done, and I think very happy with the execution that we've done on that roughly $800 million or so over the last month. And so we continue to have that additional $400 million of authorization. At the same time, our teams have made significant progress with some of our internal programs over the course of 2021 and now we see some opportunities that we'll talk about on November 17 to make incremental investments in our internal assets and programs to move some things along, where now we have the evidence support the logic for moving them along and advancing them and adding those investments to our plan that weren't necessarily there in the past. And then as Jonathan said, we also have greater clarity in terms of our internal thinking, I would say, around the potential opportunity set in the BD arena. So there are different ways, as you know, to deploy your capital over time. And we're always going to toggle between those in different ways. But in the short term, we wanted to make a clear statement on the share count reduction with the return of capital, and now we're just going to be a little bit more flexible in terms of how we look at those different opportunities. And then the last thing I just wanted to say is on 946, I can remember this from a year or even maybe more ago, we knew, as Sarah said, that we wanted to generate some data in a, given hemolytic anemia. And at the time that we were moving forward with the healthy volunteer study, sickle cell disease seems to be the most logical one to add to that protocol to get some early data in a given hemolytic anemia disease. And I think you'll hear on November 17, some other rates that we have for AG-946, and I will leave it at that. Thank you for your questions.

Great. And just a follow-up, Jackie, how many BD people do you guys have now?

Well, it depends on how you look at it. So we have two or three dedicated people, but then we've also got kind of leaders within each functional area that contribute to the efforts. So when we're looking at something. So there would be somebody in Bruce's shop who contributes to looking at assets, there will be somebody in Serashops who contribute to Linkings also, of course, Bruce's team is generating ideas for complementary types of mechanisms or targets that we would want to be looking at and then we've got a small BD -- small but mighty BD team out there canvassing the landscape.

Okay. And then just on 946, if you do pivot in sickle cell and 946, how far behind mitapivat would you estimate you are?

So just to be clear, we're not anticipating that we're going to pivot to 946. We're moving fast and furiously with the mitapivat. There's a chance that non-anticcell one day is a complementary asset in portfolio, it's as likely that we see some data for 946 in sickle cell disease that tells us something about how the product is performing in a given hemolytic anemia, and then we have the healthy volunteer data. And there are then maybe other indications that we would feel comfortable moving even faster into based on the totality of what we've seen across the class of PKR activators and all of the work that we've done and 946 specifically.

Our next question comes from Danielle Brill with Raymond James. Your line is open.

I guess a couple on the sickle cell and thalassemia trials. I know you're excluding patients who are in active voxelator DBO, but will you permit enrollment of patients with prior exposures to those drugs. And then similarly for the Energized Trials, are you permitting enrollment of patients who had prior treatment with luspatercept

So yes and yes is the answer. So we are allowing patients to have been exposed to those prior therapies and then have a proper washout period before enrolling into our trial. And then the same for the thalassemia trials in which priority exposure is allowed. And then I mentioned earlier, hydroxyurea for the sickle cell disease trial is allowed as a concomitant medication.

Just a quick follow-up. So obviously, your mechanism is different, but is there any criteria around whether those patients had to be responders to the prior treatments or not?

No, there is not.

And I'm currently showing no further question at this time. I'd like to turn the call back over to Jackie Fouse for closing remarks.

Thank you, operator, and thank you, everyone, for the questions this morning. We look forward to an exciting time ahead with the February 17, 2022 PDUFA date coming up for mitapivat in PK deficiency in the U.S. We're also looking forward to the ongoing MAA review for same indication in Europe, the initiation of three pivotal studies by year-end across thalassemia and sickle cell disease in adult patients, the initiation of pediatric PK deficiency clinical program in 2022, an Investor Day on November and multiple upcoming data presentations at ASH. So you can see we have a lot going on. As always, I would like to thank my Agios colleagues for their dedication and passion for making a difference for patients. I also want to thank all the patients, caregivers and physicians who partner with us in many ways and especially those participating in our mitapivat clinical trials across indications. Thank you again for joining us today. You may now disconnect. See you soon.

This concludes today's conference call. Thank you for participating. You may now disconnect.