Good morning, and welcome to Agios' First 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' First 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.

Chris Bowden, our Chief Medical Officer; Daren Miles, our Chief Commercial Officer; and Jonathan Biller, our Chief Financial Officer and Head of Legal and Corporate Affairs. 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 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 Jackie..

Thank you, Holly. Good morning, everyone, and thanks for joining our first quarter 2021 results call. The first three months of this year were extremely productive.

We closed the sale of our Oncology business, accelerated our late-stage clinical programs for mitapivat and prepared for our first regulatory filings and subsequent commercial launch in pyruvate kinase deficiency.

Back in December, we announced our strategy to focus on genetically defined diseases, including accelerating and unlocking the full potential of mitapivat across its three initial indications in hemolytic anemias as well as leveraging our overall expertise in PK activation and our other research programs.

To enable this focus, we also announced the decision to sell our oncology programs to Servier to facilitate and fund this strategy. Since that time, nearly a third of our organization has been actively involved in the important and complex process of ensuring a smooth transition of our assets and people to Servier.

The transaction was approved by Agios shareholders on March 25, and on April 1st, we announced the closing of the sale.

To each and every oncology employee who helped create truly meaningful differentiated therapies for patients over the past decade, we are grateful for your impassioned work at Agios, and we look forward to watching these programs is with Servier.

As we look ahead, Agios is poised for a bright and focused future that will build on the important progress we are making now in Q2.

This includes finalizing our global regulatory filings for mitapivat and pyruvate kinase deficiency; preparing to initiate two Phase III trials of mitapivat in thalassemia and a Phase II/III trial of mitapivat in sickle cell disease..

hydrovane kinase deficiency, thalassemia and sickle cell disease. In pyruvate kinase deficiency, we reported top line data from the ACTIVATE and ACTIVATE-T Phase III studies, evaluating mitapivat in adults with pyruvate kinase deficiency who are not regularly transfused and those who were regularly transfused, respectively..

Thank you, Chris. Today, I will first briefly review consumer performance for Q1, which is the last period for which Agios is accountable for sales of the product. I will then summarize our progress on cross-functional launch preparedness in anticipation of the potential approval of mitapivat in 2022.

TIBSOVO net sales in Q1 reached $37 million, largely driven by market increases in utilization across newly diagnosed and relapsed/refractory AML, partially offset by higher expenses related to Q1 Part D coverage gap seasonality and increased volume moving through the 40B institutions. Turning to mitapivat launch readiness.

The team made progress on a number of fronts, including PK deficiency education, physician and patient profiling and the ongoing field in build.

In November, we have announced the launch of the Anemia ID program, a partnership with Perkinelmer to offer free genetic testing to help patients and physicians reach a definitive diagnosis for patients with suspected hereditary anemia.

The program has been well received and is increasingly utilized to help patients with their diagnosis by simplifying the testing requirements attended with reaching a definitive diagnosis of a patient's hemolytic anemia.

The program also provides Agios with the identified patient level information, which adds meaningfully to our understanding of the PK deficiency patient profile.

Our experience with this program highlights the magnitude of unmet need in the community and the deepening sense of urgency to improve the diagnosis of patients with hemolytic anemias, like PK deficiency. As Jackie mentioned, in March, 23 & Me added a new PK deficiency carrier status report to their library of genetic insights and tools.

Members who are either carriers are homozygous for the R486W variant and the PKLR gene, the most common Southern European PKR variant, are invited to receive the customized report with more information regarding their risk of developing PK deficiency and additional resources.

The report included a summary of signs and symptoms of PK deficiency and other relevant clinical and genetic information. We expect that a number of patients who are carriers will seek genetic counseling for more robust testing, potentially through Anemia ID and other mechanisms resulting in a definitive diagnosis.

We have also made good progress in expanding our ability to provide important information about PK deficiency to patients with questions. We intend to launch a robust PK deficiency patient education program by the end of the quarter, administered through existing Agios infrastructure, MyAgios Patient Support..

Thanks, Darrin. Our first 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 Jackie mentioned, the sale of the Oncology business to Servier closed on March 31st, and as a result, the first quarter results related to our oncology business can be found in the discontinued operations note to our financial statements. I will first address our continuing operations for the business.

Research and development for the first quarter was $57.7 million, an increase of $2.3 million compared to the first quarter of 2020. The modest year-over-year increase in R&D was driven primarily by start-up costs associated with the Phase III studies of mitapivat in thalassemia and sickle cell disease.

Selling, general and administrative expenses for continuing operations were $33.1 million for the first quarter, representing a $1.5 million increase over first quarter of 2020. The increase in SG&A expense was primarily due to certain onetime workforce expenses.

For our discontinued operations, total revenue for the first quarter was $41.4 million, which included $37 million of net sales of TIBSOVO. Also included in discontinued operations is $50.2 million of operating expenses that were primarily attributable to professional fees and workforce expenses directly related to the Servier transaction.

We ended the quarter with cash, cash equivalents and marketable securities of $2.4 billion.

We expect that this cash balance, together with anticipated interest income, future product sales of mitapivat and royalties on TIBSOVO will fund our current operating plan through major catalysts and to cash flow positivity without the need to raise additional equity.

As previously disclosed, our Board of Directors authorized the repurchase of up to $1.2 billion of our outstanding shares using the proceeds from the sale of the Oncology business.

And earlier this month, we closed the repurchase of the approximately 7.1 million shares of Agios’ common stock held by BMS and its affiliates for an aggregate purchase price of $344.5 million or $48.38 per share.

In addition, we have put in place a 10b5-1 plan designed to efficiently repurchase a meaningful portion of the remaining shares by year-end. As is customary, we will report on repurchases made pursuant to these plans and any open market or privately negotiated repurchases in our future quarterly earnings reports.

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

Thank you. Our first question comes from Alethia Young with Cantor..

Congrats on all the progress. I just wanted to talk a little bit about maybe potential pipeline or indication expansion for both mitapivat and potentially 946, just kind of how you are thinking about some of the potential new indications that you might be moving forward with based on what you know about the biology here. Thanks..

Alethia, it is Chris Bowden here. We think about pyruvate kinase in two ways at this point. There is a PKR part of it, and I spoke in my - and you are familiar with the advanced stage programs, where we are going after registration in pyruvate kinase deficiency, thalassemia and sickle cell disease.

There are a couple of other indications that we are thinking about where we can approach pyruvate kinase from activating wild type. And there is a number of them, including hereditary spherocytosis. We have some interest in myelodysplastic syndrome.

The anemia of myelodysplastic syndrome can potentially be addressed through the activation of wild-type PKR, again, addressing and improving the red cell health. And then we have been talking about the potential for activating PKM2 as opening up a number of doors and some other indications.

Why don't I stop at that point and let Bruce Car, who is on the call with us today talk a little bit about PKM2, and we are looking forward to the second half of the year and opening that up a little more at Research Day. But Bruce, why don't you provide a little more color, please..

Yes. Thanks very much, Chris. So just by analogy, PKR is deficient - of course, in PK deficiency in red cells and it is relatively deficient in many different hemolytic anemias. When one looks at the tissues that express PKM 2, its generation of ATP and function is abnormally in many disease states as well.

So since early last year, we have been studying the tissue distribution and the involvement of PKM two in a variety of different disease processes. Based on that work, we have then identified several likely indications for PKN 2. And they are really quite broad, depending on the place it is expressed.

It is expressed in the brain, in the retina, in regenerating muscle and many other tissues, in the gut wall.

We have been conducting appropriate nonclinical models to evaluate the potential for these disease indications, and we are actually just starting to get some very promising data in recent months, suggesting the indications that we could possibly go into in, many of which would, of course, require on partnering well outside of our hematology expertise.

And we hope to be able to talk about these indications perhaps sometime later in the third quarter at an R&D Day. But the work is going very well at the moment, and some of these indications are actually yielding spectacular nonclinical results to the extent we understand a translatable.

We are not sure yet, but a lot of promise for any additional indication for PKM 2..

That is helpful. Thank you very much..

Thank you. Our next question comes from Mohit Bansal with Citigroup. Your line is open..

Thanks for taking my questions, congrats on the project. A couple of questions from my side. One is regarding the pricing, I may sound like a book of record because I have asked it in the past as well.

But given you would be launching in an ultra-rare indication like PKD, how are you thinking about pricing right now because more rare indication like sickle cell is still not probably like four-years away, four-years after the PKD indication. And I will pause here..

This is Darren. No booking record at all. Happy to address any questions on pricing. Now I won't tell you the pricing that we are thinking about. But I can give you some indications of how we are thinking about it, right. So as you know, it is an ultra orphan indication.

We are going to price in a way that reflects the clinical value, particularly now that we have seen both of the Phase III studies, but we are pricing the way that represents or reflects the clinical value for this patient population.

As we have shared in the past, our takeaway from engagements with the payer community is that we believe that, that pricing should also extend to thalassemia. Going to sickle cell, you have a different payer mix, a different mix of patient population and associated payer mix change as well.

So there is the potential that we would adjust price for the sickle cell market. But right now, we think the price that we launched with -- at for PKD will carry over a well into fall, and then we will revisit as we go into super cell..

Just add one thing Mohit, it is Jackie. As Darrin alluded to, I think we will also price for sickle cell based on the totality of the clinical data from the pivotal program for sickle cell. So we will need to see what that yields in terms of both of the endpoints that we have built into that program..

Very helpful and one more question I may, probably for Jackie again. So given that, I mean, your strong balance sheet and even in the buyback plan, it leave a lot of cash on hand.

So when you look at your pipeline and cash at hand, do you think you could look at the external opportunities as well or do you think you have enough on your plate right now with the preclinical and the clinical programs right now?.

So I think one of the things that is most exciting about where we are as we start the next chapter in our Agios life, it is the number of things that we have in the pipeline and some of the opportunities that Bruce alluded to, where I think that we are going to start to see support for those and where we might be able to go with them, including also the indications that Chris highlighted for potentially mitapivat, 946, where you could move quite quickly into the clinic.

So we have a ton of things that we wholly own, we know the chemical matter very well and the biology and everything else. So those are our top priorities for the moment. That being said, we do keep our eyes on other things that are out there, and we don't want to miss anything that might be complementary or relevant for us.

And we always do that and we will continue to do that. So it is not out of the realm of possibility that we might do something on the early side because that is kind of been what is been in our sweet spot. But we have a ton of things that we think are pretty cool going on right now that are really what we have got the team focused on. Thanks..

Got it, thank you Jacqualyn, I really appreciate it..

Thank you. Our next question comes from Peter Lawson with Barclays. Your line is open..

Hey, thanks for taking the questions. Just a question for Jonathan, just on the share repurchase and kind of how quickly you think about doing that, and if you have got a kind of a goal in mind by year-end sort of share count and when that repurchase starts..

Sure. Thanks for the question. So as we have talked about, we made a nice start with our share repurchase program, successfully negotiating the repurchase of the 10% stake that Bristol owned. We think we got that at an attractive price. And around that same time, we put in plan our own plans to be repurchasing in the market through 10b5-1 plans.

And I think we have disclosed the current plan that is in place would buy up to $600 million, and the timing of that depends if we have algorithms and other things in place. So it depends on stock price movements and things like that.

But we would expect that by the end of the year, we would have, in combination with the Bristol stake, have exceeded half or more of the purchases that repurchases that we intend to make. The exact amount is hard to predict because it does depend to some extent on the volatility that we will see in our stock price and macro volatility as well..

Great. And then just a quick question for Jackie or Chris maybe around. The work with 23 & Me on PK deficiency carrier status.

Do you think that was going to help and has that led to any kind of better understanding around both the incidents and prevalence of PKD?.

Yes. I think Darrin is the best place to answer that.

Do you want to jump in, Darrin?.

Yes, sure. Happy to. So yes, I think it adds meaningfully to our understanding of the overall patient's patient profile. It is important to note that the 23andMe chip looks at one variant. It is an important variant, what is most commonly referred to in the literature. But if you recall, we got upwards of 300 mutations or so for PKD.

So it is while important and it is giving us some very meaningful insights based on the population that have taken the 23andMe tests, certainly, it wouldn't be sufficient, right. So we are looking at multiple sources to be able to help us to better understand the true prevalence of the disease.

But what we have seen thus far is very encouraging, and at least in the 23andMe data set. And the fact that those patients who then are carriers or are homozygous for the 486 mutation or variant are getting direct information to help them understand then what they should do based on that, right.

And then we have created additional mechanisms or channels around those patients to help them to be able to pursue additional genetic testing potentially through an Anemia ID. And then eventually, once we launch the Myagios PK or part of the kinase deficiency patient support program by the end of the quarter.

Potentially, those patients will then opt into our patient support program, which will then allow them to be able to get timely information about their disease and then after approval, access to medicate..

Okay, thank you. Thank you so much for taking the questions..

Thank you. Our next question comes from Anupam Rama with Jpmorgan. Your line is open..

Good morning guys. This is Tessa on the call for Anupam. Thank you for taking our question. Just one from us. Can you remind us if there are any additional key analyses at EHA in June that we should be looking at specifically around the thalassemia or PKD programs? Thank you so much..

Yes. Hi, it is Chris Bowden here. I think that for part of a kinase deficiency, this is the first time that we are that the results from the pivotal studies, ACTIVATE and ACTIVATE-T, will be presented. So I think that the key analyses are multiple. There is of course the primary endpoints, there is the safety.

I think one really important component of ACTIVATE, it is a randomized trial. So you will - it will be the first time we will be able to see the results - the safety results of mitapivat against a placebo-controlled where both patients and clinicians are blinded.

So that will give a much better and, I would say, balanced view of what the safety profile looks like over a substantial dosing period. Of course, the patient-reported outcomes as well in a placebo-controlled trial are very important. So there will be multiple components of that that will be important.

For thalassemia, the build on the previous data that we showed to see how durable those hemoglobin responses look like will be very important because this is another program that we are taking forward into Phase III.

And since we see made mitapivat as a drug that continues to demonstrate with this safety profile, that it can be given for long periods of time, it is compatible with chronic dosing, that the durability of responses are very important as well. I think those are the key components.

And there will also be additional data around long-term safety with mitapivat and as well as other descriptions of the disease burden of pyruvate kinase deficiency. So there will be many analyses and the overall picture will be extensive that we will present on mitapivat across those two diseases..

Okay, great. Thanks so much for taking the questions..

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

Just on the upcoming readouts from your academic collaborators working in sickle cell disease.

I'm wondering if the NIH readout will include results from the extension study or will it more likely focus on the core study period? And also, what can we reasonably expect in terms of the number of efficacy evaluable patients from the Utrecht study? And could you remind us of the main differences between the Utrecht and NIH trials in terms of study design? Thanks for taking the question..

Well, I will take the back part first. The NIH study, it is an eight-week dosing period that ranges with eight-week continuous dosing period with the dose escalation build in, starting at five milligrams to 20 to 50 to 100 in, and then there is a taper and then patients are eligible to go into an extension study.

The Utrecht study is enrolling up to 10 patients and they started 20, then they go to 50 and they get 100 and they stay on with chronic dosing. So I think those are the major differences. Overall, the patient populations from an trial eligibility criteria are roughly comparable.

So now your question around what will be presented by the NIH is still up in the air, and I think that depends on - it will really depend on how many patients come into the extension, how much follow-up they have at the time of when they perform their data cut in order to prepare for whatever meeting they are going to submit this to.

I will just remind you, this is an investigator-sponsored study, so they hold the IND and are the primary decision-maker on those issues. We collaborate with them, and things are going really well. But at this point, they haven't really gotten around to thinking through that level of detail.

In terms of overall evaluable patients from the Utrecht study, the way that protocol is written is that they are going to be looking for at least up to 10, I should say..

Okay, got it. And very quickly on thalassemia, I'm wondering if you can tell us what the planned distribution is between European versus U.S.

clinical sites in the ENERGIZE trials and to what extent is COVID creating an obstacle for opening clinical sites, especially in Europe right now?.

So we will be able to provide a site list, and we will do that in the trials in progress type session or something like that. So that information will be forthcoming. At this point, we are not running into any turbulence with activating the study and getting it up and running with regards to the pandemic.

However, that is something that we really keep our close eye on because things can change very rapidly. But no problems as of this juncture, I'm knocking on my desk wood here..

Alright, sounds good. Thanks for taking the questions..

Our next question comes from Michael Schmidt with Guggenheim Securities..

It is Kelsey on for Michael. We had a couple on mitapivat in PKD.

I guess now that we are almost, I guess, about a year out from launch, I guess, how are you thinking about the speed of uptake and how maybe the education efforts might accelerate this? And then have you been able to get any initial feedback from physicians on the data so far, maybe just that presented in the top line press releases?.

Got you. Darin here. So yes, so we are about a year out from approval, and so we have been building - expanding the team in order to be able to get a lead on -- get ahead on all of patient profiling, physician profiling efforts, right, which ultimately will help with help with uptake post approval. So as I mentioned, we have hired the full sales team.

We expect them to be trained and then out in the field by the end of the quarter. So we have also added some clinical educators. We will also engage with practices to help them with understanding - increasing overall awareness and understanding of the disease.

That is on top of the expanded patient finding efforts, all of which will help us to ensure that we are we have got a good understanding of the overall market, including the number of potential diagnosed patients by the time we get through approval, and then we will continue those efforts through approval.

When it comes to uptake post-approval, obviously, those patients that are identified - or those physicians who have patients that are identified will be at top of the list in terms of promotional efforts by the team. The key regulator on uptake is going to be, obviously, physician inclination to prescribe, but also payer management, right.

And so it will take a few months for policies to be written. So that is important but doesn't necessarily have to be an obstacle for adoption. It just may require physicians, before payers fully adopted a policy or crafted a policy, to seek - to get involved in terms of helping patients to be able to get access. But that is not unusual.

That is customary in all approvals. In terms of early physician response to the data set, we have been working with anonymized data to be able to get some physician and payer reaction to the overall profile, which has been quite encouraging for us.

It is mostly consistent with what we have seen or heard from the community when we were using just the target profile data. But actually, what we see in terms of responses, the overall profile of the patient population as well as the PRO, quality of life data, it actually is even more encouraging in many respects on what we have heard before.

So I think all in all, we are in good shape, leading up to the approval and being able to raise all awareness and enthusiasm for prescribing mitapivat once we get through approval..

Great, that is super helpful. Thank you so much..

Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open..

This is Elizabeth on for Salveen.

Regarding the Anemia ID program, just wondering how many indications that might open up for you? And then are you thinking of pursuing similar programs to the 23andme initiative for other rare indications and potentially expanding for other variants of PKD?.

Sure. So this is Darrin here. I will address this first. For Anemia ID as well as 23andMe, they are both focused on helping us to improve our understanding of PKD specifically.

So though in Anemia ID, the panel that is used can help a physician to identify any number of hemolytic anemias, what we are focused on is those data associated with pyruvate kinase deficiency and seeing the 23andMe. Now we haven't yet discussed how those programs may be helpful as we look ahead to the expanded indications for mitapivat.

But given what we have observed with the program this fall, I think the success we are having with PKD, I would say that those are probably viable options for us for the additional indications as well..

Thank you..

Thank you. Our next question comes from Marc Frahm with Cowen & Company. Your line is open..

Hi this is for Mark. I have a follow-up question to your earlier comments regarding the thalassemia data that we presented at EHA.

In terms of - would the data set be large enough to be a long enough follow-up to start capturing the impact of the improved hemoglobin level? And then second question regarding the ENERGIZE trials, how long do you expect enrollment to take? And should we expect both trials to be on a similar time line or is one likely to take less time to complete besides the fact that they have different and for enrollment?.

Yes. It is Chris here. Thank you for your question. Our initial presentation of the data that gave at EHA last year, I think illustrated what we defined as proof of clinical concept, where we saw the majority of patients having a greater than one gram per deciliter increase.

So I think one of the important findings in this presentation is now, a year later, with 20 patients accrued with longer-term follow-up, the durability of those responses and the safety will be a very important part of that presentation. Now with regards to the time lines, the time lines of accrual of one trial versus the other.

It is too early for us to guide to that, but I can refer you to the slide that we presented today, where our first goal - our most immediate goal is initiating both of these studies in the second half of this year. And we are very much on-track to do so with anticipated approvals in the 2025 time frame.

So we will be able to provide more details as things go along. And right now, we are just entering into the, what I call the second stage of the operations, that is we are beyond the beginning of the beginning and now we are getting into IRBs, dealing with sites and all that.

So it is too early for us to guide to one trial finishing - the timing of one versus the other. We very much set our timelines based on detailed feasibility and then, of course, track things along the way.

And if we see important movements in either direction, things going faster or slower, then it is our job to talk about that once we are very confident of it and what the implications are. But right now, we are very encouraged by how we are tracking in terms of starting the study and sticking with our anticipated approval guidance of 2025..

Okay, thank you for taking the call..

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

Thank you operator, I'm very excited about the progress we have made so far this year, including the transition of our Oncology business to Servier. We look forward to making a meaningful difference in the lives of patients with diseases that lie within our focus areas as we move into our future as a transformed Agios, starting with PK deficiency.

To close, 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 of the patients, caregivers and physicians who participate in our clinical trials. Without them, we could not do what we do. And thank all of you for joining us today. Take care..

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