Good morning and welcome to Agios' Second 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 Jessica Rennekamp, Director of Corporate Communications..

Thank you, operator. Good morning, everyone, and welcome to Agios' second quarter 2021 conference call. You can access Slides for today's call by going to the investors section of our website agios.com..

Thanks, Jessie. Good morning, everyone, and thanks for joining our second quarter 2021 financial results call. We are pleased to report another quarter of strong progress at Agios, the first full quarter since the close of the sale of our oncology business to Servier.

The team is focused, energized, and excited for the future as we continue to advance our pipeline in genetically defined diseases led by Mitapivat across its three initial indications in hemolytic anemias.

We achieved significant recent milestones with the submission of our NDA for Mitapivat in adults with pyruvate kinase deficiency in June, as well as with the submission of our MAA to the EMA the same month. We look forward to working with the FDA and EMA as they complete their reviews.

With these two filings, we are one step closer to delivering the first potentially disease modifying therapy for people with pyruvate kinase deficiency. These regulatory submissions are supported by strong Phase 3 data from the ACTIVATE and ACTIVATE-T studies.

Full results from both were recently presented at the European Hematology Association, or EHA, Virtual Congress in June. Our preparations for the commercial launch of Mitapivat in PK deficiency continued to advance and we remain on track for anticipated approval and launch in 2022.

In addition, we would like to extend our congratulations to the Pyruvate Kinase Deficiency Foundation and the Thrive with Pyruvate Kinase Deficiency Organization, both of which recently launched as the first two US-based advocacy organizations dedicated to PK deficiency.

Both organizations are patient-led and it's very exciting to see how this community has coalesced and the momentum they are gaining in raising awareness in advocating for those living with this disease..

Thanks, Jackie. As Jackie mentioned, we are excited about the potential we have to impact the lives of individuals with genetically defined diseases. We achieved important milestones for both Agios and the PK deficiency community this past quarter with the submission of our global regulatory filing for Mitapivat in the US and EU.

We are pleased to share that our MAA has passed validation, which triggered the start of the MAA review procedure. For the NDA, the FDA has 60-days from submission to determine whether the application is accepted, so we expect to hear from them in mid-August.

Information about whether the application is accepted, whether Mitapivat has been granted priority review, and the PDUFA date will all be communicated by the agency at that time. Overall, we are very pleased with our progress and believe we have significant momentum, as we look to a busy second half of 2021.

At EHA, we presented full data from the ACTIVATE and ACTIVATE-T Phase 3 studies evaluating Mitapivat in adults with PK deficiency, who are not regularly transfused and those who are regularly transfused, respectively.

Both studies met their primary and secondary endpoints including patient reported outcomes that address symptom burden and quality of life impact of PK deficiency. Mitapivat was generally well tolerated and the safety profile observed in both studies was consistent with previously published data. During our EHA investor event, we also heard from Dr.

Andreas Glenthoj, who highlighted the significant impact PK deficiency has on patient's quality of life, the limitations of the current PK deficiency treatment landscape, and the potential for Mitapivat to serve as the first disease modifying therapy for these individuals. Moving to thalassemia.

We also presented data at EHA on all 20 patients in the core period of our Phase 2 study of Mitapivat in non-transfusion dependent alpha and beta thalassemia.

Consistent with previously announced proof-of-concept data, the study met its primary endpoint with 16 of the 20 patients achieving a hemoglobin increase of greater than or equal to 1 gram per deciliter from baseline at one or more assessments during weeks four through 12.

In addition, a sustained hemoglobin response and improvements in hemolysis and ineffective erythropoiesis were observed in both alpha and beta thalassemia patients treated with Mitapivat. Mitapivat was also well tolerated with a safety profile consistent with previous studies.

We believe these results underscore the potential of Mitapivat to meaningfully improve hallmarks of thalassemia, including hemolysis and ineffective erythropoiesis. We are also excited to see data generated for the first time in alpha thalassemia demonstrating an increase in hemoglobin from baseline in all five patients in this subgroup.

Our two global placebo controlled pivotal trial of Mitapivat in thalassemia, ENERGIZE and ENERGIZE-T, are on track to initiate this year, as we continue the process of submitting these trial protocols globally and prepare sites for enrollment..

Thank you, Chris. We continued to make strong progress on commercial launch preparations for Mitapivat in PK deficiency. All customer facing and patient support infrastructure and talent are hired and fully trained.

Our field team, comprised of both sales representatives and credentialed nurse clinical educators, are now fully engage with physicians potentially managing patients with PK deficiency across the US and are focused on profiling accounts, raising disease awareness, and executing patient support and profiling plans through disease education.

An important feature of their work is educating physicians on the availability of the Agios sponsored genetic testing service Anemia ID.

With now well over 1,000 test kits requested, we expect Anemia ID to become an increasingly important program to help support patients seeking a definitive diagnosis of their hemolytic anemia and in aid and accelerating our PK deficiency patient profiling efforts.

Our market research now shows that 70% of responding physicians routinely order additional diagnostic test for their patients with hemolytic anemias of unknown etiology. This is an important insight, which favorably portends future adoption of genetic testing for accurate diagnosis of hemolytic anemias including PK deficiency.

Response to the Anemia ID program has been very enthusiastic and, in our research, responding physicians indicated they are inclined to test a significant portion of their patients with hemolytic anemia of unknown etiology based on the breadth of mutations included in the panel and its relative ease of use.

In June, we also launched the re-imagined myAgios Patient Support Services dedicated to people living with PK deficiency and their caregivers leveraging our learnings and much of the technical infrastructure from the oncology myAgios program, while incorporating insights from PK deficiency patients and clinicians to create a customized program designed to meet the specific needs of this community.

Enrolled patients and caregivers are connected with a dedicated and clinically trained patient support manager to provide ongoing tailored support, educational resources and opportunities to connect with other patients and caregivers in the PK deficiency community.

Amongst other educational efforts, our field team is educating physicians and their staff on the availability of the service and how they can support patients with enrollment.

Following the disclosure of the ACTIVATE and ACTIVATE-T findings at EHA in June, we fielded new market research to update our insights into general physician awareness and understanding of PK deficiency and the potential implications for disease management assuming Mitapivat's approval next year.

We found that PK deficiency disease awareness metrics are improved over the same time period in 2020 with 85% of academic and community physician respondents now familiar with PK deficiency and more than half indicating that they manage one to two previously diagnosed PK deficiency patients.

This is encouraging because it indicates that physicians are increasingly recognizing and diagnosing PK deficiency, which we intend to continue to support with additional educational activities in the months leading up to approval in 2022..

Thanks, Darrin. Our second 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 second quarter financial results discussion only includes our continuing operations on a comparative basis, which excludes results from our divested oncology business. Research and development for the second quarter was $62 million, an increase of $7.9 million, compared to the second quarter of 2020.

The year-over-year increase in R&D was driven primarily by start-up costs associated with the Phase 3 studies of Mitapivat in thalassemia and sickle cell disease and the filing of our NDA and MAA for Mitapivat in PK deficiency, as well as our launch preparation efforts.

Selling, general and administrative expenses were $29.2 million for the second quarter, essentially flat compared to SG&A expenses for the second quarter of 2020. We also recorded $2 million in TIBSOVO income from royalties in the second 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 $1.7 billion. With this cash balance, we expect to be able to execute our current operating plan through major catalysts and to cash flow positivity without the need to raise additional equity.

In Q2, we executed on $529 million of the up to $1.2 billion of share repurchases authorized by our Board of Directors, inclusive of the shares acquired from Bristol-Myers Squibb.

Specifically, we repurchased just under 10.5 million shares, at an average price of $50.41, reducing our total shares outstanding by approximately 15% to 59.9 million shares at quarter-end. As previously disclosed, the 10b5-1 plan we put in place in early Q2 provides for maximum additional share repurchases of approximately $415 million at year-end.

The ultimate amount of additional share repurchases through year-end will depend upon the volatility of our share price over this time period. Operator, please open the line for questions..

Operator Thank you. Our first question comes from Alethia Young with Cantor Fitzgerald. Your line is open..

Hey guys. Thanks for taking my question and congrats on all the progress. I want to talk a little bit about Mitapivat and maybe just, as you're doing some of the education for patient support.

How frequently do these people, kind of, see their physicians and like what kind of outreach and effort needs to be done there or is it more just kind of like a structural, kind of, a warehousing effect or is there actually work that needs to be done to bring these people back under care? Thanks..

Hey Alethia, this is Darrin. The issue is not going to be necessarily getting patients to come back in because they're usually under - for those who've been diagnosed and obviously attached to a physician, they are under some sort of monitoring plan, right.

Those with more severe disease are going to see their physicians more regularly and those with less severe disease will have a longer - typically have a longer time span between physician visits. But remember, they're continuing to have the iron load monitored, hemoglobin monitored.

So, the frequency of physician visits isn't necessarily where we would focus. I think what we're doing now is focusing on the patient profiling, identification and physician education and patient education on the disease. And I think that's where we need to continue, even post launch, to focus much of our efforts.

The physician-patient relationship should be fine and we don't need to - there's nothing there that we need to delve into. We just need to make sure that they're aware and once that's done, I think everything else follows from there..

Great. Thank you..

Thank you. Our next question comes from Kennen MacKay with RBC Capital Markets. Your line is open..

Hi. Thanks for taking the question. First off, Chris, I'm sorry to hear about your departure, but looking forward to meet your successor Sarah and glad to hear that you're staying on into next year with the transition. Maybe one quick question on the regulatory filings here for Mitapivat.

Wondering, which branch of the FDA you are interacting with, with those regulatory submissions in PKD.

Is that hematology or the rare disease division?.

Hey Kennen, it's Chris. The FDA teams that we're working with are in the cardiology, renal and the oncology, hematology divisions. The submission itself is in the cardiology, renal. So, it's an interesting setup actually because the people who have been most involved with us and are most active on the submission are in the hematology division..

That is just what I was going to sort of follow-up with and just wondered around some of the interactions so far. You've got division sort of up to speed on rare diseases and PKD or what have the interactions to-date been like? Thank you..

The group - the team that we've been working with, with FDA, has been with the program for - has been advising us and interacting with us since I joined the company. So, they are very well acquainted with the disease and the special nature of what it takes when you're in a rare disease population. So, I don't have any concerns there.

And I think the consistency - and I think importantly over the years, as you've heard us talking about the guidance and why we designed the trials we have in an effort to provide them as much data as they're going to need to make a decision for us to demonstrate clinical benefit, it's been a consistent group of people..

Thank you..

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

Hi guys. Thanks so much for taking the question. Perhaps a broader strategic question. I think many of us on the Street we model a price cut for Mitapivat longer term to account for the SCD indication.

What threshold of peak sales in SCD does Mitapivat have to meet in your view to justify a price cut versus, say, maximizing the value of the product by keeping ultra orphan pricing? Thanks so much..

It would be premature to talk about what peak sales would be in sickle cell. What I can tell you is that it would require, assuming you just wanted to at least breakeven, right, as you move from the first two indications and into sickle cell, then you account for cut.

What we think would be required, it would only require less than 4%, 3% share in that market to be able to at least breakeven across the whole program. So, it doesn't take a whole lot because the size of sickle cell is significant for you to be able to accommodate that cut.

That's why we're so optimistic about the incremental value that we will be able to gain once we move into sickle cell despite competition..

And it's Jackie, I'm just going to jump in real quick. As we said many times, I think both Chris and Darrin have said this often, we'll make those pricing decisions based on the totality of the clinical data that we have at that point in time and the product profile of course.

So, you can imagine there is lot going on when you think about that with respect to hemoglobin increase, VOC reduction, all the secondary endpoints and the patient reported outcomes, and all of that. So, lots of things to think about when we make that pricing decision at some point in the future..

Thanks so much for taking our questions..

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

Great. Good morning and thank you for taking our question. This is Elizabeth on for Salveen.

Could you just remind us if you intend to launch simultaneously in both the US and EU for Mitapivat in PKD? And then knowing that you're sort of discussing this at your Investor Day in 4Q, maybe if you could just comment on the structure and size of the launch team and your progress in terms of identifying more patients? And then how many patients with PKD have been identified to-date? Thank you..

Got you. Alright Salveen, this is Darrin. There's a lot in there, so let me see if I can unpack that. Let me start with the structure question first. So, as I mentioned in our prepared comments earlier, we fully hired our internal and external teams, right.

That's about just under 20 representatives, sales representatives, and then a small contingent of nurse educators that will collaborate with them and that's for the US team. For the EU, as we've shared previously, we got boots on the ground there already, right.

So, we have an MSL team that's established and then we have a small group of experts that have been dedicated to building awareness and extending or advancing our patient profiling efforts in each of the major markets in the EU.

And we continue to do the work, particularly on the critical path activities, to ensure that we will be able to launch Mitapivat in the EU shortly after approval. But we've also shared that we're evaluating a number of options, right.

Considering the opportunity to be able to engage with a partner, who's got a footprint that's already - that already exists in the EU and hopefully outside or beyond the EU, given the amount of value for Mitapivat that extends - patient value that extends beyond the major markets.

That can overlay Mitapivat or include Mitapivat in their existing infrastructure and that's where we've been focusing our efforts. So, the idea is keep things moving to enable a launch particularly in Germany where you can launch immediately and have pre-pricing.

And then - but also be able to then transition network to a potential partner once we find the sort of deal that we believe fairly reflects the value that Mitapivat will bring..

Great. Thank you.

And then maybe if you could just comment on the patient identification efforts and patients identified to date?.

Yes. So, we continue to do the work behind what we referred to as patient profiling efforts, right, being able to identify more patients.

We previously shared that we've identified about 1,000 patients between the US and the EU and that's inclusive of pediatric patients, patients that are enrolled in our various clinical programs, as well as patients - selective patients that we come across as we're engaging with physicians.

And it's an important number that I know everyone wants to hear more and more about, and we do keep on top of that. That's not where I would focus though, because particularly as we move closer to the launch here in the US, what we really need to do is be able to then attach each of those patients who already identified to us.

So we don't know their personal - their identified information, but you want to attach them to an individual physician, you want to ensure that they're getting tested, see if the physician is inclined to use Anemia ID to confirm the diagnosis even further.

And then we've also made our patient support program available in the last month and ideally those physicians would then see value in referring their patients to the programs and that helps you to get a better sense of the absolute confirmed patient population here in the US. So, that's where we're focusing our efforts, right.

Continuing to advance the diagnostic differential and get those patients the appropriate support that they need, get them the education that they can - that myAgios can provide, which then will lead us up to and through the approval..

Thank you. That's very helpful..

No problem..

Thank you. Our next question comes from Michael Schmidt with Guggenheim Securities. Your line is open..

Hey, this is Kelsey Goodwin on for Michael. Thanks for taking our question.

Maybe actually building off of that one a bit, I guess going forward how do you kind of see the rate and slope of the PKD diagnoses kind of evolving as you continue these efforts? I guess what kind of assumptions do you kind of build in over the next near-term, long-term of this launch?.

We have some indication from what we're observing with Anemia ID, which is still in its early days and some indication from the Spanish IST - screening IST that reported about - I think about 20% of those hemolytic anemia patients that were screened ultimately were diagnosed with PKD.

We get a good sense for what your diagnosis rate may end up being amongst those patients who are tested, particularly those patients, who have diagnosis of hemolytic anemia, but hemolytic anemia of unknown etiology.

That I'm less - I'm not concerned about that in terms of the ramp for the launch, because I think we continue to - we're doing everything that we need to do to facilitate testing. I expect we'll see that accelerate, now that we have a full contingent in the field to help educate practices and our Agios support to educate patients.

The thing that's outstanding for me and I think we're focused on better understanding is what the access profile will look like, particularly in those first six to nine months of launch, right where we know that for a number of payers you're going to have a new to market block that will require physician seeking medical exception and that will then extend the time between when you're diagnosed and when you're ultimately - when treatment is ultimately made available to the patient.

So, the demand - and we have this confirmed in our recent quantitative work. The demand is going to be there so we have the desire to be able to treat broadly for these patients.

We've got all the programs in place like Anemia ID, the work that we shared with you last time on 23andMe to help increase overall awareness drive, support patients in having better testing options available to them. And then - so the script, the opportunity for the patients to receive the treatment, I think, is going to be high.

The question is the amount of time in those first months for the physicians to be put to work through the access challenges..

Got it. Okay. Super helpful. Thank you so much..

No problem..

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

Hey, good morning guys. Congrats on the forward progress and Chris, of course we're sorry to see you go as well.

I'm just wondering with regard to the pivotal trial in sickle cell disease, if you can comment on what the main gating items are that remain before this trial can be initiated? And in terms of the ACTIVATE sickle cell trials with data that we might see later this year, can you maybe give us a sense for how many patients to expect from the Utrecht trial and just remind us the main differences between this study and the NIH study? Thanks so much..

Okay. It's Chris here. Launching any of the Phase 3 in thalassemia and the Phase 2/3 study would be a global study, so the protocols are written and finalized and now we're in that heavy lift of operationalizing the studies. And that's a whole list of activities that involve regulatory agencies, sites, CROs.

And in addition of the protocol, there's all the logistics that come with setting up your IVRS; that is your randomization systems, setting up all the translational medicine, laboratory assays, how those things are going to flow.

So, it's a very complicated series of activities that some of them can run - many of them run in parallel, but in each individual country and within each individual country at individual sites, you're contracting and going through just a number of activities.

So there are too many to name, but it's a well-described and well acknowledged that it's a complicated series of activities that our team has done several times now successfully and it takes some time to get everything up and running. The key piece that we are focused on in all of that is identifying sites that have patients throughout the world.

It would be global study and to really look to everything we can do to make the trials accessible for patients and have maximum terminal velocity. So, the first patient in is very important and the last patient out is perhaps even more important. So, that's that piece and that's one of the fun things about doing this job.

Then the second piece in terms of the sickle cell, the Utrecht study will enroll up to 10 patients. That group is very skilled and well known in terms of their ability to look at both red cell metabolism as well as using the oxygen scanner to look at blood sickling and other components that are important biomarkers in the sickle cell area.

That trial starts patients at 20 milligrams and then they can go to 50 milligrams and then go up to 100 milligrams and then they are on study for at least a year.

So, that's different from the NIH study where the NIH study with the first study in adults with sickle cell disease where they started at 5 milligrams, 20 milligrams, 50 milligrams and then they may the amendment to 100 milligrams.

So, it's a total of eight weeks of treatment and then there's this taper and then patients who are willing and able can then go into an extension. So, I think there's a lot of similarities in terms of understanding the important endpoints that we talked about and you get a sense of efficacy and safety from both.

The Utrecht study I think gives you immediately over time some further understanding of chronic dosing that the NIH study doesn't give you quite immediately because those patients are on eight weeks of therapy and then we'll definitely get more long-term data from patients who go into the extension.

But we don't know yet how many of those patients that's at the end of the day going to be. So, I'll stop there..

Okay. Super helpful.

And then just a very quick follow-up is that, is the Phase 2/3 going to be inclusive of African trial sites?.

Yes..

All right, thank you..

Thank you. We have a question from Danielle Brill with Raymond James. Your line is open..

Hi, good morning. Thanks so much for the questions. I guess first can you remind us where your expectations are for an AdCom meeting and maybe what your internal expectations are for priority review? And then Darrin, I wanted to clarify something from your prepared remarks, excuse me.

Did you say that your market research indicates 70% of providers already order genetic testing for anemias of unknown etiologies or that they would like to? Thank you..

Let me answer the second one and then I'll leave the room for Chris to be able to answer you on the first.

So, the 70% number refers to the proportion of physicians who are routinely ordering more tests to try to be able to get to a more definitive diagnosis for those patients who are diagnosed with hemolytic anemia but of unknown etiology, which means that they are inclined to either order enzyme tests or a genetic panel or both, which some they do reflexively.

And the reason why I mentioned - I provided that insight is because then it means then we have a highly receptive audience then to Anemia ID and give us an indication of what further uptake would look like, particularly now that we've got more folks out there educating the community about it. So with that, let me turn it over to Chris..

Hi.

Your question was with regards to priority review for the pyruvate kinase deficiency submission, right?.

Yes..

Yes. So, we'll find out the FDA's view on that, their decision 60 days from when we filed, so that should be sometime in the August timeframe, middle of August or so..

Okay. I guess.

Sorry, we lost you..

What are your thoughts on Advisory Committee meeting?.

In AdCom, too early to tell, sometimes you get some signals early on, but we're early in the stage yet so it's too early to know..

Understood. Thank you..

Thank you. And there are no other questions in the queue. I'd like to turn the call back to Jackie Fouse for closing remarks..

Thank you, operator, and thank you, everyone, for the questions this morning. As we move into our very bright future, as a transformed Agios, we look forward to making a meaningful difference in the lives of patients with genetically defined diseases, starting with our potential launch in PK deficiency next year.

I would like to thank my Agios colleagues for their dedication and passion for making a difference for our patients. I also would like to thank all the patients, caregivers, and physicians who partner with us in so many ways. And today a special thanks to Chris.

We will have more interactions with him, I'm sure with you all over the next couple of months. We're very, very happy and pleased that he is willing to stay engaged with us and Agios through the end of 2022 at least as a strategic advisor because we'll continue to benefit from his wisdom and insight.

So, thank you very much, Chris, and we look forward to a few parties over the next couple of months to celebrate your next chapter. Thank you everybody for joining us today. You may now disconnect. Take care..

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