Agios Pharmaceuticals, Inc. Q3 FY2021 Earnings Call

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 serve as 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 healthcare providers and our disease education efforts continue to accelerate. We are also working diligently on startup 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 in 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 toward 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 deficiency, 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 committee. In the EU, as expected for the procedure, we received questions from the regulator and the critical assessment of those. 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 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 mitapivat, ENERGIZE and ENERGIZE-T, have been initiated. Our first site has opened, and we look forward to enrolling the first patient soon. As a reminder, ENERGIZE will evaluate 171 patients randomized 2:1 to 100 milligrams of mitapivat twice daily or placebo in both alpha and beta thalassemia patients who are not regularly transfused. The primary endpoint is hemoglobin response defined as an equal or more than 1 gram per deciliter increase in average hemoglobin concentration from week 12 to week 24 compared with baseline. ENERGIZE-T will evaluate 240 patients randomized 2:1 to 100 milligrams of mitapivat twice daily or placebo in both alpha and beta thalassemia patients who are regularly transfused, defined as 6 to 20 red blood cell units transfused during the 24 weeks prior to randomization. The primary endpoint of transfusion reduction response is defined as a 50% or greater reduction in transfused blood cell units, with a reduction of equal or more than two units of transfused red blood cells in any consecutive 12-week period through week 48 compared with baseline. We are excited to advance these studies and believe mitapivat has the potential to be a meaningful treatment option for patients with both alpha and beta thalassemia. At ASH, we also expect to share longer-term extension data on the non-regularly transfused alpha and beta thalassemia patients who completed the Phase II core period. In sickle cell disease, we remain on track to initiate our pivotal Phase II/III clinical trial by the end of the year. As Jackie stated, we recently unveiled the name of this program 'RISE UP'. The name was developed in collaboration with a global team of sickle cell warriors and it has significant meaning for the community. We were excited to first share the name at the Sickle Cell Disease Association of America Convention last month, and we have been gratified by the positive feedback. This Phase II/III study will include patients who are 16 years of age or older who have had between 2 and 10 sickle cell pain crises in the past 12 months and have hemoglobin within the range of 5.5 to 10.5 grams per deciliter during screening. The Phase II portion of 'RISE UP' will randomize 69 patients 1:1 to 50-milligram mitapivat twice daily or matched placebo. The primary endpoints are hemoglobin response defined as equal or more than 1 gram per deciliter increase in average hemoglobin concentration from week 10 to week 12 compared to baseline and the type of adverse events. This data will be used to establish a clear dosing paradigm for the Phase III portion. The Phase III portion of 'RISE UP', which will commence after the Phase II analysis, will randomize 198 patients 2:1 to the selected Phase II dose of mitapivat or matched placebo. The study will have two primary endpoints: the hemoglobin response defined as equal or more than 1 gram per deciliter increase in average hemoglobin from baseline to week 52, and the annualized rate of sickle cell pain crises. We believe the design of this Phase II/III study minimizes risks to the approval platform of mitapivat in this challenging disease and maximizes the likelihood of a label with a broad indication. In addition, we continue to work with our collaborators at the NIH and the University of Utrecht on their studies of mitapivat in sickle cell disease. Data from both studies are expected to be presented at ASH. At the NIH, Dr. Tan enrolled 17 patients in the core study and continues to enroll in the expansion study. We anticipate the data sets at ASH will provide additional efficacy, safety and translational data that continue to support the clinical development of mitapivat in people with sickle cell disease. Leveraging our pioneering expertise in PK activation, we're also advancing our novel PK activator, AG-946, which is currently being evaluated in a Phase I study with a healthy volunteer component followed by a sickle cell disease component, which we plan to initiate in 2022. Data from the ongoing Phase I healthy volunteer portion will be presented at ASH. As Jackie mentioned, we plan to talk in more detail about our research and development pipeline at our Investor event on November 17.

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 healthcare 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 origin, most of whom are likely eligible for genetic testing, in an attempt to help them reach a definitive diagnosis, including potentially PK deficiency. Among those physicians profiled who were confirmed to currently treat PK deficiency, many have one to two confirmed PK deficiency patients diagnosed and under management. Additionally, with 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 patients' hemolytic anemia, which may include but is not limited to PK deficiency. In the coming months, we expect to expand this service by supporting direct patient access to genetic counselors who can provide additional assistance to them. We believe this will empower even more patients seeking to initiate the testing process on their own and better manage their disease once diagnosed. Once the patient's PK deficiency diagnosis is confirmed, our hemolytic anemia specialist team educates practices on the disease education and other support provided through our patient assistance service, myAgios. The team encourages practices to inform diagnosed patients about the service, and we can then continue on to the enrollment process. This puts Agios in the best possible position to tailor support for diagnosed PK deficiency patients and connect them with the broader PK deficiency community. We've also continued engagement with payers over the quarter, educating them about the natural history and burden of disease, including morbidities and complications for the spectrum of PK deficiency patients, regardless of transfusion history, and an overview of the Phase III data. In the process, we learned more about their pressing questions and what they expect of Agios at the time of potential approval. We know formulary coverage of a new treatment takes time before you're able to reach optimal access, especially in the first 9 to 12 months post-approval, as payers convene P&T committee schedules. These exchanges are also helpful in shaping strategies to support payers as they develop coverage policies. Overall, we have growing momentum heading into the expected approval in 2022, with each week bringing a new high with respect to physician and patient profiling and education and steady progress towards launch readiness. I look forward to discussing details with respect to commercial strategy, including progress with patient profiling, distribution and more at Investor Day in November. With that, I'll now turn it over to Jonathan to review third quarter financials. Jonathan?

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, 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 filing of the 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?

Thank you for your question. This is Sarah, the new CMO. Regarding the first question about the Phase III study and the endpoints, we have two distinct primary endpoints. This design is intentional, as it includes an alpha split between the two primary endpoints, which enables us to proceed to testing the secondary endpoints if we meet one or both of the primary endpoints. The endpoints are the hemoglobin response and the annualized rate of sickle cell pain crises. As for your second question, we do require that patients have experienced between 2 and 10 pain crises in the year leading up to their 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 with 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 through stratification on hydroxyurea in the clinical trial.

And did you see any different effect with hydroxyurea versus not?

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

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

Hi guys. Thanks very much for taking my 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 changed over time. Thank you.

Sure. It's Darrin. 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 countries, so assume somewhere between 1,500 to 4,000 in the U.S. We're still in the early days 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 for our planning. However, 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 ICD-10 for PK deficiency. But that was just recently approved, 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 my question. I know that the AG-946 Healthy Volunteer data will be 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 the next steps for this program? 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. We are 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 discussing more with you on November 17.

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

Thank you for taking my question. I would like to follow up on the patient prevalence work that Darrin has been doing. Can you provide some insight into the TIBSOVO test results? Are they still aligning with your initial experience? I recall that in the early days you indicated they were, but that was still early on. I’m interested to know if that trend is being upheld. Additionally, could you clarify the increase in demand for those tests in Q3? How does that compare quarter-over-quarter to the first half of the year? Did you see as many tests in Q3 as in the entire first half, or was it a smaller or larger amount?

There's a lot in there, but it's a good question. 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 growing momentum. But also, first of all, for that we've had the field, field team in place. They've been helping to educate the practices and agencies who would like to order the test. So I think we're just shy of about 2,000 tests by the end of Q3. In terms of what we're seeing, I expect it to fluctuate, particularly as the volume of test results are requested and conducted, and then the results are reported. And there is a material difference between the controlled setting in which the Spanish study was conducted, versus the broader experience that we have in the U.S. in which the testing allows physicians to look at the potential explanations for the patient's hemolytic anemia. 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 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. I think we have very strong pockets of utilization, and I'd like to see it used more broadly. I'd like to see more confirmed tests come through before we start reporting 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 my question and congrats on the progress. A lot of people have addressed my questions about the market, 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 meet to ensure reimbursement that you would expect for mitapivat in PK deficiency?

Sure. Sure. I'll put forth the work that's preparing to provide that information to you at the Investor Day later this month, but I'll give you a preview now. We expect that the mix for PK deficiency will be 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 an even split 15% or so, Medicare, 50% Medicaid and then the balance number of other DOD and cash. What we can expect is that there is going to be a ramp, right? So you will have complete formulary coverage for patients, particularly commercial patients. That will, in large part, depend on when commercial payers are going to hold their P&T committee meetings. This will take time to reach 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 is that we have 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 a solid understanding of the natural history of the disease, the long-term morbidities and complications associated with PK deficiency, then the unmet need, the severity of the disease, regardless of transfusion history, is pretty well accepted and understood by the community. Once we establish that story and present the clinical data, the safety efficacy data is pretty clear and compelling. Thus, there's little convincing we have to do there. We just have to make sure people understand it. Once that is in place, we expect favorable access which will differ based on individual patients in benefit designs. We would expect pretty good access. The key will come down to what the final label looks like and the price we choose, which will ensure that we're optimizing the business opportunity while optimizing the ability for all patients to access the treatment as their physician sees fit.

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

Well, PerkinElmer is the partner that we work with to provide the genetic test. Not every patient is going to necessarily get a genetic test. The commonly used test will be the enzyme assay. The genetic test is helpful and may serve as confirmation, but they are not limited to using our tool. What we are intending to do is to have a central hub, right? For every script that is written, the physicians will submit the script to go to myAgios, our patient support service, and patients will then opt into the service accordingly. This will give us the opportunity to ensure we have the appropriate confirmation of the patient diagnosis, helping them with supporting their engagement with payers, and enabling us to educate patients and practices on all the appropriate disease education, connecting them with other patients in the PK deficiency community as well as providing adherence support for the patient. On your central question regarding physicians, they are limited only to our genetic tests. But through the prescription fulfillment process, we provide a seamless service to ensure the patient can successfully get on treatment. This gives us the best visibility 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 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? I'm also wondering if you're seeing any pharmacodynamic thresholds that 946 needs to clear in healthy volunteers to justify continued development in terms of 2,3 DPG reduction and maybe ATP increases, things like that. What would you see as a best-case scenario from the healthy volunteer data?

The current protocol is typical for a single ascending dose and multiple ascending dose study in healthy volunteers. We are aiming for pharmacodynamic engagement within this group to maximize and generate safety data, which is standard Phase I work. The protocol includes specific decisions based on the pharmacodynamic engagement observed in healthy volunteers, which will guide us in determining the appropriate doses for the 946 sickle cell disease part of the trial. Sickle cell is prioritized due to the significant unmet medical need, and we intend to develop multiple therapies for these patients. However, development will involve go/no-go decisions to establish the best path forward for each molecule. While we are generating data for sickle cell disease, we also intend to use that data to inform decision-making across various indications.

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

This is Elizabeth on for Salveen. As you start thinking about the pediatric population in PK deficiency with the pivotal study set to initiate next year, we wanted to get your thoughts on how patient identification efforts for pediatrics could differ from those for older patients. Are there any particular differences that you would highlight here?

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

Maybe just to add, the efforts we're currently employing to support patient identification in the community are limited to adults. We're also coming across pediatric patients as we engage with individual practices. We maintain a 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 would that be 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 do, given the progress we've made with repurchases thus far, which totals just over 16 million shares and reduces our starting share count by a little over 23%, and 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 this year, there could be a probability of finding executable complementary BD opportunities. We've paused share repurchases. 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 authorization, is opportunities to accelerate our pipeline and engage potential business development. There is 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. As that plays out, we'll make determinations regarding how much, if any, of the additional authorization we will execute.

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

Andy, it's Jackie. No one's asked me a question, so 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 closed the oncology divestiture with Serie and we brought those funds in at the end of March, we were always flexible in terms of how we thought about our capital allocation. However, we knew that we were in a unique situation given our place in the Agios life cycle and having undertaken a relatively large transaction for a company of our size. Given the amount of capital we've raised over our history, our initial priority for the $1.2 billion share repurchase was to reset our capital structure by returning some of that capital to our shareholders, which we have now executed and I think we are very happy with that execution on roughly $800 million so far. 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 will discuss on November 17, allowing incremental investments in our internal assets and programs to enhance them, which weren't necessarily present in the past. As Jonathan mentioned, we have greater clarity in terms of our internal thinking regarding the potential opportunity set in the BD arena. There are various ways to allocate capital over time, and we're going to adjust our approaches between these options. 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 going to be more flexible regarding how we view different opportunities. Lastly, I want to note regarding 946 that we knew we wanted to generate data in a hemolytic anemia context. At the time we established the healthy volunteer study, sickle cell disease seemed the most logical one to add as it provided early data in a hemolytic anemia disease. I think you'll hear on November 17 about some other potential pathways 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. We have two or three dedicated people, but then we've also got leaders within each functional area who contribute to the efforts. So when we're looking at something, there would be somebody in Bruce's team who contributes to looking at assets, there will be somebody in Sarah's shop who contributes to linkages. Also, of course, Bruce's team is generating ideas for complementary mechanisms or targets we would want to be looking at. So we've got a 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 mitapivat. There is a chance that AG-946 one day serves as a complementary asset in the portfolio. It's as likely that we see some data for AG-946 in sickle cell disease that informs us on how the product performs in a given hemolytic anemia, then we have the healthy volunteer data. There may also be other indications that we would feel comfortable pursuing even faster based on comprehensive evidence we've gathered across the PK activators and all work done on AG-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 on active voxelator DBO, but will you permit enrollment of patients with prior exposures to those drugs? And similarly for the Energized Trials, are you permitting enrollment of patients who had prior treatment with luspatercept?

So yes and yes is the answer. We are allowing patients to have been exposed to those prior therapies and then have a proper washout period before enrolling into our trial. The same for the thalassemia trials, in which prior exposure is allowed. Hydroxyurea for the sickle cell disease trial is also permitted 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 questions 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 the 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 17, 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.