Agios Pharmaceuticals, inc (AGIO) Q3 2021 Earnings Call Transcript

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Agios Pharmaceuticals, inc (AGIO 2.30%)
Q3 2021 Earnings Call
Nov 3, 2021, 8:00 a.m. ET

Contents:

• Prepared Remarks
• Questions and Answers
• Call Participants

Prepared Remarks:

Operator

Good morning and welcome to Agios' Third Quarter 2021 Conference Call. At this time, all participants are in 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.

Holly Manning -- Senior Director, 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 Gheuens, 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.

Jacqualyn Fouse -- Chief Executive Officer

Thanks, Holly. Good morning, everyone, and thanks for joining our third quarter 2021 results call. Strong clinical and operational execution continue 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 start-up activities for three pivotal studies in thalassemia and sickle cell disease, all of which we expect to initiate by the end of 2021. These trials underscore the potential of mitapivat to serve as a pipeline within a single drug and an important new treatment option for people with these underserved, profoundly challenging lifelong hemolytic anemias.

Beyond mitapivat, we continue to advance our earlier stage clinical and R&D efforts to build sustainable future growth potential based on our leading expertise 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 to the end of the year and 2022, Agios is extremely well positioned to enter our next phase of growth with our first genetically defined disease commercial launch on the horizon, three pivotal adult trials, two pivotal pediatric PK deficiency trials, and a robust pipeline filled with optionality and possibility.

With that, I will now turn the call over to Sarah to walk through our clinical development programs in more detail. Sarah, welcome to your first quarterly results call as our Agios' CMO.

Sarah Gheuens -- Chief Medical Officer

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 continued 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 E.U. 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 dialog to date, we are currently not expecting an advisory committee meeting. In the E.U., as expected for the procedure, we received the questions from the rapporteur and the critical assessment of build by the core rapporteur. 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 see Phase 3 studies in non-regularly transfused and regularly transfused adults with PK deficiency, which both meets our 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 a pediatric clinical program in PK deficiency in 2022.

Moving to thalassemia, our two global placebo-controlled clinical trials of mitapivat, ENERGIZE and ENERGIZE-T, have been initiated. Our first site had their start initiation visit and we look forward to enrolling the first patient soon. As a reminder, ENERGIZE will evaluate 171 patients, randomized 2:1 to 100-milligram 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 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-milligram 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 is transfusion reduction response defined as a 50% or greater reduction in transfused red blood cell units with a reduction of equal or more than two units of transfused red blood cells is 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 2 core period.

In sickle cell disease, we remain on track to initiate our pivotal Phase 2/3 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 2/3 study will include patients who are 16 years of age older 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 2 portion of RISE UP will randomize 69 patients 1:1:1 to 50-milligram mitapivat twice-daily, 100-milligrams of 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. These data will be used to establish a clear dosing paradigm for the Phase 3 portion.

The Phase 3 portion of RISE UP, which will commence after the Phase 2 analysis, will randomize 198 patients 2:1 to the selected Phase 2 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 also annualized rate of sickle cell pain crises. We believe the design of this Phase 2/3 study minimizes risk to the approval path for 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. Ben enrolled 17 patients in the core study and continues to enroll the extension 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 the sickle cell.

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 1 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 1 healthy volunteers 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.

I will now turn the call over to Darrin, our Chief Commercial Officer.

Darrin Miles -- Chief Commercial Officer

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 pre-approval disease education, patient and physician profiling and overall launch readiness. The third quarter was our first with the 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 educational 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 etiology, most of whom are likely eligible for genetic testing via Anemia ID in an attempt to help them reach a definitive diagnosis of their hemolytic anemia, 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, 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 request for Anemia ID tests 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 between 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 PK deficiency diagnosis is confirmed, our hemolytic anemia specialists team educates practices on the disease education and other support provided through our patient assistance service by Agios. The team encourages practices to inform diagnosed patients about the service, who 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 3 data. In the process, we learned more about their pressing questions and what they expect of our 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 committees on such 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 toward 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?

Jonathan Biller -- Chief Financial Officer and Head of Legal and Corporate Affairs

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 3 studies of mitapivat in thalassemia and sickle cell disease and our disease education and engagement efforts for mitapivat in 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 to 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 had completed approximately $783 million or just under two-thirds of the $1.2 billion share repurchases authorized by our Board of Directors.

The base our 10-Q also reflects repurchases from September 30 to the date of the filing of the Q, it shows a total year-to-date share count reduction of more than 60 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 had mentioned, in 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.

Questions and Answers:

Operator

Thank you. [Operator Instructions] Our first question is from John Newman with Canaccord Genuity. Your line is open.

John Newman -- Canaccord Genuity -- Analyst

Hi, guys. Good morning. Thank you very much for taking my question. The question is on the mitapivat Phase 3 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 3 study? Thanks.

Sarah Gheuens -- Chief Medical Officer

Thanks for your question. So the answer to -- so, this is Sarah, the new CMO. So to the first question around the Phase 3 and the endpoints, the primary endpoints, so there are two separate primary endpoints. And that is a very deliberate design with an alpha split over two primary endpoints that allows us to move on to secondary endpoint testing, if we hit on one or both primary endpoints. And the endpoints are the hemoglobin response and an annualized rate of sickle cell pain crises. And then to the second question, yes, so we do -- the inclusion criteria, there is a requirement for patients to have at least 2 up to 10 pain crises in the year prior to enrollment.

John Newman -- Canaccord Genuity -- Analyst

Okay, great. Thank you.

Operator

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

Alethia Young -- Cantor Fitzgerald -- Analyst

Hey, guys. Thanks for taking my questions. I was just curious about kind of the sickle cell pivotal and are you allowing hydroxyurea in combination? And do you think it will work with mitapivat? Thank you.

Sarah Gheuens -- Chief Medical Officer

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

Alethia Young -- Cantor Fitzgerald -- Analyst

And is there any different effect with hydroxyurea versus not?

Sarah Gheuens -- Chief Medical Officer

Well, what was the question?

Alethia Young -- Cantor Fitzgerald -- Analyst

Any difference in effect when mitapivat was combined versus not?

Sarah Gheuens -- Chief Medical Officer

And that is too early to tell, right. So that would be something that we would be looking to look at in a subgroup analysis at the end of Phase 3.

Alethia Young -- Cantor Fitzgerald -- Analyst

Great, thank you.

Operator

Our next question comes from Kennen MacKay with C Capital Markets [Phonetic]. Your line is open.

Kennen MacKay -- RBC Capital Markets -- Analyst

Hi. Thanks for taking the question. Can you talk maybe to your current thinking on the incidence and prevalence of pyruvate kinase deficiency, based on your ongoing patient monitoring and patient identification efforts from the PK deficiency Natural History Study or your PEAK registry? And maybe for Darrin, as we get closer to launch and these efforts are intensifying, just wondering how those prevalence estimates have sort of evolved over time or change over time? Thank you.

Darrin Miles -- Chief Commercial Officer

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

Operator

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

Anupam Rama -- JP Morgan -- Analyst

Hey, guys. Thanks so much for taking the question. Now that the AG-946 healthy vol data are going to 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 next steps for this program and will we maybe get a better sense about at R&D Day in a couple of weeks? Thanks so much.

Sarah Gheuens -- Chief Medical Officer

Yes. Hi. 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 healthy volunteer portion with the second part to the clinical trial that is focused on sickle cell disease. And we're excited about that, because it will allow us to generate data in the context of hemolytic anemias. And then we have a lot of optionality based on that. So looking forward to discuss more with you on November 17.

Anupam Rama -- JP Morgan -- Analyst

Thanks for taking our question.

Operator

Our next question comes from Frahm [Phonetic] with Cowen and Company. Your line is open.

Marc Frahm -- Cowen & Company -- Analyst

Hi. Thanks for taking my question. Maybe just a little bit followup on patient prevalence work that Darrin has been doing. Whether -- can you give us an idea of the Anemia ID test results? Are they tracking in line with the Spanish experience? So I think in the very early days, you said they were, but it was early, so curious to see if that's being maintained. And then maybe could you ask to quantify when you say that the volumes of -- demand for this test has increased the greatest Q-over-Q in Q3, can you maybe quantify that versus the first half? I mean, did you see as many volumes -- as many tests in Q3 as all of the first half or do you have something smaller or something bigger than that?

Darrin Miles -- Chief Commercial Officer

Oh, there's a lot in there, but it's a good question. All right. It's a package. So -- as I mentioned in my prepared remarks, but we did see a very significant uptick in requests for the test in Q3. And that's in large part related to -- think of this as growing momentum, but also, it's the first full quarter that we've had the field team in place, right. So they've been helping to educate the practices, the practices and patients as well, who liked to order the tests. So I think we're just shy of about 2,000 tests by the end of Q3. In terms of what we're seeing -- in terms of the results, the -- I expected it to fluctuate, right, particularly as the volume of test results just requested and the results -- the actual tests are conducted and then the results are reported. And there is a meaningful -- there's a material difference between what we -- the setting in which the Spanish study was conducted, which is a controlled-study setting versus the all-comer kind of experience that we have in the U.S. Plus, where the testing in the U.S. allows physicians to be able to look at a whole host of potential explanations for the patient's hemolytic anemias.

So in the Spanish experience, we saw about 20%. We expected it to be lower, but we think didn't know exactly what that would be. So I would say 20% continues to be the upper end of the range. I think it would be misleading, I think, to tell you exactly where we are today, because I would love to be able to see this further adopted more uniformly across the country. We have very strong pockets of utilization, I'd like to be able to see it used more broadly and I'd like to see us have more confirmed tests come through, before we start reporting routinely on what we're observing there.

Marc Frahm -- Cowen & Company -- Analyst

Okay, that's very helpful. Thank you.

Darrin Miles -- Chief Commercial Officer

No problem.

Operator

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

Michael King -- H.C. Wainwright & Company -- Analyst

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

Darrin Miles -- Chief Commercial Officer

Sure. Sure. Now, I put all this work into preparing to be able to provide that information to you at the Investor Day later this month, but I'll give you a preview now.

Michael King -- H.C. Wainwright & Company -- Analyst

Thanks for indulging me.

Darrin Miles -- Chief Commercial Officer

Sure. So we expect that it's going -- that the -- what we'll observe for PKD is reflective of what we would observe for the overall U.S. population. So about 55% or so of patients we expect, 55% to 60% should be commercial. Just about even split, 15% or so Medicare, 50% Medicaid and then the balance number of other DOD and cash. What we've -- what we are -- what we can expect is that you're going to have a ramp right until you have complete formulary coverage for the patients, particularly commercial patients. That will -- is in large part dependent on when commercial payers are going to hold their P&T committee meetings, which are on these tests, right. So that will take time to be able to get to universal coverage there. Medicaid and Medicare usually lag, so that may be a little slower than commercial.

In terms of what payers need from us, I think the thing that's been pretty clear, at this point now, we've had a host of one-on-one discussions with individual payers and a fair amount of research on this at this point. So if we're successful in making -- in establishing a firm understanding of the natural history of the disease, the long-term morbidities and complications associated with PKD, then the unmet need, the severity of the disease, regardless of transfusion history, is pretty well accepted and understood by the community, right, once we make the story. And so then -- and the clinical data, right, so the safety efficacy data are pretty clear and compelling, so there's little convincing you have to do there. You just have to make sure people have a good understanding of it.

Once you have that, then we expect fairly favorable access, which you'll have differences based on individual patients, individual benefit designs, but we would expect pretty good access. The key will come down to, right, what the label looks like at the end of the day and what price we choose, right, to make sure that we're sort of optimizing the business opportunity, but making sure that we're also optimizing the ability for all patients to be able to access the treatment as their physician warrants appropriate.

Michael King -- H.C. Wainwright & Company -- Analyst

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

Darrin Miles -- Chief Commercial Officer

Well, the -- so PerkinElmer, right, is the partner that we work with to provide the genetic tests, right. And not every patient is going to necessarily get a genetic test, right. So, commonly used test will be the enzyme -- with the enzyme assay, right. The genetic test is helpful and can be -- and just confirmatory there, right. So they're not limited to using the tool that we support.

Now, what we are intending to do is to have a mandated hub, right. So for every script that is written, the physicians will submit the script to go to myAgios, right, our patient support service. And patients then will opt in to the service accordingly, right. So that will give us the opportunity then to ensure that the appropriate confirmation of the patient diagnosis is in place, and helping them with supporting their engagement with payers, and then be able to engage with the patients and the practices on all of the appropriate disease education, connecting them with other patients in the PKD community, things along those lines and provide sort of surround sound in terms of adherence support for the patient as well. So the physicians aren't limited to -- to go back to your central question, the patients aren't -- the physicians aren't limited only to our -- the genetic tests that we provide. But we -- but through the prescription and then fulfillment process, right, we're able to provide a seamless service to ensure the patient is able to get on treatment successfully. And it gives us the best line of sight to individual patients as well.

Michael King -- H.C. Wainwright & Company -- Analyst

Okay. Yeah, OK. Terrific. Thanks so much for taking the questions.

Darrin Miles -- Chief Commercial Officer

No problem.

Operator

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

Mark Breidenbach -- Oppenheimer -- Analyst

Hey, good morning, and thanks for taking the question. This is probably a follow-up to Anupam's earlier question. It's probably directed to Sarah regarding AG-946. I was just wondering kind of what factors are leading to the decision to first put 946 into a sickle cell cohort as opposed to some of the other hemolytic anemias? And also, I'm wondering if you're seeing any pharmacodynamic thresholds that 946 needs to clear in healthy volunteers to justify continued development in terms of 2, 3-DPG reduction and maybe ATP increases, things like that. What would you kind of see as a best-case scenario from the healthy volunteer data? Thanks for taking the questions.

Sarah Gheuens -- Chief Medical Officer

Okay, great. So the current protocol, the way it is set up is it generates -- it's a very typical single ascending dose, multiple ascending dose study in healthy volunteers. And we're, of course, looking for pharmacodynamic engagement within that group and looking to max out and also generate appropriate safety data, which is like very classical Phase I type work. And then the protocol is set up with certain decisions around the pharmacodynamic engagement observed in healthy volunteers to move forward with the proper doses in the 946 sickle cell disease component of the trial.

In regards to why sickle cell, the sickle cell disease, clearly, there is a huge unmet medical need, and we're looking to further advance multiple therapies there for those patients. However, as with any development after any phase of clinical development, there will be go, no-go decisions to decide what is the best path forward for a specific molecule. Regardless -- despite -- it generates data for sickle cell disease, but because we're looking for hemolytic anemia and also what we've observed in the topicals across different hemolytic anemias, we are looking at that data as generating optionality for the rest of the decision-making across different indications.

Mark Breidenbach -- Oppenheimer -- Analyst

Okay, fair enough. Thank you. Our next question comes from Salveen Richter of Goldman Sachs. Your line is open.

Elizabeth Webster -- Goldman Sachs -- Analyst

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

Sarah Gheuens -- Chief Medical Officer

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

Darrin Miles -- Chief Commercial Officer

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

Elizabeth Webster -- Goldman Sachs -- Analyst

Thank you.

Operator

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

Andrew Berens -- SVB Leerink -- Analyst

Hi. Thanks for taking my questions. 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 two-thirds to date, and it did sound in your prepared comments as if there was some flexibility with the remaining one-third. Is there a possibility you may allocate that to external BD activities or are you committed to repurchasing shares? If it's the latter, just some idea of what the timing will be? Should we expect a similar cadence as what we've seen over the last 12 months? And then just a comment on 946, since it's going to be tested in sickle cell, are you still planning to advance mitapivat in sickle cell disease? And how far behind the 946 if that becomes the lead candidate for sickle cell disease?

Jonathan Biller -- Chief Financial Officer and Head of Legal and Corporate Affairs

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

Sarah Gheuens -- Chief Medical Officer

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

Jacqualyn Fouse -- Chief Executive Officer

Hi, Andy. It's Jackie. Nobody has asked me a question yet, so I'm getting -- I'm feeling neglected, so I'm going to jump in. So thank you for asking your two questions. I just also wanted to point out that after we closed the oncology divestiture with Servier and then we brought those funds in at the end of March, we were always flexible in terms of how we were going to think about our capital allocation. But what we knew at the time was that we were in a unique situation, given where we were in terms of the Agios life cycle and having undertaken what was a relatively large transaction for a company of our size. And given the amount of capital that we had raised over our history, our initial priority, and that's where we had the $1.2 billion share authorization was to kind of, what I'd call, reset our capital structure by giving some of that back to our shareholders, which we now have done, and I've been very happy with the execution that we've done on that -- this roughly $800 million or so over the last month. And so we continue to have that additional $400 million of authorization.

At the same time, our teams have made significant progress with some of our internal programs over the course of 2021. And now we see some opportunities that we'll talk about on November 17 to make incremental investments in our internal assets and programs to move some things along, where now we have the evidence to support the logic for moving them along and advancing them and adding those investments to our plan that weren't necessarily there in the past. And then as Jonathan said, we also have greater clarity in terms of our internal thinking, I would say, around the potential opportunity set in the BD arena. So there are different ways, as you know, to deploy our capital over time and we're always going to toggle between those different ways. But in the short term, we wanted to make a clear statement on the share count reduction with the return of capital. And now we're just going to be a little bit more flexible in terms of how we look at those different opportunities.

And then the last thing I just wanted to say is on 946, I can remember this from a year or even maybe more ago, we knew, as Sarah said, that we wanted to generate some data in, A, given hemolytic anemia, and at the time that we were moving forward with the healthy volunteer study, sickle cell disease seems to be the most logical one to add to that protocol to get some early data in a given hemolytic anemia disease. And I think you'll hear on November 17 some other ideas that we have for AG-946. And I will leave it at that. Thank you for your questions.

Andrew Berens -- SVB Leerink -- Analyst

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

Jacqualyn Fouse -- Chief Executive Officer

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

Andrew Berens -- SVB Leerink -- Analyst

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

Jacqualyn Fouse -- Chief Executive Officer

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's a chance that 946 and sickle cell one day end up complementary asset in that portfolio. It's as likely that we see some data for 946 in sickle cell disease that tells us something about how the product is performing in a given hemolytic anemia. And then we have the healthy volunteer data. And there have been maybe other indications that we would feel comfortable moving even faster into, based on the totality of what we've seen across the class of PKR activators and all of the work that we've done in 946 specifically.

Andrew Berens -- SVB Leerink -- Analyst

Okay. Thanks for allowing the questions.

Operator

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

Danielle Brill -- Raymond James -- Analyst

Hi, guys. Good morning. Thanks so much for the questions. I guess a couple on the sickle cell and thalassemia trials. I know you're excluding patients who are in active voxelotor, hydroxyurea, but will you permit enrollments of patients with prior exposures to those drugs? And then similarly for the ENERGIZE trials, are you permitting enrollment of patients who had prior treatment with luspatercept? Thank you.

Sarah Gheuens -- Chief Medical Officer

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

Danielle Brill -- Raymond James -- Analyst

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

Sarah Gheuens -- Chief Medical Officer

No, there is not.

Danielle Brill -- Raymond James -- Analyst

Got it. Thank you so much.

Sarah Gheuens -- Chief Medical Officer

Yeah. You're welcome.

Operator

Thank you. 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.

Jacqualyn Fouse -- Chief Executive Officer

Thank you, operator, and thank you, everyone, for the questions this morning. We look forward to an exciting time ahead with the February 17, 2022 PDUFA date coming up for mitapivat in PK deficiency in the U.S. We're also looking forward to the ongoing MAA review for same indication in Europe, the initiation of three pivotal studies by year-end across thalassemia and sickle cell disease in adult patients, the initiation of pediatric PK deficiency clinical program in 2022, and 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.

Operator

[Operator Closing Remarks]

Duration: 47 minutes

Call participants:

Holly Manning -- Senior Director, Investor Relations

Jacqualyn Fouse -- Chief Executive Officer

Sarah Gheuens -- Chief Medical Officer

Darrin Miles -- Chief Commercial Officer

Jonathan Biller -- Chief Financial Officer and Head of Legal and Corporate Affairs

John Newman -- Canaccord Genuity -- Analyst

Alethia Young -- Cantor Fitzgerald -- Analyst

Kennen MacKay -- RBC Capital Markets -- Analyst

Anupam Rama -- JP Morgan -- Analyst

Marc Frahm -- Cowen & Company -- Analyst

Michael King -- H.C. Wainwright & Company -- Analyst

Mark Breidenbach -- Oppenheimer -- Analyst

Elizabeth Webster -- Goldman Sachs -- Analyst

Andrew Berens -- SVB Leerink -- Analyst

Danielle Brill -- Raymond James -- Analyst

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