Agios Pharmaceuticals Inc (AGIO) Q4 2020 Earnings Call Transcript

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Agios Pharmaceuticals Inc (AGIO -0.57%)
Q4 2020 Earnings Call
Feb 25, 2021, 8:00 a.m. ET

Contents:

• Prepared Remarks
• Questions and Answers
• Call Participants

Prepared Remarks:

Operator

Good morning, and welcome to Agios' Fourth Quarter 2020 Conference Call. [Operator Instructions]

I would now like to turn the call over to Holly Manning, Director of Investor Relations.

Holly Manning -- Investor Relations

Thank you, operator. Good morning everyone, and welcome to Agios' fourth quarter 2020 conference call. You can access slides for today's call by going to the Investors section of our website, agios.com. With me on the call today with prepared remarks are Dr. Jackie Fouse, our Chief Executive Officer; Dr. Chris Bowden, our Chief Medical Officer; Darrin Miles, our Chief Commercial Officer; and Jonathan Biller, our Chief Financial Officer and Head of Legal and Corporate Affairs. Dr. Bruce Car, our Chief Scientific Officer, will join for Q&A.

Before we get started, I would like to remind everyone, 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 statement as a result of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC, and any other future filings that we may make with the SEC.

With that, I will turn the call over to Jackie.

Jacqualyn Fouse -- Chief Executive Officer

Thanks, Holly. Good morning, everyone, and thanks for joining our fourth quarter 2020 results call. Before we get into the exciting work we have ahead of us in 2021, I want to take a moment to reflect on this past year and acknowledge the extraordinary challenges faced by all of us at Agios, the patients we serve and the global community at large.

One year ago, when I spoke on the Q4 2019 call, we did not know that just a few weeks later, the COVID-19 outbreak would escalate into a global pandemic, shutting down our offices and halting life as we knew it. For many of our employees, working from home included balancing new challenges in their personal lives, such as virtual school, taking care of young children and new worries about health and wellbeing in a pandemic. And patients around the world, including those in clinical trials, struggled with reduced access to travel and medical centers. At the same time, the US faced significant civil and political unrest that further exposed the realities of the racial and social divides in our country. In the wake of these challenges, I have been overwhelmed by the generosity, determination and spirit of the Agios team in support of each other, patients and our communities.

As of last week, our cross-functional coronavirus task force wrapped up their first year, having responded to nearly 750 inquiries from patients or healthcare providers across dozens of countries. For each request, the team worked tirelessly to reduce the risk to patients and/or the burden to healthcare systems due to COVID-19 and went to great lengths to ensure patients could continue to have access to our medicines, despite the unprecedented circumstances. Our facilities and HR teams have gone above and beyond the call of duty to ensure our labs and offices remain safe for employees who need to work on site, including providing access to testing and contact tracing.

For the teams working from home, they've organized personal and professional resources like webinars on avoiding burnout, access to educational materials and activities for our children, virtual employee interactions to maintain our connections and ongoing team building activities to adapt our culture during this time and beyond. On a community level, we led a diversity initiative at Agios that included speakers and workshops on valuing differences to heighten our awareness and help us learn together.

As you can see in the photos on Slide 5, we continue to support causes important to us through fundraisers and events and in December, our employees donated gifts to families with children suffering from life-threatening diseases. With the realities and struggles of 2020 continuing in 2021, I nevertheless find myself incredibly hopeful for the future and more confident than ever in our ability to overcome whatever comes our way.

From a business perspective, we have much to be excited about as we embark on the next chapter of Agios with a sole focus on genetically defined diseases. In December, we announced our refocused strategy and the decision to sell our oncology assets to Servier, a successful patient-focused global pharmaceutical company with a deep commitment to expanding its emerging oncology portfolio. As part of the transaction, which is subject to a shareholder vote on March 25, Agios will receive cash consideration of up to $2 billion, including $1.8 billion in upfront cash and $200 million in a potential future cash milestone payment as well as 5% royalties on US net sales of TIBSOVO from transaction close through loss-of-exclusivity and 15% royalties on US net sales of vorasidenib from first commercial sale through loss-of-exclusivity.

After returning $1.2 billion to shareholders, residual proceeds will be retained to fund the company through major value-driving catalysts into profitability without the need for any additional equity raises. These decisions will allow the oncology portfolio to grow and thrive with Servier and will provide Agios with the capital required to maximize the potential for promising therapies for genetically defined diseases, ultimately enabling the greatest overall positive impact for patients. For more details, you can access our press release, investor presentation and proxy statement on our website at agios.com.

Over the last few months, we've made significant strides with our most advanced medicine, mitapivat, across our three initial therapeutic areas of focus, and this progress sets us up for a catalyst-rich year ahead, which Chris will cover in a moment. In addition, we are also moving other genetically defined disease programs through our clinical and research pipelines.

On the oncology side, we've continued to execute on both, the clinical and commercial fronts. We closed out the second full year of TIBSOVO net revenue with $121 million, exceeding our $115 million net revenue target. Looking ahead to the evolution of our commercial business, I'm pleased to announce that Darrin Miles has been promoted to the role of Chief Commercial Officer. He has served in numerous roles at Agios since joining us in 2015, including most recently as Senior Vice President of US Commercial and Global Marketing. Darrin has done a tremendous job leading our team to superior TIBSOVO commercial performance while also preparing us for our first genetically defined disease launch with PK deficiency in 2022. Darrin's thoughtful and genuine leadership style is felt throughout our company. We are very optimistic about our bright future and our ability to continue to bring transformative therapies to more patients than ever with our renewed focus and financial strength.

With that, Chris, let me turn it over to you.

Chris Bowden -- Chief Medical Officer

Dr. Chris Bowden

Thanks, Jackie. Looking back at 2020, I'm humbled by the dedication and resourcefulness of our clinical organization on both the oncology and genetically defined disease sides of the business to advance our clinical programs over and above expectations for patients, despite the challenges of the pandemic.

As we enter 2021 we are excited about our future in genetically defined diseases and have significant work ahead of us as we advance our late stage programs and make decisions about our next wave of research. I will start with our most advanced genetically defined disease program mitapivat. Our first in class PKR activator currently being evaluated across three distinct clinic hemolytic anemias, pyruvate kinase deficiency, Thalassemia and Sickle cell disease. In pyruvate kinase deficiency, we recently reported top line data from the ACTIVATE and ACTIVATE-T Phase 3 studies, evaluating mitapivat in adults with pyruvate kinase deficiency who were not regularly transfused and those who were regularly transfused, respectively.

In the ACTIVATE study, 40% of patients treated with mitapivat achieved the primary endpoint of a sustained hemoglobin increase compared to zero placebo patients, a highly statistically significant result. Statistical significance was also achieved for all prespecified key secondary endpoints for ACTIVATE, demonstrating an improvement compared to placebo, including in patient-reported outcomes based on changes from baseline and pyruvate kinase deficiency diary score and pyruvate kinase deficiency impact assessment score at week 24. We anticipate that these data will be supportive of our submission for regulatory approval as well as in interactions with access providers. In ACTIVATE-T, more than a third of patients achieved a meaningful reduction in transfusion burden and 22% were transfusion-free during the 24-week fixed-dose period. In both studies, the safety profile was consistent with previously reported data in PK deficiency patients.

Data from both studies, including the PRO data, will be submitted for presentation at the European Hematology Association Virtual Conference, which is being held June 9 through June 17 this year. These data support the potential for mitapivat to be the first disease-modifying therapy for pyruvate kinase deficiency and will be the basis for our global regulatory filing that is currently in process. We anticipate filing for regulatory approval in the US in the second quarter of 2021 and in the EU in mid-2021 with a potential 2022 commercial launch in both geographies.

Moving to the Phase 2 study of mitapivat in Thalassemia. We completed enrollment last year with 20 patients. And in June, we presented updated data on 13 efficacy evaluable patients at the virtual EHA meeting. The data showed that treatment with mitapivat induced a hemoglobin increase of greater than or equal to 1 gram per deciliter in 12 of 13 evaluable patients during weeks four through 12, including four of four alpha-thalassemia patients for whom there have been no new treatment options in decades. In addition, seven of eight beta-thalassemia patients achieved a sustained hemoglobin response during weeks 12 through 24. As of November 2020, 17 patients remained in the extension portion of the trial. We expect to submit the full data set from all 20 patients in the core period from this study for presentation at EHA.

In December, we shared a first glimpse of our two global pivotal trials of mitapivat and thalassemia, ENERGIZE and ENERGIZE-T. As you can see at the top of Slide 11, ENERGIZE will evaluate 171 patients randomized 2:1 to 100 milligrams of mitapivat BID or placebo in beta and alpha-thalassemia patients who are not regularly transfused. The primary endpoint is the percent of patients with a mean hemoglobin increase of greater than or equal to 1 gram per deciliter from baseline over a 24-week core period. ENERGIZE-T will evaluate 240 patients randomized 2:1 to 100 milligrams of mitapivat BID or placebo in beta and alpha-thalassemia patients who are regularly transfused, defined as six to 20 red blood cell units transfused during the 24 weeks prior to randomization. The primary endpoint is the percent of patients with a 50% reduction in transfusion burden in any 12-week rolling period during the 48-week core period. We are in the process of operationalizing both studies and look forward to initiating these trials by the end of the year.

Now, let's turn to sickle cell disease. Last year, mitapivat was the first PKR activator to demonstrate proof-of-concept in this disease, based on initial data from a study being conducted in collaboration with Dr. Swee Lay Thein of the National Institutes of Health. As outlined on Slide 12, at ASH in December, the NIH presented updated data from 11 patients, demonstrating mitapivat's impact on hemoglobin improvement in conjunction with improvements in markers of hemolysis. Dr. Thein continues to enroll patients in the core study as well as an extension study and expects to provide an update at a medical meeting this year.

In addition, our collaborators at the University of Utrecht initiated an investigator-sponsored trial of mitapivat in sickle cell disease late last year, and they also plan to submit data from this study for presentation at a medical meeting this year. In parallel with these clinical activities, we completed US, EU regulatory meetings focused on advancing our sickle cell disease program into pivotal development. Their input led to the development of a robust and thoughtful pivotal development strategy, which I'm excited to share with you today. We believe this plan derisks the approval path for mitapivat in this challenging disease and maximizes the likelihood of a label with a broad indication in 2026.

The advice we received from FDA and EMA about the pivotal trial design for mitapivat in sickle cell disease was based on the currently available data, our initial clinical trial design and the evolving treatment landscape. Specifically, we heard that hemoglobin alone is not considered an established surrogate for clinical benefit in sickle cell disease. An interim hemoglobin analysis is highly unlikely to result in an accelerated approval and the unblinding at interim has the potential to compromise the sickle cell pain crisis endpoint. We have been strongly advised to develop data across two dose levels to further understand the pharmacodynamics and safety profile in sickle cell disease, given the complexity of this disease relative to other hemolytic anemias.

Based on this feedback, we've designed the operationally seamless Phase 2/3 study of mitapivat in adults with sickle cell disease that you see here on Slide 13. The study will include patients who are 16 years of age or older, and have had two to 10 sickle cell crises in the past 12 months and have a hemoglobin of greater than or equal to 5 and 5.5 and less than 10.5 grams per deciliter during screening. Patients currently receiving treatment with voxelotor, crizanlizumab or any other agent intended to increase hemoglobin oxygen affinity are excluded. Treatment with hydroxyurea is allowed.

The Phase 2 on your left were randomized 69 patients in 1:1:1 to 50 milligrams mitapivat BID, 100 milligrams mitapivat BID or matched placebo. The primary endpoint is a hemoglobin response defined as greater than or equal to 1 gram per deciliter change from baseline to week 12, and the data will be used to establish a clear dosing paradigm for the Phase 3 portion. On the right, the Phase 3, 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, hemoglobin response defined as greater than or equal to 1 gram per deciliter change from baseline to week 52 and the annualized rate of sickle cell pain crises. We are on track to initiate the trial by the end of the year. As a result of these changes to our initial pivotal plan for mitapivat in sickle cell disease, we now expect a regulatory approval in the 2026 timeframe instead of our original guidance of an approval in the end of 2025. We believe that by addressing the FDA and EMA feedback prior to the start of the Phase 2/3 trial, this new plan increases the likelihood of a broad competitive label that is inclusive of both hemoglobin and sickle cell pain crises endpoints at the time of launch.

Here on Slide 14, you can see the robust pipeline we're building with mitapivat across these three initial indications. As we did with TIBSOVO, our focus is to advance mitapivat from pivotal development to regulatory approval as quickly as possible. Starting with pyruvate kinase deficiency next year, we believe we have the opportunity to meaningfully expand the labeled indications for mitapivat over the next five years to address three serious hemolytic anemias that desperately need new treatment options.

Beyond mitapivat, we're also advancing our next-generation PKR activator, AG-946, through a Phase 1 healthy volunteer study. The trial began enrolling last fall, and we expect to submit data from the single ascending dose and the multiple ascending dose cohorts for presentation at a medical meeting by the end of the year. Our analysis of the totality of the AG-946 healthy volunteer data will inform next steps for the clinical development of this molecule.

Bruce's team has been hard at work producing a robust and promising pipeline of research within the PK activation mechanism, and we plan to make decisions on the next wave of indications for these as well as our clinical stage drugs by the end of the year. We also have significant non-pyruvate kinase opportunities within our research pipeline, including a stabilizer of the enzyme deficient and phenylketonuria that degrades phenylalanine and a unique approach to treating aminoacidemias and acidurias associated with inborn errors of metabolism. Our deep expertise created around cellular metabolism to elucidate cancer cell biology has been exploited to great effect in understanding multiple genetically defined conditions and has allowed us to build a deep portfolio of genetically defined targets. We look forward to sharing more about these programs at an R&D Day in the second half of the year.

On slide 16, we've outlined all of our 2021 key milestones. And I'll now focus on our oncology programs, where we have been hard at work making important progress across a number of late-stage programs in malignant hematology and solid tumors. Last month at the ASCO-GI meeting, we reported a full analysis of the final data in the global Phase 3 ClarIDHy trial of TIBSOVO in patients with previously treated IDH1-mutant cholangiocarcinoma. The final analysis showed that median overall survival for patients randomized to TIBSOVO was 10.3 months compared to 7.5 months for patients randomized to placebo. The hazard ratio for overall survival did not meet statistical significance. However, a high proportion of patients in the placebo arm, 70.5%, crossed over to TIBSOVO. A prespecified crossover-adjusted analysis showed a median overall survival for patients in the placebo arm of 5.1 months and the hazard ratio for overall survival was statistically significant. The safety profile observed in the study was consistent with previous published data. And last year, we reported positive, highly statistically significant progression-free survival data.

Based on these data, we are on track to submit a supplemental new drug application for TIBSOVO in previously treated IDH1-mutant cholangiocarcinoma in the first quarter of 2021. In addition to cholangiocarcinoma, we are exploring utility of IDH inhibition in low-grade glioma in our Phase 3 INDIGO trial of vorasidenib. Vorasidenib is our brain-penetrant dual IDH1/2 inhibitor that has the potential to treat the roughly 80% of low-grade glioma patients with an IDH mutation. Enrollment is ahead of expectations, despite the pandemic, reflecting physician enthusiasm for the potential of vorasidenib in this trial. And finally, the AG-270 Phase 1 dose escalation combination arms with taxanes continued to enroll patients. On the hematologic malignancy side, enrollment in our Phase 3 frontline AML combination studies of TIBSOVO as well as our MDS expansion are ongoing, with AGILE in the MDS cohort expected to complete enrollment by year-end.

With that, I'll turn it over to Darrin to discuss our fourth quarter commercial performance.

Darrin Miles -- Senior Vice President, US Commercial and Global Marketing

Thank you, Chris. Despite the resurgence of COVID-19 in Q4 and continued limitations on in-person sales promotion, our team delivered TIBSOVO net sales of $39.1 million in Q4, a 23% increase over the third quarter. That brings 2020 net sales to $121 million or a 102% increase year-over-year, exceeding the upper end of our updated guidance by $6 million. Performance in the quarter was driven by growth in new scripts and refills and favorable gross to net.

We continue to see double-digit growth in both, the academic and community settings, driven by a 15% increase in new prescribers over Q3. Physician preference for TIBSOVO in the frontline-intensive chemo-ineligible and first relapsed settings remain strong as do all leading indicators of physician perception, including the prevailing belief that TIBSOVO is the standard of care for newly diagnosed and relapsed/refractory IDH1-mutant patients.

Though promotional efforts are limited to FDA-approved uses of TIBSOVO only, we still observe that approximately half of TIBSOVO use in both settings is in combination most frequently with an HMA. We've also observed continued growth of TIBSOVO use for patients with cholangiocarcinoma. The line of sight to the extent of that use is limited to only the third of the volume that moves through the specialty pharmacy channel. Looking forward, we expect continued strength in AML through 2021, culminating net sales in the range of $160 million to $170 million in 2021.

Turning to mitapivat and pyruvate kinase deficiency. Launch preparations are on track and further energized by the disclosure of the positive ACTIVATE and ACTIVATE-T trial results. Last quarter, we announced the launch of Anemia ID, our partnership with PerkinElmer Genomics to offer no cost genetic testing to patients with suspected hereditary anemias. This 50-gene panel can help to provide a definitive diagnosis of the underlying cause of their anemia and represents an essential part of our multipronged effort to accelerate patient identification and disease education in the US.

Though COVID-19 continues to present challenges related to commercial promotion, there are a number of important learnings from our experience in AML sales and marketing that are informing a more efficient build for PK deficiency, including sales force sizing and our marketing mix. I want to take this opportunity to express my appreciation to the entire Agios oncology team for their work throughout the year, made all the more impressive when we consider the circumstances. Resilience, grit and unwavering commitment to patients undergird this performance, and thousands of patients and all of Agios are grateful for it.

I'll now turn it over to Jonathan for Q4 financials.

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

Thanks, Darrin. Our fourth quarter and full year 2020 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-K filing later today.

Total revenue for the fourth quarter was $44 million, bringing total revenue for the full year of 2020 to $203.2 million, an increase of $85.3 million compared to 2019. As Jackie and Darrin mentioned, product sales of TIBSOVO were $39.1 million for the fourth quarter and $121.1 million for the full year 2020, an increase of $61.2 million compared to 2019.

Collaboration revenue was $2 million for the fourth quarter and $71.8 million for the full year 2020, an increase of $24.3 million compared to 2019. The higher collaboration revenue in 2020 was due to recognition of the remainder of the deferred revenue balance related to the completion of the metabolic immuno-oncology collaboration with Celgene BMS. Our full year 2020 revenue also includes $10.3 million in royalty revenue from net global sales of IDHIFA, $2.9 million of which was recognized during the fourth quarter. As a reminder, we sold the IDHIFA royalty revenues to Royalty Pharma in Q2 2020, but continue to book the royalty revenue under GAAP. Cost of sales for the fourth quarter was $1 million and $2.8 million for the full year 2020. This year-over-year increase of $1.5 million was driven by ex-factory sales.

Turning to operating expenses. R&D expenses for the fourth quarter were $95.7 million and $367.5 million for the full year 2020, a decrease of $43.4 million compared to the full year 2019. This year-over-year decrease in R&D was largely driven by winding down of the ClarIDHy study and Phase 1 study of TIBSOVO in hematologic malignancies, the deprioritization of AG-636 and lower milestones incurred for HOVON.

Selling, general and administrative expenses were $39.8 million for the fourth quarter and $149.1 million for the full year 2020. This represents a $17 million increase over full year 2019, driven primarily by increased workforce expenses in the US and EU, and professional fees related to the Servier transaction.

We ended the quarter with cash, cash equivalents and marketable securities of $670.5 million. We expect that this cash balance, together with anticipated product revenue, interest income and expense reimbursements under our collaboration agreements, but excluding any additional program-specific milestone payments, will fund our current operating plan to the end of 2022.

Following the closing of the Servier transaction and net of the planned capital return, Agios expects to be able to fund its operations through major catalysts and to cash flow positivity without the need to raise additional equity. As previously communicated, we plan to realign our capital structure to reflect the profile of our focused, genetically defined disease company by returning $1.2 billion of capital as share repurchases over a 12 to 18-month period following closing. We will provide more information with respect to share repurchase tactics and mechanics in due course.

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

Questions and Answers:

Operator

[Operator Instructions] Our first question comes from the line of Peter Lawson with Barclays.

Peter Lawson -- Barclays -- Analyst

Hey. Thanks for taking my questions. Just on the sickle cell, just a quick question around, I guess, the 100-milligram dosing. When could we see more of that data, just the timing around that? And, if you think that's an important component in moving forward in sickle cell?

Chris Bowden -- Chief Medical Officer

Hi Peter, it's Chris Bowden here. Well, we're not guiding to the Phase 2 portion of the trial that I went through in my prepared remarks yet. And as we get that up and running and get some sense of the accrual, we'll be able to provide further information there. Certainly, over the coming year, we're going to see more data coming out from the trials that are ongoing at the NIH and then Utrecht, where we would be able -- we'll be bringing some more [Technical Issues] sorry, clinical data forward.

Operator

Your next question comes from the line of Tyler Van Buren with Piper Sandler.

Tyler Van Buren -- Piper Sandler -- Analyst

Hey guys. Good morning. Thanks for the updates. Question related to the sickle cell trial design. I guess, if I'm not mistaken, the Oxbryta or voxelotor HOPE trial just had the hemoglobin response rate primary endpoint, whereas here it's kind of two primary endpoints. Do you -- I guess, was the addition of the sickle cell pain crises endpoint kind of primarily required by the FDA, or was that something you guys chose to add in?

And is -- do you have to hit on both of those to receive approval? And it would be helpful to understand that also in the context of the fact that you have the two -- the cutoff on the lower bound of sickle cell pain crises in the past 12 months of two as opposed to one. I was surprised to learn that the HOPE trial had 42% of patients that had one crises. So, do you -- I guess, you expect that to increase the signal there as well.

Chris Bowden -- Chief Medical Officer

Yes. Tyler, it's Chris here. So, a number of different issues you touched on. Voxelotor received accelerated approval on the basis of the increase in hemoglobin. And as you and we've all been following, they have not demonstrated a statistically significant reduction in vaso-occlusive crises. In our interactions with health authorities, VOCs, whether it's a primary endpoint or a very high-ranking secondary endpoint, is crucial in assessing the therapeutic index, if you will, clinical benefit of the molecule.

Specifically for the trial that we're putting forward, having two primary endpoints that we hit on either one of the study is positive. And then, the interesting part will be what the regulatory view and the clinical benefit of that trial. By designing it this way, if we hit on one, we have a positive trial. And we think we're going to design the trial so that we have a compelling case for clinical benefit if we hit on either endpoint. Ultimately, that's a function of the data. And if you hit on both, of course, that's our best case scenario. And we think the mechanism of action of mitapivat supports us designing the trial and having some reason to believe that that could be the case.

I think, one of the main things that we want to get across, and this is consistent with what we've talked about with pyruvate kinase deficiency, is that in a setting where -- like sickle cell disease, where raising hemoglobin is important, you have to have other supportive data with that. And so, linking back to pyruvate kinase deficiency, we've long heard very consistently that if you show up with an increase in hemoglobin that's statistically significant, but there's no other clinical data to support that patients are feeling better you're addressing hemolysis, then you're going to have a tough sell.

Operator

Thank you. And your next question comes from the line of Anupam Rama with JP Morgan.

Anupam Rama -- JP Morgan -- Analyst

Hey guys. Thanks so much for taking the question. I think, we've talked about around 1,100 patients with PKD kind of identified in the U.S. and core OUS regions. I think that update was a while ago, maybe ASH 2019. What's the updated patient count here? How has patient identification gone in 2020? And how do we think about patient identification going forward? Thanks so much.

Darrin Miles -- Chief Commercial Officer

Hi Anupam, this is Darrin here. So, you're correct. Last, we've discussed it actually most -- as recently as our last webinar regarding the mitapivat program, we restated our current count at about 1,000 patients or so. COVID has made it more challenging to identify patients at the rate we would have wanted, given the need to be able to engage with physicians at various conference settings and their practices, things along those lines. But, we do continue to add to that number over time. We expect that that will accelerate over the course of this year.

I think, what's really important and has actually been a bit surprising for us is having a good understanding of the complete suite of activities that we're employing or tactics we're employing in order to accelerate the patient finding activities, one of which is the Anemia ID program, which we've talked about. Just recently, I received an update on where we are with it. We're on pace by the end of this quarter to actually exceed the number of tests distributed that we had anticipated for the full year of 2021.

And we're seeing a PKD positivity rate that approximates what we saw with the Spanish experience or Spanish IST that we talked about previously. So we believe that that's going to be a very important contributor to our patient finding activities this year and indicates to us that the sense of urgency, the level of interest around this disease and hopefully then mitapivat exceeds -- is already exceeding our expectations.

Jacqualyn Fouse -- Chief Executive Officer

Yeah. And it's Jackie here. I think, underneath everything that Darrin said, also along the way, having the ACTIVATE and ACTIVATE-T data as well as what we announced today, which I think is very important, having hit statistical significance on the key prespecified secondary endpoints for ACTIVATE, including the PRO data, is a really nice package of information to continue all of the efforts that Darrin and his team have -- and our medical affairs people are working on. And it's -- I think, it's going to be a very compelling message with both physicians as well as patients that -- look, it's not just efficacy data. We're also hearing from -- or not hearing, we're seeing in the PRO data from patients on this trial that there is benefit. So, I think, it's a pretty strong message.

Operator

Thank you. And our next question comes from the line of Kennen MacKay with RBC Capital Markets.

Kennen MacKay -- RBC Capital Markets -- Analyst

Hi. Thanks for taking the question. And Jackie, to your point, what a year, and congrats on finishing on plenty of strength. Maybe just a question on the mitapivat program in sickle cell disease. Sort of wondering about -- excluding patients who are either receiving voxelotor or crizanlizumab or any of the other agents that change hemoglobin oxygen affinity, it seems like that could make enrollment, at least in the U.S., somewhat challenging. I'm just wondering sort of how that's going to change enrollment into the trial versus some of the prior studies where there wasn't anything available. Thank you.

Chris Bowden -- Chief Medical Officer

Yes. Kennen, it's Chris here. I think, you touched on one of the interesting things that we encountered somewhat of a similar situation in leukemia and AML with the IDH inhibitors as we were coming in with TIBSOVO and IDHIFA in a rapidly changing landscape. There are things you can predict and things you can't predict. If you just sort of take those drugs in order. Voxelotor, if we were going to permit that, then you would need to understand is there a drug-drug interaction, number one. And you'd probably need to set up your trial in some way to do some sort of comparison.

So, the fact that we can do a placebo-controlled study is an advantage of sorts. But, there certainly will be patients in the United States who are on voxelotor, their hemoglobin has gone up. And, in the eyes of their physician as well as the individual, they will be satisfied. And there will be also individuals who may be on both drugs, crizanlizumab and voxelotor. So, certainly, there will be a wave of changes as new drugs become available to patients.

At the same time, there'll be -- sickle cell is a global disease. And so, we're going to expand our recruitment efforts. And that's a big part of our feasibility. And Hydrea will clearly be allowed. It's a standard of care. Many patients are on it. So, I think that -- and then, if you take the number of the significant percentage of patients who don't respond to voxelotor will be looking for another option and coming on to this study will be an attractive one for them, we hope.

So, I think overall, certainly, the development of new therapies is a good thing for patients. They have more options. At the same time, it also raises awareness in the community. None of these drugs are 100% effective, and they certainly have gaps in their target product profile. We need to define whether we can address those gaps. But I think that given the data we generated to date and the attractiveness of the mechanism of action, we think we have a good chance. And our early feasibility is telling us that people are very interested in talking to patients about coming on to the study.

Operator

Thank you. And our next question comes from the line of Michael Schmidt with Guggenheim.

Michael Schmidt -- Guggenheim -- Analyst

Hey guys. Good morning. Thanks for taking my questions. I had another one for Chris on the sickle cell disease study design. It sounds like the -- much of the FDA discussion may have been focused also on the dose selection. And I was just curious if you could talk a little bit more about what some of their considerations were when asking you to look at both the 50 and the 100-milligram dose and not just settle on 100, like you're doing it in the thalassemia trial. So, thanks so much.

Chris Bowden -- Chief Medical Officer

Yes. It's that 50 to 100 milligrams where based on the data we have so far, you see an increase in the pharmacodynamic changes. And you can't -- at this point, we think we are pretty close to maximal hemoglobin response is 50. Although in thalassemia, we felt like we picked up a few more patients. Their feedback, which is somewhat consistent with EMA, is that it's a complicated disease. They've seen a lot of drugs fail.

So, we advise that -- and you will help us in terms of understanding the risk-benefit of your drug and what you take the Phase 3 by doing a Phase 2 investigation component and understanding further what this pharmacodynamic 2, 3-DPG ATP relationship, hemoglobin relationship and safety looks like across these two doses before you make a decision to take one forward. And that was one of the drivers there. And then, they were very clear on some of the-- that component around hemoglobin that I talked about in terms of the trial design.

Operator

Your next question comes from the line of Mohit Bansal with Citi.

James Shontz -- Citi -- Analyst

Hey. Good morning, guys. This is James on for Mohit. Thanks for taking our questions. Just a quick one on AG-946. What do you need to see from the SAD and MAD trials to open the sickle cell disease cohort? And I guess, just like -- one like related topic is, does 946 have a longer half-life and can it offer once-a-day dosing?

Chris Bowden -- Chief Medical Officer

So, the answer to the last part of your question is, possibly it could offer once-a-day dosing. And then, what we would need to see to take it forward would be we need to see it clear its hurdles in terms of what we would expect to see from reductions in 2, 3-DPG and increases in ATP and an adequate safety profile, a predictable and reasonable pharmacokinetic profile. So, that's really the totality of data that we'd be looking at. And we'll want to be able to observe that data or analyze that data across several different cohorts, which we're in the midst of dosing now.

James Shontz -- Citi -- Analyst

Appreciate it. Thank you guys.

Operator

Our next question comes from the line of Marc Frahm with Cowen & Company.

Marc Frahm -- Cowen & Company -- Analyst

Hey. Thanks for taking my questions. And congrats on getting through what's challenging here for everyone. Maybe just following up on some of the questions on the sickle cell trial design for Chris. Can you provide any granularity kind of as to how you're splitting the alpha between the co-primary endpoints? And kind of inherent to that is, what is the powering that you're expecting to see on the on the pain crises? And are there any kind of important kind of stratification factors that we should be thinking about, maybe the hydroxyurea use or the exact rate of baseline sickle crises?

Chris Bowden -- Chief Medical Officer

A lot of interesting questions, Marc. It's not a co-primary endpoint. So, there are two primary endpoints. The trial is positive if it hits on either one. And we'll be disclosing the further details around the stats on the trial later in time, especially as we get them up and running.

Your question around VOCs related to sort of what we would expect in terms of the numbers and how hydroxyurea will come into play there, I mean, I think that's one of the hardest things to predict in this disease and only rendered more challenging by virtue of the fact that you have now with crizanlizumab, at least in the U.S. and expanding in Europe, a drug that's effective in reducing the frequency of VOCs. So, that's going to be something that we need to follow.

And so, one of the reasons why we designed the trial the way we did that it can be successful on the basis of either one of those readouts, a close to best case scenario, and we do have reason to believe that we could reduce VOCs. And I think that if you look at the history of trials and if you look at -- most recently, when you look at the voxelotor trial that clearly improves hemoglobin but wasn't able to demonstrate an improvement in the reduction in VOCs. There's clearly an unmet need there.

And there's -- the other part of your question is, I think there's just a lot of heterogeneity in this disease. And that's one of the reasons why we've received a lot of feedback from both the EMA and the FDA in terms of pulling all this together.

A trial design is a mix of many things. It's feedback from the authorities. It's talking to individuals with the disease, in this case, sickle cell, and they talk about issues with access. They talk about issues with trust of the medical community. When they talk about their symptoms, the one that really, really comes out is pain. And so, these are the types of things pulling all that together. And then, regulatory feedback is the mix of you should do this, you must do this.

And so, then, as a company, you have to take some positions, especially when you're balancing EMA versus FDA because they don't obviously give -- usually, they give you for some degree of inconsistency in that feedback. And then, you have to look at what's happening from an operations and feasibility perspective. So, pulling all that together is -- it's fun, it's challenging, it's complex. And we've been working hard to come up with the plan that we have today, which we think balances all those factors and give us the best chance of having a positive trial that demonstrates clinical benefit for individuals with sickle cell disease.

Operator

Thank you. Your next question comes from the line of John Newman with Canaccord.

John Newman -- Canaccord -- Analyst

Hi guys. Good morning. Thanks for taking my question. Chris, just curious, for the sickle cell disease Phase 2/3 trial, will you be able to look at any sort of a PRO or any sort of measure of fatigue, etc, in patients? I know that this has been really difficult in the past for sickle cell disease, but just curious if you have anything of that sort built into the study. Thanks.

Chris Bowden -- Chief Medical Officer

Yeah. John, the patient-reported outcomes and quality of life will be an essential part of the study. And it comes back to that feedback that we've heard, starting with our foray and however many years ago in pyruvate kinase deficiency. And that data, whether it's quality of life, patient-reported outcomes, is essential in the setting of this trial. It's essential in all these trials really when you're raising hemoglobin as a primary endpoint. But, you've got to be able to show that patients are feeling better and provide some evidence that patients are feeling better, whether it's -- whereby virtue of individual responders are in your experimental arm.

So, yes, we have to collect that data. It will be a very important part of demonstrating clinical benefit in the setting of a trial that demonstrates an increase in hemoglobin but misses on VOCs because the trial could still be positive. And then, the regulators who control the approval will say, so, what other things do you have to show us that patients who have hemoglobin increase feel better? Then payers won't be asking the same question. So, that's an important part of the trial.

And there's been a lot of work in terms of trying to describe the burden of disease and reducing the burden of disease of drug therapy in patients with sickle cell disease. So, there's validated scales. There's 6-minute walk test and there's a number of things that one can look at. It's challenging, and we don't -- we go into this with our eyes wide open. Like I said, a lot of drugs that have either been positive or marginally positive, what have you, have not been able to demonstrate those improvements. So, it's a very challenging area, but it's absolutely essential.

Operator

Thank you. And our next question comes from the line of Mark Breidenbach with Oppenheimer.

Kalpit Patel -- Oppenheimer -- Analyst

Yes. Hi. This is Kalpit on for Mark. And thanks for taking our question. Just a quick one for Chris. Are you planning on implementing any titration or tapering schedules for the upcoming Phase 2/3 sickle cell study? Thanks.

Chris Bowden -- Chief Medical Officer

With mitapivat, we will -- since we went into pyruvate kinase deficiency, we think we recommend tapering the drug. We don't recommend abrupt stoppage. So, that won't change. In terms of the Phase 2 portion, we'll just start patients at 50 and 100 milligrams. They won't titrate up.

Operator

Thank you. And our next question comes from the line of Andrew Berens with SVB Leerink.

Christopher Liu -- SVB Leerink -- Analyst

Hey. This is Chris on for Andy. Thanks for taking our question. I know you said that you'll provide more specifics around the planned share buybacks later on. But, I was just wondering if there could be any help or color on general aspects of it, such as do you expect to start it as soon as the process is completed, or -- and will it be at the market or a potential tender?

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

Hey. This is Jonathan. Thanks for the question. Implicit in your question is there's many different ways to execute share repurchases. We have a fairly significant amount of repurchases to do as a percentage of our market cap. So, I think, it's fair to say you could -- and we've guided that we'll do it over 12 to 18 months. So, I think, it's fair to expect that they'll likely be more than one mechanism by which we'll do it. Our planning right now is ongoing, and it's really designed to try to make sure that we do it in the most efficient way that we can and in the way that will be most likely to increase long-term shareholder value. We'll give more guidance as we get closer to executing. And we would expect that we will be commencing share repurchases at some point in due course, following closing, but more to come on that.

Operator

Thank you. I'll now turn the call back over to Chief Executive Officer, Jackie Fouse, for any closing remarks.

Jacqualyn Fouse -- Chief Executive Officer

Thank you very much, operator, and thank you very much all of you for joining us this morning. We look forward to more interactions with you over the coming weeks and months. I just want to reiterate that despite the challenges and uncertainties that lay ahead, I remain very excited about the progress we're making across our focus areas this year as well as the progress that our team has delivered across our oncology programs as well.

To close, I would like to thank very much my Agios colleagues for their dedication and passion for making a difference for our patients, both in oncology and genetically defined diseases. I also want to thank all the patients, caregivers and physicians who participated in our clinical trials. Without them, we could not do what we do.

Thank you again for joining us today. Take care.

Operator

[Operator Closing Remarks]

Duration: 50 minutes

Call participants:

Holly Manning -- Investor Relations

Jacqualyn Fouse -- Chief Executive Officer

Chris Bowden -- Chief Medical Officer

Darrin Miles -- Senior Vice President, US Commercial and Global Marketing

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

Darrin Miles -- Chief Commercial Officer

Peter Lawson -- Barclays -- Analyst

Tyler Van Buren -- Piper Sandler -- Analyst

Anupam Rama -- JP Morgan -- Analyst

Kennen MacKay -- RBC Capital Markets -- Analyst

Michael Schmidt -- Guggenheim -- Analyst

James Shontz -- Citi -- Analyst

Marc Frahm -- Cowen & Company -- Analyst

John Newman -- Canaccord -- Analyst

Kalpit Patel -- Oppenheimer -- Analyst

Christopher Liu -- SVB Leerink -- Analyst

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