Q3 2021 Agios Pharmaceuticals Inc Earnings Call

Operator: Today's conference is scheduled to begin shortly. Please continue to stand by. Thank you for your patience.

Today's conference is scheduled to begin shortly please continue to standby. Thank you for your patience.

Unnamed Speaker: [inaudible] BF-WATCH TV 2021. Good morning, and welcome to AGIOS's third...

Operator: Good morning and welcome to Agios' third quarter 2021 conference call. At this time, all participants are enlisted in only. There will be a question and answer session. Please be advised that this call is being recorded. I would now like to turn the call over to Holly Manning, Senior Director of Investment. 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 Investor section of our website, agios.com.

[music].

Okay.

Good morning, and welcome to our third.

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 and Rgs request I would now like to turn the call over to Holly Manning Senior director of Investor Relations.

Holly Manning: With me on the call today with prepared remarks are Dr. Jackie Faust, our Chief Executive Officer, Dr. Sarah Gheuens, our Chief Medical Officer, Darren Miles, our Chief Commercial Officer, Jonathan Biller, our Chief Financial Officer and Head of Legal and Corporate Affairs, and Dr. Bruce Carr, 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.

Thank you operator, good morning, everyone and welcome to Icf's third quarter 2021 Conference call you can access slides for today's call by going to the investors section of our website.

At that time.

On the call today with prepared remarks are Dr. Jackie Fouse, our Chief Executive Officer, <unk>, 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 <unk>, 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.

Holly Manning: With that said, 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 filing with the SEC and any other future filings that we may make with the SEC. Thanks, Holly. Good morning, everyone.

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 filing with the SEC and any other future filings that we may make with the SEC with that I will turn the call over to Jeff.

Thanks Ali good morning, everyone and thanks for joining our third quarter 2021 results call.

Jeff: 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 Minipivat, which has the potential to serve as the first disease-modifying therapy for pyruvate kinase deficiency. Additionally, our patient support infrastructure is in place. Our field team of sales representatives and nurse clinical educators is fully engaged with healthcare providers, and our disease education efforts continue to accelerate.

Strong clinical and operational execution continues at <unk>.

With our NDA and MAA filings on track our commercial team is focused on launch preparations for <unk>.

Which has the potential to service the first disease modifying therapy for pyruvate kinase deficiency or.

Our patient support infrastructure is in place our field team of sales Representatives and nurse clinical educators are fully engaged with health care providers and our disease education efforts continue to accelerate.

Jeff: We are also working diligently on startup activities for three pivotal studies in thalassemia and sickle cell disease, all of which we expect to initiate by the end of 2021. These trials underscore the potential of Medipivac 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.

We are also working diligently on startup activities for three pivotal studies in thalassemia and sickle cell disease.

All of which we expect to initiate by the end of 2021.

These trials underscore the potential of mid tier that 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.

Jeff: Beyond the PIV app, we continue to advance our earlier stage clinical and R&D efforts to build sustainable future growth potential based on our leading expertise in TK activation and cellular metabolism, all within our core focus on genetically defined... 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 de On November 17th, 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 Medivac and 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.

Beyond that if you back when continue to advance our earlier stage clinical and R&D efforts to build a sustainable future growth potential based on our leading expertise in PK activation in cellular metabolism.

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, Dallas, EMEA and PK deficiency.

On November 17th 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 <unk> in PK deficiency.

As we look to the end of the year end 2022 are Joseph 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 anti robot.

Jeff: 3 Pivotal Adult Trials, 2 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. Thanks, Jackie.

Pipeline filled with Optionality impossibility.

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 CMO.

Thanks, Jackie we are extremely excited about the potential we have to impact the lives of individuals with genetically defined diseases, beginning with Mcdonald's for PK deficiency, and other hemolytic anemias with significant unmet medical need.

Sarah Gheuens: We are extremely excited about the potential we have to impact the lives of individuals with genetically defined diseases, beginning with metabolism for PK deficiency and other hemolytic anemias with significant unmet medical needs. As I will discuss, we continue to build momentum across all of our clinical programs in the third quarter. Thank you very much for working with regulators in the U.S. and EU as they conduct their reviews of our regulatory submissions for Mitapheva.

As I will discuss we continue to momentum across all of our clinical programs in the third quarter.

You gave the efficiency, we continue to work with regulators in the U S and EU as they conduct their reviews of our regulatory submission for me talking about we are encouraged by the positive engagement and consistent with the review process. We are correctly replying to questions from both the U S and EU regulators.

Sarah Gheuens: We are encouraged by the positive, and consistent with the review process, we are currently replying to questions from both the U.S. and EU regulators. As the FDA granted priority review to our new drug application, we remain on track for the February 17th PDUFA date. Based on the dialogue to date, we are not currently expecting an advisory committee. In the EU, as expected in the procedure, we received the questions from the rapporteur and the critical assessment of those by the co-rapporteur. Our marketing authorization application remains on track for potential approval in the second half of 2020. These filings include data from the Activate and Activate Plus studies.

As the FDA granted priority review to our new drug application, we remain on track for the February 17th the due date.

Based on the dialogue to date, we are currently not expecting an advisory Committee meeting.

In the EU as expected spread of procedure, we received questions from the rapid tour and a critical assessment of those by the pool record tour, our marketing authorization application remains on track for potential approval in the second half of 2022.

These filings include data from the activate and activate T phase III studies in non regularly transfused in regularly transfused adults with PK deficiency, which both Mr primary endpoints as well as important secondary endpoints and patient reported outcomes as well as supportive data from the ongoing extension stuff.

Sarah Gheuens: Phase III studies in non-regularly transfused and regularly transfused adults with PK deficiency, which both met their primary endpoints as well as important secondary endpoints in patient reported outcomes, as well as supportive data from the two ongoing extensions. The data package underscores the potential of Mitapiva 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.

Please.

The data package underscores the potential of me stepping back 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.

Sarah Gheuens: We also remain on track to initiate the Pediatric Clinical Program in PK Deficiency in 2020. Moving to thalassemia, our two global placebo-controlled typical trials of metaprevab, ENERGYSE and ENERGYSE-T, have been initiated. Our first site has our site initiation visit, and we look forward to enrolling the first patient. As a reminder, ENERGYZE will evaluate 171 patients randomized 2 to 1 to 100 mg of metapithactylase daily or placebo in both alpha and beta thalassemia patients who are not regularly in transit.

We also remain on track to initiate the pediatric clinical program in PK deficiency in 2022.

Moving to sell a senior our two global placebo controlled pivotal trials of Mr. Energized and energized T have been initiated.

Our first sites at their site initiation visits and we look forward to enrolling the first patient soon.

As a reminder, energized will evaluate 171 patients randomized two to one to 100 milligram with me talking about twice daily or placebo in both alpha and beta thalassemia patients who are not regularly transfused.

Sarah Gheuens: The primary endpoint is hemoglobin response, defined as an equal or more one gram per deciliter increase in average hemoglobin concentration from week 12 through week 24 compared with baseline. NRGI-C will evaluate 240 patients randomized 2-to-1 to 100mg of metabaptized daily or placebo in both alpha and beta thalassemia who are regularly checked.

The primary endpoint is hemoglobin response defined as an equal or more one gram per deciliter increase in average hemoglobin concentration from week 12 to week 24 compared with baseline.

Energy D will evaluate 240 patients randomized two to one to 100 community came up with stuff about twice daily or placebo in both alpha and Bethel a female patients who are regularly transfused defined six to 20 Red blood cell unit transfused during the 24 weeks prior to randomization.

Sarah Gheuens: The final 6 to 20 red blood cell units transduced 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 usage, and a reduction of equal or more than 2 units of transfused red blood cells in any consecutive 12-week period through week 48 compared with baseline. We are excited to advance these studies and believe MITAPIVOT has the potential to be a meaningful treatment option for patients with both alpha and beta thalassemia.

The primary end point of transfusion reduction response defined as a 50% or greater reduction in transfusion red blood cell units with a reduction of equal or more than two units of transfused red blood cells in any consecutive 12 week to week 48 compared with baseline.

We're excited to advance these studies and believe me its up about has the potential to be a meaningful treatment option for patients with both alpha and beta thalassemia.

Sarah Gheuens: At ASH, we also expect to share longer-term extension data on the non-regularly transfused alpha and beta thalassemia patients who completed the Phase II core period. In sickle cell disease, we remain on track to initiate our Pivotal Phase II-III clinical trial by the end of the year. As Jackie stated, we recently unveiled the name of this program, RISE UP.

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 two core period.

In sickle cell disease, we remain on track to initiate our pivotal phase two three clinical trial by the end of the year.

Jackie status, we recently unveiled the name of this program right up the.

Sarah Gheuens: The name was developed in collaboration with a global team of sickle cell warriors, and it has significant meaning for them. We were excited to first share the name at the Sickle Cell Disease Association of America Convention last month, and we have been gratified by the positive feedback. This Phase II-III study will include patients who are 16 years of age or older, have had between 2 and 10 sickle cell pain crises in the past 12 months, and have hemoglobin within the range of 5.5 to 10.5 grams per deciliter during screening. The Phase II portion of RISUP will randomize 69 patients 1-1-1 to 50 mg metaphevac twice daily, 100 mg metaphevac twice daily, or matched placebo.

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 the 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 two three study will include patients who are 16 years of HR older have had between two would've been sickle cell pain crisis in the past 12 months and have hemoglobin within the range of $5 five to 10 five grams per deciliter doing screening.

The phase two portion of Rice will randomize 69 patients want to want to want to 50 milligram bid stuff. That's about twice daily 100 milligram moved up about twice daily or matching placebo.

Sarah Gheuens: The primary endpoints are hemoglobin response, defined as an equal or more 1 gram per deciliter increase in average hemoglobin concentration from week 10 through week 12 compared to baseline, and the type of adverse event. These data will be used to establish a clear dosing paradigm for the Phase III portion. The Phase III portion of RISUP, which will commence after the Phase II analysis, will randomize 198 patients, 2 to 1, to the selected Phase II dose of metaphezote or matched placebo.

Endpoints arent people globin response defined as equal or more than one gram per deciliter increase in average hemoglobin concentration from week 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 III portion.

The phase three portion of rise up which will commence after the phase two analysis will randomize 198 patients to want to select the phase two dose of them exactly that's or matched placebo. The study will have two primary endpoints the heme.

Sarah Gheuens: The study will have two primary endings. The hemoglobin response, defined as equal or more than one gram per deciliter increase in average hemoglobin from baseline to week 52, and also annualized rate of sickle cell pain crisis. We believe the design of this space, This study minimizes the risks to the approval path for metabazote in this challenging... 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 metaphylating sickle cells.

Globin response defined them equal or more than one gram per deciliter increase in average hemoglobin from baseline to week 52, and also annualized three of sickle cell pain crisis.

We believe the design of this phase three study minimize the risks to the approval path for me to pick up 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 <unk>.

Today. She is on their studies will be stepping back in sickle cell disease.

Sarah Gheuens: Data from both studies are expected to be presented at ASH. At NIH, Dr. Tan 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 mitopibab in people with sickle cell disease. Leveraging our pioneering expertise in PK activation, we're also advancing our novel PK activator AG946, currently being evaluated in a Phase I study with a healthy volunteer component, followed by a single-cell disease component, which we plan to initiate in 2020

Data from both studies are expected to be presented at ash at the NIH doctors been enrolled 17 patients and of course study 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 me talking about the people.

With the single side.

Yeah.

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 one 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 one healthy volunteer portion will be presented at ash.

Sarah Gheuens: 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 7th. I will now turn the call over to Darren, our Chief Commercial Officer. Thank you, Sarah.

As Jackie mentioned, we plan to talk in more detail about our research and development pipeline at our Investor event on November 17th.

I will now turn the call over to Darren our Chief commercial officer.

Thank you Sir with.

With approximately four months to go before U S product approval and launch.

Very pleased with our progress with respect to the preapproval disease education patient to physician profiling and overall launch readiness.

The third quarter was our first with a full complement of our customer facing teams in place, including sales representatives and clinical nurse educators and patient support leathers.

Darren: It's approximately four months to go before a U.S. product approval and launch, and we are very pleased with our progress with respect to pre-approval disease education, patient-to-physician profiling, and oral launch rates. The third quarter was our first with the full complement of the customer-facing team, including sales representatives, clinical nurse educators, and patient support managers. We ramped up personal and digital disease education activities, including live health care provider education programming and patient-focused seminars.

Personal and digital disease education activities, including life health care 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, what we anticipate it would be about 2600 positions.

The process of profiling field team has confirmed what we saw in our most recent quantitative market research, which is 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 EMEA IP and an attempt to help them reach a definitive diagnosis.

Darren: 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. Through 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 3-5 hemolytic anemia patients of unknown etiology, most of whom are likely eligible for genetic testing via Anemia ID, in an attempt to help Many have one to two confirmed PK deficiency patients diagnosed and under management due to the recent approval of the new ICD-10 code for people.

So there she didn't with academia, including potentially PK deficiency.

Among those physicians profile were confirmed to currently treat PK deficiency. Many have one to two confirmed PK deficiency patients diagnosed and under management. Additionally.

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, IV and answering questions about the service.

In the third quarter, we observed the largest quarter over quarter increase request for BVI because since the launch of the program in December.

<unk>, both the impact of our educational efforts and the communities eagerness to identify their patients' hemolytic anemia, which may include continued 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.

Darren: We expect to be able to further refine targeting efforts to find previously diagnosed patients with PK2. Our sales team, referred to as hemolytic anemia specialists, and clinical nurse educators are also educating practices on the availability of anemia ID and answering questions about the service. In the third quarter, we observed the largest quarter-over-quarter increase in requests for BBID kits since the launch of the program in December.

Once a patient PK deficiency diagnosis confirmed our hemolytic anemia specialist team educates practices on the disease education and other support provided through our patient assistance service by Andreas the team encourages practices to inform them diagnose patients about the service. We can then continue on to the enrollment process.

Archie also the best possible position to tailor support for diagnose PK deficiency patients in Quebec.

At them with a broader PK deficiency community.

<unk> also continued engagement with payers over the quarter educating them about the natural history of the burden of disease, including morbidity and complications for the spectrum of PK deficiency patients regardless of transfusion history, and an overview of the phase III data in.

Darren: This reflects both the impact of our educational efforts and the community's eagerness to identify their patients' hemolytic anemia, which may include duplicate deficiency. In the coming months, we expect to expand the service by supporting direct patient access to genetic counselors who can provide additional assistance. 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 a patient's PK deficiency diagnosis is confirmed, our hemolytic anemia specialist team educates practices on the disease education and other support provided through our patient-assisted service, MyOngio. The team encourages practices to inform diagnosed patients about the service, who can then continue on to the enrollment process.

In the process, we learn more about their pressing questions and what they expect about yields at the time of potential approval. We know formulary coverage of a new treatment takes time before you were able to reach optimal access, especially in the first nine to 12 months post approval as payers convenient P&C committees offset schedules. These exchanges are also helpful in shape.

<unk> strategy is to support peers as they develop coverage policies.

Overall, we have growing momentum heading into the expected approval in 2022 with each week, bringing a new high with respect to physician and patient profiling and education and steady progress towards launch readiness I look forward to discussing details with respect to commercial strategy, including progress with patient profiling distribution and more at investor.

Your day in November with that I'll now turn it over to Jonathan to review third quarter financials Jonathan.

Thanks, Darrin, our third quarter 2021 financial results can be found in the press release, we issued this morning, which I'll summarize more detail will be included in our 10-Q filing later today.

Darren: 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 learn more about their pressing questions and what they expect of Agios at the time of potential approval.

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.

Search and development expenses for the third quarter was $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 startup costs associated with the phase III studies.

To that in thalassemia, and sickle cell disease, and our disease education and engagement efforts are committed to that and 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 into sogo 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.

Darren: We know formulary coverage of a new treatment takes time before you are able to reach optimal access, especially in the first 9-12 months post-approval, as payers convene P&T committees on set schedules. These exchanges are also helpful in shaping strategies to support payers as they develop coverage policies.

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 five 3 million shares for $254 million representing.

Representing an average price per share of $47.94.

Since commencing share repurchases through the third quarter, we have completed approximately $783 million or just under two thirds of the $1 $2 billion share repurchases authorized by our board of directors.

Darren: Overall, we have growing momentum heading into the expected approval in 2022, with each week bringing a new high with respect to physician and patient profiling and education and steady progress towards launch ready. 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 the third quarter financials.

The face of our 10-Q also reflects repurchases from September 30 to the date of the filing the Q and shows a total year to date share count reduction of more than 16 million shares or just over 23% of them are 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 <unk> complementary business development opportunities that could arise we continue to.

To have the optionality to repurchase shares within our remaining authorization.

As Jack and I have mentioned at our Investor Day on November 17th 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.

Thank you to ask a question you will need to press star one of your telephone to withdraw your question press the pound key reacts.

Jonathan: Thanks, Darren. 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 10-2 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.

We ask that you please limit yourself to one question. Please standby, while we compile the Q&A roster.

Our first question is from John Newman with Canaccord Genuity. Your line is open.

Hi, guys. Good morning, Thank you very much for taking my question.

Question is on the <unk> phase three study in sickle cell disease. I'm. Just curious first question is are are the endpoints co primary endpoints and the second question is.

Are you looking to enroll patients at baseline that have a minimum number of pain crises for that phase III study. Thanks.

Thanks for your question so the answer to it. So this is Sarah the new CMO.

So the first two.

Jonathan: The year-over-year increase in R&D was driven primarily by start-up costs associated with the Phase III studies of midipibad and thalassemia and sickle cell disease and our disease education and engagement efforts for midipibad and 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 for the third quarter of 2020.

The first question around the phase III and the endpoints. The primary endpoints that are two separate primary endpoints and that is a very deliberate design.

With an alpha split over the two primary endpoints that allows us to move on to secondary endpoint testing. If he gets on one or both primary endpoints and the endpoints are the hemoglobin response and analyzed a range of sickle cell pain crises and then to the second question, Yes, we do the inclusion criteria.

There is a requirement for patients to have at least two up to 10.

Pain crisis in the year.

Higher.

Two enrollment.

Okay, great. Thank you.

Okay.

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

Jonathan: We also recorded $2 million in TSOBO 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 for cash flow positivity without the need to raise additional equity.

Hey, guys. Thanks for taking my question.

I was just curious about that.

The sickle cell type with pivotal and then are you, allowing hydroxyurea.

But Nathan and do you think it would work well with Medicare that thank you.

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

Jonathan: In Q3, we repurchased approximately 5.3 million shares for $254 million, representing an average price per share of $47.95. Since commencing share repurchases through the third quarter, we have completed approximately $783 million, or just under two-thirds of the $1.2 billion share repurchases authorized by our Board of Directors. The face of our 10Q also reflects repurchases from September 30th to the date of the filing of the 10Q and shows a total year-to-date share count reduction of more than 16 million shares, or just over 23% of our starting share count, and a total spend of just over $800 million.

And then anything any different in fact with hydroxyurea versus not.

Well that's a question.

Any difference in the fact, when I say that was combined versus not.

No and that is to too early to tell right. So that would be something that we would be looking to to look at in a subgroup analysis at the end of phase III.

Great. Thank you.

Yeah.

Our next question comes from Kennan Mackay with <unk> capital markets. Your line is open.

Alright, Thanks for taking my question.

Thank you.

Todd maybe to your current thinking on the incidence and prevalence of part of it.

As you can see based on your ongoing patient monitoring and patient identification efforts.

Jonathan: 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 complement three business development opportunities that could arise. We continue to have the optionality to repurchase shares within our remaining authorization. As Jackie and Sarah have mentioned, at our Investor Day on November 17th, 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. Thank you. To ask a question, you will need to press star 1 on your telephone.

<unk> deficiency natural history study or your your peak registry.

Maybe for Darren.

Closer to launching.

These efforts are intensifying just wondering how.

Those prevalence estimates.

Malte over time that turns over time. Thank you.

Sure Darren.

<unk>.

It's still early days right. So the we've guided to.

Prevalence.

Number between 3000 8000 between the U S and the.

Five of us so assume somewhere between 500 to 4000.

In the U S.

We're still early days obviously.

Patient finding and we know that they'll continue.

To grow leading to the launch that should accelerate even further once once we get through through the approval.

So right now for our planning purposes, we stay within that range, we assume that we're somewhere around around 3000 is.

Thats, what we what we do our planning around but that will be able to confirm that as we as we move forward. The something that's gonna be helpful. Moving forward as they as 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.

Operator: To withdraw your question, press the pound. We ask that you please limit yourself to one question. Please stand by while we compile the Q&A. Our first question is from John Newman with Canaccord Genuity. Hi, guys. Good morning.

By the community.

Okay.

Yes.

Okay.

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

John Newman: Thank you very much for taking my question. The question is about the Mitopivet Phase 3 study in sickle cell disease. I'm just curious.

Hey, guys. Thanks, so much for taking the question no.

Note that the AG 946 healthy ball data presented at Ash.

Sarah Gheuens: The 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 for your question. The answer to that is, this is Sarah, the new CMO. To the first question around 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 the two primary endpoints that allows us to move on to secondary endpoint testing if we hit on one or both primary endpoints.

Please.

Had an optional sickle cell cohort there've been some additional indications outlined in the slides today.

What are the 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.

Yeah.

Yes, hi, so indeed, you will be seeing more of the 18 94 six development programs at the Investor Day on November 17th So right now it's indeed in a healthy volunteer portion with.

Part two this 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 anemia and then.

Sarah Gheuens: And the endpoints are the hemoglobin response and an analyzed 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 two, up to ten, pain crises in the year prior to enrollment. Okay, great, thank you. Our next question comes from Alicia Young with Kent, North Carolina. Hey, guys.

We have a lot of optionality based on that.

Looking forward to discuss more with you on November 17.

Okay.

Thanks for taking my question.

Yeah.

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

Hi, Thanks for taking my question.

Just a follow up on patient prevalence.

Work that Darren has been doing.

One of them.

Can you give some idea of the anemia I'd test results are tracking in line with the Spanish experience. So I think in the very early days you said they were but it wasn't really curious to see if thats being maintained.

Alicia Young: Thanks for taking my question. I was just curious about the kind of sickle cell pivotal. Are you allowing hydroxyurea in combination, and do you think it would work with metapivat?

And then maybe could you also quantify when you say that the volumes of <unk>.

Sarah Gheuens: Thank you. Yeah, sure. So we do allow hydroxyurea into the trial. We actually have generated data in sickle cell disease patients who have been, you know, taking hydroxyurea while being exposed to metapibat. And so the way we address that is by stratification on hydroxyurea in the clinical trial. And did you see any different effect with hydroxyurea versus not? Well, what's the question? Is there any difference in fact when the PIVOT was combined versus not?

Demand for those tests increase with greatest Q over Q and Q3.

Can you maybe quantify that versus the first half I mean did you see as many as many tests in Q3 is always the first half for something smaller or something bigger than that.

Oh, there's a lot of there, but it's a good question alright. So.

Packet. So so the as I've mentioned in my prepared remarks, but we did see a very significant.

Uptake.

In requests for for the test.

In Q3.

In large part related to growing momentum, but also so first full quarter that we've had the field our field team to place right. So they've been they've been helping to educate the practices the practices.

Sarah Gheuens: No, and that is too early to tell, right? So that would be something that we would look at in a subgroup analysis at the end of phase three. Great, thank you. Our next question comes from... Hi, thanks for taking the question. Can you talk, maybe, about 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 patients as well.

Bob will elect to order order the test so I think we.

We're just we're just shy of about 2000 tests.

<unk> 2000 tests by the end of Q3 in terms of what we're seeing.

In terms of the results that I expected it to fluctuate right, particularly as the volume of test results.

Requested in the results or the actual tests are conducted and the results are.

Our reported.

And there is a meaningful theres a material difference between what we the setting in which the Spanish study was conducted which has a control setting setting versus the all comer kind of experience that we have in the U S plus the test in the U S allows physicians to be able to look at a whole host.

Sarah Gheuens: And maybe for Darren, as we get closer to launch and these efforts are intensifying, just wondering how those prevalence estimates have sort of evolved over time or changed over time. Thank you. Sure. It's still early days, right?

Our potential.

Explanations for the patient's hemolytic anemias, so in the Spanish experience, we saw about 20%.

Darren: So, we've guided to a prevalence number between 3,000 to 8,000 between the U.S. and the 5EU. So, assume somewhere between 1,500 to 4,000 in the U.S. We're still in the early days, obviously, of patient finding, and we know that that will continue to grow leading to the launch, and it should accelerate even further once we get through the approval process. So, right now, for our planning purposes, we stay within that range. We assume that we're somewhere around 3,000, so that's what we do our planning around, but we'll be able to confirm that as we move forward.

We expected it to be lower but we think she doesn't know exactly what that would be so I would say, 20% continues to be the upper end 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've got very strong pockets.

Of utilization, but I'd like to be able to see it used more broadly and I would like to see us have more confirm test come through.

Before we start reporting routinely.

We're observing there.

Yeah.

Okay. That's very helpful. Thank you.

No problem.

Our next question comes from Mike with H C. Wainwright Your line is open.

Hi, guys. Good morning, Thanks for taking my question and congrats on the progress.

A lot of people have addressed my question is about.

Darren: The one thing 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'll take a while before we see that universally employed by the government. Thank you.

The market, perhaps so I think all.

Let me shift to understanding.

Reimbursement Darren can you maybe talk about your expectations.

Regarding what proportion of patients you think will be covered by private pay versus either Medicare or Medicaid.

What.

Ana Palma: Our next question comes from Ana Palma. Hey guys, thanks so much for taking the question. I know that the AG946 Health Evolved data are going to be presented at ASH. I think this trial had an optional sickle cell cohort.

It requirements you guys are going to have to have to.

Attain the.

Yeah.

Reimbursement that that you would expect for that.

Sure sure no I put all of this work into preparing to be able to provide that information to you at the at the Investor Day. Later later this month, but I'll give you a preview now so we <unk>.

Sarah Gheuens: There have been some additional indications outlined in the slides today. What are the next steps for this program, and will we maybe get a better sense of that at R&D day in a couple of weeks? Thanks so much.

So we expect that it's good that the local observed for <unk> is reflective of what we would reserve for the overall U S population. So.

About 55% or so of patients we expect it's about 60% should be commercial.

Just about an even split.

<unk> are a percent or so.

Medicare, 50% Medicaid and then the balance number.

<unk>.

Sarah Gheuens: Yes, hi. So, indeed, you will be seeing more on... at the Investor Day on November 17th. And we're excited about that because it will allow us to generate data in the context of hemolytic anemia, and then we have a lot of optionality based on that. So looking forward to discussing more with you on November 7th.

Our deal with the EBIT and cash.

The what we've what we are what we can expect is that.

You're going to have a ramp right. So you'll have.

Complete formulary coverage for patients, particularly commercial patients that will book that is in large part dependent on when commercial payers are going to hold there Theyre P&C committee meetings, which are on the CEP IV sets.

Right. So so that.

That will take time to be able to get to universal.

So coverage their Medicaid and Medicare usually lag.

So that may be a little slower than than commercial.

Operator: Thanks for taking our question. This question comes from Ram with Cowan & Company. Your line is, Thanks for taking my question. Just a little bit of follow-up on the patient prevalence work that Darren's been doing. Well, can you give some 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.

In terms of what what payers need from us.

The thing Thats been pretty clear.

At this point now we've had a host of one on one discussions with individual payers.

And the fair amount of research on this at this point. So it worked if we're successful in making in establishing a firm understanding of the natural history of the disease, but long term morbidity and complications associated with P. T. D. Then the unmet need the severity of the disease, regardless of transfusion history.

Ram: So I'm curious to see if that's being maintained. And then maybe could you also quantify when you say that the volumes of demand for this test 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 you did in all of the first half, or did you have something smaller, something bigger?

<unk> is pretty well accepted and understood by the by the community right. Once we make the story.

And so then in the <unk>.

Clinical data right. So the safety efficacy data are pretty clear and compelling so theres a little sort of convincing you have to do there you just have to make sure people have good understanding of it once we have that then.

We expect a fairly favorable.

Access, which you'll have differences based on individual patients at a pro benefit designs, but we would expect pretty good pretty good access the key will come down to what the label looks like at the end of the day.

Darren: Oh, there's a lot in there, but it's a good question. All right, so the packet. So, as I've mentioned in my prepared remarks, we did see a very significant uptick in requests for the test in Q3. And that's in large part related to, you know, some growing momentum, but also the first full quarter that we had the field team in place, right?

And what pricing 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, where it's appropriate.

If I might if I might just ask a quick follow up are you guys anticipating.

Darren: So they've been helping to educate practices, and practices, and patients as well, will elect to order the test. So I think we're just shy of about 2,000 tests by the end of Q3. In terms of what we're seeing.

Single point of contact for their.

The genetic testing versus.

Genetic testing versus actually getting patients enrolled onto but appear that therapy.

Darren: In terms of the results, I expected them to fluctuate, particularly as the volume of test results increases, tests are requested, and the results are; the actual tests are conducted, and then the results are reported. And there's 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 the test 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 didn't know exactly what it would be.

Therapy or.

What I would hate to see us.

Got confusion, either with access to genetic testing in the transfer over to physicians.

Physician, writing a script for that patient how is that process going to be going to be managed.

Well, the so perkin Elmer breakfast the partner that we work with to provide the genetic test right.

Not every patient is going to necessarily get genetic tests right. So.

Commonly used test will be the enzyme with enzyme assay rise. The genetic test is helpful and can defend this confirmatory there right. So they are not limited to using using.

Are the two that we support.

Darren: So I would say 20% continues to be the upper end of the range. 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, but 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. Okay, that's very helpful. Thank you. No problem. Our next question comes from me. Hi guys, good morning.

Now what we what we are intending to do is to us too.

Have a.

Mandated right. So for every script that is written.

Physicians will submit the script to two <unk> to my audio throughout our patient support service at patients that will opt in opt into the service accordingly, right. So that will give us the opportunity then to ensure that the appropriate.

Confirmation of the patient's diagnosis is in place, we're helping them with with supporting their engagement with payers.

B.

To engage in.

Engage with the patients and their practices on all of the appropriate disease education connecting them with other other patients in the community things along those lines and and provide.

Sort of surround sound in terms of adherence supported the war <expletive>.

Ah patients as well so so that physicians aren't limited to go back to your central question the benefits.

Operator: Thanks for taking the question and congrats on the progress. A lot of people have addressed my questions about the market preparation, so I think I'll... Maybe shift to understanding reimbursement, Darren. Can you maybe talk about your expectations regarding what proportion of patients you think will be covered by private pay versus either Medicare or Medicaid? And, you know, what?

And if it does start limited only to our.

Two are the genetic tests that we provide but but but through the prescription and then fulfillment process right we're able to.

To provide a seamless.

Services to the choice of patients able to get on on treatment successfully and it gives us the best line of sight to two individuals.

Yeah, Yeah, Okay terrific. Thanks, so much for taking the questions.

No problem.

Our next question comes from Mark <unk> with Oppenheimer. Your line is open.

Darren: requirements you guys are going to have to have to attain the reimbursement that you would expect for Medipivac and PKD. 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. So we... Thanks for indulging me.

Hey, good morning, and thanks for taking the question.

There's probably a follow up to unencumber earlier question, probably directed to Sara.

<unk> 946, I was just wondering kind of what factors are leading to the decision to first.

Put 96 into a sickle cell cohort as opposed to some of the other hemolytic anemias.

Darren: So we expect that 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 an even split, 15% or so Medicare, 50% Medicaid, and then the balance number of other DOD and cash.

And also I'm wondering if you're seeing any.

Pharmacodynamic thresholds that $9 six needs to clear in healthy volunteers to justify continued development.

In terms of <unk> reduction and maybe ATP increases things like that.

What would you kind of see it as a best case scenario from the.

<unk> healthy volunteer data thanks for taking the questions.

Darren: What we can expect is that you're going to have a ramp until you have complete formulary coverage for patients, particularly commercial patients. That is in large part dependent on when commercial payers are going to hold their P&T committee meetings, which are on these sets. 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.

Okay great.

So the current protocol the way it is set up is it generates you know it's.

A very typical single ascending dose multiple ascending dose.

Buddy in healthy volunteers.

And we're of course looking for Pharmacodynamic engagement within.

Within that group, then looking to Max out and also generate appropriate safety data, which is.

Very classical phase one type work and in the protocol is set up with certain decisions around the pharmacodynamic engagement observed in healthy volunteers to move forward with the appropriate doses in the 94 six.

Darren: In terms of what payers need from us, I think the thing that's been pretty clear, and at this point, we've had a host of one-on-one discussions with individual payers and a fair amount of research on this at this point, is that if we're successful 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 And the clinical data, the safety and 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.

Sickle cell disease component of the trial.

In regards to what.

Sickle cell disease sickle cell disease, clearly, there's a huge unmet medical need and we're looking to.

Further at San smoked multiple therapies and there for those patients however, as with any development. After any phase of clinical development that will be go no go decisions to decide what is the best path forward for specific molecule.

Regardless.

Despite it all it generates data for sickle cell disease, but because we're looking for hemolytic anemia and also what we've observed in you're talking about the gross different hemolytic anemia.

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

Looking at that data and generate the optionality for the rest of the decision making across different indications.

Okay fair enough. Thank you.

Yeah.

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

Great. Good morning, and thank you for taking our question. This is Elizabeth on for Celgene. So as you start thinking about the pediatric population and PK D with the pivotal studies to initiate next year.

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.

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

Well so right now of course, the patient identification is focused on the feasibility of the clinical trials. So we have taken a very standard approach, while engaging with sites to them to understand how many patients. They have how many patients would fit into the eligibility criteria.

Of the.

The clinical trial for pediatric development and so that is the states where we're currently at.

You know our pediatrics plant and so we're very much looking forward to initiate those studies in 2022.

Darren: Well, Perkinelmer, right, is the partner that we work with to provide the genetic test, right? And not every patient's going to necessarily get a genetic test, right? So a commonly used test will be the enzyme, the enzyme assay, right?

And maybe I missed that.

The efforts that we're currently employing to to.

To support patient identification and patient profiling in the community.

Isn't limited to adults right. So we're also coming across.

Pediatric patients as we as we engage with the individual practices. So we're maintaining sort of inventory of that as we.

Darren: The genetic test is helpful and is confirmatory there, right? So they're not limited to using our 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 myAGIOS, our patient support service. And patients will then opt in to the service accordingly, right? So that will give us the opportunity then to ensure that the appropriate confirmation of the patient's diagnosis is in place, helping them with supporting their engagement with payers, and then be able to engage with the patients and the practices on all 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.

As we collect more market information.

Thank you.

Yeah.

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

Thanks for taking my questions.

A couple for me just wanted 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 was that 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.

Yes.

If it's the latter.

Idea of what the timing will be so we expect a similar cadence as what we've seen over the last 12 months and then just a comment on our noncore six.

Since it's gonna be tested in sickle cell are you still planning to advancement of sickle cell disease have how far behind is 946, if that becomes a lead candidate for sickle cell disease.

Darren: So the physicians aren't limited, to go back to your central question, the physicians aren't limited only to the genetic test that we provide. But through the prescription and then fulfillment process, we're able to provide a seamless service to ensure that the patient's able to get on treatment successfully. And it gives us the best line of sight to individual patients.

Okay. This is Jonathan I'll start with the share repurchase question. So what we've decided to given the progress we've made.

When we purchased now.

Just over 16 million shares, reducing our starting share count by a little over 23% and see observing some opportunities in our internal programs to potentially accelerate them as well as just looking at the external BD landscape and same valuations coming down fairly significantly over the last.

Darren: Yep. Okay. Terrific. Thanks so much for taking the questions. No problem.

Operator: Our next question comes from Mark Beck with Oppenheimer University. 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 AG946. 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.

Yes.

Most of this year that there could be a possibility for a higher likelihood of finding executable complementary BD opportunities, we paused share repurchases. So we still retain the optionality, we have a <unk> plan in place. So we can 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.

Susan.

And one third outside one third of our.

Sarah Gheuens: And also, I'm wondering if you're seeing any pharmacodynamic thresholds that 946 needs to clear in healthy volunteers to justify continued development, you know, 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 question. Okay, great.

Share repurchases of $400 million. So that's what that's where we are now there is no set timing on when we may or may not repurchase additional shares and it will be a balancing act of seeing what opportunities, we have internally and potentially with BD and as that plays out we'll make a determination.

John.

With respect to how much if any of the additional.

Authorization that will execute.

And then to your last question around me talking about the sickle cell disease development, we were Super excited about continuing to progress we talked about through the proper clinical development.

Sarah Gheuens: So the current protocol, the way it is set up, is it generates a very typical single ascending dose, multiple ascending dose study in healthy volunteers. And we're, of course, looking for pharmacodynamic engagements within that group and looking to max out and also generate appropriate safety data, which is, like, very classical phase one 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 trial in regards to what... Why sickle cell disease?

Yes.

And it's high and it's Jackie I'm Nobody's asked me a question, yes I'm getting.

I'm feeling neglected jump in so thank you for asking me or two questions. I. Just also wanted to point out that.

After we close the oncology divestiture with salary and then we brought those funds.

And at the end of March.

We're 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 our.

Where we were in terms of the Ontario's lifecycle and having undertaken what was a relatively large transaction for our company.

Sarah Gheuens: So sickle cell disease, clearly, there's a huge 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 of the decision-making across different indicators. Okay, fair enough.

Our size and given the amount of capital that we had rights over our history.

Initial priority and that's where we had the $1 $2 billion share authorization was to kind of what I call reset our capital structure by giving some of that back.

Shareholders, which we now have done enough that I'm very happy with the execution that we've done on that there's roughly 800 million or so over the last six months and so we continue to have that additional $400 million of authorization at the same time, our teams have made significant progress with some.

Operator: Thank you. Our next question comes from Salveen Richter. Great, good morning, and thank you for taking our question. This is Elizabeth on behalf of Salveen.

Our internal programs over the course of 2021 and now we see some opportunities that we'll talk about on November 17th to make incremental investments in our internal assets and programs to move some things along where now we have the evidence or the logic for moving them along and advancing them in at.

Elizabeth: So as you start thinking about the pediatric population and PKD with the pivotal studies 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? Well, so right now, of course, patient identification is focused on the feasibility of the clinical trials, so we have taken a very standard approach when 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 space where we're currently at with our pediatric plan, and so we're very much looking forward to initiating those studies. And maybe I'm sad to be...

Adding those investments to our plan.

Werent necessarily there in the past and as Jonathan said, we also now have greater clarity in terms of our internal thinking I would say around the potential opportunity set.

D D.

So there.

There are different ways as you know and deploy our capital over time, and we're always going to toggle between those dates.

Why is that in the short term we wanted to make it 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.

Then the last thing I just wanted to say is on.

Non four six I can remember this from a year or even maybe more a go 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.

Sarah Gheuens: The efforts that we're currently employing to support patient identification or patient profiling in the community aren't limited to adults, right? So we're also coming across pediatric patients as we engage with individual practices. So we're maintaining sort of an inventory of that as we collect more market information. Thank you. Our next question comes from Andrew Berens. Hi, thanks for taking my questions. There are a couple for me.

It will sell that they seem to be the most logical one to add.

To that protocol to get some early data in a given hemolytic anemia, a disease and I think you'll hear on November 17th some other ideas that we have for.

<unk> gone for six.

Leave it at that thank you for your question.

Great. Thanks, and just a follow up.

Jackie how many people do you guys have now.

Well it depends on how you look at it. So we have a we have a two or three dedicated people. But then we've also got kind of.

Leaders within each functional area that contribute to.

The effort when we when we're looking at something until there it would be something at Bruce a shop and contributes to looking at assets that would be something Sarah shops, who contributed something like again, who is also.

Andrew Scott Berens: 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.

Of course, Bruce it team is generating ideas for complementary.

The mechanisms are targets that we would want to be looking at and then we got a small IBD small, but mighty BD team out there canvassing the landscape.

Okay and then just on 94 six if you do pivot.

Andrew Scott Berens: Should we expect a similar pace as what we've seen over the last 12 months? And then just to comment on 9-4-6, since it's going to be tested in sickle cell, are you still planning to advance medipivet in sickle cell disease? And how far behind is 9-4-6 if that becomes a lead candidate for sickle cell disease? Okay, this is Jonathan.

South of 946.

How far behind that or pay that what would you estimate you are.

So just to be clear, we're not anticipating that we're going to pivot to nine four states, we're moving fast and furious with the mid tier that theres, a chance that noncore stakes in sickle cell one day as a complementary asset in the.

Our folio, it's as likely that we see some data for enough our stakes in sickle cell disease that tells us something about how the product is performing in a given hemolytic anemia, and then we have the health volunteer data that there than maybe other indications that we would feel comfortable moving even faster into that.

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, looking at the external BD landscape and seeing valuations coming down, you know, fairly significantly over the last, you know, most of this year, We've paused share repurchases. So we still retain the optionality.

Just on the totality of what we've seen across the class a PK or providers in all of the work that we've done.

And non force things specifically.

Okay, thanks for allowing the questions.

Yeah.

Our next question comes from didn't umbrella with Raymond James Your line is open.

Hey, guys. Good morning, Thanks, so much for the questions I guess.

A couple on the particular style and <unk> trials.

We're excluding patients learn actis Aqua littler payout, but will you permit enrollment of patients with prior exposure to those guys and then similarly for the.

Jonathan: We have a 10B18 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 BD. The remaining one-third, I'm sorry, one-third of our share repurchase, 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, you know, a balancing act of seeing what opportunities we have internally and potentially with BD.

The <unk> trials are you promoting enrollment of patients who had prior treatment with patterns that thank you.

So, yes, and yes is the answer so we are allowing patients that have been exposed to those prior therapies and then have a proper a washout period before you're rolling into our trial and then the same for the South senior trials, which prior looks better set exposure is allowed.

And then I had mentioned earlier hydroxyurea for the sickle cell disease Strauss is allowed as a concomitant medication.

Just a quick follow up so I understand obviously your mechanism different but is there any criteria around whether the patient has to be responders cause it to the prior treatments or not.

Jonathan: And as that plays out, you know, we'll make determinations on how much, if any, of the additional authorization that we'll execute. And then, to your last question around Mitopivot and sickle cell disease development, we're super excited about continuing to progress Mitopivot through the proper clinical development. Hi Andy, it's Jackie.

No there is not.

Got it thank you so much.

Okay.

Thank you and I'm currently showing no. Further question. This time I'd like to turn the call back over to Jackie Fouse for closing remarks.

Thank you operator, and thank you everyone for the questions. This morning.

We look forward to an exciting time ahead, where the February 17th 2022, <unk> date coming up for a minute there that in PK deficiency in the U S.

Jackie: Nobody's asked me a question yet, so I'm getting, you know, 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, you know, after we closed the oncology domestic market for Ferrier 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 lifecycle and having undertaken what was a relatively large transaction for a company of our

We're also looking forward to the ongoing MAA review for the same indication in Europe. The initiation of three pivotal studies by year end across balance even in sickle cell disease in adult patients the initiation of the pediatric PK deficiency clinical program in 2022 and Investor Day on November.

17th and multiple upcoming data presentations at Ash I can see we have a lot going on as always I would like to thank my <unk> 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.

Jackie: And given the amount of capital that we've raised over our history, our initial priority, and that's where we have the $1.2 billion share authorization, was to kind of reset our capital structure by giving some of that back to our shareholders, which we have now. Now I've done enough, and I'm very happy with the execution that we've done on that. There are roughly 800 million or so over the last...

Clinical trials across indications. Thank you again for joining us today.

May now disconnect he is doing.

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

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Jackie: And so we continue to have that additional $400 million in 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, which 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.

Jackie: And as Jonathan said, we also now have greater clarity in terms of our internal thinking, I would say, around the potential opportunities set in the BD arena. So there are different ways, as you know, to deploy your 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.

Jackie: And then the last thing I just wanted to say... 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 on a given hemolytic anemia and at the

Jackie: to that protocol to get some early data on a given hemolytic.

Jackie: or AG946. And I will leave it at that. Thank you for your questions. Great. Thanks. And just to follow up, Jackie, how many VD people do you guys have now? 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.

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Jackie: Thank you for the effort when we when we're looking at something so there will be somebody somebody

Jackie: for supplementary types of mechanisms or targets that we would want to be looking at, and then we've got a small but mighty BD team out there canvassing the landscape. Okay, and then just on 946, if you do pivot and circle south to 946, how far behind the pivot would you estimate you are?

Jackie: So just to be clear, we're not anticipating that we're gonna pivot to 946. We're moving fast and furious with MediPivot. There's a chance that 946 in sickle cell disease one day is a complementary asset in the 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 health volunteer data, that there then may be other indications that we are comfortable moving even faster into, based on the totality of what we've Okay, thanks for allowing the question. Our next question comes from Danielle Brill with Raymond James. Good morning.

Operator: Thanks so much for the questions. I guess a couple on the Stiklisol and Thalassemia trials. I know you're excluding patients who are on active oxalatoid or dexayo, but will you permit enrollment of patients with prior exposure to those drugs? And then, similarly, for the ENERGIZE trials, are you permitting enrollment of patients who have prior treatment with Patercev? Thank you. So, yes, and yes is the answer.

Sarah Gheuens: So we are allowing patients to have video, do those prior therapies, and then have a proper washout period before enrolling into our trial. And then the same for the thalassemia trials in which prior was a better setting is allowed. And then, as I mentioned earlier, hydroxyurea for the sickle cell disease trials is allowed as a concomitant medication. Just a quick follow-up. Obviously, your mechanism is different, but is there any criteria around whether those patients had to be responders to prior treatments or not? No, there is not.

Sarah Gheuens: Got it. Thank you so much. Thank you. And I'm currently showing no further questions.

Operator: Thank you, Operator, and thank you, everyone, for the questions. We look forward to an exciting time ahead with a February 17th, 2022 PDUFA date coming up for minipivad and PK deficiency in the U.S. We're also looking forward to the ongoing MAA review for the same indication in Europe, the initiation of three pivotal studies by year end across thalassemia and sickle cell disease in adult patients, the initiation of the pediatric PK deficiency clinical program So, you can see we have a lot going on.

Jackie: 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 minipivad clinical trials across indications. Thank you again for joining us today. You may now disconnect. This concludes today's conference call. Thank you for participating. My outro for my 20th birthday

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