Q2 2021 Agios Pharmaceuticals Inc Earnings Call

[music].

Okay.

Operator: Good morning, and welcome to Agio's second quarter 2021 conference call.

Good morning, and welcome to Rga's second quarter 2021 conference call.

Operator: At this time, all participants are in a listen-only mode. There will be a question-and-answer session at the end. Please be advised...

At this time all participants are in a listen only mode. There will be a question and answer session. At the end. Please be advised that this call is being recorded at I I T O.

Operator: So this call is being recorded at Agios' request. I would now like to turn the call over to Jessica Rennekamp, Director of Corporate Communications.

Request I would now like to turn the call over to Jessica <unk> director of corporate.

Operator: I would now like to turn the call over to Jessica Rennekamp, Director of Corporate Communications.

Jessica Rennekamp: Thank you, operators. Good morning, everyone, and welcome to Agios' second quarter 2021 conference call. You can access slides for today's call by going to the investors section of our website, agios.com. With me on the call today with prepared remarks are Dr. Jackie Faust, our Chief Executive Officer; Dr. Chris Bowden, our Chief Medical Officer; Darren Miles, our Chief Commercial Officer; Jonathan Biller, our Chief Financial

Communications.

Thank you operator, good morning, everyone and welcome to <unk> second quarter 2021 conference call.

You can access slides for today's call by going to the investors section of our website at <unk> Dot 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 day.

Darrin miles, our chief commercial officer, Jonathan Biller, our Chief Financial Officer, and head of legal.

Jessica Rennekamp: Chief Financial Officer

Jessica Rennekamp: 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. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in our most recent filings with the FEC and any other future filings that we may make with the FEC.

Got it.

Keith.

Who will join for <unk>.

Q&A.

Before we get started.

Everyone that some other statements we make on this call will include forward looking statements.

Events and results could differ materially from those expressed or implied by any forward looking statements as a result of various risks uncertainties.

In corporate 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 Jacky.

Jackie Faust: Thanks, Jesse. Good morning, everyone, and thanks for joining our second quarter 2021 financial results call. We are pleased to report another quarter of strong progress at Agios, the first full quarter since the close of the sale of our oncology business to Serviette. The team is focused, energized, and excited for the future as we continue to advance our pipeline in genetically defined diseases led by Mitopivat across its three initial indications in hemolytic anemia.

Thanks, Jessie good morning, everyone and thanks for joining our second quarter 2021 financial results call.

We are pleased to report another quarter of strong progress at <unk>. The first full quarter since the close of the sale of our oncology business to survey.

The team is focused energized and excited for the future as we continue to advance our pipeline in genetically defined diseases land.

<unk> made a pivot across its 3 initial indications in hemolytic anemias.

Jackie Faust: We achieved significant recent milestones with the submission of our NDA for midipivate in adults with pyruvate kinase deficiency in June, as well as with the submission of our MAA to the EMA the same month. We look forward to working with the FDA and EMA as they complete their reviews. With these two filings, we are one step closer to delivering the first potentially disease-modifying therapy for people with pyruvate kinase deficiency. These regulatory submissions are supported by strong Phase III data from the ACTIVATE and ACTIVATE-T studies.

We achieved significant recent milestones with the submission of our NDA from middle <unk> in adults with pyruvate kinase deficiency in June as well as with the submission of our MAA to the EMA.

The same month.

We look forward to working with the FDA and EMA as they complete their reviews.

With these 2 filings we are 1 step closer to delivering the first potentially disease modifying therapy for people with pyruvate kinase deficiency.

These regulatory submissions are supported.

By strong phase III data from the activate and activate T studies full results from both were recently presented at the European Hematology Association or E. H, a virtual Congress in June.

Jackie Faust: Full results from both were recently presented at the European Hematology Association, or EHA, Virtual Congress in June. Our preparations for the commercial launch of Minipivot and PK deficiency continue to advance, and we remain on track for anticipated approval and launch in 2022. In addition, we would like to extend our congratulations to the Pyruvate Kinase Deficiency Foundation and the Thrive with Pyruvate Kinase Deficiency Organization, both of which recently launched as the first two U.S.-based advocacy organizations dedicated to PK deficiency. Both organizations are patient-led, and it's very exciting to see how this community has coalesced.

Our preparations for the commercial launch of me to pay that in PK deficiency continue to advance and we remain on.

My 4 anticipated approval on launch in 2022.

In addition, we would like to extend our congratulations to the pyruvate kinase deficiency Foundation and the thrive with pyruvate kinase deficiency organization, both of which recently launched as the first 2.

On Triad U S based advocacy organizations dedicated to PK deficiency.

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

Jackie Faust: Beyond PK deficiency, we are also making excellent progress with the late stage development of midipivate and thalassemia and sickle cell disease. At EHA, we presented positive results from our Phase 2 open-label study of

Beyond PKU.

K deficiency, we are also making excellent progress with our late stage development of min pay that in thalassemia and sickle cell disease.

At <unk>, we presented positive results from our phase 2 open label study admit a pivot in adults with non transfusion dependent alpha or beta thalassemia.

Jackie Faust: with non-transfusion dependent alpha or beta thalassemia. These data continue to validate the potential of PK activation as an entirely new mechanism for treating thalassemia and represent the first clinical data generated in alpha thalassemia patients.

These data continuing to.

<unk> made the potential of PK activation as an entirely new mechanism for treating thalassemia and represented the first clinical data generated in alpha thalassemia patients.

Jackie Faust: We remain on track to initiate our two registrational phase three trials, Energize and Energize-T, in not regularly transfused and regularly transfused adults with thalassemia, respectively, this year. In sickle cell disease, we also remain on track to initiate a pivotal phase 2-3 trial of minipivet by the end of the year. Beyond Minipivot, we are building on our expertise in PK activation and cellular metabolism and are advancing our earlier stage research programs in genetically defined diseases to position us for sustainable growth and momentum. In the fourth quarter, we plan to host Investor Day to share more information about our commercial launch planning for minipat and PK deficiency and talk more in detail about our research.

We remain on track to initiate our 2 registrational phase III trials, and or Josh and energize T and not regularly transfused.

Views and regularly transfused adults with thalassemia, respectively. This year.

In sickle cell disease. We also remain on track to initiate a pivotal phase 2.3 trial on <unk> by the end of the year.

Beyond that we are building on our expertise in PK activation in cellular metabolism and are advancing.

Validly or stage research programs and genetically defined diseases to position us for sustainable growth and momentum in.

In the fourth quarter, we plan to host an investor day to share more information about our commercial launch planning for a minute that in PK deficiency and talk more in detail about.

Jackie Faust: Our research and development pipeline.

Our research and development pipeline.

Jackie Faust: Before I turn the call over to Chris to provide an update on our clinical development programs, I wanted to take a moment to share that Chris has decided to retire from his role as Chief Medical Officer at Agios after a terrific seven years on our leadership team. After a transition period to his successor over the coming months, I am very pleased that Chris will remain part of our team as a strategic advisor.

Before I turn the call over to Chris to provide an update on our clinical development programs I wanted to take a moment to share the Chris has decided to retire from his role as Chief Medical Officer Adriano <unk>. After a terrific 7 years on our leadership team.

Our transition period to his successor over the coming months I'm very pleased that Chris will remain part of our team as a strategic adviser through at least the end of 2022.

We're excited for him as he enters this new chapter of his life and want to thank him for his leadership and many years of service Center.

After those.

Jackie Faust: Strategic Advisor through at least the end of 2022.

Among his many accomplishments and contributions he oversaw the build out of our medical and clinical development organizations acted as Aussie doses lead medical representative internally and externally navigated complex regulatory interactions in order to bring important drugs to patients.

Jackie Faust: We are excited for him as he enters this new chapter of his life and want to thank him for his leadership and many years of service at Agios. Among his many accomplishments and contributions, he oversaw the build out of our medical facility.

I'll, just and played a key role in the evolution of our organization and culture. He's been an integral part of our team and his work will continue impacting the lives of patients for many years to come on.

Jackie Faust: Clinical Development Organizations, acted as Agios' lead medical representative internally and externally, navigated complex regulatory interactions in order to bring important drugs to patients, and played a key role in the evolution of our organization and culture. He's been an integral part of...

On behalf of everyone at <unk> I wish Chris all the best in the future.

I'm equally excited.

Cited to announce the Doctor steroid Gwinn's, who has up to now served as our head of clinical development for genetically defined diseases.

I'll assume the role of Chief Medical Officer effective September 1.

Sarah has been with audience for almost 2 years and it's been an impactful and energizing leader across the organization.

Listen during her tenure among Sarah is most significant accomplishments in all Geos. She played an integral role in the work associated with the PK deficiency filings and the design and strategy for our sickle cell disease pivotal programs.

Jackie Faust: We look forward to impacting the lives of patients for many years to come.

All aspects of our programs inside and out and has a genuine.

Jackie Faust: I'm equally excited to announce that Dr. Sarah Gheuens, who has up to now served as our Head of Clinical Development for Genetically Defined Diseases, will assume the role of Chief Medical Officer, effective September 1. Sarah has been with Agios for almost two years and has been an impactful and energizing leader across the organization during her tenure. Among Sarah's most significant accomplishments at Agios, she played an integral role in the work associated with the PK deficiency filings and the design and strategy for our Sickle Cell Disease Pivotal Program. She knows all aspects of our programs, inside and out, and has a

Passion for serving people with genetically defined diseases.

Prior to our channel Sarah held roles of increasing responsibility at Biogen in safety and risk management Medical Affairs, and clinical development and she is a neurologist about training.

Look forward to continuing to see great.

Genuine him her as she takes on this new level of responsibility.

With that I will now turn the call over to Chris.

Thanks Jackie.

As Jackie mentioned, we are excited about the potential we have to impact the lives of individuals genetically defined diseases.

We achieved important miles.

Things from both modules and the PK deficiency community this past quarter with the submission of our global regulatory filings for <unk> in the U S and EU.

We're pleased to share that our MAA passed validation, which triggered the start of the MAA review procedure.

Jackie Faust: He has a genuine passion for serving people with genetically defined diseases.

Jackie Faust: Prior to Agios, Sarah held roles of increasing responsibility at Biogen in safety and risk management, medical affairs, and clinical development, and she is a neurologist by training. We look forward to continuing to see great things from her as she takes on this new level of responsibility. With that, I will now turn the call over to Chris. Thanks, Jackie.

Yep.

60 days from submission to determine whether the application is accepted.

So we expect to hear from them in mid August.

Information about whether the application is accepted.

I'm going to pick out had been granted priority review.

Do per day, all be communicated by the agency.

But at that time.

Overall, we are very pleased with our progress and believe we have significant momentum as we look to a busy second half 2021.

Chris: As Jackie mentioned, we are excited about the potential we have to impact the lives of individuals with genetically defined diseases. We achieved important milestones for both Agios and the PK deficiency community this past quarter with the submission of our global regulatory filings for Mitopivat in the U.S. and EU. We're pleased to share that our MAA has passed validation, which triggered the start of the MAA review procedure. For the NDA, the FDA has 60 days from submission to determine whether the application is accepted, so we expect to hear from them in mid-August. Information about whether the application is accepted, whether Medipivot has been granted priority review, and the PDUPA date will all be communicated by the agency at that time. Overall, we are very pleased with our progress and believe we have significant momentum as we look to a busy second half of 2021.

At <unk>, we presented.

The full data from the activate and activate T.

Phase III studies evaluating made up to that.

In adults with PK deficiency, who are not regularly transfused and those who are regularly transfused respectively.

Both studies met their primary and secondary endpoints, including patient reported outcomes that address symptom burden and quality of life impact of PK deficiency.

It appears that in.

Generally well tolerated and the safety profile observed in both studies was consistent with previously published data.

During our <unk> Investor event, we also heard from Dr. Andreas Glenn joke, who highlighted the significant impact PK deficiency has on patients' quality of life the limitations of the.

Of the current PK deficiency treatment landscape.

On the potential for net of Tibet to serve as the first disease modifying therapy for these individuals.

Moving to talent Femia.

We also presented data at <unk> on all 20 patients from the core period of our phase 2 study of <unk> in non transfusion.

Chris: At EHA, we presented full data from the Activate and Activate Team phase 3 studies evaluating midipivav in adults with PK deficiency who are not regularly transfused and those who are regularly transfused, respectively. Both studies met their primary and secondary endpoints, including patient-reported outcomes that addressed symptom burden and quality-of-life impact of PK deficiency. The PIV app is generally well tolerated, and the safety profile observed in both studies was consistent with previously published data.

Fusion dependent alpha and beta thalassemia.

Consistent with previously announced proof of concept data. The study met its primary endpoint with 16 of the 20 patients achieving a hemoglobin increase of greater than or equal to 1 gram per deciliter from baseline at 1 or more assessments during weeks 4 to 12.

In addition, our sustained hemoglobin response and improvements in hemolysis and ineffective erythropoiesis were observed in both alpha and beta thalassemia patients treated with net of pay that.

It appeared that was also well tolerated with a.

Safety profile consistent with previous studies.

Chris: During our EHA Investor event, we also heard from Dr. Andreas Glentos, who highlighted the significant impact PK deficiency has on patients' quality of life, the limitations of the current PK deficiency treatment landscape, and the potential for Mitivativat to serve as the first disease-modifying therapy for these individuals. Moving to thalassemia, we also presented data at EHA on all 20 patients in the core period of our Phase II study of minipiva and non-transfusion-dependent alpha and beta thalassemia.

We believe.

Underscore the potential of Medicare that to meaningfully improve hallmarks of thalassemia, including hemolysis and ineffective erythropoiesis.

We're also excited to see data generated for the first time, an alpha thalassemia, demonstrating an increase in hemoglobin from baseline at all 5 patients in this.

These risks.

Our 2 global placebo controlled pivotal trial.

On the Pip out in thalassemia energizing to energize T are on track to initiate this year as we continue the process of submitting these trial protocols globally and prepare sites for enrollment.

Now turning.

Turning to sickle cell disease.

Chris: Consistent with previously announced proof-of-concept data, the study met its primary endpoint, with 16 of the 20 patients achieving a hemoglobin increase of greater than or equal to 1 gram per deciliter from baseline at one or more assessments during weeks 4 through 12. In addition, a sustained hemoglobin response and improvements in hemolysis and ineffective erythropoiesis were observed in both alpha and beta thalassemia patients treated with Nidipida.

We remain on track to initiate our pivotal phase 2.3 clinical trial by the end of this year.

The phase 2.3 study of mid a pickup in sickle cell disease will include patients who are 16 years of age or older have.

I have had between 2% to 10 sickle cell crises in the past 12 months and have.

1 of them within the range of 5.5 to 10 on the half Gram per deciliter during screening.

The phase II randomized 69 patients 1 to 1 to 1 to 50 milligrams mid to that twice daily.

Milligram net of Pip out.

Twice daily or matching placebo.

Chris: And PIVAP was also well-tolerated, with a safety profile consistent with previous studies. We believe these results underscore the potential of midipivac to meaningfully improve hallmarks of thalassemia, including hemolysis and ineffective erythropoiesis. We're also excited to see data generated for the first time in alpha thalassemia, demonstrating an increase in hemoglobin from baseline in all five patients in this subgroup. Our two global placebo-controlled pivotal trials, Amidipivat and Thalassemia, ENERGIZE and ENERGIZE-T, are on track to initiate this year as we continue the process of submitting these trial protocols globally and preparing sites for enrollment. Now, I'm turning to sickle cell disease.

The primary.

Free endpoint into 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 III portion.

Phase III, which will commence after the phase 2 analysis or randomized 198 page.

<unk> 2 to 1 to the selected phase II dose submit it to that on matched placebo.

<unk> will have 2 primary endpoints.

Hemoglobin response defined as greater than or equal to 1 gram per deciliter change from baseline to week 52, and a reduction in annualized rate of sickle cell pain crisis.

I believe the design of this phase 2.3 study minimizing risks to the approval path per minute payback in this challenging disease and maximize the likelihood of a label what they brought indication.

In addition, we continue to work with our collaborators at the NIH and the University of food trucks on their studies of <unk> in sickle cell disease.

Chris: We remain on track to initiate our Pivotal Phase 2-3 clinical trial by the end of this year. The Phase 2-3 study of midipivav and sickle cell disease will include patients who are 16 years of age or older, have had between 2-10 sickle cell crises in the past 12 months, and have hemoglobin within the range of 5.5 to 10.5 grams per deciliter during screening. Phase 2 will randomize 69 patients, 1 to 1 to 1, to 50 mg midipivac twice daily, 100 mg midipivac twice daily, or matched placebo.

Data from both studies are expected to be submitted for presentation at Ash in December.

At the NIH, Dr. Ken has completed enrollment in the core study with 17 patients and continues to enroll the extension study.

We anticipate the datasets at Ash will provide additional efficacy safety and translational.

We had that supports the clinical development of mid up to that and people with sickle cell disease.

Beyond that appear that we're also advancing our next generation PK R. Activator AG 946, and a phase 1 healthy volunteer study.

Chris: The primary endpoint is a hemoglobin response defined as greater than or equal to one gram per deciliter change from baseline to week 12, and the data will be used to establish a clear dosing paradigm for the phase three portion. Phase 3, which will commence after the Phase 2 analysis, will randomize 198 patients 2-to-1 to the selected Phase 2 dose of PIVAT or matched placebo. The study will have two primary and secondary objectives, hemoglobin response defined as greater than or equal to one gram per deciliter change from baseline to week 52, and a reduction in annualized rate of sickle cell pain crises.

The trial began enrolling last year, and we expect to submit data from presentation.

<unk> at Ash.

Our analysis of the totality of the age of 94, 6 healthy volunteer data will inform next steps for the clinical development of this molecule.

As part of our Investor event. This fall, we will talk in more detail about our research and development pipeline.

Before I turn it over to Darren to discuss.

Our commercial activities.

I want to thank all of my <unk> colleagues for the privilege of working with you over the last 7 years.

It has been so rewarding and fun and the accomplishments speak for themselves my.

My successor, Sarah Glens is poised to lead our team to more great accomplishments and I look forward to watching the audio story continue.

Chris: We believe the design of this Phase 2-3 study minimizes risks to the approval path for minipivac in this challenging disease and maximizes the likelihood of a label with a broad indication. In addition, we continue to work with our collaborators at the NIH and the University of Utrecht on their studies of medicevac and sickle cell disease. Data from both studies are expected to be submitted for presentation at ASH in December.

To unfold Darrin.

Thank you Chris.

We continue to make strong progress on commercial launch preparations from the pivotal PK deficiency on.

Customer facing and patient support infrastructure and talent are hired and fully trained.

Our field team comprised of both sales representatives and credentials nurse clinical educators and all.

Engage with physicians potentially managing patients with PK deficiency across the U S and are focused on profiling accounts raising disease awareness and executing pay supports and profiling plans through disease education.

Chris: At the NIH, Dr. Ken has completed enrollment in the core study with 17 patients and continues to enroll the extension study. We anticipate the data sets at NASH will provide additional efficacy, safety, and translational data that support the clinical development of this drug in people with sickle cell disease. Beyond Medipivot, we're also advancing our next generation PKR activator, AG946, in a phase one healthy volunteer study. The trial began enrolling last year, and we expect to submit data for presentation at ASH.

An important feature of their work of educating physicians on the availability of the audio sponsor genetic testing service anemia.

Fully Heidi.

Now well over 1000 test kits requested we expected.

On to become an increasingly important program to help support patients seeking a definitive diagnosis other hemolytic anemia, and even accelerating our PK deficiency patient profiling efforts.

Our market research now shows that 70.

Santa responding physicians routinely order additional diagnostic test for their patients with hemolytic anemias of unknown etiology.

This is important insight, which favorably pretends future adoption of genetic testing for accurate diagnosis of hemolytic anemias, including PK deficiency.

Chris: Our analysis of the totality of the AG946 healthy volunteer data will inform next steps for the clinical development of this molecule. As part of our investor event this fall, we will talk in more detail about our research and development pipeline. Before I turn it over to Darren to discuss our commercial activities, I want to thank all of my AGIOS colleagues for the privilege of working with you over the last seven years.

Response to the anemia program.

It's been very enthusiastic and our research responding physicians indicated they are inclined to test a significant portion of their patients from hemolytic anemia unknown etiology based on the breadth of mutations included in the panel and its relative ease of use.

In June we also launched a re imagined my audio speaker support service.

Dedicated to people living with PK deficiency, and their caregivers leveraging our learnings and much of the technical infrastructure from the oncology modules program, while incorporating insights from PK deficiency patients and clinicians to create a customized program designed to meet the specific needs of this community.

Chris: It has been so rewarding and fun, and the accomplishments speak for themselves. My successor, Sarah Gheuens, is poised to lead our team to more great accomplishments, and I look forward to watching the Agios story continue to unfold. Darren.

Enrolled patients from.

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

Darren: Thank you, Chris. We continue to make strong progress on commercial launch preparations for Mitipivad and PK-Deficient. All customer-facing and patient support infrastructure and talent are hired and fully trained. Our field team, comprised of both sales representatives and credentialed nurse clinical educators, is now fully engaged with physicians potentially managing patients with PK deficiency across the U.S. and are focused on profiling accounts, raising disease awareness, and executing patient support and profiling plans through disease education.

Amongst other educational efforts on field team is educating physicians and their staff on the availability of the service.

And how they can support patients with enrollment.

Following the disclosure of the activate and activate T findings at <unk> June we feel that new market research to update our insights into general physician awareness and understanding of PK deficiency and the potential implications for disease management, assuming mitigate that's approval next year.

We found.

On that PK deficiency disease awareness metrics are improved over the same time period in 2020 with 85% of academic and community physician respondents now familiar with PK deficiency and more than half, indicating that they manage 1 to 2 previously diagnosed PK deficiency patients.

Darren: An important feature of their work is educating physicians on the availability of the agiosponsor genetic testing service, Anemia ID. Now with well over a thousand test kits requested, we expect Anemia ID to become an increasingly important program to help support patients seeking a definitive diagnosis of their hemolytic anemia and an aid in accelerating our PK deficiency patient profiling effort. Our market research now shows that 70% of responding physicians routinely order additional diagnostic tests for their patients with hemolytic anemias of unknown etiology.

This is encouraging because it indicates that physicians.

<unk> are increasingly recognizing and diagnosing PK deficiency, which we intend to continue to support with additional educational activities in the months, leading up to approval in 2022.

Our research also suggests that based on their understanding of the phase III data. Many physicians will consider prescribing the pivotal PK deficiency patients with differently.

Sales of disease severity, including with respect to transfusion history and hemoglobin level.

While prescribing will be based on individual patient history presentation and parameters of the approved label for net it too that we are encouraged by these responses and the overall increase in physician understanding of the burden of disease.

Darren: This is an important insight which favorably predicts future adoption of genetic testing for accurate diagnosis of hemolytic anemias, including PK deficient. The response to the Anemia ID program has been very enthusiastic. In our research, responding physicians indicated they are inclined to test a significant portion of their patients with hemolytic anemia of unknown etiology based on the breadth of mutations included in the panel and its relative ease of use.

Overall.

We're very pleased by the progress we've made with launch preparations across each function at <unk> and the response from the treating community to the broad disease education efforts.

We expect this to accelerate in the coming months now that we have our full complement in the field and his excitement about what we'll be able to do for patients growth.

Hopefully activate disclosures.

Now I'll turn it over to Jonathan to review second quarter financials.

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

Darren: In June, we also launched the reimagined MyAGIOS patient support. Dedicated to people living with PK deficiency and their caregivers, it leverages our learnings and much of the technical infrastructure from the Oncology MyOGOS program while incorporating insights from PK deficiency patients and clinicians to create a customized program designed to meet the specific needs of this community. Enrolled patients and caregivers are connected with a dedicated and clinically trained patient support manager.

As a reminder, our second quarter financial results discussion only includes our continuing operations on a comparative basis, which excludes results from our divested oncology business.

Research and development for the second quarter was $62 million, an increase of $7.9 million compared to the second quarter of 2020.

Really the year over year increase in R&D was driven primarily by startup costs associated with the phase III studies on <unk> and palace see me on sickle cell disease, and the filing of our NDA and MAA permitted pivot in PK deficiency.

Darren: And we provide ongoing TALET support, educational resources, and opportunities to connect with other patients and caregivers in the PK deficiency community, amongst other educational activities. The educational field team is educating physicians and their staff on the availability of the service and how they can support patients with enrollment. Following the disclosure of the Activate and Activate P findings at EHEIM June, we conducted new market research to update our insights into general physician awareness and understanding of PK deficiency.

As well as our launch preparation efforts.

Selling general and administrative expenses were 20.

$92 million for the second quarter, essentially flat compared to SG&A expenses for the second quarter of 2020.

We also recorded $2 million in <unk> income from royalties from the second quarter of 2021, which is included within the gain on sale of oncology business line item in our income statements.

<unk> 9 we ended the quarter with cash cash equivalents in marketable securities of approximately $1.7 billion.

With this cash balance we'd expect to be able to execute our current operating plan through major catalysts and to cash flow positivity without the need to raise additional equity.

Darren: Potential Implications for Disease Management Assuming Medepivac's approval next year, we found that PK deficiency disease awareness metrics are improved over the same time period in 2020, with 85% of academic and community physician respondents now familiar with PKD, and more than half indicating that they manage one to two previously diagnosed PK deficiency patients. This is encouraging because it indicates that physicians are increasingly recognizing and diagnosing PKD. We intend to continue to support this with additional educational activities in the months leading up to approval in 2022.

In Q2, we.

We executed a $529 million of the up to $1.2 billion of share repurchases authorized by our board of directors inclusive of the shares acquired from Bristol Myers Squibb.

Specifically, we repurchased just under $10.5 million shares at an average price of $50.41, reducing our total.

Statements is outstanding by approximately 15% to $59.9 million shares at quarter end.

Yeah.

As previously disclosed <unk> 5.1 plan we put in place in early Q2 provides for maximum additional share repurchases of approximately $415 million through year end.

Darren: Our research also suggests that based on their understanding of the phase three data, many physicians will consider prescribing EPIVA to PK deficiency patients with differing levels of disease severity, including with respect to transfusion history, although prescribing will be based on individual patients.

The ultimate amount of additional share repurchases through year end will depend upon the volatility of our share price over this time period.

Operator, please open the line for questions.

Thank you and as a reminder, if you would like to ask a question press. The Star then the 1 key on your Touchtone telephone.

Jonathan: We are encouraged by these responses and the overall increase in physician understanding of the burden. I'm very pleased by the progress we've made with launch preparations across each function at OGS and the response from the treatment community to the broad disease education. We expect this to accelerate in the coming months, now that we have our full complement in the field and with excitement about what we'll be able to do for patients' growth related to the Activate Disclosure. Now I'll turn it over to Jonathan to review second quarter finance. Thanks, Darren.

Our first question comes from Alicia Young with Cantor Fitzgerald. Your line is open.

Hey, guys. Thanks for taking my question and congrats on all the progress I wanted to talk a little bit about <unk> and maybe just as youre doing some of the education from <unk>.

To support you know how frequently do these people kind of see their physicians and like what kind of outreach and effort needs to.

We done there or is it more just kind of like a structural kind of warehousing effect or is there actually a work that needs to be done to bring these people back on your care.

Thanks.

Hey, Alethia this is doing.

The issue is not going to be necessarily getting patients to come back in because they're usually under for those who have been diagnosed.

And obviously you touched on with physician.

They're under some sort of monitoring plan right those with more severe disease, we're going to see or see their physicians more more regularly those with less severe disease will have a longer.

Typically you'll have a longer time span between.

Jonathan: Our second quarter 2021 financial results can be found in the press release we issued this morning, which I will summarize. More detail will be included in our 10-2 filing later today. As a reminder, our second quarter financial results discussion only includes our continuing operations on a comparative basis, which excludes results from our divested on-college business. Research and development for the second quarter was $62 million, an increase of $7.9 million compared to the second quarter of 2020.

<unk> physician visits, but remember there theyre continuing to have their iron iron load.

Good.

Monitored hemoglobin monitored so the frequency of physician visits isn't necessarily where we want to where we would focus I think what we're doing now is focusing on on the patient profiling identification and.

And physician education patient education on the disease, and I think that's where.

We need to continue even post launch to focus much of much of our efforts on the physician patient relationship be fine and we don't need to there's nothing there that we need to we need to delve into it we just need to make sure that they are aware of.

And once that's done I think everything else flows from there.

Great. Thank you.

Thank you. Our next question comes from Kennan Mackay with RBC capital markets. Your line is open.

Jonathan: The year-over-year increase in R&D was driven primarily by startup costs associated with the Phase III studies of midipivet and thalassemia and sickle cell disease and the filing of our NDA and MAA for MIDA-PIVET and PKG, as well as our launch, selling gentlemen's administrative services for $29.2 million for the second quarter, although basically flat compared to SG&A expenses for the second quarter We also recorded $2 million in FITSOBO income from royalties in the second quarter of 2021, which is included within the gain on sale of oncology business line item in our income.

Hi, Thanks for taking my question first on Chris I'm, sorry to hear about your departure, but looking forward to moving your successor, Sarah on cotton to hear that you're staying on into next year with the transition maybe.

Maybe 1.1 quick question on the regulatory filings here for free.

I'm wondering which branch of the FDA you are interacting with us.

Those regulatory submissions in <unk> hematology or the rare disease Division.

Hey, Ken it's Chris.

The FDA team working with her on the cardiology renal and the oncology Hematology Division.

On the submission itself as a net cardiology arena.

So it's an interest to set up actually because the people who have done most involved with us on our most.

Jonathan: We ended the quarter with cash, cash equivalents, and marketable securities of approximately $1.7 billion. With this cash balance, we expect to be able to execute our current operating plan through major catalysts and generate cash flow positivity without the need to raise additional equity. In Q2, we executed that $529 million of the up to $1.2 billion of share repurchases authorized by our Board of Directors, inclusive of the shares acquired from Bristol-Myers Swift. Specifically, we repurchased just under 10.5 million shares at an average price of $50.41, reducing our total shares outstanding by approximately 15% to 59.9 million shares a quarter.

Active on the submission on the Hematology Division.

That is just what I was going to sort of follow up with.

Just wondering around some of the interactions so far you've got division for the up to speed on.

Rare diseases, <unk> D or what have your interactions to date.

Thank you.

The.

The growth.

The team that we've been working with.

With FDA has been what's a program for <unk>.

Advising us from interacting with that since I joined the company.

They're very.

Well acquainted with the disease.

And the.

The special nature.

Jonathan: As previously disclosed, the 10B-5-1 plan we put in place in early Q2 provides for a maximum additional share repurchase of approximately $415 million through year end. The ultimate amount of additional share repurchases through year-end will depend upon the volatility of our share price over this time period.

What it takes when you're in a rare disease populations. So I don't have any.

Concerns there on I think the consistency.

And I think importantly over the years as.

You've heard us.

Talking about the guidance and why we designed the trials we have in an effort to provide them.

As much data as they are going to need to make a decision for us to demonstrate clinical benefit and that's been a consistent group of people.

Operator: Operator, please open the line. Thank you. And as a reminder, if you would like to ask a question, press the star and the one key on your touchtone telephone.

Is it.

Yeah.

Thank you. Our next question comes from the New Pom Rama with J P.

Alicia Young: Our first question comes from Alicia Young with Cantor Fitzgerald. Your line is open. Hey guys.

Morgan Your line is open.

Hi, guys. Thanks, so much for taking the question, perhaps a broader strategic question I think many of us on the street.

Alicia Young: Hey guys, thanks for taking my question and congrats on all the progress. I wanted to talk a little bit about MediPivot and maybe just, you know, as you're doing some of the education for patient support, you know, how frequently do these people kind of see their physicians and like, what kind of outreach and effort needs to be done there, or is it more just kind of like a structural kind where it's a warehousing effect, or is there actually work that needs to be done to bring these Thanks. Ailey Theodos is dying.

Model.

Price cut from it appear that longer term to account for the C. D indication what threshold of peak sales in FCB does mitigate payback how can meet in your view to justify a price cut versus say maximizing the value of the product by keeping ultra orphan pricing. Thanks, so much.

It would be it'd be premature to talk about what peak sales would be and in sickle cell. What I can tell you is is that it would require.

Assuming assuming you just wanted to at least breakeven right as you move from from the first 2 indications and it's a sickle cell when you account for it cut the what we think would be required.

Darren: The issue is not necessarily going to be getting patients to come back in because they're usually under, for those who've been diagnosed and obviously attached to, they're under some sort of monitoring plan, right? Those with more severe disease are gonna see their physicians more regularly. Those with less severe disease will have a longer, typically will have a longer time span between physician visits.

Would only would only require.

Less than 4% 3% share.

Share in that market to be able to at least breakeven.

The whole program.

So it doesn't take a whole lot because of the size of sickle cell is significant.

Darren: But remember, they're continuing to have their iron load monitored and hemoglobin monitored. So the frequency of physician visits isn't necessarily where we would focus. I think what we're doing now is focusing on patient profiling, identification, physician education, and patient education on the disease. And I think that's where we need to continue, even post-launch, to focus much of our efforts. The physician-patient relationship would be fine. And we don't need to; there's nothing there that we need to delve into.

<unk> for you to be able to accommodate.

That total that's why we're so we're still optimistic about the incremental value right that we wouldn't be able to gain once we move into the sickle cell despite competition.

And it's Jackie I'm, just going to jump in real quick as we've said many times, but I think both Chris and Darren.

And I have said this often it's well make those pricing decisions based on the totality of the clinical data that we have at that point.

And Tom and the product profile of course, so you can imagine there's a lot going on when you think about that with respect to hemoglobin increase VLC reduction.

All the secondary endpoints from patient reported outcomes.

All of that so lots of them.

Things to think about when we make that pricing decision at some point in the future.

Thanks, so much for taking our questions.

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

Darren: We just need to make sure that they're aware, and once that's done, I think everything else is OK. Great. Thank you. Thank you. Our next question comes from Kenan McKay with RBC Capital Markets. Your line is open.

Great. Good morning, and thank you for taking our question. This is Elizabeth on for solving could you just remind us if you intend to launch simultaneously in both the U S and EU for them at a pivot on PK D and.

Kenan McKay: Hi. Thanks for taking the question. First off, Chris, I'm sorry to hear about your departure but looking forward to meeting your successor, Sarah, and glad to hear that you're staying on into next year with the transition.

And then.

Now.

Knowing that you're sort of discussing this at your Investor day in 4 Q, maybe if you could just comment on me the structure and size of the launch team and your progress in terms of identifying more patients and then how many patients with PK data have been identified to date. Thank.

Kenan McKay: Maybe one quick question on the regulatory filings here for midopivot. I'm wondering which branch of the FDA you are interacting with on those regulatory submissions in PKD. Is that hematology or the rare disease division? Ed Cannon, and it's Chris.

Gotcha, Alright, soybeans as Darren a lot in there. So let me see if I can unpack that.

Let me start with the structure question first so as I mentioned in our in our prepared comments earlier, we fully hired are our internal and external teams right.

Chris: The FDA teams we're working with are in cardiology, renal, and the oncology hematology division. The submission itself is in cardiology renal. So it's an interesting setup, actually, because the people who've been most involved with us and are most active in the submission are in the hematology division. That is just what I was going to sort of follow up with and just wonder around some of the interactions so far. Is that division sort of up to speed on rare diseases and PKD, or have the interactions to date been like?

That's about just under.

'twenty representatives on our sales Representatives and then a small contingent of nurse educators that will collaborate with them on.

And that's for the U S team.

For the E U.

B you know.

You've shared previously we've got you've got boots on the ground there already right. So we have an MSL team with established.

Ablation and then we have a small group of on exports that have been dedicated to building awareness and extending our advancing our patient profiling efforts in each of the major markets in the EU.

And we continue to do the work on particularly on the critical path activities to ensure.

Chris: Thank you. The group, the team that we've been working with, and FDA has been what's the program for has been advising us and interacting with us since I joined the company. So, they're very well acquainted with the disease and the special nature of what it takes when you're in a rare disease population, so I don't have any. I think the consistency and, importantly, over the years, as you've heard us talking about the guidance and why we've designed the trials we have in an effort to provide them with as much data as they're going to need to make a decision for us to demonstrate clinical effectiveness.

Sure that we will be able to launch.

<unk> launched the pivot in the EU.

Shortly after approval.

The but we would also share that we're evaluating a number of options right considering the opportunity to be able to engage with a partner who has got a footprint that's already exist.

On the already existing in the EU and and hopefully outside on beyond the ER given the amount of value from it a pick up of extended patient day that extends beyond our beyond the major markets.

That can that can overlay on that appear that our include minutes without even on an existing infrastructure and that's where that's where we've been focusing our efforts. So the idea is.

Moving to enable a launch, particularly in Germany, where you have you can you can launch immediately in that free pricing.

And then but also be able to then transition network to a potential partner once once we find the sort of deal that we believe are fairly reflects the value of that net of pivotal break.

Chris: Thank you. The next question comes from Anupam Rama with J.P. Morgan.

Keep the great. Thank you and then maybe if you could just comment on that.

Anupam Rama: Morgan, your line is open.

The patient identification efforts in that patient on identified today.

Anupam Rama: Hi guys, thanks so much for taking the question. Perhaps a broader strategic question. I think many of us on the street model a price cut for mid-to-pivot longer term to account for the SCD indication. What threshold of peak sales in SCD does mid-to-pivot have to meet in your view to justify a price cut versus, say, maximizing the value of the product by keeping ultra orphan pricing? Thanks so much.

Yeah, Yeah, Yeah. So you know so we continue to to do the work behind will be referred to as patient profiling efforts right being able to.

To identify more.

More patients with previously share that we've we've identified about 1000 patients between the U S and the EU and that's inclusive of pediatric patients patients that are enrolled in our various clinical programs as well as patients. So that the patients that we that we come across as were engaging with with physicians and it's an important number.

Jackie Faust: It'd be premature to talk about what peak sales would be for sickle cell. What I can tell you is that it would require, assuming you just want it to break even, right, as you move from the first two indications into sickle cell, and you account for a cut, what we think would be required would only require less than 4%, 3% share in that market to be able to break even across the whole. So, it doesn't take a whole lot because the size of sickle cells is small enough for you to be able to accommodate that. That's why we're so optimistic about the incremental value.

And I know everyone wants to hear more and more about but and and we do keep on top of that that's not where I would focus though.

Particularly as we move closer to the launch here in the U S, where you really need to do is be able to then attach each of those physicians on patients who.

Where do you identified to US right, so and we don't know their personal.

They are identified information.

You wouldn't be the attention to an individual physician you wanted to ensure that they're getting tested on seat. The physician is inclined to use any idea to confirm confirmed the diagnosis.

Even further.

And then we've also made our patient support program available on the last in the last.

And ideally those physicians would then.

Jackie Faust: And it's Jackie. I'm just going to jump in real quick. As we've said many times,

See value and referring their patients to the programs and that helps you to get a better sense.

Jackie Faust: I think both Chris and Darren have said this often; it's, we'll make those pricing decisions.

The.

The absolute confirmed patient population here in the U S.

Jackie Faust: It is based on the totality of the clinical data that we have at that point in time and the product profile, of course.

So that's where we're focusing our efforts continuing to advance.

The diagnostic differential and get those patients.

Jackie Faust: So you can imagine there's a lot going on when you think about that.

Appropriate support that they need to get them the education that they can debt.

Jackie Faust: with respect to hemoglobin increase, VOC reduction, all the secondary endpoints, patient reported outcomes, and all of that. Things to think about when we make that pricing decision at some point in the future.

My Rgs can provide.

Which then will lead us.

Up to and through the <unk> approval.

Thank you that's very helpful.

Months ago problem.

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

Anupam Rama: Thanks so much for taking our questions.

Salveen Jaswal Richter: Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open. Okay, good morning, and thank you for taking our question. This is Elizabeth on behalf of Salveen.

Hey, this is Kelsey Goodwin on for Michael Thanks for taking our question, maybe actually building of a balance that I guess.

I guess going forward, how do you kind of see the.

All right and slope of debt TKD diagnose he's kind of evolving as you continue these assets I guess, what kind of assumptions do you kind of built in over the next day no near term long term of this launch.

Elizabeth: Could you just remind us if you intend to launch simultaneously in both the U.S. and EU for MetaPivot and PKD? Knowing that you're sort of discussing this at your investor day in 4Q, maybe if you could just comment on the structure and size of the launch team and your progress in terms of identifying more patients and then how many patients with PKD have been identified to date. Thank you.

Yeah. The the you know we have some indication from what we are observing with.

Paul.

EMEA idea, which is still in its early and its early days.

And some indication from the Spanish <unk> screening ISP on that.

Darren: Gotcha. All right, Salveen. This is Darren.

Reported about I think about 20% of those hemolytic anemia patients that were screened debt ultimately were diagnosed with with with <unk>.

Darren: There's a lot in there, so let me see if I can... Um, let me start with this, the structure question first. So, as I mentioned in our prepared comments earlier, we fully hired our internal and external teams, right? That's about just under 20 representatives, sales representatives, and then a small contingent of nurse educators that will collaborate with us. And that's for the U.S. For the EU, the, you know, as we've shared previously, we've got boots on the ground there already, right?

TKD.

We haven't got a good sense for for what your diagnosis rate may end up being amongst those.

Patients who.

Our tested, particularly those patients who have Douglas with hemolytic anemia, but he never hemolytic anemia of unknown unknown etiology.

But that on less.

We're concerned about that in terms of the ramp for the launch because I think we continue to we're doing everything that we need to do.

To facilitate testing I expect we'll see that.

Darren: So we have an MSL team that's established, and then we have a small group of experts that have been dedicated to building awareness and extending or advancing our patient profiling efforts in each of the major markets in the EU. And we continue to do the work, particularly on the critical path activities, to ensure that we will be able to launch some PIVET in the EU shortly after approval. But we've also shared that we're evaluating a number of options, right?

See that accelerate now that we have a full contingent in the.

In the field to help educate educate practices.

And our biofuel supports educate educate patients.

But the thing on that.

That's outstanding from me and I think we're focused on better understanding is what the what the access on profile will look like particularly in those first 6 to 9 months of launch right.

Where we know that for a number of payers you're going to have.

A new to market block.

That will require physicians seeking medical exception.

Darren: Considering the opportunity to be able to engage with a partner who's got a footprint that already exists in the EU and, hopefully, outside and beyond the EU, given the amount of patient value that extends beyond the major markets, that can overlay Medi-Piv-Ed or include Medi-Piv-Ed in the in the, And that's where we've been focusing our efforts. So the idea is to keep things moving to enable a launch, particularly in Germany, where you can you can launch immediately and have free pricing. And then but also be able to then transition that work to a potential partner once we find the sort of deal that we believe fairly reflects the value of that pivot.

And that will then extend the time between when you're diagnosed in the when you ultimately when she gets ultimately made available made available to the to the patient. So the the the demand and we have as confirmed in our on our recent.

<unk> quantitative work the demand is going to be there. So that you have the desire to be able to treat treat broadly for these patients.

Got all the programs in place like anemia.

What we shared with you last time on 23.23 and me.

To help increase.

<unk> overall awareness drive.

Support patients.

Sure.

And having better testing.

Testing options available to them.

Darren: Great, thank you. And then, maybe, if you could just comment on the

And then so.

The opportunity for the patient to receive the treatment I think is going on behind the question is is the <unk>.

Darren: the patient identification efforts and the patients identified today. Yeah, yeah, yeah. So, you know, so we continue to...

Amount of time in those first 2 first months.

For the physicians to be able to work through the access challenges.

Darren: Yeah, yeah, yeah, so we continue to do the work behind what we refer to as patient profiling efforts, right, being able to identify more patients. We previously shared that we've identified about a thousand patients between the U.S. and the EU, and that's inclusive of pediatric patients, patients that are enrolled in our various clinical programs, as well as incidental patients that we come across as we're engaging with physicians. And it's an important number that I know everyone wants to hear more and more about, and we do keep on top of that.

Got it okay Super helpful. Thank you so much.

No problem.

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

Hey, good morning, guys, congrats on the progress and Chris.

Of course, we're sorry to see you go as well.

You know I'm, just wondering with regard to be the pivotal trial in sickle cell disease. If you can comment on what the gating items are that remain before this trial can be initiated and in terms of the academic.

Darren: That's not where I would focus, though, because, particularly as we move closer to the launch here in the U.S., what you really need to do is be able to then attach each of those patients who are de-identified to us, right, so when we don't know their personal, identifiable information, but you want to be able to attach them to an individual physician. You want to ensure that they're getting tested, and see if the physician is inclined to use an EMIID to confirm the diagnosis even further.

<unk> sickle cell trials.

David that we might see later this year can you maybe give us a sense for how many patients do you expect from the attract trial.

Just remind us the main differences between this study and the NIH study. Thanks, so much.

Okay, It's Chris here.

<unk>.

Launching any any other phase III.

And Palestinians and the phase 2.3 study a global studies.

Darren: And then we've also made our patient support program available in the last month, and ideally, those physicians would then see value in referring their patients to the programs, and that helps you to get a better sense of the actual confirmed patient population here in the U.S. So that's where we're focusing our efforts, right, continuing to advance the diagnostic differential and get those patients the appropriate support that they need, get them the education that they can, that myAGIOS can provide, which then will lead us up to and through approval.

The protocols are written and finalized and now we're in that heavy lift operationalized the studies.

That's a whole list of activities that are involved.

Regulatory agencies site.

CRE loans.

And in addition to the protocol, there's all the logistics accomplish setting up your ABR ash that is your randomization systems.

Setting up on the.

Translational Medicine laboratory assays, how those things are going to flow.

It's a very complicated.

On.

Series of activities that are some of them can run on many of them on in parallel.

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

But in each individual country.

Operator: Your line is open.

And within each individual country at individual sites, you're contracting on an <unk>.

Kelsey Goodwin: Hey, this is Kelsey Goodwin on behalf of Michael. Thanks for taking

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

So just a number of activities. So there are too many to name, but it's a well described in and well acknowledge that its a complicated series of activities that our team has done several times now successfully.

And it takes some time to get everything up and running the key piece that we are.

<unk> focused on and all of that.

Darren: Yeah, the, you know, we have some indication from, you know, what we were observing with anemia ID, which is still in its early days, and some indication from the Spanish IST, screening IST, that reported about, I think about 20% of those hemolytic anemia patients that were screened that ultimately were diagnosed with, with, PKD. We get a good sense for what your diagnosis rate may end up being amongst those patients who are tested, particularly those patients who have, are diagnosed with hemolytic anemia, but hemolytic anemia of unknown or unknown etiology.

Is identifying sites that have patients throughout the world. It will be global studies and to really look to everything we can do to make the trial is accessible.

<unk> for patients and have maximum terminal velocity. So the first patient in is very important.

And the last patient out is perhaps even more important.

So thats that piece and that's 1 of the fun things about doing this this.

Job on this.

And then the second piece in terms of.

The sickle cell the attract study will enroll up to 10 patients.

That group is very skilled and well known in terms of their ability to look at both red cell metabolism as well as using the oxygen scanner to look at point of cycling and other components that are Inc.

Darren: The that I'm less, I'm not concerned about that in terms of the ramp for the launch, because I think we continue to we're doing everything that we need to do to facilitate testing, I expect we'll see that see that accelerate now that we have our full contingent in the in the field to help educate, educate practices, and our biogeo support to educate, educate, The thing that's outstanding for me, and I think we're focused on better understanding, is what the access profile will look like, particularly in those first six to nine months of launch, where we know that for a number of payers, you're gonna have a new-to-market block that will require physicians seeking medical exception, and that will then extend the time between when you're diagnosed and when you're ultimately, when treatment's ultimately made available to the patient. So the demand, and we have this confirmed in our in our recent quantitative work, the demand is going to be there so that you have the desire to be able to treat broadly for these, We've got all the programs in place, like Anemia ID, the work that we shared with you last time on 23andMe, to help increase overall awareness drive, support patients and having better testing options available And then, so the opportunity for the patient to receive the treatment, I think is going to be high. The question is the amount of time in those first months for the physicians to be able to work through the access.

Important biomarker.

Markers in the sickle cell area.

That trial starts patients at 20, and then they can go to 50 and then.

Got up to a 100 milligrams.

And then they're on study for at least a year. So that's different from the NIH study where that was just the NIH study.

Per study in adults with sickle cell disease, where they started at $5.2015, and they made the amendment to 100. So it's a total of 8 weeks of treatment and then there's this taper and then.

<unk> who are.

Willing enable can then go into an extension so I think theres a lot of similarities in terms of understand.

Standing.

The important endpoints that we've talked about.

And you get a sense of efficacy and safety from both.

The <unk> study I think.

It gives you immediately.

Over time, some further understanding of chronic dosing that.

The NIH study doesn't give you quite immediately because those patients are on 8 weeks of therapy, and then we will definitely get more long term data from patients who go into the extension, but we don't know yet how many of those patients.

At the end of the day going to be.

So I'll stop there.

Okay Super.

Super helpful and just a very quick follow up is the phase III 3 going to be inclusive of African trial sites.

Kelsey Goodwin: Got it. Okay, super helpful. Thank you. Thank you. Our next question comes from Mark Breidenbach with Oppenheimer. Your line is open.

Yes.

Alright, thank you.

Yeah.

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

Hi, good morning. Thanks, so much for other questions I guess first can you remind us what your expectations are for an AD comm meeting and maybe what your internal expectations are for priority review and then Darren I wanted to clarify something from your per script.

Mark Alan Breidenbach: With Oppenheimer, your line is open.

Operator: Good morning, guys. Congratulations on the forward progress. And Chris, of course, we're sorry to see you go as well.

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

Prepared remarks, excuse me did you say that your market research into.

70% on providers already ordered genetic testing framing is an unknown etiologies or that they would like to thank you.

Let me answer the second 1 and then I'll leave the room for Chris to be able to answer you on the first so the 70% number.

Refers to the proportion of physicians who routinely.

<unk> ordering more tests to try to be able to get to a defendant.

When a definitive diagnosis for those patients who are diagnosed with hematologic anemia, but other unknown etiology right, which means that they are inclined to either order.

Chris: Launching any of the phase 3 in thalassemia and the phase 2-3 studies, the global studies, so the protocols are written and finalized, and now we're in that heavy lift of operationalizing the studies, and that's a whole list of activities that involve regulatory agencies, CITES, and CRO. And in addition to the protocol, there's all the logistics that come with setting up your IBRS, that is your randomization system, setting up all the translational medicine laboratory assays, and how those things are going to flow.

Enzyme test for genetic origin, Hettick panel or both.

Somebody do reflects.

The cable and the reason why I mentioned I provided that insiders. Because then it means when we have a highly receptive audience than to Oh.

2 anemia I D.

But there was an indication of what further uptick or look like particularly now that we've got got more more folks out there educating the community about it.

So.

With that let me turn it over to Chris.

Hi, Your question was with regards to priority review for the perfect kind of sufficiency submission there.

Chris: So it's a very complicated series of activities that some of them can run, many of them run in parallel, but in each individual country and within each individual country, at individual sites, you're contracting and going through just a number of activities. So there's too many to name, but it's well-described and well-acknowledged that it's a complicated series of activities that our team has done several times now successfully, and it takes some time to get everything up and running.

Yes, yes.

Yes.

So we will find out.

The Fda's view on that their decision 60 days.

From when we filed so that should be sometime in August.

<unk> timeframe middle of August or so.

Okay I guess.

Yeah.

Sorry, we lost you.

What are your thoughts on Advisory Committee meeting.

Oh, an ad com.

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

Understood. Thank you.

Chris: The key piece that we're focused on in all of that is identifying sites that have patients throughout the world, it could be global studies, and to really look at everything we can do to make the trials accessible for patients and have maximum terminal velocity. So the first patient in is very important. And the last page, now that's perhaps even more important. So that's that piece, and that's one of the fun things about doing this job.

Thank.

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

Thank you operator, and thank you everyone for the questions. This morning, as we move into our very bright future as a transformed audio so we look forward to making a meaningful difference in the lives of patients with genetically.

<unk> defined diseases.

Starting with our potential launch in PK deficiency next year.

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

Chris: And then the second piece in terms of sickle cell, the UTREX study will enroll up to 10 patients. That group is very skilled and well-known in terms of their ability to look at both red cell metabolism as well as using the oxygen scanner to look at point of sickling and other components that are important biomarkers in the sickle cell area. That trial starts patients at 20, and then they can go to 50 and then go up to 100 milligrams, and then they're unstudied for at least a year.

And today, a special thanks to Chris we will have more interactions with him I'm sure are with you all over the next couple of months, we're very very happy and pleased that he is willing to stay.

Engaged with us all geos that through the end of 2022 at least as a.

Inc.

Advisor, but those will continue to benefit from his wisdom and insight. So thank you very much Chris and we look forward to a few parties over the next couple of months.

Chris: So that's different from the NIH study, which was the first study in adults with sickle cell disease, where they started at five, 20, 50, and then they made the change to 100. So it's a total of eight weeks of treatment. And then there's this paper, and then patients who are willing and able can then go into an extension. So I think there are a lot of similarities in terms of understanding the important endpoints that we've talked about.

Alright, your next chapter.

Chapter.

Thank you everybody for joining US today, you may now disconnect take care.

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

Yeah.

Okay.

Yeah.

Good job everybody.

[music].

Chris: And you get a sense of efficacy and safety from both. The Utrecht study, I think, gives you immediately over time some further understanding of chronic dosing that the NIH study doesn't give you quite immediately because those patients are on eight weeks of therapy. And then we'll definitely get more long-term data from patients who go into the extension, but we don't know yet how many of those patients are, at the end of the day, going.

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

Danielle Brill: Hi, good morning. Thanks so much for the questions.

Danielle Brill: I guess, first, can you remind us what your expectations are for an ADCOM meeting and maybe what your internal expectations are for priority review? And then, Darren, I wanted to clarify something from your presentation. Prepared Remarks. Excuse me. Did you say that your market research...

Darren: Thank you.

Chris: Let me answer the second one, and then I'll leave the room for Chris to be able to answer you on the first. So the 70% number refers to the proportion of physicians who are routinely ordering more tests to try to be able to get to a definitive diagnosis for those patients who are diagnosed with hematopoietic anemia but of unknown etiology, which means that they're inclined to either order enzyme tests or a genetic panel, or both, which some may do reflexively.

Chris: And the reason why I mentioned I provided that insight is because then it means that we have a highly receptive audience for Anemia ID and gives us an indication of what further uptake will look like, particularly now that we've got more folks out there educating the community about it. So with that, I'll turn it over to Chris. Hi, your question was with regard to priority review for the primary kinase deficiency submission, right? Yes. Yeah, so we'll find out the FDA's view on that, and their decision 60 days from when we file, so that should be sometime in the August timeframe, the middle of August or so.

[music].

Chris: What are your thoughts on the advisory committee meeting? Oh, and

Chris: Oh, and Adcom. Too early to tell. Sometimes you get some signals early on, but we're early in the stage yet, so it's too early to know.

Danielle Brill: understood. Thank you.

Operator: Thank you, and there are no other questions in the queue. I'd like to turn the call back to Jackie Faust for closing remarks.

Jackie Faust: Thank you, operator, and thank you, everyone, for the questions this morning. As we move into our very bright future as a transformed AGIOS, we look forward to making a meaningful difference in the lives of patients with genetically-defined diseases, starting with our potential launch in TK deficiency next year. I would like to thank my Agios colleagues for their dedication and passion for making a difference for our patients. I also would like to thank all of the patients, caregivers, and physicians who partner with us in so many ways.

Jackie Faust: And today, a special thanks to Chris. We will have more interactions with him, I'm sure, with you all over the next couple of months. We're very, very happy and pleased that he's willing to stay with us, Agios, through the end of 2020.

Jackie Faust: 2022, at least as a strategic advisor because we'll continue to benefit from his wisdom and insight.

Jackie Faust: Thank you very much, Chris, and we look forward to a few parties over the next...

Jackie Faust: Over the next couple of months, write your next chapter.

Operator: Thank you everybody for joining us today. You may now disconnect. Take care. This concludes today's conference call. Thank you for participating.

Operator: Thank you for participating. You may now disconnect.

Unnamed: Good job, everybody!

Unnamed: [inaudible] Thanks for watching! In the name of the Father, and of the Son, and of the Holy Spirit. Amen.

Operator: Good morning, and welcome to Agio's second quarter.

Operator: At this time, all participants are in a listen-only mode. There will be a question and answer session at the end. Please be advised that this call is being recorded.

Operator: This call is being recorded at Agios' request.

Jessica Rennekamp: I would now like to turn the call over to Jessica Renneken, Director of Corporate Communications.

Jessica Rennekamp: Thank you, operators. Good morning, everyone, and welcome to Agios' second quarter 2021 conference call. You can access slides for today's call by going to the investors section of our website, agios.com. With me on the call today with prepared remarks are Dr. Jackie Faust, our Chief Executive Officer, Dr. Chris Bowden, 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 Before we get started, I would like to remind everyone that some of the statements we make on this call will

Jessica Rennekamp: will include forward-looking statements. However, actual events and results could differ materially.

Jessica Rennekamp: [inaudible]

Jackie Faust: Thanks, Jesse. Good morning, everyone, and thanks for joining our second quarter 2021 financial results call. We are pleased to report another quarter of strong progress at Agios, the first full quarter since the close of the sale of our oncology business to Serviette. The team is focused, energized, and excited for the future as we continue to advance our pipeline in genetically defined diseases led by Mitopivot across its three initial indications in hemolytic anemia.

Jackie Faust: We have achieved significant recent milestones with

Jackie Faust: with the submission of our NDA for Minipivet and Adonis.

Jackie Faust: and adults with pyruvate kinase deficiency in June, as well as with the submission of our MAA to the EMA the same month. We look forward to working with the FDA and EMA as they complete their reviews.

Jackie Faust: With these two filings, we are one step closer to delivering the first potentially disease-modifying therapy for people with pyruvate kinase deficiency. These regulatory submissions are supported by strong Phase III data from the ACTIVATE and ACTIVATE-T studies, full results from both of which were recently presented at the European Hematology Association.

Jackie Faust: Association, or EHA, Virtual Congress in June.

Jackie Faust: Our preparations for the commercial launch of Mitopivat and for PK deficiency continue to advance, and we remain on track for anticipated approval and launch in 2022. In addition, we would like to extend our congratulations to the Pyruvate Kinase Deficiency Foundation and the Thrive with Pyruvate Kinase Deficiency Organization, both of which recently launched as the first two U.S.-based Both organizations are patient-led, and it's very exciting to see how this community has coalesced around the momentum.

[music].

Jackie Faust: and the momentum they are gaining in raising awareness and advocating for those living with this disease.

Jackie Faust: Beyond PK deficiency, we are also making excellent progress with the late stage development of midipivac.

Jackie Faust: and Thalassemia and Sickle Cell Disease.

Jackie Faust: At EHA, we presented positive results from our Phase 2 open-label study of midipivad in adults with non-transfusion-dependent alpha or beta thalamic acid.

Jackie Faust: or beta-thalassemia.

Jackie Faust: These data continue to validate the potential of PK activation as an entirely new mechanism for treating thalassemia.

Jackie Faust: and represent the first clinical data generated in alpha thalassemia patients.

Jackie Faust: We remain on track to initiate our two registrational Phase 3 trials, ENERGIZE and ENERGIZE-T, in adults not regularly transfused and regularly transfused adults without

Jackie Faust: All adults with thalassemia, respectively, this year.

Jackie Faust: In sickle cell disease, we also remain on track to initiate a pivotal Phase 2-3 trial of Minipivot by the end of the year. Beyond Minipivot, we are building on our expertise in PK activation and cellular metabolism and advancing our earlier stage research programs in genetically defined diseases to position us for sustainable growth and momentum. In the fourth quarter, we plan to host an Investor Day to share more information about our commercial launch planning for minifat and PK deficiency and talk more in detail about

Good morning, and welcome to.

<unk> second quarter 2021 conference call at this time, all participants are in a listen only mode, but will be a question and answer session. Afghan. Please be advised that this call is being recorded at other edgy else's request I would now like to turn the call over to Jessica running Kim director of corporate Communications.

Jackie Faust: about our research and development pipeline.

Jackie Faust: Before I turn the call over to Chris to provide an update on our clinical development programs, I wanted to take a moment to share that Chris has decided to retire from his role as Chief Medical Officer at Agios after a terrific seven years on our leadership team. After a transition period to his successor over the coming months, I'm very...

Thank you operator, good morning, everyone and welcome to <unk> second quarter 2021 Conference call you can access slides for today's call by going to the investors section of our website at <unk> Dot 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.

Jackie Faust: I'm very pleased that Chris will remain part of our team as a strategic advisor through at least the end of 2022.

Jackie Faust: We are excited for him as he enters this new chapter of his life and want to thank him for his leadership and many years of service at Agios. Among his many accomplishments and contributions, he oversaw the build-out of our

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.

Jackie Faust: Medical and Clinical Development Organizations acted as Agios' lead medical representative internally and externally, navigated complex regulatory interactions in order to bring important drugs to patients, and played a key role in the evolution of our organization.

Before we get started I would like to remind everyone that some of the statements. We make on this call will include forward looking statements actual events and results.

Jackie Faust: Organization and Culture

Jackie Faust: He has been an integral part of our team, and his work will continue impacting the lives of our patients.

Could differ materially from those expressed or implied by any forward looking statements as a result of various risks uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC with that I will turn the call over to Jacky.

Jackie Faust: We are impacting the lives of patients for many years to come. On behalf of everyone at Agios, I wish Chris all the best for the future.

Jackie Faust: I'm equally excited to announce that Dr. Sarah Gheuens, who has up to now served as our Head of Clinical Development for Genetically Defined Diseases, will assume the role of Chief Medical Officer, effective September 1st. Sarah has been with Agios for almost two years and has been an impactful and energizing leader across the organization during her tenure. Among Sarah's most significant accomplishments at Agios, she played an integral role in the work associated with the PK deficiency filings and the design and strategy for our Sickle Cell Disease Pivotal Program. She knows all aspects of our programs inside and out.

Thanks, Jessie good morning, everyone.

We won and thanks for joining our second quarter 2021 financial results call.

We were pleased to report another quarter of strong progress at <unk> is the first full quarter since the close of the sale of our oncology business to Serbia.

The team is focused energized and excited.

In the future as we continue to advance our pipeline in genetically defined diseases landfall pivot across its 3 initial indications in hemolytic anemias.

We achieved significant recent milestones with the submission of our NDA for <unk> in adults with pyruvate kinase.

Jackie Faust: He has a genuine passion for serving people with genetically defined diseases.

<unk> deficiency in June as well as with the submission of our MAA to the MAA the same month.

Jackie Faust: Prior to Agios, Sarah held roles of increasing responsibility at Biogen in safety and risk management, medical affairs, and clinical development, and she is a neurologist by training. We look forward to continuing to see great things from her as she takes on this new level of responsibility. With that, I will now turn the call over to Chris. Thanks, Jackie.

We look forward to working with the FDA and EMA as they complete their reviews.

With these 2 filings we are 1 step closer to delivering the first potentially disease modifying therapy.

For people with pyruvate kinase deficiency.

These regulatory submissions are supported by strong phase III data from the activate and activate T studies full results from both were recently presented at the European Hematology Association or <unk> H a virtual.

Chris: As Jackie mentioned, we are excited about the potential we have to impact the lives of individuals with genetically defined diseases. We achieved important milestones for both Agios and the PK deficiency community this past quarter with the submission of our global regulatory filings for Mitopivat in the U.S. and EU. We're pleased to share that our MAA has passed validation, which triggered the start of the MAA review procedure. For the NDA, the FDA has 60 days from submission to determine whether the application is accepted.

Congress in June.

PREPA.

On a nice for the commercial launch of me to pay that in PK deficiency continue to advance and we remain on track for anticipated approval on launch in 2022.

In addition, we would like to extend our congratulations to the pyruvate kinase deficiency Foundation and the thrive with pyruvate.

<unk> kinase deficiency organization, both of which recently launched as the first 2 U S based advocacy organizations dedicated to PK deficiency.

Chris: So we expect to hear from them in mid-August; information about whether the application is accepted, whether Medipivot has been granted priority review, and the PDUPA date will all be communicated by the agency at that time. Overall, we are very pleased with our progress and believe we have significant momentum as we look to a busy second half of 2021. At EHA, we presented full data from the Activate and Activate Team phase 3 studies evaluating midipivab in adults with PK deficiency who are not regularly transfused and those who are regularly transfused, respectively.

On the organizations are patient lead and it's very exciting to see how this community has coalesced and the momentum they are gaining.

In raising awareness and advocating for those living with this disease.

Beyond PK deficiency, we are also making excellent progress with the late stage development admit a pivot in thalassemia and sickle cell disease.

At <unk>, we presented positive results from our phase 2 open label study of <unk> in.

In adults with non transfusion dependent alpha or beta thalassemia.

These data continue to validate the potential of PK activation as an entirely new mechanism for treating thalassemia and represent the first clinical data generated in Alpha Palace EMEA patients.

We remain on track to initiate our.

2 registrational phase III trials, and or Josh and energize T and not regularly transfused and regularly transfused adults with thalassemia, respectively. This year.

Chris: Both studies met their primary and secondary endpoints, including patient-reported outcomes that addressed symptom burden and quality-of-life impact of PK deficiency. The PIV app is generally well-tolerated, and the safety profile observed in both studies was consistent with previously published data.

In sickle cell disease. We also remain on track to initiate a pivotal phase 2.3 trial on many people that by the end of the year.

Beyond.

Beyond that we are building on our expertise in PK activation in cellular metabolism and are advancing our earlier stage research programs and genetically defined diseases to position us for sustainable growth and momentum.

Chris: During our EHA Investor event, we also heard from Dr. Andreas Glentos, who highlighted the significant impact PK deficiency has on patients' quality of life, the limitations of the current PK deficiency treatment landscape, and the potential for Mitivibat to serve as the first disease-modifying therapy for these individuals. Moving to thalassemia, we also presented data at EHA on all 20 patients from the core period of our Phase II study of mid-epivap and non-transfusion-dependent alpha and beta thalassemia.

In the fourth quarter, we plan to host an investor day to share more information about our commercial launch planning.

<unk> for a minute that in PK deficiency and talk more in detail about our research and development pipeline.

Before I turn the call over to Chris to provide an update on our clinical development programs I wanted to take a moment to share the Chris has decided to retire from his role as.

Chief Medical Officer, Adriano <unk> after a terrific 7 years on our leadership team.

After a transition period to his successor over the coming months I'm very pleased that Chris will remain part of our team as a strategic advisor through at least the end of 2022.

We're excited for.

The interest in this new chapter of his life and want to thank him for his leadership and many years of service since our Jos.

Chris: Consistent with previously announced proof-of-concept data, the study met its primary endpoint, with 16 of the 20 patients achieving a hemoglobin increase of greater than or equal to 1 gram per deciliter from baseline at one or more assessments during weeks 4 through 12. In addition, a sustained hemoglobin response and improvements in hemolysis and ineffective erythropoiesis were observed in both alpha and beta thalassemia patients treated And PIVAP was also well-tolerated, with a safety profile consistent with previous studies.

Among his many accomplishments and contributions he oversaw the build out of our medical and clinical development organizations acted as obvious as lead medical representative internally and externally.

For him navigated complex regulatory interactions in order to bring important drugs to patients.

And played a key role in the evolution of our organization and culture.

He's been an integral part of our team and his work will continue impacting the lives of patients for many years to come.

On behalf.

Everyone at Andreas I wish Chris all the best in the future.

I'm equally excited to announce the doctor steroid Gwinn's, who has up to now served as our head of clinical development for genetically defined diseases.

Assumed the role of Chief Medical Officer effective September 1.

Sarah has been with.

On a lease for almost 2 years and it's been an impactful and energizing leader across the organization during her tenure.

Chris: We believe these results underscore the potential of midipivac to meaningfully improve hallmarks of thalassemia, including hemolysis and ineffective erythropoiesia. We're also excited to see data generated for the first time in alpha thalassemia, demonstrating an increase in hemoglobin from baseline in all five patients in this subgroup. Our two global placebo-controlled pivotal trials, Amidipivat and Thalassemia, ENERGIZE and ENERGIZE-T, are on track to initiate this year as we continue the process of submitting these trials, protocols globally, and preparing sites for enrollment. Now, turning to sickle cell disease.

Among Sarah is most significant accomplishments at <unk>. She played an integral role in the work associated with the PK deficiency filings and the design and strategy for our sickle cell disease.

These pivotal programs.

She knows all aspects of our programs inside and out and has a genuine passion for serving people with genetically defined diseases.

Here to Adriano, Sarah held roles of increasing responsibility at Biogen in safety and risk management Medical affairs and clinical development.

Object and she is a neurologist about training.

Look forward to continuing to see great things from her as she takes on this new level of responsibility.

With that I will now turn the call over to Chris.

Thanks Jackie.

Chris: We remain on track to initiate our Pivotal Phase 2-3 clinical trial by the end of this year. The Phase 2-3 study of midipivav and sickle cell disease will include patients who are 16 years of age or older, have had between 2-10 sickle cell crises in the past 12 months, and have hemoglobin within the range of 5.5 to 10.5 grams per deciliter during screening. Phase 2 will randomize 69 patients, 1 to 1 to 1, to 50 mg midipivac twice daily, 100 mg midipivac twice daily, or matched placebo.

As Jackie mentioned, we are excited about the potential.

Have to impact the lives of individuals genetically defined diseases.

We achieved important milestones for both modules and the PK deficiency community. This past quarter with the submission of our global regulatory filings for me to put that in the U S and EU.

We're pleased to share that our MAA.

And then perhaps validation, which triggered the start of the MAA review.

Its future.

The NDA the FDA has 60 days from submission to determine whether the application is accepted so.

Chris: The primary endpoint is a hemoglobin response defined as greater than or equal to one gram per deciliter change from baseline to week 12, and the data will be used to establish a clear dosing paradigm for the phase three portion. Phase 3, which will commence after the Phase 2 analysis, will randomize 198 patients 2-to-1 to the selected Phase 2 dose of Mitopivac or MATCH placebo. The study will have two primary and secondary objectives: hemoglobin response defined as greater than or equal to one gram per deciliter change from baseline to week 52, and a reduction in annualized rate of sickle cell pain crises.

So we expect to hear from them in mid August.

Information about whether the application is accepted.

Mid to pick up.

Granted priority review.

Do per day, all be communicated by the agency at that time.

Overall, we are very pleased with our progress and believe we have significant momentum as we look to a busy second half 'twenty 'twenty 1.

At <unk>, we presented full.

I think the activate and activate T.

Phase III study evaluating.

On an adult PK deficiency.

Not regularly transfused and those who are regularly transfused respectively.

Chris: We believe the design of this Phase 2-3 study minimizes risks to the approval path for minipivac in this challenging disease and maximizes the likelihood of a label with a broad indication. In addition, we continue to work with our collaborators at the NIH and the University of Utrecht on their studies of medicevac and sickle cell disease. Data from both studies are expected to be submitted for presentation at ASH in December.

Both studies met their primary and secondary endpoints, including patient reported outcomes that address.

Net symptom burden and quality of life impact of PK deficiency.

<unk> was generally well tolerated and the safety profile observed in both studies was consistent with previously published data.

During our Investor event, we also heard from Dr. Andreas <unk>, who highlighted the significant.

Data from impact PK deficiency has on patients' quality of life.

Chris: At the NIH, Dr. Ken has completed enrollment in the core study with 17 patients and continues to enroll the extension study. We anticipate the data sets at NASH will provide additional efficacy, safety, and translational data that support the clinical development of this drug in people with sickle cell disease. Beyond Medipivot, we're also advancing our next generation PKR activator, AG946, in a phase one healthy volunteer study. The trial began enrolling last year, and we expect to submit data for presentation at ASH.

The limitations.

Of the current PK deficiency treatment landscape.

Potential permitted payback to serve first disease modifying therapy for these individuals.

Moving to balance EMEA.

We also presented data on that.

<unk> all 20 patients from the core period of our phase II study of mid up to that and non transfusion dependent alpha and beta thalassemia.

Consistent with previously announced proof of concept data.

Study met its primary endpoint with 16 of the 20 patients achieving on hemoglobin increase.

Later than or equal to.

2.1 gram per deciliter from baseline at 1 or more assessments during weeks 4 to 12.

In addition on sustained hemoglobin response and improvements in hemolysis and ineffective erythropoiesis were observed in both alpha and beta thalassemia patients treated with net of pay that.

Chris: Our analysis of the totality of the AG946 healthy volunteer data will inform next steps for the clinical development of this molecule. As part of our investor event this fall, we will talk in more detail about our research and development pipeline. Before I turn it over to Darren to discuss our commercial activities, I want to thank all of my AGIOS colleagues for the privilege of working with you over the last seven years.

And to.

It was also well tolerated safety.

Safety profile consistent with previous studies.

We believe these results underscore the potential of Medicare that to meaningfully improve hallmarks of balance.

Putting him on what sorts of ineffective erythropoiesis.

We're also excited to see data generated from the first time.

That with balance senior demonstrating an increase in hemoglobin from baseline and all 5 patients in this subgroup.

Chris: It has been so rewarding and fun, and the accomplishments speak for themselves. My successor, Sarah Gheuens, is poised to lead our team to more great accomplishments, and I look forward to watching the Agios story continue to unfold. Beren?

Our 2 global placebo controlled pivotal trial mid pivot in thalassemia energized and energized team are on track to initiate this year as we continue the process of submitting.

On the Alpha trial protocols globally and prepare sites for enrollment.

Now turning to sickle cell disease.

We remain on track to initiate a pivotal phase 2.3 clinical trial by the end of this year.

Darren: Thank you, Chris. We continue to make strong progress on commercial launch preparations for Mitipivad and PK-Deficient. All customer-facing and patient support infrastructure and talent are hired and fully trained. Our field team, comprised of both sales representatives and credentialed nurse clinical educators, is now fully engaged with physicians potentially managing patients with PK deficiency across the U.S. and are focused on profiling accounts, raising disease awareness, and executing patient support and profiling plans through disease education.

The phase 2.3 study a bit of a pickup in sickle cell disease will include patients who are 16 years.

Many of these are older have.

Have had between 2% to 10 sickle cell crises in the past 12 months and have hemoglobin within the range of 5.5 to 10 on a half gram per deciliter during screening.

The phase II randomized 69 patients 1 to 1 to 1 to 50 milligrams admitted to that twice daily.

100 milligram twice.

<unk> twice daily or matching placebo.

The primary endpoint in the 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 III portion.

Phase III, which will commence after the phase 2 analysis will randomize 198 patients 2 to 1 to the selected phase II dose submit it prevent or matched placebo study.

Darren: An important feature of their work is educating physicians on the availability of the agio-sponsored genetic testing service, Anemia ID. Now with well over a thousand test kits requested, we expect Anemia ID to become an increasingly important program to help support patients seeking a definitive diagnosis of their hemolytic anemia and an aid in accelerating our PK deficiency patient profiling effort. Our market research now shows that 70% of responding physicians routinely order additional diagnostic tests for their patients with hemolytic anemias of unknown etiology.

The study will have 2 primary endpoints hemoglobin response defined as greater than or equal to 1 gram per deciliter change from baseline to week 52.

And a reduction in annualized rate of sickle cell pain crisis.

We believe the design of this phase III study minimizing risks to the approval path for me to pay that in this challenging disease and maximizes the likelihood of a label what they brought indication.

In addition, we continue to work with our collaborators.

<unk> at the NIH and the University of food trucks on their studies of <unk> in sickle cell disease.

Darren: This is an important insight which favorably predicts future adoption of genetic testing for accurate diagnosis of hemolytic anemias, including PK deficiency. The response to the Anemia ID program has been very enthusiastic. In our research, responding physicians indicated they are inclined to test a significant portion of their patients with hemorrhagic anemia of unknown etiology based on the breadth of mutations included in the panel and its relative ease of use

Data from both studies are expected to be submitted for presentation at Ash in December.

At the NIH Dr. <unk> Chen has completed enrollment in the core study with 17 patients and continues to enroll the extensions.

<unk> study.

We anticipate the datasets at Ash will provide additional efficacy safety and translational data.

Supports the clinical development of Medicare that and people with sickle cell disease.

Beyond that appear that we're also advancing our next generation PK R. Activator AG 946, and a phase 1.

On healthy volunteer study.

Darren: In June, we also launched the reimagined myRGS patient support, dedicated to people living with PK deficiency and their caregivers, leveraging our learnings and much of the technical infrastructure from the oncology myogels program while incorporating insights from PK deficiency patients and clinicians to create a customized program designed to meet the specific needs of this community. Enrolled patients and caregivers are connected with a dedicated and clinically trained patient support manager and others who provide ongoing tailored support, educational resources, and opportunities to connect with other patients and caregivers in the PK deficiency community, amongst other educational activities. The field team is educating physicians and their staff on the availability of the service and how they can support patients with enrollments.

The trial began enrolling last year, and we expect to submit data from presentation at ash.

Our analysis of the totality of the AG 9 or 6 healthy volunteer data will inform next steps for the clinical development of this molecule.

Part of our Investor event. This fall we will.

I'll talk in more detail about our research and development pipeline.

Before I turn it over to Darren to discuss our commercial activities.

Want to thank all of my <unk> colleagues for the privilege of working with you over the last 7 years.

It has been so rewarding and fun and the accomplishments speak for themselves my.

My successor Sarah.

Is poised to lead our team to more great accomplishment and I look forward to watching the audio story continue to unfold Darrin.

Thank you Chris.

We continue to make strong progress on commercial launch preparations from the pivotal PK deficiency or.

All customer facing and patient support infrastructure and talent are hired and Felipe.

Blending on.

Darren: Following the disclosure of the activated active AP findings at EHIM June, we fielded new market research to update our insights into general physician awareness and understanding of PK deficiency. Potential Implications for Disease Management Assuming Mitopivot's approval next year, we found that PK deficiency disease awareness metrics will be improved over the same time period in 2020. 85% of academic and community physician respondents are now familiar with PKW, and more than half indicate that they manage one to two previously diagnosed PK deficiency patients.

Field team comprised of both sales representatives and credentialed nurse clinical educators are now fully engaged with physicians potentially managing patients with PK deficiency across the U S and are focused on profiling accounts raising disease awareness and executing piece support and profiling plans through disease education.

Police from feature of their work was educating physicians on the availability of the <unk> sponsored genetic testing service anemia with.

With now well over 1000 test kits requested we expected <unk>.

To become an increasingly important program to help support patients seeking a definitive diagnosis other hemolytic anemia and in <unk> and <unk>.

Accelerating our PK deficiency patient profiling efforts.

Our market research now shows that 70% of responding physicians routinely order additional diagnostic test for their patients with hemolytic anemias of unknown etiology.

Darren: This is encouraging because it indicates that physicians are increasingly recognizing and diagnosing PK disease. We intend to continue to support this with additional educational activities in the months leading up to approval in 2022. Our research also suggests that, based on their understanding of the phase three data, many physicians will consider prescribing medepivac to PK deficiency patients with differing levels of disease severity, including with respect to transfusion history, although prescribing will be based on individual patients.

This is important insight, which favorably pretends future adoption of genetic testing for accurate diagnosis of hemophilia.

And important he is including PK deficiency.

Response to the anemia program has been very enthusiastic.

Our research responding physicians indicated they are inclined to test a significant portion of their patients hemolytic anemia unknown etiology east on the breadth of mutations included in the panel and its relative ease of use.

In June we also launched a re imagined mariachi on speaker support service dedicated to people living with PK deficiency and their caregivers leveraging our learnings and much of the technical infrastructure from the oncology modules program.

Operating insights from PK deficiency patients and clinicians to create a customized program.

Darren: We are encouraged by these responses and the overall increase in physician understanding of the burden. We're very pleased by the progress we've made with launch preparations across each function and object and the response from the treatment community to the broad disease education. We expect this to accelerate in the coming months, now that we have our full complement in the field and excitement about what we'll be able to do for patients' growth related to the Activate-disclosure. Now I'll turn it over to Jonathan to review the second quarter financials. Thanks, Darren.

Miletich designed to meet the specific needs of this community.

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

Amongst other educational.

All efforts on field team is educating physicians and their staff on the availability of the service and how they can support patients with enrollment.

Following the disclosure of the activate and activate T findings at <unk> on June we feel that new market research to update our insights into general physician awareness and understanding of PK deficiency and the potential implications.

Graham Creek disease management, assuming the peanuts approval next year.

Jonathan: Our second quarter 2021 financial results can be found in the press release we issued this morning, which I will summarize. More detail will be included in our 10-Q filing later today. As a reminder, our second quarter financial results discussion only includes our continuing operations on a comparative basis, which excludes results from our divested on-college business. Research and development for the second quarter was $62 million, an increase of $7.9 million compared to the second quarter of 2020.

We found that PK deficiency disease awareness metrics are improved over the same time period in 2020 with 85% of academic and community physician respondents now familiar with PK deficiency and more than half, indicating that they manage 1 to 2 previously diagnosed.

Most PK deficiency patients.

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

Our research also suggests that based on their understanding of the phase.

Patient share many physicians will consider prescribing the day pivot to PK deficiency patients with differing levels of disease severity, including with respect to transfusion history and hemoglobin levels.

Jonathan: The year-over-year increase in R&D was driven primarily by startup costs associated with the Phase III studies of midipivet and thalassemia and sickle cell and the filing of our NDA and MAA for MidaPivet and PKG, as well as our launch, selling gentlemen administrative $29.2 million for the second, essentially flat compared to SG&A expenses for the second quarter of 2020. We also recorded $2 million in TIPSOBO income from royalties in the second quarter of 2021, which is included within the gain on sale of oncology business line item in our income. We ended the quarter with cash, cash equivalents, and marketable securities of approximately $1.7 billion. With this cash balance, we expect to be able to execute our current operating plan through major catalysts and to cash...

Prescribing will be based on individual patient history presentation and parameters of the approved label for me to pick up we are encouraged by these responses.

3 day overall increase in physician understanding of the burden of disease.

Overall.

We're very pleased by the progress we've made with launch preparations across each function of Ipos and the response from the treating community to the broad disease education efforts.

We expect this to accelerate in the coming months now that we have our full complement.

And from the field and his excitement about what we'll be able to do for patients growth related to the activate disclosures.

Now I'll turn it over to Jonathan to review second quarter financials.

Thanks, Darrin, our second 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.

As a reminder, our second quarter financial results discussion only includes our continuing operations on a comparative basis, which excludes results from our divested oncology business.

Jonathan: In Q2, we executed a $529 million deal.

Jonathan: $129 million of the up to $1.2 billion of share repurchases authorized by our Board of Directors, inclusive of the shares acquired from Bristol-Myers Swift. Specifically, we repurchased just under 10.5 million shares at an average price of $50.41, reducing our total shares outstanding by approximately 15% to 59.9 million shares at quarter end. As previously disclosed, the 10B-5-1 plan we put in place in early Q2 provides for a maximum additional share repurchase of approximately $415 million through year end. The ultimate amount of additional share repurchases through year-end will depend upon the volatility of our share price during this time.

Research and development for the second quarter was 62 million.

An increase of $7.9 million compared to the second quarter of 2020.

The year over year increase in R&D was driven primarily by startup costs associated with the phase III studies of <unk> in thalassemia, and sickle cell disease, and the filing of our NDA and MAA permitted pivot in PK deficiency.

As well.

Launch preparation efforts.

Selling general and administrative expenses were $29.2 million for the second quarter.

Really flat compared to SG&A expenses for the second quarter of 2020.

We also recorded $2 million in tips Stobo income from royalties from the second quarter of 2021.

As on which is included within the gain on sale of oncology business line item in our income statement.

Operator: Operator, please open the line. Thank you. And as a reminder, if you would like to ask a question, press the star and the one key on your touchtone telephone.

We ended the quarter with cash cash equivalents in marketable securities of approximately $1.7 billion.

With this cash balance we'd expect to be able to execute our current operating plan through major catalysts.

Alicia Young: Our first question comes from Alicia Young with Cantor Fitzgerald. Your line is open. Hey guys.

Free cash flow positivity without the need to raise additional equity.

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

Alicia Young: Hey guys, thanks for taking my question and congrats on all the progress. I wanted to talk a little bit about MediPivot and maybe just, you know, as you're doing some of the education for patient support, you know, how frequently do these people kind of see their physicians and like, what kind of outreach and effort needs to be done there, or is it more just kind of like a structural kind of warehousing effect, or is there actually work that needs to be done to bring these people back under care? Thanks. Ailey Theodos of Daring

Specifically, we repurchased just.

And $10.5 million shares at an average price of $50.41, reducing our total shares outstanding by approximately 15% to $59.9 million shares at quarter end.

As previously disclosed <unk> 5.1 plan, we put in place in early Q2.

It provides for maximum additional share repurchases of approximately $415 million through year end.

The ultimate amount of additional share repurchases through year end will depend upon the volatility of our share price over this time period.

Darren: The issue is not necessarily going to be getting patients to come back in, because they're usually under, for those who've been diagnosed and obviously attached to, they're under some sort of monitoring plan, right? Those with more severe disease are going to see their physicians more regularly. Those with less severe disease will typically have a longer time span between physician visits. But remember, they're continuing to have their iron load monitored, and hemoglobin monitored.

Operator, please open the line for questions.

Thank you and assets.

Thunder Minder, if he would like to ask a question press. The Star then the 1 key on your Touchtone telephone.

Our first question comes from Alicia Young with Cantor Fitzgerald. Your line is open.

Hey, guys. Thanks for taking my question on congrats on all the progress I wanted to talk a little bit about <unk> and maybe just you know as youre doing some of the education.

Based on support you know how frequently do these people kind of see their physicians and like what kind of outreach and effort needs to be done there or is it more just kind of like a structural kind of where the warehousing effect or is there actually a work that needs to be done to bring these people back on your care.

<unk>.

Hey, Alethia this is darin.

The issues.

She was not going to be necessarily getting patients to come back in because they are usually under those who have been diagnosed and obviously you touched on your position.

Darren: So the frequency of physician visits isn't necessarily where we would focus. I think what we're doing now is focusing on patient profiling, identification, and physician education, and patient education on the disease. And I think that's where we need to continue, even post-launch, to focus much of our efforts. The physician-patient relationship will be fine, and we don't need to; there's nothing there that we need to delve into. We just need to make sure that they're aware. And once that's done, I think everything else falls from there.

They're under some sort of monitoring plan right those with more severe disease, we're going to see there where it's either.

Other physicians more more regularly those with less severe disease will have a longer typically.

<unk> longer time span between between.

And visits but remember there theyre continuing to have their iron Ironwood mom.

Monitored hemoglobin monitored so the frequency of physician visits isn't necessarily where we want to where we would focus I think what we're doing now is focusing on on the patient profiling.

<unk> identification.

And physician education patient education on the disease and I think that's where we need to continue even post launch to focus much of much of our efforts.

The physician patient really should be fine and we don't need to there's nothing there that we need to we need to delve into it we just need to make sure.

Operator: Thank you. The next question comes from Kenan McKay with RBC.

And once that's done I think everything else flows from there.

Kenan McKay: And then McKay with RBC Capital Markets, your line is open. Hi. Thanks for taking the question. First off, Chris, I'm sorry to hear about your departure but looking forward to meeting your successor, Sarah, and glad to hear that you're staying on into next year with the transition.

Great. Thank you.

Thank you. Our next question comes from Kennan Mackay with RBC capital markets. Your line is open.

Hi, Thanks for free.

Taking my question first off Chris I'm, sorry to hear about.

Your departure, but looking forward to meeting your successors, Sarah on glad to hear that youre staying on into next year with the transition.

Kenan McKay: Maybe one quick question on the regulatory filings here for MediPivot. I'm wondering which branch of the FDA you are interacting with on those regulatory submissions in PKD. Is that hematology or the rare disease division? Ed Cannon and Chris.

1.1 quick question on the regulatory filings here.

Per for mid up his I'm wondering which branch of the FDA you are interacting with us those regulatory submissions in pizza.

But if they were hematology or the rare disease division.

And Ken it's Chris.

The FDA team that we're working with other on that cardiology rain on and the oncology Hematology Division.

Chris: The FDA teams we're working with are in cardiology, renal, and the oncology hematology division. The submission itself is in cardiology renal. So it's an interesting setup, actually, because the people who've been most involved with us and are most active in the submission are in the hematology division. That is just what I was going to sort of follow up with and just wonder around some of the interactions so far. Is that division sort of up to speed on rare diseases and PKD, or what have the interactions been like to date?

The submission itself as.

And net cardiology rein them.

So it's an interest to set up back from it because the people who have been most involved with us on our most active on the submission on the Hematology Division.

That is just what are what I was going to sort of follow up with.

Just wonder around some of the interactions.

So far.

You've got division for the up to speed on.

Chris: Thank you. The group, the team that we've been working with, and FDA has been what's a program for, advising us and interacting with us since I joined the company. So, they're very well acquainted with the disease and the special nature of what it takes when you're in a rare disease population, so I don't have any. I think the consistency, and I think, importantly, over the years, as you've heard us talking about the guidance and why we've designed the trials we have in an effort to provide them with as much data as they're going to need to make a decision for us to demonstrate clinical

Rare diseases M P J D or happy interactions to date benchmark. Thank you.

The other.

On the group.

Team that we've been working with us.

With FCA has been what's the program for.

It has been advising us from interacting with that since I joined the company.

So they're very.

Well acquainted with the disease.

On the special nature of what it takes when you're in a rare disease population.

Asian, So I don't have any.

Operator: Thank you. The next question comes from Anupam Rama with JP Morgan.

Concerns there on I think the consistency.

And I think importantly over the years as you've heard us.

Anupam Rama: All with J.P. Morgan. Your line is open. Hi guys.

Talking about the guidance and why we designed the trials we have in an effort to provide them.

Anupam Rama: Thanks so much for taking the question. Perhaps a broader strategic question. I think many of us on the street model a price cut from mid-to-pivot longer term to account for the SCD indication. What threshold of peak sales in SCD does mid-to-pivot have to meet, in your view, to justify a price cut versus, say, maximizing the value of the product by keeping ultra orphan pricing? Thanks so much.

Much data is theyre going to need to make a decision and for us to demonstrate.

Straight clinical benefit that's been a consistent group of people.

Is it.

Yeah.

Thank you. Our next question comes from the New Pom Rama with J P.

Morgan Your line is open.

Yeah.

Hi, guys. Thanks, so much for taking the question perhaps.

Perhaps a broader strategic question I think many of US on the street, we model a price cut from it appear that longer term to account for the <unk> indication.

Jackie Faust: It'd be premature to talk about what peak sales would be in sickle cell. What I can tell you is that it would require, assuming you just want to at least break even, right? As you move from the first two indications into sickle cell, then you account for a cut. What we think would be required would only require a less than 4%, 3% share in that market to be able to at least break even across the whole. So, it doesn't take a whole lot because the size of sickle cell is small enough for you to be able to accommodate that. That's why we're so optimistic about the incremental value that we will be able to gain once we move into sickle cell.

What threshold of peak sales in FCB does pay about have to meet in your.

To justify a price cut versus say maximizing the value of the product by keeping ultra orphan pricing. Thanks, so much.

It would be premature to talk about what peak sales would be and in sickle cell. What I can tell you is is that it would require.

Our beauty <unk>.

Moving assuming you just wanted to at least breakeven right as you move from from the first 2 indications into sickle cell. When you account for it cut the what we think would be required.

Jackie Faust: And it's Jackie. I'm just going to jump in real quick, as we said.

Jackie Faust: I've said it many times, but I think both Chris and Darren have said this often; it's, we'll make those pricing decisions.

Would only would only require.

Less than 4% 3%.

Sure.

Share in that market to be able to at least breakeven.

Jackie Faust: based on the totality of the clinical data that we have at that point in time and the product profile, of course. So you can imagine there's a lot going on when you think about that with respect to hemoglobin increase, VOC reduction, all the secondary endpoints, patient-reported outcomes, and all of that. So lots of things to think about when we make that pricing decision at some point in the future.

Across the whole program. So so it doesn't take a whole lot because of the size of sickle cell is significant.

For you to be able to accommodate.

That COVID-19, that's why we're so optimistic about the incremental value right that we will be able to gain.

Moving to into sickle cell on despite competition.

And that it's Jackie I'm, just going to jump in real quick as we've said many times, but I think both Chris and Darren have said this often it's well make those pricing decisions based on the totality of the clinical data that we have at that point income.

Once you net product profile of course, so you can imagine there is a lot going on when you think about that with respect to hemoglobin increase VLC reduction all the secondary endpoints from patient reported outcomes.

Anupam Rama: Thanks so much for taking our questions.

Operator: Thank you. The next question comes from Salveen Richter with Goldman Sachs.

All of that so lots of.

Things to think about when we make that pricing decision.

And at some point in the future.

Salveen Jaswal Richter: Goldman Sachs, your line is open.

Thanks, so much for taking our question.

Elizabeth: Elizabeth, on for Salveen. Could you just remind us if you intend to launch MetaPivot and PKD simultaneously in both the U.S. and EU?

Thank you our next question.

It comes from <unk> Richter with Goldman Sachs. Your line is open.

Great good.

Morning, and thank you for taking our question. This is Elizabeth on for <unk> could you just remind us if you intend to launch simultaneously on both the U S. On an EU farm at a pivot on PK D and then.

Elizabeth: and, you know, um..., knowing that you're sort of discussing this at your investor day

Operator: Investor Day and 4Q. Maybe if you could just comment on the structure and size of the launch team and your progress in terms of identifying more patients and then how many patients with PKD have been identified to date. Thank you. Gotcha. All right, Salveen. This is Gary.

Now.

Knowing that you are sort of discussing this at your Investor day in 4 Q, maybe if you could just comment.

To me the structure and size of the launch team on.

And your progress in terms of identifying more patients and then how many patients with PK P have been identified to date.

Darren: Got you. All right, Salveen, this is Darren.

Yeah.

Got you alright, so I mean this is Darren a lot in there. So let me see if I can unpack that.

Darren: There's a lot in there, so let me see if I can unpack it. Let me start with this structure question first. So, as I mentioned in our prepared comments earlier, we fully hired our internal and external teams, right? That's about just under 20 representatives, sales representatives, and then a small contingent of nurse educators that will collaborate with us. And that's for the U.S. For the EU, you know, as we've shared previously, we've got boots on the ground there already, right?

Let me start with the structure.

Don question first.

So as I mentioned in our in our prepared comments earlier.

Fully hired are our internal and external teams right.

That's about just under 20 representatives on our sales Representatives and then a small contingent of nurse educators that will collaborate with them.

Structure on and that's for the U S team.

For the EU.

B.

We've shared previously we've got got boots on the ground there already right. So we have an MSL team with established and then we have.

Darren: So we have an MSL team that's established, and then we have a small group of experts that have been dedicated to building awareness and extending or advancing our patient profiling efforts in each of the major markets in the EU. And we continue to do the work, particularly on the critical path activities, to ensure that we will be able to launch some PIVET in the EU shortly after approval. But we've also shared that we're evaluating a number of options, right?

A small group of experts.

Experts that have been dedicated to building awareness.

Extending our advancing our patient profiling efforts in each of the major markets in the EU.

And we continue to do the work on particularly on the critical path activities to ensure that we will be able to launch.

Launch it would appear that in the EU.

Uh huh.

And shortly after approval.

But we've also shared that we are evaluating a number of options right considering the opportunity to be able to engage with a partner who has got a footprint that is already exist there already exists.

Darren: Considering the opportunity to be able to engage with a partner who's got a footprint that already exists in the EU and, hopefully, outside and beyond the EU, given the amount of patient value that extends beyond the major markets, that can overlay Medi-Piv-Ed or include Medi-Piv-Ed in that information, and that's where we've been focusing our efforts. So the idea is to keep things moving to enable a launch, particularly in Germany, where you can launch immediately and have free pricing, and then but also be able to then transition that work to a potential partner once we find the sort of deal that we believe fairly reflects the value of that.

EU and and hopefully outside on beyond that given the amount of value from it a pick up on extended patient.

And diabetics and beyond beyond the major markets.

That can that can overlay on that a pit that are include minutes of that and on an existing infrastructure and that's where that's where we've been focusing our efforts. So the ideas keep things moving to enable a launch, particularly in Germany, where you have you can you can launch immediately in that free pricing.

And.

And then but also be able to then transition network to a potential partner once once we find the sort of deal debt that we believe are fairly reflects the value of that net of pivotal break.

Darren: Great, thank you. And then maybe you could just comment on the patient identification efforts and the patients identified today. Yeah, yeah, yeah. So, you know, we continue to...

Great. Thank you and then maybe if you could.

Just comment on that.

The patient identification efforts and the patient on identified today.

Yeah, Yeah, Yeah. So you know so we continue to to do the work behind.

Darren: Yeah, yeah, yeah. So, you know, we continue to do the work behind what we refer to as patient profiling efforts, right, being able to identify more patients. We previously shared that we've identified about a thousand patients between the U.S. and the EU, and that's inclusive of pediatric patients, patients that are enrolled in our various clinical programs, as well as incidental patients that we come across as we're engaging with physicians. And it's an important number that I know everyone wants to hear more and more about, and we do keep on top of that.

<unk> will be referred to as patient profiling efforts right being able to identify.

More patients with previously.

Share that we've we've identified about 1000 patients between the U S and the EU and that's inclusive of pediatric patients patients that are enrolled in our various clinical programs as well as patients. It's a total patients that we that we come across as were engaging with with physicians and it's an important number that I know everyone wants to hear more and more about but and.

And we do keep on top of that that's not where I would focus though.

Darren: That's not where I would focus, though, because, particularly as we move closer to the launch here in the U.S., what you really need to do is be able to then attach each of those patients who are de-identified to us, right, so we don't know their personal or identifiable information, but you want to be able to attach them to an individual physician. You want to ensure that they're getting tested, and see if the physician is inclined to use an I.D.

Particularly as we move closer to the launch here in the U S, where you really need to do is be able to then attach each of those physicians on patients.

You identified to US right. So we don't know their personal.

<unk> information.

But you wouldn't be the attention to an individual physician you wanted to ensure that they're getting tested seek the physician is inclined to use I mean, the idea to confirm.

Darren: to confirm the diagnosis even further. And then we've also made our patient support program available in the last month, and ideally, those physicians would then see value in referring their patients to the programs, and that helps you to get a better sense of the absolute number of confirmed patients here in the U.S. So that's where we're focusing our efforts, right, continuing to advance the diagnostic differential and get those patients the appropriate support that they need, get them the education that they can, that myAGIOS can provide, which then will lead us up to and through.

From the diagnosis.

Even further.

We've also made our patient support program available in the last in the last month.

And ideally those physicians.

And.

See value and referring their patients to the programs and that helps you to get a better sense.

On the absolute confirmed patient population here in the U S.

So that's where we're focusing our efforts right continuing to advance the diagnostic a differential.

With and get those patients.

The appropriate support that they need get from the education that they can that <unk> can provide.

Which then will lead us off.

Operator: Thank you. Our next question comes from Michael Schmidt with Guggenheim.

Up to and through the the approval.

Thank you that's very helpful.

Problem.

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

Eric Thomas Schmidt: Eric Schmidt, with Guggenheim Securities, your line is open.

Kelsey Goodwin: Hey, this is Kelsey Goodwin on for Michael. Thanks for taking our question. Maybe actually building off of that one a bit, I guess, going forward, how do you kind of see the rate and slope of the PKD diagnoses kind of evolving as you continue these efforts? I guess what kind of assumptions do you kind of build in over the next, you know, near-term, and long-term of this launch?

Hey, this is Kelsey Goodwin on for Michael Thanks for taking our question, maybe actually building off a bow on it that I guess.

I guess going forward, how do you kind of see the rate and slope on the kidney diagnosis.

Agnos, he's kind of evolving as you continue these efforts I guess, what kind of assumptions do you kind of built in over the next you know near term long term of this launch.

Kelsey Goodwin: Yeah, the, you know, we have some indication from, you know, what we were observing with, with anemia ID, which is still in its early days, and some indication from the Spanish IST, screening IST, that reported about, I think, about 20% of those hemolytic anemia patients that were screened that ultimately were diagnosed with, with, PKD. We get a good sense for what your diagnosis rate may end up being amongst those patients who are tested, particularly those patients who have, are diagnosed with hemolytic anemia, but hemolytic anemia of unknown or unknown etiology. I'm not concerned about that in terms of the ramp for the launch because I think we're doing everything that we need to do to facilitate testing.

Yes.

We have some indication from what we are observing with.

With anemia, I D, which is still in.

It's early and it's early days.

And some indication from the Spanish <unk> screening I S T.

The reported about I think about 20% of those hemolytic anemia patients that were screened that ultimately were diagnosed with with with PPD.

We haven't got a good sense for.

For what your diagnosis rate may end up being amongst those patients who are tested, particularly those patients who have are vital for hemolytic anemia, but human hemolytic anemia of unknown unknown etiology.

But that on less I'm not concerned about that in terms of the ramp.

Because I think we continue to we're doing everything that we need to do profit facilitate testing I expect we'll see that see that accelerate now that we have a full contingent in the in.

Darren: I expect we'll see that accelerate now that we have our full contingent in the field to help educate practices and our biogeo support to educate people. The thing that's outstanding for me, and I think we're focused on better understanding, is what the access profile will look like, particularly in those first six to nine months of launch, where we know that for a number of payers, you're gonna have a new-to-market block that will require physicians seeking medical exception, and that will then extend the time between when you're diagnosed and when you're ultimately, when treatment's ultimately made available to the patient.

In the field to help educate educate practices.

And our biofuel supports educate educate patients.

The thing I'm I'm.

That's that's outstanding from me and I think we're focused on better understanding is what the what the access on profile will look like particularly in those first 6 to 9 months of launch right.

We know debt for a number of payers you're going to have.

A new to market block that will require physician.

Physicians seeking medical exception.

And that will then extend the time between when you're diagnosed and then when you ultimately.

When she gets ultimately made available.

To the to the patient so the the the demand and we have as confirmed in our on our recent quantitative work the demand.

Darren: So the demand, and we have this confirmed in our recent quantitative work, the demand is going to be there so that you have the desire to be able to treat broadly for these. We've got all the programs in place, like Anemia ID, the work that we shared with you last time on 23andMe, to help increase overall awareness, support patients, and have better testing options available. And then, so the opportunity for the patient to receive the treatment, I think The question is the amount of time in those first months for physicians to be able to work through the system.

It's going to be there. So that you have the desire to be able to treat treat broadly for these patients. We've got all the programs in place like a mini ICD work.

The work that we shared with you last time on 23.23 and me.

To help increase overall awareness drive.

Port patients.

And having.

Better testing.

Testing options available to them.

And then so.

The opportunity for patients to receive the treatment I think is going on behind the question is is the <unk>.

Amount of time in those first 2 first months.

For the physicians to be put on.

Work through the access challenges.

Kelsey Goodwin: Got it. Okay, super helpful. Thank you. Thank you. Our next question comes from Mark Breidenbach with Oppenheimer. Your line is open.

Got it okay Super helpful. Thank you very much.

Got it.

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

Operator: Oppenheimer, your line is open.

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

Mark Alan Breidenbach: That's on the forward progress. And Chris, of course, we're sorry to see you go as well.

Just wondering with regard to be pivotal trial in sickle cell disease. If you can comment on what the gating items are that remain before.

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

Trial can be initiated and in terms of the academic sickle cell trials.

With David that we might see later this year can you maybe give us a sense for how many patients do you expect from the attract trial and just remind us the main differences between this study and the NIH study. Thanks, so much.

Okay, It's Chris here.

Chris: Launching any of the Phase III in thalassemia and the Phase II-III study, the global studies, so the protocols are written and finalized, and now we're in that heavy lift of operationalizing the studies. And that's a whole list of activities that involve regulatory agencies, CITES, and CRO. And in addition to the protocol, there's all the logistics that come with setting up your IBRS, that is your randomization system, setting up all the translational medicine laboratory assays, and how those things are going to flow.

The.

Launching any any other phase III.

And Palestinians and the Phase III study global studies.

The protocols are written and finalized and now we're in that heavy lift.

Operationalize the study.

That's a whole.

<unk> list of activities that are involved.

On a regulatory agencies sites.

<unk>.

And in addition to the protocol Theres all the logistics that come with setting up your ABR asset is your randomization systems.

Setting up on me.

The.

Translational Medicine laboratory assays.

Those things are going to flow.

It's a very complicated.

Chris: So it's a very complicated series of activities that some of them can run, many of them run in parallel, but in each individual country and within each individual country, at individual sites, you're contracting and going through just a number of activities. So there are too many to name, but it's a well-described and well-acknowledged complicated series of activities that our team has done several times now successfully, and it takes some time to get everything up and running.

On.

Series of activities that are some of them can run many of them on in parallel.

In each individual country and within each individually.

On a country at individual sites youre contracting and going through just a number of activities.

So there are too many to name, but it's a well described and well acknowledge that its a complicated series of activities that our team has done several times now successfully.

And it takes some time.

To get everything up and running the key piece that we are.

Chris: The key piece that we're focused on in all of that is identifying sites that have patients throughout the world, these will be global studies, and to really look at everything we can do to make the trials accessible for patients and have maximum terminal velocity. So the first patient in is very important. And the last patient out is perhaps even more important. So, that's that piece, and that's one of the fun things about doing this job.

Focused on in all of that.

Is <unk>.

<unk> declined sites that have patients throughout the world. It will be global studies and to really look to everything we can do to make the trial is accessible for patients and have maximum.

From a terminal velocity. So the first patient in is very important.

And the last patient out is perhaps even more important.

So that's that piece and that's 1 of the fun things about doing this.

Job.

Chris: And then the second piece in terms of sickle cell, the UTREX study will enroll up to 10 patients. That group is very skilled and well-known in terms of their ability to look at both red cell metabolism, as well as using the oxygen scanner to look at point of sickling and other components that are important biomarkers in the sickle cell area. That trial starts patients at 20, and then they can go to 50 and then go up to 100 milligrams, and then they're on study for at least a year.

And then the second piece in terms of the sickle cell <unk>.

Study will enroll up to 10 patients.

That group is very skilled and well known in terms of their ability to look at both red cell metabolism as well as using the oxygen scanner to look at point of cycling and other components that are.

Important biomarkers in the sickle cell areas.

Correct.

That trial starts patients of 'twenty and then they can go to 50, and then got to a 100 milligrams.

And then they're on study for at least a year. So that's different from the NIH study were that the NIH study was the first study in adults.

Chris: So that's different from the NIH study, which was the first study in adults with sickle cell disease, where they started at five, 20, 50, and then they made the change to 100. So it's a total of eight weeks of treatment. And then there's this taper, and then patients who are willing and able can then go into an extension. So I think there are a lot of similarities in terms of understanding the important endpoints that we've talked about.

Adults with sickle cell disease, where they started at a $5.2050, and then they made the amendment to 100. So it's a total of 8 weeks of treatment and then there's this taper and then.

Patients who are.

<unk> enable can then go into an extension so I think theres a lot of similarities in terms of understanding.

The important.

<unk> endpoints that we've talked about.

Chris: And you get a sense of efficacy and safety from both. The Utrecht study, I think, gives you immediately, over time, some further understanding of chronic dosing that the NIH study doesn't give you quite immediately because those patients are on eight weeks of therapy. And then we'll definitely get more long-term data from patients who go into the extension, but we don't know yet how many of those patients are, at the end of the day, going.

And you get a sense of efficacy and safety from both the <unk> study I think.

Gives you immediately.

Over time, some further understanding of chronic dosing.

The NIH study doesn't give.

You are quite immediately because those patients are on 8 weeks of therapy, and then we will definitely get more long term data from patients who go into the extension, but we don't know yet how many of those patients.

At the end of the day going to be.

Operator: Thank you. We have a question from Danielle Brill, with Raymond James.

So I'll stop there.

Okay Super helpful. And then just a very quick.

Follow up is the phase III 3 going to be inclusive of African trial sites.

Danielle Brill: Hi, good morning.

Danielle Brill: Thanks so much for the questions. I guess, first, can you remind us what your expectations are for this webinar?

Yes.

Alright, thank you.

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

Danielle Brill: I want to know what your internal expectations are for an ADCOM meeting and maybe what your internal expectations are for priority review. And then, Darren, I wanted to clarify something from your pre-presentation prepared remarks. Excuse me. Did you say that your market research?

Hi, good morning.

So much for other questions I guess first can you remind us what your expectations are for an AD comm meeting and maybe what your internal expectations are for priority review and then Darren I wanted to clarify something from your.

Prepared remarks, excuse me did you say that your market research indicate 70 per.

Darren: 70% of providers already order genetic testing for anemias of unknown etiologies or say that they would like to. Thank you.

I sent him providers already ordered genetic testing for anemia of unknown etiologies or that they would like to thank you.

Chris: Thank you. Let me answer the second question, and then I'll leave the room for Chris to be able to answer you on the first. So the 70% number refers to the proportion of physicians who are routinely ordering more tests to try to be able to get to a definitive diagnosis for those patients who are diagnosed with hematopoietic anemia but have an unknown etiology, which means that they're inclined to either order enzyme tests or a genetic panel or both, which some may do reflexively.

Let me answer the second 1 and then I'll leave the room for Chris to be able to answer you on the first so the 70 per cent number.

First to the proportion of physicians, who routinely ordering.

More tests to try to be able to get towards the center.

When a definitive diagnosis of those patients who are diagnosed with hematologic anemia, but of unknown etiology, right, which means that they are inclined to either order.

Enzyme test for genetic origin, Edick panel or both.

Somebody do reflexively.

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

Reason why I mentioned I provided that insiders because then it means that we have a highly receptive audience then too.

To anemia I D.

And give us an indication of what further uptake of look like particularly now that we've got we've got more more folks out there educating the community about it.

So with that let me turn it over to Chris.

And then your question was with regards to priority review for the pardon me kinase deficiency submission there.

Chris: Hi, your question was with regard to priority review for the primary kinase deficiency submission, right? Yes. Yeah. So we'll find out the FDA's view on that, and their decision 60 days from when we file. So that should be sometime in the August timeframe, middle of August or so.

Yes.

Yeah.

So we'll find out.

The Fda's view on that their decision 60 days from when we filed so that should be some time in.

The August timeframe middle of August yourself.

Okay I guess.

Okay.

Sorry, we lost you.

Chris: What are your thoughts on advisory committee meetings?

What are your thoughts on an advisory Committee meeting.

Chris: Oh, and Ann Palm. Too early to tell. Sometimes you get some signals early on, but we're early in the stage yet, so it's too early to know.

Oh, an ad com.

Too early to tell you.

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

Danielle Brill: understood. Thank you.

Understood. Thank you.

Operator: Thank you, and there are no other questions in the queue. I'd like to turn the call back to Jackie Faust for closing remarks.

Thank you and there are no other questions on the queue I would like to turn the call back.

Jackie Fouse for closing remarks.

Jackie Faust: Thank you, Operator, and thank you, everyone, for the questions this morning. As we move into our very bright future as a transformed AGIOS, we look forward to making a meaningful difference in the lives of patients with genetically...

Thank you operator, and thank you everyone for the questions. This morning, as we move into our very bright future as a transformed Andrea So we look forward to making a meaningful difference from the lives of patients with genetically defined diseases.

Jackie Faust: and others

Jackie Faust: Starting with our potential launch in PK deficiency next year.

Starting.

Being with our potential launch in PK deficiency next year.

Jackie Faust: I would like to thank my AGIOS colleagues for their dedication and passion for making a difference.

I would like to thank my colleagues for their dedication and passion for making a difference for our patients.

Jackie Faust: I also would like to thank all of the patients, caregivers, and physicians who partner with us in so many ways. And today, a special thanks to Chris. We will have more interactions with him, I'm sure with you all, over the next couple of months. We're very, very happy and pleased that he's willing to stay with us, Agios, so through

I would like to thank all of the patients caregivers and physicians, who partner with us in so many ways.

And today, a special thanks to Chris we will.

We'll have more interactions with him I'm sure are with you all over the next couple of months, we're very very happy and pleased that he is willing to stay.

Engaged with us on Geo sat through the end of 2022 at least as a strategic.

Jackie Faust: through the end of 2022, at least as a strategic advisor because we'll continue to benefit from his wisdom.

Pfizer, but those will continue.

To benefit from his wisdom and insight. So thank you very much Chris and we look forward to a few parties over the next couple of months.

Jackie Faust: Thank you very much, Chris, and we look forward to a few parties over the next couple of days.

Jackie Faust: Thank you, and we'll see you in the next couple of months to write your next chapter.

Operator: Thank you everybody for joining us today. You may now disconnect. Take care.

Alright your next.

Thank you everybody for joining US today, you may now disconnect take care.

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

This concludes today's conference.

Carl Thank you for <unk>.

And you may now disconnect.