Q4 2020 Agios Pharmaceuticals Inc Earnings Call

Good morning, and welcome to <unk> fourth quarter 2020 conference call. At this time all participants are in a listen only mode. There will be a question and answer session at the end.

Operator: Good morning, and welcome to Agios' fourth quarter 2020 conference call. At this time, all participants are in a listen-only mode.

Operator: There will be a question and answer session at the end. Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Holly Manning, Director of Investor Relations. Thank you, operator.

Please be advised that this call is being recorded at ideal says request I would now like to turn the call over to Holly Manning director of Investor Relations.

Thank you operator, and good morning, everyone and welcome to <unk> fourth quarter 2020 Conference call you can access slides for today's call. Thanks to the investors section of our website <unk> dot com with.

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

On the call today with prepared remarks are Dr. Jackie Fouse, our Chief Executive Officer Chocolate Crisp on our Chief Medical Officer, Darrin miles, our Chief commercial officer, and Jonathan Biller, Our Chief Financial Officer, and head of legal and corporate Affairs.

Chris Carr, our Chief Scientific officer will join for Q&A.

Holly Manning: 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. However, actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. With that, I will turn the call over to Jackie.

We get started I would like to remind everyone on some of the statements. We make on this call will include forward looking statements.

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

Jackie Fowlkes: Thanks, Holly. Good morning, everyone, and thanks for joining our fourth quarter 2020 results call. Before we get into the exciting work we have ahead of us in 2021, I want to take a moment to reflect on this past year and acknowledge the extraordinary challenges faced by all of us at Agios, the patients we serve, and the global community at large. One year ago, when I spoke on the Q4 2019 call, we did not know that just a few weeks later the COVID-19 outbreak would escalate into a global pandemic, shutting down our offices and halting life as we knew it.

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Thanks, Holly good morning, everyone and thanks for joining our fourth quarter 2020 results call.

Before we get into the exciting work. We have ahead of us in 2021, I want to take a moment to reflect on this past year and acknowledge the extraordinary challenges faced by all of US at all Geos. The patients we serve and the global community at large one year ago. When I spoke on the Q4 2019 call.

We did not know there just a few weeks later the COVID-19 outbreak would escalate into a global pandemic shutting down our offices and halting life as we knew it.

For many of our employees working from home included balancing new challenges in their personal lives such as virtual school, taking care of young children, and new worries about health and wellbeing in a pandemic.

Jackie Fowlkes: For many of our employees, working from home included balancing new challenges in their personal lives, such as virtual school, taking care of young children, and new worries about health and well-being during a pandemic. And patients around the world, including those in clinical trials, struggled with reduced access to travel and medical centers. At the same time, the U.S. faced significant civil and political unrest that further exposed the realities of the racial and social divides in our country.

And patients around the world, including does in clinical trials struggled with reduced access to travel on medical centers at the same time, the U S face significant civil and political unrest that further expose the realities of the racial and social divides in our country.

In the wake of these challenges ive been overwhelmed by the generosity determination and spirit of the algae oils team in support of each other patients and our communities.

Jackie Fowlkes: In the wake of these challenges, I have been overwhelmed by the generosity, determination, and spirit of the Agios team in support of each other, patients, and our community. As of last week, our cross-functional coronavirus task force wrapped up its first year, having responded to nearly 750 inquiries from patients or health care providers across dozens of countries. For each request, the team worked tirelessly to reduce the risk to patients and or the burden to health care systems due to COVID-19 and went to great lengths to ensure patients could continue to have access to our medicines despite the unprecedented circumstances.

As of last week, our cross functional Coronavirus task force wrapped up their first year.

<unk> responded to nearly 750 inquiries from patients or health care providers across dozens of countries for each request. The team worked tirelessly to reduce the risk to patients and or the burden to health care systems due to COVID-19, and went to great lengths to ensure patients could continue to have access to our med.

Listen despite the unprecedented circumstances.

Jackie Fowlkes: Our facilities and HR teams have gone above and beyond the call of duty to ensure our labs and offices remain safe for employees who need to work on-site, including providing access to testing and contact tracing. For the teams working from home, they've organized personal and professional resources like webinars on avoiding burnout, access to educational materials and activities for our children, virtual employee interactions to maintain our connections, and ongoing team building activities to adapt our culture during this time and beyond.

Our facilities and HR teams have gone above and beyond the call of duty to ensure our labs and offices remain safe for employees, who need to work on site, including providing access to testing and contact tracing.

For the teams working from home they organized personal and professional resources like Webinars on avoiding burn out access to educational materials and activities for our children virtual employee interactions to maintain our connections and ongoing team building activities to adapt our culture. During this time and beyond.

On a community level, we let in diversity initiative. It argues that included speakers and workshops on valuing differences to heighten our awareness and help us learn together.

You can see in the photos on slide five we continue to support calls it is important to us through fund raisers on events and in December our employees donated gifts to families with children suffering from life threatening diseases.

With the realities and struggles in 2020 and continuing in 'twenty and 'twenty, one I. Nevertheless, find myself incredibly hopeful for the future and more confident than ever on our ability to overcome whatever comes our way.

From a business perspective, we have much to be excited about as we embark on the next chapter of our Joe's with a sole focus on genetically defined diseases in December we announced our refocused strategy and the decision to sell our oncology assets to survey a successful patient focused global pharmaceutical company with a deep commitment to.

Jackie Fowlkes: On a community level, we led a diversity initiative at Agios that included speakers and workshops on valuing differences to heighten our awareness and help us learn together. As you can see in the photos on slide 5, we continue to support causes important to us through fundraisers and events, and in December, our employees donated gifts to families with children suffering from life-threatening diseases. With the realities and struggles of 2020 continuing in 2021, I nevertheless find myself incredibly hopeful for the future and more confident than ever in our ability to overcome whatever comes our way.

Expanding its emerging oncology portfolio.

As part of the transaction, which is subject to a shareholder vote on March 25th I'll, just well received cash consideration of up to $2 billion, including $1 $8 billion in upfront cash and $200 million on a potential future cash milestone payment as well as five per cent royalties on U S net sales of tip salvo.

From transaction closed through loss of exclusivity and 15% royalties on U S. Net sales of voice on NIM from Kurt first commercial sale through loss of exclusivity.

After returning $1 $2 billion to shareholders residual proceeds will be retained to fund the company through major value driving catalysts and to profitability without the need for any additional equity raises.

These decisions will allow the oncology portfolio to grow and thrive with survey and will provide us with the capital required to maximize the potential for promising therapies for genetically defined diseases.

Jackie Fowlkes: From a business perspective, we have much to be excited about as we embark on the next chapter of Agios with a sole focus on genetically defined diseases. In December, we announced our refocus strategy and the decision to sell our oncology assets to Servier, a successful patient-focused global pharmaceutical company with a deep commitment to expanding its emerging oncology portfolio. As part of the transaction, which is subject to a shareholder vote on March 25, Agios will receive cash consideration of up to $2 billion, including $1.8 billion in upfront cash and $200 million in a potential future cash milestone payment, as well as 5% royalties on U.S. net sales of Tibsovo from the transaction closed through loss of exclusivity and 15% royalties on U.S. net sales of Vorosodinib from the first After returning $1.2 billion to shareholders, residual proceeds will be retained to fund the company through major value-driving catalysts and to profitability without the need for any additional equity raises.

Ultimately, enabling the greatest overall positive impact for patients.

For more details you can access our press release Investor presentation, and proxy statement on our website at <unk> Dot com.

Over the last few months, we've made significant strides with our most advanced medicine mid up here that across our three initial therapeutic areas of focus and this progress sets us up for a catalyst rich year ahead, which Chris will cover in a moment.

In addition, we are also moving other genetically defined disease programs through our clinical and research pipelines on the oncology side, we've continued to execute on both the clinical and commercial fronts. We closed out the second full year of chip, so low net revenue with $121 million exceeding our 150.

$15 million net revenue target.

Looking ahead to the evolution of our commercial business I'm pleased to announce that Darrin miles has been promoted to the role of Chief Commercial officer. He has served in numerous roles at <unk> since joining us in 2015, including most recently as senior Vice President of U S commercial and global marketing Darren has done a tremendous.

Job, leading our team to superior Kipp, so low commercial performance, while also preparing us for our first genetically defined disease launch with PK deficiency in 'twenty 'twenty, two Darren thoughtful and genuine leadership style is felt throughout our company.

We are very optimistic about our bright future and our ability to continue to bring transformative therapies to more patients than ever with our renewed focus and financial strength with that Chris Let me turn it over to you.

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

Jackie Fowlkes: These decisions will allow the oncology portfolio to grow and thrive with Cervier and will provide Agios with the capital required to maximize the potential for promising therapies for genetically defined diseases, ultimately enabling the greatest overall positive impact for patients. For more details, you can access our press release, investor presentation, and proxy statement on our website at agios.com. Over the last few months, we've made significant strides with our most advanced medicine, Midipivet, across our three initial therapeutic areas of focus, and this progress sets us up for a catalyst-rich year ahead, which Chris will cover in a moment.

As we entered 2021, we're excited about our future and genetically defined diseases and have significant work ahead of us as we advance our late stage programs and make decisions about our next wave of research.

I'll start with our most advanced genetically defined disease program made a pay back our first in class PK R. Activator currently being evaluated across three distinct chronic hemolytic anemia.

<unk> kinase deficiency, thalassemia and sickle cell disease.

In pyruvate kinase deficiency, we recently reported topline data from the activate and activate T phase III studies.

<unk> made a payback in adults with pyruvate kinase deficiency, who are not regularly transfused and those who are regularly transfused respectively.

Jackie Fowlkes: In addition, we are also moving other genetically defined disease programs through our clinical and research pipeline. On the oncology side, we've continued to execute on both the clinical and commercial fronts. We closed out the second full year of TIBSOVO net revenue with $121 million, exceeding our $115 million net revenue target. Looking ahead to the evolution of our commercial business, I'm pleased to announce that Darren Miles has been promoted to the role of Chief Commercial Officer.

In the activate study 40 per cent of patients treated with <unk> achieved the primary endpoint other sustaining hemoglobin increases compared to zero placebo patients a highly statistically significant result.

Statistical significance was also achieved all pre specified key secondary endpoints for activate demonstrating an improvement compared to placebo.

Including in patient reported outcomes based on changes from baseline.

Pyruvate kinase deficiency diary score Inc.

Part of the day kinase deficiency impact assessment score at week 24.

We anticipate that these data will be supportive of our submission for regulatory approval as well as in interactions with access providers.

Jackie Fowlkes: He has served in numerous roles at Agios since joining us in 2015, including most recently as Senior Vice President of U.S. Commercial and Global Marketing. Darren has done a tremendous job leading our team to superior TIBSOVO commercial performance while also preparing us for our first genetically defined disease launch with PK deficiency in 2022. Darren's thoughtful and genuine leadership style is felt throughout our company. We are very optimistic about our bright future and our ability to continue to bring transformative therapies to more patients than ever with our renewed focus and financial strength. With that, Chris, let me turn it over to you. Thanks, Jackie. Looking back, at 20,...

Inactivate Chi more than a third of patients achieved a meaningful reduction in transfusion burden and 22% with transfusion free during the 24 week dosing period.

In both studies the safety profile was consistent with previously reported data in PK deficiency patients.

Data from both studies, including the PRA will.

It will be submitted for presentation at the European Hematology Association Virtual conference, which is being held June nine through the <unk> This year.

These data support the potential permitted pip out to be the first disease modifying therapy for pyruvate kinase deficiency and will be the basis for our global regulatory filing that is currently in process.

We anticipate filing for regulatory approval in the U S. In the second quarter of 2021 and in the EU in mid 2021 with a potential 2022 commercial launch in both geographies.

Christopher J. M. Taylor: I'm humbled by the dedication and resourcefulness of our clinical organization on both the oncology and genetically defined disease sides of the business to advance our clinical programs over and above expectations for patients despite the challenges of the pandemic. As we enter 2021, we're excited about our future in genetically defined diseases and have significant work ahead of us as we advance our late stage programs and make decisions about our next wave of research.

Moving to the phase two study of me to pay that debt was senior we completed enrollment last year with 20 patients.

In June we presented updated data on 13 efficacy evaluable patients at the virtual <unk> meeting.

The data showed that treatment with he made a pivot induced a hemoglobin increase of greater than or equal to one gram per deciliter in 12 of 13 evaluable patients during weeks four through 12, including four before I'll bet that was senior patients for whom there have been no new treatment options from decades. In addition.

Christopher J. M. Taylor: I'll start with our most advanced genetically-defined disease program, Mitopibat, our first-in-class PKR activator currently being evaluated across three distinct chronic hemolytic anemias, part of a kinase deficiency, thalassemia, and sickle cell disease. In pyruvate kinase deficiency, we recently reported top-line data from the ACTIVATE and ACTIVATE-T Phase 3 studies evaluating midopibat in adults with pyruvate kinase deficiency who were not regularly transfused and those who were regularly transfused, respectively.

Seven of eight beta thalassemia patients achieved a sustained hemoglobin response during weeks 12 through April.

As of November 2000, 2017 patients remained on the extension portion of the trial.

We expect to submit the full dataset from all 20 patients in the core period from this study for presentation at E on.

In December we share your first glimpse at our two global pivotal trials have made up for that and that was seen yet.

Energize and energized team.

As you can see at the top of Slide 11, energized will evaluate 171 patients randomized two to one to 100 milligrams admitted pivot b I D or placebo in beta thalassemia patients who are not regularly transfused.

Christopher J. M. Taylor: In the ACTIVATE study, 40% of patients treated with midipibab achieved the primary endpoint of a sustained hemoglobin increase compared to zero placebo patients, a highly statistically significant result. Statistical significance was also achieved for all pre-specified key secondary endpoints for ACTIVATE, demonstrating an improvement compared to placebo, including inpatient-reported outcomes based on changes from baseline, and Pyruvate Kina We anticipate that these data will be supportive of our submission for regulatory approval as well as in interactions with access providers.

The primary endpoint as a percentage of patients with a mean hemoglobin increase of greater than or equal to one gram per deciliter.

From baseline over a 24 week period.

Energize T will evaluate 240 patients randomized two to one to 100 milligrams admitted Tibet.

EBITDA for placebo in beta and Alpha thalassemia patients, who are regularly transfused defined at 6% to 20 Red blood cell unit transfused during the 24 weeks prior to randomization.

The primary endpoint as a percentage of patients with a 50% reduction in transfusion burden in any 12 week rolling period during the 48 week period.

We are in the process of operationalized in both studies on looks forward to initiating these trials by the end of the year.

Now, let's turn to sickle cell disease.

Last year. They did pay that was the first PK activator to demonstrate proof of concept in this disease based on the initial data from the study being conducted in collaboration with Dr. Xu Lei Chen of the National Institutes of health.

Christopher J. M. Taylor: In active AT, more than a third of patients achieved a meaningful reduction in transfusion burden, and 22% were transfusion-free during the 24-week fixed-dose period. In both studies, the safety profile was consistent with previously reported data in PK deficiency patients. Data from both studies, including the PRO data, will be submitted for presentation at the European Hematology Association virtual conference, which is being held June 9th through the 17th this year. These data support the potential for Mitopibat to be the first disease-modifying therapy for pyruvate kinase deficiency and will be the basis for our global regulatory filing that is currently in process. We anticipate filing for regulatory approval in the U.S. in the second quarter of 2021 and in the E.U. in mid-2020, with a potential 2022 commercial launch in both geographies.

As outlined on slide 12 at Ash in December at the NIH presented updated data from 11 patients demonstrating mitigated that impact on hemoglobin improvement in conjunction with improvements in markers of hemolysis.

But your churn continues to enroll patients from the core study as well as an extension study and expect to provide an update at a medical meeting this year.

In addition, our collaborators at the University of <unk> initiated an investigator sponsored trial.

On the payback in sickle cell disease late last year and they also plan to submit data from this study for presentation at a medical meeting this year.

In parallel with these clinical activities.

We completed U S EU regulatory meetings focused on advancing our sickle cell disease program into pivotal development.

Their input led the development of a robust and thoughtful pivotal development strategy, which I'm excited to share with you today.

We believe this plan de risks the approval path from it would pay that in this challenging disease and maximizes the likelihood of a label with a broad indication in 2026.

The advice, we received from FDA and EMA about the pivotal trial design for me to put that in sickle cell disease was based on the currently available data.

Our initial clinical trial design and the evolving treatment landscape.

Specifically, we heard that hemoglobin alone is not considered an established surrogate for clinical benefit in sickle cell disease.

An interim hemoglobin analysis, it's highly unlikely to result in an accelerated approval and began blinding at interim has the potential to compromise a sickle cell pain crisis endpoint.

Christopher J. M. Taylor: Moving to the Phase 2 study of midipivatin thalassemia, we completed enrollment last year with 20 patients. And in June, we presented updated data on 13 efficacy-evaluable patients at the virtual EHA meeting. The data showed that treatment with midipibat induced a hemoglobin increase of greater than or equal to 1 gram per deciliter in 12 of 13 evaluable patients during weeks 4 through 12, including 4 of 4 alpha thalassemia patients for whom there have been no new treatment options in decades.

We have been strongly advised to develop data across two dose levels to further understand the pharmacodynamics and safety profile in sickle cell disease, given the complexity of this disease relative to other hemolytic anemias.

Based on this feedback we have designed the operationally seamless phase II III study I've made a payback in adults with sickle cell disease that you see here on slide 13.

The study will include patients who are 16 years of age or older.

I've had 2% to 10 sickle cell crises in the past 12 months and have a hemoglobin upgrades on the new equal to five five and less than 10 five grams per deciliter during the screening.

Christopher J. M. Taylor: In addition, 7 of 8 beta-thalassemia patients achieved a sustained hemoglobin response during weeks 12 through 20, as of November 2020. 17 patients remained in the extension portion of the trial. We expect to submit the full data set from all 20 patients in the core period from this study or presentation at. In December, we shared a first glimpse at our two global pivotal trials of Metapivet and Velosimib, Energize, and Energi

Patients currently receiving treatment with Fox on the tour Krizan lives, a mab or any other agent intended to increase hemoglobin oxygen affinity are excluded.

Treatment with Hydroxyurea is allowed.

Phase two on your left randomized 69 patients in one to one to one to 50 milligrams net of pay that PID 100 milligrams net of pay back PID or matched placebo.

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 III portion.

On the right phase III, which will commence after the phase two analysis will randomize 198 patients two to one to the selected phase two dose submitted Tibet on matched placebo.

Christopher J. M. Taylor: As you can see at the top of slide 11. ENERGYSE will evaluate 171 patients randomized 2-to-1 to 100mg of metapibat, BID, or placebo in beta and alpha thalassemia patients who are not regularly transfused. The primary endpoint is the percent of patients with a mean hemoglobin increase of greater than or equal to 1 gram per deciliter from baseline over a 24-week core period. ENERGIZE-T will evaluate 240 patients randomized 2-to-1 to 100 mg of metabat BID or placebo in beta and alpha thalassemia patients who are regularly transfused, defined as 6-20 red blood cell units transfused during the 24 weeks prior to randomization.

The study will have two primary endpoints.

<unk> Mclaughlin response defined as greater than or equal to one gram per deciliter change from baseline.

A week 52, and the annualized rate of sickle cell pain crisis.

We are on track to initiate the trial by the end of the year.

As a result of these changes to our initial pivotal plan for mid tier that in sickle cell disease.

We now expect a regulatory approval in the 2026 timeframe instead of our original guidance from an approval.

On the end of 2025.

We believe that by addressing the FDA and EMA feedback prior to the start from the phase III trial. This new plan increases the likelihood of a broad competitive label that is inclusive of both hemoglobin and sickle cell pain crises and points at the time of launch.

Here on Slide 14, you can see the robust pipeline, we're building with mid pay that across these three initial indications.

As we did with tips sogo, our focus is to advance the pip out from pivotal development to regulatory approval as quickly as possible.

Christopher J. M. Taylor: The primary endpoint is the percent of patients with a 50% reduction in transfusion burden in any 12-week rolling period during the 48-week core period. We are in the process of operationalizing both studies and look forward to initiating these trials by the end of the year. Now, let's turn to sickle cell disease.

Starting with pyruvate kinase deficiency next year, we believe we have the opportunity to meaningfully expand the labeled indications permitted to that over the next five years to address three serious hemolytic anemia that desperately need new treatment options.

Beyond admitted to that we're also advancing our next generation PK R. Activator AG 946 through a phase one healthy volunteer study.

Christopher J. M. Taylor: Last year, MedPIVAP was the first PKR activator to demonstrate proof of concept in this disease based on initial data from a study being conducted in collaboration with Dr. Sui-Lei Tien of the National Institutes of Health. As outlined on slide 12, at ASH in December, the NIH presented updated data from 11, demonstrating Minitibet's impact on hemoglobin improvement in conjunction with improvements in markers of hemolysis. Dr. Chen continues to enroll patients in the core study as well as an extension study and expects to provide an update at a medical meeting this year.

The trial began enrolling last fall and we expect to submit data from the single ascending dose and multiple ascending dose cohorts.

For presentation at a medical meeting by the end of the year.

Our analysis the totality of the AG 946 healthy volunteer data will inform next steps with the clinical development of this molecule.

This team has been hard at work producing a robust and promising pipeline of research within the PK activation mechanism and.

And we plan to make decisions on the next wave indications disease as well as a clinical stage drugs by the end of the year.

We also have significant non pyruvate kinase opportunities within our research pipeline, including a stabilizer of the enzyme deficient in phenylketonuria that degrades spend on <unk>.

And a unique approach to treating amino acids and asset areas associated with inborn errors of metabolism.

Christopher J. M. Taylor: In addition, our collaborators at the University of Utrecht initiated an investigator-sponsored trial of midipibap and sickle cell disease late last year, and they also plan to submit data from this study for presentation at a medical meeting this year. In parallel with these clinical activities, we completed U.S. and E.U. regulatory focused on advancing our sickle cell disease program into pivotal development. Their input led to the development of a robust and thoughtful pivotal development strategy, which I'm excited to share with you today.

Our deep expertise created around cellular metabolism to elucidate cancer cell biology since been exploited to great effect in understanding multiple genetically defined conditions and this has allowed us to build a deep portfolio of genetically defined targets.

We look forward to sharing more about these programs at an R&D day in the second half of the year.

On slide 16, we've outlined all of our 2021 key milestones and I will now focus on our oncology programs, where we have been hard at work, making important progress across a number of late stage programs and malignant hematology and solid tumors.

Last month at the <unk> meeting, we reported a full analysis of the final data from that.

Christopher J. M. Taylor: We believe this plan de-risks the approval path for midipibia in this challenging disease and maximizes the likelihood of a label with a broad indication in 2026. The advice we received from FDA and FEMA about the pivotal trial design for midipibap and tickle cell disease was based on the currently available data. Our initial clinical trial design and the evolving treatment. Specifically, we learned that hemoglobin alone is not considered an established surrogate for clinical benefit in sickle cell disease.

Global Phase III clarity trials tip, so low in patients with previously treated <unk> mutant cholangiocarcinoma.

The final analysis showed that median overall survival for patients randomized the tip Savo was 10 three months compared to seven five months for patients randomized to placebo.

The hazard ratio for overall survival did not meet statistical significance. However, a high proportion of patients from the placebo on <unk>.

75% crossed over to chip.

A prespecified crossover adjusted analysis showed a median overall survival for patients in the placebo on a 5.1 months and the hazard ratio for overall survival was statistically significant.

Christopher J. M. Taylor: An interim hemoglobin analysis is highly unlikely to result in an accelerated approval, and the unblinding at interim has the potential to compromise a sickle cell pain crisis. We have been strongly advised to develop data across two dose levels to further understand the pharmacodynamics and safety profile of sickle cell disease, given the complexity of this disease relative to other hemolytic anemia. Based on this feedback, we've designed the Operationally Seamless Phase 2-3 study of midipibat in adults with sickle cell disease that you see here on slide 13.

The safety profile observed in this study was consistent with previous published data.

And last year, we reported positive highly statistically significant progression free survival data.

Based on these data we are on track to submit a supplemental new drug application for <unk>, So low and.

From previously treated <unk> mutant cholangiocarcinoma in the first quarter from 'twenty to 'twenty one.

In addition to Cholangiocarcinoma, we are exploring the utility of <unk> inhibition in low grade glioma, and our phase III indigo trial aboard seismic.

Christopher J. M. Taylor: The study will include patients who are 16 years of age or older. I've had 2 to 10 sickle cell crises in the past 12 months and have a hemoglobin of greater than or equal to 5.5 and less than 10.5 grams per deciliter during sleep.

<unk> is our brain penetrant dual <unk> <unk> inhibitor that has the potential to treat the roughly 80% of low grade glioma patients with an <unk> mutation.

Enrollment is ahead of expectations, despite the pandemic, reflecting physician enthusiasm for the potential of voice side in this trial.

Christopher J. M. Taylor: Patients currently receiving treatment with Foxelitor, Grizolizumab, or any other agent intended to increase hemoglobin oxygen affinity are excluded; treatment with hydroxyurea is allowed. The phase 2 on your left will randomize 69 patients in 1 to 1 to 1 to 50 mg Mitopibat BID, 100 mg Mitopibat BID, or matched placebo. The primary endpoint is a hemoglobin response defined as greater than or equal to 1 gram per deciliter change from baseline to week 12, and the data will be used to establish a clear dosing paradigm for the phase 3 protein.

And finally, the AG 270 space on one dose escalation combination arms with tax sales continue to enroll patients.

On the hematologic malignancy side enrollment in our phase III frontline AML combination studies of <unk> as well as our Mds expansion are ongoing.

<unk> in the Mds cohort expected to complete enrollment by year end.

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

Thank you Chris.

Despite the resurgence of COVID-19 in Q4 and continued limitations on in person sales promotion our team delivered chip civil net sales of $39 $1 million in Q4 of 23% increase over the third quarter.

<unk> 2020, net sales to $121 million or 102% increase year over year exceeding the upper end of our updated guidance by $6 million per.

Performance in the quarter was driven by growth in new scripts on refills on favorable gross to net.

Christopher J. M. Taylor: On the right, Phase 3, which will commence after the Phase 2 analysis, will randomize 198 patients 2 to 1 for the selected phase 2 dose of midipibap or MATCH plus. This study will have two primary endpoints.

We continue to see double digit growth on both the academic and community settings, driven by a 15% increase in unique prescribers over Q3.

Physician preference for <unk> in the frontline intensive chemo ineligible and first relapse settings remains strong as do all leading indicators of physician perception, including the prevailing belief that chip sogou is the standard of care from newly diagnosed and relapsed refractory <unk> patients.

Christopher J. M. Taylor: Hemoglobin response defined as greater than or equal to one gram per deciliter change from baseline to week 52, and the annualized rate of sickle cell pain. We are on track to initiate the trial by the end of this year, as a result of these changes to our initial pivotal plan for metapivatin sickle cell disease. We now expect a regulatory approval in the 2026 timeframe instead of our original guidance of an approval at the end of 2020.

So promotional efforts are limited to FDA approved uses a tip Subaru only we still observed that approximately half of <unk>. So we use in both settings is a combination most frequently with an HMA.

We've also observed continued growth so we'll use for patients with Cholangiocarcinoma. The line of sight to the extent that you use is limited to only the third of the volume that moves through the specialty pharmacy channel.

Looking forward, we expect continued strengthening of Mel through 2021, culminating in net sales in the range of $160 million to $170 million in 2021.

Turning to me to pivot and protein kinase deficiency launch preparations are on track and further energized by the disclosure of the positive activate and activate T trial results last quarter, we announced the launch of anemia I D. A partnership with Perkin Elmer genomics to offer no cost genetic testing for patients with suspected hereditary anemias.

Christopher J. M. Taylor: We believe that by addressing the FDA and EMA feedback prior to the start of the Phase 2-3 trial, this new plan increases the likelihood of a broad competitive pipeline that is inclusive of both hemoglobin and sickle cell pain crises and points at the time of. Here on slide 14, you can see the robust pipeline we're building with MediPivot across these three initial indications. As we did with TIBSOVO, our focus is to advance MidaPIVAP from pivotal development to regulatory approval as quickly as possible. Starting with pyruvate kinase deficiency next year, we believe we have the opportunity to meaningfully expand the labeled indications for midipibat over the next five years to address three serious hemolytic anemias that desperately need new treatment.

This 50 gene panel and hope to provide a definitive diagnosis on the underlying cause of their anemia and represent from a central part of our multi pronged effort to accelerate patient identification and disease education in the U S.

From COVID-19 continues to present challenges related to commercial promotion or a number of important learnings from our experience in AML sales and marketing are informing a more efficient build for PK deficiency, including sales force sizing and our marketing mix.

Want to take this opportunity to express my appreciation to the entire ordeals oncology team for their work throughout the year made all the more impressive when considering the circumstances resilience grit and unwavering commitment to patients undergo this performance and thousands of patients and all of our Geos are grateful for it.

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

Thanks, Darrin, our fourth quarter and full year 2020 financial results can be found on the press release, we issued this morning, which I'll summarize more detail will be included in our 10-K filing later today.

Christopher J. M. Taylor: Beyond a minute to that, we're also advancing our next generation PKR activator, AEG946, through a phase one healthy volunteer study. The trial began enrolling last fall, and we expect to submit data from the single ascending dose and the multiple ascending dose cohorts for presentation at a medical meeting by the end of. Our analysis of the totality of the AG946 Healthy Volunteer data will inform next steps for the clinical development of this. Bruce's team has been hard at work producing a robust and promising pipeline of research within the PK activation mechanism.

Total revenue for the fourth quarter was $44 million.

Bringing total revenue for the full year 2020 to $203 2 million, an increase of $85 3 million compared to 2019.

As Jackie and Darren mentioned product sales up from silver was $39 1 million for the fourth quarter and $121 1 million for the full year 2020, an increase of $61 2 million compared to 2019.

Collaboration revenue was $2 million for the fourth quarter from $71 8 million for the full year 2020, an increase of $24 3 million compared to 2019.

The higher collaboration revenue in 2020 was due to recognition of the remainder of the deferred revenue balance related to the completion of the <unk>.

Christopher J. M. Taylor: And we plan to make decisions on the next wave of indications for these, as well as for our clinical stage drugs, by the end of the year. We also have significant non-pyruvate kinase opportunities within our research pipeline. , including a stabilizer of the enzyme deficient in phenylketonuria that degrades phenylalanine, and a unique approach to treating aminoacidemias and acidurias associated with inborn errors of metabolism.

Metabolic immuno oncology collaboration with Celgene and BMS.

Our full year 2020 revenue also includes $10 $3 million on royalty revenue from net global sales of ICU from <unk>.

$2 9 million of which was recognized during the fourth quarter.

As a reminder, we sold the depo royalty revenues to royalty pharma in Q2 2020, but continue to book the royalty revenue under GAAP.

Cost of sales for the fourth quarter was $1 million and $2 8 million for the full year 2020. This year over year increase of $1 $5 million was driven by ex factory sales.

Christopher J. M. Taylor: Our deep expertise in cellular metabolism to elucidate cancer cell biology has been exploited to great effect in understanding multiple genetically defined conditions and has allowed us to build a deep portfolio of genetically defined targets. We look forward to sharing more about these programs at an R&D day in the second half of the year. On slide 16, we've outlined all of our 2021 T-Miles, and I'll now focus on our oncology programs, where we have been hard at work making important progress across a number of late-stage programs in malignant hematology and solid tumor.

Turning to operating expenses R&D expenses for the fourth quarter were $95 $7 million and $367 $5 million for the full year 2020, a decrease of $43 4 million compared to the full year 2019.

This year over year decrease in R&D was largely driven by winding down of the clarity study and phase one study of <unk> in hematologic malignancies. The day prioritization of aging 66, and lower milestones incurred for hold on.

Selling general and administrative expenses were $39 $8 million for the fourth quarter and $149 $1 million for the full year 2020. This.

This represents a $17 million increase over full year 2019, driven.

Driven primarily by increased workforce expenses in the U S and EU and professional fees related to the 30 day transaction.

Christopher J. M. Taylor: Last month at the ASCO meeting, we reported a full analysis of the final data in the Global Phase III Clarity Trial of TIBSOVA in patients with previously treated IDH1 mutant cholangiocarcinoma. The final analysis showed that median overall survival for patients randomized to PIB-SOBO was 10.3 months compared to 7.5 months for patients randomized to placebo. The hazard ratio for overall survival did not meet statistically. However, a high proportion of patients in the placebo group.

We ended the quarter with cash cash equivalents in marketable securities of $675 million.

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

Following the closing of the <unk> transaction and net of the planned capital return Rgs expects to be able to fund its operations major catalysts and to cash flow positivity without the need to raise additional equity.

As previously communicated we plan to realign our capital structure to reflect the profile of our focus genetically defined disease company.

Christopher J. M. Taylor: 70.5% crossed over to Chitsobo. A pre-specified crossover-adjusted analysis showed a median overall survival for patients in the placebo arm of 5.1 months, and the hazard ratio for overall survival was statistical. The safety profile observed in the study was consistent with previous published data.

Turning $1 $2 billion of capital to share repurchases over a 12 to 18 month period. Following the closing we will provide more information with respect to share repurchase tactics and mechanics in due course.

With that operator, please open the line for questions.

Certainly if you ask a question you will need to press star one on your telephone.

Christopher J. M. Taylor: Last year, we reported positive, highly statistically significant, progression-free survival. Based on these data, we are on track to submit a supplemental new drug application for TIBSOVO and previously treated IDH1 mutant cholangioprosinoma in the first quarter of 2021. In addition to cholangiocarcinoma, we are exploring the utility of IDH inhibition and low-grade cholangiocarcinoma, and our phase 3 indigo trial of boroside. Borosidinib is our brain penetrant dual IDH1-2 inhibitor that has the potential to treat the roughly 80% of low-grade glioma patients with an IDH mutation.

Draw your question press the pound key.

Due to time constraints, we ask that you please limit yourself to one question.

Our first question comes from the line of Peter Lawson with Barclays.

Hey, Thanks for taking my questions just on on the cyclic so just a quick question around I.

I guess, the 100 milligram dosing when could we see more of that data.

Just the timing around that and if you think thats a important component in moving forward in sickle cell.

Hi, Peter it's Chris Bowden here.

Well, we are not guiding to the phase II portion of the <unk>.

Trial that I went through in my prepared remarks, yet.

And as we get that up and running and get some sense of the accrual will be able to provide further information there certainly over the coming year, we are going to see more data coming out from the trials that are ongoing at the NIH and that attract well.

Christopher J. M. Taylor: Enrollment is ahead of expectations despite the pandemic, reflecting physician enthusiasm for the potential of borosidinib and bisporinib. And finally, the AG-270 phase 1 dose escalation combination arms with TaqSAMES continue to enroll patients with hematologic malignancies. Enrollment in our Phase III Frontline AML Combination Studies of PIB-SOBO, as well as our MDS expansion, is ongoing, with Agile in the MDS cohort expected to complete enrollment by year. With that, I'll turn it over to Darren to discuss our fourth quarter commercial performance. Thank you, Chris.

We would be able that we'll be bringing some more.

Alright, thank you.

<unk> clinical data forward.

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

Hey, guys. Good morning, thanks for the updates.

Question related to the sickle cell trial design.

I guess from.

I'm not mistaken.

The occupied other books sold Port Hope trial, just had the hemoglobin response primary endpoint.

Here, it's kind of on two primary endpoints.

Do you I guess was the addition of the sickle cell pain crises endpoint.

Kind of primarily.

Required by the FDA or was that something you guys chose to add it in.

Do you have to hit on both of those to receive approval in.

It would be helpful to understand that also on the context of the fact that you have the two the cut off on the lower bound of sickle cell pain crisis in the past 12 months of two as opposed to one I was surprised to learn that the hope trial had 42% on patients that had one crises.

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

So do you.

I guess, you expect that to increase the signal there as well.

Yeah, Tyler it's Chris here so.

A number of of <unk>.

A different issues you touched on.

<unk> received.

Celebrated approval on the basis of the increase in hemoglobin.

And as you are you at.

All been following they have not demonstrated a.

Darren Miles: We continue to see double-digit growth in both the academic and community settings driven by a 15% increase in unique prescribers over Q3. Physician preference for Typsovo in the frontline intensive chemo-ineligible and first relapse settings remains strong, as do all leading indicators of physician perception, including the prevailing belief that Typsovo is the standard of care for newly diagnosed and relapsed refractory ID21 mutant patients. Promotional efforts are limited to FDA-approved uses of TIPSOVO only.

A statistically significant reduction in basal occlusive crises.

And our interactions with the.

The health authorities.

Voc's, whether it's a.

The primary endpoint.

Or a very high ranking secondary endpoint is crucial in this SME on <unk>.

Pudic index, if you will clinical benefit of the molecule specifically for the trial that we're putting forward having two primary endpoints if we hit on either one the study is.

Positive.

And then the.

The interesting part will be.

What the regulatory view as the clinical benefit of that trial by designing it this way.

If we hit on one we have a positive trial and we think we're going to design. The trial. So that we have a compelling case for clinical benefit if we hit on either endpoint ultimately that's a function of the data and if you hit on both of course, that's our.

Darren Miles: We still observe that approximately half of the placebo use in both settings is in combination, most frequently with an HMA. We've also observed continued growth of Tibsovo use for patients with cholangiocarcinoma. The line is tied to the extent of that use, which is limited to only a third of the volume that moves through the specialty pharmacy channel. Looking forward, we expect continued strength in AML through 2021, culminating in net sales in the range of $160 to $170 million in 2021.

Best case scenario, and we think that the mechanism of action of made a pivot supports us designing the trial and having some reason to believe that that could be the case I think the main debt one of the main things that we want to get across and this is consistent with what we've talked about with pyruvate kinase deficiency is that in a setting where.

Like sickle cell disease, where raising hemoglobin is important.

You have to have other supportive data for that and so linking back to pyruvate kinase deficiency. We've long heard very consistently that if you show up with an increase in hemoglobin that's.

Darren Miles: Turning to midipivad, in part because of the kinase deficiency, launch preparations are on track and further energized by the disclosure of the positive Activate and Activate T trial results. Last quarter, we announced the launch of Anemia ID, our partnership with Perkin Elmer Genomics to offer no-cost genetic testing to patients with suspected hereditary anemia. This 50 June panel can help to provide a definitive diagnosis of the underlying cause of their anemia and represents an essential part of our multi-pronged effort to accelerate patient identification and disease education in the U.S.

That's statistically significant but there is no other.

Clinical data to support the patients are feeling better youre addressing hemolysis and youre going to have a tough sell.

Yeah.

Thank you.

And our next question comes from the line of <unk> Rama with JP Morgan.

Hey, guys. Thanks, so much for taking the question I think we've talked about around 1100.

Patients with PK D kind of identified in the U S and core O U S regions, I think that update with the <unk>.

While ago, maybe ash 2019.

What's the updated patient count here.

How patient identification gone in 2020, and how do we think about patient identification going forward. Thanks, so much.

I don't know Paul this is darrin here so the debt you're correct last week discussing achieved most of as recently as are our life less webinar regarding them into the program we restated our.

Darren Miles: So COVID-19 continues to present challenges related to commercial promotion. There are a number of important learnings from our experience in AML sales and marketing that are informing a more efficient build for PK deficiency, including sales force sizing and marketing. I want to take this opportunity to express my appreciation to the entire AGIOS Oncology team for their work throughout the year made all the more impressive when you consider the circumstances. Resilience, grit, and an unwavering commitment to patience undergird this, and thousands of patients and all of Agios are grateful. I'll now turn it over to Jonathan for Q4. Thanks, Darren.

Current accounts at about 1000 patients or so on co.

Covid has made it more challenging.

To identify patients at the rate we would've wanted.

Given the need to be able to engage with with physicians at various conferences settings in their practices things along those lines, but we do continue to add to that number over time, we expect that that will accelerate over the course over the course of this this year I think what's really important and has actually been a bit.

<unk> for us is.

Having a good understanding of the complete suite of activities that we're employing our tactics were employing in order to accelerate the.

Ah patient finding activities.

Jonathan Biller: Our fourth quarter and full year 2020 financial results can be found in the press release we issued this morning, which I will summarize. More detail will be included in our 10K filing later today. Total revenue for the fourth quarter was $44 million, bringing total revenue for the full year 2020 to $203.2 million, an increase of $85.3 million compared to 2019. As Jackie and Darren mentioned, product sales of Subsobo were $39.1 million for the fourth quarter and $121.1 million for the full year 2020, an increase of $61.2 million compared to 2019. Collaboration revenue was $2 million for the fourth quarter and $71.8 million for the full year.

One of which is leading the IV program, which we've talked about.

Just recently received an update on where we are with it.

We're on pace by the end of this quarter to actually exceed the number of AV test distributed.

That we'd anticipated for the full year of between 21, and we're seeing a PK D positivity rates.

That approximates what we saw with the Spanish experience or Spanish ice tea, but we've talked about previously.

So we believe that that's going to be.

That's going to be a very important contributor to our patient finding activities.

This year on and indicates to us that they love the sense of urgency the level of interest around.

This disease and hopefully then it appeared that.

Exceeds.

Already exceeding our expectations.

Yes, it's Jackie here.

The I think on.

Underneath everything that Darin said also along the way, having the activate and activate T data as well as what we announced today, which I think is very important.

Having hit statistical significance on the key Prespecified secondary endpoints for activate including the P. R. O data is a really nice package of information to continue all of the efforts that Darren and his team have for now.

Jonathan Biller: An increase of $24.3 million compared to 2019. The higher collaboration revenue in 2020 was due to recognition of the remainder of the deferred revenue balance related to the completion of the metabolic immuno-oncology collaboration with cell gene BMX. Our full year 2020 revenue also includes $10.3 million in royalty revenue from net global sales of IDFA, $2.9 million of which was recognized during the fourth quarter. As a reminder, we sold the ID for Royalty Rights to Royalty Pharma in Q2 2020 but continue to book the royalty revenue under GAAP. The cost of sales for the fourth quarter was $1 million, and $2.8 million for the full year 2020.

Our medical affairs people are working on and it's I think it's going to be a very compelling message with both.

Physicians as well as patients that look its not just efficacy data. We're also hearing from or hearing we're seeing in the PRN data from patients on this trial that there's there's benefit so I think it's a pretty strong strong message.

Thank you and our next.

Question comes from the line of Kennan Mackay with RBC capital markets.

Hi, Thanks for taking the question and.

Adjusted to your point.

What a year and congrats on finishing on them.

On a point of strength.

Maybe just a question on the middle pivotal program in sickle cell disease.

Wondering about excluding patients who are other receiving a box on a tour or.

Jonathan Biller: This year-over-year increase of $1.5 million was driven by ex-factory sales. Turning to operating expenses, R&D expenses for the fourth quarter were $95.7 million. $367.5 million for the full year 2020, a decrease of $43.4 million compared to the full year 2019. This year-over-year decrease in R&D was largely driven by the winding down of the CLARITY study and Phase I study at TIPSOVO in hematologic, as well as the Deprioritization of AG-636 and Lower Milestones Incurred for HOVA. Selling, general, and administrative expenses were $39.8 million for the fourth quarter and $149.1 million for the full year 2020.

Prison, lithium mob or any day.

The other agents that change hemoglobin oxygen.

Then it would be it seems like that could meet the enrollment in the U S.

Somewhat challenging I'm, just wondering sort of how.

That's going to change enrollment into the trial versus some of the prior studies, where there wasn't anything available. Thank you.

Yeah trend and it's Chris share I think you've touched on one of the interesting things.

We encountered some other similar situations and leukemia on AML with the <unk> inhibitors, as we were coming in with Tim So low and I define a rapidly changing landscape.

There are things you can predict and things you can't predict.

If you just sort of take those those drugs.

In order.

Bob Schalow tour.

If we were going to permit that.

Then you would need to understand is there a drug drug interaction number one.

And you'd probably need to set up your trial in some way to do some sort of comparison. So the fact that we can do a placebo controlled study.

Jonathan Biller: This represents a $17 million increase over full year 2019, given primarily by increased workforce expenses in the U.S. and EU and professional fees related to the Servier transaction. We ended the quarter with cash, cash equivalents, and marketable securities of $670.5 million.

Isn't advantage of sorts.

But there certainly will be patients in the United States, who are on <unk> Choi their hemoglobin has gone up and in the eyes of their position as well as the individual they will be satisfied and there will be also individuals who may be on both drugs because it moves on that and.

Jonathan Biller: We expect that this cash balance, together with the anticipated product revenue, Interest Income, and Expense Reimbursements under our collaboration, excluding any additional program-specific milestones, will fund our current operating plan to the end of 2022. Following the closing of the Cervier transaction, net of the planned capital, Agios expects to be able to fund its operations through major catalysts and to cash flow positively without the need to raise additional equity. As previously communicated, we plan to realign our capital structure to reflect the profile of our focused, genetically defined disease by returning $1.2 billion of capitalist share repurchases over a 12 to 18 month period following closing.

Buck solid tour, so certainly there will be a wave of changes.

And as new drugs to come available to patients at.

At the same time, there will be.

Sickle cell is a global.

Disease, and so we're going to expand our recruitment efforts and that's a big part of our feasibility.

And Hydrea will clearly be allowed it to standard of care many patients are on it.

So I think that and then if you take the number of Theres, a significant percentage of patients who don't respond to bulk sell it tomorrow, we will be looking for another option and coming on to this study.

We'll be at attractive one for them.

Hope so I think overall certainly the development of new therapies is a good thing for patients.

More options at the same time it also raises awareness in the community.

None of these drugs there are 100% effective.

Jonathan Biller: We will provide more information with respect to share repurchase tactics and mechanics in due course. With that, operator, please open the line for questions. Yes. To ask a question, you will need to press star 1 on your telephone.

And they certainly have gaps in their target product profile, we need to define whether we can address those gaps, but I think that given the data we've generated to date and the attractiveness of the mechanism of action.

Operator: To withdraw your question, press the pound key. Due to time constraints, we ask that you please limit yourself to one question. Our first question comes from the line of Peter Lawson with Barclays. Hey, thanks for taking my questions. Just on the sickle cell, just a quick question around I guess the 100 milligram doses, when can we see more of that data? Just the timing around that and if you think that's an important component in moving forward in sequencing. Hi Peter, it's Chris Bowden here.

We think we have a good chance on our early feasibility is telling us that people are very interested in.

Talking to patients about coming onto the study.

Yes.

Yes.

Thank you and our next.

Next question comes from the line of Michael Schmidt with Guggenheim.

Hey, guys. Good morning, Thanks for taking my questions I had another one for Chris on the sickle cell disease study design it seems sounds like the.

Much of the F D a.

You know discussion may have been.

Focus also on the dose selection and I was just curious if you could.

Talk a little bit more about what some of their considerations, where when asking you choose to look at both the 50 and the 100 milligram dose and not just settle on 100 like you are doing it in the pharmacy net.

Christopher J. M. Taylor: Well, we're not yet guiding to the phase two portion of the trial that I went through in my prepared remarks yet. And as we get that up and running and get some sense of the accrual, we'll be able to provide further information there. Certainly, over the coming year, we're going to see more data coming out from the trials that are ongoing at the NIH and at Utrecht, where we would be able... Thank you. I did the Mellon-Garrett-Graham clinical data, and our next question comes from the line of Tyler Van Buren with Piper Sandler. Hey guys, good morning.

Trial, so thanks, so much.

Yes, it's that.

50 to 100 milligrams, where.

Based on the data we have so far.

You see.

On an increase in the Pharmacodynamic changes.

And you can't.

At this point.

Think we're pretty close to maximal.

Hemoglobin responses 50, although in thalassemia and we felt like we picked up a few more patients.

There.

Feedback, which is somewhat consistent with with EMA is that it's a complicated disease, they've seen a lot of drugs fail.

So we advised that debt and you will help us in terms of understanding the risk benefit of your drug on what you take the phase III by doing a phase two investigation component and understanding.

Operator: Thanks for the updates. A question related to the sickle cell trial design. I guess...

Operator: If I'm not mistaken, the Oxpiride or Voxelotor HOPE trial just had the hemoglobin response rate as the primary endpoint, whereas here it's kind of two primary endpoints. I guess, was the addition of the sickle cell pain crisis endpoint kind of primarily required by the FDA, or was that something you guys chose to add in, and do you have to hit on both of those to receive approval, and it would be helpful to understand that also in the context of the fact that you have the cutoff for the lower bound of sickle cell pain crises in the past 12 months of two as opposed to one. I was surprised to learn that the Yeah, Kyle. It's Chris here.

Further what this pharmacodynamic two.

<unk> ATP relationship hemoglobin relationship from safety looks like across these two doses.

Before you decide to make a decision to take one forward.

And that was one of the drivers there.

And then they were very clear on some of the debt component around hemoglobin that I talked about in terms of the trial design.

Yeah.

Great. Thank you.

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

Hey, Good morning, guys. This is James thanks.

Thanks for taking my question.

Just a quick one on 80 946, what do you need to see from the sad Mad trials to open the sickle cell disease cohort and I guess, just like one like related topic is the non core six has a longer half life in Canada offer once a day dosing.

So the answer to the last part of your question, possibly it could offer once a day dosing.

Christopher J. M. Taylor: So a number of different issues you touched on, Voxelotor received an accelerated approval on the basis of the increase in hemoglobin. And as you and we've all been following, they have not demonstrated a statistically significant reduction in vaso-occlusive crises and our interactions with the health authorities. VOCs, whether it's a primary endpoint or a very high-ranking secondary endpoint, is crucial in assessing the Therapeutic Index, if you will, clinical benefit of the molecule, specifically for the trial that we're putting forward, which has two primary endpoints.

And then what we would need to see to take it forward.

Would be.

We need to see it clear it's hurdles in terms of what we would expect to see from reductions in <unk> and increases in ATP.

And an adequate safety profile.

On a predictable and <unk>.

Reasonable pharmacokinetic profiles. So that's really the totality of data that we'd be looking at.

They will want to be able to observe that data or analyze that data across several different cohorts, which we're in the midst of dosing now.

I appreciate it thank you guys.

Our next question comes from the line of Marc Frahm with Cowen and company.

Hi, thank for taking my questions and congrats on getting through this.

Christopher J. M. Taylor: If we hit on either one, the study is positive. And then the interesting part will be, what the regulatory view is the clinical benefit of that trial by designing it this way? If we hit on one, we have a positive trial, and we think we're going to design the trial so that we have a compelling case for clinical benefit if we hit on either end point. Ultimately, that's a function of the data. And if you hit on both, of course, that's our best case scenario.

I'm here for everyone.

Maybe just following up on some other questions on the sickle cell trial design for Chris.

Can you provide any granularity as to how.

You are splitting the alpha between the debt.

Primary endpoints.

Kind of inherent to that is what is the powering that youre expecting to see on the.

On the pain crises and are there any kind of important.

Okay.

The stratification factors that we should be thinking about maybe on the hydroxyurea use or the exact rate of baseline cyclical crises.

Christopher J. M. Taylor: And we think the mechanism of action of mid-PIVOT supports us in designing the trial and having some reason to believe that that could be the case. I think one of the main things that we want to get across, and this is consistent with what we've talked about with pyruvate kinase deficiency, is that in a setting where, like sickle cell disease, where raising hemoglobin is important, you have to have other supportive data for that.

On a lot of interesting questions Mark.

Not a co primary endpoint.

There are two primary endpoints.

The trial is positive if it hits on either one.

And we will we'll be disclosing the.

Further details around the stats on the trial.

Later.

In time, especially as we get them up and running.

Christopher J. M. Taylor: And so, linking back to pyruvate kinase deficiency, we've long heard very consistently that if you show up with an increase in hemoglobin that's statistically significant, but there's no other clinical data to support that patients are feeling better, you're addressing hemolysis, then you're going to have a tough cell. Thank you. And our next question comes from the line of Anupam Rama with JP Morgan. Hey guys, Thanks so much for taking the question. I think we've talked about around 1100. Patients with PKD have been identified in the US and core OUS regions. I think that update was a while ago, maybe ASH 2019.

Your question around.

Seeds.

Related to sort of what we would expect in terms of the numbers.

And how hydraulics, the Ria will come into play there.

I think thats all from one of the hardest things.

<unk> in this disease and only vendor more challenging by virtue of the fact that you have now, let's say that listen Matt, but we sit in the U S and expanding in Europe, a drug that is effective in reducing the frequency of the ocs.

So so so that's going to be something that we need to follow and so on and the reason why we designed the trial on the way it did.

That it can be successful on the basis of either one of those readouts are closer to best case scenario and we do have reason to believe that we could reduce vlccs.

But I think that if you look at the history of trials and if you look at.

Most recently when you look at the <unk> trial on it clearly improves hemoglobin, but wasn't able to demonstrate an improvement from the reduction of <unk>.

Clearly an unmet need there.

And.

The other the other part of your question is I think there's just a lot of heterogeneity in this disease.

Operator: What's the updated patient count here? How's patient identification going to be in 2020? And how do we think about patient identification going forward? Thanks so much. Hi, everyone. This is Darren here.

And Thats one of the reasons why we've received a lot of feedback from both the EMA and the FDA in terms of on.

And all this together our trial design is as a mix of many things its feedback from the authorities.

Talking to two individuals with the disease in this case sickle cell and <unk>.

Darren Miles: So, you're correct. Last we discussed, actually, as recently as our last webinar regarding the Medi-Pivot program, we restated our current count at about 1,000 patients or so. COVID has made it more challenging to identify patients at the rate we would have wanted, given the need to be able to engage with physicians at various conference settings and in their practices, things along those lines. But we do continue to add to that number over time.

They talk about.

Issues with access they talk about issues with trust on the medical community when they talk about their symptoms and one that really really comes out as pain.

Jim.

And so these are the types of things pulling all that together and then regulatory feedback is the mix of you should do this.

You must do this and so then they as a company you have to take.

Some physicians, especially on your balance and EMA versus FDA, because they don't always give you usually they give you some degree of inconsistency and that feedback.

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

And then you have to look at what's happening from an operations and feasibility perspective, so pulling all that together is it's.

It's fun, it's challenging it's complex and we've been working hard.

Come up with the plan that we have today, which we can balance all those factors and gives us the best chance.

Having a positive trial to demonstrate clinical benefit for individuals with sickle cell disease.

Yeah.

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

Hi, guys. Good morning, Thanks for taking my question.

Chris just curious for the sickle cell disease phase III trial.

Will you be able to look at any sort of a CRO or any sort of measure.

Uh huh.

Peak et cetera on patients with no debt.

This has been really difficult in the past for sickle cell disease, but just curious if you have anything on that sort of built into the study. Thanks.

John.

Darren Miles: And we're seeing a PKD positivity rate that approximates what we saw with the Spanish experience or Spanish ISP that we talked about. So we believe that that's going to be... That's going to be a very important contributor to our patient finding activity. [inaudible] The Bulletproof Executive 2013 Yeah, and it's Jackie here.

The patient reported outcomes and quality of life will be a central part of the study.

And it comes back to debt.

Feedback that we've heard starting with our foray in however, many years ago in pyruvate kinase deficiency.

And that data, whether it's quality of life fish patient reported outcomes.

Is essential.

In the setting of this trial to essential on all these trials really one year, when you're raising hemoglobin as the primary endpoint.

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

But you've got to be able to show that patients are feeling better provide some evidence that patients are feeling better whether it's whereby a virtue of individual responders are on your experimental arm. So yes, we have the kit we have to collect that data would be a very important part of demonstrating.

Clinical benefit in a setting of a trial that demonstrates an increase in hemoglobin, but misses on the seats because the trial could still be positive.

And then.

The regulators who control the approval will say so what other things do you have to show us.

That patients who have the Haynesville, Inc. Hemoglobin increase feel better and Payors will be asking the same question.

Operator: Thank you. And our next question comes from the line of Kenan McKay with RBC Capital Markets. Hi, thanks for taking the question, and Jack, to your point, what a year, and congrats on finishing on a point of strength. Maybe just a question on the Mitopivap program in sickle cell disease, wondering about excluding patients who are either receiving Voxelotor or Crizanalizumab or any of the other agents that change hemoglobin oxygen affinity. It seems like that could make enrollment, at least in the U.S., somewhat challenging, and just wondering sort of how that's going to change enrollment into the trial versus some of the prior studies where there wasn' Yeah, Trenton. It's Chris here.

An important part of the trial and there's been a lot of work in terms of trying to describe the burden of disease and reducing the burden of disease with drug therapy in patients with sickle cell disease. So there's validated scales or six minute walk test and Theres a number of things that one that one can look at.

It's challenging and we don't we go into this with our eyes wide open like I said, you know a lot of a lot of drugs that have.

Either have been positive.

Marginally positive what have you had have not been able to demonstrate those improvements. So it's a very challenging area, but it's absolutely essential.

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

Yes, Hi, this is counting on for Mark and thanks for taking my question.

Just just a quick one for Chris are you are you planning on implementing any titration or tapering schedule is for the upcoming phase III three sickle cell study. Thanks.

Christopher J. M. Taylor: I think you touched on one of the interesting things, that we encountered somewhat of a similar situation in leukemia and AML with the IDH inhibitors as we were coming in with TIBSOVO and IDFA in a rapidly changing landscape. There are things you can predict and things you can't predict. If you just sort of take those drugs in order. Voxelotor, if we were going to permit that.

With with.

Net of Pip at.

We will since we went into pyruvate kinase deficiency, we think we recommend.

Tapering the drug.

We don't recommend abrupt stoppage.

One change in terms of the phase II portion will just start patients at 50, and 100 milligrams they won't titrate up.

Okay.

Thank you and our next question comes from the line of Andrew Burd.

Your line is from with SBB Leerink.

Christopher J. M. Taylor: Then you would need to understand whether there is a drug-drug interaction, number one. And you'd probably need to set up your trial in some way to do some sort of comparison. So the fact that we can do a placebo-controlled study is an advantage of sorts. But there certainly will be patients in the United States who are on Vuxelatoy, and their hemoglobin has gone up, and in the eyes of their physician as well as the individual, they will be unsatisfied, and there will also be individuals who may be on both drugs. Voxelotor.

Hey, this is Chris on for Andy Thanks for taking the question.

I know you said that you will provide more specifics around.

The planned share buybacks later on but I was just wondering if there could be any uh huh.

Copper color on general aspects of it.

Such as our deep.

Do you expect to start it as soon as.

Uh huh.

The process is completed or.

And will it be at the market or potential tender.

Hey, this is Jonathan thanks, Thanks for the question.

Implicit in your question is theres many different ways.

To execute share repurchases.

Christopher J. M. Taylor: So certainly, there will be a wave of changes as new drugs become available to patients. At the same time, sickle cell will be a global disease, and so we're going to expand our recruitment efforts, and that's a big part of our feasibility, and Hydrea will clearly be allowed. It's a standard of care.

We have a fairly significant amount of repurchases to do as a percentage of our market cap. So I think it's fair to say you could.

We've guided that we'll do it over 12 to 18 months.

So I think it's fair to expect that.

Be more than one mechanism by which we will do it are planning right now is ongoing and it's really designed to try to make sure that we do it in the most efficient way that we can and in a way that will be most likely to increase long term shareholder value.

Christopher J. M. Taylor: Many patients are, So I think that, and then if you take the number of this, the significant percentage of patients who don't respond to voxelotor will be looking for another option, and coming onto this study will be an attractive one for them, we hope. So I think overall, you know, certainly the development of new therapies is a good thing for patients. They have more options.

We'll give more guidance as we get closer to executing.

We would expect debt, we will be commencing share repurchases at some point in due course, following closing, but more to come on that.

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

Christopher J. M. Taylor: At the same time, it also raises awareness. None of these drugs are 100% effective, and they certainly have gaps in their target product profile. We need to define whether we can address those gaps, but I think that, given the data we've generated to date and the attractiveness of the mechanism of action, we think we have a good chance.

Thank you very much operator, and thank you very much all of you for joining us this morning.

We look forward to more interactions with you over the coming weeks and months I just want to reiterate that despite the challenges and uncertainties that lay ahead I remain very excited about the progress we're making across our focus areas. This year as well as the progress that our team has delivered across our oncology programs.

Operator: And our early feasibility is telling us that people are very interested in talking to patients about coming onto this. Thank you. And our next question comes from the line of Michael Schmidt with Guggenheim. Hey guys, good morning.

As well to close I would like to thank very much on my own jails colleagues for their dedication and passion for making a difference for our patients both in oncology and genetically defined diseases. I also want to thank all of the patients caregivers and physicians who participate in our clinical trials without them, we could not do what we do thank you again.

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

For joining us today take care.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating and you may now disconnect.

Yes.

Yes.

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Yes.

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Christopher J. M. Taylor: Yeah, it's that 50 to 100 milligrams where, based on the data we have so far, you see an increase in the pharmacodynamic changes. And you can't, at this point, we think we are pretty close to maximal hemoglobin response at 50.

Christopher J. M. Taylor: Although in thalassemia, we felt like we picked up a few more patients. Their feedback, which is somewhat consistent with EMA, is that it's a complicated disease. They've seen a lot of drugs fail.

Okay.

Yes.

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Moving on.

Christopher J. M. Taylor: So we advise that you do that, and you will help us. In terms of understanding the risk-benefit of your drug and what you take to phase three by doing a phase two investigation component and understanding further what this pharmacodynamic 2,3-DPG-ATP relationship, hemoglobin relationship, and safety look like across these two doses. Before you decide, make a decision to take one forward. And that was one of the drivers there.

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Yes.

Okay.

Yes.

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Yes.

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Christopher J. M. Taylor: And then they were very clear on some of the components around hemoglobin that I talked about in terms of the trial. Great, thank you. Your next question comes from the line of Mohit Bansal, Wood City. Hey, good morning, guys. This is James Wong from OHIT.

Operator: Thanks for taking our question. Just a quick one on AD946. What do you need to see from the SAD-MAD trials to open the sickle cell disease cohort? And I guess just one related topic is, does 946 have a longer half-life and can it offer once-a-day dosage?

Yes.

Yeah.

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Great.

Yes.

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Christopher J. M. Taylor: So the answer to the last part of your question, possibly it could offer once-a-day dosing, and then what we would need to see to take it forward. We need to see it clear its hurdles in terms of what we would expect to see from reductions in 2,3-DPG and increases in ATP and an adequate safety profile, a predictable and reasonable pharmacokinetic profile, so that's really the totality of data that we'd be looking at. I appreciate it.

Yes.

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Okay.

Net.

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Operator: Thank you, guys. Our next question comes from Mark Fram with Cohen & Company. Thanks for taking my questions and congrats on getting through what was challenging here for everyone. Maybe just following up on some of the questions on the sickle cell trial design for Chris. Can you provide any granularity to how you're splitting the alpha between the...

Operator: The co-primary endpoints and kind of inherent to that are, you know, what is the powering that you're expecting to see on the pain crises and are there any kind of important... I can't decide, stratification factors that we should be thinking about, maybe the hydroxyurea use or the exact rate of baseline sickle crisis. Um, a lot of interesting questions, Mark. It's not a co-primary.

Yeah.

Okay.

Sure.

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On.

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Christopher J. M. Taylor: So there are two primary endpoints, and the trial is positive if it hits on either one. And we'll, we'll be disclosing further details around the stats on the trial later in time, especially as we get them up and running. Um, your question around VOCs, related to sort of what we would expect in terms of the number and how hydroxyurea will come into play there. I mean, I think that's one of the hardest things to predict in this disease and only rendered more challenging by virtue of the fact that you now have, at least in the U.S., and expanding in Europe, a drug that's effective in reducing the frequency of DOCs.

Christopher J. M. Taylor: So that's gonna be something that we need to follow, and it's one of the reasons why we designed the trial the way we did, that it could be successful on the basis of either one of those readouts. Of course, the best case scenario, and we do have reason to believe that we could reduce VOCs.

Christopher J. M. Taylor: I think that if you look at the history of trials and, most recently, when you look at the voxelatory trial that clearly improved hemoglobin but wasn't able to demonstrate an improvement in the reduction of VOC, there's clearly an unmet need there. And there's, you know, the other part of your question is that I think there's just a lot of heterogeneity in this disease. And that's one of the reasons why we've received a lot of feedback from both the EMA and the FDA in terms of pulling all this together.

Christopher J. M. Taylor: You know, a trial design is a mix of many things. It's feedback from the authorities, talking to individuals with the disease, in this case sickle cell, and they talk about issues with access, they talk about issues with trust in the medical community. When they talk about their symptoms, the one that really, really comes out is pain.

Christopher J. M. Taylor: And so, you know, these are the types of things pulling all that together. And then regulatory feedback is the mix of, you should do this, you must do this. And so then, as a company, you have to take some positions, especially when you're balancing EMA versus FDA, because they don't always give you, usually they give you some degree of inconsistency in that. And then you have to look at what's happening from an operations and feasibility perspective.

Christopher J. M. Taylor: So pulling all that together is fun, it's challenging, it's complex, and we've been working hard to come up with the plan that we have today, which we think balances all those factors and gives us the best chance of having a positive trial that demonstrates clinical benefit for individuals with sickle cell disease. Thank you. And our next question comes from the line of John Newman with Canaccord. Hi guys, good morning.

Operator: Thanks for taking my question. Chris, just curious about the sickle cell disease phase 2, 3 trial. Will you be able to look at any sort of PRO or any sort of measure of PEG, etc.

Christopher J. M. Taylor: in patients? This has been really difficult in the past for sickle cell disease, but just curious if you have anything of that sort built into the study. John, patient-reported outcomes and quality of life will be an essential part of the study. And it comes back to that feedback that we've heard, starting with our 4A and however many years ago, about pyruvate kinase. And that data, whether it's quality of life, patient-reported outcomes, is essential.

Christopher J. M. Taylor: In the setting of this trial, it's essential in all these trials, really, when you're raising hemoglobin as a primary, but you've got to be able to show that patients are feeling better, provide some evidence that patients are feeling better, whether it's by virtue of individual responders or in your experimental. So yeah, we have to collect that data. It would be a very important part of demonstrating clinical benefit in the setting of a trial that demonstrates an increase in hemoglobin but misses on VOCs because the trial could still be positive.

Christopher J. M. Taylor: And then the regulators who control the approval will say, so what other things do you have to show us? that patients who have a hemoglobin increase feel better, and payers won't be asking the same question. So that's an important part of the trial, and there's been a lot of work. [inaudible] Drugs that either have been positive or marginally positive, what have you, have not been able to demonstrate those improvements.

Christopher J. M. Taylor: So it's a very challenging area, but it's absolutely essential. Thank you. And our next question comes from the line of Mark Breidenbach with Oppenheimer. Yes, hi, this is Kalpadan for Mark, and thanks for taking your question. Just a quick one for Chris.

Operator: Are you planning on implementing any titration or tapering schedules for the upcoming phase two, three sickle cell study? With with, you made a pivot. We will, since we went into pyruvate kinase deficiency, think, we recommend tapering the drug. We don't recommend abrupt stoppage.

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Christopher J. M. Taylor: So that won't change. In terms of the Phase II portion, we'll just start patients at 50 and 100. They're multi-trade.

Christopher J. M. Taylor: Thank you. And our next question comes from the line of Andrew Berens. Your line is with S.V.B. Leary. Hey, this is Chris on behalf of Andy.

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

Jonathan Biller: Hey, this is Jonathan. Thanks. Thanks for the question. You know, implicit in your question is that there are many different ways.

Jonathan Biller: We have a fairly significant amount of repurchases to do as a percentage of our market cap, so I think it's fair to say you could, and we've guided that we'll do it over 12 to 18 months. So I think it's fair to expect that.

Jonathan Biller: They'll likely be more than one mechanism by which we do it. Our planning right now is ongoing, and it's really designed to try to make sure that we do it in the most efficient way that we can and in the way that will, you know, be most likely to increase long-term shareholder value. We'll, you know, we'll give more guidance as we get closer to executing, and, you know, we would expect that we would be commencing share repurchases at some point. Thank you.

Jonathan Biller: I'll now turn the call back over to Chief Executive Officer Jackie Faust for any closing remarks. Thank you very much, Operator, and thank you very much, all of you, for joining us this morning. We look forward to more interactions with you over the coming weeks and months. I just want to reiterate that, despite the challenges and uncertainties that lay ahead, I remain very excited about the progress we're making across our focus areas this year, as well as the progress that our team has delivered across our oncology programs as well.

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

Jackie Fowlkes: Thank you again for joining us today. Take care. Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect.

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