Q4 2019 Earnings Call

Good morning, and welcome to ideals fourth quarter aim for year 2019 conference call. At this time, all participants are not listen only mode. There will be a question and answer session. At the end. Please be advised city school is being recorded at Chills request I would now like to turn the call over two wholly Manny.

Operator: Welcome to Agios' fourth quarter and full year 2019 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, Associate Director of Investor Relations. Thank you, operator.

Associate director of Investor Relations.

Thank you operator, good morning, everyone and welcome to our <unk> fourth quarter full year 2019 conference call you can access slides for today's call by going to the Investor section of our website <unk> Dot com.

Holly Manning: Good morning, everyone, and welcome to Agios' fourth quarter and full year 2019 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 Faust, our Chief Executive Officer, Dr. Chris Bowden, our Chief Medical Officer, Darren Miles, our Senior Vice President of U.S. Commercial and Global Marketing, and Andrew Hurst, our Chief Financial Officer and Head of Corporate Development. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statement as a result of various risks, uncertainties, and other factors, including those set forth in the risk factors section of our most recent Form 10-Q filed with the FCC and any other filings that we may make with the FCC.

With me on the call today was prepared remarks are dr., Jackie sell our Chief Executive Officer, Dr., Chris Bowden, Our Chief Medical Officer, Darren miles or senior Vice President of U.S. commercial global marketing and Andrew first our Chief Financial Officer, and head of corporate development before we get started I would like to remain.

And everyone that some of the statements. We make on this call will include forward looking statement actual events or results could differ materially from those expressed or implied by any forward looking statement out through the various risks uncertainties and other factors, including those set forth in that respect or section of our most recent form 10-Q filed with the assay.

C and any other filings that we may make with the FCC with that ill turn the call over to Jackie.

Jackie Faust: Thanks, Holly. Good morning, everyone, and thanks for joining us on our fourth quarter 2019 results call. I took on the role of CEO at Agios a year ago, and at the time, I was excited about the work the company does and our ability to make a meaningful difference in the lives of patients. Today, I'm even more excited about where we are as we go into 2020. I've spent the last 12 months listening and learning from my colleagues, supporting the execution of several notable firsts for the company, and evaluating ways to build on our past successes and further focus the business to create value for patients and all of our stakeholders. I have more confidence than ever about the quality of our science, the strength of our team, and our impressive portfolio of preclinical, clinical, and commercial programs that are truly differentiated.

Thanks Ali good morning, everyone and thanks for joining our fourth quarter 2019 results call.

I took on the role as CEO at all just a year ago and at the time I was excited about the work the company does and our ability to make meaningful difference in the lives of patients.

Today, I mean, I'm more excited with where we are as we go into 2020.

I've spent the last 12 month listening and learning from our colleagues supporting the execution of several notable first for the company and evaluating ways to build on our past successes and further focus the business to create value for patients and all of our stakeholders.

More confidence than ever about the quality of our science strengthen our team and our impressive portfolio were preclinical clinical and commercial programs that is truly differentiated.

Jackie Faust: It is with this excitement and confidence that we rolled out our 2025 Strategic Vision in January, sharing for the first time what the company could look like as our portfolio progresses over the next six years. By the end of 2025, we expect the company to have four marketed medicines, all discovered and developed at Agios, generating at least $1 billion in product revenue across at least eight indications across our three focus areas of hematologic malignancies, solid tumors, and rare genetic diseases. We'll have six or more molecules in the clinic, four of which will be entirely new molecules generated by our internal research discovery engine. And we will be cashflow positive within the six-year time frame. This long-term vision is built on the foundation of our 2019 achievements and our existing clinical and late-stage preclinical programs.

It is with the excitement in confidence that we rolled out or 2025 strategic vision in January sharing for the first time, what the company could look like it was our portfolio progress is over the next six years.

By the end of 2025, we expect the company to have a word marketed medicine.

All discovered and developed in Ontario, generating at least $1 billion in product revenue from at least eight indications across our three focus areas of hematologic malignancies solid tumors and rare genetic diseases.

We'll have six or more molecules in the clinic or of which will be entirely new molecules generated by our internal research discovery engine, and we will be cash flow positive within the six year timeframe.

This long term vision was built on the foundation of our 2019 achievements and our existing clinical in late stage preclinical programs within our base case plan. I also think we have tremendous optionality and an opportunity to potentially exceed our goal.

Jackie Faust: Within our base case plan, I also think we have tremendous optionality and an opportunity to potentially exceed our goals. Our steps on the path to 2025 are already underway with an ambitious set of objectives we've set for 2020 across our Malignant Hematology, Solid Tumor, and Rare Genetic Disease Program. In fact, this is one of the most compelling aspects of our six-year vision. We have significant milestone events occurring every year over the next six years. My colleagues will discuss our programs and objectives in more detail in a moment. But before I wrap up, I'd like to publicly welcome our new Chief Scientific Officer, Dr. Bruce Carr, who joined Agios last month. Bruce, together with his scientific leadership team, will be ushering the next wave of programs from research to the clinic to help us achieve our 2025 vision, and we're excited to have him on board during this pivotal time. We look forward to having Bruce join us on future results calls. With that, I now turn the call over to Chris to provide our clinical and regulatory update.

Our steps on the past 2025 are already underway with an ambitious set of objectives. We said for 2020 across our malignant hematology solid tumor and rare genetic disease programs.

In fact this is one of the most compelling aspects of our six your vision, we have significant milestone events occurring every year over the next six years.

My colleagues will discuss our programs and objectives in more detail in a moment.

Before I wrap up I'd like to publicly welcome our new Chief Scientific Officer, Dr., Bruce car, who joined all Geos last month.

Bruce together with his scientific leadership team will be assuring the next wave of programs from research to the clinic to help us achieve our 2025 vision and we're excited to have him onboard during this pivotal time.

We look forward to having Bruce join us on future results call.

With that I now turn the call over to Chris to provide our political and regulatory update.

Thanks Jackie.

Christopher J. M. Taylor: Underpinning our 2025 aspirations are multiple early and late stage clinical programs spanning hematologic malignancies, solid tumors, and rare genetic diseases, and in 2020, we aim to make meaningful progress across each of these therapeutic areas. I'll start with rare genetic diseases, where we expect to have several important milestones for our PKR activation program across three different hemolytic anemias in 2020. Our initial area of focus is pyruvate kinase deficiency, where midipivate activates a mutated PKR enzyme and has the potential to be the first disease-modifying therapy for this chronic anemia, which currently has no approved treatment option. We are conducting two pivotal studies of midipivate and PK deficiency. The ACTIVATE-T study is in regularly transfused patients, and the ACTIVATE study is in patients who do not receive regular transfusions. Enrollment is now closed in both studies, and we plan to share top-line data by the end of the year.

Underpinning our 2025 aspirations are multiple early and late stage clinical programs spanning hematologic malignancies solid tumors and rare genetic diseases, and then twentytwenty, we aim to make meaningful progress across each of these therapeutic areas.

I'll start with rare genetic diseases, where we expect to have several important milestones for our PK art activation program across three different hemolytic anemias and Twentytwenty.

Our initial area of focus is higher they kinase deficiency or made a pivot activates a mutated PK our enzyme and has the potential to be the first disease modifying therapy for this chronic anemia, which currently has no approved treatment options.

We are conducting two pivotal studies amid a pivot and PK deficiency.

The activate T study isn't right you don't really transfused patients and the activates studies in patients who did not receive regular transfusions.

Enrollment is now closed in both studies and we plan to share topline data by the ended the year.

In addition, we are moving forward with our plan to study met a pivot in pediatric PK deficiency patients.

Christopher J. M. Taylor: In addition, we are moving forward with our plan to study Mitopivet in pediatric PK deficiency patients. Through our regulatory interactions and advisory boards, we are confident in our ability to advance Medipivet in this patient population. And we expect to initiate a clinical trial in 2021. In 2019, we expanded the clinical application of Mitopivat to thalassemia and sickle cell disease, where it has the potential to provide therapeutic benefit by activating wild-type PKR. In December, we announced achievement of proof of concept in the ongoing Phase II thalassemia study where we demonstrated treatment with midipivet induced a hemoglobin response greater than or equal to a gram per deciliter in seven of eight evaluable patients. Additional data from this study, including data from patients without the thalassemia, in addition to Beta Thalassemia, will be submitted for presentation at the European Hematology Association Congress in June.

Through our regulatory interactions and advisory boards, we're confident in our ability to advance committed to that in this patient population and we expect to initiate a clinical trial 2021.

In 2019, we expanded the clinical application amid a pivot into fallacy Mia and sickle cell disease, where it has the potential to provide therapeutic benefit by activating the wild type PK are.

In December we announced achievement proof of concept in the ongoing phase two fellas EEMEA study, where we demonstrated treatment with mid appeared that induced to hemoglobin response greater than or equal to a gram per deciliter in seven of eight evaluable patients.

Additional data from this study, including data from patients with out the Alice EEMEA. In addition to beta thalassemia will be submitted for presentation at the European Hematology Association Congress in June.

Christopher J. M. Taylor: We are actively developing a pivotal strategy for midipivet and thalassemia, which we plan to finalize by the end of the year. In sickle cell disease, we are collaborating with Dr. Sui-Lei Chin at the National Institutes of Health for a proof-of-concept study under a Cooperative Research and Development, The goal of the study, which will enroll up to 25 patients, is to evaluate safety and tolerability, Changes in laboratory parameters, including reticulocytes and levels of hemoglobin, pharmacokinetics, and pharmacodynamic markers, such as levels of 2,3-DPG and ATP, as well as tickling and red blood cells.

We are actively developing a pivotal strategy permitted to that that was senior which we plan to finalize by the end of the year.

And second sell disease, we are collaborating with doctors, we laid Chen at the National Institutes help for a proof of concept study under a cooperative research and development agreement.

The goal of the study, which will enroll up to 25 patients is to evaluate safety and tolerability.

Changes in laboratory parameters, including ridiculous sites in levels of hemoglobin pharmacokinetics and Pharmacodynamic markers such as levels in two three DPG and ATP as well as signaling in red blood cells.

Christopher J. M. Taylor: Enrollment is going well, and we expect Dr. Tian to submit data from this study for presentation at EHOM. Beyond Amidipivat, we have developed a next-generation PKR activator, AG946, and plan to submit the investigational new drug application this quarter. Once the IND has cleared, we will initiate a study in healthy volunteers in the second quarter.

Enrollment is going well and we expect Dr. agendas submit data from this study for presentation Uh Huh.

Beyond the made a pit that we have developed the next generation PK, our activator AG 946 and plan to submit the investigational new drug application this quarter.

Once the I Andy has cleared we will initiate a study in healthy volunteers in the second quarter.

Moving to hematologic malignancies, we made rapid progress over the last several years, securing U.S. approval for Tim So by monotherapy and IDH, one you relapse refractory frontline AML well generating important data from the phase one study combining tips of always standard of care frontline therapy.

Christopher J. M. Taylor: Moving to hematologic malignancies, we've made rapid progress over the last several years securing U.S. approval for TIBSOVA monotherapy in IDH1 mutant, relapsed refractory, and frontline AMs, while generating important data from the Phase I studies combining TIBSOVA with standard-of-care frontline therapy. The next phase of TIBSOVA development is focused on global label The Phase III Agile Study of TIBSOVO in combination with azacitidine and the HOVON-150 study of TIBSOVO and IDFA in combination with standard induction and consolidation chemotherapy both continue to enroll patients. In the EU, we have submitted our day 120 responses for our tensovo filing and relapse-refractory AML, and we are now waiting on the list of outstanding items from the European Medicines Association. The EMA recently disclosed that Celgene BMS withdrew the ID for marketing authorization application because the single-arm phase one trial did not fully address the major objections raised by the CHMP to support a positive benefit risk assessment for the proposed indication.

Yes.

The next phase of himself with development is focused on global labels in frontline combination setting, which will allow us to reach the largest number of AML patients with an IDH one mutation.

The phase three agile study of TEMCELL Boe in combination with they decided deep in the home on 150 study of himself an idea in combination with standard induction and consolidation chemotherapy, both continue to enroll patients.

In the EU, we have submitted our day 120 responses for our team so filing and relapse refractory AML.

And now are now waiting on the Navy list of outstanding items on the European Medicines Association.

The EMA recently disclosed at Celgene BMS withdrew the I'd for marketing authorization application because the single arm phase one trial did not fully address the major objections raised by the CHF <unk> to support a positive benefit risk assessment and the proposed indication.

Our goal remains to make.

Christopher J. M. Taylor: Our goal remains to make TIBSOVO available to patients in Europe, and we continue to move our MAA through the EMA review process. Outside of AML, we are advancing TIBSOVO development and myelodysplastic syndrome, and recently reopened the MDS arm of the Phase I study in IDH1 mutant hematologic malignancy. We have increased the trial size to a maximum of 25 MDS patients and expect to complete enrollment by the end of the year. TIPSOVA received breakthrough therapy designation in this indication, and our goal is to generate sufficient data from the expanded Phase I arm to pursue a potential U.S. regulatory filing in MDS. Lastly, the Phase I study of AG636, our DHODH inhibitor, in advanced lymphoma continues to enroll patients. We plan to have sufficient data by the end of the year to determine the next steps for this program.

Himself available to patients in Europe, and we continued to move our an a. through the E M. A review process.

Outside of and now we're advancing himself or development and Myelodysplastic syndrome recently reopened the M.D.S. arm phase one study an IDH one mute hematologic malignancies.

We have increased the trial size or a maximum 25, mds patients and expect to complete enrollment by the ended the year.

Silva received breakthrough therapy designation in this indication and our goal is to generate sufficient data from the expanded phase one arm to pursue a potential U.S. regulatory filing in Mds.

Lastly, phase one study of AG Sixthree six hour D. H O DH inhibitor in advance lymphoma continues to enroll patients.

We plan to have sufficient data by the ended the year to determine the next steps for this program.

For solid tumors and 2019, we established a utility of IDH inhibition in treating solid tumors with the positive read out of the clarity phase three study of tip Sobo previously treated IDH, one you cholangio carcinoma.

Christopher J. M. Taylor: For solid tumors, in 2019, we established the utility of IDH inhibition in treating solid tumors with a positive readout from the Clarity Phase III study of TIPSOVO in previously treated IDH1 mutant cholangiocarcinoma. The study showed that Tibsovo reduced the risk of disease progression or death by 63%, with significant improvement in landmark analyses for PFS at 6 and 12 months. Mature overall survival data from the CLARITY study is expected in mid-2020, and we plan to submit a supplemental new drug application including these data by year end. As we shared in January, our phase 3 indigo study of voracidinib, our brain penetrant pan-IDH inhibitor, in low-grade glioma was initiated at the end of 2019. The team is currently focused on site activations for this global study.

The study showed that himself will reduce the risk of disease progression or death by 63% with significant improvement and landmark analyses for PFS at six and 12 months.

Mature overall survival data from the clarity study is expected in mid 2020, and we plan to submit a supplemental new drug application, including these data by year end.

As we shared in January our phase three Indigo study, a Boris I hadn't had our brain penetrant Pan IDH inhibitor and low grade Glioma was initiated at the end of 29 team.

The team is currently focused on site Activations for this global study.

Christopher J. M. Taylor: Our other solid tumor program is a MAP2A inhibitor, AG270, and it's currently being evaluated in combination with standard of care taxanes in two arms of a phase one study, one in non-small cell lung cancer and the other in pancreatic. Over the next two years, we aim to gather sufficient clinical data in these two patient populations to see if we can replicate the impressive synergy between AG270 and taxanes that we demonstrated I will now turn the call over to Darren to discuss our commercial performance. Thanks, Gregory.

Our other solid tumor program as a matter to weigh inhibitor AG 270, and is currently being evaluated in combination with standard of care Taxane and two arms of a phase one study one in non small cell lung cancer and the other in pancreatic cancer.

Over the next two years, we aim to gather sufficient clinical data and these two patient populations to see if we can replicate the impressive synergy between AG 270, and Taxanes that we demonstrated preclinically and these indications.

I will now turn the call over to Darren to discuss our commercial performance.

Thanks, Chris I'm pleased to share fourth quarter 2019 results as well as our first full year product revenue since launch in mid 2018.

Darren Miles: Thanks, Chris. I'm pleased to share our fourth quarter 2019 results as well as our first full year of product revenue since launch in mid 2018. In the fourth quarter, we recorded $20 million in net sales of TIPSOVO, bringing total 2019 TIPSOVO net sales to $60 million. Fourth quarter growth was largely driven by continued uptake in both the relapsed or refractory and frontline AML settings and continued expansion of the unique prescriber base by 15% over Q3. Our market research continues to show that tipsova-containing regimens are the most preferred treatment for newly diagnosed and first relapse AML patients with an IDH1 mutation.

Fourth quarter, we recorded $20 million of net sales of civil bringing total 2019 tips on net sales to $60 million.

Fourth quarter group was largely driven by continued uptake in both the relapsed or refractory and frontline AML settings, and continued expansion of the unique prescriber base by 15% over Q3.

Our market research continues to show the chip silver containing regimens are the most preferred treatment for newly diagnosed and first relapse CML patients with an IDH mutation.

Looking ahead, we guided to 2020 U.S. tip civil net sales of $105 million to $115 million, which represents an approximate 80% increase at the midpoint of our range over 2019.

We expect to see continued growth in both the newly diagnosed and relapsed refractory settings to.

To date, the largest driver revenue growth is increasing treatment duration, which were observing across both the ml labels, though not promoted by our team roughly half of both newly diagnosed and relapse refractory patients treated with them. So both are treated in combination primarily with Hypomethylating agent.

Darren Miles: Looking ahead,

Darren Miles: We've guided to 2020 U.S. tipsovo net sales of $105 to $115 million, which represents an approximate 80% increase at the midpoint of our range over 2019. We expect to see continued growth in both the newly diagnosed and relapsed refractory setting. To date, the largest driver of revenue growth is increasing treatment duration, which we're observing across both AML labels. Though not promoted by our team, roughly half of both newly diagnosed and relapsed refractory patients treated with Tipsovo are treated in combination primarily with a hypomethylating agent.

We anticipate this will continue to have a positive impact on average duration, which we expect to settle close to the five month Mark by the end of 2020.

Moving to rare genetic disease, our teams expanding our pre launch efforts in anticipation of the potential approval admitted Tibet late next year as we shared in January we've already identified approximately 1000 PK deficiency patients in the U.S. any you five and we continue to work on driving patient identification, increasing disease awareness and proving testing for this series.

Chronic anemia.

Andrew Scott Berens: We anticipate this will continue to have a positive impact on average duration, which we expect to settle close to the five-month mark by the end of 2020. Moving to rare genetic diseases, our team is expanding its pre-launch efforts in anticipation of the potential approval of midipivat late next year. As we shared in January, we've already identified approximately 1,000 PK deficiency patients in the U.S. in EU5, and we continue to work on driving patient identification, increasing disease awareness, and improving testing for this serious chronic anemia. This work is driven by our existing global medical affairs and marketing. And over the course of 2020, we'll begin to build a modest field team to support our market development. I want to thank the tremendous team at Agios who have been the driving force behind our success in 2019 and laid the foundation to support many more patients in 2020. I'll now turn the call over to Andrew to discuss our fourth quarter financials.

This work is driven by our existing global Medical affairs, and marketing teams and over the course of Twentytwenty will begin to build a modest fuel team to support our market development efforts I.

I want to thank the tremendous team at all Geos had been the driving force behind our success in 2019 and leave the foundation to support many more patients in 2020, I'll now turn the call over the Andrew to discuss our fourth quarter financials. Thanks, Darren our fourth quarter and full year financial results can be found in the press release, we issued this morning, which I will summarize.

More detail will be included in our 10-K filing next week.

Total revenue for the fourth quarter was $35 million, bringing total revenue for the full year 2019, so $118 million, an increase of $23.5 million compared to 2018.

Product sales of several grew $46 million year over year offset by a decline in collaboration revenue due to the recognition of a milestone from celgene and the upfront payment from system totaling $27 million.

Cost of sales for the fourth quarter was $287000 and $1.3 million for the full year 2019.

Andrew Scott Berens: Thanks, Darren.

Turning to operating expenses R&D for the fourth quarter was $106 million and $411 million for the full year 2019, an increase of $70 million compared to the full year 2018.

Andrew Scott Berens: Thanks, Darren. Our fourth quarter and full year 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 next week. Total revenue for the fourth quarter was $35 million, bringing total revenue for the full year 2019 to $118 million, an increase of $23.5 million compared to 2018. Product sales of Tibsovo grew $46 million year over year, offset by a decline in collaboration revenue due to the recognition of a milestone from Celgene and the upfront payment from Seastone, totaling $27 million. Cost of sales for the fourth quarter was $287,000 and $1.3 million for the full year 2019. Turning to operating expenses, R&D for the fourth quarter was $106 million and $411 million for the full year 2019, an increase of $70 million compared to the full year 2018.

The year over year increase in R&D was largely driven by clinical trial activity for me to pivot and PK deficiency and Falcigno.

Startup cost for the fourth side and the phase three indigo study in low grade glioma as well as required clinical pharmacology studies and companion diagnostic work.

Ongoing recruiting efforts and that's himself phase three adrenalin Hove on frontline AML combination studies and ongoing research efforts across our discovery platform programs.

Selling general and administrative expenses were $35 million for the fourth quarter and $132 million for the full year 2019.

This represents an $18 million increase over full year 2018, driven primarily by increased investment in marketing activities in preparation for the potential launch a bit of Tibet and personnel costs related to increased headcount to support our growing operations.

We ended the quarter with cash cash equivalents and marketable securities of $718 million.

We expect that this cash balance in addition to expected product revenue royalties and anticipated expense reimbursements under our collaboration and license agreements, but excluding any additional collaboration related payments will fund our operating plan through at least the end of 2021.

Andrew Scott Berens: The year-over-year increase in R&D was largely driven by clinical trial activity for Mitopivat in PK deficiency and thalassemia, startup costs for the voracidinib phase 3 indigo study in low-grade glioma, as well as required clinical pharmacology studies and companion diagnostic work, ongoing recruiting efforts in the TIBSOVO, Phase III Agile, and HOBON frontline A Selling General and Administrative Expenses were $35 million for the fourth quarter and $132 million for the full year 2019. This represents an $18 million increase over full year 2018, driven primarily by increased investment in marketing activities in preparation for the potential launch of Medipivad and personnel costs related to increased headcount to support our growing operation. At the end of the quarter, we had cash, cash equivalents, and marketable securities of $718 million. We expect that this cash balance, in addition to expected product revenue, royalties, and anticipated expense reimbursements under our Collaboration and License Agreement, but excluding any additional collaboration-related payments, will fund our operating plan through at least the end of 2021.

With that operator, please open the line for questions.

Thank you, ladies and gentlemen, easy I've a question at this time just press star in the normal wonky of your touched on telephone.

To withdraw your question press the pound key please standby we've compiled <unk> roster.

And our first question is from Mohit Bansal with Citi.

Great. Thanks for taking my questions and congrats on the progress a couple of questions from my side.

<unk> is on your it's all European filing.

Would you. Please help us understand is there anything different with it so what's his idea.

Which would make couldn't give us a little bit more confidence that its syllable filing has enough data to satisfy your me at this point and then I have a commercial question.

Thank you.

I know, it's Chris Bowden here. Thanks for your question.

So I think there are some pretty important differences between.

The undecided NIM dataset in our approach and what we're doing it too so.

From the Celgene BMS perspective, they decided to withdraw after.

Not being able to fully meet the questions and from the M&A from the EMA. They also have a phase III study and relapse refractory.

Operator: With that said, operator, please open the line for questions. Thank you. And ladies and gentlemen, if you have a question at this time, just press the star and the number one key of your touchtone telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. And our first question is from Mohit Bansal with CDC. Great, thanks for taking my questions, and congrats on the progress. A couple of questions from my side. One is on your Dibsovo European filing. Could you please help us understand, is there anything different with TIPSOVO versus IDESA that could give us a little bit more confidence that the TIPSOVO filing has enough data to satisfy EMA at this point? And then I have a commercial question.

Disease in India indication, they're seeking so their view was they would withdraw the application and then reconsider what to do once they have the readout from identified.

So that's a pretty important aspect because the frequency of the IDH. One mutation is pretty low overall and then when you start to cut that down in the relapse refractory disease. One of things that we found out pretty early on that doing a randomized trial was not feasible.

So our arguments in terms of Howard framing. This is that this is the best dataset that we're going to get in this rare patient population.

And therefore, given the unmet need and the fact that these patients have used up all they really don't have any other treatment options. We think we have a different and strong argument there and there are some other other important aspects of this submission that we're emphasizing as well we've been able to go in and tap real world data outcomes.

Christopher J. M. Taylor: Hi Mohit, it's Chris Bowden here. Thanks for your question. So I think there are some pretty important differences between the endocytinib data set and our approach and what we're doing with Tidsobo. So from the cell gene BMS perspective, they decided to withdraw after not being able to fully meet the questions from the MAA and from the EMA. They also have a phase three study in relapsed refractory disease in the indication they're seeking. So their view was they would withdraw the application and then reconsider what to do once they had the readout from identity.

From a number of European data centers, and we think that can play a pretty important role in terms of ascertaining the risk benefit and then one other aspect that we think is pretty important news that there's some.

Data, indicating that IDH, one mutations have a poor prognosis and certainly patients with IDH, one mutation seem to do worse in patients with IDH mutation in the relapse refractory setting overall so.

That's not to say that it's not a challenge when you submit a non randomized data set to the European but we think there's some important differentiators and that's why we're pushing forward and and remain optimistic that we're going to have a positive outcome, but we'll see that as we move through the process and as we've guided you previously we don't expect the decision until the second half of the year.

Christopher J. M. Taylor: So, that's a pretty important aspect because the frequency of the IDH1 mutation is pretty low overall. And then when you start to cut that down in relapse-refractory disease, one of the things that we found out pretty early on that doing a randomized trial was not feasible. So our arguments in terms of how we're framing this are that this is the best data set that we're going to get in this rare patient population. And therefore, given the unmet need and the fact that these patients have used up all their options, they really don't have any other treatment options, we think we have a different and strong argument there. There are some other important aspects of this submission that we're emphasizing as well.

Got it and then because they had and then on the east side I think that and you mentioned that you have about thousand patients identified.

So the one part is can you help us understand how much is this U.S. <unk> Europe, and what sort of challenges do you see got good the details into 8000 patient box you are.

Thank you very much.

Absolutely absolutely so it's roughly half and half between us and an ex us the majority of actually west being in.

Christopher J. M. Taylor: We've been able to go in and tap real-world data outcomes from a number of European data centers, and we think that could play a pretty important role in terms of ascertaining risk benefit. And then one other aspect that we think is pretty important is that there's some data indicating that IDH1 mutations have a poor prognosis, and certainly, patients with IDH1 mutations seem to do worse than patients with IDH2 mutations in the relapsed refractory setting overall. So that's not to say that it's not a challenge when you submit a non-randomized data set to the Europeans, but we think there are some important differentiators, and that's why, We'll see that as we move through the process, and as we've guided you previously, we don't expect a decision until the second half of the year.

And you five the the I think that's the challenge always with with disease on this end of the rare disease spectrum is getting a from hand on the on the actual.

Prevalence number so the reason that we're increasing our field. Our field team is to is to focus more effort on being able to accelerate that like we've been successful over the last over the last year plus.

We expect to accelerate that quite a bit over the course of 2020 and expect them to have a to be able to adopt document perhaps twice the number by the time, we get to approval.

Approval at the end of are up 21.

Thank you.

Thank you. Our next question comes from Kennen Mackay with RBC capital.

Hi, Thanks for taking the questions and congrats on the quarter and the execution or maybe one for Chris first and then a follow up for Jakone standard for our Chris on on Mds and the breakthrough designation there for some sort of both committed help us a little bit on the timelines associated with the phase one expansion potential.

Darren Miles: And then, this is very helpful, and then on the PKD side, I think, Darren, you mentioned that you have about 1,000 patients identified, so one part is, can you please help us understand how much this is the U.S. versus Europe, and what sort of challenges do you see to get to the 3,000 to 8,000 patient marks you are citing in your slide? Thank you very much.

So registration filing there and also when that data.

Could be presented a then for Jack and Andrew I loved the.

Babe Ruth style point and I have to bleachers from the 1 billion guide by 2025.

Darren Miles: Absolutely, absolutely. So it's roughly half and half between the U.S. and the ex-U.S., the majority of the ex-U.S. being in EU5. I think the challenge with diseases on this end of the rare disease spectrum is always getting a firm hand on the actual prevalence numbers. So the reason that we're increasing our field team is to focus more effort on being able to accelerate that. We've been successful over the last year plus, and we expect to accelerate that quite a bit over the course of 2020 and expect then to be able to document perhaps twice the number by the time we get to approval at the end of 2020.

Can you give it maybe give us a little bit of background on the decision to put that aspirational figure out there and also help us with sort of speak the contribution of components of that figure thanks, and congrats again.

Okay, Hey, Ken it's Chris here.

So we're we're in that all important phase of getting sites up and running and moving the amendment through because many of the sites that.

I've been participating in that that important though a one study for us are just going to reactivate that amendment with the FDIC cohort in there. So that's a really key part of what we're doing at this point.

Christopher J. M. Taylor: Thank you. Our next question comes from Kenan MacKay with RBC Capital. Hi, thanks for taking the questions and congratulations on the quarter and the execution.

And so so that operational aspect as well as the kinetics of patients coming in and being identified and getting and try and onto the trial, who really determined the timeline and when we can publish data.

Christopher J. M. Taylor: Maybe one for Chris first and then a follow-up for Jackie and Andrew. For Chris, on MDS and the breakthrough designation there for PITSOBO, could you maybe help us a little bit on the timelines associated with the Phase I expansion and the potential for registration filing there and also when that data could be presented? And for Jackie and Andrew, I love the Babe Ruth-style pointing at the bleachers and the one billion guide by 2025. Can you maybe give us a little bit of background on the decision to put that aspirational figure out there and also help us with, so to speak, the contribution of each component of that figure? Thanks and congrats again.

People are pretty comfortable with.

Certainly using 10, so vote in in Mds, but I will remind you that the frequency of the mutations around 1% to 3%.

So we're optimistic we'll be able to accrue by the end of year and as we get a close as we get more.

Confidence around that that war and your progress is that will give us some sense of when we can publish and talk about the data, which we're really looking forward to doing.

Hi, Ken and things for the question I Didnt play both fast pitch and follow up I mean, Oh, yeah fast pigeons hopefully it's also the analogy is a good one I guess I'm so the with with the vision on the whole, including though the 1 billion at least of revenue we.

Christopher J. M. Taylor: Okay. Hey, Ken. It's Chris here.

Christopher J. M. Taylor: So, we're in that all-important phase of getting sites up and running and moving the amendment through because many of the sites that I've been participating in that important study for us are just going to reactivate that amendment with the MDS cohort in there. So that's that's a really key part of what we're doing at this point. And so it is so that.

In 2025 bought 125, we wanted to put some stakes in the ground is not only around the revenue, but it's also around indications that we could be and a number of programs that will be in the clinic and the reason why we wanted to put that out there is it because we see the potential to achieve those things with assets that we have in our hands now.

Christopher J. M. Taylor: The operational aspects as well as the kinetics of patients coming in and being identified and getting under the trial will really determine the timeline and when we can publish data. I think people are pretty comfortable with using TIBSOBO in MDS, but I will remind you that the frequency of the mutation is around one to three percent. So we're optimistic we'll be able to approve it by the end of the year. And as we get more confidence around that, and as the year progresses, that'll give us some sense of when we can publish and talk about the data, which we're really looking forward to.

Now that are either on the market already so talking about himself <unk> or in the clinic. So these are or de risk assets by some definition of de risking when we think about the revenue a number in particular that includes a substantial contribution from the ongoing evolution of chips, although in email.

I would also include Cholangio and that would start to include some revenues in T.K. de from mid appear that most importantly, I think what it does not include would be Celsion me sickle cell disease.

Jackie Faust: Hi, Kenan. Thanks for the question. I did play both fast pitch and slow pitch softball. I mean, yeah, fast pitch and slow pitch softball. So the analogy is a good one, I guess.

Glioma, because all of those in our assumptions are very late in that six year timeframe and we have not assumed anything in there for the potential to negotiate something with personal around ideas I just to make that are very very clear.

Jackie Faust: So, with the vision on the whole, including the $1 billion, at least, of revenue, in 2025, by 2025, we wanted to put some stakes in the ground. Not only around the revenue, but it's also around the indications that we could be in, the number of programs that will be in the clinic. And the reason why we wanted to put that out there is because we see the potential to achieve those things with assets that we have in our hands now that are either on the market already, so talking about TIPSOVO, or in the clinic. So these are de-risked assets by some definition of de-risking. When we think about the revenue number in particular, that includes a substantial contribution from the ongoing evolution of TIPSOVO and AML.

Thank you very much.

Thank you and our next question comes from Alethia Young with Cantor.

Hey, guys. Thanks for taking my question Congrats on the progress over the past couple of months maybe.

Maybe to for me. Following this trend I'm can you maybe help us thinking about the differences between alpha and beta thal. Unlike maybe you know is there any kind of rationale to believe that because he should be different in one versus the other and then you know the other one probably is forgive me I. Just wanted you to kind of sounds about a year I'm just kind of reflect on how you think about where.

This is like R&D organization was a year ago, when you join versus where you're taking it in sort of maybe we have a love.

You know thoughts on about your potential your new hire see us out as well. Thank you.

Jackie Faust: It would also include Colangio, and it would start to include some revenues in PKD from Mitopivat. Most importantly, I think what it does not include would be thalassemia, sickle cell disease, and glioma because all of those in our assumptions are very late in that six-year time frame, and we have not assumed anything in there for the potential to negotiate something with Bristol around IDFA just to make that very, very clear

Okay and leave PS, Chris I'll go first.

Yeah, the there's the genotype and some of the molecular distinctions around that we'll see me out that they can be important in terms of clinical outcomes and potentially a molecular approach.

From our perspective, given that were activating wild type PK, our it and looking to improve overall red cell how.

We would I would say that we're likely to see we don't think there should be discernible differences, but that's one of the reasons why we're enrolling those patients and we have a number who have come in now because we need to answer that question I think what is the key distinction for fallacy me as likely to remain in our view of transfusion dependent versus non.

Christopher J. M. Taylor: Thank you very much. Thank you. And our next question comes from Alicia Young with Cantor.

Operator: Hey guys, thanks.

Not regularly transfused those are really important clinical regulatory pieces.

Christopher J. M. Taylor: Congratulations on the progress over the past couple months, maybe two for me since we're following this trend. Can you maybe help us think about the differences between Alpha and Beta Thal and, like, maybe, there is any kind of rationale to believe the efficacy should be different in one versus the other? And then, you know, the other one probably is for Jackie.

And and the Alfalfa Simi apart for US is is at this time a point of differentiation because most of the data clinical data that's been generated from other molecules out there has been a beta thalassemia and clinicians have told US. This is an important group as well because they do fall into both of these categories on transfer.

Christopher J. M. Taylor: I just wanted you to kind of, since it's been a year, just kind of reflect on how you think about where...

Asian, and transfusion and that and have a high unmet medical need given their underlying disease process.

Operator: Thank you.

Christopher J. M. Taylor: Okay, Alethea. It's Chris. I'll go first.

[noise] highly yeah. So thanks for the question on R&D and our new S.U.S., how we're very excited about where we are with things I think I'm very high level I would just like to point out that of our.

Christopher J. M. Taylor: You know, there's the genotype and some of the molecular distinctions around thalassemia that can be important in terms of clinical outcomes and potentially a molecular approach. From our perspective, given that we're activating wild-type PKR and looking to improve overall red cell health, I would say that we're likely to see, we don't think there should be discernible differences, but that's one of the reasons why we're enrolling those patients, and we have a number who have come in now because we need to answer that question. I think the key distinction for thalassemia is likely to remain, in our view, of transfusion-dependent versus not regularly transfused, so those are really important clinical regulatory pieces. And the alpha-thalassemia part, for us, is, at this time, a point of differentiation; most of the data, clinical data that's been generated from other molecules out there has been in beta thalassemia, and clinicians have told us this is an important group as well because they

Roughly 550 employees about 400 of those are spread across now what we call our rds or a research discovery I Sciences group and our clinical group. So that shows you what the emphasis is that we have here on a boat early and.

Early research in late stage clinical development and that has not changed I think if we go back and looked at the track record of Oh Gee I was in terms of bringing innovative science to the diseases that we're targeting to treat we've brought IDH inhibition to team into logic malignancies and now into solid.

Tumors and now we're bringing our PK our activation of science, along with mid a pivot and the next generation non were six molecule that will follow the I Andy on it soon and those are tremendous accomplishment. So when we talk about this platform in cellular metabolism.

A company certainly has delivered on that we'll continue to deliver on that and I think we're doing that in a very focused way. We you know innovation comes in waves will all of you wants to move faster, yes. He will do we yes, we do we want to that with quality, but I think it that's again back to the <unk>.

Christopher J. M. Taylor: , and clinicians

Christopher J. M. Taylor: and have a high-end medical need given their underlying disease.

Jackie Faust: Hi Alethea, so thanks for the question on R&D and our new CSO. We're very excited about where we are with things. At a very high level, I would just like to point out that of our roughly 550 employees, about 400 of those are spread across what we call our RDS, or Research Discovery Sciences, group and our clinical group. So that shows you what the emphasis is that we have here on both early and early research and late stage clinical development, and that has not changed. I think if we go back and look at the track record of Agios in terms of bringing innovative science to the diseases that we're targeting to treat, we've brought IDH inhibition to hematologic malignancies and now into solid tumors, and now we're bringing our PKR activation science along with Mitopivot and the next generation 946 molecule that will follow the IND on soon, and those are tremendous accomplishments We, you know, innovation comes in waves. Will all of you want us to move faster? Yes, you will.

A question about between 25 vision one of the reasons why we want to put some spikes in the ground is we've made a lot of investments up to this point in where we are with the portfolio. I think we're just in a terrific oh position to deliver some amazing things for patients and some great thing our business model over the next.

Six years, when Scott Biller joined the company almost a 10 years ago and I think we thank Jim on the last call that Oh, we had there were a handful sciences here that Rts team now led by Bruce has about 160 to 170, a internal Adriano employees and I think Scott did a terrific.

John one of the things that he did was institutionalized some of the ways that we prosecute the science here and he built a great team and now we're very much looking forward to a Bruce is fresh center buys on things and the contributions and experiences based is that he's going to bring so I think it's.

It's quite I, an amazing achievement to have put we're about to put our eight molecule internally discovered in to the I Andy filing and.

Jackie Faust: Do we? Yes, we do. We want to do that with quality, but I think that's again back to the question about the 2025 vision. One of the reasons why we wanted to stake some ground is that we've made, you know, a lot of investments up to this point, and where we are with the portfolio, I think we're just in a terrific position to deliver some amazing things for patients and some great things for our business model over the next six years. When Scott Biller joined the company almost ten years ago, and I think we thanked him on the last call that we had, there were a handful of sciences here that the RDS team, now led by Bruce, has about 160 to 170 internal Agios employees, and I think Scott did a terrific job.

Everything that we've got in that isn't out to 2025 as internally discovered and Adriano said, we want to continue to build on the things that were really good at do that maybe a little bit more focus on a go forward basis even.

Thank you.

Thank you.

Our next question comes from I know Palm Rama with JP Morgan.

Hi, guys. Thanks for taking my question.

Two quick ones for me core from.

Hmm Forsake you know how are you thinking about the long term PK, our franchise and maybe remind us of any pharmacologic differences between 9.6 admitted pit that and we doubt senior sickle cell coming mid year. How are you thinking about the long term development of 9.6, and then a quick one just a clarification.

Jackie Faust: One of the things that he did was institutionalize some of the ways that we do science here, and he built a great team, and now we're very much looking forward to Bruce's fresh set of eyes on things and the contributions and experience base that he's going to bring. So I think it's quite an amazing achievement to have put, we're about to put our eighth molecule internally discovered into the IND filing, and everything that we've got in that vision out to 2025 is internally discovered at Agios, and we want to continue to build on the things that we're really good at and do that maybe with a little bit more focus on a go-forward basis.

Points in the press release is very specific about felt senior data being at EEI, Jay but sickle cell was noted to be midyear. So should we think about the sickle cell so update sort of outside of the scope of the conference at this point.

Thanks, so much.

And upon its Chris here, Thanks for the question.

We anticipate and you should that sickle cell data will be showing it so it's a double feature.

Fallacy man sickle cell the sickle cell trial as we stated is is sponsored through a credit agreement with the NIH. So.

The they'll be lubi, certainly collaborating them and providing with input, but it's an investigator sponsored study if you will.

Operator: Thank you. The next question comes from Anupam Rama with J.P. Morgan. Hey guys, thanks for taking the question. Just two quick ones from me. For AG946, you know, how are you thinking about the long-term PKR franchise and maybe remind us of any pharmacologic differences between 946 and mid-epivad and, with thalassemia sickle cell coming mid-year, how are you thinking about the long-term development of 946? And then, just a clarification point. So the press release is very specific about the thalassemia data being at EHA.

So now then nine four cents of particularly interesting.

Clinical development, a meal issue for us because we've got a drug admitted to that knowledge and in the clinic for several years. When we provided the community with updated data at Ash from drive PK and looking at stability of hemoglobin in safety.

So now along comes our follow on molecule as United for six and out what decisions and how do we think about the next wave of development for that molecule should it yet.

Pass muster in healthy volunteers and have a safety profile and and other aspects that make it day compelling option to move forward into clinical development.

Christopher J. M. Taylor: but sickle cell was noted to be mid-year, so should we think about the sickle?

Christopher J. M. Taylor: [inaudible] Thanks so much.

So that really looking across all three diseases will need to think about that and then that gets into somebody's pharmacological differences that you've asked me to comment on so entirely kinase deficiency.

Christopher J. M. Taylor: And if I'm Chris here, thanks for the questions. We anticipate, and you should expect, that the sickle cell data will be shown at EHA. So it's a double feature: Thalassemia and Sickle Cell. The Sickle Cell trial, as we stated, is sponsored through a CRADA agreement with the NIH, so we'll certainly be collaborating with them and providing input, but it's an investigator-sponsored study. So, now then, 946, a particularly interesting clinical development issue for us because we've got a drug, imidapivac, now that's been in the clinic for several years, and we provided the community with updated data So now, along comes our follow-on molecule, AG946, and what decisions and how do we think about the next wave of development for that molecule, should it pass muster in healthy volunteers and have a safety profile and other aspects that make it a compelling option to move forward in clinical development across all three diseases? So that's really looking across all three diseases. We'll need to think about that.

The drug has the potential to have a broader spectrum of action against some of the mutations that are missense mutations.

That made a pill that hasn't been active again, so it could broaden the spectrum of activity.

There are some other aspects that we think it may have potential to be once daily dosing and be a more potent activator of wild type. So that would then daily dosing could be a convenience factor across all three indications in a more pad activator of wild type could translate to some increase efficacy is should we.

Whether it's in Dallas him, yet or sickle cell, if we demonstrate proof of concept there.

What the ultimately what the steps are and how you develop it.

As a follow on replacing what have you really is way too early to go there and I'm like I have we say over time it would it would be a data driven decision combined with is met a pit that looked like a need any of these indications at given point in time and you start to make some of these decisions how is the market evolving.

Christopher J. M. Taylor: And then that gets into some of these pharmacological differences that you've asked me to comment on. So in pyruvate kinase deficiency, the drug has the potential to have a broader spectrum of action against some of the mutations that are missense mutations that have made a pivot and haven't been active again. So it could broaden the spectrum of activity. There are some other aspects that we think it may have the potential to be once daily dosing and be a more potent activator while, So that would then be a convenience factor across all three indications and a more potent activator of wild type. Could translate to some increased efficacy, whether it's in thalassemia or sickle cell, if we demonstrate proof of concept there.

So I hope of flow of thing.

Nice to have options yes.

Hi, Thanks for taking my questions.

Thank you Sir our next question comes from Alexandre Duncan with Piper Sandler.

Hi, Thanks for the question just wanted to ask a follow up questions. Your thoughts on working with the DNA. So does the idea.

Hey situation changed your thoughts on how to approach pipeline development and oncology and the way you maximize the ex us opportunities.

Hi, just Chris here I'll I'll take that one.

I don't think so in this sense that.

When we put the IDH inhibitors into the clinic back in 2013 in 2014.

We saw immediate evidence of clinical benefit.

In a very high unmet need population.

And if with both of those molecules I'd fun too so.

Christopher J. M. Taylor: Ultimately, what the steps are and how you develop it as a follow-on, a replacement, what have you, really is way too early to go there. And like we say all the time, it would be a data-driven decision combined with, what does meta-PIVOT look like, any of these indications at a given point in time, and you start to make some of these decisions, how is the market evolving, just a hope.

We stated we did move very quickly because our interactions with the FDA with investigators around the world indicated this was a therapy that could change patient outcomes in the relapse refractory setting and that it had the potential to improve clinical benefit dramatically for.

20% in patients with AML, if you combine I'd been Tim So, though IDH frequency overall, so those are the underlying drivers.

Operator: [inaudible]

Christopher J. M. Taylor: Great, thanks for taking our question.

Christopher J. M. Taylor: Our next question comes from Alexander Duncan with Piper Sandler. Hey, thanks for the question. Just wanted to ask a follow-up question to your thoughts on working with the EMA. So does the IDPA-MAA situation change your thoughts on how to approach pipeline development in oncology in the way you maximize ex-U.S. opportunities?

Do we understand that when you take a non randomized single line dataset into other parts of the world that you will encounter some significant challenges more so than the challenges we encountered in our submission in the U.S. with FDA of course, we do we do.

Christopher J. M. Taylor: It's Chris here. I'll take that one. I don't think so, in the sense that when we put the IDH inhibitors into the clinic back in 2013 and 2014, we saw immediate evidence of clinical benefit in a very high-end MET need population and with both of those molecules, IDFA and TIBSOVO. We stated, and we did move very quickly, because our interactions with the FDA and with investigators around the world indicated this was a therapy that could change patient outcomes in the relapse-refractory setting and that it had the potential to improve clinical benefit dramatically for 20% of patients with AML if you combined IDFA and Tibsovo IDH frequency overall. So those are the underlying drivers. Do we understand that when you take a non-randomized, single-arm dataset to other parts of the world, you will encounter some significant challenges, more so than the challenges we encountered in

Good way back when take a oh look very carefully or should we do a randomized trial and relapse refractory IDH one AML patients. We we looked at a really hard and we said this isn't feasible the best use of our resources and the chance to have the greatest impact for patients in the front line side. So.

That's how we focused and I would guess qualitatively we would do at the same thing all over again and when these opportunities come up we'll continue to operate the sway.

Great. Thank you.

Thank you. Our next question comes from Chris Shibutani when Collyn.

Thanks, very much good morning, I could ask two questions one a little bit more concretely appreciate the guidance for keep cellphone 2020, recalling last year. The first quarter, we perhaps a little bit more seasonality I think you guys reported that and we saw this across other category, we're about halfway through the quarter now.

Now can you comment about how we should be thinking a little bit about the quarterly trends and in particular was what we saw last year with that seasonality and the you know started doing that whole affects et cetera, and appear support and patient support programs a continuing trend. This year and then I'll have a follow up.

Christopher J. M. Taylor: FDA. Of course, we do.

Christopher J. M. Taylor: We did take a look very carefully at whether we should do a randomized trial in relapsed refractory IDH1AML patients. We looked at it really hard, and we said this isn't feasible. The best use of our resources and the chance to have the greatest impact for patients are at the forefront. So that's how we focus, and I would guess, qualitatively, that we would do the same thing all over again. And when these opportunities come up, we'll continue to operate this way.

Hi, Chris This is Derek yes, so we we assumed that when we set the guidance for this year that we would see a similar a similar trend as we saw in Q1 last year.

Weve actually enhanced our patient services supports to be able to I'll try to try to get ahead of it as much as possible.

Operator: Thank you. Our next question comes from Chris Shibutani with Collin.

Darren Miles: Thanks very much. Good morning.

Particularly emphasizing with with practices the need to check in with their patients given the the likelihood that the pieces me experienced an updated or a change in their overall benefits benefit design and potential call share outpatient cost burden. So.

Darren Miles: If I could ask two questions. One, a little bit more concretely, I appreciate the guidance for KeepSilver in 2020. Recalling last year, the first quarter, we perhaps saw a little bit more seasonality. I think you guys reported that, and we saw this across other categories.

So so yes. The answer your question, we've we've assumed a similar impact in 2020.

Great and then we're not really looking forward to bear amid a pivot data at E. Com can you just remind us after the ash debut of the data and talent female that was about eight patients give us a sense, perhaps for the number of patients and potentially any kind of girl ability that we might be able to expect when the data presented at E com.

Darren Miles: We're about halfway through the quarter now. Can you comment on how we should be thinking a little bit about the quarterly trends and, in particular, was what we saw last year with that seasonality and the sort of donut hole effects, et cetera, and peer support and patient support programs, a continuing trend this year? And then I'll have a follow-up. Hi Chris, this is Darren.

And would there be any advanced sort of abstract tight information that would make the that result available prior to the meeting itself. Thank you.

Darren Miles: Yes, so we assumed that when we set the guidance for this year, we would see a similar trend to what we saw in Q1 last year. We've actually enhanced our patient services support to be able to try to get ahead of it as much as possible, particularly emphasizing with practices the need to check in with their patients, given the likelihood that patients may experience an update or change in their overall benefits, benefit design, and potential cost share or patient cost burden. So, to answer your question, we've assumed a similar impact in 2020. Great And then we're naturally looking forward to the mid-pivot data at EHA.

I, our abstract we were right in a manner that gives us the highest chance oh.

Getting a a slot getting admitted to the meetings I really can't comment on on what details will be in there will certainly become forthcoming when there when their lease.

Accrual is going well and we anticipate that will get will finish accrual.

17 patients.

And certainly with before we get to eat.

And so you'll see additional data new data on fallacy. It on Alcatel assuming patients and then we'll certainly be able to talk about the overall duration of a follow up and that will give you some sense of how durable. The hemoglobin response is our how they evolve over time.

Christopher J. M. Taylor: Can you just remind us, after the ASH debut of the data on thalassemia, I think there were about eight patients...

So so I think that this would be really the first time are presenting data for mid to pivot in Dallas EEMEA. So we intend on providing a pretty comprehensive overview for people from an efficacy safety.

Christopher J. M. Taylor: Give us a sense, perhaps, for the number of patients and potentially any kind of durability that we might be able to expect when the data is presented at EHA. And would there be any advanced sort of abstract-type information that would make that result available prior to the meeting itself?

And pharmacodynamics perspective, since we think those are all important results.

Great. Thank you are looking forward to be updates, especially with that program thinking.

Thank you. Our next question comes from Mark Breidenbach with Oppenheimer.

Christopher J. M. Taylor: Thank you.

Christopher J. M. Taylor: I, our abstract we will write in a manner that gives us the highest chance of getting a slot and getting admitted to the meetings. I really can't comment on what details will be in there. It will certainly become forthcoming when they're released. Accrual is going well, and we anticipate that we'll get, we'll finish accrual. These 17 patients before we get to EHOP, and so you'll see additional data, new data on alpha-thalassemia patients, and then we'll certainly be able to talk about the overall duration of follow-up, and that will give you some sense of how durable the hemoglobin responses are, how they evolve over time. So I think that this will be the first time we're presenting data for midipivet and th So we intend on providing a pretty comprehensive overview for people from an efficacy, safety, and pharmacodynamics perspective since we think those are all important.

Hey, good morning, guys. Thanks for taking the questions maybe two quick ones one for Chris and maybe one for Darren as well first for Chris I was wondering if you could give us a little bit more color on the patients that are being enrolled in the NIH sickle cell trial.

I I'm curious if there if it's been a pivot is being layered on top of standard of care therapies, including Hydroxyurea and maybe maybe if you will see any potential combinations.

With that products right in this trial, a and also what would you define as a successful proof of concept in sickle cell disease.

[noise] so the patient can be on hydro yet.

And that that's certainly in eligibility criteria are there other drugs.

Mark sell a tour and others will not be permit it because we really want to understand the effects of.

Amid a pit that and isolate that as much as we can.

Christopher J. M. Taylor: Great. Thank you. Looking forward to the updates, especially with that program.

And well understanding that some drugs like high degree our real standard care are essential for patients.

Operator: Thank you. Our next question comes from Mark Breidenbach with Oppenheimer. Hey, good morning guys, thanks for taking the questions. Maybe two quick ones, one for Chris and maybe one for Darren as well.

I think a proof of concept is what data will we need to see to declare proof of concept really boils down to sort of some really key aspects one of them as how well do patients tolerate the drug over that six week dosing period what different.

Christopher J. M. Taylor: First, for Chris, I was wondering if you could give us a little bit more color on the patients that are being enrolled in the NIH sickle cell trial. I'm curious if Minipivot is being layered on top of standard of care therapies including hydroxyurea, and maybe if we'll see any potential combinations with Oxbrida in this trial. And also, what would you define as a successful proof of concept in sickle cell disease?

This is if any can we discern between the lowest dose in the highest dose in terms of safety.

What does exposure look like and what happens to oxygen Association.

Yes, if anything over those three doses that we test do we see any changes in hemoglobin and are we able to tease out that's a dose flash exposure related to effect.

Christopher J. M. Taylor: So the patient can be on Hydrea, and that's certainly an eligibility criterion. Other drugs like Voxelotor and others would not be permitted because we really want to understand the effects. I'm going to pivot and isolate that as much as we can, and with a good understanding that some drugs like hydrea are a real standard of care and are essential for patients. I think the proof of concept is what data we need to see to declare proof of concept really boils down to some really key aspects.

And importantly, can we demonstrate and sickle sells some of the effects, we've been able to demonstrate and red cells from patients are being kinase deficiency or healthy volunteers. When we've been able to most cleanly define our to treat DPG and ATP profile changes you know when you go into the.

These patients that have these various diseases and get a little more complicated than tomorrow because of the.

The red cell population and it's a little more challenging to handle been in healthy volunteer who has a quote healthy on rental compartment.

Christopher J. M. Taylor: One of them is how well do patients tolerate the drug over that six-week dosing period? And what differences, if any, can we discern between the lowest dose and the highest dose in terms of safety? What does exposure look like, and what happens to oxygen dissociation curves, if anything, over those three doses that we test? Do we see any changes in hemoglobin, and are we able to tease out that that's a dose-slash-exposure-related effect? And importantly, can we demonstrate in sickle cells some of the effects we've been able to demonstrate in red cells from patients with pyruvate kinase deficiency or in Healthy Volunteers, where we've been able to most cleanly define our 2,3-DPG and ATP profile changes? You know, when you go into these patients that have these various diseases, things get a little more complicated in the marrow because of the red cell population, and it's a little more challenging to handle than a healthy volunteer who has a, quote, healthy, unquote, red cell compartment.

So we are thinking throughs. Additionally, a lot about the criteria for demonstrating proof of concept.

And I think the other thing that you should be thinking about how will be thinking about this is scott.

What will be the next steps for for development and we had a previous question would you go how what aspects are you thinking on when you do more phase two where phase three work et cetera. So these are all.

Things that will be driven by the totality of data number of patients we have in the duration.

A follow up as well.

All right. That's very helpful. And then a quick follow up for Derryn going back to the thousand patient PKD patient population that you've identified I was wondering if you could just give us the split between transfusion dependent in transfusion independent patients in that group and also if they've been.

Rigorously genetically characterized it to confirm that they all have to the types of mutations that would potentially confer sensitivity to sum it up thank you.

Hey, Mark So I don't have that that detail that had I think that something we might be able to follow up with a at this point I think the important thing here is that we've been focusing on.

Christopher J. M. Taylor: So we are thinking through, additionally, a lot about the criteria for demonstrating proof of concept. And I think the other thing that you should be thinking about and how we'll be thinking about this is that. What will be the next steps for development? And we had a previous question, would you go? What aspects are you thinking about? Will you do more phase two work, phase three work, et cetera? So these are all things that will be driven by the totality of data, the number of patients we have and the duration of follow-up.

In both in the E U N and certainly in the U.S.

Focusing on raising the urgency around diagnosis offering a support for testing, which is which is the sort of the key fundamentals we need to have in place in order to be able to.

To fully get to the the the actual for the questions that you're at that you're asking here as well, but I think we might be able to follow up afterwards with more detail.

Thank you.

As Chris you're out it's just there's a couple of of.

Fundamentals on on the disease that we don't think that we think are fundamental one of them is at 80% of patients have a missense mutation, so those patients or potentially addressable.

Christopher J. M. Taylor: All right, that's very helpful. And then a quick follow-up for Darren, going back to the 1,000 PKD patient population that you've identified, I was wondering if you could just give us the split between transfusion-dependent and transfusion-independent patients in that group, and also if they've been rigorously genetically characterized to confirm that they all have the types of mutations that would potentially confer sensitivity to mid-i Thank you.

Hey that person's that 20% who have to non missense mutation.

So I think that's a really important aspect of how we think about overall, there's 300 and more mutations being described so you know specific genotype Cabot phenotype genotype that is gene and GB versus outcomes. How can we spent time looking at but when you think.

Now number of mutations.

There's a lot of on known or unknown there.

Sure that's helpful.

Thank you.

Our next question comes from John Newman with Canaccord.

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

Darren Miles: Hey Mark, so I don't have that detail at hand. I think that's something we might be able to follow up on at this point. But I think the important thing here is that we've been focusing, both in the EU and certainly in the US, on raising the urgency around diagnosis and offering support for testing, which is the sort of key fundamentals that we need to have in place in order to be able to fully get to the answers to the questions that you're asking. But I think we might be able to follow up afterwards with...

So.

The bold prediction on the 1 billion, that's I think pick my hand off the on that.

Just curious I don't think the case it didn't sound like it from your prepared remarks, but.

Is that 1 billion dollar target allow for the possibility of any sort of M&A. It didnt seem like it but I just wanted to ask thanks.

Hi, John It's Jackie the no there's no business development or M&A included in that this is what we think we can deliver at least fell repeat at least with what we see in our hands today with cielo and the current portfolio.

Darren Miles: Okay, thank you.

Christopher J. M. Taylor: It's Chris here. I was just, there are a couple of... Fundamentals of the disease that we think are fundamental. One of them is that 80% of patients have a missense mutation. So those patients are potentially addressable.

Great. Thank you.

Thank you.

Our next question is from Georgia farmer with BMO capital markets.

Hi, good morning.

My question.

Two.

I get a better understanding maybe Darren you can answer this about silva penetration in email setting in combination with H. amazing now that you're seeing some increased pickup in the combo setting how Howard docs thinking about cycling between.

Christopher J. M. Taylor: of PIVAP versus that 20% who have...

Christopher J. M. Taylor: So I think that's a really important aspect of how we think about it overall. There are 300 and more mutations being described. So, you know, specific genotype, you know, genotype, that is, gene A and gene B versus outcomes, something we spend time looking at. But once you think about the number of mutations... There's just a lot of unknown unknowns.

Tips of.

The class in combination with <unk>.

[laughter] showed the I think the couple things to maybe fully first established I think the the we continue to see in our in our research.

From believed in the importance of targeting the target, meaning if you got to targeted therapy.

Christopher J. M. Taylor: Sure. That's helpful. Thank you. Our next question comes from John Newman on the Kahn Accords. Hey guys, good morning.

For identifiable mutation and.

Operator: Thanks for taking the question. Pretty bold prediction on the $1 billion. I'll take my hat off to you on that.

Physicians are more inclined to want to use it.

The.

What's important along with that is that there's also firm belief in the in that at each one mid to late each one is a driver mutation in this in this setting and degree in early driver mutations.

Jackie Faust: Just curious; I don't think that this is the case. It didn't sound like it from your prepared remarks. But does that $1 billion target allow for the possibility of any sort of M&A? It didn't seem like it, but I just wanted to ask. Thanks.

So so that did I think is what that along with the clinical outcomes data or what you are driving the adoption of tip Sobo, both single agent as well as in combination in the front in the frontline setting, but we only promote to the to the single agent use.

Jackie Faust: Hi John, it's Jackie. No, there's no business development or M&A included in that. This is what we think we can deliver, at least, I'll repeat at least, with what we see in our hands today with TIPSOVO and the current portfolio.

Operator: Great, thank you. Thank you. Thank you. Thank you. Our next question is from George Farmer with BMO Capital Markets.

The data that we've seen.

And it's continued to improved quarter over quarter.

Operator: Hi, good morning. Thanks for taking my question. I'd like to... Get a better understanding, maybe Darren, you can answer this.

Now suggests that it or indicates that it is the most preferred <unk> regimen about half of the overall use both in the frontline setting as well as in the relapse setting is in combination with with H. amaze against I can we don't we don't promoted but this the uses likely prompted by greater awareness of a combination data.

Darren Miles: Sovo Penetration in the ML setting in combination with HMAs, and now that you're seeing some increased pickup in the combo setting, how are docs thinking about cycling before Tips of an Etiquette?

Darren Miles: So, I think a couple of things to maybe fully first establish. I think we continue to see in our research a firm belief in the importance of targeting the target, meaning if you've got a targeted therapy for an identifiable mutation, and physicians are more inclined to want to use it, I think what's important along with that is that mutated IDH1 is a driver mutation in this setting, particularly an early driver mutation. So, that, I think, is what, along with the clinical outcomes data, is driving the adoption of TIPSOVO at both single-agent as well as in combination in the frontline setting, which we only promote to single-agent use. The data that we've seen, and it's continued to improve quarter over quarter, now indicates that it is the most preferred regimen.

We've updated at Congress or over the last two or the last two years. It. Most recently had at ash in terms of how they they will cycle between but at a clocks and and such so I think at the end. It remember our focus in the frontline setting for the monotherapy indication at least as in is focusing on those patients.

Who had been previously exposed to an H. me and I think we get we have resident residents that Mr hasn't been residents with the with the community there and then as they become more aware of the emerging of the emerging didn't combination they're finding it a compelling overall clinical profile on this leading them to expand their use beyond beyond that portion of the.

Patient patient population.

So and I think based at this stage, it's still sort of early days as rich as the community begins to figure out just what are going to be there established treatment algorithms because of the the influx of new of new treatments.

Darren Miles: About half of the overall use, both in the frontline setting, as well as in the relapse setting, is in combination with HMAs. Again, we don't promote it, but the use is likely prompted by greater awareness of the combination data that we've updated at Congress over the last two years or, most recently, at ASH. In terms of how they will cycle between Venetoclax and Tibsovo, I think at the end of November, our focus in the front-line setting for the monotherapy is focusing on those patients who have been previously exposed to an HMA. And I think we get, we have good resonance, that message has good resonance with the community there. And then, as they become more aware of the emergence...

In the front line as well as though relapse setting.

Okay. That's very helpful. And then regarding that made a pivot how are you, saying, how how should we think about a drug activity against the mutant form of the ends on versus the wild type form the enzyme and the right subtle differences and are there are there are there any concerns about you know overshooting hemoglobin levels.

Things that had been a problem that had been an issue in the early earlier stages, the development and again, just as genotype matter and that's it.

Operator: www.cdc.gov.au So, and I think at this stage it's still sort of early days as the community begins to figure out just what their established treatment algorithms are going to be because of the influx of new treatments in the frontline as well as the relapse setting.

Yes.

This is Chris here.

Genotype matters entirely kidney deficiency.

And.

Because you've got to have protein.

And in order for the drug to buying and we have found that non missense mutations as it as a general rule are less stable and there's not as much protein around where there is no place for the drug online because it's been a large deletion.

Christopher J. M. Taylor: That's very helpful. And then, regarding mid-pivot, how should we think about drug activity against the mutant form of the enzyme versus the wild type form of the enzyme? Are there any subtle differences, and are there...

So so Gina type and molecular features are really important in terms of higher they kinase proficiency and ability to activate the enzyme.

Christopher J. M. Taylor: Are there any concerns about, you know, overshooting hemoglobin levels? I think that was an issue in the earlier stages of development. And again, does genotype matter in that sense, do you think?

And that will see me.

And sickle cell our approach is to activate the wild type.

Enzyme in the same aim higher big kinase, that's in anyone's red cells that they don't have enough.

Christopher J. M. Taylor: Yes, this is Chris here. Genotype Matters and Pyruvate Kinase, because you've got to have protein in order for the drug to bind. And we have found that non-misfense mutations, as a general rule, are less stable, and there's not as much protein around, or there's no place for the drug to bind because there's been a large deletion. So genotype and molecular features are really important in terms of pyruvate kinase deficiency and ability to activate the enzyme. In thalassemia and sickle cell, our approach is to activate the wild-type enzyme, the same pyruvate kinase that's in anyone's red cells if they don't have an underlying hemoglobin deficiency or they don't have a pyruvate kinase deficiency. Now, one of the things that could be interesting is whether the outcomes when you activate wild-type PKR will be a function of, for instance, the type of thalassemia, whether you have alpha or beta or the various globinopathies that can present within that disease, or in sickle cell, whether you're SS or you're S-thal. Those will be some things that we'll be looking at.

Got it obviously are they don't have higher big kinase deficiency.

Now one of the things that could be interesting is that will outcomes. When you activate wild type PK I'd be a function of the for instance, the type of fallacy EMEA.

What do you have alpha beta or the various globally not piece that that can present within that disease or in sickle cell. If your ass asked where you were asked how.

Those will be some things that we'll be looking out. So we tend to think of these three diseases as as separate.

We do you will hear us lumps somewhat fallacy in sickle cell together because were approaching where we're activating wild type PK, our whereas in part of a kind a sufficiency, we're activating the mutant form of the disease. So part of a kinase deficiency, there's less ATP because of that mutated enzyme whereas.

As it needs a wild type approaches there is a relatively there's I wouldn't say normal, but there's more AHGP, though we're trying to push up the pea level, so that that those red cells can tolerate their underlying.

Disease process.

And live longer.

Christopher J. M. Taylor: So we tend to think of these three diseases as separate. We do, you will hear us lump together thalassemia and sickle cell together because we're approaching a point where we're activating wild-type PKR, whereas in pyruvate kinase deficiency, we're activating the mutant form of the enzyme. So in pyruvate kinase deficiency, there Whereas in these wild-type approaches, there's a relatively, I wouldn't say normal, but there's more ATP there. We're trying to push up the ATP level so that then those red cells can tolerate their underlying disease and Live Longer.

Great. Thank you.

[noise], Thank you and I'm not showing any further questions in the case I would like to turned a quota Jackie south for her final remarks.

Thank you operator.

2020 is a pivotal year for I'll, just as we execute against important milestones across our business. We expect significant progress in our clinical pipeline for all of our three therapeutic focus areas.

Outstanding growth in our product revenues and continued productivity from our research engine with a new I indeed be filed this quarter.

Christopher J. M. Taylor: Thank you, and I'm not showing any further questions in the queue. I would like to turn the call over to Jackie South for her final remarks.

I would like to thank all of the tremendous employees at our jails for their dedication and passion to making a difference for our patients 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 today, but also like to thank all of you for joining us on our call today, and we will see you soon.

Jackie Faust: Thank you, operator. 2020 is a pivotal year for Agios as we execute against important milestones across our business. We expect significant progress in our clinical pipeline for all of our three therapeutic focus areas, outstanding growth in our product revenues, and continued productivity from our research engine with a new IND to be filed this quarter. I would like to thank all of the tremendous employees at Agios for their dedication and passion to making a difference for our patients. 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 today.

And with that ladies and gentlemen, we thank you for participating you may now disconnect.

[noise].

Operator: I would also like to thank all of you for joining us on our call today, and we will see you soon.

Operator: And with that, ladies and gentlemen, we thank you for participating. You may now disconnect. © BF-WATCH TV 2021, ??? ???