Q3 2019 Earnings Call

Ladies and gentlemen, please standby and the conference call will begin momentarily once again, ladies and gentlemen, please stand alone.

Operator: Ladies and gentlemen, please stand by. Your conference call will begin momentarily. Once again, ladies and gentlemen, please stay on the line.

Unnamed Speaker: [inaudible] Copyright 2020, New Thinking Allowed Foundation BF-WATCH TV 2021

Unnamed Speaker: Good morning and welcome to Agios' third quarter 2019 conference call. At this time, all participants are in a listen-only mode. There will be a question and answer session at the end. Please be advised this call is being recorded at Agios' request. I would now like to turn the call over to Kendra Adams, Vice President, External Communications and Investor Relations.

Kendra Adams: Thank you, Kevin. Good morning, everyone, and welcome to Agios' third quarter 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 Hirsch, our Chief Financial Officer and Head of Corporate Development. Dr. Scott Biller, our Chief Scientific Officer, will also be available for Q&A. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual 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 factor section of our most recent Form 10-Q filed with the SEC and any other filings that we may make with the SEC. With that, I'll turn the call over to Jackie.

Good morning, welcome to our deals third quarter 2019 conference call. At this time all participants are in listen only mode there'll be a question answer session. At the end. Please be advised as cost being recorded adios request I would now like turn the call over the counter Adams, Vice President external communications and Investor Relations.

Jackie Faust: Thanks, Kendra. Good morning everyone, and thanks for joining us on our third quarter 2019 results call. Q3 was an exciting one for us as we achieved several of the ambitious goals we set for 2019 across our research, clinical, and commercial activities. As Chris will describe in detail, we achieved several clinical milestones within our oncology portfolio that set the foundation for multiple opportunities. In September at ESMO, we shared the first full data from our positive phase 3 clarity study of Tinsovo in previously treated IDH1 mutant cholangiocarcinoma.

Thank you Kevin Good morning, everyone and welcome to our Geos third quarter 2019 Conference call you can access slides for today's call by going to the Investor section of our website audio stock comp with me on the call. Today was prepared remarks are dr., Jackie, though our chief Executive Officer, Dr., Chris Bowden, Our Chief Medical Officer Darren.

While our senior Vice President of U.S., commercial and global marketing and Andrew Burns, Our Chief Financial Officer, and head of corporate development Dr., Scott Miller, Our Chief Scientific Officer will also be available for Q and before we get started I would like to remind everyone that some of the statements. We make on this call will include forward looking statement actual results could.

Jackie Faust: We believe Tibsobo has the potential to be the first targeted therapy for these patients, and our team is now focused on preparing that supplemental NDA. During the quarter, we obtained guidance from the FDA and EMA on the endpoints for our phase 3 trial of voracidinib in low-grade IDH mutant glioma, and we are now preparing for trial initiation.

For 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 the risk factor section of our most recent Form 10-Q filed with the FCC and any other filings that we may make or the FCC with that I'll turn the call over to Jackie.

Jackie Faust: And earlier this week at the TRIPLE meeting, we presented data from the dose escalation portion of our Phase 1 study of AG270 and a variety of mTAP-deleted tumors. The trial has advanced to dose expansion, and patients are now enrolling in two combination arms evaluating AG270 plus standard of care in non-small cell lung and pancreatic cancer. Within our Rare Genetic Disease portfolio, we published updated data in the New England Journal of Medicine from the Phase II-derived PK study of menopivac and PK deficiency. These data represent the first publication of clinical data in adults with PK deficiency and demonstrate the clinical benefit of midipivet in this chronic anemia.

Thanks, Kendra good morning, everyone and thanks for joining us on our third quarter 2019 results call.

Q3 wasn't exciting one for us as we achieved several of the ambitious goals. We set for 2019 across our research clinical and commercial activities as Chris will describe in detail, we achieved several clinical milestones within our oncology portfolio that set the foundation for multiple opportunity.

Yes.

In September at ESMO, we shared the first full data from our positive phase three clarity study of TEMCELL Boeing previously treated IDH, one mutant cholangio carcinoma [laughter], we believed himself well has the potential to be the first targeted therapy for these patients and our team is now focused on preparing that supplemental India.

Jackie Faust: On the commercial side, TIBSOVO U.S. revenue grew by 27% during the third quarter, and Darren will get into more commercial detail later in the call. Outside the U.S., our team in Europe is executing on a gated build of our EU commercial infrastructure in preparation for potential approval of Tibsovo in relapsed refractory AML in the second half of next year. Finally, I would like to highlight the tremendous work happening within our research organization. With more than 15 active discovery programs spanning target discovery to drug candidate, our talented team of scientists is making important discoveries every day in order to usher in the next wave of AGIOS medicine. We will share more about these programs as we move them along. Heading into year end, we're focused on executing against our remaining key milestones.

[laughter] during the quarter, we've obtained guidance from the F.D.A., an email on the endpoints for our phase three trial of Borisov mid and low grade IDH mutant glioma.

We're now preparing for trial initiation.

And earlier this week at the Triple meeting, we presented data from the dose escalation portion of our phase one study of AG 270 in a variety of in tap deleted tumors. The trial has advanced to dose expansion in patients are now enrolling into combination arm evaluating AG 270, plus.

Standard of care, and non small cell lung and pancreatic cancers.

In our rare genetic disease portfolio, we publish updated data in the new England Journal of Medicine from the phase to drive PK study of mid appear that in PK deficiency.

Jackie Faust: These include completing enrollment in both of our Phase 3 Activate and Activate T studies for Minipivet, submitting a supplemental new drug application for Kipsovo and previously treated IDH1 mutant cholangiocarcinoma, advancing our Phase III indigo trial of borosodinib and IDH mutant low-grade glioma, and achieving proof of concept in our Phase II study of menopi These milestones, combined with our remaining data presentations this quarter at both Snow and Ash, are critical to realizing the value creation potential across both our oncology and rare genetic disease portfolios in 2020 and beyond. I will now turn the call over to Chris to provide our clinical and regulatory updates.

These data represent the first publication of clinical data in adults with PK deficiency and demonstrate the clinical benefit of mid to pivot in this chronic anemia.

On the commercial thought himself a U.S. revenue grew by 27% during the third quarter and Derek will get into more commercial detail later in the call.

Outside the U.S. our team in Europe is executing on a gated build of are you commercial infrastructure in preparation for potential approval of Tim So in relapsed refractory I emailed in the second half of next year.

Finally, I would like to highlight the tremendous work happening within our research organization with more than 15 active discovery programs spanning target discovery to drug candidate our talented team of scientists is making important discoveries every day in order to Usher in the next wave of all children medicines, we will share more about lease.

Christopher J. M. Taylor: Thanks, Jackie. As we laid out at the beginning of the year, our clinical development strategy for each of our programs is to expand across multiple disease areas where we have the potential to make an impact on the lives of patients. For our IDH inhibitors, we've established the clear benefit of these medicines in AML with approvals as single agents and for relapse refractory and newly diagnosed disease. Our phase 3 combination studies in newly diagnosed AML patients continue to enroll and progress as planned. Over the last 10 years, we have been leading the scientific and clinical understanding of IDH mutations and hematologic malignancies, and at the ASH annual meeting in December, we will share clinical and translational data for our IDH program that underscores our unique insight into this target and its implications for the AML treatment landscape.

Program as we move them along.

Heading into year end, we're focused on executing against our remaining key milestones.

These include completing enrollment for both of our phase three activate and activate T studies from an appeal that.

Submitting a supplemental new drug application for himself going previously treated IDH, one mutant colorectal carcinoma.

Advancing our phase three indigo trelleborg, Assad NIM and IDH mutant low grade glioma and achieving proof of concept in our phase two study of minutes here that in Dallas EEMEA.

These milestones combined with our remaining data presentations this quarter at both snow and ash are critical to realizing the value creation potential across both our oncology and rare genetic disease portfolios and 2020 Amnion I'll now turn the call and Chris to provide our clinical and regulatory update.

Thanks Jackie.

As we laid out at the beginning of the year, our clinical development strategy for each of our programs is to expand across multiple disease area. We have the potential to make an impact on the lives of patients.

Christopher J. M. Taylor: An area of great focus for agioscientists is expanding our data on mutational clearance and minimum residual disease from patients who achieve a response with TIBSOVA. At ASH, we will have the opportunity to highlight some of this data in frontline AML patients who have received TIBSOVO plus PIDASA in our ongoing Phase 1 trial. We'll share more about AASP presentations when abstracts go online next week on November 6th.

For our IDH inhibitors, we've established a clear benefit of these medicines in AML with approvals at a single agent and relapse refractory newly diagnosed disease.

Our phase three combination studies and newly diagnosed AML patients continue to enroll and progressing as planned.

The last 10 years, we have been leaving the scientific and clinical understanding of IDH mutation in hematologic malignancies and at the Ash annual meeting in December we will share clinical and translational data for our IDH programs and underscores our unique insight into this target and its implications for the AML treatment landscape.

Christopher J. M. Taylor: Beyond AML, we reopened the myelodysplastic syndrome arm of the TIBSOVA Phase I study in hematologic malignancies with the goal of enrolling up to 25 additional patients and generating sufficient data to pursue a potential regulatory filing in this indication. This quarter, we made exciting progress toward advancing our solid tumor oncology program. A clarity study of TIBSOVO and previously treated IDH1 mutant cholangiocarcinoma was the first randomized study in this patient population.

Okay.

An area of great focus for RG scientists is expanding our data on mutational class a minimal residual disease from patients who achieve a response with 10 so.

As we will have the opportunity to highlight some of this data in frontline AML patients, who have received himself plus by data and our ongoing phase one trial.

Well share more about asked presentation. When abstracts go online next week on November six.

Christopher J. M. Taylor: As a discussant, Dr. Ian Chow at ESMO pointed out, these positive results help to establish the practice-changing role that this targeted therapy can play in the treatment paradigm for patients with an IDH1 mutation. The study showed that TIBSOVA reduced the risk of disease progression or death by 63%. In addition, Tibsovo significantly improved progression-free survival compared to placebo, with notable 6- and 12-month PFS rates of 32% and 22%, respectively. By contrast, no placebo patients were free from progression at six months or beyond. While preliminary, the overall survival data are supportive of the therapeutic benefit of TIPSOVO and are especially impressive when adjusting for cross-infection. In addition, Tibsovo is well-tolerated, and the safety profile is consistent with previous reports.

Beyond the M.L., we reopened the Myelodysplastic syndrome arm of the 10 Salvo phase one study in hematologic malignancies with the goal of enrolling up to 25 additional patients and generating sufficient data to pursue a potential regulatory filing in this indication.

This quarter, we made exciting progress toward advancing our solid tumor oncology programs.

The clarity study of tip Sobo previously treated IDH, one you cholangio carcinoma.

As a first randomized study in this patient population.

As a discussing Dr yen Chow at ESMO pointed out these positive results helped to establish the practice changing or all that this targeted therapy can play in the treatment paradigm for patients with an IDH one mutation.

The study showed that Tim sobo reduces the risk of disease progression or death by 63%.

Christopher J. M. Taylor: We are on track to submit a supplemental new drug application for this indication by year end, on the heels of this positive phase 3 study in an aggressive, rapidly progressive solid tumor. We are increasingly confident in the potential for an IDH inhibitor to have a meaningful impact in IDH mutant low-grade gliomas, where patients desperately need new treatment options. Borosidinib is our brain penetrant and IDH inhibitor that we will study in patients with IDH mutant, low-grade gliomas after surgical resection who are in a watch-and-wait setting, a clinical approach often employed in this disease to avoid the toxicities associated with chemotherapy and radiation. Borosidinib has previously been evaluated in a Phase 1 study demonstrating 77% stable disease with a mean treatment duration of 22 months and no significant improvement.

In addition to sub assist significantly improved progression free survival compared to placebo with notable six and 12 month PFS rates up 32% and 22% respectively.

By contrast, no placebo patients were free from progression at six months or beyond.

Well preliminary the overall survival data are supportive of the therapeutic benefit dip so in our especially impressive when adjusting for crossover.

In addition to itself I was well tolerated and the safety profile, it's consistent with previous reports.

We are on track to submit a supplemental new drug application for this indication by year end.

On the heels of this positive phase three study in an aggressive rapidly progressive solid tumor.

We are increasingly confident and the potential for an IDH inhibitor to have a meaningful impact an IDH mutant low grade glioma, where patients desperately need new treatment options.

Christopher J. M. Taylor: In addition, a perioperative study of voracidinib and ivosidinib showed the ratio of tumor-to-plasma drug concentration is much higher for voracidinib and is associated with more consistent 2HG suppression, consistent with our preclinical work. We will share updated data from the perioperative study at the Society of Neuro-Oncology meeting in November. Today, I will walk you through the Borsite Nib Global Phase III Study Design.

For a side and it is our brain penetrant Pan IDH inhibitor that we will study in patients with IDH mutant low grade glioma, suppose surgical resection, who are in a watch and wait setting.

Clinical approach often employed in this disease to avoid the toxicities associated with chemotherapy and radiation.

Or side and it has previously been evaluated a phase one study demonstrating 77% stable disease with a meat treatment duration of 22 months and non enhancing.

Christopher J. M. Taylor: The study that we have named Indigo will evaluate 366 patients with IDH mutant grade 2 non-enhancing glioma in a one-to-one double-blind randomization to either 50 milligrams of borosidinib once daily or placebo. Patients enrolled in this study must have had at least one prior surgery for glioma, with the most recent surgery at least one year and no more than five years before the date of randomization, and no other prior anti-cancer therapy, including chemotherapy and radiotherapy. The primary endpoint is progression-free survival, as assessed by a blinded, independent review. A number of secondary endpoints will be included, such as safety and tolerability, tumor growth rate as assessed by volume, seizure control, time to next intervention, neurocognitive function, and quality of life. Crossover from placebo to voracitinib will be permitted.

In addition, a Perry operative study aboard side and I have a seismic showed the ratio of tumor to plasma drug concentration is much higher for more side and is associated with more consistent to HCCI suppression consistent with our preclinical work.

We will share updated data from the Perry operative study at the society of Neuro oncology meeting in November .

Today I will walk you through the Boris side, and then global Phase three study design.

The study that we have named Indigo, well evaluate 366 patients with IDH mutant grade to non enhancing glioma and a one to one double blind randomization to either 50 milligrams of fourth side, and then once daily or placebo.

Patients enrolled in this study must have had at least one prior surgery for glioma with the most recent surgery at least one year no more than five years before the date of randomization and no other prior anti cancer therapy, including chemotherapy and radio therapy.

Christopher J. M. Taylor: The team is actively preparing for initiation of the Phase III indigo study later this quarter. Continuing with solid tumors, I'll move to our AG270 program in MTAP-deleted tumors, where we reported the first data on 39 patients from the completed single-agent dose escalation portion of our Phase I study at the AACR NCI EORTC meeting earlier this year. The goal of this portion of the Phase 1 study was to establish a recommended dose based on the safety, pharmacokinetics, and pharmacodynamics of MAP2A inhibition. On Sunday, Dr. Rebecca Heiss from Massachusetts General Hospital gave an oral presentation, followed by a poster presentation on Monday that showed AG270 generates reductions in biomarkers, plasma SAM concentrations, and in levels of tumor SDMA at well-tolerated The average reductions in plasma SAM concentrations were approximately 60 to 80% and within the range associated with maximum tumor growth inhibition in preclinical models. The maximum tolerated dose was determined to be 200 mg daily. Confirmed partial response was observed in a patient with high-grade neuroendocrine carcinoma on the lung.

The primary endpoint as progression free survival as assessed by a blinded Independent review Committee.

A number of secondary endpoints will be included such as safety and Tolerability tumor growth rate as assessed by volume seizure control time to next intervention narrow cognitive function and quality of life.

Crossover from placebo divorce side, and then well be permit.

The team is actively preparing for initiation of the phase three Indicus study later this quarter.

Continuing with solid tumors I'll move to our AG 270 program and MTAP deleted tumors, where we reported the first data on 39 patients from the completed single agent dose escalation portion of our phase one study at the A.C.R. and see I feel RTC meeting earlier this week.

The goal of this portion of the Phase one study was to establish a recommended dose based on the safety pharmacokinetics and pharmacodynamics amount to a inhibition.

On Sunday Dr., Rebecca Heis from Massachusetts General Hospital gave an oral presentation, followed by a poster presentation on Monday that showed.

Agee to 70 generates reductions in the Biomarkers plasma Sam concentrations and in levels of tumor SDM, a well tolerated doses.

Christopher J. M. Taylor: Two additional patients experienced prolonged stable disease, including one patient with a sex-cord stromal tumor with stable disease after 12.8 months of treatment with AG-270 once daily, and one patient with bile duct cancer with stable disease after six and a half months of treatment with AG-270 once daily. On the basis of these clinical data, as well as preclinical data that were also presented at the TRIPLE meeting that support our combination strategy, we We are enrolling patients in two combination arms of the Phase I study. One arm will test AG270 in combination with docetaxel in up to 40 patients with mTAP-deleted non-small cell lung cancer who have had no more than two prior lines of cytotoxic therapy. The second arm will test HE270 in combination with nampactlitaxel and gemcitabine in up to 45 patients with MTAP-deleted pancreatic ductal adenocarcinoma who have had no more than one prior line of cytotoxic therapy.

The average reductions in plasma Sam concentrations were approximately 60% to 80% and within the range associated with maximum tumor growth inhibition in preclinical models.

The maximum tolerated dose was determined to be 200 milligrams daily.

I confirmed partial response was observed in the patient with high grade neuroendocrine carcinoma belong.

Two additional patients experienced prolonged stable disease, including one patient with a six cord struggled tumor was stable disease. After 12.8 months of treatment with AG 270, once daily and one patient with the bile duct cancer was stable disease after six and a half months of treatment with AG 270.

Once daily [noise].

Based on these clinical data as well as preclinical data that were also presented at the Triple meeting that support our combination strategy.

We are enrolling patients into combination arms of the phase one study.

One arm will test AG 270 in combination with Ddos attacks, so and up to 40 patients with MTAP deleted non small cell lung cancer, who have had no more than two prior lines of cytotoxic therapy.

Christopher J. M. Taylor: The goal of each arm is to gather sufficient data in a homogeneous patient population to better understand AG270's clinical profile when combined with standard of care, which will allow us to determine next steps in clinical development. Moving to our PKR activator program, where we are currently studying midipivet and several hemolytic anemias. Our initial area of focus has been pyruvate kinase deficiency, where midipivet activates a mutated PKR enzyme.

The second arm will touch 82, 70 in combination with Nab Paclitaxel gems cytarabine in up to 45 patients with MTAP deleted pancreatic ductal adenocarcinoma, who have had no more than one prior lines of cytotoxic therapies.

The goal of each arm is to gather sufficient data in a homogeneous patient population to better understand AG two seventys clinical profile when combined with standard of care, which will allow us to determine next steps in clinical development.

Christopher J. M. Taylor: Earlier this year, we expanded clinical development into thalassemia and sickle cell disease, where Midipivat has the potential to provide therapeutic benefit through the activation of wild-type PK. Beginning with PK deficiency, we have two ongoing Phase 3 clinical studies. Activate, and Activate-T, where enrollment is expected to complete by the end of the year. In September, we announced that updated data from our Phase II DRIVE-PK study were published in the New England Journal of Medicine and showed that hemoglobin responses were maintained in 19 patients in the extension phase of the study for a median treatment duration of almost 30 months. Additional follow-up data for dry PK have been accepted for presentation at ASH, as well as findings from the Natural History Study aimed at better understanding the burden of disease in adults with PK deficiency.

Moving to our PK, our activator program, where we are currently studying made up to that and several hemolytic anemias.

Our initial area of focus has been pirate <unk> kinase deficiency or admitted to that activates a mutated PK our enzyme.

Earlier this year, we expanded clinical development into Dallas female and sickle cell disease, where mid to that has the potential to provide therapeutic benefit through the activation of wild type T.K. our.

Beginning with PK deficiency, we have to ongoing phase three clinical studies.

Activate and activate T where enrollment is expected to complete by the end of the year.

In September we announced that updated data from our phase to drive PK studies were published in the New England Journal of Medicine and show that hemoglobin responses were maintained 19 patients in the extension phase of the study or a median treatment duration them almost 30 month.

Additional follow up data for drive PK have been accepted for presentation at ash as well as findings from the natural history study aimed at better understanding the burden of disease and adults with PK deficiency.

Christopher J. M. Taylor: Enrollment for the Thalassemia Phase 2 study is going well, and we are on track to have sufficient data internally to establish proof of concept by year. For sickle cell disease, we are utilizing an IST strategy, which includes a cooperative research and development agreement with Dr. Sui-Lei Chen at the National Institutes of Health. Dr. Tan expects to enroll up to 25 patients, and to date, interest in the study has been strong. As the first PKR activator in clinical development, we continue to have confidence in the important role that midipivac can play for patients with chronic debilitating hemolytic disease. I'll now turn the call over to Darren to review our commercial activities. Thanks, Chris.

Enrollment for the salad seeming a phase two study design is going well and we're on track to have sufficient data internally to establish proof of concept by year end.

And sickle cell disease, we are utilizing an I.S.T. strategy, which includes a cooperative research and development agreement with Dr. suite Lei Chen at the National Institutes of health.

After 10 expects to enroll up 25 patients and to date interest and the study has been.

As the first PK, our activator in clinical development, we continue to have confidence in the important role that met a pivot can play for patients with chronic debilitating hemolytic anemia.

I'll now turn the call ever to Darren to review our commercial activities.

Darren Miles: Thanks, Chris. As I shared last quarter, our top priorities are execution and expansion. In the third quarter, we maintained our focus on continued execution in support of TIPSOVO's frontline and relapse refractory labels, preparing for the potential launch of TIPSOVO for the treatment of cholangiocarcinoma, and advancing pre-launch preparation activities in support of the potential approval of midepibat for PK deficiency. With respect to our third-quarter results, I'm pleased to report that the This represents an increase of 27% over Q2, bringing year-to-date Tibsovo revenue to $40.2 million.

Thanks, Chris.

As the should last quarter, our top priorities are execution and expansion.

In the third quarter, we maintained our focus when continued execution supportive so those frontline and relapse refractory labels preparing for the potential launch of silver for the treatment of Cholangio carcinoma.

And advancing pre launch preparation activities in support of a potential approval admitted to the PK deficiency.

With respect to where third quarter results I'm pleased to report that the strength. We saw in Q2 continued through the third quarter, resulting into civil net revenue of $17.4 million. This represents an increase of 27% over Q2, bringing year to date of civil revenue to $40.2 million growth in Q3 is largely due.

Darren Miles: Growth in Q3 is largely due to strong gains in both the newly diagnosed and relapsed refractory AML setting. In the front-line setting, our research suggests that the majority of treating physicians now believe in the importance of IDH inhibitors for newly diagnosed patients, and this belief is translating into a substantial increase in adoption in the front line setting. Though we only promote approved uses of Tibsovol monotherapy, we've observed an increase in front-line use in combination with HMAs. We've also seen a corresponding improvement in median duration on therapy between four and five months, continuing a steady upward trend over prior quarters. Overall, we're making meaningful progress expanding utilization across new users and practice settings. Unique prescribers continue to grow, up 27% over Q2 and up 65% since Q1.

The strong gains in both the newly diagnosed and relapse refractory AML settings in the frontline setting our research suggests that the majority of treating physicians now believes in the importance of IDH inhibitors for newly diagnosed patients and this belief is translating into a substantial increase in adoption in the front line.

So we only promote approved uses of silver monotherapy, we've observed an increase in frontline use in combination with H. makes we've also seen a corresponding improvement in median duration on therapy of between four and five months, continuing a steady upward trend over prior quarters.

Overall, we're making meaningful progress expanding utilization across new users and practice settings unique prescribers continued to grow up 27% over Q2 and up 65%. Since Q1, we continue to see strong double digit growth in both the academic and community setting and while the academic setting represents the largest treatment volume.

Darren Miles: We continue to see strong double-digit growth in both the academic and community setting. And while the academic setting represents the largest treatment volume, increased adoption in the community setting has been exceptionally strong and has increased as a proportion of overall tipsoval volume relative to the first half of 2019. This is important as we observe more patients being co-managed between academic and community practices. I'm quite proud of the accomplishments of our team so far, successfully executing two launches in less than a year, and tirelessly advocating each day for IDH mutation-positive patients. I look forward to sharing even more progress on our next call as we continue to execute and expand. I will now turn the call over to Andrew to discuss our third quarter financials.

Just adoption in the community setting has been exceptionally strong and has increased as a proportion overall, Tim so volume relative to the first half of 2019.

This is important as we observed more patients being co managed between academic and community practices I'm quite proud of the accomplishments of our teams. So far successfully executing two launches in less than a year and tirelessly advocating each state for IDH mutation positive patients I look forward to sharing even more progress on our next call as we continue to execute.

And expand I'll now turn the call over to Andrew to discuss our third quarter financials. Thanks Darren.

Andrew Hirsch: Thanks, Darren. Our third quarter results can be found in the press release we issued this morning, which I'll summarize. More detail will be included in our 10-Q filing later today. Total revenue for the third quarter was $26 million, which consisted of $17.4 million of net U.S. sales of Tibsovo. $5.9 million of collaboration revenue and $2.7 million of IDFA royalty revenue. Revenue increased compared to Q3 2018 by $10.8 million, which was largely driven by an increase in net U.S. sales of Tubsovo of $13 million. TPSOVO revenue growth of 27% compared to the prior quarter was largely driven by underlying demand; Gross to Net and Inventory Levels remain consistent with the prior quarter.

Third quarter results can be found in the press release, we issued this morning, which I'll summarize.

More detailed will be included in our 10-Q filing later today.

Total revenue for the third quarter was $26 million, which consisted of $17.4 million of net U.S. sales of Tim Soho.

$5.9 million of collaboration revenue and $2.7 million of IP for royalty revenue.

Revenue increased compared to Q3, 2018 by $10.8 million, which was largely driven by an increase in net us sales of Sobo $13 million.

So revenue growth of 27% compared to the prior quarter was largely driven by an underlying demand.

Gross to net inventory levels remain consistent with the prior quarter.

Andrew Hirsch: Cost of sales for the quarter was $393,000. Turning to operating expenses, R&D for the third quarter was $101.7 million, an increase of $19.1 million compared to the same period in 2018. The year-over-year increase in R&D was largely driven by startup costs for the planned Phase III indigo study of voracidinib in low-grade glioma. Clinical Trial Activity for Mitopivet and PK Deficiency, Thalassemia, and Sickle Cell Disease, and Cost of the Ongoing TIBSOVO Combination Phase III Trials in the Frontline AML Section.

Cost of sales for the quarter was $393000.

Turning to operating expenses R&D for the third quarter was $101.7 million, an increase of $19.1 million compared to the same period of 2018.

The year over year increase in R&D was largely driven by startup costs for the plan to phase three indigo study before side they have been low grade glioma.

Cynical trial activity for me to pivot and PK deficiency, Dallas, Simeon sickle cell disease and cost of the ongoing Tim So combination phase III trials in the frontline AML setting.

Operator: Selling general and administrative expenses were $33 million for the quarter, representing a $1.9 million increase over the third quarter of 2018. We ended the quarter with cash, cash equivalents, and marketable securities of $540.5 million and a cash burn of $83.5 million for the quarter. We expect that this cash balance, in addition to expected product revenue, expense reimbursements, and royalties... but excluding anticipated program-specific milestone payments, will fund our current operating plan through at least the end of 2020. With that, Operator, please open the line for questions.

Selling general and administrative expenses were $33 million for the quarter, representing a 1.9 million dollar increase over the third quarter of 2018.

We ended the quarter with cash cash equivalents and marketable securities of $540.5 million, a cash burn of $83.5 million for the quarter.

We expect that this cash balance in addition to expected product revenue expense reimbursements and royalties, but excluding anticipated program specific milestone payments will fund our current operating plans where at least the end of 2020.

With that operator, please open the line for questions.

Ladies and gentlemen, if you have a question or comment at this time. Please press the star than the one key on your Touchtone telephone. If your question has been answered or you were somewhat yourself from acute please press the pound <unk>. Our first question comes from underground wrong with JP Morgan.

Anupam Rama: Ladies and gentlemen, if you have a question or a comment at this time, please press the star, then the one key on your touchtone telephone. If your question has been answered or you wish to move yourself from the queue, please press the pound key. Our first question comes from Anupam Rama on behalf of J.P. Morgan.

Anupam Rama: Hey guys, thanks for taking the question and congrats on all the progress.

Hey, guys. Thanks for taking the question and congrats on all the progress just a couple of questions on it.

Anupam Rama: Yes, just a couple questions on Ash.

So for the drive PK extension study is there going me any new analyses, we should be thinking about or is the focus really here on duration and then for proof of concept in the thalassemia program, maybe you can walk us through what a win scenario looks like for establishing proof of concept. Thanks. So much.

Anupam Rama: So for the DRIVE-PK Extension Study, are there going to be any new analyses we should be thinking about, or is the focus really here on duration? And then, for proof of concept in the thalassemia program, maybe you can walk us through what

Anupam Rama: What a win scenario looks like?

Anupam Rama: Proof of Concept. Thanks so much.

I had a palms, Chris Bowden here.

Anupam Rama: Thanks so much.

Christopher J. M. Taylor: Adam Palms, Chris Bowden For DRY-PK, the main thrust of that abstract is really to give people a sense of the durability of responses and what safety looks like over that extended period of time, given the activity we've observed to date and the way we're thinking about treatment for this disease. Long-term safety is really important, as well as the durability of the hemoglobin response. So really, DRY-PK is a pivotal trial in terms of the foundation support for that premise, and then our ACTIVATE studies would continue to validate that, would be our expectation.

But for drive PK. The main thrust of that abstract is related people a sense of the durability of responses and whats safety looks like over that extended period of time given that given the activity we've observed to date and the way we're thinking about treatment for this disease.

Long term safety is really important as well as durability of the.

Hemoglobin response, so really drive PK as a pivotal trial in terms of the foundation support for that premise and then our activate studies.

Continue to validate that would be our expert expectation and look for guides the fallacy me.

Christopher J. M. Taylor: And with regard to thalassemia, just let me back up for a minute and remind people on the call that this is an open-label phase 2 study with 17 patients, approximately 17 patients, where we're studying 50 to 100 milligrams over a treatment period of several months, and then patients can go into an extension. So what we're looking to understand is the percentage of patients who have a one gram or higher increase in hemoglobin over the treatment period. So success for us will really be predicated on the percentage of patients who have a hemoglobin response and how robust that hemoglobin response is. We also want to look at markers of ineffective erythropoiesis. It will be really important to understand whether we're able to cool off the bone marrow, if you will, or make it more efficient.

Just let me back up for a minute.

Remind people on the call that this is an open label phase two study with 17 patients approximately 17 patients where we're studying 50 to 100 milligram silver.

Treatment period of several months and then patients can go into an extension. So what we're looking to understand as a percentage of patients who have a one gram or higher increase in hemoglobin over the treatment period.

So success for us will really be predicated on the percentage of patients who have the hemoglobin response, our bus that hemoglobin response is we also want to look at markers of ineffective retro cohesiveness I'd be really important to understand whether were able to cool off the bone marrow, if you will or make.

More efficient.

Christopher J. M. Taylor: This is the first trial where we're testing in the clinic our ability to activate wild-type PKR in a hemoglobinopathy. So those are all the questions we're asking. In terms of success, we're going to look at the response rate. We're going to look at the safety overall, and then think about what we see in terms of what things we think are coming in this disease in terms of other treatments that are coming for patients. Talk to investigators, and then that data and the totality of those data will be what will inform our decision.

This is the first trial where were testing in the clinic, our ability to activate wild type PK are in Hemoglobinopathies.

So those are all the questions are asking in terms of success, we're going to look at the response rate.

We're going to look at the safety overall and then.

Think about.

What that what we see in terms of what things. We think are coming in this disease in terms of other treatments that are coming from patients talk to investigators and then that will those data and the totality of those data will be what will inform our decision.

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

Great. Thanks for taking my question.

Our next question comes from Michael Schmidt with Guggenheim.

Michael: Good morning and thanks for taking my question. I actually had one on IDFA, and obviously acquisitions can be disruptive sometimes, but I was just wondering how committed Bristol is to potentially maximizing the commercial potential of IDFA. For example, what are their plans to initiate additional early extending enabling studies in AML and other indications?

Good morning, and thanks for taking my question I actually had one on I'd fine obviously.

Can be disruptive, sometimes but I'm just wondering what your sense of how committed breadth.

Potentially maximizing the commercial potential too.

For example.

In addition on they make spending.

Studies name now.

Jackie Faust: Hi Michael. It's Jackie.

I know that became.

Hi, Michael its Jackie So let me start with this one I mean, we can't predict what Bristol Celgenes going to do nor exactly how they're thinking about this I mean, they've certainly had a lot on their plate. The partnership that we have with Celgene that will transfer too.

Jackie Faust: So let me start with this one. I mean, we can't predict what Bristol Celgene is going to do, nor exactly how they're thinking about it. I mean, they've certainly had a lot on their plate. But the partnership that we have with Celgene that will transfer to us continues to go well. We've had a great partnership with them for the last nine years, and I expect we'll continue to have a great partnership with them. In terms of the ongoing trials for IDFA, I mean, as I think you probably know, there's the IDENTIFY trial that's ongoing for the drug in combination with azacitidine, and then there's the HOBON trial where both drugs, TIPSOVO and IDFA, are being So those are ongoing. Those will contribute to label expansions for both drugs. And as far as the rest of it is concerned, let Bristol and Celgene get their deal closed and do their portfolio prioritization, and see what happens.

Well continues to go well, we've had a great partnership with them for the last nine years and I expect we'll continue to have a great partnership with them in terms of the ongoing trials for I defer to I mean, as I think you probably know theres the identify a trial that.

Ongoing for the drug in combination with I decided Dean and then there is the whole Bon trial that both drugs tips elbow and on depot are being studied in in the.

Intensive therapy treatment eligible patient population. So those are ongoing those will contribute to label expansions for both drugs overtime and as far as the rest of it let's let bridgestone cells and get their deal closed and do their portfolio prioritization and see what happens.

Michael: Okay, great. Thank you.

Okay, great. Thank you and then a question on PKD.

Christopher J. M. Taylor: And then a question about PKD. I mean, when we talk to physicians about this, it sounds like the range of symptoms can be from very mild to severe. And I guess, maybe two questions. How is your work going in terms of patient identification at this point? And then based on that, I guess, what percentage of PKD patients do you believe are potential treatment candidates for Metapivot, assuming success in trials next year?

Talk decisions about this.

It sounds like the.

And then comes.

From a very mild.

I guess, maybe maybe two questions I guess, how if you were going in terms of patient identification at this point and then based on that I guess, what percentage of PKD patients.

Public pension treatment county that pivot assuming success and trials. Thanks.

Okay, Great and it's Chris here, Chris Bowden.

Christopher J. M. Taylor: Okay, great. It's Chris here, Chris Bowden.

Christopher J. M. Taylor: So our patient ID efforts are ongoing globally, and I think we've done a really good job and gained momentum as we've been going since we started this program however many years ago. You know, this started out as a learning experience for Agios in the rare disease space, and as we brought in more expertise and put more resources into it, we now have people distributed throughout the world interacting with hematologists and physicians in terms of identifying patients. I would say one piece of tangible evidence around that is our ability to accrue more patients than we initially anticipated in the Activate piece. So, it's something that we're going to continue to do because, you know, one of the challenges when you have a rare disease where there are no existing therapies is that there's not much of a reason, or there's not a lot of motivation to identify patients because there's nothing that you can do for them. So, as we continue to move forward, education and awareness will be a really important component of that.

So our patient I'd efforts are ongoing globally and I think we've done a really good job and gained momentum as we've been going.

As we started this program however, many years ago.

Yes, the started out as a learning experience for our Geos and the rare disease space and as we brought in more expertise and put more resources on it.

We now have people distributed throughout the world.

Interacting with Hematologist and physicians in terms of identifying patients I would say one piece of tangible evidence around that is our ability to accrue more patients than we initially anticipated in the activate T study.

So it's something that we're going to continue to do because one of the one of the challenges when you have a rare disease, where there are no existing therapies as there's not much of a reason that there's not a lot of motivation.

To identify patients because there's nothing that you can do for them. So as we continued to move forward education and awareness will be.

Really important component to that.

Christopher J. M. Taylor: Now, the second part of your question, there are a number of ways you can approach it, and that is the percentage of patients who are potential treatment candidates. And you start from the premise that all patients who have a diagnosis and have anemia are potentially eligible to be treated. We are thinking about what their symptom burden is, what their disease burden is, and that's not just their anemia, but if over time we're able to develop and demonstrate improvements in other aspects of the overall disease burden, then physicians may take that into consideration as they think about treating a patient.

The second part of your question.

Theres a number of ways you can approach that as a percentage of patients who are potential treatment candidates and you start from the premise that all patients who have a diagnosis and have anemia are potentially eligible to be treated.

We are thinking about what their symptom burden as what their disease burden as and that's not just the their anemia, but over time, we're able to develop we're able to demonstrate improvements and other.

Aspects of the overall disease burden physicians may take that into consideration as they think about treating a patient if you take a more.

Strict view and you think about our trials we've.

Selected patients who have in the activate study who have a hemoglobin less than 10 and then there are various genotype profiles you have to have at least when missense mutation, which represents about 80% of the adult population.

Christopher J. M. Taylor: And then there are various genotype profiles. You have to have at least one missense mutation, which represents about 80% of the adult population. On the Activate T side, again, we put the same genotype aspects on it, so we're looking at about 80% of those patients. So I think you have to balance those and hold those two perspectives in terms of thinking about what the percentage of potentially eligible patients is. And I think that, assuming successful trials, I think there is a possibility that clinicians may even consider patients with two non-missense mutations if, in fact, we haven't characterized the activity of our drug against those mutations. They might give them an empiric course of treatment for several weeks, and if they don't respond, then stop. So it's definitely going to be an evolving picture in terms of the percentage of eligible patients based on what you pointed out, the spectrum of disease severity, molecular features, what our data looks like, and sort of physicians' comfort with empirical treatment.

On the activate T side again, we put the same genotype aspects on so we're looking at about 80% of those patients. So I think you have to you have to balance those and hold those two perspectives in terms of thinking about what the percentage of potentially.

Eligible patients are and I think that assuming successful trials I think.

There is a possibility that clinicians may even consider patients with two non missense mutations if in fact, we havent characterize the activity of our drug again says mutations they might give them and empiric course of treatment for several weeks and if they don't respond and stock. So it's.

On to be definitely and involving picture in terms of.

The percentage of eligible patients based on what you pointed out spectrum of disease severity molecular features what our data looks like.

And that sort of physicians comfort with empirical treatment regimens.

Christopher J. M. Taylor: Thank you for listening.

Thank you.

Our next question comes from kind of macabre RBC capital markets.

Kenan McKay: Our next question comes from Kenan McKay with RBC Capital Markets.

Darren Miles: Thanks for taking the questions and congrats on the operational and commercial quarter here. Maybe on that note, just a question on what we're seeing in terms of trends of TIPSOVO usage in frontline AML. Specifically, I was wondering about some of the conversation around the frontline combo with HMAs, and I was wondering specifically if that combination with HMAs was what was driving the increase in duration that was mentioned on the call from four to five months versus frontline patients who are essentially unfit for other therapy and might otherwise be moving to hospice. And on that note, I was just wondering sort of what data stood out or what you're hearing from physicians for justify Thank you.

Hi, Thanks for taking my question. Thanks, Congrats on the our operational and commercial commercial quarter here.

No just a question on what we're seeing in terms of trends.

Uh huh.

Frontline AML specifically.

I was wondering around some of the conversation around the.

Frontline combo with Hmm.

And.

So wondering specifically if that combination with h. amazed with what was driving.

Kristen duration, but it was mentioning mccall from four to five among.

Versus before on pushing through essentially unfit for otherwise therapy, there might otherwise moving to hospitals and on that note.

Just wondering sort of what what data stood out or what you're hearing for from position for.

Justifying you spread what really is.

Incentivizing patient to use.

That combination.

Darren Miles: Kenan, thanks for the question. This is Darren here.

Got it thanks for the question the Darren here, the I think as I mentioned on the call with than we've seen we've seen nice growth in both the frontline and the end in relapsed refractory setting given the makeup of our distribution channel. It's we have limited visibility into exact patient composition characters.

Darren Miles: I think as I mentioned on the call, we've seen nice growth in both the frontline and in the relapse refractory setting. And given the makeup of our distribution channel, we have limited visibility into exact patient composition characteristics in the first line versus the relapse refractory setting. But what our market research indicates to us is that we're seeing continued growth in both newly diagnosed and relapsed patients. This includes also the observation that roughly half of the use in the frontline setting is in combination with HMAs. I think it's important to note that we only promote monotherapy use in both frontline and the relapse setting, but I think it's reasonable, and actually based on the feedback that we're getting from our advisors and additional antidotes, I think what the adoption of combo in the frontline setting reflects is growing awareness and comfort with the data coming out of MD Anderson, evaluating the combination of both Ivo and HMA, which we've updated a couple times this year, and we'll have additional updates and publication in the future.

Sticks in the.

I would characterize the first line versus the lesser resetting, but what our market research indicates to us as that we're seeing continued growth in both newly diagnosed and relapse relapsed patients. The the this includes also the observation that.

That roughly half of the used in the frontline setting is in combination with.

Hmm, but it's important to note.

We only promote monotherapy use in both frontline and and the relapse setting.

But I think it's reasonable.

Actually based on the feedback that we're getting from our advisors.

And additional antidotes I think what what the adoption of a combo in the frontline setting reflects is growing awareness and comfort with the data coming out of MD Anderson.

Evaluating the.

The combination of both IPO and and HMH, which we've updated.

Couple of times this year and we'll have additional updates in the publication in the future on so I think thats whats driving.

Darren Miles: So I think that's what's driving the adoption in that setting, and I think what those data reflect is a significant observation in terms of complete response rate and CRH rate as well in those newly diagnosed patients. And I think that ultimately, since efficacy rules the day and a fairly well-tolerated safety profile, that's what's driving the utilization in the frontline setting.

Driving.

The adoption in that setting I think what those data reflect is.

A significant.

Observation terms of Buck complete response rate and CRH rate as well and in those newly diagnosed patients.

And I think that ultimately since efficacy ruled the day and a fairly well tolerated safety profile.

That's what's driving the utilization in the frontline setting.

And then maybe just going back to ash.

Darren Miles: And then maybe just going back to ASH, last year there was a big conversation about IDH inhibitors sort of versus something like venetoclax, especially in some of these earlier stage patients who might be more tolerable of drugs with a more challenging side effect profile. Wondering your thoughts on going into ASH this year.

Lastly are those that there was a big conversation about.

IDH inhibitors sort of versus something like <unk>, but not to talk to especially in some of these earlier stage patients.

Who might be more tolerable of or more of drugs rhythm more.

Challenging side effect profile.

I just.

Wondering what your thoughts on.

Going to ask this year is there any chance we could feed data from the.

Darren Miles: Is there any chance we could see data from the combination of the IDH inhibitors with Venclexta? And again, on that same topic, wondering any sort of feedback you're hearing in terms of how physicians are making the choice between, for example, an IDH combo with HMAs versus a Venclexta combo with HMAs. Thanks for taking the questions.

Combination.

Inhibitors venclexta.

And again I'll now turn topics wondering any sort of feedback you're hearing in terms of how physicians are making the choice between like an IDH combo.

Hmm pursuit of and Carpenter combo with picture me. Thanks for taking my question.

Darren Miles: So, we don't expect to see an update on the Ven Plus Ivo combination, which is a study being conducted by Courtney DiNardo out of MD Anderson. I will just note that the study is being expanded to include newly diagnosed patients as well in combination with HSD. To your point, I think it's an interesting conversation that's going on in the community around the various options that are newly available for them.

So we don't expect to see an update on the on the van Den plus IPO combination.

Which is a study being conducted by our quarterly dinardo out of MD Anderson.

I will just note that study is being expanded to include our newly diagnosed patients as well in combination with with H. amaze on to your point I think the the it's initially conversation thats going on in the community around around the various options that are being newly available for them. So were I think we're just heading into the.

Darren Miles: So I think we're just heading into the norming stage after a significant storming phase where physicians are just trying to figure out how to use all of these new agents and in what particular patients. I think in this setting, in particular, again, what rules the day is going to be safety and efficacy. I think our strategy has been to focus monotherapy on those patients who were previous or secondary AML patients or those patients who've been previously exposed to HMA for an antecedent disease like MDS. And from what we can tell from the feedback that we get in our market research as well as from the community, that's largely where we see monotherapy use. I think it's important to make sure that we focus on what's driving these sorts of choices here.

Norming stage after a significant storming phase where physicians are just trying to figure out.

How to use all of these old these new agents and in one particular patients I think in this setting particular.

Again, what rules a day is gonna be safety safety and efficacy I think the our strategy has been to focus monotherapy and in those patients who were previously secondary AML patients are those patients with the previous exposed to actually make work and that seems disease like like Mds and that from.

From what we can tell from the feedback that we get in our market research as well as.

From the community, that's largely where we see the monotherapy use.

I think it's important to make sure that we focus on what's driving sort of choices here you have group of patients who.

Darren Miles: You have a group of patients who are, these are very sick patients, right? Oftentimes, these are older patients, many of them previously treated for another disease. And so are unwilling or unable to withstand the cytopenia associated with HMA or HMA-based combinations. And what they appreciate about our data is the complete response rate, CR, CRH rate, and the durability of that response and the safety profile. What physicians, I think, often appreciate is the clinical data supporting transfusion independence as well as the time to recovery for platelets and neutrophils. I think that is what we hear consistently from those who are steady users of ibucitin in the frontline setting.

These are very sick patients right often times. These are older patients many of them previously treated for for another another disease.

And so are unwilling or unable to.

To withstand the cytopenias associated with some each remain where they generation may base combinations.

And what we what the what they did get appreciate about our data is the the complete response rates CR CRH rate and the durability of that response and the safety profile on what positions I think often appreciate is the.

Is the.

The.

Clinical data supporting the transfusion independence as well as the time to recovery on platelets and and neutrophils I think that is what we hear consistently from those who are.

Work steady users of.

Outside and had been frontline setting.

Thank you very much Super helpful color and one final question, if I know it seems like an enrollment to your point and activate.

Darren Miles: Thank you very much. It's super helpful, Cora.

Kenan McKay: And one final question, if I may. It seems like enrollment, to your point, in ACTIVATE-T has gone sort of well above expectations with that trial actually getting better, and I have a lot of confidence in that getting fully enrolled by year-end. If one of these trials, for instance, ACTIVATE-T does complete enrollment by year-end, and ACTIVATE is still enrolling, is there a chance these data readouts could come at sort of separate time points next year as these independently reach their Phase III endpoints? I just wanted to take your temperature on whether that, or the confidence in that completion of enrollment in ACTIVATE by year-end. Is there a chance that could be sort of early 2020, or is it really looking on track for year-end 2019?

TV has gone sort of well above expectations would that trial actually getting.

Upside and I think a lot of confidence and not getting fully enrolled by by yearend.

One of these trials for instance, accurate team does complete enrollment by year end activated still enrolling.

Is there a chance whose data read outs could be could comment sort of separate PON points.

Okay independently reach there.

Theres three endpoints and just wanted to take Youre, a comparator on on whether that's the confidence in completion of enrollment and activate.

By year end, new fair chance that could be sort of early.

2020 or is it really looking on track for for your in 19.

Hi, Ken it's Chris here.

Christopher J. M. Taylor: Hi Ken, it's Chris here.

Christopher J. M. Taylor: We're guiding to completing accrual by the end of the year. We're working really hard to get patients who are screened, randomized, and into treatment for Activate, and Activate T is, as you've said, accruing nicely. It's certainly possible that the readouts for the two trials could be disengaged, but I think that when you think about when we look at them to see how they're accruing and then you've got the time on treatment and follow-up periods and all that, they're more likely to be engaged. But yes, it's possible.

Guiding to completing accrual by the ended the year, we're working really hard to get.

Patients who are screened at randomized and into treatment for activate and activate T is as you've said has been accruing nicely, it's certainly possible that.

The to the Readouts for the two trials could be disengage, but I think that when you think about.

When we look at them to see how their accruing are and then you've got the timeline treatment follow up periods and all that they're more likely to be to be engaged but yes, sorry, it's possible.

Thanks for taking my questions appreciate it guys and congrats again on the quarter.

Kenan McKay: Thanks again for taking the questions, I appreciate it guys, and congrats again on the quarter.

Our next question comes from Mohit Bansal with Citi.

Mohit Bansal: Our next question comes from Mohit Bansal with Citi.

Great. Thanks for taking my question in a very good morning.

Mohit Bansal: Great. Thanks for taking my question and a very good morning. So one question I have is about your glioma trial. Could you please walk us through why you are choosing this particular population? Because IDH mutations tend to be a positive diagnosis factor for low-grade glioma, so how should we think about this particular control, this particular subset of patients, and your expectations for the control arm. How would that arm perform? And I have a follow-up appointment after that.

So.

One question I had is on your deal much Ryan.

Could you.

Could you. Please walk us through why you are choosing this but you bid population asking for because IDH mutation tend to be.

We'll pause it to go doses factor for low grade deal. So how should we think about this particular control.

Hello.

Subset of patients and your expectation for around control, how could that how would that that outperform and I have follow up after that.

Yes. This has always been an interesting aspect of developing and drug as Chris Bowden here in this indication because you have a when you look at published data whether its natural history data or from randomized trials with active treatment.

Christopher J. M. Taylor: Yeah, this has always been an interesting aspect of developing a drug. It's Chris Fowlton here in this indication because when you look at published data, whether it's natural history data or from randomized trials with active treatment, you will see long results in terms of progression-free survival and overall survival that are far longer than what you're used to seeing in trials where patients would have metastatic advanced solid tumors. And the question has been, what's the unmet need? And what are the logistics of doing a trial in this patient population? So let's start with the unmet need.

We'll see a long.

Results in terms of per day.

Progression free survival.

Overall survival that is far longer than what you're used to seeing in trials, where patients would have metastatic advanced solid tumors and the question has been once the unmet need and one of the logistics of doing a trial in this patient population. So let's start with the unmet need on the majority of patients who are diagnosed.

Christopher J. M. Taylor: The majority of patients who are diagnosed with low-grade glioma are younger relative to how you think about many of the solid tumor trials that you look at. Or, for instance, the AML patients that Darren was just talking about in the previous discussion, around 40 years of age, 40 to 50. So you have patients who, on the one hand, have a survival rate of 10 years plus, if you look at the entire population, yet at the same time, if you're given a diagnosis at the age of 40 of below-grade glioma, you undergo a resection. And then the unfortunate part is, for most patients, there's a long, slow, inexorable decline. And that decline is typified by gradual progression of the disease, the use of radiation therapy, chemotherapy, steroids, and other supportive measures that carry with them an enormous treatment-related burden, in addition to the problems of having a progressive disease in the brain, which brings with it neurocognitive deficits and other problems.

Low grade glioma are younger relative to how you think about many of the solid tumor trials that you look bad or for instance, the AML patients that Darren was just talking about in the previous discussion around 40 years of age 40 to 50, So you have patients who.

On the one hand, having a survival of as measured in 10 years, plus if you look at the entire population yet at the same time, if you've given a diagnosis at the age of 40 below grade Glioma, you undergo resection and then the unfortunate part is for most patients as a long slow and exit.

We will decline and that decline.

His typified by gradual progression of disease, the use of radiation therapy chemotherapy steroids, another supporting measures that carry with them an enormous treatment related burden. In addition to the problems of having a progressive disease in the brain.

Which brings with it neuro cognitive deficits and other problems. So what has been a long long use clinical strategy given all of that knowledge in discussions with patients once you've had your initial surgery.

Christopher J. M. Taylor: So what has been a long-used clinical strategy, given all of that knowledge, is discussions with patients. Once you've had your initial surgery, we can watch and wait until you have progression, and then institute radiation and Chemotherapy and other and more surgeries and other disease controlling measures. So as we were developing our drug and showing long-term stable disease, as well as evidence of tumor regression when we looked at our waterfall plots, this population emerged in discussion with investigators on the basis of the fact that we have a well-tolerated drug that can be given once a day for long periods of time in a group of patients who would like to stave off the use of agents like chemotherapy and radiation therapy. So that sets the stage for the Indigo study, where we have a carefully characterized group of patients who will have had surgery only, and then eligible patients will be randomized to daily voracidin versus placebo, with the intent to delay progression and, as a secondary endpoint, delay the need for chemotherapy and radiation therapy and all the problems associated with that.

We can watch and wait until you have progression and then institute radiation and chemotherapy and other and more surgery and other disease controlling measures.

So as we were developing androscoggin, showing a long term stable disease as well as evidence of tumor regression. When we look at our waterfall plots. This population emerged in discussion with investigators on the basis of the fact that we have a well tolerated drug that Pete can be given once a day for long periods of time and a group of patients.

I would like to stave off the use of agents like chemotherapy and radiation therapy. So thats set the stage for the Indigo study, where we have carefully characterize group of patients who will have had surgery only.

And then eligible patients will be randomize to daily bore side, and then versus placebo with the intent to delay progression and as a secondary endpoint.

Delay the need for chemotherapy and radiation therapy, and all the problems associated with that.

Mohit Bansal: How should we think about the control arm expectations here in terms of months of PFS?

And then how do how should we think about the control.

Expectation said in terms of months off PFS.

Christopher J. M. Taylor: So, we have disclosed some of the initial details around the trial design today, and we will certainly update you with statistical information in the future. I think it's important to both know what the control arm is, what we expect the control arm performance to be, as well as what we expect the performance to be in the active arm, because that's how we can set up a sample size that allows us to accrue a trial in a reasonable period of time based on our feasibility discussions with investigators. So that information is forthcoming.

So we.

Disclose some of the initial details around the trial design today and we we'll certainly update you with the statistical information.

In the future I think it's important to both now and what the control arm, what we expect to control arm performance to be as well as what we expect the performance to be in the active on because that's how we can set up a sample size. It allows us to accrue at trial in a reasonable period of time based on our feasibility discussion with invests.

Together, so that information is forthcoming.

Mohit Bansal: Great, thank you. And then there is one housekeeping kind of question.

Great. Thank you and then one.

Housekeeping kind of question, Phil you mentioned that and Yeah. Matt you are currently more penetrated the academic setting.

Darren Miles: So you mentioned that in AML, you are currently more penetrated in the academic setting. Can you please give us some color on what percent of patients right now on TIPSO are coming from academic versus community and what is the general population, what is the breakup in these two settings for your target patient population? Thank you.

Can you.

Give us some color on what percent of patients right now.

On the tool coming from academic questions community and what is the journal.

General population.

Okay coping these too.

Setting so far what are your target patient population. Thank you.

No problem. So the its not its has been our practice to disclose the exact split between those patients coming from the academic and the.

Darren Miles: No problem. So it hasn't been our practice to disclose the exact split between those patients coming from the academic setting versus the community setting. I think it's fair to assume, though, that a significant portion will come out of the academic setting. What's important to note, what we observed in the third quarter continues to be a similar trend to what we've seen elsewhere, which is what we're seeing in prior quarters, and that is that we've got good, strong growth in both settings, both in terms of scripts, our new patient starts, but also the number of new treaters that are identified in both of those settings as well.

Versus versus the community setting I think it's fair to assume no that up a significant portion will come out of the come out of the academic setting what's important to note.

What we observed in the third quarter continues to be the similar trend to what we've seen elsewhere. How much of what were happening are seeing print in prior quarters and that is that we've got good strong growth in both settings.

Both in terms of scripts are new patient starts but also.

The number of new treaters that are identified in both of those settings as well.

Darren Miles: Go ahead; have a good day. Thank you.

Got it has the pack thank you.

Chris Taylor: Again, ladies and gentlemen, if you have a question or a comment at this time, please press the star and then the one key on your touchtone telephone. Our next question comes from Chris Shibutani-McAllen.

Again, ladies and gentlemen, if you have a question or comment at this time. Please press the star than the one key on your touched on telephone.

Our next question comes from Chris Shibutani Macfarlane.

Chris Taylor: Thanks very much. If I could just ask a series of sort of upcoming go-no-go decisions, particularly just to clarify what timelines and what we should expect. The first you mentioned for the proof-of-concept data for mid-pivot in thalassemia, you said you would have that in-house by the end of the year. When can we expect you to share that information? That would be number one.

Thanks, very much if I could just ask a series of sort of upcoming go no go decisions, particularly just to clarify what timelines and what we should expect the first you mentioned for the proof of concept data for me to pivot in Thalassemia. You said you will have that in house by the end of the year when can we expect Q.

Share that information that would be number one number two.

Chris Taylor: Number two, in MDS, you're continuing to enroll now again in phase one, which you had mentioned in a previous quarter as well. When might we expect some information there, and what kind of timeline would that be for making that go-no-go decision? And then finally, for AG270, I believe now that we've had the data disclosure that Celgene has a five-month period for which they'll make a go-no-go decision about whether they'll continue to partner with AG270. Jackie, you've talked a little bit about being able to contemplate now, so many years into the relationship with Celgene, thinking about possible ways that a reconsideration of how that relationship Is that ongoing, and is that at all tied to HE270? It would be helpful to know, again, what your thinking is there. Thank you.

In Mds, you're continuing to enroll now again in the phase one, which you had mentioned I believe in a previous quarter as well when might we expect some information there and.

What kind of timeline would that be for making that go no decision and then finally for AG 270, I believe now that we've had the data disclosure that celgene has a five month.

Good for which they'll make a go no go decision about whether they'll continue to partner that.

Jackie you've talked a little bit about.

Being able to contemplate now so many years into their relationship with Celgene.

Thinking about possible ways that reconsideration of how that relationship is structured.

Is that ongoing and is that it all tied to 82 70.

That would be helpful to know again, what you're thinking is there. Thank you.

Jackie Faust: Hi Chris. Thanks for the questions. I'm going to just jump in and start with 270 and then let Chris come back on the Thal and MDS questions. So, we have triggered the opt-in period with Celgene, so we have submitted the data package to them under the contractual agreements. They have up to 150 days. They don't have to take 150 days, but they can take up to 150 days to ask us for additional analyses or ask us for more data, and then go away and evaluate that data package.

Hi, Chris Thanks for the questions, Jeff I'm going to just jump in and start with 270, and then let Chris come back on the Fallon Mds said questions. So the we have triggered the opt in a period with Celgene. So we have submitted the data package to them under the contractual agreements they have up.

To 150 days, they don't have to take 150 days, but they can take up to 150 days too.

Ask us for additional analyses are asked us for more data and then go way and evaluate that data package. So again I can't speak for what Celgene in Bristol together are going to do as you know we have multiple components to the relationship one of them is around I'd.

Jackie Faust: So, again, I can't speak for what Celgene and Bristol together are going to do. As you know, we have multiple components to the relationship. One of them is around IDFA, which is more of a commercial partnership, and then we have The Metabolic Immuno-Oncology Research Collaboration that is also ongoing, and we have this program with 270 where they potentially may opt in to that program. So we have to let them do what they're going to do in terms of getting their deal closed and look at their various portfolio prioritization decisions.

FFO, which is more of a commercial partnership and then we have.

The metabolic immuno oncology research collaboration that is also ongoing and we have this.

Program went to 70, where they have potentially.

May opt in to that program so.

I think you have to let them do what they're going to do in terms of getting their deal closed and look at their various portfolio prioritization decisions on what I've said in the past is I think they've been great partners in the past by continuing to be a great partners I think they will be great partners in the future and I only see opportunity associated with that ongoing relation.

Christopher J. M. Taylor: What I've said in the past is that I think they've been great partners in the past. They continue to be great partners. I think they will be great partners in the future. And I only see opportunity associated with that ongoing relationship. I don't see any downsides for Agios from the Bristol-Celgene merger. And that's about all we can say on that. And I'll give it to Chris for the other two questions.

If I don't see any downsides to our sales from.

Bristol's challenging merger that's about all we can sound that I'll give it to Chris for the other question.

Christopher J. M. Taylor: Okay, thanks Jackie. This is Chris Bowden here. So myelodysplastic syndrome, Chris, is up and running, and sites are open for accrual. I can't give you an estimate of when we think we're going to have that data in, but hopefully, as we get a little more clarity around the ramp-up and patients coming in, then we'll be able to provide that information at a later date. MDS is about IDH1 mutation-positive patients represent about 3% overall of the MDS population. We're going after relapse refractory patients who really have high unmet need because they've all seen HMAs and other therapies. So it's a relatively small percentage, especially if you think about it in the context of IDH-1 and AML, where we're looking more like 8 to 10 percent. Nevertheless, given that we're working with the same sites that did our initial study, they're all centers of excellence, we think there'll be lots of interest in getting patients onto the study.

Okay. Thanks, Jackie Chris Bowden here, So Myelodysplastic syndrome, Chris is up and running and sites are open for accrual can't guide to when we think we're going to have that date in but hopefully as we get a little more clarity around the ramp up and patients coming and then we'll be able to provide that information at a later date Mds is about.

IDH one mutation positive patients represent about 3% overall, the Mds population were going after relapse refractory patients, who really have high unmet need because they've all CNH amaze another therapies.

So it's a relatively small percentage, especially if you think about it in the context of IDH, one in AML, and where we're looking more like 8% to 10%.

Nevertheless, given that we're working with the same sites that did our initial study of they're all centers of excellence, we think there'll be lots of interesting getting patients onto the study so more to come there as far as the foul proof of concept timing goes our goal is to have adequate information in house to enable a.

Christopher J. M. Taylor: So more to come there. As far as the Thal proof-of-concept timing goes, our goal is to have adequate information in-house to enable a decision on whether we've achieved proof-of-concept or not by the end of the year. When we choose to communicate that, whether we have achieved that goal or not, is something that we're still looking at, whether it would be at the end of this year or sometime early next year. This is something I'm

Vision on whether what we've achieved proof of concept or not by the end of the year when we choose to communicate that.

Whether we have achieved that going on is something that we're still looking at whether it would be at the end of this year sometime early next year.

Chris Taylor: Great. Thank you for some additional insights. I appreciate it, and congratulations on the commercial progress.

This is something that we're working on.

Great. Thank you for some additional insights appreciate it and congrats on the commercial progress.

Tyler Van Buren: Ladies and gentlemen, in the interest of time, we ask that you limit yourself to one question. Our next question comes from Tyler Van Buren with Piper Jaffray.

Thank you.

Ladies and gentlemen in the interest the time, we as a true limit yourself to one question.

Our next question comes through tolerant Andrew on the Piper Jaffray.

Tyler Van Buren: Hey guys, good morning. Just one last follow-up on the Medepivac Betafowel proof of concept. Specifically, can you say what minimum response rate you think you need to see to achieve proof of concept? And, just as a quick follow-up, does time to response matter as well?

Hey, guys. Good morning, just one last follow up on the middle to that but I felt proof of concept.

Specifically can you say what minimum response rate you guys think you need to see to achieve proof of concept and just as a quick follow up does time to response matter as well.

Christopher J. M. Taylor: Well, I think that's all. The interesting question is, what do you need to see a minimum response rate as well as time to response? I'm just touching on some of the aspects I've commented on earlier. First, this is an open-label pilot study, or a study where we're trying to understand whether the drug works or not. And that's the primary efficacy variable in terms of how we're looking at an increase in hemoglobin of one gram or higher. It's a great question.

Well I think that that saw the interesting question is.

What do you need to see a minimum response rate as well as time to response I am just touch on some of the the aspects I've I've commented on earlier.

First this is say open label.

Pilot study here study, where we would trying to understand does the drown work or not and that's the primary.

Efficacy variable in terms of how we're looking that as the increase in hemoglobin of one gram or higher.

It's a great question. If you do that does how does that impact us if it takes a long time to get there versus a very short time in patients pirated kinase deficiency, we see a relatively rapid onset of response and that has a lot of interesting characteristics about that are generally favorable.

Christopher J. M. Taylor: How does it impact us if it takes a long time to get there versus a very short time? In patients with pyruvate kinase deficiency, we see a relatively rapid onset of response, and that has a lot of interesting characteristics that are generally favorable. So, but I wouldn't hang my hat on that, um, just like the other aspect of, Do you, if you see a high percentage of patients who have a one-gram increase and a very small percentage of patients who have a, you know, a higher increase, that might impact terms of how we look at whether we have achieved proof of concept or not. And then duration and safety are also important. We know a fair amount about this drug now from our trials in patients with pyruvate kinase deficiency, and we don't expect to see any major changes in the safety profile, but, you know, assumptions you have to test and you have to verify. So I can't emphasize enough how important that safety component is as well.

So, but but I wouldn't hang my hat on that.

Just like if the other aspect of.

If you see a let's say a high percentage of patients who have a one gram increase and a very small percentage of patients who have a higher increase that might impact on terms of how we.

Look at have we achieve proof of concept or not and then duration and safety is also important we know a fair amount about this drug now from.

Our trials in patients with part of a kinase deficiency and we don't expect to see any major changes in the safety profile.

But.

Assumptions you have to test and you have to verify them. So I can't emphasize enough how important that safety calm.

Christopher J. M. Taylor: So I'm not giving you a specific answer about what response rate we need to see, because there are a number of components that come into that phrase that you hear me use a lot, which is the totality of data, and we tend to look at things that way, especially in earlier phases of development in single-arm, open-label studies, whether it's in oncology or rare genetic diseases. Got it. Thanks for providing that color.

Component as well so im not giving you a specific answer of what response rate that we need to see.

Because there are number of components that come into that phrase that you hear me use a lot which is the totality of data and we tend to look at things that way, especially in early phase earlier phases of development in single arm Open label studies, whether it's in oncology a rare genetic diseases.

Got it thanks for providing that color.

Tyler Van Buren: Thanks for providing that color.

Our next question comes from Salveen Richter with Goldman Sachs.

Salveen Jaswal Richter: Our next question comes from Salveen Richter of Goldman Sachs.

Salveen Jaswal Richter: Great. Thanks for taking the question. Just touching on the AG270 data from the TRIPLE meeting, the maximal tumor reduction in marine models is observed within a range of 60 to 80 percent of the SAM reduction. In your view, how translatable are these levels of reduction from the mouse models to humans? And then I have a follow-up.

Great. Thanks for taking the question.

Touching on the 270 data from the Triple meeting the maximum tumor reduction remodels sizes are within the range of 60% to 80% magnitude of that Sam reduction.

In your view how translated by these levels a production from the mouse models to human and then I've a follow up.

Yes, Hi, this is Scott Biller here, yes, that's the range that we achieved and see a effects in preclinical models, but we see a range of activities within that lowering of Sam to some really sensitive models that have that we see actually tumor regression mode.

Scott Biller: Yeah, hi, this is Scott Biller here. Yeah, that's the range that we achieve and see effects in preclinical models, but we see a range of activities within that, lowering SAM to some really sensitive models that have, we see actually tumor regression, but most models are actually, you're seeing effectively stable disease or cytostatic effects. Translating that to a patient, a set of very highly pre-treated patients and rapidly progressing patients is really difficult. And it was always our intention to get into earlier lines of therapy in combination because our preclinical data on that combination were so very compelling. So we're sticking with our strategy, and those are the clinical trials that are starting up now.

Just models are actually you are seeing effectively stable disease or side of static effects translating that to now page a set of very highly pretreated patients are rapidly progressing patients is really difficult.

And it was always our intention to get into earlier lines of therapy in combination.

Because our preclinical data on that combination with so very compelling.

So that's that's we're sticking with our strategy and those are the clinical trials starting up now.

Salveen Jaswal Richter: Great, thanks. And then, if you could just comment on any updates or additional work being done around diagnostic testing in Colangeo, specifically the ongoing efforts with Insight to promote diagnostic testing ahead of their launch.

Great. Thanks, and then if you could just comment on any updates or additional work being done around diagnostic testing and cholangio specifically in the ongoing efforts with insight to promote diagnostic testing out of their launch.

Darren Miles: This is Darren here. As you may know, Thermo Fisher is our partner for the companion diagnostic that would be approved at the time of the Colangio indication approval, which we expect by the end of next year. In terms of collaborations, the opportunity here is the sort of rising tide lifting all boats. You now have two new effective treatments in a setting where there are little to no effective options for these patients. And there's an opportunity to both educate on the importance of testing for both mutations, education on mechanisms of disease, and then following the approval of both products, education on the clinical profiles of the products. So I'm not prepared to discuss any work that could potentially be done in collaboration with Insight at this time. I would say that I would expect that we both be in the community discussing these pre-approval disease education programs for our respective products.

So this is Darren here. So as you May know Thermo Fisher is our partner for the companion diagnostic that would be approved at the time of the Cholangio indication approval, which we expect us backed by the end of next year. The the in terms of collaborations the.

The the opportunity here is this sort of rising tide lifts all boats you have to now too.

New effective treatments.

In a setting where there is little to no.

Effective options for for these patients on there's an opportunity to both educate on the importance of testing for both mutations.

Education on mechanisms mechanism of disease and then following the.

Following the approval of both.

Products the.

Question on the corporate costs with the products.

I'm not prepared to discuss any work that we that could potentially be done in collaboration with with insight at this time I would say that we would I would expect that we'd both be in the community discussing those pre approval.

Salveen Jaswal Richter: Got it. Very helpful. Thanks for the questions.

Our next question comes from Mark Breidenbach with Oppenheimer.

Mark Alan Breidenbach: Our next question comes from Mark Breidenbach with... Hey, good morning guys. I'll keep this quick. So, given the trends you're seeing in Tubsovo use in newly diagnosed AML patients, I'm just wondering if there's a chance we might get an interim readout from the Hogan study sometime in 2020. And a real quick follow-up question is, do you have plans or can you give comments on what you see as the best course for potential label expansion into newly diagnosed cholangiocarcinoma patients, assuming a successful SNDA process once that's under review?

In newly diagnosed CML patients I'm, just wondering if there's a chance we might get an interim readout from the who've on study sometime in 2020 and a real quick follow up is is do you have plans or can you give comments on what you see us as the best course for potential label expansion into.

Newly diagnosed cholangio carcinoma patients assuming a successful sndk process once that's under review.

Yes.

So we.

Christopher J. M. Taylor: Thank you.

Mark Alan Breidenbach: So, we, there should be no expectations that there will be any information around readout or efficacy from the HOVON study. That trial is a large phase three trial that's being conducted by cooperative groups internationally, so we're very excited about the trial and now we're working really hard with the groups to get all the sites up and running and to really, really get momentum going around accrual. So, there will be no, you should not have any expectations around any interims on that next year. And then the second question around what to do in newly diagnosed patients with IDH1 cholangiocarcinomas, one that's of great interest to us, we're in active discussions both internally with investigators on what the best study designs are, thinking about feasibility and some of those aspects as we consider moving into that setting.

There should be no expectations that there will be.

Any information around the read out or efficacy from the have on study.

That trial is a large phase III trial, that's being conducted by cooperative groups in.

Internationally. So we're very excited about the trial and and now we're working really hard with that but the groups.

And then the second question around what the duo in newly diagnosed patients with IDH, one Cholangio Carcinomas one that's a great interest to us were in active discussions today, both internally and with investigators on what the best study designs are thinking about feasibility in some of those aspects as we consider moving into that setting.

Thanks for taking the questions.

Christopher J. M. Taylor: Thanks for taking the questions. Our next question comes from John Newman with Canaccord.

Our next question comes from John Newman with Canaccord.

John Newman: Hey guys, good morning. Thanks for taking my question.

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

John Newman: Just wondered if you disclosed or talked about the dose levels at all for AG270 in the combination studies. Awesome, nice initial data at ACR, partial response, stable disease, which was great. I think you mentioned the maximum tolerated dose was 200 milligrams. Just curious if you're going to be looking at a range of AG270 doses in combination or if you'll have

Just wondered if you have disclosed talked about the dose levels at all for AG 270 of the combination study Uh huh.

Initial data to see our.

On.

That's great.

Thank you mentioned.

I can tolerated dose is 200 milligram just curious if you're going to be looking at.

A range of.

Christopher J. M. Taylor: Yeah, hi John, it's Chris here. It's always a little bit of a challenge, I'd say, when you move from monotherapy to combinations with chemotherapy. Both of those regimens that we're testing, docetaxel, as well as abraxane, gemcitabine, and pancreatic cancer, bring with them a fair amount of toxicity such that when given alone, just those agents stand alone, there's a lot of guidance in terms of dose reductions, whether it's for hematologic or non-hematologic toxicity. So that's the first component that one needs to Where we're starting is with 100 milligrams daily. And if you think back to the comment, the question that Scott Biller answered earlier, it's because at that dose, the data that we showed on, that Dr. Heiss showed, and that we discussed on Sunday night shows that we've reached our target in terms of SAM reduction in that 60 to 80% range, and we'll explore that initially in the first patients that we treat. We could go up to 200 milligrams in combination with those two regimens that I mentioned, but we're very comfortable that we can operate in that range and get the exposure that's associated with the pharmacodynamic modulation that we're targeting. We're not going to do a whole lot of dose exploration.

Yes, Hi, John it's Chris here.

It's always.

A little bit of a challenge I say when you move from monotherapy and the combinations with chemotherapy.

Both of those regimens that we're testing ddos attacks, so as well as.

Abraxane, Jim site of being in pancreatic cancer bring with them a fair amount of toxicities such that when given alone just does it does agent Standalone. There's a lot of guidance in the label in terms of dose reductions weather Fritz for hematologic or non hematologic toxicity. So that's the first component that that one need so.

Keep in mind as you're getting ready to add another drug in this case agee to 70 to those combinations.

Where we're starting as with 100 milligrams daily and if you think back to the comment the question that Scott Biller answered earlier as because that at that dose data that we showed on the Doctor High showed that we discussed on Sunday night shows that Weve reached our target in terms of Sam reduction in that 60% to 80% range.

Yeah.

And we'll explore that initially in the first patients that we treat it we could go up to 200 milligrams in combination with those two regimens that I I mentioned, but we're very comfortable that we can operate in that range and get the exposure that's associated with the pharmacodynamic modulation that that.

Targeting we're not going to do a whole lot of dose exploration. We don't think we need to do that based on the data that we got out of our phase one trial.

John Newman: Great, thank you.

Great. Thank you.

Christopher J. M. Taylor: Our next question comes from George Farmer with VMO Capital Markets. Hi. Thanks for taking my question. For Sidnib, I'm curious as to why you're not thinking about moving forward into later stage gliomas like glioblastoma where you possibly can get a faster readout.

Our next question comes from George from BMO capital markets.

Hi, Thanks for taking my question.

Before it Didnt have I'm curious as to why you're not thinking about moving forward into later stage.

Christopher J. M. Taylor: Yeah, it's Chris Bowden here. So if you go back and look at some of our phase one data, we first let's just talk about the data and then make a few comments on why that may be. We did study some patients with GBM in our initial phase one trial with TIPSOVO, and we've published that data a couple of times now. And when you look at it, patients progress pretty rapidly. So that's the first thing.

Yes, it's Chris Bowden here. So if you go back and you look at some of our phase one data we.

We did study some patients with GBM.

Initial phase one trial with tip Sobo, we publish that data couple of times now and when you look at it patients progress pretty rapidly.

Christopher J. M. Taylor: If you think about the frequency of IDH1 mutations in GBM, it's pretty low, and those tend to be secondary. So what they are is this percentage of patients with low-grade glioma who then, near the end of their life, unfortunately, transform into GBM. And that transitions to why is that? Because the molecular profile of the tumor, at the end of the day, at that point, has changed pretty remarkably. And the amount of drive to that tumor that's coming from IDH1 versus resistance mutations that have come up as a function of time, as a function of treatment with alkylating agents, as a function of treatment with radiation therapy means the ability to impact with this monotherapy in an IDH1 inhibitor makes the probability of And we're not alone there.

Life, Unfortunately transform into GBM, and that's a very difficult situation to handle and that transition. So why is that because the molecular.

Profile of the tumor at that point has changed pretty remarkably and the amount of dry up to that tumor that's coming from IDH one versus.

Resistance mutations that have come up.

As a function of time as a function of.

Treatment with alkylating agents as a function of treatment with radiation therapy in the ability to impact with the monotherapy and IDH. One inhibitor makes the probability of technical success pretty low and we're not alone. There I think about all the drugs that have gone into treatment in the GBM setting and there's not a lot of new treatments.

Christopher J. M. Taylor: Think about all the drugs that have gone into treatment in the GBM setting, and there's not a lot of new treatments there. So that's a really high unmet medical need. And if our data spoke to us in that way, we would certainly go there, because you're right, you can go faster, um, So as we think about the low-grade glioma population based on, A, our findings in the clinic and a lot of the work that we've also published in terms of making some historical comparisons of our data against similar data sets that we've been able to pull out from collaborations with academic institutions like MGH and Dana-Farber and UCLA and others, we feel like that biologically it makes the most sense to go there.

So as we think about below gray glioma population based on a our our findings in the clinic and a lot of the work that we also published in terms of.

With academic institutions like.

Christopher J. M. Taylor: And we've put together a trial that we're confident can be done and demonstrate clinical benefit in a patient population that, while, yes, it has longer survival than patients with GBM, but that doesn't mean that there's not a high unmet need. So we're going there because we think we have the highest probability of clinical and regulatory success in an area where there is an unmet need and where the use of a single agent drug oral therapy can offer some pretty significant benefits for these patients.

Then patients with GBM, but that doesn't mean that there's not a high unmet need there so with that we're going there because we think we have a highest probability of clinical and regulatory success in the area, where there is an unmet need and where the use of a single agent drugs oral therapy can offer some pretty significant benefits for these people.

Christopher J. M. Taylor: Okay, great. Our next question comes from Andrew Berens with SVP. Hi, good morning. Thanks, guys.

Okay, great. Thanks very much.

Our next question comes from Andrew Burns with SVP Larry.

Andrew Scott Berens: I have a question on the glioma program and then, if you'll allow me, a question on the mid-appetite program. We looked at the glioma program before in low-intermediate grade. It really seems like it could take a while for a clinical benefit to be realized in a drug that's primarily for a stable disease and a disease that's primarily indolent. Can you give us just some general idea of when we might see a benefit from the trial? How long could that take to show?

Hi, good morning, Thanks, guys.

I've a question on the Glioma program and then if you allow a question on the Middle pilot program.

I'm not going to we're not going to provide guidance on the accrual timelines or or time to approval submission and approval and the setting of positive study.

Christopher J. M. Taylor: I'm not going to, and we're not going to provide guidance on the accrual timelines or time to approval, submission, and approval in the setting of a positive study. I think, as per some of the previous comments, we've done a lot of work to understand what the outcome will be in a control arm in terms of progression-free survival in a disease where once you do progress in the swatch and wait setting, you're getting chemotherapy and radiation therapy. And in fact, in our discussions with patients and investigators, they don't characterize that as an indolent occurrence. And so that's one of the reasons why we set the trial up the way it is. I think the other aspect that I just want to remind everybody on the call is that our trials are ongoing, and we'll be updating the perioperative data at SNO, and that will, of course, give you some insight, further insight into that trial that we previously published, and then we'll, of course, update some efficacy data there as well.

I think as per or some of the previous comments, we've done a lot of work to understand what the outcome will be in the control arm in a control arm in terms of progression free survival in a disease that.

Once you do progress in this watch and wait setting youre getting chemotherapy and radiation therapy in fact, our and our discussions with patience and investigators.

They don't characterize that as an indolent occurrence and so thats one of the reasons why with.

Setting the trial.

I think the other.

Aspect that I, just want to remind everybody on the call as it were our trials are ongoing and we'll be updating the peri operative data. It's now in that will of course give you some insight further insight into that trial there.

Obviously published and then we'll of course update some efficacy data there as well.

Christopher J. M. Taylor: Okay, I guess in the mid-pivot program and beta-thal specifically, can you give us a little color on what type of patients you're enrolling in that trial? Are they going to be transfusion-independent or transfusion-dependent? And are there any biomarkers specifically that you're looking at that could potentially show a benefit for Medpivot versus some of the other options they have? Yes, they are.

Okay.

I guess in the middle to the program and beta Thal specifically.

Can you give us a little color I guess from what type of patient sheer enrolling in that trial are they going to be transfusion.

Depend the transfusion dependent and are there any bio marker specifically that you're looking at it could potentially.

Show a benefit for me to pivot versus some of the other options they have.

Yes, they are adults.

Christopher J. M. Taylor: They are adults who are not regularly transfused, who have a hemoglobin less than nine. And as per some of the work you've seen us publish with Mitopivat in pyruvate kinase deficiency and other chronic hemolytic anemia, we're interested in effects on bilirubin indirectly. We're looking at erythropoietin and other markers of ineffective erythropoiesis, reticulocyte counts, LDH, a whole slew of things. We've also done some pretty neat, elegant work over the years in PKD.

So we're not regularly transfuse.

Who have a hemoglobin less than nine.

And as poor as some of the work you've seen US publish it was made a pivot in herve kindness deficiency and other chronic hemolytic anemia, we're interested in effects on belly Ruben indirect.

We're looking at different points and in other markets and effective refer polices, particularly site counts LDH.

Whole slew of thing.

We've also done some pretty.

Christopher J. M. Taylor: You'll recall in volunteers, we saw nice changes in 2,3-DPG and ATP. When we translated that and started to look at that data in patients, we saw a trend in 2,3-DPG. The ATP data wasn't quite as clear, and our group, our metabolism group, did some really nice work in terms of looking at flux through that pathway in patients who responded versus those who did not. And that was very helpful for us in terms of further validating that the unequivocal clinical effect we were seeing was driven by the mechanism of action of the drug.

Very helpful for us and tons of further validating that that that unequivocal clinical effect, where we're seeing was driven by the mechanism of action of the drug.

Okay are there any specific biomarkers that you might look for to enrich the population from it appears that or is it just generally all beta fell patients that are not transfusion dependent.

Christopher J. M. Taylor: Okay, are there any specific biomarkers that you might look for to enrich the population from it a pivot, or is it just generally all beta-file patients that are not transfusion dependent?

Christopher J. M. Taylor: Yeah, that's a really interesting question, perspective, because in pyruvate kinase deficiency, we're activating a mutated enzyme. The reason why we've always been interested in both thalassemia and sickle cell is that if you think about that battery slide that we sometimes show, we're activating wild-type PKR in patients with thalassemia or sickle cell Your one hypothesis is that by providing more energy through increased activity through the pathway, you're generating more ATP and allowing those cells to have better defense mechanisms against the stress of their underlying hemoglobinopathy.

Yeah, that's a really interesting.

PK are.

In patients with that with senior sickle cell you're you're.

Christopher J. M. Taylor: So at this point, we do not have any data that would suggest there are nuances.

Christopher J. M. Taylor: Okay. Thank you very much for the questions. I appreciate it. Our next question comes from Michael Schmidt with Guggenheim.

Nuances within Wild type PK are that we would do for their selection.

Okay. Thank you very much for the questions appreciate it.

Our next question comes from Michael from Guggenheim.

Michael Schmidt: Hi Guys, thanks for taking that follow-up. Just a question on the AG270 combination studies. We noticed that in your slides, the lung cancer cohort is now, I guess, focusing on frontline non-small cell lung cancer patients looking at AG270 in combination with docetaxel. And we were just wondering if that's a change relative to your prior plans. And I guess, you know, I guess docetaxel isn't routinely used in frontline lung cancer. I'm just wondering if there's a particular, I guess, rationale.

Hi, guys. Thanks for taking the follow up just a question on the Agee to 70 combination studies.

Notice that in your slides the land kinds of cohort is no I guess focusing on frontline non small cell lung cancer patients.

Looking at 82 70 in combination with Ddos attacks, so and it was just wondering if that's changed relative to your prior plans and I guess two.

I guess.

Yes attacks.

Routinely used in front line lung cancer, just wondering if there is a particular I guess.

Rationale behind looking at those patients.

Christopher J. M. Taylor: Yeah, well, docetaxel was approved a long time ago for the second-line setting, and that's where we expect the majority of patients who will be coming through. They will probably have had at least platinum-based therapy, and they will also probably, in this day and age, have a high probability of having had a checkpoint. So we would expect that they would have had several prior therapies. And it's being pointed out to me that there's an error on the slide we showed. So think about dosotaxel in the context of its current indication and how it's used in the clinic as second-line therapy. So you can have had two or three, on honestly, I think that, you know, there are just some pretty good treatments in the frontline setting now that clinicians are not going to reach for docetaxel as first-line treatment for patients and that went. So, right, that's an error. Yeah, cool, cool.

The later line setting.

Yeah, well Ddos attacks will it is is it was approved a long time ago and the second line setting and Thats, where we expect the majority of patients who who will be coming through they will have had.

Probably at least platinum based therapy and they will also probably in this day in and have a high probability of having had a checkpoint inhibitor. So we expect.

That they would have had.

Several prior therapy.

And it's being pointed out to meet as an error on our on the slide we showed so think about ddos attacks. So in the context of its current indication and how it's used in the clinic in second line therapy. So you can have had two or three.

On honestly I think that.

If.

There's just some pretty good treatments in the frontline setting now that clinicians are not going to reach for Ddos attacks. So as first line treatment for patients and that wouldn't be feasible.

Right, that's an area yeah cocoa. Thanks for clarifying that makes a lot of fans and I guess, how fast do you expect those combination arms tenant rose.

Michael Schmidt: Yeah, cool, cool. Thanks for clarifying. That makes a lot of sense. And I guess, how fast do you expect those combination arms to enroll?

Well, we the faster the better we don't.

Christopher J. M. Taylor: Well, the faster the better. They're open now, and we'll be able to provide guidance as we get some momentum going and start to get some numbers in that we feel we can guide to, but nothing at this point.

There are open now and.

Michael Schmidt: Okay, well, thanks for clarifying.

Ladies and gentlemen, does conclude the given a portion of today's conference I'd like turn the call or just your thoughts for closing comments.

Operator: Ladies and gentlemen, this concludes the Q&A portion of today's conference. I'd like to turn the call over to Jackie Faust for closing comments.

Jackie Faust: Thank you, Operator. 2019 is an important year for AGIOS as we work to execute across our broad oncology and rare genetic disease portfolios. I would like to wrap up by thanking 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 of the patients, caregivers, and physicians who participate in our clinical trials. Without them, we could not do what we do. Thank you for joining us today. We'll see you soon.

Thank you operator, 2019 is an important near projects as we work to execute across our broad oncology and rare genetic disease portfolios I would like to wrap up by thanking all of the tremendous employees at our Joe's for their dedication and passion to making a difference for our patients.

So I want to thank all of the patients caregivers and physicians, who participate in our clinical trials without them. We cannot do what we do thank you for joining US today, we'll see you soon.

Operator: Ladies and gentlemen, this concludes today's presentation. You may now disconnect and have a wonderful day.

Ladies and gentlemen concludes todays presentation you may now disconnect number one.