Agios Pharmaceuticals, Inc.
Q3 2020 Earnings Call Transcript

Published: 31 Oct 2019

[Operator:]

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 that this call is being recorded at Agios' request.I would now like to turn the call over to Kendra Adams, Vice President, External Communication 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 Investors section of our website, agios.com.With me on the call today with prepared remarks are Dr. Jackie Fouse, our Chief Executive Officer. Dr. Chris Bowden, our Chief Medical Office. Darrin 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 statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent Form 10-Q filed with the SEC and any other filings that we may make with the SEC.With that I will turn the call over to Jackie.

[Jackie Fouse:]

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’ve 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 three clarity study of TIBSOVO and previously treated IDH1 mutant cholangiocarcinoma. We believe TIBSOVO 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've obtained guidance from the FDA and EMA on the endpoints for our phase three trial of vorasidenib in low-grade IDH mutant glioma. We are now preparing for trial initiation. And earlier this week at the triple meeting we presented data from the dose escalation portion of our phase 1 study of AG-270 in a variety of MTAP-deleted tumors. The trial has advanced two dose expansion and patients are now enrolling in two combination arms evaluating AG-270 plus standard of care and non-small-cell lung and pancreatic cancers.Within our rare genetic disease portfolio we published updated data in the New England Journal of Medicine from the phase two drive PK study of mitapivat and PK deficiency. These data represents the first publication of clinical data in adults with PK deficiency and demonstrate the clinical benefit of mitapivat in this chronic anemia. On the commercial side TIBSIVO U.S. revenue grew by 27% during the third quarter and Darrin 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 medicines. We will share more about these programs as we move them along.Heading into yearend is we are focused on executing against our remaining key milestones. These include completing enrollment for both of our phase 3 ACTIVATE and ACTIVATE T studies for mitapivat submitting a supplemental new drug application for TIBSOVO and previously treated IDH1 mutant cholangiocarcinoma advancing our phase three INDIGO trial of vorasidenib in IDH mutant low-grade glioma and achieving proof of concept in our phase 2 study of mitapivat and thalassemia. These milestones combined with our remaining data presentations this quarter at both [indiscernible] 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 Chris to provide our clinical and regulatory updates.

[Chris Bowden:]

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 a single agent and 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 mutation in 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.An area of great focus for Agios scientist is expanding our data on mutational clinic and minimal residual disease from patients who achieved a response with TIBSOVO. At ASH we will have the opportunity to highlight some of this data in front-line AML patients who have received TIBSOVO plus azacitidine in our ongoing phase 1 trial.We'll share more about ASH presentations when abstracts go online next week on November 6. Beyond AML we reopened the myelodysplastic syndrome arm of the TIBSOVO 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 towards advancing our solid tumor oncology programs. A clarity study of TIBSOVO and previously treated IDH1 mutant cholangiocarcinoma was the first randomized study in this patient population. As a discussant Dr. Iian Chow at ESMA pointed out these positive results helped 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 TIBSOVO 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 months PFS rates of 32% and 22% respectively. By contrast no placebo patients were free from progression at 6 months or beyond. While preliminary the overall survival data are supportive of the therapeutic benefit of TIBSOVO and are especially impressive when adjusting for crossover.In addition, TIBSOVO is well tolerated and the safety profile is 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 3 study and 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 glioma where patients desperately need new treatment options.Vorasidenib is our brain penetrant an IDH inhibitor that we will study in patients with IDH mutant low-grade gliomas post 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.Vorasidenib has previously been evaluated in the phase 1 study demonstrating 77% stable disease with a meet treatment duration of 22 months and non-enhancing glioma. In addition a perioperative study of vorasidenib and ivosidenib showed the ratio of tumor to plasma drug concentration is much higher for vorasidenib and is associated with more consistent to HG 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 vorasidenib global phase 3 study design. The study that we have named INDIGO will evaluate 366 patients with IDH mutant grade 2 non-enhancing glioma in a 1 to 1 double-blind randomization to either 50 milligrams of vorasidenib 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 committee. A number of secondary endpoints will be included such as safety and tolerability, tumor growth rate is assessed by volume, seizure control, time to next intervention, neurocognitive function and quality of life. Cross over from placebo from vorasidenib will be permitted. The team is actively preparing for initiation of the phase three INDIGO study later this quarter.Continuing with solid tumors I'll move to our AG-270 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 one study at the AACR-NCI-EORTC meeting earlier this week.The goal of this portion of the phase 1 study was to establish a recommended dose based on the safety pharmacokinetics and pharmacodynamics of MAT2A inhibition. On Sunday Dr. Rebecca Heist from Massachusetts General Hospital gave an oral presentation followed by a poster presentation on Monday that showed AG-270 generates reductions in the biomarkers, plasma SAM concentrations and in levels of tumor SDMA at well tolerated doses.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. A confirmed partial response was observed in a patient with high-grade neuroendocrine carcinoma of the lung. Two additional patients experienced prolonged stable disease including one patient with sex cord-stromal tumor for stable disease after 12.8 months of treatment with AG-271 daily and one patient with the bile duct cancer with stable disease after 6.5 months of treatment with AG-270 once daily.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 in two combination arms of the phase one study. One arm will test AG-270 in combination with docetaxel 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. The second arm will test AG-270 in combination with nab-paclitaxel 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 goal of each arm is to gather sufficient data in a homogeneous patient population to better understand AG-270’s clinical profile when combined with standard of care which will allow us to determine the next steps in clinical development.Moving to our PKR activator program where we are currently studying mitapivat in several hemolytic anemias. Our initial area of focus has been pyruvate kinase deficiency where mitapivat activates the mutated PKR enzyme.Earlier this year we expanded clinical development in thalassemia and sickle cell disease where mitapivat has potential to provide therapeutic benefit through the activation of wild-type TKR.Beginning with PK deficiency we have two 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 2 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 or a median treatment duration of almost 30 months.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 in adults with PK deficiency.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-end. In sickle-cell disease we are utilizing an IST strategy which includes a cooperative research and development agreement with Dr. [indiscernible] at the National Institutes of Health. Dr. [Chen] expects to enroll up to 25 patients and to date interest in the study has been high.As the first PKR activator in clinical development we continue to have confidence in the important role that mitapivat can play for patients with chronic debilitating hemolytic anemia.I'll now turn the call over to Darrin to review our commercial activities.

[Darrin Miles:]

Thanks Chris. In the last quarter our top priorities are execution and expansion. In the third quarter we maintained our focus on continued execution support TIBSOVO frontline and relapsed/refractory labels preparing for the potential launch of TIBSOVO for the treatment of cholangiocarcinoma and advancing pre-launch preparation activities in support of a potential approval of mitapivat to PK deficiency. With respect to our third quarter results I am pleased to report that the strength we saw in Q2 continued through the third quarter resulting in TIBSOVO net revenue of $17.4 million. This represents an increase of 27% over Q2 bringing year-to-date TIBSOVO revenue to $40.2 million. Growth in Q3 is largely due to strong gains in both the newly diagnosed and relapsed refractory AML settings.In the frontline 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 frontline. Though we only promote approved uses of TIBSOVO mono therapy 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. We continue to see strong double-digit growth in both the academic and community setting 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 overall TIBSOVO volume relative to the first half of 2019. This is important as we observe more patients being co-manage 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.

[Andrew Hirsch:]

Thanks Darrin. 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 ID for 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 TIBSOVO [$13 million]. TIBSOVO revenue growth of 27% compared to the prior quarter was largely driven by an underlying demand. Gross to net inventory levels remain consistent at the prior quarter. 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 of 2018. The year-over-year increase in R&D was largely driven by start-up costs for the plan to phase three INDIGO for vorasidenib and low-grade glioma. Clinical trial activity for mitapivat and PK deficiency, thalassemia and sickle cell disease and cost of the ongoing TIBSOVO combination phase three trials in the frontline AML setting. 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 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 by excluding anticipated program specific milestone payments will fund our current operating plans at least the end of 2020.With that operator please open the line for questions.

[Operator:]

[Operator Instructions] Our first question comes from Anupam Rama with JPMorgan.

[Anupam Rama:]

Hey guys thanks for taking the question and congrats on all the progress. Just a couple of questions on ASH. So for the DRIVE PK extension study is 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 a win scenario looks like for establishing proof of concept? Thanks so much.A - Chris BowdenFor DRIVE 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 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 is a pivotal trial in terms of the foundation support for that promise and then our activates studies would continue to validate that would be our expectation.And then for [indiscernible] 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 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 1 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 how robust that hemoglobin response is. We also want to look at markers of ineffective erythropoiesis and will be really important to understand whether we're able to cool off the bone marrow if you will or make it more efficient.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 you 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 for patients, talk to investigators and then that will, those data and the totality of those data will be what will inform our decision.

[Anupam Rama:]

Great. Thanks for taking our questions.

[Operator:]

Our next question comes from Michael Schmidt with Guggenheim.

[Michael Schmidt:]

Good morning and thanks for taking my questions. I actually had one on ID define obviously acquisitions can be disruptive sometimes but I was just wondering what would your sense is how committed [indiscernible] is to potentially maximizing the commercial potential to [indiscernible] for example what are there plans to initiate additional [indiscernible] expanding in a big studies and other indications.

[Jackie Fouse:]

Hi Michael. It's Jackie so let me start with this one. I mean we can't predict what [indiscernible] cell genes 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 cell gene that will transfer to and 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 [indiscernible] I mean as I think you probably know there's the identify trial that's ongoing for the drug in combination with either [indiscernible] and then there's the whole bond trial that both drugs TIBSOVO and [indiscernible] are being studied in the intensive therapy treatment eligible patient population.So those are ongoing. Those will contribute to [indiscernible] expansions for both drugs of overcome and as far as the rest of it let [indiscernible] and get their deal closed and do their portfolio prioritization and see what happens.

[Michael Schmidt:]

Okay. Great. Thank you. And then a question 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 I guess 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 a potential treatment candidates from mitapivat assuming success in trials next year.

[Chris Bowden:]

Okay. Great. It's Chris here, Chris Bowden. 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 as we started this program however many years ago. 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 on 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 T study. So it's something that we're going to continue to do because one of the challenges when you have a rare disease where there are no existing therapies is 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 continue to move forward education and awareness will be a really important component of that.Now the second part of your question there's 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 potential 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, we are able to demonstrate improvements in other aspects of the overall disease burden then 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 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 one missense mutation which represents about 80% of the adult population.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 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 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 going to be definitely an evolving picture in terms of the percentage of eligible patients based on what you pointed out a spectrum of disease, severity molecular features, what our data looks like and sort of physicians comfort with empirical treatment regimens.

[Michael Schmidt:]

Thank you.

[Operator:]

Our next question comes from Kennen MacKay with RBC Capital Markets.

[Kennen MacKay:]

Hey, thanks for taking the questions and congrats on the operational commercial quarter here. Maybe on that note just a question on what we're seeing in terms of trends of TIBSOVO usage in frontline AML. Specifically I was wondering around some of the conversation around the front-line 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 the frontline patients who are essentially unfit for otherwise therapy and might otherwise move into hospital.And on that note, I was just wondering sort of what data stood out or what you're hearing for some physicians for justifying use there. What really is infantilizing patients to use that combination? Thank you.

[Darrin Miles:]

Ken, thanks for the question, this is Darrin here. I think as I mentioned on the call that we've seen nice growth in both the frontline and then relapse for factory setting. Given the makeup of our distribution channel, it's we have limited visibility and to exact patient composition, characteristics or CapEx first line versus here also free 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 used in the frontline setting is in combination with HMA.So, think it's important to note that we only promote monotherapy used 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 of times this year will have additional updates in publication in the future.And so, I think that's what's driving the adoption in that setting. And I think that those data reflect is 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 probably well targeted safety profile, that's what's driving the utilization in the frontline setting.

[Kennen MacKay:]

And then maybe, just going back to ASH last year, those 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 more, I've got with a more challenging side effect profile.I guess, wondering your thoughts on going into ASH this year, any chance we could see data from the combination of IDH inhibitors with then collected and again on that same topic, wondering any sort of feedback you're hearing in terms of how physicians to making the choice between like that an IDH combo with HMA versus being collected to combo with HMA.Thanks for taking the questions.

[Jackie Fouse:]

So, we don’t expect to see an update on the when then plus IVO combination which is a study being conducted by Courtney DiNardo of MD Anderson. I will just note that study is being expanded to include newly diagnosed patients as well in combination with HMAs.

[Chris Bowden:]

And to your point I think the it's a missing compensation that's going on in the community around the various options that are newly available for them. So, we're I think we're just heading into the norming stage after a significant storm in these. We're positioned so just trying to figure out how to use all of these agents and in what particular patients.I think on this setting in particular, again what rules the day is going to be safety, safety and efficacy. I think our strategy is been to focus monotherapy in those patients who are previous -- secondary and all patients or those patients who've been previously exposed to HMA for you have seen disease like MDS.And that 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 used. I think it's important to make sure that we focus on what's driving sort of choices here.You've group of patients who these are very sick patients, right, off the time these are older patients many of them previously treated for another disease. And so, or unwilling or unable to withstand the cytopenias associated with some HMA, with HMA or HMA based combinations.And what they're going to appreciate bout our data is the complete response rates CRCRH rate and the durability of that response and the safety profile. What physicians I think often appreciate is the clinical data supporting the transfusion independence as well as the time to recovery on platelets and neutrophils.I think that is what we hear consistently from those who are who worked steady users of ivosidenib in the frontline setting.

[Kennen MacKay:]

Thank you, very much. Super help with color and one final question if I may. Seems like the enrolment to your point in ACTIVATE-T has gone sort of well above the expectation with that trial actually getting upside. And I think 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. ACTIVATE is still enrolling. Is there a chance these data readouts could be could comment sort of step a 10 points next year as these independently reach there their phase III endpoints.And just wanted to take your temperature on whether that's 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 working on track for year-end '19?

[Chris Bowden:]

Hi Ken, it's Chris here. Regarding to completing the crew by the end of the year. We're working really hard to get patients who are screened and randomized and into treatment for ACTIVATE and ACTIVATE-T is as you've said is been accruing nicely. It's certainly possible that to 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 or and then you've got the time on treatment follow-up periods and all that. They're more likely to be engaged but yes sorry it's possible.

[Kennen MacKay:]

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

[Operator:]

Our next question comes from Mohit Bansal with Citi.

[Mohit Bansal:]

Great, thanks for taking my question then a very good morning. So, one question I have is on your glioma trial. Could you please walk us through why you are choosing this particular population, asking for because IDH mutation tend to be more positive prognosis factor for low grade glioma?So, how should we think about this particular control, this particular sub set of patients and your expectations around control, how could that, how would that better perform. And I have a follow-up after this.

[Chris Bowden:]

Yes, this has always been an interesting aspect of developing a drug. This is Chris Bowden here. And the indication because you have a when you look at published data whether it's natural history data or from randomized trials of active treatment.You will see a long results in terms of progression free survival and overall survival that is far longer than what you're used to seeing in trials where patients who would have metastatic advanced solid tumors. And the question has been what's the unmet need and what is the logistics of doing a trial in this patient population.So, let's start with the unmet need. 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 with Darrin were 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 that's measured in 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, low grade glioma, you undergo a reception.And then the unfortunate part is this for most patients it's a long slow inexorable decline. And that decline is typified by gradual progression of disease, these radiation therapy, chemotherapy, steroids and other 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 neurocognitive deficits and other problems. So, what has been a long use clinical strategy given all of that knowledge is discussions with patients once you've had your initial surgery is we can watch and wait until you have progression and then institute radiation and chemotherapy and other ends more surgery and other disease controlling measures.So, as we were developing one drug and showing the long-term stable disease as well as evidence of tumor regression when we look at our waterfall plots, this population emerge 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 end ago study where we have carefully characterized group of patients who will have had surgery only and then eligible patients will be randomized to daily vorasidenib 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:]

Alright. And then, how do you how should we think about the control expectations in terms of months of VSS?

[Chris Bowden:]

So, we disclosed some of the initial details around the trial design today and we will certainly update you with the statistical information in the future. I think it's important to both know what to control on what we expect to control on performance to be as well as what we expect the performance to be in the active one.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 discussed with investigators. So, that information is worth counting.

[Mohit Bansal:]

Great, thank you. And then, one housekeeping kind of question. So, you mentioned that in AML you are currently more planted into academic setting. Can you please give us some color on what percent of patients right now on to it? So, coming from academic questions, community and what is the journal of internal population.What is the breakup in these two settings for your target patient population? Thank you.

[Darrin Miles:]

No problem. So the -- it's hasn’t been our practice to disclose the exact split between those patients coming from the academic and the versus the community setting. And I think it's there 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 albeit to similar trends what we've seen elsewhere, how much is what we're having or seeing quick in prior quarters and that is that we've got good strong growth in both settings both in terms of scripts or new patients starts. But also the number of new treaters that are identified in both of those settings as well.

[Mohit Bansal:]

Got it, it has been. Thank you.

[Operator:]

[Operator Instructions] Our next question comes from Chris Shibutani with Cowen.

[Chris Shibutani:]

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. That first you mentioned for the proof-of-concept data for mitapivat in glucemia, you said you will have that in house by the end of the year.When can we expect you to share that information, that'd be number one?Number two, in NDS, you are continuing to enroll now again in the phase I 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 note decision.And then finally for AG-270, I believe now that we have the data disclosure that Celgene has a five month period for which to make a go no go decision and that whether though continue to partner that. Jackie, you've talked a little bit about being able to contemplate now so many years in to the relationship with Celgene.And thinking about possible ways that a reconsideration of how that relationship is structured is that ongoing and is that at all tied to AG -270. That would be helpful to know again what your thinking is there. Thank you.

[Jackie Fouse:]

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 balance NDS questions. So, the we have triggered the octane period with Celgene. So, we have submitted the data package to them under the contractual agreements I have up to 150 days they'll have to take 150 days if they can take up to 150 days to ask us for this.So now, these are access for more data and then go away and evaluate that data package. So again, I can't speak for what Celgene and Bristol together are going to do. We have multiple components to the licentiateship. One of them is around IDHIFA 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 the various portfolio progress license decisions.What I've said in the past is I think they've been great partners in the past. They continue to be great partners and think they will be great partners in the future. And I only see opportunity associated with that ongoing relationship and seem to downsized Agios from the Bristol, Celgene merger. And that's all we can say on that.Now, I'll give it to Chris for the other two questions.

[Chris Bowden:]

Okay, thanks Jackie, Chris Bowden here. So, Myelodysplastic Syndrome, Chris, is up and running and sites are opened for accrual. I can't guide to when we think we're going to have that date in but hopefully is we get a little more clarity around the ramp up and patients coming in and then we'll be able to provide that information at a later date.MDS is about IDH1 mutation positive patients represent about 3% of the MDS population. We're going after relapse refractory patients who really have high on that 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 IDH1 and AML while we're looking more like 8% to 10%.I mean the last given that we're working with the same sites that did our initial study or they are all centers of excellence, we think they'll be lots of interest in getting patients on to the study. So, more to come there. As far as it's now proof-of-concept timing goes our goal is to have adequate information in house to enable a decision of whether we've achieved proof-of-concept or now by the end of the year.When we choose to communicate that whether we have achieved that going on to something that we're still looking at whether it would be at the end of this year or sometime early next year is something that we're working on.

[Chris Shibutani:]

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

[Chris Bowden:]

Thank you.

[Operator:]

[Operator Instructions] Our next question comes to Tyler Van Buren with Piper Jaffray.

[Tyler Buren:]

Hey guys, good morning. Just one last follow-up the mitapivat bit has helped proof-of-concept. Specifically can you say it what minimum response rate you guys think you need to see to achieve proof-of-concept and just as a quick follow-up. There's time to response matter as well.

[Chris Bowden:]

I think that that's the interesting question is what do you need to see a minimum response rate as well as time to response. I'm just touch on some of the aspects I've commented on earlier. Best is to say open label kinoid study here. A study where we're trying to understand does the drug work or not. And that's the primary efficacy variable in terms of how we're looking that as the increase in hemoglobin of 1 gram or higher.It's a great question. If you do that does how does it impact us if it takes a long time to get there versus a very short time in patients pyruvate kinase deficiency we see relatively rapid onset of response and that has a lot of interesting characteristics about that that are generally favorable.So, but I wouldn’t hang my head on that. Just like if the other aspect of the if you see a let's say a high percentage of patients who have a 1 gram increase in a very small percentage of patients who have a higher increase that might have impact on terms of how we look at, how we achieve proof-of-concept or not. And then duration in safety is 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 assumptions you have to test and you have to verify them. So, I can't emphasize enough how important that safety component and is well.So, I'm not giving you a specific answer of what response rate that we need to see. Because there are a number of components to come into that phrase that you hear me is a lot which is a totality of data and we tend to look at things that way especially in earlier stages of development and single arm open label studies whether it's in oncology or rare genetic diseases.

[Tyler Buren:]

Got it. Thanks for providing that color.

[Operator:]

The next question comes from Salveen Richter with Goldman Sachs.

[Salveen Richter:]

Great, thanks for taking the question. Just touching on the AG-270 data from the triple meeting. The maximal tumor reduction remodels are is served with like a range of 60% to 80% magnitude, the same reduction. In your view, how translated by these levels production from the mice model to the human.And then I will follow-up.

[Scott Biller:]

Yes, hi. This is Scott Biller here. yes, that's the range that we achieve and see effects in pre-clinical 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 aggression. But most models are actually using affectively stable disease or cytostatic effects.Translating that to now a set of very highly pre-treated patients and rapidly progressing patients that, it's really difficult. And it was always our intention to get into to earlier lines of therapy in combination because our pre-clinical data on that combination was so very compelling. So, that's we're sticking with our strategy and those are the clinical trials that are starting up now.

[Salveen Richter:]

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

[Darrin Miles:]

So, this is Darrin 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 by the end of next year. The in terms of collaborations, the opportunity here is this sort of rising tide lifts or all boats to now to new effective treatments in a setting where there is little to know effective options for these patients.And there's an opportunity to both educate on the importance of testing on for both mutations, education on mechanism, mechanism disease and then following the approval of both our of both products we educational need kind of propose with the products. So, and I'm not prepared to discuss any work that we that could potentially be done in collaboration with insight at this time.And I would say that we would I would expect to rebuild the in the community, I'm discussing those pre-approval, disease education and with a core respective products.

[Salveen Richter:]

Got it, very helpful. Thanks for the questions.

[Operator:]

The next question comes from Mark Breidenbach with Oppenheimer.

[Mark Breidenbach:]

Hey, good morning guys. I'll keep this quick. So, given the trends you're seeing in TIBSOVO use in newly-diagnosed AML patients. I'm just wondering if there is a chance we might get interim readout from the hormone study sometime in 2020.And a real quick follow-up 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 its successful sNDA process, once that's under review. Thank you.

[Chris Bowden:]

So we, there should be no expectations, it'll be any information around the readout or efficacy from the hormone 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 now we're working really hard with that with the group to get at this.All the sites' up and running and they really get momentum going around accrual. So, that will be no, you should have no expectations around any interims on that next year.

[Mark Breidenbach:]

Okay.

[Chris Bowden:]

And then, the second question around what to do in the newly diagnosed patients with IDH1 cholangiocarcinoma is one that's of great interest to us. We're in active discussions both internally and with investigators and what the best study designs are.Thinking about feasibility in some of those aspects as we consider moving into that setting.

[Mark Breidenbach:]

Thanks for taking the question.

[Operator:]

Our next question comes from John Newman with Canaccord.

[John Newman:]

Hey guys, good morning. Thanks for taking my question. Just wondered if you have disclosed or talked about the dose levels at all for AG-270 in the combination study. And often nice initial data I think you are partial response stabilities which was great. I think you mentioned nice and tolerated dose is 200 milligrams.Just curious if you're going to be looking at a range of AG-270 doses and combination or if you'll have a set dose there?

[Chris Bowden:]

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 regiments that we're testing docetaxel as well as abraxane, gemcitabine in pancreatic cancer.Bring within the fair amount of toxicity such that when given alone just as if that agent standalone, there's a lot of guidance in the label in terms of dose reductions whether for hematologic and non-hematologic toxicity. So, that's the first component that one needs to keep in mind as you're getting ready to add another drug in this case AG-270 to those combinations.Where we're starting is with a 100 milligrams daily and if you think back to the comment the question that Scott Biller answered earlier is because at that dose the data that we showed on the Dr. High 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. And we could go up to 200 milligrams in combination with those two regiments that I match in. but we're very comfortable that we can operate in that range and get the exposure that's associated with the pharmacodynamics or modulation that we're 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 I trial.

[John Newman:]

Great, thank you.

[Operator:]

Our next question comes from George Farmer with BMO Capital Markets.

[George Farmer:]

Hi, thanks for taking my question. On vorasidenib, I'm curious as to why you're not thinking about moving forward into later stage glioma like in glioblastoma where you possible to get faster readout?

[Chris Bowden:]

Yes. It's Chris Bowden here. So, if you go back and you look at some of our phase I data, we first let's just talk about the data and then I'll have few comments on why that may be. We did study some patients with GBM in our initial phase I trial with TIBSOVO.And we published that data a couple of times now. And when you look at it, patients progressed pretty rapidly. And so, that's the first thing. 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 nearly end of their life unfortunately transform into GBM and that's a very difficult situation to handle.And that transition's why is that because the molecular profile of the tumor at that point has changed pretty remarkably and the amount of drive to that tumor that's coming from IDH1 versus resistance mutations has come up as a function of time, as a function of treatment with alkylating agent as a function of treatment with radiation therapy give the ability to impact with this monotherapy and IDH1 inhibitor makes a probability of technical success pretty low.And we are not alone there. 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 on 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.So, as we think about the low grade glioma population based on AR 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 again similar data sets that we've been able to pull out from collaborations with academic institutions like NGH and Dana Farber and UCLA and others.We feel like that biologically it makes the most sense to go there and we put together a trial that we're confident can be done and demonstrate clinical benefit in a patient population that while yes it has a longer survival than patients with GBM. But that doesn't mean that this is not a high end med need there.So we, that's we're going there because we think we have a highest probability of clinical and regulatory success in there where there is a unmet need and where the use of a single agent drugs oral therapy can offer some pretty significant benefits for these people.

[George Farmer:]

Okay great, thanks very much.

[Operator:]

Our next question comes from Andrew Berens with SVB Leerink.

[Andrew Berens:]

Hi good morning, thanks guys. I have a question on the glioma program and then if you allow a question on the MIDD pilot program. When we look at the glioma program before in a low and a medium grade, it really seem like it could take a while for a clinical benefit to be realized in a drug that's primarily stable disease and a disease that's primarily endolin.Can you give us sort of some general idea of when we might see a benefit from the trial, how long that could take to show?

[Chris Bowden:]

I'm going to, 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 comment, we've done a lot of work to understand what these outcome will be in the control, in a control arm in terms of the progression free survival.In a disease that once you go progress in this watch 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 in endolin occurrence and so that's one of the reasons why we're on setting the trial up the way it is.I think the other aspect that I just want to remind everybody on the call is that we're our trials are ongoing and we'll be updating the carry upward in data and it's now and that will of course give you some insight further insight into that trial that you previously published and then we'll of course update some efficacy data there as well.

[Andrew Berens:]

Okay. And I guess, in the MIDD to the program and beta cells specifically. Can you give us a real color I guess on what type of patients you're enrolling in that trial? Are they going to be transfusion dependent and are there any biomarker specifically that you're looking at it could potentially show a benefit former to that versus some of the other options they have?

[Chris Bowden:]

Yes, 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 was mitapivat in pyruvate kinase deficiency and other chronic hemolytic anemia. We're interested in effects on bilirubin indirect. We're looking at erythropoietin and other markers that ineffective erythropoiesis reticulate that counts LDH a host liver thing.We've also done some pretty neat elegant work over the years in PKD over call and volunteers we saw nice changes in 2,3-DPG and ATP. When we translated that sort of then look at that data and patients we saw and 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 and patients who responded versus those who did not.And that was very helpful for us in terms of further validating that on a equivocal clinical effect we were seeing was driven by the mechanism of action of the drug.

[Andrew Berens:]

Okay. Are there any specific biomarkers that you might look for to enrich the population from mitapivat or is it just generally all data for our patients that are not transfusion dependent?

[Chris Bowden:]

Yes, that's a really interesting question perspective because in pyruvate kinase deficiency we're activating a mutated enzyme. And 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 sometime show, by activating wild-type PKR in patients with thalassemia and sickle cell.Your one hypothesis is like providing more energy in through increased activity through the pathway you're generating more ATP and allowing those cells to have better defense mechanisms from the stress their underlying hemoglobinopathy. So, at this point we do not have any day that would suggest there are nuances within wild-type PKR that we would do further selection.

[Andrew Berens:]

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

[Operator:]

Our next question comes from Michael Schmidt with Guggenheim.

[Michael Schmidt:]

Hi guys, thanks for taking the follow-up. It's just a question on the AG-270 combinations that is. We noticed that in your slides the lung cancer cohort is now I guess focusing on frontline most of lung cancer patients we're looking at AG-270 in combination with docetaxel and we were just wondering if that change or just to your prior plans and I guess docetaxel is importantly used in frontline lunch cancer.We were just wondering if there is a particular I guess rationale behind looking at those patients as per to lay the line setting.

[Chris Bowden:]

Yes. Well, docetaxel is a once approved a long time ago in the second line setting and naturally expect the majority of patients who will be coming through. They will have had probably at least platinum based therapy and they will also probably in this day and age of a high probability of having had a checkpoint inhibitor.So, we will expect that they would have had several prior therapy. And I just being pointed out to me there is an error on our on the slide we showed. So, think about docetaxel in the context of its current indication and how it's used in the clinic as a second line therapy.So, even you can have had two or three --. 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 docetaxel as first line treatment for patients now undefeatable. So, right that's an error.

[Michael Schmidt:]

Yes, cool. Thanks for clarifying that might fill our sense. And then, I guess how fast do you expect those combination arms to enroll?

[Chris Bowden:]

Well, we the fast the better, we don’t 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.

[Michael Schmidt:]

Okay. Well, thanks for clarifying.

[Operator:]

Ladies and gentlemen, that concludes the Q&A portion of today's conference. I'd like to turn the call over to Jackie Fouse for closing comment.

[Jackie Fouse:]

Thank you, operator. 2019 is an important year for us just as we work to execute our broad oncology and rare genetic disease for all the others. I would like to wrap up by thanking all of the tremendous employees at Agios for their dedication and passion in making a difference for our patients.I also want to thank all of the patients, caregivers and physicians to participate in our clinical trials. Without them, we could not do what we do.Thank you, for joining us today and we'll see soon.

[Operator:]

Ladies and gentlemen, that concludes today's presentation. You may now disconnect. And have a wonderful day.