Q3 2020 Agios Pharmaceuticals Inc Earnings Call

November 5, 2020

[music].

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

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

Operator: There will be a question and answer session at the end. Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Holly Manning, Director of Investor Relations. Thank you, Operator. Good morning, everyone, and welcome to Agios' third quarter 2020 conference call. You can access slides for today's call by going to the Investor section of our website, agios.com.

And she's be advised that this call is being recorded Oh Gee I asked her question I would now like to turn the call over to Holly Many director of Investor Relations.

Thank you operator, good morning, everyone and welcome to idea third quarter 2020 conference call you can access slides for today's call by going to the investors section of our website Adios Dot com with me on the call today with prepared remarks are Dr., Jackie South are Chief Executive Officer, Dr., Chris Bowden, our chief medical.

Holly Manning: 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 Jonathan Biller, our Chief Financial Officer and Head of Legal and Corporate Affairs. Dr. Bruce Carr, our Chief Scientific Officer, will join for Q&A. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. However, actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in the risk factor section of our most recent Form 10-Q filed with the FCC and any other filings that we may make with the FCC. With that, I will turn the call over to Jackie.

Hello, There Darren Myles, our senior Vice President of the U.S. commercial mobile marketing and Jonathan Biller, Our Chief Financial Officer, and head of legal and corporate Affairs Dr., Bruce Carr, our Chief Scientific officer will join for queuing <unk> before we get started I would like to remind everyone that some of the statements. We make on this call will include forward looking.

Statements actual events and results could differ materially from those expressed or implied by any forward looking statements. As a result of various risks uncertainties and other factors, including those set forth in the risk factor section of our most recent form 10-Q filed with the FCC and any other filings that we may make with the FCC.

With that I will turn the call over to Jackie.

Jackie Faust: Thanks, Holly. Good morning, everyone, and thanks for joining us on our third quarter 2020 results call. Our activities this quarter were focused on execution against our key priorities for 2020, significant planning in preparation for a catalyst-rich fourth quarter in 2021, and a clear commitment to doing what's right for patients and our people as we continue to navigate the ongoing impact of the COVID-19 pandemic. We made important strides toward getting our medicines to patients who need them. This included generating mature overall survival data from the CLARITY study, which enables our first solid tumor regulatory filing, and initiating our healthy volunteer study of AG946, our next generation PKR activator. Behind the scenes, we've been hard at work preparing for important milestones coming later this year and throughout 2021, including top-line data readouts for our ACTIVATE and ACTIVATE-T studies, the Supplemental NDA submission for Tysobo and cholangiocarcinoma, and the initiation of our global pivotal studies of midipivate in thalassemia and sickle cell disease.

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

Our activities this quarter was focused on execution against our key priorities for 2020.

Significant planning and preparation for a catalyst rich fourth quarter, and 2021, and a clear commitment to doing what's right for patients and our people as we continue to navigate the ongoing impact of the COVID-19 pandemic.

We made important strides toward getting our medicines to patients who need them.

This includes generating mature overall survival data from the clarity study, which enables our first solid tumor regulatory filing.

And initiating our healthy volunteer study of AG non four six our next generation PK our activator.

Behind the scenes, we've been hard at work preparing for important milestones coming later this year and throughout 2021, including topline data readout for activate and activate T studies.

Supplemental India euphemism for kids, although in claims you'll carcinoma and the initiation of our global pivotal studies of mid a pivot in Dallas EEMEA in sickle cell disease.

No lead us toward these key value inflection point.

We appointed Jonathan Bill or to the role of Chief Financial Officer head of legal and corporate Affairs in September.

Jackie Faust: Jonathan is a longtime colleague of mine whose expertise has been a welcome addition to our leadership team since he joined in November of last year. You'll hear from him later in the call as we discuss our quarterly financial... We also dealt with some challenges, including the need to withdraw our marketing authorization application for TIPSOVO in the relapsed refractory AML setting in the EU. Our ongoing Phase III combination studies of TIPSOVO in the frontline AML setting remain on track for those much larger patient populations. The decision to withdraw our MAA will not result in any near-term changes to our approach in the region.

Nothing is a longtime colleague of mine, whose expertise has been a welcome addition to our leadership team since he joined in November of last year.

You'll hear from him later in the call as we discuss our quarterly financials.

We also dealt with some challenges, including the need to withdraw our marketing authorization application for tips, although in the relapse refractory AML setting in the E U R.

Our ongoing phase three combination studies of itself all in the frontline AML setting remain on track for those much larger patient populations.

The decision to withdraw our M&A will not result in any near term changes to our approach in the region.

Jackie Faust: Our Lean EU team is largely focused on supporting Agios clinical trial and medical affairs activities and PKD market development efforts, including patient advocacy, disease education, and patient identification. Investment in the EU will continue to be gated and aligned with the timing of future product approvals in the region. Looking ahead to the remainder of the year, we have a number of key events for our MidaPivot program that will further elucidate the potential value of the PKR activation mechanism to treat serious hemolytic anemias. First, on November 19th, we will hold an investor webinar focused on our PKR franchise, which will include a deep dive into the mechanism of action, the unmet patient needs in thalassemia, sickle cell disease, and PK deficiency, our view of these market opportunities, and the commercial preparations underway for our first potential rare disease launch.

Our lean you team is largely focused on supporting our deals clinical trial in medical affairs activities, and P.J.D. market development efforts, including patient advocacy disease education and patient identification.

Investment in the E U will continue to be gated and aligned with the timing of future product approvals in the region.

Looking ahead to the remainder of the year, we have a number of key events for a minute pivot programs. It further and lose the day the potential value of the Teekay, our activation mechanism to treat serious hemolytic anemias birds on November 19th we will hold an investor webinars, focusing on our PK or friends Dons, which will include.

Deep dive into the mechanism of action.

Unmet patient needs in Dallas, EEMEA, sickle cell disease, and PK deficiency, our view of these market opportunities in the commercial preparations underway for our first potential rare disease long.

In conjunction with Ash, we will host an investor event on December Eightth. This year the updated data from the NIH phase one study have been a pivot in sickle cell disease as well as an overview of our phase three plans in Dallas EEMEA.

Jackie Faust: In conjunction with ASH, we will host an investor event on December 8th to share the updated data from the NIH Phase I study of metapivat and sickle cell disease, as well as an overview of our Phase III plans in thalassemia. And finally, we now expect top-line data from the ACTIVATE study of metapivat in non-transfusion-dependent PK deficiency by the end of the year, thanks We have a busy few months ahead of us, and I want to thank each and every Agios employee for continuing to advance our programs for patients while balancing the pandemic's continued impact on their personal and professional lives. Bruce, I now turn it over to you. Thanks, Jackie.

And finally, we now expect topline data from the activate study of mid a pivot in non transfusion dependent PK deficiency by the end of the year. Thanks to the tremendous efforts of our team.

We have a busy few months ahead of us and I want to thank each and every audience employee for continuing to advance our programs for patients while balancing the pandemics continued impact on their personal and professional lives grid.

Let me now turn it over to you.

Thanks Jackie.

Starting with mid to pivot our first in class PK, our activator currently being evaluated across three distinct hemolytic anemia.

Christopher J. M. Taylor: I'll start with Mitopibat, our first-in-class PKR activator currently being evaluated across three distinct hemolytic anemias. As Jackie highlighted, we anticipate several important milestones in the coming weeks that will advance all three of our MedivPIVAP programs. I'll start with our most advanced program in pyruvate kinase deficiency, where we are running two phase three clinical trials and have the potential to provide the first disease-modifying therapy for this disease. Earlier this year, we got top-line data for the Activate and Activate T studies sometime between the end of this year and mid-2021, anticipating some delays as a result of the pandemic. Thanks, in large part, to the extraordinary commitment of our team at Agios, we're now able to narrow those timelines.

As Jackie highlighted we anticipate several important milestones in the coming weeks that will advance all three of our mid of two about programs.

I'll start with our most advanced program Empire, the economy sufficiency, well, we're running two phase three clinical trials and have the potential to provide the first disease modifying therapy for this disease.

Earlier this year, we got it you top line data for the activate and activate T study sometime between the end of this year 2021, anticipating some delays as a result of the pandemic.

Thanks in large part to the extraordinary commitment of our team at odd years, we're now able to narrow those timelines.

Well I conveyed the randomized placebo controlled phase three study in 80 adults would probably big kinase deficiency, who are now regularly transfused, we anticipate top line data by the end.

2020.

We're activate T based three single arm open label study in 27 adults with PK deficiency, who are regularly transfused, we anticipate top line data in the first quarter of 2021, given the longer follow up time in the study.

Christopher J. M. Taylor: For ACTIVATE, the randomized placebo-controlled phase 3 study in 80 adults with pyruvate kinase deficiency who are not regularly transfused, we anticipate top-line data by the end of 2020. For ACTIVATE-T, the Phase III single-arm open-label study in 27 adults with PK deficiency who are regularly transfused, we anticipate top-line data in the first quarter of If positive, we expect to file for regulatory approval for a broad label for adults with PK deficiency in both the US and EU next year with a potential 2022 commercial launch in both geographies. Moving to the Phase 2 study of midipibatin thalassemia, we completed enrollment earlier this year with 20 patients. And in June, we presented updated data on 13 efficacy-evaluable patients at the virtual EHA meeting.

If positive we expect to file for regulatory approval for a broad label in adults with PK deficiency in both U.S. you next year would be potential 2020 two commercial launch in both geographies.

Moving to the phase two study admitted Tibetans outlets CBS, we completed enrollment earlier this year with 20 patients and in June we presented updated data on 13 efficacy evaluable patients at the virtual Amit.

The data showed that treatment with mid to that induce the hemoglobin increase of greater than or equal to one gram per deciliter.

12, or 13 evaluable patients during weeks four through 12, including four out of four office that was seen in patients where there have been no new treatment option indicated.

In addition, seven of eight dataset will see me a patients achieved to sustain hemoglobin response during weeks 12 to 24.

We expect to submit the full dataset from this study the presentation at a medical meeting and 2021.

This quarter, we've been working through U.S. Yoo regulatory feedback to our pivotal program.

Christopher J. M. Taylor: The data showed that treatment with Mitopivat induced a hemoglobin increase of greater than or equal to 1 gram per deciliter in 12 of 13 evaluable patients during weeks 4 through 12, including 4 out of 4 alpha thalassemia patients where there have been no new treatment options in decades. In addition, 7 of 8 beta thalassemia patients achieved a sustained hemoglobin response during weeks 12 through 24. We expect to submit the full data set from this study for presentation at a medical meeting in 2021. This quarter, we've been working through the U.S. and E.U.

At our actually back in December we expect to share details of our robust pivotal development plan.

Yes, Bose Alpha and beta thalassemia.

As well as transfusion dependent and non transfusion dependent patient population.

We anticipate initiating our pivotal program in 2021.

Now, let's turn to sickle cell disease, we're collaborating with Dr. suite led Chen the National Institutes of health on the proof of concept study with min.

In June we announced the clinical proof of concept was established based on a preliminary analysis of data from eight patients.

The data showed that over a six to eight week dosing period 78 patients experienced at hemoglobin increase with five of the patients achieving a hemoglobin increase of greater than or equal to one gram per deciliter from baseline.

Christopher J. M. Taylor: regulatory feedback to our pivotal program. At our ASH event in December, we expect to share details of our robust pivotal development plan that spans both alpha and beta thalassemia, as well as transfusion-dependent and non-transfusion-dependent patient populations. We anticipate initiating our pivotal program in 2021. Now, let's turn to sickle cell disease, where we're collaborating with Dr. Sui-Lei Chen of the National Institutes of Health on a proof-of-concept study with midopibia. In June, we announced that clinical proof of concept was established based on a preliminary analysis of data from eight patients. The data showed that over a six- to eight-week dosing period, seven of eight patients experienced a hemoglobin increase, with five of eight patients achieving a hemoglobin increase of greater than or equal to one gram per deciliter from baseline.

Enrollment in this study was temporarily paused in the spring due to the COVID-19 pandemic and has reopened as of mid August.

As of today. The study has enrolled 13 patients.

Ash Dr. Chen will give an oral presentation with updated data from at least 11 patients.

The eight patients from the preliminary analysis and approximately three additional patients expected to complete the study in time to be included in the presentation.

A total of five patients.

Two from the topline preliminary all three newly enrolled patients received 100 milligram dose and will be included in the ash presentation.

Data from the fully enrolled trial will be submitted for presentation at a medical meeting next year.

Moving forward the NIH recently approved the new protocol, allowing all patients in the phase. One study we continue to receive mid to pick that in an extension phase for up to two years.

The extension will provide valuable long term safety and efficacy data in sickle cell disease what.

The patients have the potential to be on therapy for many years, perhaps for life.

In parallel with these clinical activities, we're working rapidly to obtain U.S. Yoo regulatory feedback to advance our sickle cell disease pivotal development plan.

Christopher J. M. Taylor: Enrollment in the study was temporarily paused in the spring due to the COVID-19 pandemic, and it has reopened as of mid-August. As of today, the study has enrolled 13 patients. At ASH, Dr. Chen will give an oral presentation with updated data from at least 11 patients, including the eight patients from the preliminary analysis, and approximately three additional patients expected to complete the study in time to be included in the presentation. A total of five patients, to from the top-line preliminary, all three newly enrolled patients received 100 milligram BID dose and will be included in the ASH presentation. Data from the fully enrolled trial will be submitted for presentation at a medical meeting next year. Moving forward, the NIH recently approved a new protocol allowing all patients in the Phase I study to continue to receive midipivac in an extension phase for up to two years.

We expect to share an overview of the pivotal program design in the first half of 2021 and initiate the study within the year.

I'll now move to our Milligan hematology programs.

Last month, we shared our decision to withdraw a marketing authorization application for Twod cell both in relapse refractory AML as a result of the feedback received but the oral explanation in September.

Despite our learnings from the idea experience and the additional end work from our team we were unable to fully address the major objections raised by this huge MP to support a positive benefit risk assessment and the proposed indication based on a single arm non comparative phase one two study.

While we are disappointed that patients and that you will not have access to so though in the near term we continue to enroll the giant and home on phase III combination trials and I see eligible in IC ineligible frontline AML.

Trials are positive we anticipate pursuing approvals in the U.S. and you.

Christopher J. M. Taylor: The extension will provide valuable long-term safety and efficacy data in sickle cell disease, where patients have the potential to be on therapy for many years, perhaps for life. In parallel with these clinical activities, we're working rapidly to obtain U.S. and E.U. regulatory feedback to advance our sickle cell disease pivotal development plan.

The vast majority of newly diagnosed AML patients are eligible to receive intensive or non intensive therapy. So these studies provide the opportunity to reach the largest number of patients.

Switching gears to our solid tumor programs.

Last year, we reported positive highly statistically significant progression free survival data from the clarity phase three study.

Christopher J. M. Taylor: We expect to share an overview of the pivotal program design in the first half of 2021 and initiate the study within the year. Now, I'll move to our Milligan hematology program. Last month, we shared our decision to withdraw our marketing authorization application for Tibsobo and relapse refractory AML as a result of the feedback received at the oral explanation in September. Despite our learnings from the IDPA experience and the additional in-depth work from our team, we were unable to fully address the major objections raised by the CHMP to support a positive benefit-risk assessment in the proposed indication based on a While we are disappointed that patients in the EU will not have access to TIBSOVO in the near term, we continue to enroll the Agile and Hovon Phase 3 combination trials in IC-eligible and IC-ineligible frontline AMIs. If the trials are positive, we anticipate pursuing approvals in the U.S. and the EU. The vast majority of newly diagnosed AML patients are eligible to receive intensive or non-intensive therapy.

Oh, good sogo previously treated IDH, one you can cholangio carcinoma.

Last month, we shared a topline market mature overall survival effect.

Nondairy endpoint in the study.

Treatment with kids, so, but it was associated with a non statistically significant improvement in overall survival compared to placebo.

Given that 70% of patients crossover between the placebo arm to the Ivas sideline. We consider this positive trend in overall survival could be important supportive data for approval.

We will be sharing these data with FDA and are planning to submit a supplemental new drug application for twod. So both in previously treated IDH. One you cleanse your carcinoma in the first quarter of 2021.

Additionally, we have submitted the clarity final overall survival data set for potential presentation at ASCO Gi in January.

The impressive and statistically robust PFS results supported the inclusion of Twod. So both in the NCCN treatment guidelines at a level recommendation on par with approved therapies for other biomarkers selected populations.

This level of endorsement from the expert physicians is an encouraging recognition of the clinical benefit too so.

In addition to cleanse your carcinoma, we are exploring the utility of IDH inhibition in low grade glioma, and our phase three indigo trial aboard side NIM.

Christopher J. M. Taylor: So these studies provide the opportunity to reach the largest number of patients. Switching gears to our solid tumor program, last year, we reported positive, highly statistically significant progression-free survival data from the Clarity Phase III study of Tibsovo and previously treated IDH1 mutant cholangiocarcinoma.

Or a side note is our brain penetrant dual IDH one two inhibitor that has the potential to treat the roughly 80% of low grade glioma patients with an IDH mutation.

Site startup activities are ahead of expectations, despite the pandemic, reflecting physician enthusiasm for the potential for a side note and this trial.

Christopher J. M. Taylor: And last month, we shared a top-line look at mature overall survival, a secondary endpoint in the study. Treatment with Qubestovo was associated with a non-statistically significant improvement in overall survival compared to placebo. Given that 70% of patients crossed over from the placebo arm to the iosidinib arm, we consider this positive trend in overall survival with the important support of data for approval. We will be sharing these data with FDA and are planning to submit a supplemental new drug application for TIBSOBO and previously treated IDH1 mutant cholangiocarcinoma in the first quarter of 2021. Additionally, we have submitted the Clarity Final Overall Survival Dataset for potential presentation at ASCO GI in January. The impressive and statistically robust PFS results supported the inclusion of TIBSOVO in the NCCN treatment guidelines at a level of recommendation on par with approved therapies for other biomarker-select populations. This level of endorsement from the expert positions is an encouraging recognition of the clinical benefit of TIBSOVO. In addition to cholangiocarcinoma, we are exploring the utility of IDH inhibition in low-grade glioma in our Phase III indigo trial of oracidinib.

And finally, the AG 270 phase one dose escalation combination arms with Taxanes continue to enroll patients.

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

Thanks, Chris.

The momentum we observed in the first half of 2020 continued through the third quarter, resulting in $32 million of net sales of civil a 15% increase over Q2.

Performance in the quarter was driven by a significant increase in new scripts and refills and continued improvement in duration to approximately five months.

We continue to see growth in both the academic and community setting increased use in the community setting was particularly strong and they reflect the trend and the increased coal management of patients between academic and community positions likely accelerated by the COVID-19 pandemic.

We continue to see steady increases in physician preference share per trip, so little different line intensive chemo ineligible and personal upsetting old.

All leading indicators of physician perceptions of civil are encouraging including a significant improvement in those physicians, who believed silver standard of care for newly diagnose since a chemo ineligible patients.

Well our promotional efforts are limited to the on label email opportunity. We observed an increase in commercial volume attributed to Cholangio carcinoma. Following the addition of two civil to the NCCN guidelines in June so.

So visibility into indication specific uses is limited to the specialty pharmacy channel, which represents about a third of civil commercial volume.

Increased utilization Cholangio carcinoma, following the update and practice guidelines made this noteworthy.

Darren Miles: Our side nib is our brain penetrant dual IDH1-2 inhibitor that has the potential to treat the roughly 80% of low-grade glioma patients with an IDH mutation. Cite's startup activities are ahead of expectations despite the pandemic, reflecting physician enthusiasm for the potential of borosidinib and this trial. And finally, the AG270 Phase I Dose-Escalation Combination Arms with Taxanes continue to enroll patients. With that, I'll turn it over to Darren to discuss our third quarter commercial performance. Thanks, Chris.

While we've seen some easing in certain geographies face to face customer interaction, particularly with academic customers remains largely restricted and we anticipate that restrictions will tighten again as we head into the fall and winter months. Nevertheless.

Nevertheless, our team has been effective in using virtual communication and educational tools to continue live customer engagement. As a result, we were able to increase the number of new customers by 17%.

The outlook for the fourth quarter was strong, but not without some potential headwinds.

Leading indicators and performance in the early weeks of Q4 indicate similar trends for Q3. However.

We also anticipate disruption in the number of AML patients diagnosed and potentially treated as could be 19 sections and hospitalizations are expected to increase through the end of the year.

Darren Miles: The momentum we observed in the first half of 2020 continued through the third quarter, resulting in $32 million of net sales of Tibsovo, a 15% increase over Q2. Performance in the quarter was driven by a significant increase in new scripts and refills and continued improvement in duration to approximately five months. Though we continue to see growth in both the academic and community setting, increased use in the community setting was particularly strong and may reflect a trend in the increased co-management of patients between academic and community physicians, likely accelerated by the COVID-19 pandemic. We continue to see steady increases in physician preference share for Typsolol, the frontline intensive chemo-ineligible and first relapse center. All leading indicators of physician perceptions of TIPSOVO are encouraging, including a significant improvement in those physicians who believe TIPSOVO is standard of care for newly diagnosed intensive chemo-ineligible patients.

In addition, we may see increased volumes through Medicaid and reported be channels in Brazil to dependent which can apply increased pressure on gross to net.

Considering our year to date performance and our outlook for the remainder of the year, we're narrowing our guidance for 2020, let us to EPS civil sales from between $105 million to $115 million to $113 million to $115 million.

I want to thank the Adrs team for not only adapting the thriving in the face of these uncertain times fueled by passion to ensure no patients denied the opportunity to benefit from our treatments.

Now I'll turn it over to Jonathan to discuss our third quarter financials.

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

Total revenue for the second quarter was $35 million, which consisted of $32 million of net sales or so ago.

$2 million of collaboration revenue and $700000 in royalty revenue compare.

Compared to the third quarter of 2019 total revenue grew 33% driven by an 82% increase in tip Somo sales offset by a decrease in collaboration revenue due to completion of the research and development service obligation with Celgene and Q2.

Darren Miles: While our promotional efforts are limited to the on-label AML opportunity, we observed an increase in commercial volume attributed to cholangiocarcinoma following the addition of Tipsovo to the NCCN guidelines in June. However, visibility into indication-specific uses is limited to the Specialty Pharmacy Channel, which represents about a third of Kibsogo commercial volume. The increased utilization of cholangiocarcinoma following the update and practice guidelines warrants this note.

In addition, royalty revenue was impacted by an adjustment in sales reserves taken this quarter by BMS relating to prior periods.

So revenue grew by $4 million compared to Q2 2020, driven by increased demand.

Gross to net for the quarter was within the expected range, we continue to monitor Medicaid and Phs unit utilization.

Cost of sales for the quarter was $637000 turning to operating expenses R&D for the third quarter was $90 million, a decrease of $12 million compared to the third quarter of 2019.

Darren Miles: While we've seen some easing in certain geographies... face-to-face customer interaction, particularly with academic customers, remains largely restricted. And we anticipate that restrictions will tighten again as we head into the late fall and winter months. Nevertheless, our team has been effective at using virtual communication and educational tools to continue live customer engagement. As a result, we were able to increase the number of new customers by 17%.

This year over year reduction in R&D was largely driven by a decrease and took syllable clinical development costs, including winding down the clarity phase three study.

Selling general and administrative expenses were $35 million for the quarter, representing a 2 million dollar increase over third quarter 2019, driven primarily by increased workforce expenses offset by a decrease in external spending due to COVID-19 and cost savings initiatives.

We ended the quarter with cash cash equivalents and marketable securities of $722 million.

We expect that our Q3 ending cash balance in addition to expected product revenue, but excluding anticipated program specific milestone payments will fund our current operating plan to the end of 2022.

Darren Miles: The outlook for the fourth quarter is strong, but not without some potential headwinds. Leading indicators and performance in the early weeks of Q4 indicate similar trends to Q3. However, we also anticipate disruption in the number of AML patients diagnosed and potentially treated as COVID-19 infections and hospitalizations are expected to increase through the end of the year. In addition, we may see increased volume moving through Medicaid and 340B channels as a result of the pandemic, which can apply increased pressure on growth to net. Considering our year-to-date performance and our outlook for the remainder of the year, we're narrowing our guidance for 2020 net U.S. tipsobo sales from between $105 to $115 million to between $113 to $115 million.

With that operator, please open the line for questions.

Thank you.

A reminder to ask question, you'll need to press star one on your telephone to withdraw your question. Please press the pound cake. Please stand by while we compile the <unk> roster.

Our first question comes from Ana Palm Rama from JP Morgan Your line is open.

Hey, guys.

Thanks for taking the question just a quick one on aging nine four stake how should we be thinking about sort of timelines for the healthy volunteer data I know it just the trial just started but importantly, starting that SCB cohort that you have and for the 9% and thinking about that in terms of also timing of the mid to pay that.

The three that you've outlined last year. Thanks, so much.

Hey on upon its Chris here, Chris Bowden.

So demand for six study is ongoing and healthy volunteers.

And those as.

As per what we did with mid to pivot in healthy volunteers as a single dose.

Jonathan Biller: I want to thank the AGIOS team for not only adapting but thriving in the face of these uncertain times, fueled by a passion to ensure no patient is denied the opportunity to benefit from our treatment. I'll now turn it over to Jonathan to discuss our third quarter financial results. Thanks, Darren.

Those cohorts and then we move into the multi ascending dose cohorts and then following that we have planned to open a second show cohort.

So it's too early for us to provide guidance as to when we think we might moving there to that fade as well as when we think we might be able to publish data certainly as per previous once we feel like we have a critical mass of safety and PK and PD data.

Jonathan Biller: This third-quarter results can be found in the press release we issued this morning, which I will summarize. More detail will be included in our 10-Q filing later today. Total revenue for the second quarter was $35 million, which consisted of $32 million of net sales of Sovo, $2 million of collaboration revenue, and $700,000 in royalties.

Then we would try to get that out there and perhaps around that time be able to inform when the sickle cell cohort might be opening now with regards to our phase three start with much more to that in sickle cell. That's next year.

Jonathan Biller: Compared to the third quarter of 2019, total revenue grew 33%, driven by an 82% increase in TIPSOVO sales, offset by a decrease in collaboration revenue due to the completion of the research and development service obligation with Celgene and Q2. In addition, royalty revenue was impacted by an adjustment in sales reserves taken this quarter by BMS relating to prior periods. TSOBO revenue grew by $4 million compared to Q2 2020, driven by increased demand. Gross to net for the quarter was within the expected range. We continue to monitor Medicaid and PHS utilization. Cost of sales for the quarter was $637,000.

Jonathan Biller: Turning to operations, R&D for the third quarter was $90 million, a decrease of $12 million compared to the third quarter of 2019. This year-over-year reduction in R&D was largely driven by a decrease in Tilovo clinical development costs, including winding down the clarity phase. Selling, general, and administrative expenses were $35 million for the quarter, representing a $2 million increase over third quarter 2019, driven primarily by increased workforce expenses, offset by a decrease in external spending due to COVID-19 and cost savings initiatives. We ended the quarter with cash, cash equivalents, and marketable securities of $722 million.

I'm looking at a change from baseline and what <unk>.

<unk> the design of the study of patients keep escalating.

They started five and then they can go up to 50 or once we put the amendment and.

They could go up to 100.

That includes all.

All of those they patients whether they responded or not so.

So I think that trying to dissect the the differences in 50 from 100 and the table is a little bit challenging.

From our perspective remember, what we talked about in the high level top line.

I actually made it <unk>, where five eight patients had one grammar higher increase in hemoglobin cause we're all at 50.

Operator: We expect that our Q3 ending cash balance, in addition to expected product revenue, but excluding anticipated program-specific milestone payments, will fund our current operating plan to the end of 2022. With that, operator, please open the line for questions. Thank you. As a reminder, to ask a question, you'll need to press star 1 on your telephone. To withdraw your question, please press the pound key.

So we definitely have an active does he put the milligram, we know from some of our house, who volunteer work in the number of things that will probably see more activation.

Yep quality quantitatively when we go from 50 to 100 it varies from patient the patient and I think one of the most important thing about this is that there's the possibility for upset for people to have a range of doses. So whether it's 50 or 100 or 50 M 100, and something that we're still thinking about.

Another way to look at it is that if you were to get let's say, a gram and a half increase at 50, and another 0.7 or half a gram increase when you went up to 100.

Operator: Please stand by while we compile the Q&A roster. Our first question comes from Anupam Rama from J.P. Morgan. Your line is open. Hey guys.

Given some of the database emerging around hemoglobin and outcomes that that could definitely be up clinical benefit and a physician and patient interest if the safety profile of comparable which which it does across if you do 100.

Anupam Rama: Thanks for taking the question. Just a quick one on AG946. How should we be thinking about sort of timelines for the Healthy Volunteer data? I know just the trials have started, but importantly, starting that STD cohort that you have for the 946 and thinking about that in terms of also timing the Mid-Eclat Phase 3 that you outlined last year. Thanks so much. Hey Anupam, it's Chris here, Chris Bowden.

So so the date of that we've been generated from this trial from some of our other studies really gives us a lot of confidence around.

Or does selection on the way to design on trial, and we'll be able to provide more details around that in the first half of 2021.

Okay, maybe maybe just one follow up so you mentioned 11 patients that will be reported on it ash and eight at the 100, Meg B I D dose and three are new and fiber from the existing patient so that our dose escalated are they all big.

Christopher J. M. Taylor: So the 946 study is ongoing in healthy volunteers, and as per what we did with Mitopibat, and these are single dose cohorts. So then we move into the multi ascending dose cohorts, and then following that, we have planned to open a sickle cell cohort. So, it's too early for us to provide guidance as to when we think we might move there to that phase, as well as when we think we might be able to publish data.

<unk> waited up to 100 milligrams PID in the same timeframe or or in the same course, and if not does that matter in terms of hemoglobin response.

I think if I understand your question is that.

You're on drugs or to your on dose.

For two weeks five milligrams for two weeks 20 milligrams for two weeks 50 milligrams for two weeks and now 100 milligrams. So two weeks so there's no break in between.

Christopher J. M. Taylor: Certainly, as per previous ones, we feel like we have a critical mass of safety and PK and PD data, and we would try to get that out there and perhaps around that time be able to inform when the sickle cell cohort might be opening. Now, with regard to our phase three start with the new Tibetan sickle cell, that's next year. And so we're all, as in my remarks, we're in full gear there, developing the protocol, interacting with the health authorities, and we'll be able to update further on that next year as well. Great, thanks for taking our questions. Thank you. Our next question comes from Tyler Van Buren with Piper Sandler. Your line is open.

The patients are enrolled sequentially.

So it's not like the whole cohort comes in in there and they're all in all at the same time, but the dosing frequency is similar for all patients.

Okay. That's helpful clarification. Thank you.

Yeah.

Thank you. Our next question comes from Mark from what's Cowan account Carolina seven.

Hi, Thanks for taking my questions and Christmas to fall Apart comment you made before.

I'm Gonna go on.

100 milligrams verses guessing some method 50, the long term extension because that's gonna be at 100 milligrams or is there kind of individuals vice dosing and they're based on whatever the patient prefers and then.

Tyler Van Buren: Hey guys, good morning. Thanks for taking the questions. I wanted to ask about the mid-pivot sickle cell update at ASH and specifically your confidence in the 100 mg BID dose generating a more significant clinical benefit than the 50 mg BID, and especially in particular in hemoglobin. In the abstract, you know, it was a 0.9 increase in hemoglobin relative to 1.2 for the 50 mg. Obviously, there were only two patients at 100 mg versus eight at all others. And so, there could have been something specific about those two patients, but wanted to maybe hear your explanation on that. And again, your confidence that the 100 milligram dose will show improved benefits. Yeah, thanks.

Many of these patients actually rolled off trial right back on the back of the spring. So do they have to kind of just escalate back up or do you think you can just put them straight back onto the truck.

So so what what they'll do is get them to what is and what they think is an optimal dose and that 50 to 100 milligrams.

Range and they're just gonna come in at at 50.

Alright, and then the existing patient.

These newer patients will just start rolling straight into the into that truck.

They they will be able to just just move into the extension that's correct.

Okay and would that involve another washout period to test that hole.

Stepping down and tight trading out that you've been doing or do you <unk>, yeah, maybe not <unk>.

Yeah, so will they they taper.

It's a separate protocol so that they will need to finish the paper and then come back in that's why I don't we don't I don't feel like we need additional data around the taper beyond what we've got set up in the in the ongoing study now.

Christopher J. M. Taylor: So I think the important thing with this is that those values that you're looking at are changed from baseline. And, you know, what we call the design of the study is patients keep escalating. They start at five, and then they can go up to 50 or once we put the amendment in.

Okay, Great and then just one thing on the abstract it discloses a possible second mechanism of action on through Kardos can you explain explain the what's making you think that and then also maybe contrasts with what's been studied on Carlos before and sickle cell because obviously, there's got high profile.

Christopher J. M. Taylor: They could go up to 100. That includes all those eight patients, whether they've responded to the drug or not. So I think that trying to dissect the differences in 50s from 100s in the table is a little bit challenging. From our perspective, remember what we talked about in the high-level top-line remarks we made at EHA, where five of eight patients had a one-gram or higher increase in hemoglobin. Those were all at

A free program there before.

Yeah, so that that that has been something that has been of interest both for our.

From our research team as a potential mechanism and now from the investigators based on this in.

In increase in the knee crepuscular volume, what's what's called the M C b and given that you're increasingly overall red So hell and perhaps the guard is channel which is.

Christopher J. M. Taylor: So we definitely have an active dose of 50 milligrams. We know from, you know, some of our healthy volunteer work and a number of things that we'll probably see more activation, you know, qualitatively when we go from 50 to 100. It varies from patient to patient, and I think one of the most important things about this is that there's a possibility for us to have, for people, a range of doses. So whether it's 50 or 100 or 50 and 100 is something that we're still thinking about.

Had some.

Directly involved in Red saw hydration that that could also be a mechanism by which medical that is providing clinical benefit.

Sales of them on leather healthier better hydration state, which may include decrease the preliminary nation on that fiber.

Christopher J. M. Taylor: And another way to look at it is that if you were to get, let's say, a gram and a half increase at 50 and another 0.7 or half a gram increase when you went up to 100, given some of the data that's emerging around hemoglobin and outcomes, that could definitely be a clinical benefit and a physician and patient interest if the safety profile is comparable, which it is across 50 to 100. So the data that we've been generating from this trial and from some of our other studies really gives us a lot of confidence in our dose selection and the way we design our trial. And we'll be able to provide more details on that in the first half of 2021. Okay, maybe just one follow-up question.

Okay, and I guess is there any difference there between kind of how you think this is working and what hasn't been studied before Ricardo.

I think that phase III trial actually.

Obviously failed on Vse's, but in terms of anything Saturday, but even showed a trend to cancel the drug right.

Yeah that that was that that was an interesting trial because that guard is channel blockers showed some improvement in hemoglobin them off but was stopped because of a question around seats and safety.

We work very differently, we don't directly affect the guard I was chana you know I drove it specific for activating pyruvate kinase in it and as we can emphasize.

Emphasize.

Impact on the glycolytic pathway by by activating PKI the increases ATP, where you see a number of positive effects.

Christopher J. M. Taylor: So you've mentioned 11 patients that will be reported on at ASH, and eight at the 100 mg BID dose, and three are new, and five are from the existing patients, so they are dose-escalating. Are they all being dose-escalated up to 100 mg BID in the same timeframe or over the same course? And if not, does that matter in terms of hemoglobin response?

In terms of Red cell health, and then by dropping to three P. P. G, which is along to demonstrate to be elevated in patients with sickle cell you. The reason to believe there is it will decrease the formation of fibers that caused the abnormal shape of the red cells and sick women all the bad things that happened that so it's a very.

Christopher J. M. Taylor: I think, if I understand your question correctly, is that you're on drugs for two weeks, you're on the dose for two weeks. 5 mg for 2 weeks, 20 mg for 2 weeks, 50 mg for 2 weeks, and now 100 mg for 2 weeks. So there's no break in between.

It's it's it's an observation that we may be improving.

Uhm the ability for that God is channeled to to do increase Red zone duration, but it's <unk>, it's fundamentally through that mechanism of action of increase in a T. P by activating P. K R.

Christopher J. M. Taylor: The patients are enrolled sequentially. So it's not like the whole cohort comes in, and they're all enrolled at the same time, but the dosing frequency is similar for all patients. Okay, that's helpful clarification. Thank you.

Okay, great. Thanks, a lot.

Thank you.

Your next question comes from Peter Lawson with Barclays. Your line is open.

Hi, guys. This is will lead off for Peter Thanks for taking my questions and sort of question around upcoming P. K D date US where do you see the bar is what would be considered clinically meaningful results as we move to data you're in the first quarter of 21 a both.

Christopher J. M. Taylor: Thank you. Our next question comes from Mark Fromm with Cowan & Co. Your line is, Thanks for taking my questions.

Mark Fromm: Chris, just to follow up on a comment you made earlier, just a minute ago, The Long-Term Extension, is that going to be at 100 mg, or is there kind of individualized dosing in there based on, you know, whatever that patient prefers? And then, you know, many of these patients actually rolled off the trial right back in the spring. So do they have to kind of dose escalate back up, or do you think you can just put them straight back on drugs?

Christopher J. M. Taylor: So what they'll do is get them to what they think is an optimal dose in that 50 to 100 milligrams range, and they're just going to come in at 5. And then the existing patients, the idea is these newer patients will just start rolling straight into that trial. They will be able to just move into the extension that's been collected. Okay, and would that involve another washout period to test that whole, you know, the stepping down and titrating out that you've been doing, or do you think you have enough experience? Yeah, so will they taper off?

Christopher J. M. Taylor: It's a separate protocol, so they will need to finish the taper and then come back in. That's why I don't we don't I don't feel like we need additional data around the taper beyond what we've got set up in the ongoing study now. Okay, great. And then just one thing about the abstract: it discloses a possible second mechanism of action through GARDOS. Can you kind of explain the, you know, what's making you think that?

Lisa patients who are regularly transfused, the efficacy endpoint is 33% or greater reduction in the overall transfusion burden at the time of clearance study compared to their.

Previous one year history of transfusion.

And so Thats, an open label trial and that's the primary measure clinical that I. Just went on at the same time, you know that in those patients who are regularly transfused people look at 50% and train the 50% reduction as well as transfusion.

Christopher J. M. Taylor: And then also maybe, you know, contrast that with what's been studied on GARDOS before in sickle cell? Because obviously, there's been a high-profile phase three program there before. Yeah, so that has been something that has been of interest both from our research team as a potential mechanism and now from the investigators based on this in increasing the mean corpuscular volume, what's called the MCV. And given that you're increasing overall red cell health and perhaps the Garda channel, which is, has something directly involved in red cell hydration, that could also be a mechanism by which metaprobat is providing a clinical benefit: cells live longer, they're healthier, they have a better hydration state, which may improve or decrease the polymerization of that fiber.

And so those are the other important set.

Secondary efficacy outcome.

Well, we hope will demonstrate that.

The pivot and that group of patients.

As a.

A really big impact in terms of reducing the amount of time any to spend in the clinic getting blood transfusions, and we'll also look at secondary endpoints like iron mobilization.

What impacts you might have on the new fire installation and other endpoint.

So the the two trials in total we would like to.

Be able to use them to get a broad label and adults with powder that kind of efficiency and we think the trials as a package are set up to really demonstrate clinical benefit overall.

Okay.

Great. Thank you for taking the question.

Okay.

Thank you and.

Next question comes from Mohit Bansal with Citigroup. Your line is open.

Great. Thank you very much for taking my question first of all congratulation Jonathan for the Euro.

Christopher J. M. Taylor: Okay, and I guess, is there any difference between kind of how you think this is working and what has been studied before with GARDOS? Because I think that phase three trial actually, I mean, it obviously failed on VFCs, but in terms of hitting STATFIG, it even showed a trend against the drug. Yeah, that was an interesting trial because the GARDOS channel blocker showed some improvement in hemoglobin, but it was stopped because of questions around VOCs and safety. We work very differently.

Starting at the question I mean, I think when you first provided this 1 billion dollar guidance by 2025, obviously quoted was not there and that has been in recent year made decision, which didn't go in your favor. So could you talk a little bit more about with these uncertainties. How attainable is this $1 billion.

My 25 guidance is or are your aspiration is.

And how much wiggle room is there the pipeline et cetera to still make it happen if the current disease business doesn't go as planned. Thank you.

Christopher J. M. Taylor: We don't directly affect the GARDOS channel. You know, our drug is specific for activating pyruvate kinase, and as we emphasized, it's the impact on the glycolytic pathway by activating PKR that increases ATP, where you see a number of positive effects in terms of red cell health, and then by dropping 2,3-PPG, which has long been demonstrated to be elevated in patients with sickle cell disease, the reason to believe there is it will decrease the So it's an observation that we may be improving the ability for that Gardase channel to do increased red cell hydration, but it's fundamentally through that mechanism of action of increasing ATP by activating PKR. Okay, great, thanks a lot.

Hi, Mohit, it's Jackie.

Thanks for the question I thought I wasn't getting get to talk to in the queue at night. So I appreciate the opportunity. So as you might imagine we want to set ourselves ambitious objectives, but objectives that we feel like we have a very high probability of achieving a with respect to the 1 billion.

Our revenue guidance it is.

Mostly driven by itself, though and I am now in terms of the indication which is related to the label expansions, but we've also got some revenues in there from an active add in PKD that I personally think we've been a little bit.

Directive on and then where we've we've also not included hardly anything is.

For for Tottenham in Glioma and for me to pivot in balancing the sickle cell disease, because there we have them from a timeline standpoint in our base case assumption.

Christopher J. M. Taylor: Thank you. Our next question comes from Peter Lawson with Barclays. Your line is open. Hi guys, this is Walid on for Peter.

You know relatively late in the time horizon.

But you know even a little bit of pulling those in or a little faster revenue ramp in the launch then what you've assumed would give you plenty of room for.

Peter Lawson: Thanks for taking the questions. And I just had a question around upcoming PKD data. Where do you see the bar for what will be considered clinically meaningful results? You know, as we look to data year end and first quarter 21 in both transfusion independent and transfusion dependent patients. Yeah, so we designed it. It's Chris Bowden here.

So we're still achieving the objectives, what we've actually seen also if you notice in one.

I think 20 with itself, though we're.

Revenues is the it seems like oral oncolytics and pandemic environment.

I actually be favored and since we have been very happy with hip sales performance in the 2020, so far and we havent guided to 2021, yet but.

Christopher J. M. Taylor: We designed both of those trials with an endpoint that is, will be associated with clinical benefit, and, of course, we will be looking very carefully at secondary endpoints. So the ACTIVATE study is designed to, a responder is defined as one and a half grams or greater increase in hemoglobin for baseline, and that trial is with 80 patients one-to-one randomized to active drug or placebo and then with the ability for placebo patients to cross over at the end of the dosing period, where we have a positive study if the response rate is 35%, and we assume there'd be an approximately And we think, based on what we saw in DRIVE-PK, that over a gram has been, when you talk to people clinically, talk to clinicians in terms of clinical benefit, we've set the bar even higher.

We will do that soon and then.

Beginning of next year, and we feel quite good about where we are with its salvo in that the base case in and then also your comment about the pandemic Antelope is impacting the 1 billion in 2025 really we have not seen that as an issue.

Yes, exactly when maybe a little better than what we had originally planned.

So I feel great about it and I think Ken My comments have always been at least 1 billion in 2025, that's still wellfield. Thank God, if I may speak one more in for that and Oh. Thank you for this Jackie So I know you're going to talk a lot about it on November 19th, but if I could kind of speak.

Because when we talk about became even doctors, they offset often say that deficient publishing to small and they don't see many patients. So in this context, where are you in terms of identifying PKD patients and how what is the low hanging fruit there or how do you. How would you go about and find a deceleration. Thanks for all the expenses.

Christopher J. M. Taylor: So if we meet the primary endpoint, we have a lot of confidence that we'll have a package that's indicative of clinical benefit. There will be a number of supporting secondary endpoints that will also be important in that not regularly transfused patient population. For the ACTIVATE-T study, which is 27 patients who are regularly transfused, the efficacy endpoint is a 33% or greater reduction in the overall transfusion burden at the time of the current study compared to their previous one-year history of transfusion.

Market. Thank you.

Christopher J. M. Taylor: And so that's an open-label trial, and the primary clinical measure that I just went on. At the same time, you know that in those patients who are regularly transfused, people look at a 50% reduction as well as transfusion independence. So those are the other important secondary efficacy outcomes that we hope will demonstrate that midipibat in that group of patients has a really big impact in terms of reducing the amount of time they need to spend in the clinic getting blood transfusions. And we'll also look at secondary endpoints like iron mobilization and what impact it might have on the need for iron chelation and other endpoints. So the two trials in total, we'd like to be able to use them to get a broad label in adults with postpartum deficiency, and we think the trials as a package are set up to really demonstrate clinical benefit overall.

You and.

And the U.S.

Very helpful. Thank you Dan and Jackie you. Thank you. Our next question comes from Kennen Mackay with RBC capital markets. Your line is open.

Hey, guys. This is vikram on for Ken. Thanks, So much for taking our questions today.

Christopher J. M. Taylor: Thank you for taking the question. Thank you. And the next question comes from Mohit Bhandari.

I have a quick one on the EU regulatory feedback that you got.

Mohit Bhandari: Great, thank you very much for taking my question and, first of all, congratulations Jonathan on your new role. Starting with the question, I mean, when you first provided this $1 billion guidance by 2025, obviously COVID was not there, and there has been a recent EMA decision which didn't go in your favor, so could you talk a little bit more about with these uncertainties how attainable this $1 billion by 2025 guidance is, or your aspiration is, and how much legal room is there with pipeline, et cetera, to still make it Hi Mohit, it's Jackie.

Maybe if you can remind us what were the main concerns of the regulatory.

And see there that led to the draw all and.

Jackie Faust: Thanks for the question. I thought I wasn't going to get to talk in the Q&A today. So I appreciate the opportunity. So as you might imagine, we want to set ourselves ambitious objectives, but objectives that we feel like we have a very high probability of achieving with respect to the $1 billion, Our revenue guidance, it is mostly driven by TIPSOVO and AML in terms of the indication which is related to the label expansions, but we've also got some revenues in there for Minipivad and PKD that I personally think we've been a little bit conservative on. And then where we've also not included hardly anything is for vorosodinib and glioma and for Minipivad and thalassemia and sickle cell disease because we have them from a timeline standpoint in our base case assumption, you know, relatively late in the time horizon, but, you know, even a little bit of pulling those in or a little faster revenue ramp in the launch than what you assumed would give you plenty of room for still achieving the objectives.

ALJ.

I'd say, it's appreciated that we had clinical activity with Ted so loan relapse refractory space.

That.

The oral agent and the durable responses were appreciated the main concern when we knew this going on into there wasn't a control arm. So this is here to the CH MP historically.

Looks at the types of data sets.

Jackie Faust: What we've actually seen also, if you notice, in 2020 with TIPSOVO revenues, is that it seems like oral oncolytics in the pandemic environment may actually be favored, and so we've been very happy with TIPSOVO's performance in 2020 so far, and, you know, we haven't guided to 2021 yet, but we will do that soon. So, in this context, where are you in terms of identifying PKD patients, and is there a low-hanging fruit there, or how would you go about finding these patients and, probably, expanding the market? Thank you.

Jackie Faust: Great, thanks for the question. So, you know, we've shared publicly, right, that previously that we believe that we estimate the population for PKD to be between 3 to 8,000 between the U.S. and 5 EU countries, maybe as high as 10,000 when you include the overall EU population. The patient identification efforts that we've been executing over the last couple of years have yielded just about a thousand or so patients split between the U.S. and the five EU countries, and then a number of additional patients that have been identified beyond those major markets as well. So when you take all that into account, about a third of the population we've identified today, right, about a third, a little more than a third, of the lower end of the potential prevalence population.

Jackie Faust: But that's a lot of what the work is, and continues to be between now and approval for MIDI-PIVAC, right? So just doubling down on that patient identification work in addition to disease education, disease awareness advocacy, and whatnot. And that work is ongoing in both the EU and the U.S. Very helpful.

Bikram Mohan: Thank you, Diane and Jackie. Thank you. Hey guys, this is Bikram Mohan for Canon.

Christopher J. M. Taylor: Thanks so much for taking our questions today. I have a quick one on the EU regulatory feedback that you received. Maybe if you can remind us what were the main concerns of the regulatory agency there that led to the withdrawal and your confidence in just phase three of the studies and timeline updates for whole one and HIL. Did your thinking and confidence change after this feedback? That would be super helpful. Yeah, hi, it's Chris here. Chris.

Express where words a potential headwinds that.

Our largely unknown right. So we know that we're experiencing and we will continue to experience a resurgence we know from our experience in the initial surge that it certainly.

Christopher J. M. Taylor: So our confidence and excitement around the phase three trials, which are in newly diagnosed patients, is really important because that's where, as I said in my remarks, that's where the most patients are. And so we're very committed to those trials. They're ongoing.

Christopher J. M. Taylor: And we had to reset guidance around Agile because of the COVID effects, and we're targeting finishing accrual to the Agile study at the end of next year. And the Holon study, which is in IC-eligible patients, we haven't guided to yet. That trial is in its early operational phase, where sites are coming on board. However, we're definitely seeing nice accrual for both the IDH-1 and the IDH-2.

Christopher J. M. Taylor: So there was, no doubt, I think that it was appreciated that we had clinical activity with tipsovo in the relapse refractory space. [inaudible] That's a lot of skepticism, and we did a lot of work looking at historical control data, some of which was going to be published in ASH, to demonstrate what looked like very, very impressive effects in terms of survival compared to an IgH1 historical control with relapsed refractory disease. At the end of the day, it just wasn't enough, and without controlled clinical data in the relapsed refractory space, the CHMP was not going to give a positive opinion, and we appreciated that after our oral explanation, and that's when we made the decision to withdraw. Yeah, I mean, it's Jackie jumping back in for just a second.

Jackie Faust: I think any time one goes forward with a Phase I dataset like this without a control arm in Europe, there's a risk that you end up in this type of situation. But we thought it was the right thing for patients to give this a shot, and we gave it a very good shot.

The trial whether its.

Co primary endpoints, whether it's a sequential testing the unit.

Jackie Faust: As Chris said, you will see some data published around the historical control work that we did that I think is still very interesting data. In our base case assumptions, we had reflected some assumptions around the risk of this. As Chris said, in the relapsed refractory IDH1 patient population, it's a relatively modest size in Europe with different pricing assumptions than what you have in the U.S. So it was a modest revenue opportunity, and we're moving full speed ahead with the Phase III trials, which are the type of trials that you would expect the Europeans to want to see for the label expansions into newly diagnosed, so just a different situation with Yeah, thank you so much for that.

But I think it just goes without saying that thats those two end points are.

On the marquee Thats.

Where the clinical benefit is where patients and.

And I think the big promise.

The potential if you will for for me to pick that up.

Is that you can significantly achieved both.

On there are clearly we're seeing drugs that are have been approved for an increase in hemoglobin.

With the jury's still out on what's going on at the C reduction.

And.

I know, we're hoping to see that with longer follow up that you might see a decrease.

Statistically significant decrease in VNC flux pellet tour that will be good for patients.

Jackie Faust: And I had a quick follow-up on TIPSOVO, just revenue trends in the U.S. You did mention gross to net impacts you might be expecting in Q4 and diagnosis rates. Were you seeing low diagnosis rates in Q3 as well? I know the Q3 growth was pretty strong, and demand growth, so maybe you can talk about a little bit of the dynamics, what you're expecting going into Q4 given the resurgence of cases in the U.S. What I tried to express were words of potential headwinds that are largely unknowns, right?

Jackie Faust: So we know that we're experiencing and will continue to experience a resurgence. We know from our experience in the initial surge that it certainly had an impact in terms of patients, patient presentation, and diagnosis, even though we weathered it quite well, particularly as an oral treatment in a setting like AML, which is a highly emergency setting. In Q3, it was quite a different setting, right?

Jackie Faust: So you had, even though you had hotspots across the U.S., you'd have quite the experience that we're in the start of in Q4. And so what I wanted to ensure is that we're sort of balancing the enthusiasm for the performance that we've seen in Q3 with the potential, very real potential impacts related to COVID in Q4. Now, that said, the impact on girls to men is largely related to the potential change in the mix of coverage for patients on commercial drugs. We haven't seen a huge shift, but it is possible based on economic realities and the impact on employment and insurance coverage, perhaps an increase in Medicaid coverage as well as those patients moving through 340B or DISH hospitals. And those are the things that we're anticipating over the course of Q4 that could potentially provide some headwinds on our overall performance. And I think Darren, in his prepared remarks, also said that, with all of those caveats, the month of October put us off to a very good start for Q4. Yeah, we're pretty pleased with what we've seen so far this quarter.

Now Palestinians sickle cell.

And it continues to do very well so we don't need 946 motivate to start our pediatric plans as evidenced by the fact that we're moving forward part of a tiny sufficient.

Alright, thank payment.

Thank you. Our next question comes from Michael Smith.

<unk> your line of seven.

Hey, can I assist with Kelsey on for Michael. Thank you for taking our questions I guess to kind of build off of got last question could you. Let me just remind us how you see the next Gen. P. K R activator kind of fitting into your development plants longer term.

Jackie Faust: Okay, thank you so much for taking the question. Thank you. Our next question comes from Alethea Young. Hi, this is Emma on behalf of Alethea Young.

Walid: So just turning back to Sickle Cell, we saw that another PKR activator in development outlined a pivotal program in their ASH Abstract that included annualized VOC as a co-primary endpoint. So I know you guys are still in regulatory discussions there for the planned meta-pivot design, but is that something you think would be important to show differentiation on in order to be competitive versus that agent or also commercial drugs like Pocopren Well, I think that's Chris here.

Christopher J. M. Taylor: I think any, And, you know, if you're going to run a trial with a PKR activator, as we've said, From the get-go, you have two reasons to believe, and one is raising hemoglobin, and the other is reducing BOS. So there are a lot of ways to design the trial, whether it's co-primary endpoints, whether it's sequential testing. But I think it just goes without saying that those two endpoints are the marquee, that's where the clinical benefit is for patients, and I think the big promise, the potential, if you will, for metapivap, just that you can significantly achieve both. We clearly are seeing drugs that are approved for increasing hemoglobin, with the jury still out on what's going on with VOC reduction. And, you know, I know we're hoping to see that with longer follow-up, you might see a decrease in, a statistically significant decrease in VOCs with Fluxelator. That would be good for patients. The P-Selectin inhibitor from Novartis reduces VOCs, but it doesn't really; it has no impact on hemoglobin.

Complete accrual at the end of 2021, and then that's an event driven trial.

So we'd have to really get some sense of how fast events are coming and then we would unblind. It and then we would be that often and filings. So it's.

No that that gives you a broad sense.

For whole bond, we havent guided yet to be a cruel completion, because like I said, we're still activating sites and that's so large global trial.

We hope to get that as soon as we get these trials positive study in our hand, and we would want to get in front of book CH in PMT and other.

Christopher J. M. Taylor: And the promise for a minute, the potential, and the promise, we hope, for a minute to that is that we can address both, and that you'll be able to address the two main problems of sickle cell disease. Thank you. And then, is there any update you're able to give on the pediatric development plan, kind of across the PTR portfolio, both for mid-prep and 9-4-7? So our pediatric program with Medi-Quil-Vac is moving forward in patients with part of a kinase deficiency. And so, we're working toward getting those studies up and running. And with regard to thalassemia and sickle cell disorders for mid-pivot, certainly those will need to happen, but you know we're right now focused on pyruvate kinase deficiency, and we think we'll have those details worked out by the end of this year.

Christopher J. M. Taylor: As far as AG-946 goes, that drug has a long way to go in terms of demonstrating, you know, achieving its early development hurdles before we start thinking about what the next stage of development is for that compound. Metapibat, on the other hand, has years of efficacy and safety data, first in part of a kinase deficiency, now in thalassemia and sickle cell. And it continues to do very well.

Potential to do that.

Certainly early data with like solids or looking at a number of different important and points.

Whether it was sick.

Sibling assays in particular sites and L D H and some of those things.

When we look at our data.

Christopher J. M. Taylor: So we don't need 946 in order to start our pediatric plans, as evidenced by the fact that we're moving forward in part because of a kinase deficiency. Okay. Thanks, everyone. Our next question comes from... (inaudible) Hey guys, this is Kelsey Anson-Michael. Thanks for taking our questions. I guess to kind of build off of that last question, could you maybe just remind us how you see the next-gen PKR activator kind of fitting into your development plans in the longer term? And then for TIBSOVO, I guess if the ongoing phase 3 trials are successful, I guess when do you think the earliest you could secure European approval for TIBSOVO could be? Thank you.

At a similar point in time with all the caveat to go with different patient number is cross trial comparison different points in time Coke in communist medication, but they're really a bunch of caveat to it but we look at our overall profile that were saying whether it's.

With the the sibling after that that you're referring to whether it's L. D. H particular sites and other aspects were were very.

We feel really good about what we're seeing and that's why we to declare that we have proof of concept, where I'm moving to page three at the time of by <unk>. When you look at the initial patient data.

When I'm okay.

I think there's.

There is.

And understandable interest.

And all these new drugs coming in and we get the question I won't.

What's the value of having many pay that if it raises hemoglobin because that SWEATBOX elytroid does as well there's a V. C piece that you ask us a lot of questions about and there's also the aspect that the percentage of patients who have one grandma greater increase with like <unk>, There's about 50.

Christopher J. M. Taylor: Right, okay, so the first question is 946 and what its development path would be, and that will also depend on the type of data that we see with MitoPivac. And because we're, we're moving that forward across all three indications and based on the activity in the safety profile we've observed to date. So, you know, what we do next with 946, well, it's too early to make that call because we need to see what the actual clinical attributes of the molecule are and whether it would offer tangible, you know, important improvements for a patient across those three diseases where we're studying metapivap now. And, of course, we continue to study and investigate diseases where activation of pyruvate kinase may have the potential And so that's something that we're actively looking into. But it's just too early for us to comment on how 946 would be developed in the next stage. What we're focusing on now is whether it can even get into the situation where we can do that.

[noise] percent. So there's a number of patients who don't have any hemoglobin. That's fine. So we could see ourselves as being a very good drug for those patients just for starters.

Okay, and then I think the N. H study showed a couple of V O C either either during or at the end of the study in a few patients.

I guess can you characterize these patients for you know what their baseline or historical frequencies of you'll see where if if you have access to that data.

Yeah, we don't have.

Yeah, we don't have a lot of free.

Priest study information in terms of what was the annual number of B O C. They had how predictable was it.

Nope that'd be overall assessment from from the investigators, yes, we saw one B O C. During a taper made some alterations to the table with not seen any sense and that the there was one of the.

After.

The end of this coming to the end of the study so that after that patient had been off drugs.

Long period of time and it was several.

Precipitating factors going on and that patients like that that would have put them at risk. So.

Christopher J. M. Taylor: So, and then your question is, for Chibsovo, what's the earliest that we could get any of those frontline trials in front of the CHMP to get approval in the frontline setting? So, if you look at Agile, that's got to complete accrual at the end of 2021, and then that's an event-driven trial. So, we'd have to really get some sense of how fast events are coming, then we would unblind it, and then we would be off and filing. So, it's just, you know, that gives just a broad sense.

It's something we continued to follow if you look at any of the trials.

B O C are part and parcel with the with the development.

One of our Big question, that's why you need a control to really get a handle on what's going on.

For that for that endpoint.

Okay. Thank you very much Chris.

And I know you're welcome comes from.

But.

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Okay.

Hey, Thanks. This is Chris on for Andy just had a question about the heart rate increase but you guys saw in the abstract just wondering how well characterized that is that is if it has to do with an arrhythmia or just tachycardia and if you've seen.

Any other cardiac events and other studies or in preclinical study.

Christopher J. M. Taylor: For HOBON, we haven't guided yet to accrual completion because, like I said, we're still activating sites in this large global trial. We hope to get, as soon as we get these trials, a positive study in our hands, and we would want to get it in front of both the CHNP, the FDA, and other regulators as soon as we can. It's just too early for us to be able to provide specific guidance on it. Okay, thank you.

That show what that is is an asymptomatic.

Heart rate over 100 beats per minute and if you look at the.

Common toxicity criteria does not require intervention in that day symptomatic.

We we have not see any indication that we have a cardiac didn't know what this drug and so what's happening is that patients are coming in or getting evaluated and then part of their vital signs there.

Christopher J. M. Taylor: Thank you. Our next question comes from Mark Breidenbach with Oppenheimer. Yeah.

Three individuals who had heart rate above 100, but otherwise felt by hadnot symptoms associated with it.

Christopher J. M. Taylor: Hi, guys. This is Calpedon for Mark, and thanks for taking our questions. I had a couple on the NIH study, specifically with the markers of polymerization, the P50 and T50. Do you believe these changes that we have seen to date in the ASH abstract are clinically meaningful to show long-term reduction in VOCs? And then, if you could also comment on how these changes compare to what we've previously seen with Oxprida in earlier stage trials, thanks.

That's that's the gist of it and we've not seen any other signals across any of our other trials suggest there's anything from a cardiac standpoint, it would be concerned about.

We continue following safety and all and you know in the broadest sense across all of the trials and so.

This is not something that we've had any need to focus on at this point and I don't think that the three patients with a symptomatic heart rate above 100 is is something that's gonna set us off on.

Christopher J. M. Taylor: Yeah, so we do think that this definitely has the potential to reduce VOCs, what we're seeing with our P50 and T50 assays. One of the challenges has been that there's not a direct correlation. For example, this much improvement is associated with this much reduction in the frequency of VOCs.

In a way that that concerns us or altered to safety profile and what we've reported to date in any way.

Got it and one more question if that's all right I'm just wondering about that got us channel.

Potential mechanism for the other products that was in the pipeline that was specifically for Cardiff channel. One of the proposed ideas of why they increased V. O sees was due to hyper viscosity. So I'm just wondering if you had any viscosity data that could potentially.

Christopher J. M. Taylor: And so that's, but nevertheless, based on what we're seeing, we think we definitely have some potential to do that. Certainly, early data with Voxelic, who are looking at a number of just important endpoints, um, whether it was, sickling assays and particular sites and LDH and some of those things when we look at our data at a similar point in time, with all the caveats that go with different patient numbers, cross-trial comparison, different points in time, concomitant medications, so there are really a bunch of cave But when we look at the overall profile that we're seeing, whether it's the sickling assays that you're referring to, whether it's LDH, particular sites, and other aspects, we're very... We feel really good about what we're seeing. And that's why we declared that we had proof of concept.

Comply something different or counter that.

Christopher J. M. Taylor: And we're moving to phase three at the time of EHA to look at the initial patient data. One other thing I'll say is that I think there's an understandable interest in all these new drugs coming in. And we get the question of, well, you know, what's the value of having imidapibat if it raises hemoglobin because that's what oxalatory does as well. And there's the VOC piece that you ask us a lot of questions about.

Christopher J. M. Taylor: And there's also the aspect that the percentage of patients who have a one-gram or greater increase with oxalatory is about 50%. So there are a number of patients who don't have any hemoglobin response. So we could see ourselves as being a very good drug for those patients. Christopher Stardust, Okay, and then I think the NIH study showed a couple of VOCs, either during or at the end of the study in a few patients. I guess, can you characterize these patients for us? You know, what their baseline or historical frequencies of VOCs were, if you have access to the data?

Keep following this.

Breaking news.

So David develop flourish any comments about the gardens channel piece. Please.

No I think you I think you covered it pretty well.

But you know that the parameters that might lead to higher as it starts to date. He spoke to one of the tcten instead, the red cell. We believe we will address that improving.

Christopher J. M. Taylor: Yeah, I we don't have a lot of pre-study information in terms of what was the annual number of VOCs they had, and how predictable was it. The overall assessment from the investigators, yes, we saw one VOC during a taper, we made some alterations to the taper, we've not seen any since, and that there was one after the end of this, coming to the end of the study after that patient had been off drugs for a long period of time, and there were several precipitating factors going on in that patient's life that would have put them at risk. So it's something we should continue to follow. If you look at any of the trials, VOCs are part and parcel of the development, and so one of our big questions is why you need control to really get a handle on what's going on for that end point. Okay, thank you very much, Chris.

That the general health of the Red cell and their propensity for that the other significant parameter is a very.

Hi, Pat.

PC, they actually our volume.

Christopher J. M. Taylor: Thank you. And our next question comes from Andrew Berens with SVP Lee Ring on Philanthropy. Hey, thanks, this is Chris on behalf of Andy.

Christopher J. M. Taylor: I just had a question about the heart rate increase that you guys saw in the abstract. Just wondering how well characterized that is, if it had to do with an arrhythmia or just tachycardia, and if you've seen any other cardiac events in other studies or in preclinical studies. So what that is, is an asymptomatic heart rate of over 100 beats per minute, and if you look at the Common Toxicity Criteria, it does not require intervention in the face of the matter. We have not seen any indications that we have a cardiac signal with this drug. And so what's happening is the patients are coming in, they're getting evaluated, and then as part of their vital signs, there were three individuals who had a Heart Rate Above 100 but otherwise felt fine, had no symptoms associated with it.

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

Ladies and gentlemen. This concludes today's conference call. Thank you for your participation you may now disconnect everyone have a great day.

Christopher J. M. Taylor: That's the gist of it. And we've not seen any other signals across any of our other trials that suggest there's anything from a cardiac standpoint that would be concerned. We continue to follow safety and all and, you know, in the broadest sense, across all of the trials. And so this is not something that we have had any need to focus on at this point.

Christopher J. M. Taylor: And I don't think that the three patients were asymptomatic. Heart Rate Above 100 is something that's going to set us off on a way that concerns us or alters the safety profile than what we've reported to date in any way. Got it. And one more question, if that's all right. I'm just wondering about that GARDOS channel.

[music].

Christopher J. M. Taylor: Potential mechanism for the other product that was in the pipeline that was specifically for Gardash Channel. One of the proposed ideas for why they increased VOCs was due to hyperviscosity, so just wondering if you had any viscosity data that could potentially, you know, imply something different or counter that. Um, well, I think nothing specific in terms of hyperviscosity data. Bruce Carr, I'll ask him to comment further on that. But I think that the aspect of what we're doing by dropping 2, 3-DPG and speaking specifically about sickling is preventing, um, the red cell from becoming sticky and deformed. So, um, I wouldn't anticipate that hyperviscosity will be a problem if, in fact, we are seeing, you know, if it turns out that we are able to, over time, see consistent increases in MCB and get some sense as to if this is really the reason why.

Christopher J. M. Taylor: So, that's not a concern, and it's interesting that some of the data that's now coming out at ASH, for instance, GBT's publication where, you know, they have a minority of patients, a small percentage of patients who had hemoglobin increases to 12 or 13, and they published remarkably that those patients had the lowest frequency of VOCs. And it may be now that, you know, this concern, which has always been there about how high you can get hemoglobin up, it's still going to be there, no doubt, with experts and clinicians who treat sickle cell disease, but now maybe things will get a little more nuanced, and we'll just have to keep following this breaking news as these data develop. Any comments about the Garda's Channel piece, please? I think you covered it pretty well. Chris, the parameters that might lead to hyperviscosity, you spoke of one of the adhesiveness of the red cell.

Christopher J. M. Taylor: We believe we have addressed that in proving the general health of the red cell and the propensity for that. The other significant parameter is the very high PCV, or PCV-packed cell volume. That's something that we're not likely to get, and you also mentioned that in We seem to be doing pretty well anyway, so I don't think there's anything additional that one can draw from a study where the active agent has such a profoundly different mechanism of action from our drug. So I think drawing an extrapolation between the two mechanisms of action relative to concerns about this potential side effect is probably not appropriate. I got it.

Christopher J. M. Taylor: Thank you very much. Thank you. And I'm currently showing no other callers.

[music].

Jackie Faust: I'd like to hand the call back over to Jackie Faust-Rennie for the rest of the call. Thank you, Operator. I just would like to reiterate that despite the challenges and uncertainties that continue to prevail in the world today, I and the whole Agios team remain very excited about the progress that we are making across our focus areas this year, and we're looking forward to a catalyst-rich 2021 as well. To close, I would like to thank my Agios colleagues for their dedication and passion for making a difference for 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 today, and I would like to thank all of you for joining us on our call today. We will see you soon.

Operator: This concludes today's conference call. Thank you for your participation. ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ???.

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Holly Manning: . Copyright 2020, New Thinking Allowed Foundation. Good morning, and welcome to Agios' third quarter 2020 conference call. At this time, all participants are in a listen-only mode. There will be a question and answer session at the end. Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Holly Manning, Director of Investor Relations. Thank you, Operator. Good morning, everyone, and welcome to Agios' third quarter 2020 conference call. You can access slides for today's call by going to the Investors section of our website, agios.com.

Jackie Faust: 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 Jonathan Biller, our Chief Financial Officer and Head of Legal and Corporate Affairs. Dr. Bruce Carr, our Chief Scientific Officer, will join for Q&A. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. However, actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in the risk factor section of our most recent Form 10-Q filed with the FCC and any other filings that we may make with the FCC. With that, I will turn the call over to Jackie.

Jackie Faust: Thanks, Holly. Good morning, everyone, and thanks for joining us on our third quarter 2020 results call. Our activities this quarter were focused on execution against our key priorities for 2020, significant planning in preparation for a catalyst-rich fourth quarter in 2021, and a clear commitment to doing what's right for patients and our people as we continue to navigate the ongoing impact of the COVID-19 pandemic. We made important strides toward getting our medicines to patients who need them. This included generating mature overall survival data from the CLARITY study, which enables our first solid tumor regulatory filing, and initiating our healthy volunteer study of AG946, our next generation PKR activator. Behind the scenes, we've been hard at work preparing for important milestones coming later this year and throughout 2021, including top-line data readouts for our ACTIVATE and ACTIVATE-T studies, the supplemental NDA submission for Tissobo and cholangiocarcinoma, and the initiation of our global pivotal studies of midipivat in thalassemia and sickle cell disease.

Yeah.

[music].

Jackie Faust: In conjunction with ASH, we will host an investor event on December 8th to share the updated data from the NIH Phase I study of metapivet and sickle cell disease, as well as an overview of our Phase III plans in thalassemia. And finally, we now expect top-line data from the ACTIVATE study of minipivot in non-transfusion-dependent PK deficiency by the end of the year, We have a busy few months ahead of us, and I want to thank each and every Agios employee for continuing to advance our programs for patients while balancing the pandemic's continued impact on their personal and professional lives. Bruce, I now turn it over to you. Thanks, Jackie.

Christopher J. M. Taylor: I'll start with Mitopivat, our first-in-class PKR activator currently being evaluated across three distinct hemolytic anemias. As Jackie highlights, we anticipate several important milestones in the coming weeks that will advance all three of our Mid-Ip Tibet programs. I'll start with our most advanced program in pyruvate kinase deficiency, where we are running two phase three clinical trials and have the potential to provide the first disease-modifying therapy for this disease. Earlier this year, we got top-line data for the Activate and Activate T studies sometime between the end of this year and mid-2021, anticipating some delays as a result of the pandemic. Thanks, in large part, to the extraordinary commitment of our team at Agios, we're now able to narrow those timelines.

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.

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

Our activities this quarter will focused on execution against our key priorities for 2020.

We made important strides toward getting our medicines to patients who need them.

This includes generating mature overall survival data from the clarity study, which enables our first solid tumor regulatory filings.

Christopher J. M. Taylor: For ACTIVATE, the randomized placebo-controlled phase 3 study in 80 adults with pyruvate kinase deficiency who are not regularly transfused, we anticipate top-line data by the end of 2020. For ACTIVATE-T, the phase 3 single-arm open label study in 27 adults with PK deficiency who are regularly transfused, we anticipate top-line data in the first quarter of 2021 If positive, we expect to file for regulatory approval for a broad label for adults with PK deficiency in both the U.S. and EU next year, with a potential 2022 commercial launch in both geographies.

And initiating our healthy volunteer study of AG non four six our next generation PK our activator.

Behind the scenes, we've been hard at work preparing for important milestones coming later this year and throughout 2021, including topline data readouts for our activate and activate T studies.

Supplemental India submission for Sid Sogo, and Cholangio carcinoma, and the initiation of our global pivotal studies have mitigated that in Dallas, EEMEA and sickle cell disease.

To help lead us towards these key value inflection points.

We appointed Jonathan Biller to the role of key financial Officer head of legal and corporate Affairs in September.

Clinton is a longtime colleague of mine, whose expertise has been a welcome addition to our leadership team since he joined in November of last year you.

Christopher J. M. Taylor: Moving to the Phase 2 study of midipibatin thalassemia, we completed enrollment earlier this year with 20 patients. And in June, we presented updated data on 13 efficacy-evaluable patients at the virtual EHA meeting. The data showed that treatment with midipibat induced a hemoglobin increase of greater than or equal to 1 gram per deciliter in 12 of 13 evaluable patients during weeks 4 through 12, including 4 out of 4 alpha thalassemia patients where there have been no new treatment options in decades. In addition, 7 of 8 beta thalassemia patients achieved a sustained hemoglobin response during weeks 12 through 24. We expect to submit the full data set from this study for presentation at a medical meeting in 2021. This quarter, we've been working through the U.S. and E.U.

You will hear from him later in the call as we discuss our quarterly financials.

We also dealt with some challenges, including the need to withdraw our marketing authorization application for tips, although in the relapse refractory AML setting in the E U.

Our ongoing phase three combination studies have to sell in the frontline AML setting remain on track for those much larger patient populations.

The decision to withdraw our M&A will not result in any near term changes to our approach in the region.

Our lean Edu team is largely focused on supporting our Geos clinical trial, and medical affairs activities and PKD market development efforts, including patient advocacy disease education and patient identification.

Investment in the EU will continue to be gated and aligned with the timing of future product approvals in the region.

Looking ahead to the remainder of the year, we have a number of key events for our mid a pivot programmed that further in loose to date the potential value of the teekay, our activation mechanism to treat serious hemolytic anemias birds on November 19th we will hold an investor web and our focus on our PK our franchise, which will include.

Christopher J. M. Taylor: regulatory feedback to our pivotal program. At our ASH event in December, we expect to share details of our robust pivotal development plan that spans both alpha and beta thalassemia, as well as transfusion-dependent and non-transfusion-dependent patient populations. We anticipate initiating our pivotal program in 2021. Now, let's turn to sickle cell disease, where we're collaborating with Dr. Sui-Lei Chen of the National Institutes of Health on a proof-of-concept study with Mitopib-L. In June, we announced that clinical proof of concept was established based on a preliminary analysis of data from eight patients. The data showed that over a 6- to 8-week dosing period, 7 of 8 patients experienced a hemoglobin increase, with 5 of 8 patients achieving a hemoglobin increase of greater than or equal to 1 gram per deciliter from baseline.

A deep dive into the mechanism of action.

The unmet patient needs and Dallas, EEMEA sickle cell disease, and PK deficiency, our view of these market opportunities and the commercial preparations underway for our first potential rare disease loans.

In conjunction with Ash, we will host an investor event on December Eightth to share the updated data from the NIH phase one study have been a pivot in sickle cell disease as well as an overview of our phase three plans and Dallas CBS and.

And finally, we now expect topline data from the activates study of minute pivot in non transfusion dependent PK deficiency by the end of the year. Thanks to the tremendous efforts of our team.

We have a busy few months ahead of us and I want to thank each and every on Joe's employee for continuing to advance our programs for patients while balancing the pandemics continued impact on their personal and professional lives.

Christopher J. M. Taylor: Enrollment in the study was temporarily paused in the spring due to the COVID-19 pandemic, and it has reopened as of mid-August. As of today, the study has enrolled 13 patients. At ASH, Dr. Chen will give an oral presentation with updated data from at least 11 patients. The eight patients from the preliminary analysis and approximately three additional patients expected to complete the study in time to be included in the presentation, a total of five patients from the top-line preliminary; all three newly enrolled patients received the 100 milligram BID dose and will be included in the ASH presentation. Data from the fully enrolled trial will be submitted for presentation at a medical meeting next year. Moving forward, the NIH recently approved a new protocol allowing all patients in the Phase I study to continue to receive midipivac in an extension phase for up to two years.

Let me now turn it over to you.

Thanks Jackie.

I'll start with mid to pivot our first in class PK, our activator currently being evaluated across three distinct hemolytic anemia.

As Jackie highlighted we anticipate several important milestones in the coming weeks that will advance all three of our mid pit that programs.

I'll start with our most advanced program and pirate Big Chinese Sufficiency, where we're running two phase three clinical trials and have the potential to provide the first disease modifying therapy for this disease.

Earlier this year, we guided to topline data for the activate and activate two studies sometime between the end of this year and 2021 anticipating some delays as a result of the pandemic.

Thanks in large part due to the extraordinary commitment of our team at our Geos were now able to narrow those timelines.

For activate the randomized placebo controlled phase three study in 80 adults with pretty big kinase deficiency, who are not regularly transfused, we anticipate topline data by the end of 2020.

We're activate T based three single arm open label study in 27 adults with PK deficiency, who are regularly transfused, we anticipate top line data in the first quarter of Twentytwenty, one given the longer follow up time in this study.

Christopher J. M. Taylor: We expect to share an overview of the pivotal program design in the first half of 2021 and initiate the study within the year. Now, I'll move to our Milwaukee hematology program. Last month, we shared our decision to withdraw our marketing authorization application for TIPSCOBO and relapse refractory AML as a result of the feedback received at the oral explanation in September. Despite our learnings from the IDEPA experience and the additional in-depth work from our team, we were unable to fully address the major objections raised by the CHMP to support a positive benefit-risk assessment in the proposed indication based on a single-arm While we are disappointed that patients in the EU will not have access to TIBSOVO in the near term, we continue to enroll the Agile and Hovon Phase 3 combination trials in IC-eligible and IC-ineligible frontline AMs. If the trials are positive, we anticipate pursuing approvals in the U.S. and EU. The vast majority of newly diagnosed AML patients are eligible to receive intensive or non-intensive therapy.

If positive we expect to file for regulatory approval for a broad label and adults with PK deficiency in both US and you next year with a potential 2020 two commercial launch in both geographies.

Moving to the phase two study admitted Tibetans Sala CEO, we completed enrollment earlier this year with 20 patients and in June we presented updated data on 13 efficacy evaluable patients at the virtual on mute.

The data showed that treatment with mid to that induce the hemoglobin increase of greater than or equal to one gram per deciliter in 12 or 13 evaluable patients during weeks four through 12, including four out of four office, our senior patients where there have been no new treatment option in decades.

In addition, seven of eight beta thalassemia patients achieved to sustain hemoglobin response during weeks 12 to 24.

We expect to submit the full data set from this study for presentation at a medical meeting and 2021.

This quarter, we've been working through us and Bu regulatory feedback to our pivotal program that.

Christopher J. M. Taylor: So these studies provide the opportunity to reach the largest number of patients. Switching gears to our solid tumor program, last year, we reported positive, highly statistically significant progression-free survival data from the Clarity Phase 3 study in Kibsovo, and previously treated IDH1 mutant cholangiocarcinoma.

At our Ash event in December we expect to share details of our robust pivotal development plan, which spans both alpha and beta thalassemia.

As well as transfusion dependent and non transfusion dependent patient populations.

We anticipate initiating our pivotal program in 2021.

Now, let's turn to sickle cell disease, where we're collaborating with Dr. suite led Chen the national Institutes of health on the proof of concept study with mid a pickup.

Christopher J. M. Taylor: And last month, we shared a top-line look at mature overall survival, a secondary endpoint in the study. Treatment with Kibsovo is associated with a non-statistically significant improvement in overall survival compared to placebo. Given that 70% of patients crossed over from the placebo arm to the ibosidinib arm, we consider this positive trend in overall survival to be important supportive data for approval. We will be sharing these data with FDA and are planning to submit a supplemental new drug application for TIBSOBO and previously treated IDH1 mutant cholangiocarcinoma in the first quarter of 2021. Additionally, we have submitted the Clarity Final Overall Survival Dataset for potential presentation at ASCO GI in January. The impressive and statistically robust PFS results supported the inclusion of TIBSOVO in the NCCN treatment guidelines at a level of recommendation on par with approved therapies for other biomarker-select populations. This level of endorsement from expert physicians is encouraging recognition of the clinical benefit of TIBSOVO. In addition to cholangiocarcinoma, we are exploring the utility of IDH inhibition in low-grade glioma in our Phase III indigo trial of borisfidinib.

In June we announced a clinical proof of concept was established based on a preliminary analysis of data from eight patients.

The data showed that over a six to eight week dosing period seven of eight patients experienced a hemoglobin increase with five of eight patients achieving a hemoglobin increase of greater than or equal to one brand progressive leader from baseline.

Enrollment in this study was temporarily paused in the spring due to the COVID-19 pandemic.

Has reopened as of mid August.

As of today. The study has enrolled 13 patients.

At Ash Dr. Chen will give an oral presentation with updated data from at least 11 patients.

The eight patients from the preliminary analysis and approximately three additional patients expected to complete the study in time to be included in the presentation.

A total of five patients.

From a top line preliminary all three newly enrolled patients received 100 milligram dose and will be included in the ash presentation.

Data from the fully enrolled trial will be submitted for presentation at a medical meeting next year.

Moving forward the NIH recently approved the new protocol, allowing all patients in the phase. One study we continue to receive mid a pivot in an extension phase for up to two years.

Extension will provide valuable long term safety and efficacy data in sickle cell disease.

Where patients have the potential to be on therapy for many years, perhaps for life.

In parallel with these clinical activities, we are working rapidly to obtain us in the regulatory feedback to advance our sickle cell disease pivotal development plan.

We expect to share an overview of the pivotal program design in the first half of 2021 and initiate the study within the year.

Ill now move to our malignant hematology programs.

Christopher J. M. Taylor: Or a side nib is our brain penetrant dual IDH12 inhibitor that has the potential to treat the roughly 80% of low-grade glioma patients with an IDH mutation. Despite this, start-up activities are ahead of expectations despite the pandemic, reflecting physician enthusiasm for the potential of borosidinib and this trial. And finally, the AG270 Phase I dose-escalation combination arms with taxanes continue to enroll patients. With that, I'll turn it over to Beren to discuss our third quarter commercial performance. Thanks, Chris.

Last month, we shared our decision to withdraw marketing authorization application for Twod cell vote in relapse refractory AML as a result of the feedback received at the oral explanation in September.

Despite our learnings from the deep experience and the additional Indepth work from our team we were unable to fully address the major objections raised by the CHP to support a positive benefit risk assessment and the proposed indication based on a single arm non comparative phase one two study.

While we are disappointed that patients and that you will not have access to so in the near term.

Darren Miles: The momentum we observed in the first half of 2020 continued through the third quarter, resulting in $32 million of net sales of Tipsovo, a 15% increase over Q2. Performance in the quarter was driven by a significant increase in new scripts and refills and continued improvement in duration to approximately five months. Though we continue to see growth in both the academic and community setting, increased use in the community setting was particularly strong and may reflect a trend in the increased co-management of patients between academic and community physicians, likely accelerated by the COVID-19 pandemic. We continue to see steady increases in physician preference share for Typsolol, the frontline intensive chemo-ineligible, and first relapse. All leading indicators of physician perceptions of TIPSOVO are encouraging, including a significant improvement in those physicians who believe TIPSOVO is standard of care for newly diagnosed intensive chemo-ineligible patients.

We continue to enroll the agile and home on phase III combination trials in IC eligible in IC ineligible frontline AML.

The trials are positive we anticipate pursuing approvals in the us and you.

The vast majority of newly diagnosed AML patients are eligible to receive intensive or non intensive therapy. So these studies provide the opportunity to reach the largest number of patients.

Switching gears to our solid tumor programs.

Last year, we reported positive highly statistically significant progression free survival data from the clarity phase three study.

Now could sogo previously treated IDH, one you can cholangio carcinoma and last month, we shared a topline market mature overall survival secondary endpoints in the study.

Treatment with tubes, Sogou is associated with a non statistically significant improvement in overall survival compared to placebo.

Given that 70% of patients crossed over from the placebo arm to the Ivas side near mine. We consider this positive trend in overall survival to be important supportive data for approval.

We will be sharing these data with FDA and are planning to submit a supplemental new drug application for tubes Sobo in previously treated IDH, one mutant cholangio carcinoma in the first quarter of 2021.

Darren Miles: While our promotional efforts are limited to the on-label AML opportunity, we observed an increase in commercial volume attributed to cholangiocarcinoma following the addition of TIPSOVO to the NCCN guidelines in June. However, visibility into indication-specific uses is limited to the Specialty Pharmacy Channel, which represents about a third of Tibsogo commercial volume. The increased utilization of cholangiocarcinoma following the update and practice guidelines warrants this note.

Additionally, we have submitted the clarity final overall survival data set for potential presentation at ASCO Gi in January.

The impressive and statistically robust PFS results supported the inclusion of tubes. So both in the NCCN treatment guidelines at a level recommendation on par with approved therapies for other biomarkers selected populations.

Darren Miles: Well, we've seen some easing in certain geography. However, face-to-face customer interaction, particularly with academic customers, remains largely restricted, and we anticipate that restrictions will tighten again as we head into the late fall and winter months. Nevertheless, our team has been effective at using virtual communication and educational tools to continue live customer engagement. As a result, we were able to increase the number of new customers by 17%.

This level of endorsement from the expert physicians is an encouraging recognition of the clinical benefit of tubes. So vote.

In addition to Cholangio carcinoma, we are exploring the utility of IDH inhibitor in low grade glioma in our phase three indigo trial aboard a side note.

Or a side note is our brain penetrant dual IDH one two inhibitor that has the potential to treat the roughly 80% of low grade glioma patients with an IDH mutation.

Site startup activities are ahead of expectations, despite the pandemic, reflecting physician enthusiasm for the potential of fore sight and this trial.

Darren Miles: The outlook for the fourth quarter is strong, but not without some potential headwinds. Leading indicators and performance in the early weeks of Q4 indicate similar trends to Q3. However, we also anticipate disruption in the number of AML patients diagnosed and potentially treated as COVID-19 infections and hospitalizations are expected to increase through the end of the year. In addition, we may see increased volume moving through Medicaid and 340B channels as a result of the pandemic, which can apply increased pressure on gross demand. Considering our year-to-date performance and our outlook for the remainder of the year, we're narrowing our guidance for 2020 net U.S. dipsobal sales from between $105 to $115 million to $113 to $115 million.

And finally, the AG 270 phase one dose escalation combination arms with Taxanes continue to enroll patients.

With that I will turn it over to Darren to discuss our third quarter commercial performance.

Thanks, Chris.

The momentum we observed in the first half of 2020 continued through the third quarter, resulting in $32 million of net sales of silver a 15% increase over Q2.

Once in the quarter was driven by a significant increase in new scripts and refills and continued improvement in duration to approximately five months.

So we continue to see growth in both the academic and community setting increased use in the community setting was particularly strong and they reflect the trend and the increased co management of patients between academic and community positions likely accelerated by the COVID-19 pandemic.

We continue to see steady increases in physician preference share for chips, so little different line intensive chemo ineligible and first relapse settings all.

All leading indicators of physician perceptions of civil are encouraging including a significant improvement in those physicians, who believe silver with standard of care for newly diagnosed and since a chemo in eligible patients.

Well our promotional efforts are limited to the on label ml opportunity, we observed an increase in commercial volume attributed to Cholangio carcinoma. Following the addition of two so both to the NCCN guidelines in June.

Darren Miles: I want to thank the AGIOS team for not only adapting but thriving in the face of these uncertain times, fueled by a passion to ensure no patient is denied the opportunity to benefit from our treatment. I'll now turn it over to Jonathan to discuss our third quarter financial results. Thanks, Darren.

Liability into indication specific uses is limited to the specialty pharmacy channel, which represents about a third of civil commercial volume the increased utilization cholangio carcinoma. Following the update and practice guidelines made this noteworthy.

Jonathan Biller: Third-quarter results can be found in the press release we issued this morning, which I will summarize. More detail will be included in our 10-Q filing later today. Total revenue for the second quarter was $35 million, which consisted of $32 million of net sales of Sobo, $2 million of collaboration revenue, and $700,000 in royalty.

Nevertheless, our team has been effective at using virtual communication and educational tools to continue live customer engagement. As a result, we were able to increase the number of new customers by 17%.

Jonathan Biller: Compared with the third quarter of 2019, total revenue grew 33%, driven by an 82% increase in TIPSOVO sales, offset by a decrease in collaboration revenue due to the completion of the research and development service obligation with Celgene and Q2. In addition, royalty revenue was impacted by an adjustment in sales reserves taken this quarter by BMS relating to prior periods. TSOBO revenue grew by $4 million compared to Q2 2020, driven by increased demand.

The outlook for the fourth quarter was strong, but not without some potential headwinds.

Leading indicators and performance in the early weeks of Q4 indicate similar trends for Q3. However.

We also anticipate disruption in the number of AML patients diagnosed and potentially treated as koby 19 sections and hospitalizations are expected to increase through the end of the year.

In addition, we may see increased volume moving through Medicaid and reported be channels. As a result of the pandemic, which can apply increased pressure on gross to net.

Considering our year to date performance and our outlook for the remainder of the year, we're narrowing our guidance for 2020, let us to double sales from between $105 million to $115 million to $113 million to $115 million.

Jonathan Biller: Gross to net for the quarter was within the expected range. We continue to monitor Medicaid and PHS utilization. Cost of sales for the quarter was $637,000.

I want to thank the arduous team for not only adapting the thriving in the face of these uncertain times fueled by passion to ensure no patients denied the opportunity to benefit from our treatments I'll now turn it over to Jonathan to discuss our third quarter financials.

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

Jonathan Biller: Turning to operations, R&D for the third quarter was $90 million, a decrease of $12 million compared to the third quarter of 2019. This year-over-year reduction in R&D was largely driven by a decrease in Tsobo Clinical Development Costs, including winding down the Clarity Phase. Selling, general, and administrative expenses were $35 million for the quarter, representing a $2 million increase over third quarter 2019, driven primarily by increased workforce expenses, offset by a decrease in external spending due to COVID-19 and cost savings initiatives. We ended the quarter with cash, cash equivalents, and marketable securities of $722 million.

Total revenue for the second quarter was $35 million, which consisted of $32 million of net sales of sobo $2 million of collaboration revenue and $700000 in royalty revenue.

Compared to the third quarter of 2019 total revenue grew 33%.

Driven by an 82% increase in tips somo sales offset by a decrease in collaboration revenue due to completion of the research and development service obligation with Celgene and Q2.

In addition, royalty revenue was impacted by an adjustment in sales reserves taken this quarter by BMS relating to prior period.

Chip Sobo revenue grew by $4 million compared to Q2 2020, driven by increased demand.

Operator: We expect that our Q3 ending cash balance, in addition to expected product revenue but excluding anticipated program-specific milestone payments, will fund our current operating plan to the end of 2022. With that, Operator, please open the line for questions. Thank you. As a reminder, to ask a question, you'll need to press star 1 on your telephone. To withdraw your question, please press the pound key. Please stand by while we compile the Q&A... Our first question comes from Anupam Rama from J.P. Morgan. Your line is open.

Gross to net for the quarter was within the expected range, we continue to monitor Medicaid and Phs unit utilization.

Cost of sales for the quarter was $637000 turning to operating expenses R&D for the third quarter was $90 million, a decrease of $12 million compared to the third quarter of 2019.

This year over year reduction in R&D was largely driven by decreased.

And took syllable clinical development costs, including winding down the clarity phase three study.

We ended the quarter with cash cash equivalents and marketable securities of $722 million.

Anupam Rama: Hey guys. Thanks for taking the question. Just a quick one on AG946. How should we be thinking about sort of timelines for the Healthy Volunteer data? I know just the trials that started, but importantly, starting that STD cohort that you have for the 946 and thinking about that in terms of also timing the Mid-Effect Phase 3 that you outlined last year. Thanks so much. Hey Anupam, it's Chris here. Chris Bowden

With that operator, please open the line for questions.

Thank you.

As a reminder to ask question you will need to press star one on your telephone to withdraw your question. Please press the pound cake. Please stand by while we compile the Q and a roster.

First question comes from Ana Palm Rama from JP Morgan Your line is open.

Christopher J. M. Taylor: So the 946 study is ongoing in Healthy Volunteers, and as per what we did with Mitopibat, and this is a single dose cohort. So then we move into the multi ascending dose cohorts, and then following that, we have planned to open a sickle cell cohort. So, it's too early for us to provide guidance as to when we think we might move there to that phase, as well as when we think we might be able to publish data.

Hey, guys. Thanks.

Thanks for taking the question.

Just a quick one on aging nine four stake how should we be thinking about sort of timelines to the healthy volunteer data I know just the trials that started but importantly, starting that SPD cohort that you have and for the 9% and thinking about that in terms of also timing of submitted pay that phase three that you've outlined last year. Thanks.

So much.

Hey on upon its Chris here, Chris album.

So the nine or six study is ongoing and healthy volunteers and there is.

Christopher J. M. Taylor: Certainly, as per previous ones, we feel like we have a critical mass of safety and PK and PD data; then we would try to get that out there and, perhaps, around that time, be able to inform when the sickle cell cohort might be opening. Now, with regard to our Phase 3 start with new Tibetan sickle cells, that's next year. And so we're all, as in my remarks, we're in full gear there, developing protocols, interacting with the health authorities, and we'll be able to update further on that next year as well. Great, thanks for taking our questions. Thank you. Our next question comes from Tyler Van Buren with Piper Sandler. Your line is open.

As per what we did with mid to pivot in healthy volunteers as a single dose cohorts and then we move into the multi ascending dose cohorts and then following that we have plans to open a sickle cell cohort.

So it's too early for us to provide guidance as to when we think we might.

Moving there to that stage as well as when we think we might be able to publish data certainly as per previous once we feel like we have a critical mass of.

Safety and PK and PD data, then we would try to get that out there and perhaps around that time be able to inform when the sickle cell cohort might be opening now with regards to our phase three start with much more to that sickle cell. That's next year.

Tyler Van Buren: Hey guys, good morning. Thanks for taking the questions. I wanted to ask about the mid-pivot sickle cell update at ASH and specifically your confidence in the 100 mg BID dose generating a more significant clinical benefit than the 50 mg BID, and especially, in particular, in hemoglobin. You know, it was the 0.9 increase in hemoglobin relative to the 1.2 for the 50 mg. Obviously, that was only two patients at the 100 mg versus eight at all others. And so, there could have been something specific about those two patients, but wanted to maybe hear your explanation on that. And again, your confidence that the 100 milligram dose will show improved benefits. Yeah, thanks.

And so.

Well as I am in my remarks, we're we're in full gear their development protocol interacting with health authorities.

And we will be able to update further on that.

Next year as well.

Great. Thanks for taking our question.

Thank you. Our next question comes from Tyler Van Buren with Piper Sandler Your line is open.

Hey, guys. Good morning, Thanks for taking the questions I wanted to ask about the benefit that sickle cell update at ash and specifically your confidence in the 100 milligram dose.

Generating a more significant clinical benefit than the 50 milligram VIP and specialty.

In particular in hemoglobin in the abstract.

Those who is the 0.9 increase in hemoglobin relative to the 1.2 for the 50 Meg obviously, there was only two patients at the 100 Mig versus eight at all others and so there could have been something specific about those two patients but wanted to maybe hear your explanation on that and again you are confident that the 100 milligram.

Christopher J. M. Taylor: So I think the important thing with this is that those values that you're looking at are changed from baseline. And, you know, what we call the design of the study is that patients keep escalating. They start at five, and then they can go up to 50, or once we put the amendment in, they could go up to 100.

Dose will show improved benefits.

Yes. Thanks.

So I think the important thing about this is that those buyers that you're looking at or change from baseline and.

What.

Recall that the design of the study patients keep escalating.

Christopher J. M. Taylor: That includes all of the patients, whether they responded or not. So I think that trying to dissect the differences in 50s from 100s in the table is a little bit challenging. From our perspective, remember what we talked about in the high-level top-line remarks we made at EHA, where five of eight patients had a one-gram or higher increase in hemoglobin. Those were all at 50.

They started five and then they can go up to 50 or or once we put the amendment in are they could go up to 100 I.

That includes.

All those patients whether they responded they are not.

So I think that trying to dissect the.

The differences and 50 from 100 from the table is a little bit challenging.

From our perspective.

Remember, what we talked about in the high level.

Topline.

In March we made it where five of eight patients had a one gram or higher increase in hemoglobin overall at 50.

Christopher J. M. Taylor: So we definitely have an active dose of 50 milligrams. We know from, you know, some of our healthy volunteer work and a number of things that we'll probably see more activation, you know, qualitatively when we go from 50 to 100. It varies from patient to patient, and I think one of the most important things about this is that there's the possibility for us to have, for people, a range of doses. So whether it's 50 or 100 or 50 and 100 is something that we're still thinking about.

So we definitely have an active dose of 50 milligram, we know from some of our healthy volunteer work and the number of things that we'll probably see more activation.

Yep quality quantitatively when we go from 50 to 100 it varies from patient to patient I think one most important thing about that is that there is the possibility for us that for people to have a range of doses. So whether it's 50 or 100 or 50, and 100 and something that we're still thinking about.

Christopher J. M. Taylor: And another way to look at it is that if you were to get, let's say, a gram and a half increase at 50 and another 0.7 or half a gram increase when you went up to 100, Given some of the data that's emerging around hemoglobin and the outcomes, that could definitely be a clinical benefit and a physician and patient interest if the safety profile is comparable, which it is across 50 to 100. So the data that we've been generating from this trial and from some of our other studies really gives us a lot of confidence in our dose selection and the way we design our trial. And we'll be able to provide more details on that in the first half of 2021. Okay, maybe just one follow-up question.

[music].

And another way to look at it is that if you were to get let's say, a gram and a half increase.

At 50.

And another 0.7 or half of that increase when they went up to 100.

Given some of the data that's emerging around hemoglobin and outcomes that could definitely be a clinical benefit and of of physician and patient interest if the safety profile of comparable which which it does across 50 to 100.

So so the data that we've been generated from this trial on from some of our other studies really gives us a lot of confidence around.

Our dose selection on the way, we define on trial and we'll be able to provide more details around that in the first half of 2021.

Okay, maybe just one follow up so you mentioned the 11 patients that will be reported on at Ash and.

Christopher J. M. Taylor: So you've mentioned 11 patients that will be reported on at ASH, and eight at the 100 mg BID dose, and three are new, and five are from existing patients, so these are dose-escalated. Are they all being dose-escalated up to 100 mg BID in the same time frame or over the same course? And if not, does that matter in terms of hemoglobin response? I think, if I understand your question, is that you're on drugs or two doses of them for two weeks, 5 mg for 2 weeks, 20 mg for 2 weeks, 50 mg for 2 weeks, and now 100 mg for 2 weeks. So there's no break in between.

Hey at the 100, Mick I'd dose and three are new and five are from the existing patients. So that are dose escalated are they all big growth.

Both escalated up to 100 milligrams the I'd in the same timeframe.

Or in the same course, and if not does that matter in terms of hemoglobin response.

I think if I understand your question is that.

That you're on drugs or to your on dose.

For two weeks five milligrams or two weeks 20 milligrams for two weeks 50 milligrams for two weeks and now 100 milligrams for two weeks.

So theres no break in between.

The patients are enrolled sequentially.

So it's not like the whole cohort comes in in there.

And they're all enrolled at the same time, but the dosing frequency is similar for all patients.

Okay. That's helpful clarification. Thank you yes. Thank.

Christopher J. M. Taylor: That's helpful clarification. Thank you. Yeah.

Christopher J. M. Taylor: Thank you. Our next question comes from Mark Fromm with Cowan & Co. Your line is, Thanks for taking my questions. Chris, just to follow up on a comment you made earlier, just a minute ago about The Long-Term Extension, is that going to be at 100 mg or is there kind of individualized dosing in there based on, you know, whatever that patient prefers? And then, you know, many of these patients actually rolled off the trial rate back in the spring. So do they have to kind of just escalate back up, or do you think you can just put them straight back on drugs? So what they'll do is get them to what they think is an optimal dose in that 50 to 100 milligrams range, and they're just going to come in at. And then the existing patients, the idea is these newer patients will just start rolling straight into that trial? They will be able to just move into the extension, that's correct. And would that involve another washout period to test that whole stepping down and titrating out that you've been doing, or do you think you have enough experience? Yeah, so will they taper off?

Thank you. Our next question comes from Marc Frahm with Cowen and co. Your line is open.

Okay.

Hi, Thanks for taking my questions, Chris just a follow up on a comment you made for just a minute ago on.

The 100 milligram versus guessing some 50, the long term extension.

It's going to be at 100 milligrams or is there kind of individual buys dosing.

In there based on whatever that patient prefers and then.

Many of these patients actually robust trial right back in the back in the spring. So do they have to dose escalate back up or do you think you can just put them straight back on the drug.

So so what what they'll do is get them to what is and what they think is an optimal dose in that 50 to 100 milligram.

Range and they're just going to come in at 50.

Correct.

And then the existing patients there that is dilutive newer patients will just start rolling straight into into that trap.

They will be able to.

Just move into the extension that's correct.

Okay and would that involve another washout period care to test that whole because again to the stepping down and hydrating now that you've been doing or do you.

Thanks, Chris.

Yes, so will the big paper.

It's a separate protocol so that they will need to finish the paper and then come back in that's why I don't we don't I don't feel like we need additional data.

Around the taper beyond what Weve got set up in the air.

And the ongoing study now.

Okay, Great and then just one thing on the abstract at the close of the possible second mechanism of action through kardos.

Can you explain explaining the what's making you think that and then also maybe contrast that with whats been studied on card to us before in sickle cell because obviously, there's been a high profile phase III program there before.

Christopher J. M. Taylor: And then also maybe, you know, contrast that with what's been studied on GARDOS before in sickle cell? Because obviously, there's been a high-profile phase three program there before. Yeah, so that that has been something that has been of interest both for our research team as a potential mechanism and now from the investigators based on this in increasing the mean crepuscular volume, what's what's called the MCV. And given that you're increasing the overall red cell health, and perhaps the Garda's channel, which is, has something, you know, is directly involved in red cell hydration, that could also be Cells live longer, they're healthier, they have a better hydration state, which may improve or decrease the polymerization of that fiber.

Yes, so that has been something that has been of interest both for our.

From our research team as a potential mechanism and now from the investigators based on this.

In.

Increasing the main purpose filler volume, what's what's called the MCV.

And given that year.

We're increasing the overall red cell Hell, and perhaps the guard as channel which is.

As you know is directly involved in red cell hydration that could also be a mechanism by which made it pulled that is providing clinical benefit.

Sales along with a healthier lives better hydration state, which may improve.

Decrease a pull on the litigation that.

Christopher J. M. Taylor: Okay, and I guess, is there any difference between kind of how you think this is working and what has been studied before with GARDOS? Because I think that phase three trial actually, I mean, it obviously failed on VFCs, but in terms of hitting stat sig, it even showed a trend against the drug. Yeah, that was an interesting trial because the GARDOS channel blocker showed some improvement in hemoglobin but was stopped because of questions around VOCs and safety. We work very differently.

Fiber.

Okay, and I guess is there any difference there between how you think this is working and what has been saved before Ricardo.

The phase three trial actually great.

If we failed on via fees, but in terms of ratings that say, but even showed a trend against the drug trade.

Yes that was.

That was an interesting trial because that guard as channel blockers showed some improvement in hemoglobin level, but was stopped because of a question around the Seaton safety.

We work very differently, we don't directly affect the guard as Jana.

Christopher J. M. Taylor: We don't directly affect the GARDOS channel. You know, our drug is specific for activating pyruvate kinase, and as we emphasized, it's the impact on the glycolytic pathway by activating PKR that increases ATP, where you see a number of positive effects in terms of red cell health, and then by dropping 2,3-DPG, which has long been demonstrated to be elevated in patients with sickle cell disease, the reason to believe there is it will decrease the So it's a very, it's an observation that we may be improving on the ability for that Gardase channel to do increased red cell hydration, but it's fundamentally through that mechanism of action of increasing ATP by activating PTR. Okay, great, thanks a lot.

Our drug is specific for activating pirate Bay kinase and as we can.

Emphasize if the impact on the glycol it a pathway by by activating PK increases ATP.

Where you see a number of positive effects on.

And in terms of Red cell health and then by dropping two three DPG, which has long been demonstrated to be elevated in patients with sickle cell you.

The reason to believe there is it will decrease the formation of fibers that that part of the abnormal shape of the red cell cycle, and then all the bad things that happen that so it's a very it's it's an observation that we may be improving.

On the ability for that got us channel to see do increase red cell hydration, it's fundamentally through that mechanism of action of increase in ATP by activating the payoff.

Okay, great. Thanks, a lot.

Christopher J. M. Taylor: Thank you. Our next question comes from Peter Lawson with Barclays. Your line is open. Hi guys, this is Walid on for Peter.

Thank you.

Our next question comes from Peter Lawson with Barclays. Your line is open.

Hi, guys. This is will lead off for Peter Thanks for taking the questions.

Peter Lawson: Thanks for taking the questions. And just had a question around upcoming PKD data. Where do you see the bar for what will be considered clinically meaningful results? You know, as we look to data year end and first quarter 21 in both transfusion independent and transfusion dependent patients. Yeah, so we designed it. It's Chris Bowden here.

Hi, the question around upcoming PK data.

Where do you see the bar is what would be considered clinically.

Clinically meaningful results.

As we look to the data you're ended first quarter 21 in both decision independent and potentially independent patients.

Yes. So so we designed as Chris Bowden here, we design both of those trials with an endpoint that is.

Christopher J. M. Taylor: We designed both of those trials with an endpoint that is, we'll be associated with clinical benefit, and, of course, we will be looking very carefully at secondary endpoints. So the ACTIVATE study is designed to, a responder is defined as one and a half grams or greater increase in hemoglobin from baseline, and that trial is with 80 patients one-to-one randomized to active drug or placebo and then with the ability for placebo patients to cross over at the end of the dosing period, where we have a positive study if the response rate is 35%, and we assume there'd be approximately 5% So that would be a positive study. And we think, based on what we saw in DRY-PK, that over a gram has been, when you talk to people clinically, talk to clinicians in terms of clinical benefit, we've set the bar even higher.

We'll be associated with clinical benefit and of course, we will.

We will be looking very carefully at secondary endpoints of the activate study is designed is designed to.

Responder.

Define as a group one of the have.

Gram or greater increase in hemoglobin from baseline.

And if that trial is that 80 patients one to one randomized two active drug or placebo and with a.

A the the ability for placebo patients across over at the end of the dosing period.

Where we have a positive study if the response rate is 35% and we assume there would be approximately 5% response rate in the control arm.

So that would be a positive study and we think based on what we saw on drive PK that.

Over a gram, but then when you talk to people clinically practical mission.

Clinical benefit we set the bar even higher so we meet the primary endpoint, we have a lot of confidence that we'll have a package thats.

Indicative of clinical benefit so there'll be a number of supporting secondary endpoints that will also be important man that non not regularly transfused patient population.

Who are the activate T study, which is 27 patients who are regularly transfused the efficacy endpoint is 33% or greater reduction in the overall transfusion burden of the time study compared to their.

Previous one year has year transfusion.

Christopher J. M. Taylor: And so that's an open-label trial, and that's the primary measure of clinical that I just went on. At the same time, you know that in those patients who are regularly transfused, people look at a 50% reduction as well as transfusion independence. So those are the other important secondary efficacy outcomes that we hope will demonstrate that midipibat in that group of patients has a really big impact in terms of reducing the amount of time they need to spend in the clinic getting blood transfusions. And we'll also look at secondary endpoints like iron mobilization and what impact we might have on the need for iron chelation and other endpoints.

And so thats, an open label trial and that the primary measure clinical that I. Just went on at the same time, you know that in those patients who are regularly transfused people look at 50% and train the 50% reduction as well as transfusion independent so those are the other important so.

Secondary efficacy outcome that will we hope will demonstrate that.

Admitted to that and that group of patients as a.

A really big impact in terms of reducing the amount of time any of the spend in the clinic getting blood transfusion. Dan. We'll also look at secondary endpoints like iron mobilization them.

Of what impacts that might have on the new flyer integration and other endpoints.

Christopher J. M. Taylor: So the two trials in total, we'd like to be able to use them to get a broad label in adults with part of their kinase deficiency, and we think the trials of the package are set up to really demonstrate clinical benefit overall. Great, thank you for taking the question. Thank you.

So the the two trials in total we we'd like to.

Be able to use them to get a broad label and adults out are they kind of efficiency and we think the trials as a package are set up to really demonstrate clinical benefit overall.

Great. Thank you for taking the question.

Okay.

Thank you. Our next question comes from Mohit Bansal with Citigroup. Your line is open.

Mohit Bhandari: Our next question comes from Mohit Banerjee. Great, thank you very much for taking my question and, first of all, congratulations Jonathan on your new role. Starting with the question, I mean, when you first provided this $1 billion guidance by 2025, obviously COVID was not there, and there has been a recent EMA decision which didn't go in your favor, so could you talk a little bit more about with these uncertainties how attainable this $1 billion by 2025 guidance is or your aspiration is and how much wiggle room there is with pipeline etc. to still make it happen if the current business Hi Mohit, it's Jackie.

Great. Thank you very much for taking my question first of all congratulation Jonathan for the Euro.

Starting at the question I mean, I think Ben.

When you first drew I did this 1 billion dollar guidance by 2025 of this we quoted was not there and that has been a recent made decision which didn't go in your favor. So could you talk a little bit more about these uncertainties. How attainable is disciplined billion dollar my 25 guidance is our audio expedition.

Yes.

And how much wiggle room is did the pipeline et cetera to still make it happen if the current business doesn't go as plan. Thank you.

Hi, Mohit, it's Jackie thanks.

Jackie Faust: Thanks for the question. I thought I wasn't going to get to talk in the Q&A today. So I appreciate the opportunity. So as you might imagine, we want to set ourselves ambitious objectives, but objectives that we feel like we have a very high probability of achieving with respect to the $1 billion, Our revenue guidance, it is mostly driven by TIPSOVO and AML in terms of the indication, which is related to the label expansions. But we've also got some revenues in there for Minipivad and PKD that I personally think we've been a little bit conservative on. And then where we've also not included hardly anything is for vorosodinib and glioma and for Minipivad and thalassemia and sickle cell disease because we have them from a timeline standpoint in our base case assumption, you know, relatively late in the time horizon, but, you know, even a little bit of pulling those in or a little faster revenue ramp in the launch than what you've assumed would give you plenty of room for still achieving the objectives.

Thanks for the question I thought I wasn't getting get to talk to the Q and eight today. So I appreciate the opportunity. So as you might imagine we want to set our sales ambitious objectives for the objectives that we feel like we have a very high probability of achieving.

With respect to the 1 billion.

Our revenue guidance it is.

Mostly driven by itself, though and AML in terms of the indication which is related to the label expansions, but we've also got some revenues in their permanent pivot in PKD that I personally think we've been a little bit conservative.

Conservative on and then where we've we've also not included hardly anything is.

For for Tottenham in Glioma and for me to pivot in balancing the sickle cell disease, because there we have them from a timeline standpoint in our base case assumption.

Relatively late in the time horizon.

But even a little bit of pulling those in or a little faster revenue ramp in the launch then what you've assumed would give you plenty of room for.

Switch still achieving the objectives, what we've actually seen also if you notice in winning.

2020 with itself, though rather.

Revenues is the it seems like oral oncolytics in the appendix Imec environment.

I actually being favored and so we've been very happy with it sales performance in at a 2020, so far and we havent guided to 2021, yet but.

We will do that soon and then at beginning of next year and we feel quite good about where we are with its overall in that.

The base case in and then also your comment about the pandemic and hope it impacting though the $1 billion in 2025 really we have not seen that as an issue.

Yes, exactly when maybe a little better than.

Sales, so I feel great about it and I think Ken My comments have always been at least 1 billion in 2025, that's still left field.

Got it if I missed it but a lot in for Darrin.

Thank you for this Jackie.

I know you're going to talk a lot about it on November 19th, but if I could get a sneak peak because when we talk about BK needed doctors, they offset off let's say that deficient publishing to small and they don't see many patients. So in this context, where are you in terms of identifying PKD patients and how what is the low hanging fruit there.

Jackie Faust: Great, thanks for the thanks for the question. So, you know, we've shared publicly before that we believe that we estimate the population for PKD to be between three to three to 8,000 right between the US and and five EU countries, maybe as high as 10,000 when you include overall, overall EU. The patient identification efforts that we've been executing over the last couple of years have yielded just about a thousand or so patients split between the U.S. and the five EU countries, and then So when you take all that into account, about a third of the population we've identified today, right, about a third, a little more than a third, of the lower end of the potential prevalence population.

How do you how would you go about and finally specialty frozen the external market. Thank you.

Great. Thanks for the thanks for the question. So so I think we've shared publicly right, but previously that we believe that we estimate the population for PKD to be between three to three to 8000 ride came to us.

And finally, you are right maybe as high as 10000. When you include overall overall.

The the patient identification efforts.

We've.

But we need thats been executing over the last couple of years.

Have yielded just about a thousand or so patients.

Split between the us and.

Five to you and then a number of additional patients that have been identified beyond beyond those major.

Major markets as well so so when you take all that into accounts about a third of the we've identified today right about a third little more than a third of the lower end of the of the potential prevalence.

Probably population, but that's a lot of what the work. It is continues to be between now and end approval on sales.

Limited to that right. So just doubling down on that on that patient identification work. In addition to disease education.

Awareness advocacy and and and whatnot and that work is ongoing in both the E U.

And the U.S.

Very helpful. Thank you that index you. Thank you. Our next question comes from Kennen Mackay with RBC capital markets. Your line is open.

Kenan MacKay: Thank you. Our next question comes from Kenan Mackay with RBC Capital Markets. Hey guys, this is Bikraman from Canon.

Hey, guys. This is vikram on for Ken. Thanks, So much for taking our questions today I have a quick one on the EU regulatory feedback that you got.

Maybe if you can remind us what were the main confirms that the regulatory.

See there that led to the draw all and.

And your confidence than just phase three studies and timeline updates for our whole on in each child.

Have your thinking and confidence change after this feedback our.

That would be super helpful.

Yes, hi, its Chris here first.

So our.

Confidence and excitement around the phase three trial, which are in newly diagnosed patients.

It is really important.

Because that's where as I said in my in my remarks.

That that's where the most patients are.

And so we're very committed to those trials they are ongoing and we.

Christopher J. M. Taylor: And we had to reset guidance around Agile because of the COVID effects, and we're targeting finishing accrual to the Agile study at the end of next year. And the Hobon study, which is in IC-eligible patients, we haven't guided to yet. That trial is in its early operational phase, where sites are coming on board. However, we're definitely seeing nice accrual for both the IDH-1 and the IDH-2.

We had to reset guidance around agile because the cobot effects and were targeting finishing accrual to the agile study at the end of next year.

The whole month study, we have which is and I see eligible patients we havent guided to yet.

That that trial is in its operational early operational phase where sites are coming on board. However, we are definitely seeing nice accrual for both the IDH one Andy IDH two that's being done in that group is committed to doing.

Christopher J. M. Taylor: That's being done by a group that's committed to doing, an international group that's committed to doing studies in this IC-eligible patient population, and they have a long track record of doing that. So we're really very satisfied with how things are going there, and they're great partners to work with, um, now with the MAA. So there was, no doubt, I think that it was appreciated that we had clinical activity with Tibsovo and Relapse Refractory Space. The main concern when we knew this was going on was that there wasn't a control arm. The CHMP historically looks at these types of data sets.

In International Group is committed to doing studies in this IC eligible patient population may have a long track record of doing that so.

We are really very very satisfied with how things are going there and they are great partners to work with.

Now with the M&A.

So there was no.

No doubt.

Thanks.

Appreciate it that we had clinical activity with CIT, so low in relapse refractory space.

On that.

That the oral agent and the durable responses were appreciating the main concern when we knew this going on into the Wasnt a control arm. So this agenda that the CH MP historically.

Christopher J. M. Taylor: That's a lot of skepticism, and we did a lot of work looking at historical control data, some of which was going to be published in ASH, to demonstrate what looked like very, very impressive effects in terms of survival compared to an IgH1 historical control with relapsed refractory disease. At the end of the day, it just wasn't enough, and without controlled clinical data in the relapsed refractory space, the CHMP was not going to give a positive opinion, and we appreciated that after our oral explanation, and that's when we made the decision to withdraw. Yeah, I mean, it's Jackie jumping back in for just a second.

Looks at these types of data sets.

That's a lot of skepticism and we did a lot of work.

Looking at historical control data some of which was going to be published in ash to demonstrate what look like there will demonstrate varian and classes effects in terms of survival compared to an IDH one historical control.

With relapse refractory disease at the end of the day it just wasn't enough and.

Without controlled clinical data in the relapse refractory space. The DCH MP was not going to give a positive opinion and we appreciated that after oral explanation and that's when we made the decision to withdraw.

Yeah, I mean, it's it's jacking jumping back in for just a second.

Jackie Faust: I think any time one goes forward with a phase one data set like this without a control arm in Europe, there's a risk that you end up in this type of situation. And we thought it was the right thing for patients to give this a shot. We gave it a very good shot.

I think any income by one goes forward with the phase one data set like this without a control arm in Europe. There is a.

A risk that you end up in this compensation and we thought it was the right thing for patients to give this a shot we gave it a very good shot as Chris then you will see some data published around the historical control work that we did that I think is still very interesting data, but in our base case assumptions we had before.

Jackie Faust: As Chris said, you will see some data published around the historical control work that we did that I think is still very interesting data. But in our, you know, base case assumptions, we had reflected some assumptions around the risk of this. And as Chris said, in the relapsed refractory IDH1 patient population, it's relatively, you know, modest size in Europe with different pricing assumptions than what you have in the U.S. So it was a modest revenue opportunity, and we're moving full speed ahead with the phase three trials, which are the type of trials that you would expect the Europeans to want to see for the label expansions into newly diagnosed, so just a Yeah, thank you so much for that.

Elected some assumptions around the risk of this and as Chris said isn't negative relapsed refractory IDH one patient population that's relatively.

Modest sized in Europe with different pricing assumptions than what you have in the U.S. So it was.

The modest revenue opportunity and were moving full speed ahead with the phase three trials, which are the type of trials that you would expect the Europeans to want to see for the label expansions at the.

Daily diagnosed so just a different situation with agile and hold on.

Yes. Thank you so much for that and I had a quick follow up on Somo just revenue trends than you up you did mention about gross to net impact you might be expecting in Q4 and diagnosis rates are.

Bikram Mohan: And I had a quick follow-up on TIPSOVO, just revenue trends in the U.S. You did mention growth to net impacts you might be expecting in Q4 and diagnosis rates. Were you seeing low diagnosis rates in Q3 as well? I know the Q3 growth was pretty strong, and demand growth, so maybe you can talk about a little bit of the dynamics, what you're expecting going into Q4 given the resurgence of cases in the U.S. What I tried to express were some potential headwinds that are largely unknowns, right?

What are you seeing low diagnosis rate in Q3 as well I know you did Q3 growth was pretty strong and demand growth.

Maybe you can talk about little bit of dynamics, what you're expecting going into Q4, given the resurgence of cases in the U.S.

Okay all.

Jackie Faust: So we know that we're experiencing and will continue to experience a resurgence. We know from our experience in the initial surge that it certainly had an impact in terms of patients, patient presentation, and diagnosis, even though we weathered it quite well, particularly as an oral treatment in a setting like AML, which is a highly emerging field. Then, in Q3, it was quite a different setting, right?

Or dish hospitals, and that's that's the that those are the things that were anticipating over the course of this over the course of two four uhm that could potentially.

Jackie Faust: Those are the things that we're anticipating over the course of Q4 that could potentially provide some headwinds on our overall performance. And I think Aaron, in his prepared remarks, also said that with all of those caveats, the month of October put us off to a very good start for Q4. Yeah, we're pretty pleased with what we've seen so far in the course. Okay, thank you so much for taking the time to answer my question. Thank you. The next question comes from Alethea Young. Hi, this is Emma on behalf of Aletheia.

Provide some headwinds on overall performance.

And I think Aaron and his prepared remarks also said that with with all of those caveat. Other month of October was put us off to a very good start for two four.

Yeah, we're pretty pleased with what we see what we've seen so far in the in the quarter.

Okay. Okay. Thank you so much for taking the question.

Thank you. Our next question comes from and Leaky again with Cantor Fitzgerald. Her in line is open.

Jackie Faust: So just turning back to Sickle Cell, we saw that another PKR activator in development outlined a pivotal program in their ASH Abstracts that included annualized VOC as a co-primary endpoint. So I know you guys are still in regulatory discussions there for the planned meta-pivot design, but is that something you think would be important to show differentiation on in order to be competitive versus that agent or also commercial drugs like Pox Well, I think that's Chris here.

Hi, This is annette on for every day, so just turning back to check us out we thought that another P. T R activator and development outline difficult program in their ash abstract age included annualized vse as a co primary endpoint.

I know you got your son regulatory discussions there for the plan mid dependent design, but is that something you think would be important to show differentiation on in order to be competitive person that agent and are also a commercial drugs like right now.

Well I think that's because you're a kink N E.

Christopher J. M. Taylor: I think any, And, you know, if you're going to run a trial with a TKR activator, as we've said, From the get-go, you have two reasons to believe, and one is raising hemoglobin, and the other is reducing VOC. So there are a lot of ways to design the trial, whether it's co-primary endpoints, whether it's sequential testing. But I think it just goes without saying that those two endpoints are, The marquee, that's where the clinical benefit is for patients, and I think the big promise, the potential, if you will, for metapibaptics is that you can significantly achieve both. There are clearly drugs that have been approved for an increase in hemoglobin, with Jerry still out on what's going on with VOC reduction.

If you're going to run a trial, which which.

As we said.

From the get go you have two reasons to believe and wanted to raise and hemoglobin and the other is is reduction in D O C.

So.

There's a lot of ways to design the trial, whether it's.

Co primary endpoints, whether it's a sequential testing alright, again, but I figured just goes without saying that those two endpoints are.

The the the the the Marquis that's that's where the clinical benefit is for patients and and and and I think that they promise.

The potential if you will for for me to pay that.

Is that you can significantly cheap both.

No I didn't clearly we're seeing drug that are have been approved for an increase in hemoglobin.

With lesser Jerry still out on what's going on with B O C reduction.

Christopher J. M. Taylor: And, you know, I know we're hoping to see that with longer follow-up, that you might see a decrease in, a statistically significant decrease in VOCs with Fluxelator, that would be good for patients. The P-Selectin inhibitor from Novartis reduces VOCs, but it doesn't really, it has no impact on hemoglobin. The promise, the potential, and the promise, we hope, for Medipibat is that we can address both, and that you'll be able to address the two main problems of sickle cell disease. Thank you.

And.

We're hoping to see that was longer follow up that you might see a decrease in a statistically significant decrease in D. O C with <unk> that would be good for patients it'd be selective inhibitor from novartis, reducing b O C, but it doesn't really.

Back on hemoglobin.

The promise for a minute with potential honestly help for medical that is that we can address bows and that and you'll be able to.

Address the two main problems with sickle cell disease.

<unk>.

Great. Thank you and then is there any update you're able to get on the pediatric <unk> kind of a coffee can I put my hands up her makeup it or 946.

Christopher J. M. Taylor: And then, is there any update you're able to give on the pediatric development plan kind of across the PCR portfolio, both for midwifery and 9-4-7? So our pediatric program with Medi-Pil-Vat is moving forward in patients with part of a kinase deficiency. And so, we're working toward getting those studies up and running. And with regard to thalassemia and sickle cell disorders for mid-PIVAP, certainly those will need to happen. But, you know, we're right now focused on pyruvate kinase proficiency, and we think we'll have those details worked out by the end of this year.

So the RP pediatric program with many pay that is moving forward and patience with part of a tiny deficiency.

And so we're working toward getting those studies up and running.

With regards to thalassemia and sickle cell for mid to that certainly those those will need to happen.

But where where right now focused on pirated Chinese proficiency and we think will have those details worked out by the end of this year.

Christopher J. M. Taylor: As far as AG946 goes, that drug has a long way to go in terms of demonstrating, you know, achieving its early development hurdles before we start thinking about what the next stage of development is for that compound. Mitopibat, right now, has years of efficacy and safety data, first in part for a kinase deficiency, now a thalassemia sickle cell, and it continues to do very So, we don't need 946 in order to start our pediatric plans, as evidenced by the fact that we're moving forward in part because of a kinase deficiency. Thanks very much. Our next question comes from my friend Anaheim. Hey, guys, this is Kelsey Anson-Michael.

As far as a G 946, Gov. After I think a long way to go in terms of demonstrating.

Yeah, <unk>, achieving its early development hurdles.

Before we start thinking about what the next stage of development is for that compound maybe pay that right now has years of efficacy and safety data for some part of a kind of deficiency now Palestinians sickle cell and it continues to do very well so we don't need 9462.

To start our pediatric plans as evidenced by the fact that I'm moving forward part of a tiny sufficient.

Okay. Thank you very much.

Thank you. Our next question comes from Michael Smith.

Your line of seven.

Hi can I assist with Kelsey on for my call. Thank you for taking our questions I get to kind of both offers bought last question could you. Let me just remind us how you see the next Gen. K R activator kind of fitting into your development plans longer term and then for 10 Sofa I guess, it's the ongoing phase three trials are successful.

Kelsey Anson-Michael: Thanks for taking our questions. I guess to kind of build off of that last question, could you maybe just remind us how you see the next-gen TKR activator kind of fitting into your development plans in the longer term? And then for TIBSOVO, I guess if the ongoing Phase III trials are successful, I guess when do you think the earliest you could secure European approval for TIBSOVO could be? Thank you.

I guess when do you think the earliest when do you think it could be the earliest that used to care European approval. So I could still do thank you.

Christopher J. M. Taylor: Right, okay, so the first question is 946 and what its development path would be, and that will also depend on the type of data that we see with Medipivac. And because we're moving that forward across all three indications based on the activity and the safety profile we've observed to date. So, you know, what we do next with 946, well, it's too early to make that call because we need to see what the actual clinical attributes of the molecule are and whether it would offer tangible, you know, important improvements for a patient across those three diseases where we're studying midopibap now. And of course, we continue to study and investigate diseases where pyruvate kinase, or activation of pyruvate kinase, may be, have the potential to improve outcomes for patients.

Christopher J. M. Taylor: And so that's something that we're actively looking into, but it's just too early for us to comment on how 946 would be developed in the next stage. What we're focusing on now is whether it can even get into the situation where we can do that. So then your question is to Jim Sobo, what's the earliest that we could get any of those frontline trials in front of the CHMP to get approval in the frontline setting? So if you look at Agile, that's got to complete accrual at the end of 2021, and then that's an event-driven trial. So we'd have to really get some sense of how fast events are coming, then we would unblind it, and then we would be off and filing.

Hi to complete a cruel at the end of 2021, and then that's an event driven trial.

So we'd have to really get some sense of how fast and that's coming in.

I'm blind it and then we would be then often and filing so it's it's <unk> no that that gives you a broad sense.

Christopher J. M. Taylor: So, it's, you know, that gives just a broad sense. For HOBON, we haven't guided yet to accrual completion because, like I said, we're still activating sites in this large global trial. We hope to get, as soon as we get these trials, a positive study in our hands, and we would want to get it in front of both the CHNP, the FDA, and other regulators as soon as we can. It's just too early for us to be able to provide specific guidance on that. Okay, thank you. Thank you. Our next question comes from Mark Breidenbach with Oppenheimer. Yeah, hi guys.

For hold on they have a guided yet to a cool completion, because like I said, we're still activating sites and is so large globe trial.

We hope you get get as soon as we get these trials positive study in our hands and we wouldn't want to get it in front of book C. H M. P. F D a and other regulators as soon as we can it's just too early for us to be able to provide specific guidance at this time.

Okay. Thank you.

Thank you and next question comes from Mark Twain spot.

Your line of seven.

Yeah, Hi, guys. This is counted on for Mark and thanks for taking our questions I had a couple on the NIH study specifically with the markers of polymerization the pieces T N T 50 uhm.

Calphadon: This is Calphadon for Mark, and thanks for taking our questions. I had a couple about the NIH study, specifically with the markers of polymerization, the P50 and T50. Do you believe these changes that we have seen to date in the ASH abstract are clinically meaningful to show long-term reduction in VOCs? And then could you also comment on how these changes compare to what we've previously seen with Oxprida in earlier stage trials? Thanks.

Uhm do you believe these changes that we've seen to date and the ash abstract as clinically clinically made meaningful.

To show, a longterm reduction U B O C.

And then if you could also comment on how these changes compared to what we've true previously seen with all spread out in earlier stage trials. Thanks.

Yeah. So we do think that this is it's definitely has potential to reduce V O. She's what we're seeing with our <unk>.

<unk> one of the challenges has been that you. There's there's not a direct correlation. This this much improvement.

So shaded with this much reduction in the frequency of V O C.

And so that uhm, but nevertheless, based on what we're seeing we think we definitely have some potential to do that.

Christopher J. M. Taylor: Certainly, early data with Voxelitor, looking at a number of just important endpoints, um whether it was, Well, sickling assays and reticulocytes and LDH and some of those things, when we look at our data at a similar point in time with all the caveats that go with different patient numbers, cross-trial comparison, different points in time, concomitant medications, so there are really a bunch of caveats to it, but we look at our overall profile that we're seeing, whether it's with the sickling assays that you're referring to, whether it's LDH, reticulocytes and other aspects, we're very... We feel really good about what we're seeing. And that's why we declared that we have proof of concept that we're moving to phase three at the time of EHOP and look at the initial patient data. One other thing I'll say is that I think there's an understandable interest in all these new drugs coming in. And we get the question of, well, you know, what's the value of having midipibat if it raises hemoglobin? Because that's what Oxalatoid does as well.

Certainly early data with solids or looking at a number of just important and points.

Whether it was.

Sibling assays in particular sites and L D H and some of those things when.

When we look at our date.

Similar appointment time with all that caveat to go with different patient number is cross trial comparison different points in time, Coke concomitant medication, but they're really a bunch of caveat to it but we look at our overall.

Profile that were saying, whether it's with the the sibling after that you're referring to whether it's L. D. A particular sites and other aspects were were very we.

We feel really good about what we're seeing and that's why we did is Clara that we have proof of concept, where I'm moving to pay three at the time, but <unk> and we look at the initial patient data.

When I'm, Okay, I'll check if that I think there's.

There is.

And understandable interest.

And all these new drugs coming in and we get the question I will.

What's the value of having at a pay that if it raises hemoglobin because that SWEATBOX elytroid does as well there's a V. O C piece that you ask us a lot of questions about and there's also the aspect that the percentage of patients who have a one grandma greater increase with <unk>, there's about 50.

Christopher J. M. Taylor: There's the VOC piece that you asked us a lot of questions about, and there's also the aspect that the percentage of patients who have a one-gram or greater increase with Oxalatoid is about 50%. So there are a number of patients who don't have any hemoglobin response. So we could see ourselves as being a very good drug for those patients. Christopher Sardis.

Percent. So there's a number of patients who don't have any hemoglobin response, so we could see ourselves as being a very good drug for those patients just for starters.

Christopher J. M. Taylor: Okay. And then I think the NIH study showed some VOCs either during or at the end of the study in a few patients. I guess, can you characterize these patients for us? You know, what their baseline or historical frequencies of VOCs were, if you have access to the data?

Okay, and then I think the N. H study showed a couple of V O C either either during or at the end of the study and and a few patients Uhm I guess can you characterize these patients for US you know.

What their baseline or historical frequencies of you'll see where if if you have access to the data.

Christopher J. M. Taylor: Yeah, I we don't have a lot of pre-study information in terms of what was the level of VOC they had, how predictable was it. The overall assessment from the investigators, yes, we saw one VOC during a taper, we made some alterations to the taper, we've not seen any since, and that there was one at the end. After all, coming to the end of this, coming to the end of the study after that patient had been off drugs for a long period of time, and there were several precipitating factors going on in that patient's life that would have put them So it's something we should continue to follow. If you look at any of the trials, VOCs are part and parcel of the development, and so one of our big questions is, that's why you need control to really get a handle on what's going on for that end point. Okay, thank you very much, Chris. Thank you, and our next question comes from Andrew Berens with SVP Lee Ring on Philanthropy. Hey, thanks. This is Chris on for Andy.

Yeah, I, we don't have.

Yeah, we don't have a lot of free.

Priest study information in terms of what was the annual number of B O C. They had how predictable was it.

The overall assessment from from the investigators, yes, we saw one B O C. During a taper we made some alterations to the table, we've not seen any sense and that the there was one of the.

After.

The end of this coming to the end of the study for that after that patient had been off drugs. So long period of time and it was several.

Precipitating factors going on and that patients like that that would.

Put them at risk. So it's something we continued to follow if you look at any of the trials B O sees are part and parcel with the with the development and so one of our Big question. That's why you need a control to really get a handle on what's going on.

For that for that endpoint.

Okay. Thank you very much Chris.

And I know you're welcome to check comes from Andrew Baroness but.

Leaving.

Okay.

Hey, Thanks. This is Chris on for Andy just had a question about the heart rate increase but you guys saw in the abstract just wondering how well characterize it is that is if it has to do with an arrhythmia or just tachycardia and if you've seen you know any other cardiac events in other studies or in preclinical study.

Christopher J. M. Taylor: I just had a question about the heart rate increase that you guys saw in the abstract. I'm just wondering how well characterized that is, if it had to do with an arrhythmia or just tachycardia. And if you've seen, you know, any other cardiac events in other studies or in preclinical studies? So what that is is an asymptomatic Heart Rate Over 100 Beats Per Minute, and if you look at the Common Toxicity Criteria, it does not require intervention if they symptomatize. We, we have not seen any indications that we have a cardiac signal with this drug. And so what's happening is the patients are coming in, they're getting evaluated, and then as part of their vital signs, there were three individuals who had a heart rate above 100 but otherwise felt fine, had no symptoms associated with it.

We met so what that is is an asymptomatic.

Heart rate over 100 beats per minute and if you look at the.

Common toxicity criteria does not require an dimension that day symptomatic.

We we have not see any indications that we have a cardiac to know what this drug and so what's happening is a patients are coming in there getting evaluated and then part of their vital signs there.

Three individuals to add heart rate above 100, but otherwise felt by symptoms associated with it.

Christopher J. M. Taylor: That's the gist of it, and we've not seen any other signals across any of our other trials that suggest there's anything from a cardiac standpoint that we'd be concerned about. We continue to follow safety and all and, you know, in the broadest sense, across all of the trials. And so this is not something that we've had any need to focus on at this point. And I don't think that the three patients were asymptomatic; a heart rate above 100 is something that's going to set us off on a way that concerns us or alters the safety profile from what we've reported to date in any way. Got it.

That's that's the gist of it and we've not seen any other signal to cross any of our other trials suggest there's anything from a cardiac standpoint because.

Turned it off.

We continue following safety at all and you know in the broadest sense across all of the trials and so yeah. This is not something that we've had any need to focus on at this point and I don't think that the three patients with a symptomatic.

Heart rate above 100 is is something that's gonna set us off on.

In a way that that concerns us or altered to safety profile and what we've reported to date in any way.

Got it and one more question if that's all right I'm just wondering about that got us channel.

Christopher J. M. Taylor: And one more question, if that's all right. I'm just wondering about that Gardos channel. Potential mechanism for the other product that was in the pipeline that was specifically for Gardash Channel. One of the proposed ideas for why they increased VOCs was due to hyperviscosity, so just wondering if you had any viscosity data that could potentially, you know, imply something different or counter that. Um, well, I think nothing specific in terms of hyper viscosity data, and Bruce Carr will, I'll ask him to comment further on that.

Potential mechanism for the other products that was in the Python that was specifically for Cardiff channel one of the proposed ideas of why they increased voc's was due to hyper viscosity. So I'm. Just wondering if you had any viscosity data that could potentially comply something different or counter.

HM.

Well.

The the I think nothing specific returns a hyper viscosity data Bruce car will I'll ask him to comment further on that.

Christopher J. M. Taylor: But I think that the aspect of what we're doing by dropping 2,3-DPG and speaking specifically about sickling is preventing, um, the red cell from becoming sticky and deformed. So I wouldn't anticipate that hyperviscosity will be a problem if, in fact, we are seeing, if it turns out that we are able to, over time, see consistent increases in MCB and get some sense as to if this is So that's not a concern, and it's interesting that some of the data that's now coming out at ASH, for instance, GBT's publication where, you know, they have a minority of patients, a small percentage of patients who had hemoglobin increases to 12 or 13, and they published remarkably that those patients had the lowest frequency of VOCs.

I think that the aspect of what we're doing by dropping two three D. P. G. I'm speaking specifically around cyclic preventing.

The red cell from becoming sticky and one.

So I wouldn't anticipate that will be a a problem Hubbard viscosity. If in fact, we are seeing you know if it turns out that we that we are able to overtime C. Consistent increases in N C b and get some sense as afford this is really the reason why.

So if that that's not a concern it is interesting that some of the the date of that now coming out and ask for instance, GB cheese publication, where you know they have a minority of patience a small percentage of patients who had hemoglobin increases the 12 and 13.

They they publish remarkably with those patients had the lowest frequency of B O C.

Christopher J. M. Taylor: And it may be now that, you know, this concern, which has always been there about how high you can get hemoglobin up, it's still going to be there, no doubt, with experts and clinicians who treat tickle cell disease. But now, maybe things will get a little more nuanced, and we'll just have to keep following this breaking news as these data develop. Any comments about the Garda Channel piece, please? I think you covered it pretty well. Chris, the parameters that might lead to hyperviscosity, you spoke of one of the adhesiveness of the red cell. We believe we address that in proving the general health of the red cell and its propensity for that. The other significant parameter is the very high PCV, or Pactel volume.

And it may be now that that this this concern which has always been there about how I can get hemoglobin up it's still gonna be there no doubt with experts inclination to treat sickle cell disease, but now maybe things will get a little more nuanced and we'll just have to keep calling this breaking news.

As the data develop Bruce any comments about the the guard is channel. Please please.

Uhm no I think he I think he covered it pretty well uhm.

But you know the the parameters that not late.

Posted eight eight you spoke to <unk>. This is the red sounds good but lately you know address that improving that the general health at the red cell and their propensity full that the other planets.

It's a very high.

Mm mm.

<unk> <unk>, that's something we don't like to get a new <unk> already nation that even at high range Uhm.

Christopher J. M. Taylor: That's something that we're not likely to get, and you also mentioned that in We seem to be doing pretty well anyway, so I don't think there's anything additional that one can draw from a study where the active agent has such a profoundly different mechanism of action from our drug. So I think drawing an extrapolation between the two mechanisms of action relative to concerns for this potential side effect is probably not appropriate. Got it. Thank you very much. Thank you, and I'm currently showing no other callers in the queue at this time. I'd like to hand the call back over to Jackie Faust for any further questions. Thank you, Operator. I just would like to reiterate that despite the challenges and uncertainties that continue to prevail in the world today, I and the whole Agios team remain very excited about the progress that we are making across our focus areas this year, and we're looking forward to a catalyst-rich 2021 as well.

Uhm, we seem to be doing pretty well anyway. So I I didn't think anything additional that one can draw from the study where the active agents had such a profoundly different mechanisms of action for from address so I think during an extrapolation between the two mechanism of action relative to uhm.

Concerns for for the potential side effects, it's probably not appropriate.

Got it thank you very much.

Thank you and I'm currently showing nowhere to call or send that to you at this time I'd like to hand, the call back over to check your house for any further remarks.

Thank you operator, uhm I, just would like to reiterate that despite the challenges and uncertainties continue to prevail in the world today I <unk> the whole largesse team remain very excited about the progress we are making across our focus areas. This year and we're.

Looking forward to a catalyst rich 20th 21, it as well to close I would like to thank my <unk> colleagues for their dedication and passion for making a difference for patients I also I want to thank all of the patients caregivers and so they just want to participate in our clinical trials without them wait did not do what we do today and I would like.

Christopher J. M. Taylor: To close, I would like to thank my Agios colleagues for their dedication and passion for making a difference for 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 today, and I would like to thank all of you for joining us on our call today. And we will see you soon. This concludes today's conference call. Thank you for your participation.

Thank all of you for joining us on our call today, and we will see you soon.

Alright, gentlemen, this concludes today's conference call. Thank you for your participation you may now disconnect everyone have a great day.

Q3 2020 Agios Pharmaceuticals Inc Earnings Call

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