Q2 2020 Agios Pharmaceuticals Inc Earnings Call

[music].

Good morning, and welcome to audio since second quarter 2020 conference call.

Simon participants are in listen only mode.

There will be a question and answer session at the end.

Please be advised that this call is being recorded audio says request.

I'd now like to turn the call over to Holly managing director of Investor Relations.

Thank you operator, good morning, everyone and welcome to idea since second quarter 2020 Conference call you can access slides for today's call by going to the Investor section of our website <unk> Dot com with me on the call today with prepared remarks.

Our Dr. Jackie Farrell, our Chief Executive Officer, Dr., Chris Bowden, our Chief Medical Officer, Darren mile. Our senior Vice President of U.S., commercial and global marketing and Andrew Hirsch, Our Chief Financial Officer, and head of corporate development.

Dr. Bruce car, Chief Scientific officer will join for acuity.

Before we get started I would like to remind everyone that somewhat the statements. We make on this call will include forward looking statements actual events or results could differ materially from those expressed or implied by any forward looking statement as a result of various risks uncertainties and other factors, including those set forth in the risk factor section of our best.

The recent form 10-Q filed with the FCC and any other filings that we may make with the FCC with that I will turn call over to Jackie.

Thanks Ali good morning, everyone and thanks for joining our second quarter 2020 results golf.

Second quarter was an incredibly productive in important Tom franchise, as we made significant progress across the business and accomplished several of the key objectives that we set for 2020.

The steps we took in Q2 solidified our strategic part is for the remainder of the year and move us closer to achieving our 2025 vision.

Seven years ago, we discovered the first power they kinase our activator bitter pill that and since then we've led the science behind this mechanism advanced the phase three program in power Veight Kinda nice deficiency and became the first company to establish that activating wild type PK, our may provide therapeutic benefit.

Other hemolytic anemias, such a cell C media and sickle cell disease.

Over the past quarter, we further underscored our leadership in this space and shared key updates that support our next phase of development for me to pivot.

To start we establish compelling proof of concept from it appears that in sickle cell disease, demonstrating the PK. Our activation has the potential to treat chronic hemolytic anemia and markers of fickling in these patients. In addition at E. Jay we presented data for the first Tom at a medical meeting for me to pivot in Dallas see me.

[laughter] showing sustained hemoglobin responses in both beta thalassemia and Alphatec, let's see me a patients.

It may DFT, a granted us orphan drug designation for this indication.

As we look ahead, we're firmly committed to the rapid advancement of middle to that across all three of these disease areas.

The remainder of 2020 will be focused on preparations for topline data from the PK deficiency phase three studies and the submission I'm in India for Medicare That's first indication.

And the indication of could've pivotal programs in both Dallas EEMEA in sickle cell disease in 2021.

In June we secured $255 million of non equity capital through the sale of our I'd defer royalty and future milestones to royalty pharma to help fund these efforts.

In addition to our progress on the rare genetic disease started their business. We've continued to drive commercial execution for tip, Sobo and advance our malignant hematology and solid tumor clinical programs.

At ASCO and he Jay we presented data underscoring the utility of IDH inhibitors in both areas and in May we published a manuscript and lancet oncology highlighting data from the clarity phase three study of tip salvo and Cholangio carcinoma.

As a result of the manuscript the NCCN guidelines were updated to recommend treatment with did so well for patients with advanced IDH, one mutant cholangio carcinoma.

We look forward to having overall survival data from the clarity study in the near future, which will support unexpected S. In D.A. submission in the first quarter of 2021.

I'm proud of our team for accomplishing all this great work, while continuing to combat the challenges in complexities caused by the ongoing cobot 19 pandemic.

The disruption to global Health care systems continues to evolve as infection rates fall in some parts of the world well rising and others, including in many states here in the U.S.

Our organizational resiliency team and clinical operations response team remained active in assessing cobot nineteens impact on every facet of our business on an ongoing basis.

While the majority of our employees continue to work from home all lab employees, who need access to our Cambridge Research Labs have returned to work under a set of operating procedures designed to protect their health and wellbeing.

In addition, as local regulations. It institutions have allowed some of our field team can interact with their customers in person again.

We continue to evaluate additional operating procedures that will allow our broader return to on Sop work.

I would like to thank each and every all jokes employee for continuing to advance our programs for patients while balancing the pandemic significant impact on their personal and professional lives.

Before I turn the call over to create something it's important to acknowledge recent events, which have once again expose the realities of racism and racial violence in our country.

And I'll, just we believe matters of Rachel and racial injustice should be acknowledged and decried and we're committed to act in ally ship against this destructive force in our communities.

All of us at all just believing the value of diversity and we're committed to making all Joseph welcoming and diverse work place where individuals of all backgrounds can thrive and contribute meaningfully to our mission on behalf of patients.

Chris Let me turn it over to you.

Thanks Jackie.

I'll start with mid to pick up.

Our first in class PK, our activator currently being evaluated across three distinct hemolytic anemias.

As Jackie highlighted we achieved important milestones for this program and the second quarter that support broad clinical development and books outlets seem yet in sickle cell disease.

Our most advanced programs in PK deficiency, or we have four years of experience in treating patients and have the potential to provide first disease modifying therapy.

Earlier this year, we completed enrollment in our two phase three studies activate and activate T.

Since the beginning of the covert 19 outbreak we have focused on ensuring patients have access to study drug and that we capture all data regardless of the patients ability to get their trial center.

This includes home visits Tele medicine approaches you use of local laboratories, and courier shipments of drug.

As a core period of both studies comes to an end later this year, we're working with our global clinical trial sites I understand the timeline to complete necessary steps for database while.

We still anticipate topline data from both activate and activate T sometime between now and that Twentytwenty in the middle of 2021.

We will narrow this timeline based on our ability to confidently predict trials fight access in the wake could be ongoing global pandemic.

We expect to file for regulatory approval in both U.S. and you next year with a potential twentytwenty to commercial launch and PK deficiency in both geography.

Moving to the phase two study admitted pay that felt was seen yeah. You completed enrollment earlier this year with 20 patients and in June we presented updated data from 13 African see a valuable patients at the virtual E H a meeting.

Data showed the treatment with many pit that induced to hemoglobin in.

Greater than or equal to one gram per deciliter in 12 or 13, a valuable patients during weeks for through 12, including for a for Alphatec Solus senior patients, where there have been no new treatment options in decades.

In addition, seven or eight beta thalassemia patients achieved this sustained hemoglobin response during weeks 12 to 24.

Our focus now is to advance the development admitted payback for these patients as quickly and efficiently as possible.

By the ended the year, we expect to finalize a robust pivotal development plan spans both alpha and beta thalassemia as well as transfusion dependent and non transfusion dependent patient populations with a goal of initiating a pivotal program 2021.

Now, let's turn to sickle cell disease, where we're collaborating with Dr. sweetly Chan of the National Institutes of held on a proof of concept study with mid to cover.

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

The data showed that over a six to eight week dosing period.

Seven or eight patients experiencing hemoglobin increase.

Hi, debate patients, achieving a hemoglobin increases greater than or equal to one gram per deciliter baseline.

Adverse event seen in this study were consistent with previously published data for me to pivot in patients with PK deficiency or expected in the context of sickle cell disease.

Based on these results were working quickly to get regulatory advocacy group input for our pivotal development plan and sickle cell disease, which will put us in position to initiate the study in 2021.

Patient enrollment in the phase one sickle cell study was temporarily halted earlier this year in the wake up to covert 19 pandemic.

And they are actively working to reopen the study this summer.

Dr. Chan plans to enroll up to 25 patients in this study and she will submit data from the trial for presentation at the Ash meeting in December.

Due to the earlier POZEN enrollment, it's not yet clear how many additional patients will be included in that presentation above the nine patients served as the basis for our proof of concept evaluation.

I'll now moved to our malignant hematology programs, we're focused on geographic and indication expansion.

IDH one inhibitor should so.

To start and you have recede a day 180 list outstanding issues structured silver filing in relapsed and refractory AML and at this time, we still anticipate receiving a C. H M. P opinion by the end of year.

In front line, even though we are enrolling two global trade Street combination studies.

<unk> hold on 150, which will allow us to further broaden chip. So much frontline label to include combination use with eight decitabine and seven plus three respectively.

We're also enrolling patients in the reopened Myelodysplastic syndrome arm of the chip silver phase one study with the goal of generating the data necessary to pursue a potential U.S. regulatory filing.

We expect to compute provisional enrollment in 2021.

In addition to these registration trials, we continue to explore and generate data with himself, though and novel combinations through our investigator initiated studies.

Data from one such study the medical X plus type, so low plus or minus eight cited Dean I S. T conducted by Dr. Dinardo, an MD Anderson are presented earlier this year at SCO and E cig showing that the combination was well tolerated.

Active with become positive complete response and 80% of patients.

In May we shared that psych startup activity has slowed and enrollment interruptions occurred at some trial starts to the pandemic.

I'm areas have begun stabilized and we continued should track recent shortages any impact on trial sites.

This time, our enrollment guidance remains unchanged for the AML and Mds studies.

I'll now moved to solid tumors.

Last year, we reported positive PFS data from the clarity phase three study of consumables in previously treated IDH, one <unk> cholangio carcinoma, and this quarter, we expect to have mature overall survival data from this study to support a potential supplemental NDA filing.

Based on the anticipated timing of the data we expect the SMB a submission is now likely to occur in the first quarter of 2021, which is the narrowed from our previous guidance.

In addition, we continue to enroll our other solid tumors studies.

The indigo trial, our phase three study or for a side note, our brain penetrant IDH inhibitor and low grade glioma.

In the AG 270 phase one combination arms in non small cell lung cancer and pancreatic cancer.

Like our other ongoing trials, we continue to monitor the pandemics impact on site startup and enrollment activity.

No updates to previous guidance at this time.

I'll turn it over to guarantee discuss our second quarter commercial performance.

Thanks, Chris.

I'm pleased to share that our commercial teams continued to deliver strong performance in twentytwenty. According $27.6 million of net sales of silver when the second quarter, 22% increase from Q1.

That's just restrictions related to cope with 19, notwithstanding quarter over quarter group was driven by an increase in boot scripts filled with the largest increases seemed to be less refractory email setting.

Furthermore, we continue to expand on prescriber base growing it's 15% in both the academic and community setting over Q1.

What the research continues to show that the majority of positions consider chips, so low to be standard of care and each one main email and the leading targeted treatment for newly diagnosed I'd each one ml patients ineligible for intensive therapy.

Though not a focus of our promotional efforts we continue to observe that approximately half of two simple use in both the relapsed refractory and frontline setting isn't combination and most frequently this occurs with Hypomethylating agent.

Our patient assistance programs Geos continues to operate on interrupted in the midst of the Qubits 19 endemic as we support patients through these challenging times.

As Jackie mentioned in response to the growing concerns related to the pandemic. The majority of our fuel teams continue to work from home since mid March though some of the gun to safely interact with their customers and person again as local guidelines and practices have allowed we've experienced access continuing to engage customers with tools, enabling removed interactions as it was.

Ultra performance through the first half of the year, we reiterate our full year Twentytwenty you list of civil net sales guidance of $105 billion to $115 billion.

I'll now turn it over to Andrew to discuss our second quarter financials.

Thanks, Dan.

Second quarter results can be found in the press release, we issued this morning, which all summer.

More detail will be including our 10-Q filing later today.

Total revenue for the second quarter was $37.3 million, which consisted of $27.6 million of net sales of TEMCELL, though.

$6.4 million of collaboration revenue and $3.3 million somebody deeper royalty revenue.

Compared to the second quarter of 29 team total revenue grew by 42% driven by a 101% increasing tip silver sales offset by a decrease in collaboration revenue.

Operator: transcript Emily Beynon, BF-WATCH TV 2021 Good morning and welcome to Agios' second quarter 2020 conference call. At this time, all participants are in 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 you.

As we announced in June.

Healthy form of purchased our tiered sales based royalty rights on worldwide net sales by default as well as rights to receive up to $55 million, an outstanding X U.S. regulatory milestone payments from BMS for $255 million.

This transaction will be accounted for under the debt method, which required us to record a liability on our balance sheet for the purchase price net of issuance costs.

We will continue to record deeper royalty through the life of the arrangement.

In addition, we will record noncash interest expense associated with a liability.

The liability will be reduced by the royalty revenue recorded in each period and increased by the noncash interest expense.

For the period in which interest expense exceeds royalty liabilities, including staying for periods in which the royalty revenue exceeded interest expense the liability is reduced.

The liability will be reduced to zero when we're no longer eligible to receive royalties in the 2010 agreed.

To several revenue grew by $4.9 million compared to Q1, 2020, which was driven by continued strong unit demand and channel inventory levels, returning to more normal levels versus where we ended Q1.

Operator: I'd now like to turn the call over to Holly Manning, Director of Investor Relations.

Holly Manning: Holly Manning, Director of Investor Relations. Thank you, Operator.

Gross to net for the quarter was within the expected range, but we have seen increases in Medicaid and phs utilization over the first half of the year I'd expect that trend to continue over the balance of the year.

Holly Manning: Good morning, everyone, and welcome to Agios' second quarter 2020 conference call. You can access slides for today's call by going to the Investor section of our website, agios.com. With me on the call today with prepared remarks are Dr. Jackie Faust, our Chief Executive Officer; Dr. Chris Bowden, our Chief Medical Officer; Darren Miles, our Senior Vice President of U.S. Commercial and Global Marketing; and Andrew Hirsch, our Chief Financial Officer and Head of Corporate Development. Dr. 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 SEC and any other filings that we may make with the SEC. With that, I will turn the call over to Jackie.

Cost of sales for the quarter was $675000.

Turning to operating expenses R&D for the second quarter was $90.9 million, a decrease of $16.5 million compared to the second quarter of 29 team.

Year over year decrease in R&D was largely driven by lower collaboration spend related to $6 million in milestone payments for AG Sixthree sex and an undisclosed early stage research programs in Q2 of 29 team.

Ramped down at the clarity phase three study of keep Sobo and hope on startup expenses incurred in Q2, 2019, and lower spend across ongoing Tim several clinical studies as a result of slowed enrollment and reduced activities due to the token 19 pandemic.

Selling general and administrative expenses were $36 million for the second quarter, representing a 3.6 million dollar increase over second quarter 2019, driven primarily by the initial needed infrastructure build of are you operations and offset by reduced travel industry engagement and our commercial organization given restrictions in place to combat the pull the 19th.

Jackie Faust: Thanks, Holly. Good morning, everyone, and thanks for joining our second quarter 2020 results call. The second quarter was an incredibly productive and important time for Agios as we made significant progress across the business and accomplished several of the key objectives that we set for 2020. The steps we took in Q2 solidified our strategic priorities for the remainder of the year and move us closer to achieving our 2025 vision.

And Doug.

We ended the quarter with cash cash equivalents and marketable securities of $794 million, which includes the amount received under the royalty farm agreement.

We now expect third Q2, ending cash balance in addition to expected product revenue, but excluding anticipated program specific milestone payment.

Jackie Faust: Seven years ago, we discovered the first pyruvate kinase R activator, Minipivat, and since then, we've led the science behind this mechanism, advanced a phase 3 program in pyruvate kinase deficiency, and become the first company to establish that activating wild-type PKR may provide therapeutic benefit in other hemolytic anemias, such as thalassemia and sick Over the past quarter, we further highlighted our leadership in the space and shared key updates that support our next phase of development for Mitopivad. To start, we established compelling proof of concept for midipivate and sickle cell disease, demonstrating that PKR activation has the potential to treat chronic hemolytic anemia and markers of sickling in these patients. In addition, at EHA, we presented data for the first time at a medical meeting for minipivat and thalassemia, showing sustained hemoglobin responses in both beta thalassemia and alpha thalassemia patients.

Jackie Faust: In May, the FDA granted us orphan drug designation for this indication. As we look ahead, we are firmly committed to the rapid advancement of Minupivat across all three of these disease areas. The remainder of 2020 will be focused on preparations for top-line data from the PK Deficiency Phase III studies and the submission of an NDA for Mitopivat's first indication, and indications for pivotal programs in both thalassemia and sickle cell disease in 2021. In June, we secured $255 million of non-equity capital through the sale of our IDFA royalty and future milestones to Royalty Pharma to help In addition to our progress on the rare genetic disease side of the business, we've continued to drive commercial execution for TIPSOVO and advance our malignant hematology and solid tumor clinical programs. At ASCO and EHA, we presented data underscoring the utility of IDH inhibitors in both areas. And in May, we published a manuscript in Lancet Oncology highlighting data from the Clarity Phase III study of Tipsovo and cholangiocarcinoma. As a result of the manuscript, the NCCN guidelines were updated to recommend treatment with Tibsovo for patients with advanced IDH1 mutant cholangiocarcinoma.

And our current operating plan, which includes pivotal programs for me to pivot and Delphine and sickle cell disease through the end of 2022.

With that operator, please open the line for question.

Ladies and gentlemen.

Question, you will need a press star one on your telephone.

Withdraw your question press the pound key.

And the interest of time, we ask that you. Please limit yourself to one question.

Please standby, while we compiled Q and a roster.

Our first question comes from elite deal Young with Cantor Your line is now.

Hey, guys. Thanks for taking my question Congrats on a the progress throughout the quarter I guess just wanted to ask maybe about mid of pet.

He and kind of any color you can give us on the timing and plan forward. There I know you said, you're moving forward, but just any color would be helpful. Thank you Greg.

Yeah I leave here, it's Chris I I didn't catch <unk>, you're looking for an update on which program.

Medicare that in the feed it can you hear me.

Okay. Yeah, you know I just didn't yet.

Right. So we're looking to initiated trials very big company deficiency next year the process of negotiating the study design and with.

Most of Europe, where the crucial part of it's a box you have to check in order to be able to file an adult indication and then you'd make a commitment that you have to be yeah. It's strictly commit to is it takes a while in so we're working through that we anticipate opening that trial in 2021.

And then our plans and that was senior and sickle cell for world.

Embark on pediatric development, there are still want coming together.

Oh, sorry, I meant PK RFP.

Like yeah.

Yeah, Yeah, yeah, Okay got it okay. So we're going to we're going to where we're targeting opening a trial in children part of the tiny sufficiency next year.

And then we will also do pediatric development.

It appears that in fact, we've seen yet and sickle cell.

But those plans remain to be defined at this point.

Okay got it thank you.

Jackie Faust: We look forward to having overall survival data from the CLARITY study in the near future, which will support an expected SNDA submission in the first quarter of 2021. I'm proud of our team for accomplishing all this great work while continuing to combat the challenges and complexities caused by the ongoing COVID-19 pandemic. The disruption to global healthcare systems continues to evolve as infection rates fall in some parts of the world while rising in others, including in many states here in the U.S. Our Organizational Resiliency Team and Clinical Operations Response Team remain active in assessing COVID-19's impact on every facet of our business on an ongoing basis. While the majority of our employees continue to work from home, all lab employees who need access to our Cambridge Research Labs have returned to work under In addition, as local regulations and institutions have allowed, some of our field team can interact with their customers in person again. We continue to evaluate additional operating procedures that will allow a broader return to on-site work.

Thank you. Our next question comes from on upon Rama with Jpmorgan. Your line is now open.

Hi, guys. Thanks for taking my question. Congrats on all of progress I had a broader kind of sickle cell question and thinking about mid to pick that one of the most frequent questions that we've gotten.

Oh, Yeah, Jay isn't it.

Ultimately think about levers for differentiation, whether it's against other PK, our activate here as well established players like GBT for example.

Thanks, so much.

Hi, Tom It's Chris here.

I'll start and some others may want to jump in I think that.

The ability for me how bad is I'm really looking at two factors.

And that will be increasing hemoglobin for patients who are experiencing and maybe as a basis of their disease and of course are they acquired some acute chests and bill paying crises and all those things.

Aspects it really hard part of the unmet need.

<unk> best case scenario for us and our early development data for us from the NIH study suggests we have the potential to affect both.

Jackie Faust: I would like to thank each and every Agios employee for continuing to advance our programs for patients while balancing the pandemic's significant impact on their personal and professional lives. But before I turn the call over to Chris, I think it's important to acknowledge recent events that have once again exposed the realities of racism and racial violence in our country. At Agios, we believe matters of racial injustice should be acknowledged and decried, and we are committed to acting in allyship against this destructive force in our community. All of us at Agios believe in the value of diversity, and we are committed to making Agios a welcoming and diverse workplace where individuals of all backgrounds can thrive and contribute meaningfully to our mission on behalf of all. Chris, let me turn it over to you. Thanks, Jim.

With regards to competitor PK our activators.

It's really going to boil down to a number of things that we've got four years plus data with.

Mid payback.

And we're getting ready to put a follow on molecule under the client we know a lot but in the leaders and finding the biology, the translational science as long as a clinical signs. So that's really going to I think shake out as an additional data emergence and I think that the safety and efficacy profile and setting while you're getting drugs. So long.

Periods of time is really important.

I think the other thing that we may see depending on how many additional drugs come on the market will be a targeted therapies could potentially be combination therapy that something else in existence and then finally, you asked about how does how to any of these drugs fit in.

Chris: Thanks, Jack. I'll start with Medipivac, our first-in-class PKR activator currently being evaluated across three distinct hemolytic anemias. As Jackie highlighted, we achieved important milestones for this program in the second quarter that support broad and clinical development in both thalassemia and sickle cell disease. Our most advanced program is in PK deficiency, where we have four years of experience in treating patients and have the potential to provide the first disease-modifying therapy. Earlier this year, we completed enrollment in our two Phase 3 studies, Activate and Activate T. Since the beginning of the COVID-19 outbreak, we have focused on ensuring patients have access to study drugs and that we capture all data regardless of a patient's ability to get to their trial center. This includes home visits, telemedicine approaches, the use of local laboratories, and courier shipments of drugs.

Chris: As the core period of both studies comes to an end later this year, we are working with our global clinical trial sites to understand the timeline to complete the necessary steps for database lock. We still anticipate top-line data from both Activate and Activate-T sometime between the end of 2020 and the middle of 2021. We will narrow this timeline based on our ability to confidently predict trial site access in the wake of the ongoing global pandemic. We expect to file for regulatory approval in both the US and EU next year, with a potential 2022 commercial launch and PK deficiency in both geographies. Moving to the Phase 2 study of midipivac and thalassemia, we completed enrollment earlier this year with 20 patients. And in June, we presented updated data on 13 efficacy of valuable patients at the virtual EHA meeting.

Given the presence of Bucks Brita and that's a drug that has accelerated approval.

To date has shown a increase in hemoglobin that were sufficient for accelerated approval in about 50% patients.

So if you just step back for a minute that that and it did not show any improvement statistically significant improvement and the reduction of the Cds. So if you just back for a minute. There's there's and you look at the potential in spite of population you can see that at least half of those patients aren't going to having adequate response.

Smoking.

I wish him a patient population for you right there.

This is there and maybe just add one more point to what Chris laid out. So I think he made the most important points in terms of of Ah differentiation in class I mean, ultimately you will come down to <unk> due to the the advantage that we that we times is gonna be the.

The breadth of our patients experience right because we'll have one two indications oh, though and the product will be very familiar to or to the to the treaters on before in other potential in class competition.

Makes it to market. So I think that that adds considerably to raising awareness from there already comfort with Oh.

Chris: Data showed that treatment with midipivac induced a hemoglobin increase of greater than or equal to 1 gram per deciliter in 12 of 13 evaluable patients during weeks 4 through 12, including 4 of 4 alpha thalassemia patients 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.

With me to pick up relative to other products.

And this is Bruce just.

Adding to that important within that we didn't class differentiation the uniqueness to the mechanism of actions of the Alistair PK are activated.

While we improved the health of this though I mean for the ATP content. So the energy of itself and learning chain three G.P.G.

We directly or heard the affinity of the hemoglobin for oxygen is complementary to the mechanism.

Increasing glove enhance like hydroxy urea and others. So we believe ultimately these mechanisms will be complementary potentially even synergistic when combined.

Chris: Our focus now is to advance the development of Minipivap for these patients as quickly and efficiently as possible. By the end of the year, we expect to finalize a robust, pivotal development plan that spans both alpha and beta thalassemia, as well as transfusion-dependent and non-transfusion-dependent patient populations, with the goal of initiating a 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 midipiva. In June, we announced that clinical proof of concept was established based on a preliminary analysis of data from this study. The data showed that over a 6-8 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. Adverse events seen in this study were consistent with previously published data from Mitopivak in patients with PK deficiency or expected in the context of sickle cell disease.

To each others have alluded.

Great. Thanks, so much for taking my questions.

Thank you. Our next question comes from Tyler Van Buren with Piper Sandler Your line is no.

It does a good morning.

Got a follow up related specifically to the middle Tibet Sickle cell program. You noted that enrollment was halted but that it should reopen the summer would trade to mean potentially in you know a month or so and that they.

Chris: Based on these results, we're working quickly to get regulatory and advocacy group input for our pivotal development plan in sickle cell disease, which will put us in position to initiate the study in 2021. Patient enrollment in the Phase 1 Sickle Cell Study was temporarily halted earlier this year in the wake of the COVID-19 pandemic, and they are actively working to reopen the study this summer.

Chris: Dr. Tan plans to enroll up to 25 patients in the study, and she will submit data from the trial for presentation at the ASH meeting in December. However, due to the earlier pause in enrollment, it's not yet clear how many additional patients will be included in that presentation above the nine patients that served as the basis for our proof of concept evaluation. I'll now move to our malignant hematology programs, where we're focused on geographic and indication expansion for our IDH1 inhibitor, PIVSOBA. To start, in the EU, we have received our Day 180 list of outstanding issues for our Kibsova filing and relapsed refractory AML, and at this time, we still anticipate receiving a CHMP opinion by the end of the year.

Eventually planned to enrol 25 patients, but it's unclear how many are both nine you'll be able to get.

Before ash so.

Talk through that a little bit more you know what gives you confidence that it should reopened.

This summer are relatively soon and then just maybe walk through the the time that would be required.

On study for these patients could get more above that nine number and in time for ash. Thank you.

Hey College, Chris here.

I think the reason why.

We think this study will reopen as because communications that getting from the NIH and some dr. cans group and that's they're anticipating.

That's a center should open within the next several weeks and then I think the second part of your question. It. So then what's the.

What's the Dataflow look like and that would depend on how many patients a day can consent enrolling permitted to treat.

It.

Maybe a function Nate I don't know whether the NIH is going to my guess is that they will be doing a stage reopen payments are really the number of patients come in will be.

To be an immense administrative issue.

The so overall Dan patients come in they have some baseline testing and then they're going to get treated for eight weeks.

I have to taper and then they go up so in terms of how many patients will be added to any ash presentation will really depend on how early they open.

Yeah, how early.

The remainder of the summer does it get opening that people can make consent and bring in.

Add on eight weeks and treatments and taper timing when they of course meats and trying to pull things together in order to get ready for presentation December. So early early days now we're encouraged by the fact that they are I'm pretty confident they're going to get open next couple of weeks and Dr. Chan or is it is working on having patients.

Chris: In frontline AML, we are enrolling two global phase 3 combination studies, Agile and Hovon-150, which will allow us to further broaden TIBSOVA's frontline label to include combination use with azacitidine and 7 plus 3, respectively. We are also enrolling patients in the reopened myelodysplastic syndrome arm of the TIBSOVO phase 1 study with the goal of generating the data necessary to pursue a We expect to complete the additional enrollment in 2021. In addition to these registration trials, we continue to explore and generate data with TIBSOVO and novel combinations through our investigator-initiated studies. Data from one such study, the Venetoclax plus Tibsovo plus or minus azacitidine IST conducted by Dr. Courtney DiNardo and MD Anderson, were presented earlier this year at ASCO and EHA, showing that the combination was well-tolerated and effective with a composite complete response in 80% of patients. In May, we shared that site startup activity had slowed, and enrollment interruptions occurred at some Some areas have begun to stabilize, but we continue to track recent surges in the impact of the trial. At this time, our enrollment guidance remains unchanged for the AML and MDF studies.

And up to come in.

They have some experience knowledge of drugs. So we're keeping our fingers crossed it will be able to get a few more patients and but we know it a minimum it will be the details on the eight patients we talked about DHX media.

Okay. That's very helpful. Thanks, so much.

Thank you.

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

Hey, Thank you thanks for taking the questions just the types of her the revenues in the number if you need.

Described this is there anything you can talk true as regards to the impact from Covidien anything you can say that off label use.

Thank you.

Sure Darren here, so we haven't been able to detect a significant impact from qubits, thus far seen nice growth in in a new new us scripts and refills are both book both of which are are continuing to move into right direction.

As we noted we had a very significant expansion of new prescribers.

In a in both the academic and community setting, but it's the fastest growth is actually occurring in the in the community setting, which is which is encouraging as well. The the there are a couple of of risk, though that are associated with coded right so or ultimately.

Darren: I'll now move to the solid tumor. Last year, we reported positive PFS data from the Clarity Phase 3 study of Kibsovo and previously treated IDH1 mutant cholangiocarcinoma, and this quarter, we expect to have mature overall survival data from the study to support a potential supplemental NDA final. Based on the anticipated timing of the data, we expect the SMDA submission is now likely to occur in the first quarter of 2021, which has been reduced from our previous guidance. In addition, we continue to enroll patients in our other solid tumor studies. The INDIGO trial, our phase 3 study of voracidinib, our brain penetrant IDH inhibitor, and low-grade glioma, and the AG270 Phase I combination arms in non-small cell lung cancer and pancreatic cancer. Like our other ongoing trials, we continue to monitor the pandemic's impact on site startup and enrollment activities and have no updates to previous guidance at this time. With that, I'll turn it over to Darren to discuss our second quarter commercial performance.

We have yet to see it but they are potentially can be an impact in terms of the initial diagnosis of patience with PML, though it's a treatment emergent disease. The reluctance of patients to show up could potentially oh manifest over overtime, but we haven't seen that significantly as of yet the continued work from home.

Restrictions on that on the Salesforce can can potentially on some pressure.

But what we've seen also is an increase in in Medicaid and Threeforty.

A utilization as well and we would expect that to continue as is and you indicated earlier and then in terms of spontaneous adoption off label use and other settings is that because we've shared many times, we've limited insight into a utilization in in indications outside.

Outside of PML, but we do have added those of those uses.

Darren: I am pleased to share that our commercial team has continued to deliver strong performance in 2020, recording $27.6 million in net sales of Tipsovo in the second quarter, a 22% increase from Q1. Access restrictions related to COVID-19 notwithstanding, quarter-over-quarter growth was driven by an increase in both new scripts and refills, with the largest increases seen in the relapse refractory AMLs. Furthermore, we continue to expand our prescriber base, growing at 15% in both the academic and community setting over Q1. Market research continues to show that the majority of physicians consider TIPSOVO to be standard of care in IDH1 mutant AML and the leading targeted treatment for newly diagnosed IDH1 mutant AML patients ineligible for intensive therapy.

Great. Thanks much.

Mhm.

Thank you.

Our next question comes from Kennen Mackay with RBC capital markets. Your line is no [laughter].

Hi, Thanks for taking my question, maybe what's just hoping you could discuss a little bit more in sickle cell be real sort of urgent need for cheaper and really any meditation that.

You've used to sort of bolstered the number of red blood cells in a situation, especially if this is acting by shipping the oxygenation curve of Red Lake Charles and Ah oxygen buying to her that's something that I think it's still maybe a little bit under appreciated in that setting.

Darren: Though not a focus of our promotional efforts, we continue to observe that approximately half of Tibsobo used in both the relapse refractory and frontline settings is in combination, and most frequently, this occurs with a hypermethylating agent. Our patient assistance program, MyAGIOS, continues to operate uninterrupted in the midst of the COVID-19 pandemic as we support patients through these challenging times. As Jackie mentioned, in response to the growing concerns related to the pandemic, the majority of our field team has continued to work from home since mid-March, though some have begun to safely interact with their customers in person again, as local guidelines and practices have allowed.

Hi, Ken This is Chris here. So you you are asking the question of tapering.

Oh, I'm, sorry, I'm on discontinuation of drug Yeah, just circling back to some of the safety events that we talked sickle cell.

Yes.

Well you know, we established with I'd make a pivot probably be kinase deficiency bad.

The best thing the ideal situation at the patient is going to stop drug is to gradually paper.

Andrew: We've experienced success continuing to engage customers with tools enabling remote interaction. As a result of performance through the first half of the year, we reiterate our full year 2020 U.S. Kipsovo Net Sales Guidance of $105 to $115 million. I'll now turn it over to Andrew to discuss our second quarter financials. Our second quarter results can be found in the press release we issued this morning, which I'll summarize. More detail will be included in our 10-Q filing later today.

And if you think about it that you've got you've got a drug that binding and stabilizing power. They kind of in this setting up quite a big kinase deficiency here and then activating it and all these diseases.

So roughly stopping and has the potential for a more rapid decline in hemoglobin than if you take rate and a rapid decline then the patient can kill me.

Andrew: Total revenue for the second quarter was $37.3 million, which consisted of $27.6 million of net sales of Tibsovo, $6.4 million of collaboration revenue, and $3.3 million of IDFA royalty revenue. Compared to the second quarter of 2019, total revenue grew by 42 percent, given by a 101 percent increase in Tibsovo sales, offset by a decrease in collaboration revenue, as we announced in June. Royalty Pharma purchased our tiered sales-based royalty rights on worldwide net sales of IDFA, as well as rights to receive up to $55 million in outstanding ex-U.S. regulatory milestone payments from BMS for $255 million. This transaction will be accounted for under the debt method, which requires us to record a liability on our balance sheet for the purchase price net of issuance cost. We will continue to record the ID4Royalty through the life of the arrangement.

Yeah as rapidly as Kent acclimate as well as if you do a slow taper.

So so that's really where that comes from now.

The aspect of one of the things I think that comes out because people are worried about compliance and because.

The statements and data that indicates that that noncompliance, maybe it more of an issue in sickle cell versus other.

Diseases.

We don't think that missing a dose here and there is likely to be a problem based on what we know about the pharmacokinetics and the biology of the molecule.

But I think that's the guidance that in the ideal situation. She wants to void abruptly stopping the drug and have it tapers like that to be present.

I'd also say that that's true for a lot of drugs with it I mean, qlogic space or other areas with chronic dosing is something that you do.

Andrew: In addition, we will record non-cash interest expense associated with the liability. The liability will be reduced by the royalty revenue recorded in each period and increased by the non-cash interest expense. For the period in which interest expense exceeds royalty revenue, the liability is increased, and for periods in which royalty revenue exceeds interest expense, the liability is reduced. The liability will be reduced to zero when we're no longer eligible to receive royalties under the 2010 agreement.

And the as noted just does as it relates to be competitive landscape to.

That's helpful.

Well it is one of them the mechanisms of middle because that is a little bit similar to.

The mechanism of Aucs brought about shifting that oxygen affinity.

Her personal pressure Curt often you maybe talk a little bit about the theoretical.

By the ability of of <unk> agents, whether that's realistic or something that a that wouldn't make sense right. So much and congrats on the the progress during the.

Yeah, well I think I think see combinability is something that we're interested in not just in sickle cell, but let's see me a as well as new products come on.

Andrew: Tibsovo revenue grew by $4.9 million compared to Q1 2020, which was driven by continued strong unit demand and channel inventory levels returning to more normal levels versus where we ended Q1. Growth to net for the quarter was within the expected range, but we have seen increases in Medicaid and PHS utilization over the first half of the year, and expect that trend to continue over the balance of the year. Cost of sales for the quarter was $675,000. Turning to operating expenses, R&D for the second quarter was $90.9 million, a decrease of $16.5 million compared to the second quarter of 2019. The year-over-year decrease in R&D was largely driven by lower collaboration spend related to $6 million in milestone payments for AG 636 and an undisclosed early stage research program in Q2 of 2019.

And I think says that complement integrity of mechanisms of action. So if you are.

He's Oh seeming example, first if you have something that enhances terminal Richard differentiation like Luspatercept is is there at least a theoretical interests that by having more cells got to that late stage. So that they can be affected by that drug list that are something that then that's you know certainly is of interest there's been recent publication.

A in the sickle cell literature, where people are saying this is the number of new drugs coming in and as offering some real potential for complementarity, specifically for permit a peer bank knock straight a it's an interesting thought it if you can get somebody up but graham with with sprayed or Graham and.

Andrew: Ramp down the Clarity Phase 3 study of Tubsovo and Hobon startup expenses incurred in Q2 2019 and lower spend across ongoing Tubsovo clinical studies as a result of slowed enrollment and reduced activities due to the COVID-19 pandemic Selling General and Administrative Expenses were $36 million for the second quarter, representing a $3.6 million increase over second quarter 2019, driven primarily by the initial gated infrastructure build of our EU operations and offset by reduced travel and industry engagement in our commercial organization given restrictions in place to combat the COVID-19 pandemic.

I have to do well they benefit from another Graham and a half by adding a p. care, a wild type activation I'll admit a pin that.

And I'm the one hand that that's appealing and then the other and you've probably heard from sickle cell docs is that there were a little more careful about how they adjust hemoglobin in these patients. So yeah. It's definitely of interest not just struck straight up but potentially for other drugs come along with it sort of artists piece left him inhibitor and <unk> and others.

I think but yeah, we just based on their data and now in sickle cell that the early data we talked about it at a eat hot and what we see in Dallas seen yet long term experience with commit to that and probably be kinds deficiency.

Operator: We end the quarter with cash, cash equivalents, and marketable securities of $794 million, which includes the amount received under the Royalty Farm Agreement. We now expect our Q2 ending cash balance, in addition to expected product revenue, but excluding anticipated program-specific milestone payments, will fund our current operating plan, which includes pivotal programs for midipivic endolysemia and sickle cell disease through the end of 2022. With that, operator, please open the line for questions. Ladies and gentlemen, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. In the interest of time, we ask that you please limit yourselves to one question. Please stand by while we compile the Q&A raw. Our first question comes from Alethea Young with Cantor.

I.

I think we I'm I'm very excited about just looking at this drug is a single agent because I think if we have the opportunity to do both.

Could address both major components of the disease and reduce said you know income that that [laughter] hyperactive bone marrow. That's that's really working hard to keep up in email I think there's a potential that we can demonstrate the patients would you better as well so yes to combinations, but I think we have varied.

Very strong ground to think that we have a single agent.

Benefit that we'll be able to provide the patient.

Okay, and just carrying on from that that Chris the patient reported outcomes being in a favorable at very favorable anecdotally for at treatments with me to pay that across the indication.

Operator: Your line is now open. Hey guys, thanks for taking my question and congratulations on the progress throughout the quarter. I guess I just wanted to ask maybe about Mitopeva and PEEDS and kind of any color you can give us on the timing and plans to move forward there. I know you said you're moving forward, but just any color would be helpful. Thank you very much.

That isn't the case with Fox Freida, notwithstanding it approval for increasing hemoglobin and importantly, violent finding of off brought it hemoglobin. It prevents the tickling. So that's a very important thing and it also loads the ability it seemed gloves and carry oxygen and that they are important and were able to persist.

Chris: Hey, Alethea, it's Chris. I didn't catch you're looking for an update on which program?

Alethea Young: MetaPivot and the P's. Can you hear me now?

Hemoglobin in healthier red cells, such that they carry more oxygen and that there's a higher seen any of the funding for oxygen. So we believe we have actually the period mechanism that to that box price.

Chris: Okay, yeah, yeah, yeah. No, I just didn't hear that piece.

Chris: Right, so we're looking to initiate a trial on higher-rate kinase deficiency next year. The process of negotiating the study design with both Europe, where the crucial part of it's a box you have to check in order to be able to file an adult indication, and then you make a commitment that you have to be, you know, strictly committed to. It takes a while, and so we're working through that, but we anticipate opening up soon.

Thank you. Our next question comes from Chris Shibutani with Cowen. Your line is now open.

Good morning. Thank you questions focused on me that pivot three of them for mid to that you had previously updated on the peak registry and patient identification any updates there I'm also describe narrowing the timelines based on ability to access trial sites to get to activate day.

Chris: And then our plans in thalassemia and sickle cell, where we'll embark on pediatric development, are still coming together.

Well, there's an assessment you obviously had to make three months ago, and just curious to know whether thus far in your senses that progress has been a quicker perhaps than you thought or more challenging any color in terms of Oh eight on how that progresses. I know you gave us the first half its the span secondly, I'm pretty.

Chris: Oh, sorry, I meant PKR, Pete. Thanks. Yeah.

Chris: Yeah.

Chris: So, we're targeting opening a trial in children with part of a kinase deficiency next year.

Chris: And then we will also do pediatric development with midipivate and thalassemia and sickle cell, but those plans remain to be defined at this point. OK.

Sickle cell disease, you have this collaboration with the NIH can you just remind us what optionality to have any plans that might be in place you do clinical work in this indication independent of the NIH or pardon tethered to then contractually I just help us understand since I think a lot of the sharing a bit.

Chris: Got it, cool, thank you. Thank you. Our next question comes from Anupam Rama with J.P. Morgan. Your line is now open. Hey guys, thanks for taking the question.

There is dependent upon decisions jointly made and perhaps if you had options to direct trials and activities on your own that would be helpful for us to now thanks.

Operator: Congratulations on all the progress. I had a broader kind of sickle cell question.

Operator: One of the most frequent questions that we've gotten Post EHA, how do you ultimately think about levers for differentiation, whether it's against other PKR activators as well as established players like GBT, for example? Thanks so much.

Okay, Hey, Chris Christopherson here.

Peak is up and running.

Multiple countries across the world.

It's enrolling well one of our ambitions is to take fee natural history study and they'll be able to pull those data, but its peak at something we're working on a bad databases from Boston children's hospitals emerging that into.

Chris: Hey Anna Thomas, Chris here. I'll start, and some others may want to jump in. I think that the ability of midipibat is really looking at two factors. And that will be increasing hemoglobin for patients who are experiencing anemia as a basis of their disease and, of course, the occurrence of acute chest syndrome, pain crises, and all those things that really are part of the unmet need. So the best case scenario for us and our early development data from the NIH study suggests we have the potential to affect both. With regard to competitor PKR activators, it's really going to boil down to a number of things, is that we've got four years plus of data with imidapibat, and we're getting ready to put a follow-on molecule into the clinic. We know a lot and have been the leaders in defining the biology, the translational signs as well as the clinical signs. So that's really going to, I think, shake out as additional data emerges, and I think that the safety...

Or.

Combining that pulling it doing that analyses.

Nothing that we're interested in doing anything to talk more about future.

So and we think that's going to be an important and ongoing important datasets for us too.

Described the burden of disease outcomes of variations in treatment approaches and we're looking forward this too.

Starting to be able to publish that and hope to be able to guide to that.

With regards to that.

Challenges in that the ups and downs of.

Clinical development.

Eric.

It's as I commented on in my remarks, I can't talk about specific places specific sites, but if you just step back for a minute and you look at how the pandemic, whose loss the United States as it moves.

From the East coast in the West coast down to the south enough and around there's a fair amount of unpredictability, there and depending on how walk down the hospital lids and how they're managing clinical trials and their clinical research staff and the fact that when they stop and then start teams acute noted that the.

Chris: I think the other thing that we may see, depending on how many additional drugs come on the market, will be targeted therapies. That's something else in existence.

It's an exact is that we're looking at and trying to.

Understand.

Yeah, how how we're going to get in there and pull a data and that's why we can provide anymore guidance at this point, but what I can tell you is that we've done a good job in terms of making sure patients stay on drought capturing data.

Chris: And then finally, you asked about how any of these drugs fit in given the presence of Oxprida? And that's a drug that has accelerated approval. The data to date has shown increases in hemoglobin that were sufficient for accelerated approval in about 50% of patients. So, if you just step back for a minute, then it did not show any improvement, a statistically significant improvement in the reduction of VOCs. So, if you just step back for a minute, and you look at the potential oxbrided population, you can see that at least half of those patients aren't going to have an adequate response, and that can establish a patient population for you right there.

Site by any of the that means that I talked about in my prepared remarks and yeah.

Well just have to see how can develop.

Before we can provide you more definitive guidance.

Which is why we didnt updated on this call and then with regards to the NIH and issues around how we choose to do development and we don't have any restrictions I mean, that's a true that's a credit agreement we have with them for a trial, we freely share. The data. We are in fact, performing a number of the assays are being done.

Darren: This is Darren. Maybe I could just add one more point to what Chris laid out, because I think he made the most important points. In terms of differentiation in class, I mean, ultimately, it'll come down to data. The advantage that we have is gonna be the depth and breadth of our patient experience, right? Because we'll have one, two indications, and the product will be very familiar to the treating physicians before any other potential in-class competition makes it to market. So I think that adds considerably to raising awareness, familiarity, and comfort with Medipivit relative to other products. And this is Bruce Carr, just adding to that important within class differentiation is the uniqueness of the mechanism of action of the allosteric PTR activator. So while we improve the health of the cells, we improve the ATP content, so the energy of the cells, and by lowering 2,3-DPG, we directly improve the affinity of hemoglobin for oxygen. This is complementary to the mechanisms that increase hemoglobin S, like hydroxyurea and others.

With.

Bruce is food show.

You know, we have freedom to operate and we're moving forward.

Yeah.

Expeditiously to get a sickle cell trial up and running at 2021, and that's not dependent on anyway have an approval from the NIH sure.

Hmm and for that matter and we have a very good relationship with them and being able to discuss and describe that data and and presented to health authorities as needed.

[noise], it's Jackie I, just wanted something first second and I think something Chris said is really important to just reiterate on the.

Activate activate T trials you have two issues that you probably want to think about one is data integrity and that is worse, Chris spoke to how good a job our team has done.

To make sure that patients stay on drug and that the trial you know they finished their travel experience. So smoothly. It inline with the protocol and then the second is timing of being able to release that or have in hand analyzer. They release that a topline data. So I think data integrity is extremely important if we were fast and getting it.

Good.

The data out, but there was a compromise or to the data that would be more serious [laughter], ensuring data integrity first and then the timing of when we I get that topline data out and were as Chris said, we feel good about that that what the team has done that support data integrity and we haven't narrowed the.

Bruce Carr: So we believe, ultimately, these mechanisms will be complementary, potentially even synergistic when combined, as others have alluded. Great, thanks so much for taking our questions. Thank you. Our next question comes from Tyler Van Buren with Piper Sandler. Your line is now open. Hey, guys. Good morning.

The timing window, just yet because we've got a little ways to go to get into the sites and see that and then I think also Chris part of your.

First question included the patient finding efforts and right now between our clinical programs and our patient finding efforts were at about 2000 patients identified thanks.

Operator: I had a follow-up related specifically to the Medepivac Sickle Cell Program. You noted that enrollment was halted, but that it should reopen this summer, which I take to mean potentially in, you know, a month or so, and that they eventually plan to enroll 25 patients, but it's unclear how many above nine you'll be able to get before ASH. So can you just talk through that a little bit more? You know, what gives you confidence that it should reopen this summer relatively soon? And then maybe walk through the time that would be required in study for these patients to get more above that nine number in time for ASH. Thank you.

Thank you for the uptick.

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

Hey, Good morning, guys. This is James on permit.

I had a question on easy to 70, another company recently announced a collaboration to explore Mac today with PRM T. One.

They publish some preclinical data showing greater potency and solubility compared to 70 have you seen this data and what are your thoughts on bear Matchday program and possibility for a combo with PRM T. One.

Hi, this is.

Chris: Hey, Tyler. It's Chris here. I think the reason why we think the study will reopen is because of the communications that we're getting from the NIH and from Dr. Kim's group, and that they're anticipating that the center should open within the next several weeks. And then I think the second part of your question is, so then what's the... What does the data flow look like? And that would depend on how many patients they can consent to, enroll, and are permitted to treat. And that may be a function they, I don't know whether the NIH is going to, my guess is that they will be doing a stage reopening. And so really, the number of patients that can come in will be an administrative issue.

I believe you're trying to the I'd add molecule yeah. The in in terms of it or the ability to pathway. They love. It ends on my side then it combination with here in E. One and ending highly appropriate one and we believe will that PRN T. Five would be at potential player in this field.

Yeah.

Thank you.

Thank you.

Our next question comes from Michael Schmidt with Guggenheim. Your line is now open.

Hey, guys. Thanks for taking my questions I had two more on six or seven one on tip syllable.

Chris: [inaudible] come in, they have some baseline testing, and then they're going to get treated for eight weeks, have the taper, and then they go off. So in terms of how many patients will be added to any ASH presentation will really depend on how early they open, how early in the remainder of the summer do they get open and how many people can they consent and bring in, add on eight weeks of treatments and paper time, and then they of course need some time to pull things together in order to get it ready for a presentation in December. So early days now, we're encouraged by the fact that they are pretty confident they're gonna get open in the next couple of weeks, and Dr. Chen is working on having patients lined up to come in, and they have some experience now with the drug, so we're keeping our fingers crossed that we'll be able to get a few more patients in, but we know at a minimum it will be the details on the eight patients we talked about at the EHA meeting.

Maybe elaborate for follow up so prior question on the phase one.

And I H a data.

I was just wondering if any additional information might be available on that that one patient that experienced a L. B O C band.

I think at the time it was up.

Classified as possibly treatment related but obviously you will see sell car at that high frequency in patients in general I was just wondering CREZ. If that's been any any any new information on that specific event that you might be able to share.

Nothing new.

The the deal she occurred.

During the during the taper we didn't see any events, while patients run active treatment, you're absolutely right that that's a.

And so on an unfortunate component of this season, one way or trying to address it should there be overseas.

We didn't see any additional funds during the taper off over the course of goes eight patients that were able to complete either six or eight weeks of dosing.

Chris: Okay, that's very helpful. Thanks so much. Thank you. The next question comes from Peter Lawson with Barclays. Your line is now open.

No so no new information.

Operator: Thank you. Thanks for taking the questions. Just on Tim Servo and their revenues and the number of unique... Describers, is there anything you can talk through as regards the impact of COVID and anything you can say about off-label use? Sure, Darren here.

And it's something we'll continue to try.

And I can't.

Given our overall sense of that in data that we've talked about it at ash is that we clearly had she proof of concept and we're excited to move forward.

Great. Thanks, and then I think you mentioned a meeting with the F.C.A. and.

Darren: So, we haven't been able to detect a significant impact from COVID thus far. However, we've seen nice growth in new scripts and refills, both of which are continuing to move in the right directions. As we noted, we had a very significant expansion of new prescribers in both the academic and the community setting, but the fastest growth is actually occurring in the community setting, which is encouraging as well. There are a couple of risks, though, that are associated with COVID, right? So, ultimately, we have yet to see it, but there potentially can be an impact in terms of the initial diagnosis of patients with EML. Though it's a treatment-emergent disease, the reluctance of patients to show up could potentially manifest over time, but we haven't seen that significantly as yet.

Discussing our plans for regulatory trials are approval a pivotal trials.

And you know given some of the.

Possible you know differentiation that we've talked about earlier just wondering how you think about you know taking advantage of data in your trial design. For example, you know what are your thoughts about pursuing an accelerated approval pathway summit two GBT using.

H.B. increase or or potentially a incorporating clinical outcomes such as VLSI reductions I guess, how do you think about those considerations.

Yeah that that's the.

Major.

Focus for our team now in terms of putting together.

Clinical development plan.

I can lead to approval accelerated or regular.

Darren: The continued work-from-home restrictions on the sales force can potentially add some pressure, but what we've seen also is an increase in Medicaid and 340B utilization as well, and we would expect that to continue, as Andrew indicated earlier. And then in terms of spontaneous adoption or off-label use in other settings, as we've shared many times, we've limited insight into utilization in indications outside of AML, but we do have antidotes for

In the United States, but in other geographies outside the U.S.

And you did that the <unk>.

The interesting part of mid of payback.

Is that.

We have the potential to we clearly have the potential to address hemoglobin, we demonstrated that.

Currently on it and we know now that activating wild type PK are.

It is a important strategy and chronic hemoglobinopathies overall, if you will mainly Palestinian circle. So we've demonstrated so far we think that we have the opportunity to reduce videos seed.

Darren: Great, thank you so much. Thank you. Our next question comes from Kenan McKay with RBC Capital Markets. Your line is now open. Hi, thanks for taking the question. Maybe I was just hoping you could discuss a little bit more about sickle cell, the real sort of urgent need for tapering, really any medication that is used to sort of bolster the number of red blood cells in circulation, especially if this is acting by shifting the oxygenation curve of red blood cells and the oxygen binding curve. That's something that I think is still maybe a little bit underappreciated in that setting. Thank you.

So then so so what I'm not saying anything.

New here the interesting part is how you combine those as well as potentially patient reported outcomes and do a package that can get you there.

Rapidly as you can but also have the greatest impacts of patients.

So we're working hard on that and we're looking forward to having those discussions with.

Both agencies as rapidly as possible. The other thing that they want to do is get input from patients and patient advocates because I think that that's going to have an important impact on that type of data.

That that weird.

That will impact patients and really compel them to use the drugs. So want to factors in play I know that accelerated approval on that.

Operator: Hi Ken, it's Chris here.

Chris: I'm sorry, on discontinuation...

Based on the increase the woman has been demonstrated with talk sprayed out.

Chris: Yeah, just going back to some of the safety events that we saw in Sickle Cell.

And that's something we're looking very hard that but we think there's there's a lot more trust to be thinking about on the basis for the mechanism of action in a minute to that any unmet need overall.

Chris: Well, you know, we established with mitopibat and pyruvate kinase deficiency that the best thing, the ideal situation if the patient's going to stop taking the drug is to gradually take it. And if you think about it, then you've got a drug that's binding and stabilizing pyruvate kinase in the setting of pyruvate kinase de So abruptly stopping it has the potential for a more rapid decline in hemoglobin than if you taper it and a rapid decline than the patient can acclimate to, as rapidly; you can't acclimate as well as if you do a slow taper. So that's really where that comes from now.

Okay, great. Thanks, and then a commercial question on tip. So I'm just curious.

If you could share watch market share.

Now is in either frontline and also left a factory am now since it seems like you've seen growth and both stops Qs what market shares at the moment and then also wondering if you've already been seeing a use and cholangio based on the recent NCCN listing.

Sure sort of Darren here.

So.

You know given given the the.

Oh population than our and our.

Chris: The aspect of one of the things I think that comes up is people are worried about compliance because of statements and data that indicate that noncompliance may be more of an issue in sickle cell versus other diseases. However, we don't think that missing a dose here and there is likely to be a problem based on what we know about the pharmacokinetics and the biology of the molecule. But I think that the guidance that in the ideal situation you want to avoid abruptly stopping the drug and have a taper is likely to be present. I would also say that's true for a lot of drugs, whether they're in the hematologic space or other areas where chronic dosing isn't an issue.

Our distribution or visibility into into.

Utilization.

I don't know exact penetration numbers by line of therapy, what I have.

Our.

The reflections of physicians through market to market Research center use by setting. So I can't give you exact kind of penetration number but what I do see is the change in utilization as stated by physicians overtime and so that's when I make statements about increased adoption.

Increased adoption in different settings, that's what I'm relying relying on and what we've seen is is continued adoption and continued improvement.

Or increased adoption to say in the frontline setting and ER and the by spiking, though in the relapse relapse setting as well and Ah we've seen actually in the last quarter increased use of the product and in combination with a with each may as well.

Chris: And maybe just as it relates to the competitive landscape here, this has, in one way, at least one of the mechanisms of midipeditis, a little bit similar to the mechanism of Oxyprida shifting that oxygen affinity curve, partial pressure curve. Can you maybe talk a little bit about the theoretical combinability of these agents, whether that's realistic or something that wouldn't make sense? Thanks so much, and congrats on the progress during the term.

And then in terms of a utilization in Cholangio, yes, we've we've heard.

We've had antidotes utilization in a in ER and the cholangio setting as well and given the recent basis again guidelines wouldn't be surprising if we.

Contingency adoption there as well.

Okay, great. Thanks for taking my question.

Chris: Yeah, well, I think the combinability is something that we're interested in, not just in sickle cell, but in thalassemia as well as new products come on in. And I think there's complementarity of mechanisms of action.

Okay.

Thank you. Our next question comes from Mark Breidenbach with Oppenheimer. Your line is now.

Hey, good morning, and thanks for taking my question Congrats on the core progress or maybe just another minute put the question following up on on one of tendons questions.

Chris: So if you use a thalassemia example first, if you have something that enhances terminal erythroid differentiation, like VAT or CEPT, is there at least a theoretical interest in having more cells get to that late stage so that they can be affected by that drugless VAT or CEPT? Then that's certainly of interest. There have been recent publications in the sickle cell literature where people are seeing the number of new drugs coming in as offering some real potential for complementarity. Specifically for mitopibat and Oxprida, it's an interesting thought if you can get somebody up a gram with Oxprida, a gram and a half, will they benefit from another gram and a half by adding PKR wild type activation with mitopibat?

It sounded like you're not really worried about central for a rebound effect in sickle cell patients who missed dosing for a day or two.

I guess I'm, just wondering what's giving you confidence around that statement and I'm also wondering why drug cheaper it doesn't appear to be necessary for patients on a write off any speculation as to why they can get away with how the T for would be very helpful. Thanks, So much.

The reason, it's Chris here. The reason why we don't think missing a dose or choose here or there is based on what we see what we know about drug finding that enzyme and sticking what we know about when you look.

Chris: And on the one hand, that's appealing, and on the other hand, you've probably heard from sickle cell docs that they're a little more careful about how they adjust hemoglobin in these patients. So yeah, it's definitely of interest, not just for Oxprida but potentially for other drugs that come along, whether it's Novartis' P-selectin inhibitor, and others. But I think that, just based on our data, and now in sickle cell, the early data we talked about at EHA, and what we see in thalassemia in our long-term experience with mitopibat and pyruvate kinase deficiency, I'm very excited about just looking at this drug as a single agent because I think if we have the opportunity to do both, address both major components of the So yes to combinations, but I think we have a very strong, It's very strong ground to think that we have a single agent benefit that we'll be able to provide the patient.

Right.

Effects from our healthy Volunteer study for example, we looked at two three GPG and ATP levels. After patients had stopped dosing they actually stayed elevated for several days.

I think that.

Some of the data that gives us.

Gives us confidence that we don't think that's going to be an issue that is you mehsud dosing suddenly you have a are you getting into some sort of withdrawal problem.

And then the second part of your.

Yeah, I'm afraid of why did they not have to taper.

Bruce May want to comment on that but one of the thing that isn't that is interesting is that when you look at or some of their phase one and two data you will see that there'd be a sees that occurred.

Patients for cutting off drug.

They just haven't attributed to drug and investigators think it's a drug related so.

That's about all I can say about that and I think that the the main thing for us in terms of differentiating versus that <unk> versus nursery section writer is going to be a percentage of patients that have a response to mid to that versus like strider and if both drugs are available in the marketplace.

Bruce Carr: And just carrying on from that, Chris, the patient-reported outcomes being favorable, very favorable anecdotally, for our treatments with Mitopibat across the indication. That isn't the case with Oxprida, notwithstanding its approval for increasing hemoglobin. And important is that the covalent binding of Oxprida to hemoglobin prevents sickling, so that's a very important thing, but it also lowers the ability of hemoglobin to carry oxygen, and that's very important. We're able to preserve hemoglobin in healthier red cells such that they carry more oxygen and that there's a higher affinity of the binding for oxygen, so we believe we have a superior mechanism there to that of Oxprida.

The overall activity versus me out to see whether we can demonstrate that or not and whether with longer follow up they will be able to.

And then there are other aspects of how the patients feel better take taking these drugs and ER I think from as I've commented earlier on if we can.

Increasing woven and address the sees what they tell that you're taking twice a day.

Back we think that has a pretty good compelling reason to use.

And just disagreeing with you that Chris the very long Pharmacodynamic effect of indicate that you know me is the reason why Oh individual needs does is a in the VIP schedule I'm not going to not a mechanism of action on between ops brought out.

And we Havent bought difference and a I mentioned previously because then bonding onto the failing the end of the physical hemoglobin the talks Freida independent and finding that's what that's why I mean, I put island bonding and it will persist clothing, hi lot and at the hemoglobin whats you are longer than 30.

Operator: Thank you. Our next question comes from Chris Shibutani with Callan. Your line is now open. Good morning, thank you. Three questions focused on mid-pivot. Three of them. For mid-pivot, you have previously updated on the peak registry and patient identification. Any updates there? You've also described narrowing the timeline.

Operator: , , , , , , , , , , , , , ,

Right in that case to hemoglobin has bounced walks fry, that's that's possibly a rate.

Thanks, so much.

Thank you. Our next question comes from George Farmer with BMO. Your line is now.

Hi, Thanks for taking her questions. This is going on for George.

Chris: Any color in terms of an update on how that progress is going? I know you gave us the first half of the span.

On the same theme has a prior colleagues that we're asking with de Dios see patient.

Chris: Secondly, for sickle cell disease, you have this collaboration with the NIH. Can you just remind us what options you have and any plans that might be in place to do clinical work?

If I remember correctly I think the the type situation the taper protocol with 12 days.

So perhaps you might be willing to comment on was that view at the pace and during the latter half perhaps of the 12 days enough I mean, maybe where you're getting your confidence that.

Chris: [inaudible]

Missing a single dose and that's probably really not going to matter and then if I remember quick I think you guys mentioned two patient.

Then he goes on the 100 milligram protocol right before the covenants and shutdown happen.

Chris: independent of the NIH.

Chris: For Are You Tethered to Them?

Wondering if you guys have seen any of.

Well the relevant responses, if I'm understanding that correctly and those season.

Because it seems like there's a really strong does the fund relationship and wouldn't be surprised or increases or.

Better there thank you.

On the the patient who experienced civeo see did indeed have it could the closer to the end of the take rate and at the beginning.

And I think the qualitatively that's.

In line with what you just heard Bruce and I talked about with regards to the ability to tolerate tolerate and not have untoward effects from missing a dose or to ER or several doses of mid of two bad.

What we talked about it.

Was that we gave.

The data that seven of the patients.

Treated in that trial had an increase in hemoglobin and that five abate.

Greece over a grand and that was across all the cohorts. So we didn't provide individual data because we want to we went to save that for the ash presentation.

To give that presentation.

The most power that it can do to forget a good slide it meeting.

So your question is a great more does going from 50 milligrams to 100 milligrams. A 200 milligrams is what is the is there and what is the extent of that.

Dose response relationship and with regard to see whether its hemoglobin here impact on oxygen Association cars, that's something we'll look at it it would be too early I, just like I said I can't comment on the hundreds versus the patient something like 50, but in and it's it's it's a small patient number.

And I want to see additional patients and adds as we.

Think about the the doug's question and cyclical.

Thank you I will remind you that Dallas seem yeah. We are in that protocol. We went from 50 to 100 and we saw some some slight.

Suggestions that we may be seem a little more buck.

50 to 100.

Whether that same thing will occur or something different in sickle cell is it remains to be see the thing we know about mid to that that I think just relate.

It gets back to that that where you always hear me talking about safety or the drop is and we understand.

On the safety profile across many years now from dosing in extension and the drive PK study. We also know that there's a range of doses that are pretty well tolerated suitable for development and I think that you know the nuances of the.

PK are in the context of the individual diseases, such as a possibility there maybe a range of doses that clinicians will want to.

Chris: And, congratulations, this helped us understand, since I think a lot of the sharing of data is dependent on...

No boundless they balance optimizing efficacy with safety. So it's a we I have an awful lot him comfort having worked with this drug melco several years.

Safety profile. So it's a very interesting question.

And.

We just need more data, but we know there's range, where we can and does this drug and it's pretty well tolerated.

[music].

Thank you.

Thank you.

I'm not showing any further questions at this time.

Now I'd like to turn the call back over to Jackie felt for any closing remarks.

Thank you operator, thank you all for joining us on our call. This morning, I would like to reiterate that despite the challenges and uncertainties that lay ahead of us all I remain incredibly excited about the progress we've made and now just across our focus areas. So far this year to close.

I would like to thank the tremendous employees that are just for their dedication and passion for making a difference for patients, particularly during this.

Uncertain time in the World I also want to thank all the patients caregivers and physicians, who participate in our clinical trials without them, we cannot do but we do thanks again for joining US today, we look forward to seeing you and hearing you soon take care.

Jackie Faust: Thank you all for joining us today.

Ladies and gentlemen. This concludes today's conference call. Thank you for participating you may now disconnect [noise].

Jackie Faust: Thanks.

Chris: Okay, hey Chris, it's Chris Stauffer here. PEEC is up and running in multiple countries across the world. It's enrolling well. One of our ambitions is to take the natural history study and be able to pool those data with PEEC. It's something we're working on. That database is from Boston Children's Hospital, so merging that into or combining that and pulling it and doing analyses is something that we're interested in doing and hope to talk more about in the future. And we think that's going to be an important and ongoing important data set for us to describe the burden of disease outcomes, and the variations in treatment approaches, and we're looking forward to starting to be able to publish that and hopefully be able to guide people to that.

[music].

Chris: With regard to the challenges and the ups and downs of clinical development in the time of a global pandemic, As I commented in my remarks, I can't talk about specific places, specific sites, but if you just step back for a minute and you look at how the pandemic has spread across the United States as it moves from the East Coast and the West Coast down to the South and up and around, there's a fair amount of un And depending on how locked down a hospital is and how they're managing clinical trials and their clinical research staff and the fact that when they stop and then start, there's a queue, those are the types of factors that we're looking at in trying to understand. Yeah, how are we going to get in there and pull our data out? And that's why we can't provide any more guidance at this point. But what I can tell you is that we've done a good job in terms of making sure patients stay on drugs and capturing data by any of the means that I talked about in my prepared remarks.

Chris: You know

Chris: We'll just have to see how things develop before we can provide more definitive guidance, which is why we didn't update it on this. And then, with regard to the NIH and issues around how we choose to do development, we don't have any restrictions. I mean, that's a CRADA agreement we have with them for a trial. We freely share the data. We're in fact, performing a number of these.

Chris: performing a number

Chris: with Grisha's group. So, you know, we have freedom to operate, and we're moving forward expeditiously to get a sickle cell trial up and running in 2021. And that's not dependent in any way on approval from the NIH, for that matter. And we have a very good relationship with them in being able to discuss and describe that data and present it to health authorities as needed.

Chris: It's Jackie. I just want to jump in for a second. And I think something Chris said is really important to just reiterate on the activate and activate T trials. You have two issues that you probably want to think about.

Jackie Faust: One is data integrity, and that is where Chris spoke about how good a job our team has done to make sure that patients stay on the drug and that the trial, you know, they finish their trial experience smoothly and in line with the protocol. And then the second is time.

Jackie Faust: And the second is the timing of being able to release that or have it in hand, analyze, and then release that top-line data. So I think data integrity is extremely important. If we were fast at getting the data out, but there was a compromise in the data, that would be more serious than ensuring data integrity first and then the timing of when we get that top-line data out.

Jackie Faust: And we're, as Chris said, we feel good about what the team has done to support data integrity, and we haven't narrowed the timing window just yet because we've got a little ways to go to get into the sites and see that. And then also, Chris, part of your first question included patient finding efforts, and right now, between our clinical programs and our patient finding efforts, we're at about 2,000 patients identified. Thanks. Thank you. Our next question comes from Mohit Bansal with Citigroup. Your line is now open. Hey, good morning, guys. This is James Ahn from OHIT.

Operator: I had a question on AG270. Another company recently announced a collaboration to explore MAC2A with PRMT1, and they published some preclinical data showing greater potency and solubility compared to AG270. Have you seen this data, and what are your thoughts on their MAC2A program and the possibility for a combo with PRMT1? This is the first half. I believe you're referring to the idem, so let's get in terms of this. The ability of these pathways to lower acidentism or sinus, in combination with PRM, is an entirely appropriate one, and we believe PRMT-5 could also be a potential player in this field.

Operator: Yeah. Thank you. Thank you. Our next question comes from Michael Schmidt with Guggenheim. Your line is now open.

Operator: Hey guys, thanks for taking my questions. I had two more on sickle cell and one on Typsovo, maybe a little bit of a follow-up to a prior question on the phase one NIH data.

Operator: I was just wondering if there was any additional information...

Operator: [inaudible]

Chris: Patients in general. I'm just wondering, Chris, if there's been any new information on that specific event that you might be able to share.

Chris: Uh, nothing new. The VOC occurred.

Chris: during the taper. We didn't see any events while patients were on active treatment. You're absolutely right that that's an unfortunate component of the disease and one we're trying to address, which is a VSC. We didn't see any additional ones during the paper over the course of those eight patients that were able to complete either six or eight weeks of dosing.

Chris: No, so no new information, and it's something we'll continue to track. And I think, you know, given our overall sense of that data that we've talked about at ASH, is that we've clearly achieved proof of concept, and we're excited to move forward. Great. Thanks. And then I think you mentioned meeting with the FDA and discussing plans for regulatory trials or approval.

Chris: Pivotal Trials

Chris: And, you know, given some of the... possible, you know, differentiation

Chris: was talked about earlier. I'm just wondering how you feel...

Chris: How do you think about taking advantage of that in your trial design? For example, what are your thoughts about pursuing an accelerated approval pathway similar to GBT using HB increase or potentially incorporating clinical outcomes such as VOC reductions? I guess, how do you think about those considerations? Yeah, that's the major focus for our team now in terms of putting together a Clinical Development Plan that can lead to approval, accelerated or regular, in the United States but in other geographies outside the U.S., and the interesting part of Medipivac is that we have the potential to, we clearly have the potential to address hemoglobin. We demonstrated that

Chris: early on, and we know now that activating wild-type PKR is an important strategy and chronic hemoglobinopathies overall, if you will, mainly thalassemia and sickle cell, we've demonstrated so far. We think that we have the opportunity to reduce VOCs. So then, I'm not saying anything new here.

Chris: The interesting part is how you combine those, as well as potentially patient-reported outcomes, into a package that can get you there as rapidly as you can but also has the greatest impact for patients. So we're working hard on that, and we're looking forward to having those discussions with both agencies as rapidly as possible. The other thing that we want to do is get input from patients and patient advocates because I think that that's gonna have an important impact on the type of data that will impact patients and really compel them to use the drug. So there are a lot of factors in play. I know that accelerated approval based on an increase in hemoglobin has been demonstrated with Oxprida, and that's something that we're looking very hard at, but we think there's a lot more for us to be thinking about on the basis of the mechanism of action and the unmet need overall. Okay, great. Thanks. And then a commercial question on Tibsobol. I'm just curious. If you could share what the market share is now in either,

Operator: https://www.patreon.com

Operator: And this is a question for you, since it seems like you've seen growth in both. I'm just curious about market share at the moment, and then also wondering if you've already been seeing growth.

Darren: We've already been seeing use in Colangeo based on the recent NCCN listing. Sure. So, Darren here.

Darren: So, you know, given the population in our country, I don't know exact penetration numbers by line of therapy. What I have are the reflections of physicians through market research and their use by setting. So I can't give you exact penetration numbers, but what I do see is the change in utilization as stated by physicians over time. And so when I make statements about increased adoption, increased adoption in different settings, that's what I'm relying on. And what we've seen is continued improvement or increased adoption, as I say, in the front line setting and a nice spike in the relapse setting as well. And we've seen, actually, increased use of the product in combination with HMA as well. And then in terms of utilization in Colangio, yes, we've had anecdotes of utilization in the Colangio setting as well, and given the recent NCCN guidelines, it wouldn't be surprising if we continue to see adoption there. Okay, great. Thanks for reading this.

Darren: Great. Thanks for taking my questions.

Operator: Thank you. Our next question comes from Mark Breidenbach with Oppenheimer. Your line is now open.

Operator: Hey, good morning, and thanks for taking my question. Congratulations on the forward progress. Maybe just another mid-to-pivot question following up on one of Kenan's questions.

Chris: It sounded like you're not really worried about the potential for a rebound effect in sickle cell patients who missed dosing for a day or two. I guess I'm less than wondering what's giving you confidence about that statement, and I'm also wondering why a drug taper doesn't appear to be necessary for patients on Oxprida. Any speculation as to why they can get away without a taper would be very helpful.

Chris: The reason why we don't think missing a dose or two here or there is based on what we know about drug binding to enzymes and sticking. What we know when you look at effects from our healthy volunteer study, for example, where we looked at T3-DPG and ATP levels after patients had stopped dosing; they actually stayed elevated for several days. So I think that's some of the data that gives us, um, gives us confidence that we don't think that's going to be an issue as you miss a dose and suddenly you have a uh, you get into some sort of withdrawal problem on. And then the second part of your...oh, yeah, x-ray. Why do they not have to taper off?

Chris: ..

Chris: Well, Bruce may want to comment on that, but one of the things that is interesting is that when you look at some of their Phase I and II data, you will see that there are VOCs that occurred as patients were coming off drugs. They just haven't attributed it to drugs, and investigators think it's not drug-related. So that's about all I can say about that, and I think that the main thing for us in terms of differentiating versus Oxpirater is going to be, A, the percentage of patients that have a response to midipivav versus Oxpirater.

Chris: So, if both drugs are available in the marketplace, the overall activity versus VOCs, whether we can demonstrate that or not, and whether with longer follow-up, they will be able to. And then there are other aspects of how patients feel better taking these drugs. And I think, as I've commented earlier, if we can increase hemoglobin and address VOCs with a pill that you take twice a day, we think that has a pretty good compelling reason to use.

Christopher J. M. Taylor: And just agreeing with you there, Chris, the very long pharmacodynamic effect of mid-PIVAD is the reason why individual missed doses in the BID schedule are not going to matter. The mechanisms of action between Oxbrida and mid-PIVAD are quite different, and I mentioned previously that covalent binding to the valine at the end of sickle hemoglobin with Oxbrida is a permanent binding, that's what's meant by covalent binding, and it will persist for the entire lifespan of the hemoglobin, which is longer than 30 days in the case of hemoglobin S bound for Oxbrida.

Christopher J. M. Taylor: That's possibly a reason. Thank you. Our next question comes from George Farmer with BMO. Your line is now open. Hi, thanks for taking our questions. This is Gobind for George.

Operator: Just on the same theme as a prior colleague that we're asking, with the VOC patients, If I remember correctly, I think the titration, the taper protocol was 12 days, so perhaps you might be willing to comment on whether that VOC patient was during the latter half, perhaps, of the 12 days? And that's maybe where you're getting your confidence that, you know, missing a single dose or not is probably really not going to matter. And then, if I remember correctly, I think you guys mentioned two patients had been dosed on the 100 milligram protocol right before the COVID-19 shutdown happened. I was wondering if you guys have seen any of the hemoglobin responses, if I'm understanding that correctly, in those patients, because it seems like there's a really strong dose-to-response relationship, and it wouldn't be.

Chris: be surprised by the increases.

Chris: The patient who experienced the VOC did indeed have it closer to the end of the taper than at the beginning, and I think that qualitatively, that was in line with what you just heard Bruce and I talk about with regard to the ability to tolerate and not have untoward effects from missing a dose or two or several doses of midopivav. What we talked about at eHab was...

Chris: I gave data that seven of the eight patients Treated in that trial had an increase in hemoglobin and that 5 of 8 had an increase over a gram, and that was across all the cohorts, so we didn't provide individual data because we want to save that for the ASH presentation to give that presentation the most power that it can have to get a good flood. So, your question's a great one.

Chris: Does going from 50 milligrams to 100 milligrams or 200 milligrams, what is there, and what is the extent of that dose-response relationship with regard to whether it's hemoglobin or impact on oxygen dissociation curves? That's something we'll look at. It would be too early to say.

Chris: Like I said, I can't comment on the hundreds versus the patients who only went to 50. And it's a small patient number where we're gonna wanna see additional patients as we think about the dose question in sequence. I will remind you that in thalassemia, in that protocol, we went from 50 to 100. And we saw some slight... um, you know suggestions that we may be seeing a little more bump when you go from 50 to 100. Whether that same thing will occur or something different in sickle cell remains to be seen. The thing we know about Mitopivat that I think is really important, it gets back to why you always hear me talking about the safety of the drug is that we understand the safety profile for many years now from dosing and extension in the DRY-PK study, but we also know that there's a range of doses that are pretty well tolerated and are suitable for development. And I think that, you know, the nuances of PKR in the context of individual diseases are such a possibility that there may be a range of doses that clinicians will want to be thinking about if they balance optimizing efficacy with safety. So it's I have a lot of comfort having worked with this drug now. [inaudible]

Operator: Thank you. I'm not asking any further questions at this time.

Jackie Faust: I would now like to turn the call back over to Jackie Faust for any closing remarks. Thank you, operator. Thank you all for joining us on our call this morning. I would like to reiterate that, despite the challenges and uncertainties that lay ahead of us all, I remain incredibly excited about the progress we've made at Agios across our focus areas so far this year. To close, I would like to thank the tremendous employees at Agios for their dedication and passion for making a difference for our patients, particularly during this uncertain time in the world. 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.

Operator: Thanks again for joining us today. We look forward to seeing and hearing you soon. Take care. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect. BF-WATCH TV 2021