Agios Pharmaceuticals, Inc.

Good morning and welcome to AGO's third quarter 2020 conference call. At this time all participants are in a listen only mode. There will be a question and answer session at the end. Please be advised that this call is being recorded at AGO's request. I would now like to turn the call over to Holly Manning, Director of Investor Relations.

Thank you, Operator. Good morning everyone and welcome to AGO's third quarter 2020 conference call. You can access slides for today's call by going to the Investors section of our website, audios.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 Jonathan Biller, our Chief Financial Officer and Head of Legal and Corporate Affairs. Dr. Bruce Carr, our Chief Scientific Officer, will join for Q&A. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in the risk factor section of our most recent Form 10-Q filed with the FCC and any other filings that we may make with the FCC. With that, I will turn the call over to Jackie.

Thanks, Holly. Good morning, everyone, and thanks for joining our third quarter 2020 results call. Our activities this quarter were focused on execution against our key priorities for 2020, significant planning and preparation for a catalyst-rich fourth quarter in 2021, and a clear commitment to doing what's right for patients and our people as we continue to navigate the ongoing impact of the COVID-19 pandemic. We made important strides toward getting our medicines to patients who need them. This includes generating mature overall survival data from the CLARITY study, which enables our first solid tumor regulatory filing, and initiating our healthy volunteer study of AG946, our next generation PKR activator. Behind the scenes, we've been hard at work preparing for important milestones coming later this year and throughout 2021, including offline data readouts for our ACTIVATE and ACTIVATE-T studies, the supplemental NDA submission for tibsovo and cholangiocarcinoma, and the initiation of our global pivotal studies of midipivate in thalassemia and sickle cell disease. To help lead us toward these key value inflection points, We appointed Jonathan Biller to the role of Chief Financial Officer, Head of Legal and Corporate Affairs in September. Jonathan is a longtime colleague of mine whose expertise has been a welcome addition to our leadership team since he joined in November of last year. You'll hear from him later in the call as we discuss our quarterly financials. We also dealt with some challenges. including the need to withdraw our marketing authorization application for TIPSOVO in the relapsed refractory AML setting in the EU. Our ongoing phase three combination studies of TIPSOVO in the frontline AML setting remain on track for those much larger patient populations. The decision to withdraw our MAA will not result in any near-term changes to our approach in the region. Our lean EU team is largely focused on supporting AGO's clinical trial and medical affairs activities and PKD market development efforts, including patient advocacy, disease education, and patient identification. Investment in the EU will continue to be gated and aligned with the timing of future product approvals in the region. Looking ahead to the remainder of the year, we have a number of key events for our MediPIVAT program that further elucidate the potential value of the PKR activation mechanism to treat serious hemolytic anemias. First, on November 19th, we will hold an investor webinar focused on our PKR franchise, which will include a deep dive into the mechanism of action, the unmet patient needs in thalassemia, sickle cell disease, and PK deficiency, our view of these market opportunities, and the commercial preparations underway for our first potential rare disease launch. In conjunction with ASH, we will host an investor event on December 8th to share the updated data from the NIH phase one study of menopivac and sickle cell disease, as well as an overview of our phase three plans and thalassemia. And finally, we now expect top line data from the ACTIVATE study of menopivac and non-transfusion dependent PK deficiency by the end of the year, thanks to the tremendous efforts of our team. We have a busy few months ahead of us, And I want to thank each and every Agios employee for continuing to advance our programs for patients while balancing the pandemic's continued impact on their personal and professional lives. Chris, let me now turn it over to you.

Thanks, Jackie. I'll start with Midipivet, our first-in-class PKR activator currently being evaluated across three distinct hemolytic anemias. As Jackie highlighted, we anticipate several important milestones in the coming weeks that will advance all three of our mid-PIVAP programs. I'll start with our most advanced program in pyruvate kinase deficiency, where we are running two phase three clinical trials and have the potential to provide the first disease-modifying therapy for this disease. Earlier this year, we got into top-line data for the ACTIVATE and ACTIVATE-T studies sometime between the end of this year and mid-2021, anticipating some delays as a result of the pandemic. Thanks in large part to the extraordinary commitment of our team at AGIOS, we're now able to narrow those timelines. For ACTIVATE, the randomized placebo-controlled Phase III study in 80 adults with pyruvate kinase deficiency who are not regularly transfused, we anticipate top-line data by the end of 2020. For ACTIVATE-T, the phase three single arm open label study in 27 adults with PK deficiency who are regularly transfused, we anticipate top line data in the first quarter of 2021, given the longer follow-up time in this study. If positive, we expect to file for regulatory approval for a broad label in adults with PK deficiency in both U.S. and E.U. next year with a potential 2022 commercial launch in both geographies. Moving to the Phase II study of mid-epivatin thalassemia, we completed enrollment earlier this year with 20 patients, and in June, we presented updated data on 13 efficacy-evaluable patients at the virtual EHA meeting. The data showed that treatment with midipivac induced a hemoglobin increase of greater than or equal to one gram per deciliter in 12 of 13 evaluable patients during weeks four through 12, including four out of four alpha thalassemia patients where there have been no new treatment options in decades. In addition, seven of eight beta thalassemia patients achieved a sustained hemoglobin response during weeks 12 through 24. We expect to submit the full data set from this study for presentation at a medical meeting in 2021. This quarter, we've been working through US and EU regulatory feedback to our pivotal program. At our ASH event in December, we expect to share details of our robust pivotal development plan that spans both alpha and beta thalassemia, as well as transfusion-dependent and non-transfusion-dependent patient populations. We anticipate initiating our pivotal program in 2021. Now let's turn to sickle cell disease, where we're collaborating with Dr. Sui-Lei Chen of the National Institutes of Health on a proof of concept study with Mitipiva. In June, we announced the clinical proof of concept was established based on a preliminary analysis of data from eight patients. The data showed that over a six to eight week dosing period, Seven of eight patients experienced a hemoglobin increase, with five of eight patients achieving a hemoglobin increase of greater than or equal to one gram per deciliter from baseline. Enrollment in the study was temporarily paused in the spring due to the COVID-19 pandemic, and it has reopened as of mid-August. As of today, the study has enrolled 13 patients. At ASH, Dr. Chen will give an oral presentation with updated data from at least 11 patients, the eight patients from the preliminary analysis, and approximately three additional patients expected to complete the study in time to be included in the presentation. A total of five patients, two from the top line preliminary, and all three newly enrolled patients received the 100 milligram BID dose and will be included in the ASH presentation. Data from the fully enrolled trial will be submitted for presentation at a medical meeting next year. Moving forward, the NIH recently approved a new protocol allowing all patients in the Phase I study to continue to receive midipivac in an extension phase for up to two years. The extension will provide valuable long-term safety and efficacy data in sickle cell disease, where patients have the potential to be on therapy for many years, perhaps for life. In parallel with these clinical activities, we're working rapidly to obtain U.S. and EU regulatory feedback to advance our sickle cell disease pivotal development plan. We expect to share an overview of the pivotal program design in the first half of 2021 and initiate the study within the year. I'll now move to our Milligan hematology programs. Last month, we shared our decision to withdraw our marketing authorization application for TIB-SOBO and relapsed refractory AML as a result of the feedback received at the oral explanation in September. Despite our learnings from the IDFA experience and the additional in-depth work from our team, we were unable to fully address the major objections raised by the CHMP to support a positive benefit risk assessment in the proposed indication based on a single-arm, non-comparative Phase I-II study. While we are disappointed that patients in the EU will not have access to TIBSOVO in the near term, we continue to enroll the Agile and Hovon phase three combination trials in IC-eligible and IC-ineligible frontline AML. If the trials are positive, we anticipate pursuing approvals in the US and EU. The vast majority of newly diagnosed AML patients are eligible to receive intensive or non-intensive therapy. So these studies provide the opportunity to reach the largest number of patients. Switching gears to our solid tumor programs, last year we reported positive, highly statistically significant progression-free survival data from the CLARITY Phase III study of TIBSOVO and previously treated IDH1 mutant cholangiocarcinoma. And last month we shared a top-line look at mature overall survival, a secondary endpoint in the study. Treatment with TIBSOVO was associated with a non-statistically significant improvement in overall survival compared to placebo. Given that 70% of patients crossed over from the placebo arm to the ibocidinib arm, we consider this positive trend in overall survival to be important supportive data for approval. We will be sharing these data with FDA. and are planning to submit a supplemental new drug application for TIBSOVO and previously treated IDH1 mutant cholangiocarcinoma in the first quarter of 2021. Additionally, we have submitted the CLARITY final overall survival data set for potential presentation at ASCO GI in January. The impressive and statistically robust PFS results supported the inclusion of TIBSOVO in the NCCN treatment guidelines at a level recommendation on par with approved therapies for other biomarker-select populations. This level of endorsement from the expert physicians is an encouraging recognition of the clinical benefit of TIB-SOVO. In addition to cholangiocarcinoma, we are exploring the utility of IDH inhibition in low-grade glioma in our Phase III indigo trial of voracidinib. Boracidinib is our brain-penetrant dual IDH1-2 inhibitor that has the potential to treat the roughly 80% of low-grade glioma patients with an IDH mutation. Site startup activities are ahead of expectations despite the pandemic, reflecting physician enthusiasm for the potential of boracidinib in this trial. And finally, the AG270 Phase I dose escalation combination arms with taxanes continue to enroll patients. With that, I'll turn it over to Darren to discuss our third quarter commercial performance.

Thanks, Chris.

The momentum we observed in the first half of 2020 continued through the third quarter, resulting in $32 million of net sales of Tipsovo, a 15% increase over Q2. Performance in the quarter was driven by a significant increase in new scripts and refills and continued improvement in duration to approximately five months. Though we continue to see growth in both the academic and community settings, Increased use in the community setting was particularly strong and may reflect a trend in the increased co-management of patients between academic and community physicians, likely accelerated by the COVID-19 pandemic. We continue to see steady increases in physician preference share for TIPSOVO in the frontline intensive chemo ineligible and first relapse settings. All leading indicators of physician perceptions of TIPSOVO are encouraging including a significant improvement in those physicians who believe TIPSOVO is standard of care for newly diagnosed intensive chemo ineligible patients. While our promotional efforts are limited to the on-label AML opportunity, we observed an increase in commercial volume attributed to cholangiocarcinoma following the addition of TIPSOVO to the NCCN guidelines in June. Though visibility into indication-specific uses is limited to the specialty pharmacy channel, which represents about a third of TIPSOVO commercial volumes, The increased utilization in cholangiocarcinoma following the update and practice guidelines made this noteworthy. While we've seen some easing in certain geographies, face-to-face customer interaction, particularly with academic customers, remains largely restricted, and we anticipate that restrictions will tighten again as we head into the late fall and winter months. Nevertheless, our team has been effective at using virtual communication and educational tools to continue live customer engagement. As a result, we were able to increase the number of new customers by 17%. The outlook for the fourth quarter is strong, but not without some potential headwinds. Leading indicators and performance in the early weeks of Q4 indicate similar trends to Q3. However, we also anticipate disruption in the number of AML patients diagnosed and potentially treated as COVID-19 infections and hospitalizations are expected to increase through the end of the year. In addition, we may see increased volume moving through Medicaid and 340B channels as a result of the pandemic, which can apply increased pressure on gross to net. Considering our year-to-date performance and our outlook for the remainder of the year, we're narrowing our guidance for 2020 net U.S. tipsovo sales from between $105 to $115 million to $113 to $115 million. I want to thank the AGIOS team for not only adapting but thriving in the face of these uncertain times. fueled by a passion to ensure no patient is denied the opportunity to benefit from our treatments. I'll now turn it over to Jonathan to discuss our third quarter financials.

Thanks, Darren. Our third quarter results can be found in the press release we issued this morning, which I will summarize. More detail will be included in our 10-Q filing later today. Total revenue for the second quarter was $35 million, which consisted of $32 million of net sales up to Sovo, $2 million of collaboration revenue, and $700,000 in royalty revenue. Compared to the third quarter of 2019, total revenue grew 33%, driven by an 82% increase in TIPSOVO sales, offset by a decrease in collaboration revenue due to completion of the research and development service obligation with Celgene and Q2. In addition, royalty revenue was impacted by an adjustment in sales reserves taken this quarter by BMS relating to prior periods. TIPSOVO revenue grew by $4 million compared to Q2 2020, driven by increased demand. Gross to net for the quarter was within the expected range. We continue to monitor Medicaid and PHS utilization. Cost of sales for the quarter was $637,000. Turning to operating expenses, R&D for the third quarter was $90 million, a decrease of $12 million compared to the third quarter of 2019. This year-over-year reduction in R&D was largely driven by a decrease in Tepsovo clinical development costs, including winding down the Clarity Phase 3 study. Selling, general, and administrative expenses were $35 million for the quarter, representing a $2 million increase over third quarter 2019, driven primarily by increased workforce expenses, offset by a decrease in external spending due to COVID-19 and cost savings initiatives. We ended the quarter with cash, cash equivalents, and marketable securities of $722 million. We expect that our Q3 ending cash balance, in addition to expected product revenue but excluding anticipated program-specific milestone payments, will fund our current operating plan to the end of 2022. With that, operator, please open the line for questions.

Thank you. As a reminder, to ask a question, you'll need to press star 1 on your telephone. To withdraw your question, please press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Anupam Rama from J.P. Morgan. Your line is open.

Hey, guys. Thanks for taking the question. Just a quick one on AG946. How should we be thinking about sort of timelines to the healthy volunteer data? I know just the trials have started, but importantly, starting that SED cohort that you have for the 946, and thinking about that in terms of also timing of the mid-PIVAT phase three that you've outlined last year. Thanks so much.

Hey, Anupam, it's Chris here, Chris Bowden. So the 946 study is ongoing in healthy volunteers, and there's, as per what we did with mid-PIVAT and healthy volunteers, is a single-dose cohort, so then we move into the multi-ascending-dose cohorts, and then following that, we have plans to open a sickle cell cohort. So it's too early for us to provide guidance as to when we think we might moving there to that stage, as well as when we think we might be able to publish data. Certainly as per previous, once we feel like we have a critical mass of safety and PK and PD data, then we would try to get that out there and perhaps around that time be able to inform when the sickle cell cohort might be opening. Now with regards to our phase three start with move to that sickle cell, that's next year. And so we're all, as in my remarks, we're in full gear there, developing protocol, interacting with the health authorities. and we'll be able to update further on that next year as well.

Great. Thanks for taking our question.

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

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

Yeah, thanks. So I think the important thing with this is that those values that you're looking at are changed from baseline. And, you know, what we call the design of the study is patients keep escalating. they start at five and then they can go up to 50, or once we put the amendment in, they could go up to 100. That includes all those eight patients, whether they responded or not. So I think that trying to dissect the differences in 50 from 100 from the table is a little bit challenging. From our perspective, remember what we talked about in the high-level top line Remarks we made at EHA where five of eight patients had a one gram or higher increase in hemoglobin. Those were all at 50. So we definitely have an active dose of 50 milligrams. We know from some of our healthy volunteer work and a number of things that we'll probably see more activation quantitatively when we go from 50 to 100 It varies from patient to patient, and I think one of the most important things about this is that there's the possibility for people to have a range of doses. So whether it's 50 or 100, or 50 and 100 is something that we're still thinking about. Another way to look at it is that if you were to get, let's say, a gram and a half increase at 50, and another 0.7 or half a gram increase when you went up to 100. Given some of the data that's emerging around hemoglobin and outcomes, that could definitely be a clinical benefit and a physician and patient interest if the safety profile looks comparable, which it does across 50 to 100. So the data that we've been generating from this trial and from some of our other studies really gives us a lot of confidence around the our dose selection and the way we design our trial. And we'll be able to provide more details around that in the first half of 2021.

Okay. Maybe just one follow-up. So you've mentioned 11 patients that will be reported on at ASH and eight at the 100-meg BID dose, and three are new and five are from the existing patients that are dose escalated. Are they all being dose escalated up to 100 milligrams BID in the same timeframe or in the same course? And if not, does that matter in terms of hemoglobin response?

I think, if I understand your question, is that you're on dose for two weeks. five milligrams for two weeks, 20 milligrams for two weeks, 50 milligrams for two weeks, and now 100 milligrams for two weeks. So there's no break in between. The patients are enrolled sequentially, so it's not like the whole cohort comes in and they're all enrolled at the same time. But the dosing frequency is similar for all patients.

Okay, that's helpful clarification. Thank you. Yeah.

Thank you. Our next question comes from Mark Fromm with Cowan & Co. Your line is open.

Thanks for taking my question. Chris, just to follow up on a comment you made before just a minute ago on the 100 milligrams versus seeing some benefit at 50. The long-term extension, is that going to be at 100 milligrams or is there kind of individualized dosing and they're based on whatever that patient prefers? And then many of these patients actually rolled off trial right back in the spring. So do they have to kind of dose escalate back up, or do you think you can just put them straight back onto a drug?

So what they'll do is get them to what they think is an optimal dose in that 50 to 100 milligram range, and they're just going to come in at 50.

Correct. And then the existing patients, the idea is these newer patients will just start rolling straight into that trial?

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

Okay, and would that involve another washout period, you know, to test that whole, you know, the stepping down and titrating out that you've been doing, or do you think you have enough experience?

Yeah, so, well, they taper, you know, it's a separate protocol, so they will need to finish the taper and then come back in. That's why. I don't feel like we need additional data around the taper beyond what we've got set up in the ongoing study now.

Okay, great. And then just one thing on the abstract. It discloses a possible second mechanism of action through GARDOS. Can you kind of explain what's making you think that And then also maybe contrast that with what's been studied on GARDOS before in sickle cell, because obviously there's been a high-profile Phase III program there before.

Yeah, so that has been something that has been of interest both from our research team as a potential mechanism and now from the investigators based on this increase in the mean corpuscular volume, what's called the MCV. And given that you're increasing the overall red cell health and perhaps the Garda's channel, which is directly involved in red cell hydration, that that could also be a mechanism by which medipivat is providing clinical benefit. Cells live longer, they're healthier, they have a better hydration state, which may improve decrease the polymerization of that fiber.

Okay. And I guess, is there any difference there between kind of how you think this is working and what has been studied before with GARDOS? Because I think that phase three trial actually, I mean, it obviously failed on VOCs, but in terms of hitting stat sig, but even showed a trend against the drug, right?

Yeah, that was an interesting trial because that Gardos channel blocker showed some improvement in hemoglobin, but was stopped because of a question around VOCs and safety. We work very differently. We don't directly affect the Gardos channel. You know, our drug is specific for activating pyruvate kinase. And as we emphasize, it's the impact on the glycolytic pathway by by activating PKR, that increases ATP, where you see a number of positive effects in terms of red cell health. And then by dropping 2,3-DPG, which has long been demonstrated to be elevated in patients with sickle cell, the reason to believe there is it will decrease the formation of fibers that cause that abnormal shape of the red cells and sickling and all the bad things that happen there. So it's a very... It's an observation that we may be improving the ability for that Garda's channel to increase red cell hydration, but it's fundamentally through that mechanism of action of increasing ATP by activating PKR.

Okay, great. Thanks a lot.

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

Hi, guys. This is Walid on for Peter. Thanks for taking the questions. I just had a question around upcoming PKD data. Where you see the bar is, what would be considered clinically meaningful results, you know, as we look to the data year-end and first quarter 21 in both transfusion-independent and transfusion-dependent patients?

Yeah, so we designed – it's Chris Bowden here. We designed both of those trials with an endpoint that is – will be associated with clinical benefit. And of course, we will be looking very carefully at secondary endpoints. So the ACTIVATE study is designed to, a responder is defined as one and a half gram or greater increase in hemoglobin from baseline. And that trial is 80 patients one-to-one randomized to active drug or placebo and then with the ability for placebo patients to cross over at the end of the dosing period. Where we have a positive study, if the response rate is 35%, and we assume there'd be an approximately 5% response rate in the control arm. So that would be a positive study. And we think based on what we saw in dry PK, that over a gram is then when you talk to people clinically, talk to clinicians in terms of clinical benefit, we set the bar even higher. So if we meet the primary endpoint, we have a lot of confidence that we'll have a package that's indicative of clinical benefit. There'll be a number of supporting secondary endpoints that will also be important in that not regularly transfused patient populations. For the ACTIVATE-T study, which is 27 patients who are regularly transfused, the efficacy endpoint is a 33% or greater reduction in the overall transfusion burden at the time of their study compared to their previous one-year history of transfusion. And so that's an open-label trial, and the primary measure of clinical death that I just went on. At the same time, you know that in those patients who are regularly transfused, people look at 50% reduction as well as transfusion independent. So those are the other important secondary efficacy outcomes that we hope will demonstrate that Medipivac and that group of patients has a really big impact in terms of reducing the amount of time they need to spend in the clinic getting blood transfusions. And we'll also look at secondary endpoints like iron mobilization and what impacts we might have on the need for iron chelation and other endpoints. So the two trials in total, we'd like to be able to use them to get a broad label in adults with putridate kinase deficiency. And we think that

Great. Thank you for taking the question.

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

Great. Thank you very much for taking my question. And first of all, congratulations, Jonathan, for your new role. Starting with the question, I mean, I think when you first provided this $1 billion guidance by 2025, obviously COVID was not there, and there has been a recent EMA decision which didn't go in your favor. So could you talk a little bit more about, with these uncertainties, how attainable is this $1 billion My25 guidance is, or your aspiration is, and how much legal room is there with pipeline, et cetera, to still make it happen if the current business doesn't go as planned? Thank you.

Hi, Mohit. It's Jackie. Thanks for the question. I thought I wasn't going to get to talk in the Q&A today, so I appreciate the opportunity. So as you might imagine, we want to set ourselves ambitious objectives, but objectives that we feel like we have a very high probability of achieving. With respect to the $1 billion revenue guidance, it is mostly driven by Tibsovo and AML in terms of the indication, which is related to the label expansions. But we've also got some revenues in there for menopivatin PKD that I personally think we've been a little bit conservative on. And then where we've also not included, you know, hardly anything is for voracidinib and glioma and for menopivatin thalassemia and sickle cell disease because they're We have them from a timeline standpoint in our base case assumption, you know, relatively late in the time horizon. But, you know, even a little bit of pulling those in or a little faster revenue ramp in the launch than what you've assumed would give you plenty of room for still achieving the objectives. What we've actually seen also, if you notice in 2020 with Sobo, revenues is the, it seems like oral oncolytics in the pandemic environment may actually be favored. And so we've been very happy with TIPSOVO's performance in 2020 so far. And, you know, we haven't guided to 2021 yet. We will do that soon and and then you know at the beginning of next year and we feel quite good about where we are with it. Sovo and that the base case in AML. So your comment about the pandemic and COVID impacting the 1 billion in 2025. Really, we have not seen that as an issue yet. In fact, we may be a little better than we'll be at original plan, so I feel great about it and. I think my comments have always been at least one billion in 2025, and that's still the way I feel.

Thanks. Got it. If I may sneak one more in for Darren. Thank you for this, Jackie. So I know you are going to talk a lot about it on November 19th, but if I could get a sneak peek, because when we talk about PKD with doctors, they often say that the patient population is small and they don't see many patients. So in this context, where are you in terms of identifying PKD patients? And is there a low-hanging fruit there, or how would you go about finding these patients and probably extend the market? Thank you.

Great. Thanks for the question. So I think we've shared publicly previously that we believe that we estimate the population for PKD to be between 3,000 to 8,000, between the U.S., and five EU, right, maybe as high as 10,000 when you include overall EU. The patient identification efforts that we've been executing over the last couple of years have yielded just about 1,000 or so patients split between the U.S. and the five EU, and then a number of additional patients that have been identified beyond those major markets as well. So when you take all that into account, about a third of the, we've identified today, right, about a third, a little more than a third of the lower end of the potential prevalence, prevalent population. But that's a lot of what the work is continues to be between now and approval for the Mid-PIVAC, right? So just doubling down on that patient identification work in addition to disease education, disease awareness advocacy, and whatnot. And that work is ongoing in both the EU and the U.S.

Very helpful. Thank you, Diana and Jackie.

Thank you. Our next question comes from Kenan Mackay with RBC Capital Markets. Your line is open.

Hey, guys, this is Bikramon for Canon. Thanks so much for taking our questions today. I have a quick one on the EU regulatory feedback that you got. Maybe if you can remind us what were the main concerns of the regulatory agency there that led to the withdrawal and your confidence in just phase three studies and timeline updates for Hovon and Agile. have your thinking and confidence change after this feedback, that would be super helpful.

Yeah, hi, it's Chris here, Chris Felden. So our confidence and excitement around the phase three trials, which are in newly diagnosed patients, is really important because that's where, as I said in my remarks earlier, that that's where the most patients are. And so we're very committed to those trials. They're ongoing. And we had to reset guidance around Agile because of the COVID effects, and we're targeting finishing accrual to the Agile study at the end of next year. And the Holon study, which is in IC-eligible patients we haven't guided to yet, That trial is in its early operational phase where sites are coming on board. However, we're definitely seeing nice accrual for both the IDH-1 and the IDH-2. That's being done in a group that's committed to doing, an international group that's committed to doing studies in this IC-eligible patient population, and they have a long track record of doing that. So we're really excited. very satisfied with how things are going there, and they're great partners to work with. Now, with the MAA, so there was no doubt, I think, that it was appreciated that we had clinical activity with Tibsovo in the relapse refractory space, that the oral agent and the durable responses were appreciated. the main concern we knew this going on is that there wasn't a control on. So this is, you know, the, the, the CHMP historically, um, looks at these types of data sets. That's a lot of skepticism. And we did a lot of work, uh, looking at historical control data, some of which was going to be published in ash to demonstrate what looked like there will demonstrate very impressive effects in terms of survival compared to an IDH one historical control. with relapsed refractory disease. At the end of the day, it just wasn't enough. And without controlled clinical data in the relapsed refractory space, the CHMP was not going to give a positive opinion. And we appreciated that after our oral explanation, and that's when we made the decision to withdraw.

Yeah, I mean, it's Jackie jumping back in for just a second. I think anytime one goes forward with a phase one data set like this without a control arm in Europe, there's a risk that you end up in this type of situation. We thought it was the right thing for patients to give this a shot. We gave it a very good shot. As Chris said, you will see some data published around the historical control work that we did that I think is still very interesting data. In our base case assumptions, we had reflected some assumptions around the risk of this, and as Chris said, in the relapsed refractory IDH1 patient population, it's relatively modest size in Europe with different pricing assumptions than what you have in the U.S., so it was a modest revenue opportunity, and we're moving full speed ahead with the Phase III trials, which are the type of trials that you would expect the Europeans to want to see for the label expansions into nearly diagnosed, so just a different situation with Agile and Hobon.

Yeah, thank you so much for that. And I had a quick follow-up on Tipsomo, just revenue trends in U.S. You did mention about growth to net impacts you might be expecting in Q4 and diagnosis rates. Were you seeing low diagnosis rates in Q3 as well? I know the Q3 growth was pretty strong and demand growth. So maybe you can talk about a little bit of dynamics, what you're expecting going into Q4, given the resurgence of cases in the U.S., of COVID cases, right?

Yeah. Sure, sure. Daniel, so, yeah, so what I tried to express were some potential headwinds that are largely unknowns, right? So we know that we're experiencing and will continue to experience a resurgence We know from our experience in the initial surge that it certainly had an impact in terms of patient presentation and diagnosis, even though we weathered it quite well, particularly as an oral treatment in a setting like AML, which is a highly emergent disease, right? The – in Q3, it was quite a different setting, right? So you had – even though you had hotspots across the U.S., you'd have quite the experience that we're in the start of in Q4. And so what I wanted to ensure is that we're sort of balancing the enthusiasm for the performance that we've seen in Q3 with the potential – very real potential impacts related to COVID in Q3. Now, that said, the impact on grace to men are largely related to the potential change in the mix of coverage for patients on commercial drug. We haven't seen a huge shift. but it is possible based on economic realities and the impact on employment and insurance coverage, perhaps an increase in Medicaid coverage as well as those patients moving through 340B or DISH hospitals. And those are the things that we're anticipating over the course of Q4 that could potentially provide some headwinds on our overall performance.

And I think Darren, in his prepared remarks, also said that with all of those caveats, the month of October put us off to a very good start for Q4.

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

Okay. Thank you so much for taking the question.

Thank you. Our next question comes from Alethea Young with Cancer Fitzgerald. Her line is open.

Hi, this is Emma on for Alethea. So just turning back to sickle cell, we saw that another PKR activator in development outlined a pivotal program in their ASH abstract that had included annualized VOC as a co-primary endpoint. So I know you guys are still in regulatory discussions there for the planned mid-pivot design, but is that something you think would be important to show differentiation on in order to be competitive versus that agent or also commercial drugs like coxbrita?

Well, I think that, as Chris here, I think any, you know, if you're going to run a trial with a PKR activator, as we've said from the get-go, you have two reasons to believe. And one is raising hemoglobin, and the other is reduction in BFCs. So, you know, there's a lot of ways to design the trial, whether it's co-primary endpoints, whether it's a sequential testing. I think it just goes without saying that those two endpoints are the marquees. That's where the clinical benefit is for patients. And I think the big promise, the potential, if you will, for mid-PIVAP is that you can significantly achieve both. Clearly, we're seeing drugs that have been approved for increasing hemoglobin. With the jury still out on what's going on with VOC reduction, and we're hoping to see that with longer follow-up, that you might see a decrease, a statistically significant decrease in VOCs with Plexilator. That would be good for patients. The P-selectin inhibitor from the has no impact on hemoglobin. The potential and the promise we hope for imidapibat is that we can address both and that you'll be able to address the two main problems with sickle cell disease with PKR actively.

Great. Thank you. And then is there any update you're able to give on the pediatric development plan kind of across the PKR portfolio, both for imidapibat or 946?

So our pediatric program with midiPIVAT is moving forward in patients with pyruvate kinase deficiency. And so we're working toward getting those studies up and running. With regards to thalassemia and sickle cell for midiPIVAT, certainly those will need to happen. But you know, we're, right now focused on pyruvate kinase deficiency, and we think we'll have those details worked out by the end of this year. As far as AG946 goes, that drug has a long way to go in terms of demonstrating, achieving its early development hurdles before we start thinking about what the next stage of development is for that compound. MediPivot right now has years of efficacy and safety data, first in pyruvate kinase deficiency, now in thalassemia and sickle cell, and it continues to do very well. So we don't need 946-Modivac to start our pediatric plans as evidenced by the fact that we're moving forward in pyruvate kinase deficiency.

Thanks very much.

Thank you. Our next question comes from Michael Smith with Guggenheim. Your line is open.

Hey, guys. This is Kelsey on for Michael. Thanks for taking our questions. I guess to kind of build off of that last question, could you maybe just remind us how you see the next-gen PKR activator kind of fitting into your development plans longer term? And then for TIBSOVO, I guess if the ongoing phase three trials are successful, I guess when do you think the earliest, when do you think it could be the earliest that you secure European approval for TIBSOVO? Thank you.

Right, okay, so the first question is 946 and what its development path would be. And that will, would also depend on the type of data that we see with mid-PIVAT. And because we're moving mid-PIVAT forward across all three indications and based on the activity and the safety profile we've observed to date. So, you know, what we do next with 946, well, it's too early to make that call because we need to see what the actual clinical attributes of the molecule are and would it have offered tangible, you know, important improvements for patients across those three diseases where we're studying mitopivac now. And, of course, we continue to study and investigate diseases where activation of pyruvate kinase may have the potential to improve outcomes for patients. And so that's something that we're actively looking on. But it's just too early for us to comment on how 946 would be developed in the next stage. What we're focusing on now is can it even get into the situation that we can do that. So then your question is for Tim Sobo, what's the earliest that we could get any of those frontline trials in front of the CHMP to get an approval in the frontline setting? So if you look at Agile, that's got to complete accrual at the end of 2021, and then that's an event-driven trial. So we'd have to really get some sense of how fast events are coming in then we would unblind it, and then we would be then off and filing. So that gives you a broad sense. For Hobon, we haven't guided yet to accrual completion because, like I said, we're still activating sites in this large global trial. We hope to get, as soon as we get these trials, positive study in our hands, and we would want to get it in front of both the CHMP, FDA, and other regulators as soon as we can. It's just too early for us to be able to provide specific guidance at this point.

Got it. Okay, thank you.

Thank you. Our next question comes from Mark Bradenbach with Oppenheimer. Your line is open.

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

Yeah, so we do think that this definitely has potential to reduce VOCs, what we're seeing with our P50 and T50 assays. One of the challenges has been that there's not a direct correlation. Oh, this much improvement is associated with this much reduction in the frequency of VOCs. And so that's, but nevertheless, based on what we're seeing, we think we definitely have some potential to do that. Certainly, early data with Buxellator, looking at a number of important endpoints, whether it was sibling assays and reticulocytes and LDH and some of those things, when we look at our data at a similar point in time with all the caveats that go with different patient numbers, cross-trial comparison, different points in time, concomitant medications, so there are really a bunch of caveats to it. But we look at our overall profile that we're seeing, whether it's with the sickling assays that you're referring to, whether it's LDH, reticulocytes, and other aspects, we're very, we feel really good about what we're seeing. And that's why we declared that we have proof of concept when we're moving to phase three at the time of EHOP, when we look at the initial patient data. One other thing I'll say is that I think there's an understandable interest in um all these new drugs coming in and we get the question that well you know what's what's the value of having um in a pivot if it raises hemoglobin because that's what acceleratory does as well um there's the voc piece that you ask us a lot of questions about and there's also the aspect that the percentage of patients who have a one gram or greater increase with acceleratory It's about 50%. So there's a number of patients who don't have any hemoglobin response. So we could see ourselves as being a very good drug for those patients, just for starters.

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

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

Okay. Thank you very much, Chris.

Thank you. You're welcome. And our next question comes from Andrew Behrens with SVV, Lee Ring. Your line is open.

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

So what that is is an asymptomatic heart rate over 100 beats per minute. And if you look at the common toxicity criteria, it does not require intervention and it's asymptomatic. We have not seen any indications that we have a cardiac signal with this drug. And so what's happening is the patients are coming in, they're getting evaluated, and then part of their vital signs, three individuals who had a heart rate above 100 but otherwise felt fine and had no symptoms associated with it. That's the gist of it, and we've not seen any other signals across any of our other trials that suggest there's anything from a cardiac standpoint that we have to be concerned about. We continue following safety in the broadest sense across all of the trials. And so this is not something that we've had any need to focus on at this point. And I don't think that the three patients with asymptomatic heart rate above 100 is something that's going to set us off in a way that concerns us or alters the safety profile from what we've reported to date in any way.

Got it. And one more question, if that's all right. I'm just wondering about that Gardos channel potential mechanism for the other product that was in the pipeline that was specifically for Gardos channel. One of the proposed ideas of why they increased VOCs was due to hyperviscosity. So just wondering if you had any viscosity data that could potentially imply something different or counter that.

Well, I think nothing specific in terms of hyperviscosity data. Bruce Carr, I'll ask him to comment further on that. But I think that the aspect of what we're doing by dropping 2,3-DPG and speaking specifically around sickling is preventing the red cell from becoming sticky and deformed. So I wouldn't anticipate that will be a problem, hyperviscosity, if in fact we are seeing, you know, if it turns out that we are able to over time see consistent increases in MCB and get some sense as to if this is really the reason why. So that's not a concern. It is interesting that some of the data that's now coming out At ASH, for instance, GBT's publication where, you know, they have a minority of patients, a small percentage of patients who had hemoglobin increases to 12 or 13, they published remarkably that those patients had the lowest frequency of VOCs. And it may be now that, you know, this concern, which has always been there about how high you can get hemoglobin up, It's still going to be there, no doubt, with experts and clinicians who treat sickle cell disease, but now maybe things will get a little more nuanced and we'll just have to keep following this breaking news as the data develops. Bruce, any comments about the Garda's channel piece, please?

I think you covered it pretty well, Chris. You know, the parameters that might lead to hyperviscosity You spoke to one of the easiness of the red cell. We believe we, you know, addressed that improving the general health of the red cell and their propensity for that. The other significant parameter is the very high pack... ..PCV, pack cell volume. That's something that we're not likely to get. And you also already mentioned that, you know, in that higher range... we seem to be doing pretty well anyway. So I don't think there's anything additional that one can draw from a study where the active agent has such a profoundly different mechanism of action from our drug. So I think drawing an extrapolation between the two mechanisms of action relative to concerns for this potential side effect is probably not appropriate.

Got it. Thank you very much.

Thank you. And I'm currently showing no other callers in the queue at this time. I'd like to hand the call back over to Jackie Faust for any further remarks.

Thank you, Operator. I just would like to reiterate that despite the challenges and uncertainties that continue to prevail in the world today, I and the whole OJOS team remain very excited about the progress that we are making across our focus areas this year, and we're looking forward to a catalyst-rich 2021 as well. To close, I would like to thank my OGLS colleagues for their dedication and passion for making a difference for patients. I also want to thank all of the patients, caregivers, and physicians who participate in our clinical trials. Without them, we could not do what we do today, and I would like to thank all of you for joining us on our call today, and we will see you soon.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone have a great day.