Agios Pharmaceuticals, Inc.

Good morning and welcome to Adios' fourth 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 Adios' request. I would now like to turn the call over to Holly Manning, Director of Investor Relations.

Thank you, Operator. Good morning, everyone, and welcome to Agios' fourth quarter 2020 conference call. You can access slides for today's call by going to the Investors section of our website, agios.com. With me on the call today with prepared remarks are Dr. Jackie South, our Chief Executive Officer, Dr. Chris Bowden, our Chief Medical Officer, Darren Miles, our Chief Commercial Officer, and Jonathan Diller, our Chief Financial Officer and Head of Legal and Corporate Affairs. After 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 statement as a result of various risks, uncertainties, and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. With that, I will turn the call over to Jackie.

Thanks, Holly. Good morning, everyone, and thanks for joining our fourth quarter 2020 results call. Before we get into the exciting work we have ahead of us in 2021, I want to take a moment to reflect on this past year and acknowledge the extraordinary challenges faced by all of us at Agios, the patients we serve, and the global community at large. One year ago when I spoke on the Q4 2019 call, we did not know that just a few weeks later the COVID-19 outbreak would escalate into a global pandemic, shutting down our offices and halting life as we knew it. For many of our employees, working from home included balancing new challenges in their personal lives, such as virtual school, taking care of young children, and new worries about health and well-being in a pandemic. And patients around the world, including those in clinical trials, struggled with reduced access to travel and medical centers. At the same time, the U.S. faced significant civil and political unrest that further exposed the realities of the racial and social divides in our country. In the wake of these challenges, I've been overwhelmed by the generosity, determination, and spirit of the AGIOS team in support of each other, patients, and our communities. As of last week, our cross-functional coronavirus task force wrapped up their first year, having responded to nearly 750 inquiries from patients or healthcare providers across dozens of countries. For each request, the team worked tirelessly to reduce the risk to patients and or the burden to healthcare systems due to COVID-19 and went to great lengths to ensure patients could continue to have access to our medicines despite the unprecedented circumstances. Our facilities and HR teams have gone above and beyond the call of duty to ensure our labs and offices remain safe for employees who need to work onsite, including providing access to testing and contact tracing. For the teams working from home, they've organized personal and professional resources like webinars on avoiding burnout, access to educational materials and activities for our children, virtual employee interactions to maintain our connections, and ongoing team-building activities to adapt our culture during this time and beyond. On a community level, we led a diversity initiative at Agios that included speakers and workshops on valuing differences to heighten our awareness and help us learn together. As you can see in the photos on slide five, we continue to support causes important to us through fundraisers and events, and in December, our employees donated gifts to families with children suffering from life-threatening diseases. With the realities and struggles of 2020 continuing in 2021, I nevertheless find myself incredibly hopeful for the future and more confident than ever in our ability to overcome whatever comes our way. From a business perspective, we have much to be excited about as we embark on the next chapter of Augios with a sole focus on genetically defined diseases. In December, we announced our refocused strategy in the decision to sell our oncology assets to Servier, a successful patient-focused global pharmaceutical company with a deep commitment to expanding its emerging oncology portfolio. As part of the transaction, which is subject to a shareholder vote on March 25th, Audios will receive cash consideration of up to $2 billion, including $1.8 billion in upfront cash and $200 million in a potential future cash milestone payment, as well as 5% royalties on U.S. net sales of TIPSOVO from transaction closed through loss of exclusivity and 15% royalties on U.S. net sales of voracitinib from first commercial sale through loss of exclusivity. After returning $1.2 billion to shareholders, residual proceeds will be retained to fund the company through major value-driving catalysts and to profitability without the need for any additional equity raises. These decisions will allow the oncology portfolio to grow and thrive with Servier and will provide Augeos with the capital required to maximize the potential for promising therapies for genetically defined diseases, ultimately enabling the greatest overall positive impact for patients. For more details, you can access our press release, investor presentation, and proxy statement on our website at agios.com. Over the last few months, we've made significant strides with our most advanced medicine, MediPivot, across our three initial therapeutic areas of focus, and this progress sets us up for a catalyst-rich year ahead, which Chris will cover in a moment. In addition, we are also moving other genetically defined disease programs through our clinical and research pipelines. On the oncology side, we've continued to execute on both the clinical and commercial fronts. We closed out the second full year of Tudsovo net revenue with $121 million, exceeding our $115 million net revenue target. Looking ahead to the evolution of our commercial business, I'm pleased to announce that Darren Miles has been promoted to the role of Chief Commercial Officer. He has served in numerous roles at AGO since joining us in 2015, including most recently as Senior Vice President of U.S. Commercial and Global Marketing. Darren has done a tremendous job leading our team to superior TIPSOVO commercial performance while also preparing us for our first genetically defined disease launch. with PK deficiency in 2022. Darren's thoughtful and genuine leadership style is felt throughout our company. We are very optimistic about our bright future and our ability to continue to bring transformative therapies to more patients than ever with our renewed focus and financial strength. With that, Chris, let me turn it over to you.

Thanks, Jackie. Looking back at 2020, I'm humbled by the dedication and resourcefulness of our clinical organization on both the oncology and genetically defined disease sides of the business to advance our clinical programs over and above expectations for patients despite the challenges of the pandemic. As we enter 2021, we're excited about our future in genetically defined diseases and have significant work ahead of us as we advance our late stage programs and make decisions about our next wave of research. I'll start with our most advanced genetically defined disease program, midipivac, our first-in-class PKR activator currently being evaluated across three distinct chronic hemolytic anemias, pyruvate kinase deficiency, thalassemia, and sickle cell disease. In pyruvate kinase deficiency, we've recently reported top-line data from the ACTIVATE and ACTIVATE-T Phase III studies evaluating midipivac in adults with pyruvate kinase deficiency who were not regularly transfused, and those who were regularly transfused, respectively. In the ACTIVATE study, 40% of patients treated with midipivap achieved the primary endpoint of a sustained hemoglobin increase compared to zero placebo patients, a highly statistically significant result. Statistical significance was also achieved for all pre-specified key secondary endpoints for ACTIVATE, demonstrating an improvement compared to placebo including inpatient reported outcomes based on changes from baseline, and pyruvate kinase deficiency diary score, and pyruvate kinase deficiency impact assessment score at week 24. We anticipate that these data will be supportive of our submission for regulatory approval, as well as in interactions with access providers. In ACTIVATE-T, more than a third of patients achieved a meaningful reduction in transfusion burden and 22% were transfusion-free during the 24-week fixed-dose period. In both studies, the safety profile was consistent with previously reported data in PK deficiency patients. Data from both studies, including the PRO data, will be submitted for presentation at the European Hematology Association Virtual Conference, which is being held June 9th through the 17th this year. These data support the potential for midipibat to be the first disease-modifying therapy for pyruvate kinase deficiency and will be the basis for our global regulatory filing that is currently in process. We anticipate filing for regulatory approval in the U.S. in the second quarter of 2021 and in the EU in mid-2021, with a potential 2022 commercial launch in both geographies. Moving to the Phase II study of midipivac and thalassemia, we completed enrollment last 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 1 gram per deciliter in 12 of 13 evaluable patients during weeks 4 through 12, including 4 of 4 alpha-thalassemia patients. for whom 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. As of November 2020, 17 patients remained in the extension portion of the trial. We expect to submit the full data set from all 20 patients in the core period from this study for presentation at EHOP. In December, we shared a first glimpse at our two global pivotal trials of midipivac and thalassemia, Energize and Energize-T. As you can see at the top of slide 11, Energize will evaluate 171 patients randomized 2 to 1 to 100 milligrams of midipivac BID or placebo in beta and alpha thalassemia patients who are not regularly transfused. The primary endpoint percent of patients with a mean hemoglobin increase of greater than or equal to 1 gram per deciliter from baseline over a 24-week core period. ENERGYZE-T will evaluate 240 patients randomized 2 to 1 to 100 milligrams of minipimet BID or placebo in beta and alpha thalassemia patients who are regularly transfused to find a 6 to 20 red blood cell units transfused during the 24 weeks prior to randomization. The primary endpoint is the percent of patients with a 50% reduction in transfusion burden in any 12-week rolling period during the 48-week core period. We are in the process of operationalizing both studies and look forward to initiating these trials by the end of the year. Now let's turn to sickle cell disease. Last year, Meditivac was the first PKR activator to demonstrate proof of concept in this disease based on initial data from a study being conducted in collaboration with Dr. Sui-Lai Kim of the National Institutes of Health. As outlined on slide 12, at ASH in December, the NIH presented updated data from 11 patients demonstrating Meditivac's impact on hemoglobin improvement in conjunction with improvements in markers of hemolysis. Dr. Chen continues to enroll patients in the core study as well as an extension study and expects to provide an update at a medical meeting this year. In addition, our collaborators at the University of Utrecht initiated an investigator-sponsored trial of midipivac and sickle cell disease late last year, and they also plan to submit data from this study for presentation at a medical meeting this year. In parallel with these clinical activities, We completed U.S. and EU regulatory meetings focused on advancing our sickle cell disease program into pivotal development. Their input led to the development of a robust and thoughtful pivotal development strategy, which I am excited to share with you today. We believe this plan de-risks the approval path permitted to that in this challenging disease and maximizes the likelihood of a label with a broad indication in 2026. The advice we received from FDA and EMA about the pivotal trial design for mid-PIVF and sickle cell disease was based on the currently available data, our initial clinical trial design, and the evolving treatment landscape. Specifically, we heard that hemoglobin alone is not considered an established surrogate for clinical benefit in sickle cell disease. An interim hemoglobin analysis is highly unlikely to result in an accelerated approval, and the unblinding, at interim has the potential to compromise a sickle cell pain crisis endpoint. We have been strongly advised to develop data across two dose levels to further understand the pharmacodynamics and safety profile in sickle cell disease, given the complexity of this disease relative to other hemolytic anemias. Based on this feedback, we've designed the operationally seamless phase 2-3 study in adults with sickle cell disease that you see here on slide 13. The study will include patients who are 16 years of age or older, have had 2 to 10 sickle cell crises in the past 12 months, and have a hemoglobin of greater than or equal to 5.5 and less than 10.5 grams per deciliter during screening. Patients currently receiving treatment with voxelotor prismizumab, or any other agent intended to increase hemoglobin-oxygen affinity are excluded. Treatment with hydroxyurea is allowed. The phase 2 on your left will randomize 69 patients in 1-to-1-to-1 to 50 mg midipibab BID, 100 mg midipibab BID, or matched placebo. The primary endpoint is a hemoglobin response defined as greater than or equal to one gram per deciliter change from baseline to week 12, and the data will be used to establish a clear dosing paradigm for the phase three portion. On the right, the phase three, which will commence after the phase two analysis, will randomize 198 patients, two to one, to the selected phase two dose of midipibap or matched placebo. The study will have two primary endpoints, hemoglobin response defined as greater than or equal to one gram per deciliter change from baseline to week 52, and the annualized rate of sickle cell pain crises. We are on track to initiate the trial by the end of the year. As a result of these changes to our initial pivotal plan for mid-pivot and sickle cell disease, we now expect a regulatory approval in the 2026 timeframe instead of our original guidance of an approval in the end of 2025. We believe that by addressing the FDA and EMA feedback prior to the start of the Phase 2-3 trial, this new plan increases the likelihood of a broad competitive label that is inclusive of both hemoglobin and sickle cell pain crises and points at the time of launch. Here on slide 14, you can see the robust pipeline we're building with MediPIVAT across these three initial indications. As we did with Tidsovo, our focus is to advance midipivap from pivotal development to regulatory approval as quickly as possible. Starting with pyruvate kinase deficiency next year, we believe we have the opportunity to meaningfully expand the labeled indications for midipivap over the next five years to address three serious hemolytic anemias that desperately need new treatment options. Beyond midipivap, we're also advancing our next generation PKR activator, AEG946, through a phase one healthy volunteer study. The trial began enrolling last fall, and we expect to submit data from the single ascending dose and the multiple ascending dose cohorts for presentation at a medical meeting by the end of the year. Our analysis of the totality of the AEG946 healthy volunteer data will inform next steps clinical development of this molecule. This team has been hard at work producing a robust and promising pipeline of research within the PK activation mechanism. And we plan to make decisions on the next wave of indications for these, as well as our clinical stage drugs by the end of the year. We also have significant non pyruvate kinase opportunities within our research pipeline, including a stabilizer of the enzyme deficient and fennel kitchen area that degrades phenylalanine, and a unique approach to treating amino acidemias and acidarias associated with inborn errors of metabolism. Our deep expertise created around cytometabolism to elucidate cancer cell biology has been exploited to great effect in understanding multiple genetically defined conditions and has allowed us to build a deep portfolio of genetically defined targets. We look forward to sharing more of these programs at an R&D day in the second half of the year. On slide 16, we've outlined all of our 2021 key milestones, and I'll now focus on our oncology programs, where we have been hard at work making important progress across a number of late-stage programs in malignant hematology and solid tumors. Last month at the ASCO GI meeting, we recorded a full analysis of the final data in the global phase 3 clarity trial of TIBSOVO in patients with previously treated IDH1 mutant cholangiocarcinoma. The final analysis showed that median overall survival for patients randomized to TIBSOVO was 10.3 months compared to 7.5 months for patients randomized to placebo. The hazard ratio for overall survival did not meet statistical significance. However, a high proportion of patients in the placebo arm, 70.5%, crossed over to Tidsovo. A pre-specified crossover adjusted analysis showed a median overall survival for patients in the placebo arm of 5.1 months, and the hazard ratio for overall survival was statistically significant. The safety profile observed in the study was consistent with previous published data, and last year we reported positive, highly statistically significant progression-free survival data. Based on these data, we are on track to submit a supplemental new drug application for TIBSOVO and previously treated IDH1 mutant cholangiocarcinoma in the first quarter of 2021. In addition to cholangiocarcinoma, we are exploring the utility of IDH inhibition and low-grade glioma in our Phase III indigo trial of boracidinib. 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. Enrollment is ahead of expectations despite the pandemic, reflecting physician enthusiasm for the potential of oracidinib in this trial. And finally, the AG270 phase I dose escalation combination arms with tefaxanes continue to enroll patients. On the hematologic malignancy side, Enrollment in our phase three frontline AML combination studies of TIBSOVO as well as our MDS expansion are ongoing, with Agile and the MDS cohort expected to complete enrollment by year end. With that, I'll turn it over to Darren to discuss our fourth quarter commercial performance.

Thank you, Chris. Despite the resurgence of COVID-19 in Q4 and continued limitations on in-person sales promotion, Our team delivered Cipsovo net sales of $39.1 million in Q4, a 23% increase over the third quarter. That brings 2020 net sales to $121 million, or a 102% increase year-over-year, exceeding the upper end of our updated guidance by $6 million. Performance in the quarter was driven by growth in new scripts and refills and favorable growth to net. We continue to see double-digit growth in both the academic and community settings, driven by a 15% increase in unique prescribers over Q3. Physician preference for TIPSOVO in the frontline intensive chemo-ineligible and first relapse settings remains strong, as do all leading indicators of physician perception, including the prevailing belief that TIPSOVO is the standard of care for newly diagnosed and relapse refractory ID21 mutant patients. Though promotional efforts are limited to FDA-approved uses of TIPSOVO only, we still observe that approximately half of Tibsovo use in both settings is in combination most frequently with an HMA. We've also observed continued growth of Tibsovo use for patients with cholangiocarcinoma, though line aside to the extent of that use is limited to only the third of the volume that moves through the specialty pharmacy channel. Looking forward, we expect continued strength in AML through 2021, culminating in net sales in the range of $160 to $170 million in 2021. Turning to midipivatin for the kinase deficiency, launch preparations are on track and further energized by the disclosure of the positive ACTIVATE and ACTIVATE-T trial results. Last quarter, we announced the launch of AnemiaID, our partnership with Perkin Elmer Genomics to offer no-cost genetic testing to patients with suspected hereditary anemias. This 50-gene panel can help to provide a definitive diagnosis of the underlying cause of their anemia, and represents an essential part of our multi-pronged effort to accelerate patient identification and disease education in the U.S. Though COVID-19 continues to present challenges related to commercial promotion, there are a number of important learnings from our experience in AML sales and marketing that are informing a more efficient build for PK deficiency, including sales force sizing and our marketing mix. I want to take this opportunity to express my appreciation to the entire Agios Oncology team for their work throughout the year, made all the more impressive when you consider the circumstances. Resilience, grit, and unwavering commitment to patience undergird this performance, and thousands of patients and all of Agios are grateful for it. I'll now turn it over to Jonathan for Q4 Financials.

Thanks, Darren. Our fourth quarter and full year 2020 financial results can be found in the press release we issued this morning, which I will summarize. More detail will be included in our 10-K filing later today. Total revenue for the fourth quarter was $44 million, bringing total revenue for the full year of 2020 to $203.2 million, an increase of $85.3 million compared to 2019. As Jackie and Darren mentioned, product sales up to Sovo were $39.1 million for the fourth quarter and $121.1 million for the full year of 2020, an increase of $61.2 million compared to 2019. Collaboration revenue was $2 million for the fourth quarter and $71.8 million for the full year of 2020, an increase of $24.3 million compared to 2019. The higher collaboration revenue in 2020 was due to recognition of the remainder of the deferred revenue balance related to the completion of the metabolic immuno-oncology collaboration with Celgene BMS. Our full year 2020 revenue also includes $10.3 million in royalty revenue from net global sales of IDFA, 2.9 million of which was recognized during the fourth quarter. As a reminder, we sold the IDFA royalty revenues to Royalty Pharma in Q2 2020, but continue to book the royalty revenue under GAAP. Cost of sales for the fourth quarter was $1 million and $2.8 million for the full year 2020. This year over year increase of $1.5 million was driven by ex-factory sales. Turning to operating expenses, R&D expenses for the fourth quarter were $95.7 million and $367.5 million for the full year 2020, a decrease of $43.4 million compared to the full year 2019. This year over year decrease in R&D was largely driven by winding down of the clarity study and phase one study of TIPSOVO and hematologic malignancies, the deprioritization of AG 636, and lower milestones incurred for HOVON. Selling general and administrative expenses were $39.8 million for the fourth quarter and $149.1 million for the full year 2020. This represents a $17 million increase over full year 2019. driven primarily by increased workforce expenses in the U.S. and EU and professional fees related to the Servier transactions. We ended the quarter with cash, cash equivalents, and marketable securities of $670.5 million. We expect that this cash balance, together with anticipated product revenue, interest income, and expense reimbursements under our collaboration agreements, but excluding any additional program-specific milestone payments, will fund our current operating plan to the end of 2022. Following the closing of the survey transaction and net of the planned capital return, RGS expects to be able to fund its operation through major catalysts and to cash flow positivity without the need to raise additional equity. As previously communicated, we plan to realign our capital structure to reflect the profile of our focused genetically defined disease company by returning $1.2 billion of capital as share repurchases over a 12- to 18-month period following closing. We will provide more information with respect to share repurchase tactics and mechanics in due course. With that, operator, please open the line for questions.

Certainly. To ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Due to time constraints, we ask that you please limit yourself to one question. Our first question comes from the line of Peter Lawson with Barclays.

Thanks for taking my questions. Just on the sickle cell, just a quick question around, I guess, the 100 milligram dosing. When can we see more of that data, just the timing around that, and if you think that's an important component in moving forward in sickle cell?

Hi, Peter. It's Chris Bowden here. Well, we're not guiding to the Phase 2 portion of the trial that I went through and I prepared remarks yet. And as we get that up and running and get some sense of the accrual, we'll be able to provide further information there. Certainly, over the coming year, we're going to see more data coming out from the trials that are ongoing at the NIH and at Utrecht. where we would be able, we'll be bringing some more. Sorry. Thank you. Clinical data forward.

Our next question comes from the line of Tyler Van Buren with Piper Sandler.

Hey, guys. Good morning. Thanks for the updates. Question related to the sickle cell trial design. If I'm not mistaken, the Oxbride or Voxelotor Hope trial just had the hemoglobin response rate primary endpoint, whereas here it's kind of two primary endpoints. I guess, was the addition of the sickle cell pain crises endpoint kind of primarily required by the FDA, or was that something you guys chose to add in? Do you have to hit on both of those two? receive approval, and it would be helpful to understand that also in the context of the fact that you have the cutoff on the lower bound of sickle cell pain crises in the past 12 months of two as opposed to one. I was surprised to learn that the HOPE trial had 42% of patients that had one crisis. So, you know, I guess you expect that to increase the signal there as well.

Yeah, Tyler Schitt here. So a number of of different issues you touched on. Voxelotor received accelerated approval on the basis of the increase in hemoglobin. And as you and we've all been following, they had not demonstrated a statistically significant reduction in vaso-occlusive crises. In our interactions with the health authorities, VOCs, whether it's a primary endpoint or a very high-ranking secondary endpoint is crucial in assessing the therapeutic index, if you will, clinical benefit of the molecule. Specifically for the trial that we're putting forward, having two primary endpoints, if we hit on either one, the study is positive. And then the interesting part will be with the regulatory view as the clinical benefit of that trial. By designing it this way, if we hit on one, we have a positive trial, and we think we're going to design the trial so that we have a compelling case to clinical benefit if we hit on either endpoint. Ultimately, that's a function of the data. And if you hit on both, of course, that's our, best-case scenario, and we think the mechanism of action of Nidipivac supports us designing the trial and having some reason to believe that that could be the case. I think one of the main things that we want to get across, and this is consistent with what we've talked about with prior-date kinase deficiency, is that in a setting where, like sickle cell disease, where raising hemoglobin is important, you have to have other supportive data. And so, linking back to pyruvate kinase deficiency, we've long heard very consistently that if you show up with an increase in hemoglobin, that's statistically significant, but there's no other clinical data to support that patients are feeling better, you're addressing hemolysis, then you're going to have a tough sell.

Thank you. And our next question comes from the line of Anupam Rama with JP Morgan.

Hey, guys, thanks so much for taking the question. I think we've talked about around 1,100 patients with PKD kind of identified in the U.S. and core OUS regions. I think that update was a while ago, maybe ASH 2019. What's the updated patient count here? How has patient identification gone in 2020, and how do we think about patient identification going forward? Thanks so much.

This is Darren here. So, you're correct. Last we discussed, actually, as recently as our last webinar regarding the MediPIVA program, we restated our current count at about 1,000 patients or so. COVID has made it more challenging to identify patients at the rate we would have wanted. given the need to be able to engage with physicians at various conference settings and their practices, things along those lines. But we do continue to add to that number over time. We expect that that will accelerate over the course of this year. I think what's really important and has actually been a bit surprising for us is having a good understanding of the complete suite of activities that we're employing or tactics we're employing in order to accelerate the patient-finding activities, one of which is the anemia ID program, which we've talked about. Just recently, I received an update on where we are with it. We're on pace by the end of this quarter to actually exceed the number of tests distributed that we had anticipated for the full year of 2021. And we're seeing a PKD positivity rate that approximates what we saw with the Spanish experience or Spanish IST that we talked about previously. So we believe that that's going to be a very important contributor to our patient finding activities this year and indicates to us that the sense of urgency, the level of interest, around this disease, and hopefully then it appears that it's already exceeding our expectations.

Yeah, and it's Jackie here. I think underneath everything that Darren said, also along the way having to activate and activate T data, as well as what we announced today, which I think is very important, the having hit statistical significance on the key pre-specified secondary endpoints for ACTIVATE, including the PRO data, is a really nice package of information to continue all of the efforts that Darren and his team and our medical affairs people are working on. And I think it's going to be a very compelling message with both physicians as well as doctors that, look, it's not just efficacy data. We're also hearing from, or hearing, we're seeing in the PRO data from patients on this trial that there's benefits. So I think it's a pretty strong, strong message.

Thank you. And our next question comes from the line of Kenan McKay with RBC Capital Markets.

Hi, thanks for taking the question, and Jack, to your point, what a year, and congrats on finishing on a point of strength. Maybe just a question on the midi-PIVF program in sickle cell disease, sort of wondering about, you know, excluding patients who are either receiving Boxelotor or Krasanlizumab or any of the other agents that change hemoglobin oxygen, it seems like that could make enrollment, at least in the U.S., somewhat challenging. I'm just wondering sort of how that's going to change enrollment into the trial versus some of the prior studies where there wasn't anything available. Thank you.

Yeah, Brandon, it's Chris here. I think you touched on one of the interesting things. that we encountered somewhat of a similar situation in leukemia and AML with the IDH inhibitors as we were coming in with Tibsovo and IDFA in a rapidly changing landscape. There are things you can predict and things you can't predict. If you just sort of take those drugs in order, voxelotor, if we were going to permit that, then you would need to understand is there a drug-drug interaction, number one. And you'd probably need to set up your trial in some way to do some sort of comparison. So the fact that we can do a placebo-controlled study is an advantage of sorts. But there certainly will be patients in the United States who are on Voxelotor, their hemoglobin has gone up, and in the eyes of their physician as well as the individual, they will be satisfied. And there will be also individuals who may be on both drugs, crizomelizumab and Voxelotor. So, certainly, there will be a wave of changes as new drugs become available to patients. At the same time, there'll be sickle cell is a global, And so we're going to expand our recruitment efforts. And that's a big part of our feasibility. And Hydrea will clearly be allowed. It's a standard of care. Many patients are on it. So I think that, and then if you take the number of this, the significant percentage of patients who don't respond to voxelotor will be looking for another option and coming on to this study. will be an attractive one for them, we hope. So I think overall, you know, certainly the development of new therapies is a good thing for patients. They have more options. At the same time, it also raises awareness in the community. None of these drugs are 100% effective, and they certainly have gaps in their target product profile. we need to define whether we can address those gaps. But I think that given the data we've generated to date and the attractiveness of the mechanism of action, we think we have a good chance. And our early feasibility is telling us that people are very interested in talking to patients about coming on to this study.

Thank you. And our next question comes from the line of Michael Schmidt with Guggenheim.

Hey, guys. Good morning. Thanks for taking my questions. I had another one for Chris on sickle cell disease study design. It sounds like much of the FDA discussion may have been focused also on the dose selection, and I was just curious if you could Talk a little bit more about what some of their considerations were when asking you to look at both the 50 and the 100 milligram dose and not just settle on the 100 like you're doing it in the thalassemia trials. Thanks so much.

Yeah. It's that 50 to 100 milligrams where based on the data we have so far, you know, you see, an increase in the pharmacodynamic changes. And you can't, at this point, we think we are pretty close to maximal hemoglobin response at 50, although in thalassemia, we felt like we picked up a few more patients. Their feedback, which is somewhat consistent with EMA, is that it's a complicated disease. They've seen a lot of drugs fail. So, we advise that, and you will help us in terms of understanding the risk-benefit of your drug and what you take to phase three by doing a phase two investigation component and understanding further what this pharmacodynamic 2,3-DPG-ATP relationship, hemoglobin relationship and safety looks like across these two doses before you decide, make a decision to take one forward. And that was one of the drivers there. And then they were very clear on some of that component around hemoglobin that I talked about in terms of the trial design. Great. Thank you.

Our next question comes from the line of Mohit Banzal with Citi.

Hey, good morning, guys. This is James. Thanks for taking our question. Just a quick one on AD946. what do you need to see from the SAD-MAD trial to open the sickle cell disease cohort? And I guess just, like, one, like, related topic is, does 9-4-6 have a longer half-life, and can it offer one-to-day dosing?

So the answer to the last part of your question is possibly it could offer one-to-day dosing. And then what we would need to see to take it forward would be, We need to see it clear its hurdles in terms of what we would expect to see from reductions in 2,3-DPG and increases in ATP and an adequate safety profile. A predictable and reasonable pharmacokinetic profiles. So, that's really the totality of data that we'd be looking at, and we'll want to be able to observe that data or analyze that data across several different cohorts, which we're in the midst of dosing now.

Appreciate it. Thank you, guys.

Our next question comes from the line of Mark Fram with Cohen and Company.

Thanks for taking my questions, and congrats on getting through what was challenging here for everyone. Maybe just following up on some of the questions on the sickle cell trial design for Chris, can you provide any granularity to how you're splitting the alpha between the co-primary endpoints and kind of inherent to that is, you know, what is the powering that you're expecting to see on a pain crisis? And are there any kind of important – of stratification factors that we should be thinking about, maybe, you know, the hydroxyurea use or the exact rate of baseline sickle crises?

A lot of interesting questions, Mark. It's not a co-primary endpoint. So there are two primary endpoints. The trial is positive if it hits on either one. And we'll be disclosing the further details around the stats on the trial later in time, especially as we get them up and running. Your question around VOCs related to what we would expect in terms of the numbers and how hydroxyurea will come into play there. I mean, I think that's one of the hardest things to predict in this disease and only rendered more challenging by virtue of the fact that you have now at least in the U.S. and expanding in Europe a drug that's effective in reducing the frequency of VOCs. So that's going to be something that we need to follow. And so one of the reasons why we designed the trial the way we did that it can be successful on the basis of either one of those readouts. Of course, the best case scenario, and we do have reason to believe that we could reduce VOCs. But I think that if you look at the history of trials, and if you look at most recently, you look at the trial that, you know, clearly improves hemoglobin, but wasn't able to demonstrate an improvement in the reduction of VOCs. Now, there's clearly an unmet need there. And there's, you know, the other part of your question is I think there's just a lot of heterogeneity in this disease. And that's one of the reasons why we've received a lot of feedback from both the EMA and the FDA in terms of pulling all this together. You know, a trial design is a mix of many things. It's feedback from the authorities. It's talking to individuals with the disease, in this case sickle cell. They talk about, you know, issues with access. They talk about issues with trust of the medical community. When they talk about their symptoms, the one that really, really comes out is pain. And so, you know, these are the types of things pulling all that together. And then regulatory feedback is the mix of you should do this, you must do this. And so then as a company, you have to take some positions, especially when you're balancing EMA versus FDA, because they don't always give you, usually they give you some degree of inconsistency in that feedback. And then you have to look at what's happening from an operations and feasibility perspective. So pulling all that together is, It's fun, it's challenging, it's complex, and we've been working hard to come up with the plan that we have today, which we can balance with all those factors and give us the best chance of having a positive trial that demonstrates clinical benefit for individuals with sickle cell disease.

Thank you. Our next question comes from the line of John Newman with Canaccord.

Hi, guys. Good morning. Thanks for taking my question. Chris, just curious, for the sickle cell disease phase 2, 3 trial, will you be able to look at any sort of a PRO or any sort of measure of fatigue, et cetera, in patients? I know that this has been really difficult in the past for sickle cell disease, but just curious if you have anything of that sort built into the study. Thanks.

John, the patient-reported outcomes and quality of life will be an essential part of the study. And it comes back to that feedback that we've heard starting with our 4A and however many years ago in pyruvate kinase deficiency. And that data, whether it's quality of life, patient-reported outcomes, is essential. In the setting of this trial, it's essential in all these trials, really, when you're raising hemoglobin as a primary endpoint. But you've got to be able to show that patients are feeling better or provide some evidence that patients are feeling better, whether it's by virtue of individual responders or in your experimental arm. So, yeah, we have to collect that data. It would be a very important part of demonstrating clinical benefit in the setting of a trial that demonstrates an increase in hemoglobin but misses on BOCs because the trial could still be positive. And then the regulators who control the approval will say, so what other things do you have to show us that patients who have a hemoglobin increase feel better? And payers will be asking the same question. So that's an important part of the trial. And, you know, there's been a lot of work in terms of trying to describe the burden of disease and reducing the burden of disease with drug therapy in patients with sickle cell disease. So there's validated scales. There's six-minute long tests. And there's a number of things that one can look at. It's challenging, and we go into this with our eyes wide open. Like I said, you know, a lot of drugs that have either been positive or, you know, marginally positive, what have you, have not been able to demonstrate those improvements. So it's a very challenging area, but it's absolutely essential.

Thank you. And our next question comes from the line of Mark Breidenbach with Oppenheimer.

Yes, hi. This is Kelpidon for Mark, and thanks for taking your question. Just a quick one for Chris. Are you planning on implementing any titration or tapering schedules for the upcoming Phase 2, 3 sickle cell study? Thanks.

With Medipivac, since we went into pyruvate kinase deficiency, we think we recommend tapering the drug. We don't recommend abrupt stoppage, so that won't change. In terms of the phase two portion, we'll just start patients at 50 and 100 milligrams. They won't titrate up.

Thank you. And our next question comes from the line of Andrew Barron. Your line is from SVB Lyric.

Hey, this is Chris on for Andy. Thanks for taking the question. I know you said that you'll provide more specifics around the planned share buybacks later on, but I was just wondering if there could be any help or color on general aspects of it, such as do you expect to start it as soon as the process is completed, or And will it be at the market or a potential tender?

Hey, this is Jonathan. Thanks for the question. You know, implicit in your question is there's many different ways to execute share repurchases. We have a fairly significant amount of repurchases to do as a percentage of our market cap. So I think it's fair to say you could expand. We've guided that we'll do it over 12 to 18 months. So I think it's fair to expect that there'll likely be more than one mechanism by which we'll do it. Our planning right now is ongoing, and it's really designed to try to make sure that we do it in the most efficient way that we can and in the way that will, you know, be most likely to increase long-term shareholder value. We'll, you know, we'll give more guidance as we get closer to executing. And, you know, we would expect that we will be commencing share repurchases, you know, at some point in due course following closing, but more to come on that.

Thank you. I'll now turn the call back over to Chief Executive Officer Jackie Faust for any closing remarks.

Thank you very much, Operator, and thank you very much, all of you, for joining us this morning. We look forward to more interactions with you over the coming weeks and months. I just want to reiterate that despite the challenges and uncertainties that lay ahead, I remain very excited about the progress we're making across our focus areas this year, as well as the progress that our team has delivered across our oncology programs as well. To close, I would like to thank very much my IGLs colleagues for their dedication and passion for making a difference for our patients, both in oncology and genetically defined diseases. I also want to thank all the patients, caregivers, and physicians who participate in our clinical trials. Without them, we could not do what we do. Thank you again for joining us today. Take care.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect.