Agios Pharmaceuticals Inc

NASDAQ:AGIO

Earnings Call Analysis

Agios Reports Growth and Future Potential in Rare Disease Therapies

In Q3 2024, Agios achieved $9 million in net revenue from PYRUKYND, marking a 22% increase year-over-year. The company noted muted growth ahead, with focus on launching in thalassemia by 2025. They also received $1.1 billion in milestone payments following FDA approval of vorasidenib, enhancing their strong cash position of approximately $1.7 billion. Agios aims to file for expanded indications in thalassemia by year-end and has completed enrollment for the Phase III RISE UP study for sickle cell disease, targeting therapeutic launches in 2026. They remain committed to cost-effective strategies while preparing for significant market opportunities.

Agios Pharma's Recent Achievements and Future Prospects

Agios Pharmaceuticals is focused on developing innovative therapies for rare diseases, particularly those affecting red blood cell health. In Q3 2024, Agios achieved a significant milestone by generating $9 million in net revenue from its lead product, mitapivat, which indicates a 22% year-over-year increase. This marks a steady progression as the company prepares for additional launches in the coming years, specifically targeting thalassemia in 2025 and sickle cell disease in 2026.

Financial Position and Strategic Goals

The company closed the quarter with a robust cash position of approximately $1.7 billion, bolstered by $1.1 billion in milestone payments following the FDA approval of vorasidenib. This financial stability is critical as Agios moves ahead with its strategic focus, allocating resources toward upcoming product launches and pipeline expansions while managing a disciplined cash allocation approach.

Future Earnings Guidance

Going forward, Agios anticipates muted growth in PYRUKYND revenue from pyruvate kinase deficiency (PKD) as it pivots toward its anticipated thalassemia launch. This transition is expected to bring variability in revenues quarter-over-quarter but remains a calculated move aimed at maximizing potential future sales in new markets.

Clinical Development and Regulatory Strategy

Agios is making notable strides in its clinical pipeline. The company aims to submit a supplemental new drug application (sNDA) for mitapivat in thalassemia by the end of 2024 to gain broad approval across all subtypes of the disease. It has also completed enrollment for the Phase III RISE UP study for sickle cell disease, which is designed to measure both hemoglobin response and reduction in pain crises with a significant sample size of 198 subjects.

Strategic Collaborations and Market Access Initiatives

Agios is enhancing its market position through collaborations, including a distribution agreement with NewBridge Pharmaceuticals to commercialize PYRUKYND in the Gulf Cooperation Council (GCC) region, encompassing roughly 70,000 thalassemia patients. Additionally, the company is focused on educating payers and health authorities about the rare diseases it targets, anticipating a streamlined process for market access as new therapies reach the market.

Future Value Creation and Market Potential

The company believes that mitapivat has multi-billion dollar potential, particularly given its application across multiple rare diseases. The team's concerted efforts in clinical trials and development, combined with a robust market strategy, position Agios well for future growth. The maturing of its commercial organization and continuous engagement with healthcare professionals and patients are expected to support successful product launches in the near future.

Earnings Call Transcript 2024-Q3

[Operator]

Good morning, and welcome to Agios' Third Quarter 2024 Conference Call. [Operator Instructions] Please be advised that today's call is being recorded at Agios' request.

I would now like to turn the call over to Chris Taylor, Vice President, Investor Relations and Corporate Communications for Agios.

[Christopher J. Taylor, executive]

Thank you, operator. Good morning, everyone, and welcome to Agios' conference call and webcast to discuss our third quarter 2024 financial results and recent business highlights. You can access the slides for today's call by going to the Investors section of our website, agios.com. On today's call, I'm joined by our Chief Executive Officer, Brian Goff; Dr. Sarah Gheuens, Chief Medical Officer and Head of R&D; Tsveta Milanova, Chief Commercial Officer; and Cecilia Jones, Chief Financial Officer.

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 we set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC.

And with that, turn the call over to Brian.

[Brian Goff, executive]

Thanks, Chris. Good morning, everyone, and thank you for joining us. Our mission at Agios is to develop and deliver transformative medicines that elevate and extend the lives of patients living with rare diseases. We are especially focused on rare diseases that result in the dysfunction and destruction of red blood cells, including pyruvate kinase deficiency or PKD, thalassemia, sickle cell disease and lower risk myelodysplastic syndrome or MDS. As red blood cells comprise over 80% of all cells in the human body, optimizing red cell health represents an important path to improved individual health.

Our lead product, mitapivat, a pyruvate kinase activator, has a novel mechanism of action that improves red blood cell metabolism and increases the amount of energy or ATP available to support red blood cell health. We are proud to have delivered positive data in Phase III programs in PKD and thalassemia and we are excited about the prospects of mitapivat for sickle cell disease.

Complementing those data readouts and the continued progress across our current pipeline, I am delighted to confirm today that Agios has received $1.1 billion in milestone payments following FDA approval in August of vorasidenib, which originated at Agios. These payments include a $905 million payment from Royalty Pharma in connection with the vorasidenib royalty purchase agreement Agios announced in May 2024 and a $200 million payment from Servier in connection with Agios' divestiture of its oncology business in 2021.

Given the positive Phase III data readouts of mitapivat in thalassemia accomplished this year and the recently announced achievement of full enrollment of the Phase III RISE UP sickle cell disease study, we aim to deploy this strong cash base to prepare for the potential launches of mitapivat in thalassemia in 2025 and in sickle cell disease in 2026.

Beyond this significant infusion of capital, we also made important progress across our advancing clinical pipeline. First, we announced top line data from the Phase III ACTIVATE-KidsT study of mitapivat in children with PK deficiency, who were regularly transfused, our first pediatric study of mitapivat.

And second, we achieved 2 milestones in our clinical development program for lower risk MDS. We announced that the FDA granted orphan drug designation to our potent PK activator, tebapivat, formerly known as AG-946, for the treatment of myelodysplastic syndromes or MDS. And we have initiated enrollment and begun patient dosing in the Phase IIb study of tebapivat in lower risk MDS, an area with profound unmet need and significant market growth.

Importantly, as we round out a very productive and successful 2024, we are on track to achieve our key remaining milestone for this year, submission of an sNDA for mitapivat in thalassemia by the end of the year, seeking a broad label that includes adults living with all subtypes of thalassemia. Sarah will provide a detailed update on our progress and upcoming milestones across R&D in just a few minutes.

Leveraging the positive data observed in the ENERGIZE and ENERGIZE-T Phase III studies of mitapivat, our expanding commercial organization is actively preparing for a potential U.S. launch of mitapivat in thalassemia in 2025. Tsveta will provide greater detail on the market opportunity in thalassemia and the team's robust preparation as well as an update on our current launch in PKD in just a bit.

Finally, as you'll hear from Cecilia, we ended the third quarter with a very strong cash position, with approximately $1.7 billion in cash and investments on the balance sheet, which includes the $1.1 billion in milestone payments we received following FDA approval of vorasidenib.

Before handing off to Sarah, I want to emphasize how incredibly proud we are for all that's been achieved thus far in 2024, how intensely focused we remain on finishing the year strongly and our enthusiasm for continued progress in 2025 and beyond.

With that, I'll now turn the call over to Sarah.

[Sarah Gheuens, executive]

Thanks, Brian. Just recently, we were able to attend 2 significant meetings where we continued engaging with the community. At both the Academy for Sickle Cell and Thalassemia Conference and the SCDAA annual convention, we were reminded once again about the difficult journey for sickle cell patients. And it reinforces our conviction for what we are aiming to bring to patients.

Turning to sickle cell disease, we are saddened by the recent events impacting this community and continue to be steadfast in our commitment to deliver a novel oral therapy that potentially improves anemia, VOCs and how patients feel and function, particularly with respect to fatigue.

Given the positive data we generated in the Phase II portion of the RISE UP study as well as the positive data we have generated in other hemolytic anemia that share a common pathophysiology, we are excited about the potential for mitapivat to become a convenient first-in-class and best-in-class treatment option that improves red blood cell health for patients living with sickle cell disease.

As announced last week, we are very pleased that we met our goal of completing enrollment in the Phase III RISE UP study by the end of the year, just over a year after we began recruiting this cohort. As a reminder, the Phase III study has a planned sample size of 198 subjects randomized 2:1 to mitapivat versus placebo across approximately 100 trial sites globally. There are 2 primary endpoints, hemoglobin response, defined as an increase of at least 1 gram per deciliter in average hemoglobin concentrations over weeks 24 to 52 compared with baseline and annualized rate of sickle cell pain crises.

Driven by a differentiated mechanism of action, we believe that mitapivat has the potential to address the high unmet need in this disease by improving anemia, reducing sickle cell pain crises and making patients feel better. We look forward to reporting top line data from the Phase III next year.

For thalassemia, we aim to deliver the first therapy approved for all thalassemia subtypes. Based on the positive data generated in both the Phase III ENERGIZE study of mitapivat in adults with non-transfusion-dependent alpha or beta thalassemia, and the Phase III ENERGIZE-T study of mitapivat in adults with transfusion-dependent alpha or beta thalassemia, we believe mitapivat has the potential to become a foundational and convenient oral treatment option for all subtypes of thalassemia, including all genotypes and all levels of transfusion burden. We are working diligently to progress the filing and continue to expect to file an sNDA by the end of this year, seeking a label that includes adults living with all subtypes of thalassemia.

In pediatric PK deficiency, we were pleased to announce top line data from the Phase 3 ACTIVATE-KidsT study of mitapivat in children with PK deficiency, who are regularly transfused. We are proud of this trial because, first, this is the first Phase III study to report data in this population and importantly, it's the first completed pediatric study of mitapivat for Agios.

While the pre-specified statistical criterion for the primary endpoint was not met, we believe these results were clinically meaningful given the percentage of patients that achieved the transfusion reduction response, including those who had a transfusion-free response with no red blood cell transfusions and those who achieved a normal hemoglobin response, defined as hemoglobin concentrations within normal limits at least once in 8 weeks or more after transfusion.

And second, safety results from mitapivat were consistent with the safety profile for mitapivat previously observed in adults with PK deficiency who are regularly transfused. With enrollment completed in the Phase III ACTIVATE-Kids trial, we look forward to an anticipated data readout next year.

In parallel with the progress we continue to make across the mitapivat development program, this quarter, we also made important advancements in our tebapivat program. First, we initiated the Phase II study of tebapivat in lower-risk MDS. This open label study will enroll a total of 60 individuals with transfusion-dependent lower risk MDS across 3 dose levels, 10 milligrams, 15 milligrams and 20 milligrams, each of which is greater than the 5-milligram dose that was evaluated in the previous Phase IIa study.

Each dose level cohort will be open for enrollment sequentially, without pauses between the cohorts, meaning that we will first enroll 20 patients in the 10-milligram dose cohort and once those slots are filled, we will begin enrolling 20 patients in the 15-milligram dose cohort and then we will do the same for the third cohort of 20 patients at the 20-milligram dose. There is a 24-week core period for each cohort, followed by a 156-week extension period.

The primary endpoint of this study will be transfusion independence, defined as remaining transfusion-free for at least 8 consecutive weeks during the core period. Secondary endpoints will include safety, change in hemoglobin and additional measures of anemia.

Similar to thalassemia, with this program, we aim to deliver the first oral therapy that addresses anemia due to ineffective erythropoiesis in lower-risk MDS, which affects approximately 75,000 to 80,000 patients in the U.S. and EU5 and accounts for approximately 70% of all MDS cases.

Also this quarter, we were delighted to receive FDA orphan drug designation for tebapivat for the treatment of MDS. This underscores the importance of bringing new oral treatment options to patients suffering from this rare disease and we expect to provide additional milestone timelines once enrollment is further along.

Looking forward, we are excited to be attending the upcoming annual meeting of the American Society of Hematology, ASH and look forward to the publication of accepted abstracts on November 5.

With that, I will now turn the call over to Tsveta.

[Tsveta Milanova, executive]

Thanks, Sarah. As we prepare for a potential launch in thalassemia, we are reminded of the significant unmet need in this disease and also the value PYRUKYND may bring to thalassemia patients across all subtypes. We continue to validate this through the powerful patient connections we experience at conferences like ASCAT and in local community meetings at selected patient centers.

Thalassemia is much more prevalent than PK deficiency, with approximately 6,000 adults diagnosed in the U.S., approximately 4,000 of whom are non-transfusion-dependent. The diagnosis rate in thalassemia is high, with many patients diagnosed before adulthood. Given the availability of claims data and ICD-10 codes, these patients are known to the health care system, which provides important clarity for our launch preparations.

Treatment options are limited, especially for patients with non-transfusion-dependent disease, with most patients relying on supportive therapy. All forms of thalassemia bring higher rates of serious morbidities, reduced quality of life and a heightened risk of premature death. The burden of disease is high and the associated cost of care is significant.

Galvanized by the positive data from the ENERGIZE and ENERGIZE-T studies, our commercial organization is actively preparing to address this high unmet need with a potential U.S. launch of PYRUKYND in thalassemia next year. We're especially enthusiastic about the potential for PYRUKYND to become the first therapy approved for all thalassemia subtypes.

Our team continues to make progress across 4 areas of launch preparation. First, we continue to conduct extensive market research and claims data-based analysis to further refine our market insights and inform our launch targeting and execution. Based on the work we've done, we estimate that PYRUKYND's initial launch focus will address approximately 65% of the adult thalassemia patient population.

We expect patients who already have regular contact with the health care system due to symptoms of their disease to be considered for therapy first. These patient segments include transfusion-dependent patients as well as non-transfusion-dependent patients, who are already experiencing complications or are living with debilitating fatigue. Our team is actively engaged in the field, deepening our insights across the different patient segments and the diverse multicultural aspects of thalassemia.

Second, our ongoing disease state education campaign has been focused on 3 areas. First, we are highlighting the pathophysiology of the disease, including ineffective erythropoiesis and hemolysis. Second, we believe it's important for patients and physicians to understand the long-term complications and burden of disease across all thalassemia subtypes, particularly for patients with non-transfusion-dependent disease who suffer from the misconception that they are at less risk.

And third, as we continue to engage with both patients and physicians, we highlight the importance of frequent disease monitoring and management so treatment plans can be tailored to the individual patient's needs.

To bring all of this together, we are pleased to share another example of the powerful Rethink Thalassemia campaign, which we have rolled out in the recent months. The striking image and headline invite closer inspection of the words depicting the hidden risks of thalassemia. The feedback from this campaign has been very positive from both patients and physicians.

They highlight how relevant and valuable they find the disease education content, not only when it comes to understanding the disease pathophysiology and complications, but also to connect that to the importance of ongoing monitoring and management.

Our third area of focus in launch preparation is the discipline expansion of our commercial and medical teams to rightsize the organization for a successful launch in this larger but still rare market. We're steadily building the team and adding additional capabilities as we approach a potential launch with a keen focus on being as capital-efficient as possible.

And fourth, our market access team is already engaging with payers on disease state education. I'm proud of the broad access our team has achieved for PYRUKYND in PK deficiency and we are aiming for the same strong outcome in thalassemia.

Outside the U.S., the Gulf Cooperation Council, or GCC region, is home to approximately 70,000 patients with thalassemia and some of the leading treatment centers in the region were part of our clinical trials. As we announced last quarter, we're pleased to have entered into a distribution agreement with NewBridge Pharmaceuticals to prepare for a potential commercialization of PYRUKYND in the GCC region. Complementing this partnership, we are delighted to have secured breakthrough medicine designation for PYRUKYND in thalassemia, granted by the Saudi FDA or SFDA. We're actively collaborating with NewBridge to develop an optimal regulatory and commercial strategy for the GCC region.

As a reminder, the access path in individual GCC countries usually begins with a price set at the regulatory level, followed by access negotiations with health authorities, local institutions and the private sector. We look forward to navigating each of these elements in collaboration with NewBridge.

Next, let me provide a brief update on the current launch of PYRUKYND in PK deficiency. In the third quarter of 2024, we generated $9 million in net PYRUKYND revenue, compared to $8.6 million in the second quarter of 2024. In the U.S., a total of 211 patients have completed a prescription enrollment form, including 10 in the third quarter of 2024, a 5% increase versus the prior quarter. This has translated into 127 net patients on therapy.

We believe the capabilities we continue to strengthen through the current launch will provide a firm foundation from which to maximize potential future U.S. launches of PYRUKYND in thalassemia in 2025 and in sickle cell disease in 2026.

In closing, we are inspired and energized by the potential to bring a new therapy to these underserved patient populations around the world.

With that, I will turn the call over to Cecilia.

[Cecilia Jones, executive]

Thanks, Tsveta. Our third quarter 2024 financial results can be found in the press release we issued this morning and more detail will be included in our 10-Q, which will be filed later today. Let me now take a moment to provide some context and highlight a few key points.

Third quarter 2024 net PYRUKYND revenue was $9 million, an increase of 22% compared to the third quarter of 2023. Consistent with other rare disease launches, gross-to-net has been and is expected to be in the 10% to 20% range on an annual basis. Going forward, aligned with our strategic shift towards preparing for the potential launch in thalassemia, for PKD revenues, we expect to see muted growth and quarter-over-quarter variability in line with what we have seen in recent quarters.

Cost of sales for the quarter was $0.8 million. R&D expenses were $72.5 million for the third quarter, a decrease of $9.4 million compared to the third quarter of 2023. This decrease was primarily driven by the $17.5 million upfront payment associated with the license agreement with Alnylam, which was recorded in the prior year.

SG&A expenses were $38.5 million for the third quarter, an increase of $12.7 million compared to the prior year quarter. This was primarily driven by an increase in commercial-related activities as we prepare for the potential approval of PYRUKYND in thalassemia in 2025.

Importantly, this quarter, we received a total of $1.1 billion in milestone payments following the FDA approval of vorasidenib. These payments include a $905 million payment from Royalty Pharma in connection with the vorasidenib royalty purchase agreement Agios announced in May 2024 as well as a $200 million payment from Servier in connection with Agios' divestiture of its oncology business in 2021, both of which were recorded under other income in the P&L. As a reminder, Agios will retain a 3% royalty on annual U.S. net sales of vorasidenib greater than $1 billion.

Including these milestone payments, we ended the quarter with cash, cash equivalents and marketable securities of approximately $1.7 billion. We expect that this balance, together with anticipated product revenue and interest income, will provide the financial independence to prepare for potential PYRUKYND launches in thalassemia and sickle cell disease, advance existing programs and opportunistically expand our pipeline through both internally and externally discovered assets.

We remain focused on creating shareholder value, including by proactively managing our cost base and deploying a disciplined cash allocation approach as we prepare to support potential future launches of PYRUKYND. As we move toward additional potential value-creating milestones in the near term, I am confident that our balance sheet will continue to enable us to execute from a position of strength.

I will now turn the call back over to Brian.

[Brian Goff, executive]

Thanks, Cecilia. Before we open the line for questions, I want to conclude with a few words. 2024 has been marked by exceptional progress at Agios. We continue to deliver on our key priorities and have a very strong financial position, allowing us to maintain this great momentum in the final months of the year and beyond.

In addition to its approved indication in PKD, mitapivat represents a significant opportunity to meaningfully elevate the standard of care for patients with thalassemia and sickle cell disease. We consistently hear firsthand from these communities that there is an immediate critical need for new regimens to treat these diseases. With this, we believe mitapivat is poised to become a first and best-in-class treatment option for multiple indications, translating into a franchise with multibillion-dollar potential.

In addition to mitapivat, we continue to drive our other promising clinical programs forward, focusing on areas where there is a high patient need and providing us with additional opportunities to create significant long-term value and impact for all stakeholders. We look forward to the future as we strive to change the trajectory of these rare diseases.

With that, I'd like to open the call for questions. Operator, please open the line.

[Operator]

[Operator Instructions] Our first question comes from the line of Greg Harrison from Scotiabank.

[Gregory Harrison, analyst]

Great to see all the progress. Two for me. First, how are you thinking about capital allocation and appetite for business development now that vorasidenib has been largely monetized? Maybe there's a particular area you guys find attractive or complementary? And then on sickle cell, maybe you can speak to expectations for the Phase III portion of the trial? And if you can comment on powering with respect to VOC.

[Brian Goff, executive]

Sure. And Greg, welcome back. Great to hear you again.

[Gregory Harrison, analyst]

Nice to be here.

[Brian Goff, executive]

Two parts. Cecilia can handle the capital allocation question and then Sarah can take over for RISE UP Phase III expectations.

[Cecilia Jones, executive]

Great. Thanks, Greg. So in terms of capital allocation, we're, of course, very proud of the strong balance sheet we have now. And in terms of how we think about that, our priorities, of course, will be the potential launches for thal and then hopefully sickle cell, continuing to advance our pipeline, which you'll hear a little bit more about MDS today as well.

And then expanding that pipeline, both internally and/or externally, we're pretty disciplined and the amount of cash we have in the balance sheet doesn't change that. We look at things with the same criteria we have in the past in terms of being rare, transformative, have a clear regulatory path and obviously create value for our shareholders. So that hasn't changed. We continue to look at that. And different areas, we've said we are agnostic in terms of modality and we'll keep looking at how we want to expand that.

[Brian Goff, executive]

And then I'll turn it over to Sarah, but I do want to just lead in by saying how proud I am of Sarah and the team for this incredible consistent executional excellence. We were really pleased with the fact that even before today's call, we were able to announce complete enrollment of the Phase III study for RISE UP. And if you're keeping track, it's been about 12 months. And I think that says a lot about the profile, the trust the community has in us. And again, very importantly, the executional excellence from the team. So with that, Sarah, how about that as a setup?

[Sarah Gheuens, executive]

Thank you, Brian. Thanks for the question. So yes, so we are very proud of the RISE UP team. We indeed accomplished complete enrollment, which was one of our milestones for this year. So we are very excited about that and are now looking forward to finish the trial, to get it to the end.

So the expectations for Phase III, so it's a 1-year duration. We have 2 primary endpoints, as you know. One is hemoglobin response. The other one is sickle cell pain crisis reduction. And that is, of course, with the goal to try to deliver a drug that can hit on the totality of sickle cell disease, meaning both hemolytic anemia and vaso-occlusion improvements. Both endpoints are powered to have 90% or slightly more, so to be able to detect that difference. So we're very excited about this and are looking forward to the end of the trial.

[Operator]

Our next question will come from the line of Danielle Brill from Raymond James.

[Alex Nackenoff, analyst]

This is Alex on for Danielle. Another one on RISE UP. Could you talk a little bit about your primary endpoints in the RISE UP study? Do you think you need to hit on both endpoints? Or will success on just one support a regulatory filing? For example, is it possible that hitting on hemoglobin response and another secondary clinical endpoint like fatigue could support a regulatory filing?

[Sarah Gheuens, executive]

Well, thanks for the question. So yes, we have 2 primary endpoints, one being hemoglobin, as I just mentioned and then the other one focused on VOCs. We did choose the 2 primary endpoints because they can provide relevant information for the totality of the disease. So in a situation in which we would not be able to hit on one endpoint, but only would hit on the other endpoint, we still have an opportunity to transfer alpha to secondary endpoint testing, which would allow us to further look for clinical benefit.

One of those endpoints is indeed fatigue. We always try to deliver with our drug across the different hemolytic anemias that we have studied the hemoglobin plus story, meaning that we improve hemolytic anemia, but then also try to hit on feel and function. And as you know, we've been able to deliver to that on PKD and thalassemia, highlighting an improvement in fatigue. Our thalassemia data also highlighted that there was an improvement in the 6-minute walk test.

And so our RISE UP study is set up in a similar way to provide multiple ways that we can speak to clinical benefit for sickle cell disease patients. In regards to what is needed for regulatory approval, that is the regulators to look at the clinical trial data at the end of the package. Of course, when we submit, we always -- we believe that there is a benefit risk profile that supports approval, but it's ultimately the regulators that do the review and decide on approval.

[Brian Goff, executive]

I would like to add, and this is, again, echoing not just the point of executional excellence, but also the scientific expertise from the team that everything that Sarah just went through was actually outlined in a poster in 2021. In other words, we didn't change the design. From day 1, it's been set up this way.

[Sarah Gheuens, executive]

Yes.

[Brian Goff, executive]

And I think that's important, particularly in the context of the recent evolution in sickle cell disease with other therapeutic options. And we're very proud of the fact that from day 1, we had a design that was intended to be a so-called hemoglobin plus design.

[Operator]

Our next question will come from the line of Greg Renza from RBC Capital Markets.

[Gregory Renza, analyst]

Congrats on the progress. Brian, you've commented on just the trust that you've earned with respect to the community on the execution and the value that you're providing in the development program for mitapivat with sickle cell. I'm just curious if you can comment on the general feedback, the potential for mistrust from the community just given the Oxbryta withdrawal and the happenings that you alluded to there.

What is Agios doing to at least track that, detect that and sort of incorporate that into your go-forward with the trial and also how you are touching patients? And just secondarily, have you had any communications or plan to with regulatory just on the potential risks that have been sort of highlighted about running trials in the Africa site? Congrats.

[Brian Goff, executive]

Yes. Thanks a lot, Greg. That's an important question that you ask because the sickle cell disease community, I think, not surprisingly to anybody, has been through a lot. It's always been limited treatment options that have been available and the community at large has certainly gone through a journey of drugs available and then not available in certain regions, and it's a real challenge.

And an example of what we do is, Sarah and I and others from the team just attended the Annual Sickle Cell Disease Association of America meeting in Atlanta. And it was a chance for us to listen, most importantly and hear what's on their mind, what their concerns are, how they think about treatment options in the future.

And again, just to echo what I'm very proud of is, we have always looked to maintain high touch with the community. And an example of that goes all the way back to when we designed the RISE UP trial, we very deliberately involved members of the sickle cell warrior community. And the input that we got was not just in the trial design, inclusion, exclusion criteria, but very importantly, how to appropriately recruit for the trial. And now you've seen the results of that. It recruited beautifully.

And then hopefully, when we get to the point of commercialization, we're leaning on that community to guide us in that regard as well. So I think the main message about trust is we try to be very visible. We listen. We listen without bias and we make sure that the community sees their fingerprint on what we do based on the input that they've provided.

[Sarah Gheuens, executive]

Yes. And then to add to that, in regards to going forward with the trial, so we continue to -- it's a Phase III trial. So obviously, we do monitoring of data as we go along. We do all of our standard procedures to make sure that we continue to execute well on this trial and we'll continue to watch carefully as this trial evolves.

And in regards to potential risk for sickle cell disease, specifically with running clinical trials, it's a tough devastating disease in which patients are suffering from a ton of comorbidities and it's a deadly disease. So there's always challenges when you run a trial like this, but it speaks to the unmet need in this patient population.

So while these trials are challenging and difficult, there's such unmet need in this patient population that we really hope to be able to deliver a drug that can be meaningful for the patient community and treat the totality of the disease.

[Brian Goff, executive]

Just maybe one more point on this to drive it home is Sarah and I also had a call with members of the sickle cell disease warrior community, actually part of the advocacy group that I just talked about. And on that call, there were 7 members of the community. And among that, 3 of them were in crisis or recently had a crisis. And we walked away with a sobering reminder about just how serious this disease is and how desperate the community is for new therapeutic options. And it should be plural form. We always cheer for progress from everybody because this is a disease that needs multiple options.

[Operator]

Our next question will come from the line of Eric Schmidt from Cantor Fitzgerald.

[Eric Schmidt, analyst]

Just sticking with this topic of the unfortunate withdrawal of Oxbryta about a month or so ago, what have you learned scientifically or what kind of thoughts do you have scientifically with regard to the mechanism of that drug and how it relates or doesn't relate to mitapivat and how it sort of maybe influences your chances of success in the ongoing study?

[Sarah Gheuens, executive]

So thanks for the question. Well, as you know, Oxbryta has a very different mechanism of action and we feel -- I should start like we really feel sad about what happened. And to Brian's earlier point, it's a sad circumstance, right, because this patient community really has barely any options. So we're sad to see this.

It is a very different mechanism of action. The clinical trials were set up differently as well. So I think that is -- we don't know what happens beyond what has been publicly declared. But then focusing on our trial, our drug works very differently and have that multimodal approach to treating -- potentially treating sickle cell disease.

So we do reduce 2, 3-DPG and increase ATP, and we think both of these components can interplay and be important to avoid sickling and to improve hemolysis and thereby the anemia component. So very different mechanism of action than Oxbryta, which then also, of course, translates into the clinical data that we have seen so far with a very -- with a Phase II clinical trial dataset that was very robust, a placebo-controlled trial and that mechanism of action has translated into us demonstrating an improvement on hemoglobin and then also observing that positive trend for hemolysis and VOC reduction. So we are excited to continue to progress this -- the drug forward in the Phase III.

[Operator]

Our next question will come from the line of Chris Raymond from Piper Sandler.

[Christopher Raymond, analyst]

Congrats to you guys. Maybe just another question with regard to the Oxbryta situation. I know you talked about engaging the sickle cell community. But this is a question that's come up with investors a lot and I'm not sure if there's a real good answer here. But do you have a sense as to how the regulatory perspective has changed on this? There's some debate that perhaps has made it raise the bar and then another debate that perhaps it's actually lowered the bar in terms of another therapy on the market. Just any sense there for how regulators might be reacting to this?

[Sarah Gheuens, executive]

Yes. And I think -- so thanks for that question because I think Brian actually touched upon it, like with the poster that we presented in 2021, which was a trial design of Phase III. From the get-go, we had a very different clinical development approach plus a regulatory approach than the pathway that Oxbryta followed. So Oxbryta had an accelerated approval by demonstrating hemoglobin improvement at the time of submission and then had the follow-on studies to further demonstrate clinical benefits.

Our goal from -- when we first designed this trial is to deliver a treatment that at the end of the clinical trial can speak to clinical meaningful benefit, meaning hemoglobin plus and sickle cell pain crises reduction. So based on what happened, we have not changed our approach to our clinical design or our approach to the regulators. As I mentioned earlier, for any data package you submit, it's always a collaboration with the regulators after they review the first package and then they'll ask us more questions. And ultimately, they get to decide on the ultimate benefit risk.

[Operator]

Our next question comes from the line of Tessa Romero from JPMorgan.

[Tessa Romero, analyst]

So switching gears a little bit to thalassemia, you outlined this morning several patient groups in your slide deck that are part of your initial launch focus for PYRUKYND. Are you able to provide a little bit more specific quantitative detail around how the epidemiology breaks out in terms of patient numbers in each of these 3 key target populations you mentioned? And how often are these patients generally seeing their health care provider across these 3 key groups?

[Brian Goff, executive]

Thanks, Tessa. I'm just going to start by saying that you're making Tsveta smile because we love the questions on sickle cell disease. We're very excited about the potential with a potential launch scenario in 2026, but even closer is thalassemia, where we've consistently messaged that we're looking forward to this potential launch in 2025. So I'm going to let Tsveta take over on your questions.

[Tsveta Milanova, executive]

Absolutely. Thanks, Tess, for the question. We are very excited with the potential of having an approval for thalassemia next year and actively preparing for launch. When we think about thalassemia, truly, it's an indication. It's a beautiful rare disease indication when it comes to commercialization for 3 main reasons.

The first thing is that we know that there are 6,000 adults diagnosed with thalassemia in the U.S., and I'm going to underline diagnosed here because these patients are known and engaged to the health care system. And we know that that's the case because there are ICD-10 codes available, which allows us to effectively and efficiently deploy our resources when it comes to launch preparation.

We talked a lot about sickle cell disease and the high unmet need there, but that's also very, very true for thalassemia as well. The unmet need is known and we continue to engage both with patients and physicians in our prelaunch efforts to continue to educate them on the burden of disease.

When it comes to which patients will be considered for our initial launch focus first, as you mentioned, we believe that about 65% of the 6,000 patients will be our focus for initial launch. And these patients are 3 groups of patients. These are patients that are very actively engaged with the health care system.

The first one is the transfusion-dependent patients who are going frequently for their transfusions and have an engagement with their hematologists. That depends on their transfusion frequency, but more or less, you can say that they are seeing and engage with the health care system is probably on a monthly basis. The second group of patients are the non-transfusion-dependent patients who have already developed comorbidities.

They require frequent monitoring and management. It depends on the specific patient population and the frequency there, but we know both from claims data and our initial account profiling that these patients are relatively regularly seen and they will be considered for management and further monitoring as well. And the third part of the patient population, which comprises the 65% are the non-transfusion-dependent patients who are experiencing debilitating fatigue. It's impacting their daily life and they will be seeking for a potential treatment option as well. We haven't provided specific details on this patient population, but as the launch progresses, we'll be providing additional information as well.

[Brian Goff, executive]

And I'll just add, too, I mean, Tsveta, with all of her rare disease launch experience is the first to remind us that launch sometimes is a sort of odd term because it's not a point in time, it's a continuum. So even on this guidance with the sequencing, if we could say it that with those segments, we'll continue. And Tsveta is constantly working on keeping the team ahead of segment 1, segment 2, et cetera. And we expect to be progressing for the long term in thalassemia and then again, hopefully, in sickle cell disease as well.

[Operator]

Our next question will come from the line of Divya Rao from TD Cowen.

[Divya Rao, analyst]

This is Divya on for Mark. One, to stay on thalassemia, would you be able to discuss how you're thinking about timing and design of the pediatric trials now that we have at least initial data or the top line data from the Kids trial in PKD? And then our second question is the initial data with tebapivat in MDS, it obviously showed a little bit of signal, but it was relatively modest for the 5-mg dose. Could you talk about what you think the bar for success is for the Phase IIb now that you're looking at dose levels that are higher than the initial dose tested?

[Sarah Gheuens, executive]

Thanks, Divya. So for thalassemia, the pediatric trials, yes, so indeed, we are very proud of the first PKD pediatric trial in which we were able to demonstrate that some children experienced transfusion independence. So we're very pleased to see that because that's definitely clinically meaningful.

For the timing and the design of the trial, so we are now -- we also now have the benefit-risk profile in the thalassemia adult patient population. So you can expect a similar approach from us as what we have taken for PKD. We have not gone into further detail on the timing of when we would initiate so that more to come at a later time point.

In regards to MDS, yes, we did have -- we did meet our pre-specified criterion for the Phase IIa in which we observed 40% of transfusion independence in the patient population we had enrolled. And to your point, we did learn there that the PK in MDS patients was different than what we had observed in healthy volunteers.

So that, of course, led to changes for our Phase IIb. And as you see, we now are -- have moved forward with the Phase IIb testing higher doses, 3 higher doses to be able to hopefully strengthen the observations that we had observed and are focused on transfusion independence in that trial and 8-week or more transfusion independence based on clinical advisory feedback that we received. So are excited to progress that trial and more to come.

[Brian Goff, executive]

And we're very excited about the potential in MDS. I know folks pay attention to others who are in this market and we took note this morning of the continued progress that we see with Reblozyl and it's a rapidly growing market. There is very high unmet need. It's similar in a way to sickle cell disease in that multiple therapeutic options will be the answer. And we're very proud of the fact that we have a very differentiated mechanism. So this is an important step for us to be able to start the Phase IIb.

[Operator]

Our next question will come from the line of Alec Stranahan from Bank of America.

[Alec Stranahan, analyst]

Two from me. First, on the thalassemia launch prep, given it is a continuum, as Brian said, I wonder if you have a sense as to how quickly payer access could come online? And would you say payers are fairly aware of mitapivat's clinical profile and its unmet need or maybe some more work to do there? And then on the upcoming full readout for ENERGIZE-T, should we expect any additional efficacy data from the readout beyond what was shown in the top line? I guess where would you direct people's attention in the next update? And it seems like ASH is probably the next most likely venue, right?

[Brian Goff, executive]

Thanks, Alec. And so Tsveta can start with the question on the payers and the thalassemia launch and then Sarah can take over with ENERGIZE-T.

[Tsveta Milanova, executive]

Absolutely. Thanks, Alec. It's a very good and relevant question. So from a payer perspective, probably as you've seen from the slides and what we communicated today, the market access is a core pillar in our launch preparation. Our market access team is already engaging with payers on disease state education.

When you look at thalassemia and you put a payer lens on it, it's a rare disease. There is a relatively low awareness of the disease. So we are definitely educating on the disease. But on the positive side of it is that it's a rare disease and we don't expect that to be high on the payer radar for management as well. So the team is preparing for launch. I must say we've had an excellent outcome in our access efforts from PK deficiency. We have a very strong team and we continue to see the same success and progress moving forward with thalassemia.

[Brian Goff, executive]

Great. And then Sarah for ENERGIZE-T?

[Sarah Gheuens, executive]

Yes. For ENERGIZE-T, so we -- in our press release, you know that we've declared our primary endpoint plus one of the secondary endpoints. So you can expect from us typical to how we do all of our Phase III readouts and intent to treat analysis with the details around key secondary endpoints as well in the safety overview. Indeed, we are hoping to be able to present at an upcoming medical meeting. ASH is currently not available yet. So abstracts will be released on November 5. So we are eagerly waiting for that as well.

[Operator]

Our next question will come from the line of Salveen Richter from Goldman Sachs.

[Lydia Erdman, analyst]

This is Lydia on for Salveen. Congrats on all the progress. Just 2 quick ones from us. So on sickle cell, now that enrollment is complete, are you able to provide any details on the number of baseline VOCs? And then just on tebapivat, can you just discuss when you plan to share data from the Phase IIb? And just remind us what will be included with this update?

[Sarah Gheuens, executive]

So for sickle cell disease, we do not present baseline characteristics. We typically tend to present everything when we release the top line results. So nothing to come before we provide the full data readout. And then in regards to tebapivat and, yes, Phase IIb, we have obviously now met our corporate milestone for this year. So we are looking forward to provide more detail and timing on the rest of the trial next year.

[Operator]

Our next question will come from the line of Andrew Berens from Leerink Partners.

[Andrew Berens, analyst]

Two for me. On 946, I think you dosed some patients in the Phase IIa trial higher than the 5 milligrams. If that's correct, how we see those data presented somewhere? And can you remind me of how much headroom you think you have on dosing before you might hit a DLT? And then I think this was touched on a bit, but we've heard that there was a problem with sepsis and malaria in the African trial sites and some investors think that this was related to problems in conduct of those sites. I think your trial is at some of those sites. And can you give us some color on what's being done to ensure that a similar problem doesn't occur?

[Brian Goff, executive]

Thanks, Andy. I'm going to let Sarah go, but I did want to first say you asked in terms of 946 and we're practicing on our end to say tebapivat. We're very proud of the new INN that we have for our second more potent PK activator. And Sarah, you want to start with the IIa?

[Sarah Gheuens, executive]

So the Phase IIa tested the 5-milligram dose. And so we did not test higher doses in that IIa. So right now the higher doses that are being tested is in the IIb portion of the trial, which is 10, 15 and 20 milligrams. In regards to when I expect to hit the DLT, I don't know, because we haven't gathered the data yet.

So the data will accrue over time and then we'll see if we observe anything that makes us not want to further explore a certain dose. So more to come on that. In regards to what you asked for mitapivat and sepsis and malaria observed in the Oxbryta trials, so malaria is endemic in certain regions of the world.

We have part of our trials in R&D conducted in Africa as well, but we have a very good geographical distribution across the board within RISE UP. So we are excited about that. The observations that have happened on Oxbryta are not observations that have happened on hydroxyurea, for instance, that have been observed in Africa. So I think our data will accrue over time and we'll observe when we have the final trial data.

[Operator]

And this concludes our Q&A. I will now turn it over to Brian for any final remarks.

[Brian Goff, executive]

All right. Thanks a lot, Victor, and thank you very much, everyone, for participating in today's call. It is clear this is a very exciting time at Agios. We truly believe that we're poised to deliver transformative new therapies for patients and to create significant long-term value for shareholders. So thanks again, and we look forward to speaking with you again soon.

[Operator]

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect. Everyone, have a great day.