Agios Pharmaceuticals Inc

NASDAQ:AGIO

Earnings Call Transcript 2024-Q1

[Operator]

Good morning, and welcome to Agios' First Quarter 2024 Conference Call. [Operator Instructions] Please be advised that today's conference 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. Please begin.

[Christopher J. Taylor, executive]

Thank you, operator. Good morning, everyone, and welcome to Agios' conference call and webcast to discuss first quarter 2024 financial results and recent business highlights. You can access 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, our 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 results and events could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC.

And with that, I'll turn the call over to Brian.

[Brian Goff, executive]

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, and we are off to a fast start in 2024. Our foundation today leverages mitapivat's novel mechanism of action, which focuses on overall red blood cell health, and has been a key driver for our recent clinical results.

On January 3, we reported positive data from the Phase III ENERGIZE study of our lead PK activator, mitapivat, marketed as PYRUKYND, in patients with nontransfusion-dependent thalassemia. This study met both the primary endpoint of hemoglobin response rate as well as both key secondary endpoints associated with change from baseline in FACIT-Fatigue score and average hemoglobin concentration, and we look forward to presenting these data at an upcoming medical meeting.

As a reminder, the nontransfusion-dependent thalassemia accounts for approximately 2/3 of thalassemia in the U.S., and has no FDA-approved treatment options. Despite not requiring regular transfusions, it is increasingly understood that these patients experience a significant impact on their quality of life, a wide range of serious morbidities and an elevated risk of premature death due to chronic hemolysis and ineffective erythropoiesis. Based on these data, our team is actively preparing for a potential launch in thalassemia in the U.S.

Complementing the ENERGIZE study in nontransfusion-dependent thalassemia, we continue to advance the Phase III ENERGIZE-T study of mitapivat in transfusion-dependent thalassemia. We expect to report data from this study in the second quarter, a slightly more refined time frame than previously communicated, and we plan to submit a single regulatory filing encompassing data from both ENERGIZE and ENERGIZE-T to the FDA by the end of the year.

In parallel, we look forward to near-term milestones across several additional clinical programs in our pipeline, including completing enrollment in the Phase III portion of the RISE UP study of mitapivat in sickle cell disease by the end of this year, and reporting data from 4 additional Phase III studies by the end of 2025. Sarah will provide a detailed update on our progress and upcoming milestones across R&D in just a few minutes.

Given the consistent positive data we've generated across the mitapivat development program and the high unmet need in our target disease areas, we believe mitapivat has the potential to transform the course of multiple hemolytic anemias by improving red blood cell health and to become a multibillion-dollar franchise.

To help realize the full commercial potential of mitapivat and based on the strength of the ENERGIZE data, our commercial organization is laser-focused on building upon the infrastructure established through our current launch in pyruvate kinase deficiency, or PKD, to prepare for potential U.S. launches of mitapivat in thalassemia in 2025 and in sickle cell disease in 2026. Tsveta will provide greater detail on the market opportunity in thalassemia and the team's robust preparation for launch, 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 first quarter with a strong cash position, with approximately $714 million in cash and investments on the balance sheet. Importantly, we have the potential to further bolster our cash position in the near term, as Servier announced FDA filing acceptance and priority review for a new drug application for vorasidenib for the treatment of certain IDH mutant diffuse glioma.

You'll recall that as part of the divestiture of Agios' oncology business to Servier, Agios retains rights to a potential $200 million milestone upon FDA approval of vorasidenib and 15% royalties on potential U.S. net sales. If approved, vorasidenib would become a first-in-class targeted therapy for patients with IDH mutant gliomas, and we look forward to the PDUFA action date of August 20, 2024.

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

[Sarah Gheuens, executive]

Thanks, Brian. As we approach top line data readout for the Phase III ENERGIZE-T study of mitapivat in transfusion-dependent thalassemia, I would like to highlight a few key elements of the mitapivat development program in thalassemia.

As a reminder, the Phase III program of mitapivat with thalassemia, namely ENERGIZE and ENERGIZE-T, was designed to deliver data across all subpopulations of thalassemia, including alpha and beta thalassemia and populations with different transfusion needs.

As Brian mentioned, only patients with transfusion-dependent beta thalassemia, which represents 1/3 of U.S. patients, have an FDA-approved treatment option. The other 2/3 of patients in the U.S., including all patients with alpha thalassemia and those patients with beta thalassemia who are nontransfusion dependent, have no approved treatment.

It is a common misperception that nontransfusion dependent or NTD thalassemia patients are less sick. When the reality is that these patients suffer from a poor quality of life and a higher rate of serious morbidities, including thrombosis and premature death. This population, which represents approximately 2/3 of total thalassemia patients in the U.S., has a high unmet need for any treatment.

This unmet need was strongly reinforced through our Phase III ENERGIZE study by the speed of enrollment, the total number of patients enrolled and the high completion and rollover rates we observe. We were very pleased to announce positive results from this study in January and are eagerly awaiting the opportunity to present more complete results at an upcoming medical meeting.

Turning to those results. Our goal is to build from our Phase II findings with a more rigorous way to measure hemoglobin response in the Phase III ENERGIZE trial, which we defined in the primary endpoint as an increase of equal or more than [ 1 gram per deciliter ] in average hemoglobin concentrations from week 12 through week 24 compared to baseline, but in a much larger trial.

We were excited to be able to announce success in this trial as treatment with 100 milligrams mitapivat BID demonstrated a highly statistically significant result on the primary endpoint of hemoglobin response rate, with 42.3% of patients in the treatment arm achieving a hemoglobin response versus 1.6% of patients in the placebo arm.

In addition, treatment with mitapivat also resulted in statistically significant improvements in both key secondary end points, including a change from baseline in average FACIT-Fatigue score, an important patient-reported measure of how patients feel.

In line with its novel mechanism of action that improves overall red blood cell health, mitapivat is the first molecule that has shown in a randomized controlled trial that it does not only improve hemoglobin, but actually makes people with thalassemia feel less fatigue.

In addition, across the primary and secondary endpoints, all prespecified subgroup analyses favored mitapivat compared to placebo, suggesting that no single subgroup was responsible for driving the results, which supports our aim to file for a broad label covering all thalassemia subtypes.

Turning to ENERGIZE-T. Let me highlight 3 key reasons why we are excited about the upcoming readout in transfusion-dependent thalassemia. First, it is important to recall that regardless of a patient's transfusion needs, thalassemia is a hemolytic anemia. By [indiscernible] PK activity and improving overall red blood cell health, mitapivat's novel mechanism of action directly addresses the underlying pathophysiology of hemolysis in all thalassemia subtypes.

Second, this is a similar approach to the one we took for our PK deficiency program. In that case, in the Phase III ACTIVATE-T study of mitapivat in regularly transfused adults with pyruvate [indiscernible] deficiency, mitapivat demonstrated a statistically significant and clinically meaningful reduction in transfusion burden.

These data, together with positive data from the Phase III ACTIVATE study in patients with PK deficiency who are not regularly transfused, led to FDA approval of mitapivat for adults with PK deficiency regardless of transfusion status, and we look forward to the potential to achieve the same in thalassemia.

And third, in line with mitapivat's mechanism of action, we have seen consistency in the data with improvements in hemolysis and ineffective erythropoiesis in clinical studies across 3 hemolytic anemias, namely PK deficiency, sickle cell disease and nontransfusion-dependent thalassemia.

As a reminder, the primary endpoint of ENERGIZE-T is a transfusion reduction response, defined as a 50% or greater reduction in transfused red blood cell units, with a reduction of equal or more than 2 units of transfused red blood cells in any consecutive 12-week period through week 48 compared with baseline.

This definition allows 2 ways for patients to achieve a reduction in transfusion burden. First, we have an increased time interval between transfusions, or second, through the use of fewer units or both. In order to standardize as much as possible the standard of care in this large global trial, each patient had a specific hemoglobin threshold value that was calculated based on their individual transfusion history prior to enrolling in the trial.

Each patient's individual hemoglobin threshold value that derms the hemoglobin value by which they will receive a transfusion in the trial. As the mechanism of action of mitapivat focuses on increasing red blood cell health and decreasing hemolysis, we are hoping to maintain hemoglobin levels above this threshold and reduce the need for transfusions.

We designed this study by incorporating learnings from prior studies as well as agency feedback, and believe the primary endpoint dynamic assessment period reflects what matters to patients and physicians as well as regulators. We now look forward to the readout of this study in the second quarter, and are planning to submit a single regulatory filing to the FDA encompassing data from both ENERGIZE and ENERGIZE-T by the end of this year, seeking a label that covers people living with all subtypes of thalassemia.

Turning to sickle cell disease. Enrollment in the Phase III portion of the RISE UP study of mitapivat continues to progress, and we are on track to complete enrollment by the end of the year. We have increasing conviction about the role of mitapivat in sickle cell disease, where we believe we have the potential to be both best-in-class and first-in-class. We look forward to reporting top line data from this 52-week study next year and believe firmly in mitapivat's potential to address the high unmet need in this disease by improving anemia, making patients feel better and reducing sickle cell [indiscernible].

We also remain on track to deliver on all milestones across the rest of our advancing pipeline. This quarter, we commenced dosing in the Phase I study of AG-181, an oral phenylalanine hydroxylase or PAH stabilizer for phenylketonuria, abbreviated as PKU, a patient population with limited treatment options. We are excited about the potential to introduce a novel mechanism of action for PKU treatment and look forward to providing an update on next steps as enrollment progresses.

Based on the data generated in the Phase IIa study of our novel PK activator AG-946 in lower-risk MDS, we plan to increase the doses evaluated in the upcoming Phase IIb study, which we expect to initiate in mid-2024.

And in pediatric PK deficiency, we expect to complete enrollment of the Phase III ACTIVATE-kids study in the middle of this year, and we also now expect to report top line data from the Phase III ACTIVATE-kids-T study in mid-2024, sooner than our original projection of year-end.

This is a very exciting time at Agios, and we look forward to providing additional readouts and progress as we proceed through the year. In particular, we are looking forward to sharing with you the set of submissions for [ eHow ] and they are made public in a couple of weeks.

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

[Tsveta Milanova, executive]

Thanks, Sarah. Today, a diagnosis of thalassemia can be daunting for patients and their families. Regardless of the disease subtype, treatment options are limited, and the burden of disease as well as the associated cost of care is significant. All forms of thalassemia, including nontransfusion dependent thalassemia brings higher rates of serious morbidities, reduced quality of life and a heightened risk of premature death.

There are approximately 6,000 diagnosed adults living with thalassemia in the U.S. Approximately 4,000 of whom are nontransfusion dependent and has no available treatment options today. As Sarah mentioned, this patient population was studied in our ENERGIZE clinical trial, which demonstrated the benefit of mitapivat in nontransfusion-dependent thalassemia patients.

The remaining 2,000 are transfusion-dependent and has no oral treatment options. We are eagerly awaiting the data from our ENERGIZE-T study in the second quarter, which is focused on these transfusion-dependent patients.

Our goal with mitapivat is to transform the treatment of thalassemia by becoming the first therapy approved for all subtypes of the disease. [indiscernible] by the positive data from the ENERGIZE study and the potential for positive data from ENERGIZE-T, our commercial organization is actively preparing to address this high unmet need, with a potential launch in thalassemia next year in the U.S.

As we have highlighted, the thalassemia market in the U.S. has more favorable commercial dynamics than PK deficiency. In addition to the data we are generating through the mitapivat clinical development program, we believe there are 3 key factors that have the potential to support adoption of mitapivat in thalassemia in the U.S.

First, driven by the availability of newborn screening and well-established IPD [indiscernible], the diagnosis rate in thalassemia is high, with many patients diagnosed before adulthood. Second, both patients and providers are concentrated in limited number of centers, with approximately 50% of all diagnosed patients treated at fewer than 150 affiliated practices, providing a clear focus for our initial launch. And third, our clinical trial site in the U.S. are in some of the main centers of excellence, so many treating physicians will have first-hand experience with mitapivat.

Given these data and mitapivat target product profile, we believe we are well positioned to provide a potential foundational treatment options for patients with thalassemia, regardless of subtype.

Our team is focused on 4 areas of thalassemia U.S. launch preparations. First, we continue to advance extensive market research and claim data analysis to further refine our market insights and our HCP targeting. Second, we are rolling out a disease education campaign in the coming weeks, designed for both patients and clinicians, highlighting the long-term complications and burden of disease across all thalassemia subtypes. Particularly, nontransfusion-dependent patients who suffer from the misconception that they are at less risk.

Third, we are executing a disciplined expansion of our commercial and medical teams to rightsize the organization for a successful launch in this larger but still rare market. And fourth, our market asset team is already engaging with payers on disease state education. I'm proud that our team has obtained broad market access for PYRUKYND in PK deficiency, and we look forward to the same strong outcome in thalassemia.

In addition to the U.S., we aim to maximize the potential of markets outside the U.S. through coordinated regulatory filings, which we intend to pursue with [ Mark 1 ] for more partners. This market includes the Gulf region, which is home to approximately 70,000 thalassemia patients and some of the leading treatment centers in our clinical trials.

Let me now provide an update on the current launch of PYRUKYND in PK deficiency. In the first quarter of 2024, we generated $8.2 million in net PYRUKYND revenue compared to $7.1 million in the fourth quarter of 2023.

In the U.S., a total of [ 188 ] patients have completed a prescription enrollment forms, including [ 10 ] in the first quarter of 2024, a 6% increase versus the prior quarter. This has translated into net 120 patients on therapy, a 10% increase versus the prior quarter. Patients on therapy continue to spend from a growing and diverse prescriber base of 162 physicians and the [indiscernible] range that is consistent with the adult PK deficiency population in the U.S.

We continue to be encouraged by the persistency of patients on treatment and remain focused on efficiently identifying providers likely to treat patients with PK deficiency. We believe the capabilities will continue to strengthen through the current launch, including efficient targeting analytics, patient and HCP awareness and education and patient access will provide a firm foundation to maximize potential future U.S. launches of mitapivat in thalassemia in 2025 and in sickle cell disease in 2026.

Above all, Agios is once again incredibly proud to be pioneering of potential new therapy for these 2 underserved patient populations.

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

[Cecilia Jones, executive]

Thanks, Tsveta. Our first 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. First quarter 2024 net PYRUKYND revenue was $8.2 million, an increase of $2.6 million compared to the first 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.

Cost of sales for the quarter was $0.6 million. R&D expenses were $68.6 million for the first quarter, an increase of $1.3 million compared to the first quarter of 2023. This increase was primarily driven by an increase in process development expenses, offset by a decrease in workforce related expenditures.

SG&A expenses were $31 million for the first quarter, an increase of $2.6 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.

As a reminder, as part of the divestiture of our oncology business to Servier, we retain rights to a potential $200 million milestone upon FDA approval of vorasidenib and 15% royalties on potential U.S. net sales.

We ended the quarter with cash, cash equivalents and marketable securities of approximately $714.3 million. We expect that this balance, together with anticipated product revenue, interest income and the potential for [indiscernible] milestone will enable the company to fund our operating expenditures and capital expenditures through several value-creating milestones and at least into 2026.

This guidance does not include cash inflows that could extend our runway beyond 2026, including the potential royalties or royalty monetization from vorasidenib, commercializing mitapivat outside of the U.S. through one or more partnerships or other potential strategic business or financial agreement.

We remain focused on creating shareholder value, including by proactively managing our cost base and deploying a disciplined cash allocation approach, and 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 strong balance sheet will enable us to execute from a position of strength.

I will now turn the call back over to Brian for his closing remarks.

[Brian Goff, executive]

Thanks, Cecilia. Driven by a novel and differentiated mechanism of action that improves red blood cell health and a clinical data package that includes positive data spanning 3 hemolytic anemias, we believe mitapivat is poised to become a first-in-class and best-in-class treatment option for multiple indications and with potential to become a multibillion-dollar franchise.

I'm very proud of our team for steadily delivering significant progress. And looking ahead, I'm truly excited about the catalyst-rich 24 months in front of us.

As we continue to take steps towards realizing our vision of becoming a leading rare disease company, we'll continue to strive to be responsible stewards of our balance sheet, and evaluate meaningful opportunities for value creation.

Finally, I'd like to thank all of our employees for their hard work and dedication to our mission of developing and delivering transformative medicines that elevate and extend the lives of patients living with rare diseases, and all of our partners, including the patients, physicians, caregivers and participants in our clinical development programs.

With that, we'll now open the call for questions.

[Operator]

[Operator Instructions] And our first question will come from the line of Gregory Renza with RBC Capital Markets.

[Gregory Renza, analyst]

Great. Brian and team, congratulations on the progress. Brian, we certainly appreciate the more precision and timing for the ENERGIZE-T data. I'm just curious, narrowing it at least from midyear to second quarter, can you just comment a bit on sort of the relevant factors now, what needs to be done and maybe some of the influences around just getting it to that narrow earlier time frame in the second quarter?

And maybe related to that, just remind us just the mechanics on patients rolling over to the open-label extension.

[Brian Goff, executive]

Sure. Thanks, Greg. I'm going to let Sarah talk about the mechanics. But I will say that we are very much looking forward to the data. It's a very special time at Agios because everyone who's followed us, and I know, Greg, you certainly have been there, knows that we were delighted to have the ENERGIZE data back in January.

And this study, ENERGIZE-T is twice the length. That was a -- ENERGIZE was a 24-week study. This is 48 weeks. And we know there's a lot of interest and so we were delighted to give, as you said, a little more granularity on the timing.

But Sarah, do you want to talk about some of the mechanics?

[Sarah Gheuens, executive]

Sure. And so the granularity of the timing is driven by the patients. The last couple of patients in the study, their decisions to roll over into open-label extension or not because, as you know, if a patient would have decided to not go into open label, then they would need to taper down the drug and then have a safety follow-up vintage which could -- which really drives the time frame that creates basically a 7-week difference between potential readouts.

So now we have much more precision around that type of information and so we can narrow our time frame. So that's why we've updated our guidance today. We're very excited about where we are right now, and the team is very focused on delivering the next steps for this specific trial.

[Brian Goff, executive]

Yes. And so this was the exact same scenario that we faced last year when we read out the RISE UP Phase II data for sickle cell disease and of course, the same for ENERGIZE in January.

The big picture that I'll just end with here is that our intent, as we noted in our prepared comments, is to file both studies together to target a label that encompasses all thalassemia patients, all subtypes. And all that said, of course, we look forward to the data, but we're already in a significant position of strength given the ENERGIZE data and the fact that, as you heard from Tsveta, that addresses already 2/3 of the population in the U.S. with nontransfusion-dependent thalassemia.

[Gregory Renza, analyst]

That's great, Brian. Maybe just a follow-up just broadly on the landscape. Certainly, with PK activation competition with the etavopivat from Novo maybe having some time lines now established. What do you make of that? How do you think about the landscape longer term? You're certainly moving fast. But as you think about the jocking between the 2 offerings for patients ultimately.

[Brian Goff, executive]

Yes. Thanks for the question. I mean certainly, we take a lot of pride in the fact that we're the worldwide leader in PK activation. And I think, given some of the recent competitive updates that have been made public, specifically with the other PK activator etavopivat from Novo Nordisk, we took note of the most recent updated time lines.

And that's why you heard in our prepared comments, that we've often said, we feel very confident in our best-in-class positioning. We feel increasingly confident now across both thalassemia and certainly sickle cell disease with first-in-class potential, and that all leads to this franchise having multibillion-dollar potential with mitapivat. We're in a real significant position of strength.

[Tsveta Milanova, executive]

Yes, absolutely. And when we think commercially for thalassemia, we are definitely very much ahead with [ third ] [indiscernible] that they'll be reading on data in [ 2026 ] for their Phase II study, and we don't know about their commitment to Phase III. So for thalassemia, we're very excited to pioneer the way in having treatment options for all thalassemia patients.

In sickle cell disease, equally exciting on our part. We are progressing with the recruitment of our clinic Phase III clinical trial. Everything going as planned. [indiscernible] with as [indiscernible] did, they are expecting sickle cell disease data in 2027, which will be -- put the [indiscernible] behind.

Our anticipated launch in [ 2026 ], again, giving us an opportunity to basically bring the first innovative product with the potential to hit all the clinically meaningful and commercially meaningful end point of hemoglobin improvement, reduction in VOC and improvement in quality of life, so we're excited to be moving forward.

[Brian Goff, executive]

And this is where we're taking full advantage of Tsveta's expertise -- deep expertise in rare disease launches. This is what you live for as a chance to change the lives of patients and thalassemia, certainly that scenario. And this launch has the potential to be next year, so coming soon.

[Operator]

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

[Divya Rao, analyst]

This is Divya on for Mark. One on the thalassemia, the transfusion-dependent thalassemia trial coming up. Can you walk us through the [ powering ] assumptions for the primary endpoint? And then I have a follow-up.

[Brian Goff, executive]

Sure. Thanks, Divya. Sarah, do you want to take that?

[Sarah Gheuens, executive]

Yes. So we haven't spoken in detail about the powering assumption underlying the number. But we, of course, have leveraged all information available to make sure that we have a very good fiscal justification for this trial and feel confident in the primary endpoint and the sample size that we have selected.

The primary endpoint, by itself, as you know, the 50% reduction in any 12-week rolling period, which we believe can provide very meaningful assessment of a reduction in transfusion burden for thalassemia patients.

[Divya Rao, analyst]

Got it. And then just quickly as a follow-up, for AG-946, can we still expect to see the full data from the Phase IIa trial in sometime this year?

[Sarah Gheuens, executive]

So we haven't spoken about when we are going to release the Phase IIa data, as the team is assessing the best opportunity on when to do so in the best conference, also in line of when we are getting the Phase IIb up and running.

So very focused on that, very excited. We have a milestone around the Phase IIb for this year. And so we're on track to deliver that.

[Operator]

And our next question comes from the line of Eric Schmidt with Cantor.

[Eric Schmidt, analyst]

Congrats on all the progress. Maybe just 2 quick ones. First for Brian and Sarah on this thalassemia filing. One, I guess, can you confirm whether it's going to be an NDA filing? It sounds like you're already preparing that filing. Just to be very specific, if for some reason, the [ TDT ] study fall short, needs to be filing for nontransfusion-dependent any patients. Is that correct?

[Sarah Gheuens, executive]

So thanks for the question. So our goal is to file the 2 studies together. As you know, we have already the first part of the data. So indeed, our filing preparations are completely underway and the team is on track to deliver. And now we're waiting for that second study.

So the fact is that we already have great data for 2/3 of the patient population. So we, of course, want the second study to deliver and make it a great story. If the study would fall short, then it truly depends on what the data would show, how we would approach that. But our intent is to file for all thalassemia patients and get that broad indication.

[Eric Schmidt, analyst]

And just a second question on the sickle cell Phase III study that's enrolling. Can you provide any kind of color on how that's going? And what percent of the study is already on board or maybe a finer [indiscernible] your time lines for next year?

[Sarah Gheuens, executive]

Sure. So we are very excited about the RISE UP study. Everything is going well, and the team is doing an amazing job getting that study completely up and running, and we are on track with our enrollment and so are completely expecting to be able to deliver towards full enrollment towards the end of this year.

We do not guide to specific numbers expected in specific weeks or months. These things are very rapidly changing in big Phase III trial, so we guide for bigger milestones.

[Eric Schmidt, analyst]

Congrats again.

[Operator]

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

[Unknown Analyst]

Just a couple from us. First, a commercial question. Assuming both transfusion and nontransfusion end up on the label, any reason to think you need to maybe tailor your sales strategy differently between these 2 patient groups? Or will it be more or less the same, given they're likely seeing the same prescribers? And then I've got a follow-up.

[Brian Goff, executive]

Sure. Thanks, Alec, and welcome to the Agios' call. And Tsveta, you want to start off?

[Tsveta Milanova, executive]

Absolutely. We are super excited with seeing the positive data from the ENERGIZE study. And as I said, we are eagerly awaiting based from the ENERGIZE-T as well.

In terms of launch preparation, we are actively in a land launch preparation mode. We believe that there is a higher met need across both patient populations, transfusion-dependent and nontransfusion-dependent. We have a lot of data that we are basing our launch preparation strategy on, including claims data availability of [ 5 ] [indiscernible].

And we have basically plan to approach in the same way both patient populations because of the same underlying [indiscernible] of the disease, the connection between the 2 patient populations. And as you said, the overlap in the prescriber base.

Of course, you'll see a little bit more concentration in the nontransfusion-dependent patients in the KOL and center of excellence setting and a bit more of the nontransfusion-dependence in the community setting, but that would not change the approach of deployment and communication and education.

[Brian Goff, executive]

The only thing I would add is that with the transfusion-dependent patients, there's obviously more regularity of clinician visits than you tend to see with the nontransfusion-dependent patients. But I'm really proud of the fact that Tsveta and the team are prepared for all scenarios.

[Unknown Analyst]

Okay. Perfect. And then just one question on the ex-U.S. opportunity. I know you've said that the plan would likely be to partner in ex-U.S. geographies. But any additional color you can provide around timing or scope of the ex-U.S. opportunity just from a modeling perspective for us.

[Tsveta Milanova, executive]

Absolutely. So in addition to actively preparing for launch in the U.S., we are also actively searching for the best possible partner for us to maximize the ex-U.S. opportunity. We've mentioned on several occasions that the Gulf region is a high priority for us, given that there are 70,000 patients with thalassemia in that region.

Sarah and the team are preparing for regulatory submissions in these regions actively as well to submit as quickly as possible that, that will allow us and we'll provide update as soon as we have progressive discussion and identify the partner, but we are in a very strong position, especially now with a positive data from ENERGIZE to have a very high-quality discussions with partners who have strong expertise in the region.

We are excited about this because our clinical studies are also done in the region, and there is a lot of [indiscernible] advocacy and experience with thalassemia and mitapivat, so equally an exciting place as the U.S. launch as well.

[Operator]

Our next question comes from the line of Tess Romero with JPMorgan.

[Tessa Romero, analyst]

A question for Cecilia here. I mean, just curious, can you walk us through the pushes and pulls on your balance sheet and how you think about means to potentially extend that runway? And what your latest thinking is there?

We noticed you included in your release today, how interested specifically are you in potentially a royalty monetization for vorasidenib? And then on the partnering side, outside of the U.S., just to clarify that as comments here, could that occur this year?

[Cecilia Jones, executive]

I can start and we can add on the ex-U.S too. So yes, we have guided that we have cash at least into 2026. And we purposely left out a couple of things that you mentioned. So I'll cover some of those, but there's other things like we obviously continue to manage our cost bases thoughtfully in a disciplined way. We now are starting to prepare for the launch, but we waited to make sure we had the data before we went ahead with that.

On the vora side, that's another option that we looked as we evaluate to extend our runway. We -- as we had in the prepared remarks. So Servier publicly announced that the FDA accepted their filing and they have a PDUFA date on August 20. And as a reminder, we have a $200 million milestone on FDA approval and 15% royalties on U.S. net sales for that, and we will evaluate opportunities to sell that, the whole amount or a portion of that as part of our way to extend the runway as we will do with other things.

The other option or the other piece that we left out, as you mentioned, is the ex-U.S. portion, that can come in different shapes and forms, and that's part of the reason we left it out. The timing, obviously, the teams are working to make sure we have the best partner, and that is reflective of where the patients are like Tsveta described, and we want to try to obviously do that as fast as possible to get access to those patients.

[Operator]

And the next question comes from the line of Salveen Richter with Goldman Sachs.

[Unknown Analyst]

This is Lydia on for Salveen. Just on the upcoming ENERGIZE-T readout, could you just discuss the clinical bar for success here and what you're hoping to see in terms of that percentage of patients with a reduction in transfusion burden? Should we expect this readout to kind of take a similar form to the earlier ENERGIZE readout?

[Sarah Gheuens, executive]

Thanks for the question. So for -- in regards to the ENERGIZE-T readout, of course, we're hoping to hit on our primary endpoint with a reduction -- 50% reduction in any 12-week rolling period. It's -- we have not spoken about the exact difference we are shooting for between placebo or mitapivat.

But in regards to the trial itself, it is -- of course, well designed to be able to hit on a primary endpoint with the assumptions that are underpinning that design.

What we know, though, is there is the clinical trial bar of what we're shooting for that 50% reduction. But in the real world, we know that the bar actually may be lower, because the -- what the compound, the product would do is basically remove some of the clinic visits for patients if they can skip transfusions, and that would have a big impact on quality of life for transfusion-dependent thalassemia patients.

I think Tsveta can maybe add a little bit on what we expect for the real world.

[Tsveta Milanova, executive]

Absolutely. You mentioned, it's our -- the clinical bar is obviously important from a regulatory perspective. But [ 1 ] [indiscernible] here, both from patient and clinician, in terms of utilization, they'll be looking to the reduce of transfusion [indiscernible] even at a lower rate, and they'll consider that clinically meaningful. Because even expanding the transfusion kind of frequency by a week, on a stations, basically, it is very meaningful on actually health care system basis as well and finishes is very meaningful. So we're super excited to and wait to see the data and getting ready actively for launch.

[Brian Goff, executive]

And I'll just give maybe one last comment, which is that, obviously, we're going for statistical significance in the ENERGIZE-T study. From past experience, we know that there could be the temptation for cross-study comparisons as well.

And I just want to emphasize that the compelling totality of the profile of mitapivat means we don't necessarily need numerical equivalents. What we need is statistical significance from the endpoint, that's what we're targeting.

But the fact that this is an oral therapy means the patients are already in the way free of the clinic relative to other alternatives, i.e., luspatercept. And we see that as on top of all else, that's another real advantage at the patient level.

[Operator]

And our last question will come from the line of Danielle Brill with Raymond James.

[Danielle Brill, analyst]

First, I wanted to ask a question about the expected placebo response for ENERGIZE-T in the [ epatercepts ] trial, I believe the placebo response rate, as you defined it for your primary, was around 6%. Curious your thoughts on how the placebo population is able to achieve that level of reduction, and are you expecting a similar outcome in ENERGIZE-T?

And then as a quick follow-up. I'm just curious how you plan to announce the data. Will this be a top line PR? Or is it possible that you're presented at EHA?

[Sarah Gheuens, executive]

Yes. So there's always fluctuation when you measure transfusion. So 6% for the placebo in regards to the primary endpoint definition is a very reasonable observation. And that is also because in clinical practice, sometimes patients get transfused based on symptom presence and things like that.

So in regards to how we are going to announce the data, yes, we typically do a top line release via press release. We will not be able to present data at EHA because the time frame for submission of data there is long gone. So that will -- that is not in the plan.

[Operator]

And this concludes today's question-and-answer session. I'll now turn the call back to Brian Goff for closing remarks.

[Brian Goff, executive]

Thanks a lot, Norma, and thank you very much, everyone, for participating in today's call. I think it's -- I hope it's clear. It's a very exciting time at Agios. We believe that we're well poised to deliver transformative new therapies for patients as well as creating significant long-term value to shareholders.

So thanks again, and we look forward to speaking with all of you again soon.

[Operator]

This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.