Agios Pharmaceuticals Inc

NASDAQ:AGIO

Earnings Call Analysis

Agios Q2 report: Revenue growth, upcoming launches, and strategic financial moves

Agios reported a 4.9% increase in Q2 net PYRUKYND revenue, reaching $8.6 million. The company highlighted promising data from its Phase III trials of mitapivat, with plans to submit a supplemental New Drug Application (sNDA) for thalassemia by year-end, aiming for a 2025 launch. Agios also announced a significant financial boost from the sale of its royalty rights on Servier's vorasidenib to Royalty Pharma, potentially bringing in $1.1 billion. The company remains focused on preparing for the launches of PYRUKYND in thalassemia and sickle cell disease, leveraging a strong financial position to support these initiatives.

Strong Q2 Financial Results and Launch Strategy

Agios Pharmaceuticals reported a net PYRUKYND revenue of $8.6 million for Q2 2024, reflecting an increase of $1.9 million from Q2 2023. This growth is attributed to a consistent increase in patient enrollment, with 201 patients completing prescription forms, leading to a 7% rise in therapy participation. As the company shifts its focus towards launching in thalassemia, muted revenue growth might be expected in subsequent quarters, indicating a need for careful management of resources.

Pathway to New Revenue Streams

In a significant move, Agios agreed to sell its rights to a 15% royalty on U.S. net sales of Servier's vorasidenib to Royalty Pharma, receiving an upfront payment of $905 million upon FDA approval. This transaction positions Agios favorably to raise a total of $1.1 billion related to vorasidenib. The anticipated PDUFA action date for vorasidenib is set for August 20, 2024, which could further bolster the company's financial stability and support potential future product launches.

Mitapivat's Role in Transforming Hematological Treatments

Agios' mitapivat has shown positive efficacy in the ENERGIZE-T Phase III study for thalassemia, marking it as the first oral treatment to achieve key endpoints in transfusion-dependent patients. The results suggest the drug can significantly improve red blood cell health, which is critical for patients suffering from various hemolytic anemias. The company plans to request expanded labeling for all thalassemia subtypes by the end of 2024, highlighting its commitment to addressing this high unmet medical need.

Innovative Approaches in Pediatric Care

Agios has also made strides in pediatric care with the recent completion of the ACTIVATE-KidsT study for children with pyruvate kinase deficiency. Although the primary endpoint was not met, significant secondary endpoints showed a transfusion-free response in the mitapivat group. This development indicates the potential for mitapivat to provide a critical treatment option for children, a demographic that currently lacks approved therapies.

Expanding Global Market Access

Agios announced a distribution agreement with NewBridge Pharmaceuticals to market PYRUKYND in the Gulf Cooperation Council (GCC) region. Saudi Arabia, hosting the largest patient population for thalassemia in the GCC, has granted Breakthrough Medicine Designation to mitapivat, enabling expedited regulatory processes. This agreement underscores Agios' strategy to enhance global market access while addressing the urgent medical needs present in the region.

Prioritizing Cost Management and Shareholder Value

With a current balance of $645 million in cash and marketable securities, Agios' financial strength is expected to support its forthcoming launches in thalassemia and sickle cell disease anticipated in 2025 and 2026, respectively. The company's emphasis on prudent cash allocation and disciplined cost management aims to optimize shareholder value while navigating upcoming market expansions and product launches.

Looking Ahead: Future Milestones and Growth Potential

The company remains focused on meeting its strategic milestones, such as the conclusion of the Phase III portion of the RISE UP study for sickle cell disease by year-end and the commencement of the Phase IIb study for lower-risk myelodysplastic syndromes. Given the current data and the potential impact of its therapies, Agios stands poised to enhance patient outcomes and create significant value for shareholders.

Earnings Call Transcript 2024-Q2

[Operator]

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

I would now like to turn the call over to Chris Taylor, VP of Investor Relations and Corporate Communications for Agile.

[Christopher J. Taylor, executive]

Thank you, operator. Good morning, everyone, and welcome to Agios conference call and webcast to discuss second 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 Research and Development; Tsveta Milanova, our Chief Commercial Officer; and Cecilia Jones, our Chief Financial Officer.

Before we get started, I'd like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in our most recent filings with the SEC, and any other future filings that we may make with the SEC.

And with that, I'm pleased to 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.

Our foundation leverages mitapivat's novel mechanism of action, which improves overall red blood cell health and has been a key driver of our positive clinical data readouts in recent years. I'm delighted to report that we continued our positive momentum in Q2 with multiple key milestones announced this quarter. First, we announced that the Phase III ENERGIZE-T study of mitapivat met both the primary endpoint and all key secondary endpoints in adults with transfusion-dependent alpha- or beta-thalassemia. Importantly, ENERGIZE-T is the first Phase III study to demonstrate efficacy of an oral disease-modifying treatment for transfusion-dependent alpha- and beta-thalassemia.

Second, data from the positive Phase III ENERGIZE study of mitapivat in adults with alpha- or beta-thalassemia who are not regularly transfused were presented by leading KOLs in 2 presentations at the recent European Hematology Association Congress in Madrid, including a plenary session. Taken together with the positive data from ENERGIZE-T, we plan to submit an sNDA for mitapivat in thalassemia based on all available data from both ENERGIZE and ENERGIZE-T by the end of 2024, seeking a label that covers people living with all subtypes of thalassemia.

Third, we announced that Agios has agreed to sell its rights to a 15% royalty on potential U.S. net sales of Servier's vorasidenib through Royalty Pharma. Under the terms of the agreement, Agios will receive an upfront payment of $905 million upon approval of vorasidenib by the FDA. Cecilia will revisit the details in a moment, and I would like to thank her for directing the process and structuring a tremendous agreement for Agios, our shareholders, and a win-win for both Agios and Royalty Pharma. This transaction will provide us with the financial independence to prepare for potential launches in thalassemia and sickle cell disease as we build a multibillion-dollar PK activation franchise, as well as the ability to opportunistically expand our pipeline.

And fourth, just this morning, we announced top line data from the Phase III ACTIVATE-KidsT Study of mitapivat in children with PK deficiency who are regularly transfused. This is truly a pioneering study for Agios, a first pediatric study of mitapivat, and representative of our commitment to pursue the potential of mitapivat as a treatment for children with rare diseases. We are also pleased to report that we have completed enrollment in the ACTIVATE-Kids Study, and we look forward to the top line readout in 2025.

Building on this progress, we look forward to several additional upcoming milestones, 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 next year. Sarah will provide a detailed update on our progress and upcoming milestones across R&D in just a few minutes.

Given the consistent and compelling data we've generated across the mitapivat development program and the high unmet need in each of 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.

Leveraging the positive data observed in the ENERGIZE and ENERGIZE-T studies of mitapivat, which together encompass all thalassemia subtypes, our expanding commercial organization is actively preparing for a potential U.S. launch of mitapivat in thalassemia in 2025, as well as a potential launch 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 PK deficiency in just a bit.

As part of our news release this morning, we were delighted to announce 2 updates related to the commercialization of PYRUKYND outside the U.S. First, we've entered into a distribution agreement with NewBridge Pharmaceuticals, a leading player in the Gulf region; and second, mitapivat has received Breakthrough Medicine Designation from the Saudi FDA. Finally, as you'll hear from Cecilia, we ended the second quarter with a strong cash position with approximately $645 million in cash and investments on the balance sheet, and we have the potential to further bolster our cash position by an additional $1.1 billion upon the potential FDA approval of vorasidenib.

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

[Sarah Gheuens, executive]

Thanks, Brian. This morning, we were very pleased to announce top line data from the Phase III ACTIVATE-KidsT Study of mitapivat in children with PK deficiency, who are regularly transfused, which is the first Phase III study to report data in this population, and importantly, the first completed pediatric study of mitapivat for Agios.

We are also pleased to report that we have completed enrollment in the complementary ACTIVATE-Kids Study of mitapivat in children with PK deficiency who are not regularly transfused. Next year, we aim to report top line data from this second study, and we'll review all available data from both the ACTIVATE-KidsT and ACTIVATE-Kids Studies.

So turning now to the data from ACTIVATE-KidsT reported today. As this first slide depicts, our Pediatric PK Deficiency Program includes 2 Phase III studies evaluating regularly transfused and not regularly transfused pediatric patients with pyruvate kinase deficiency in ACTIVATE-KidsT and ACTIVATE-Kids, respectively. Children represent approximately 20% of the total patient population in PK deficiency, and there are no therapies approved for pediatric PK deficiency.

Turning to the top line results announced this morning for the ACTIVATE-KidsT trial. A total of 49 patients were enrolled in the study, with patients randomized 2:1 to either mitapivat twice daily or placebo. The study consists of a 32-week double-blind period followed by an open-label extension period. 30 of the 32 patients in the mitapivat arm and 16 of the 17 in the placebo arm completed the double-blind period of the study. As we noted in our news release this morning, using Bayesian methodology, the prespecified statistical criterion for the primary endpoint in ACTIVATE-KidsT was not met using low or moderate borrowing of data from the ACTIVATE-T study in adults.

The results were clinically meaningful, as transfusion-free response and normal hemoglobin response, 2 key secondary endpoints in this study, were only observed in patients in the mitapivat arm. Transfusion reduction response was defined as an equal or more than 33% reduction in the total red blood cell transfusion volume from week 9 through week 32 of the double-blind period, normalized by weight and actual study drug duration compared with the historical transfusion volume standardized by weight and to 24 weeks.

28.1% of patients in the mitapivat arm achieved a transfusion reduction response, compared to 11.8% of patients in the placebo arm. In addition, a higher proportion of patients in the mitapivat arm compared to the placebo arm achieved the secondary endpoint of transfusion-free response and normal hemoglobin response, which were measured from week 9 through week 32 of the double-blind period. 6 patients, nearly 20% in the mitapivat arm, compared to 0 in the placebo arm, had a transfusion-free response with no red blood cell transfusions, and 4 patients in the mitapivat arm compared to 0 in the placebo arm achieved a normal hemoglobin response, defined as hemoglobin concentrations within normal limits at least once, 8 weeks or more after a transfusion.

Safety results for mitapivat were consistent with the safety profile for mitapivat previously observed in adults with PK deficiency who are regularly transfused. During the double-blind treatment period of the study, a similar proportion of patients had adverse events in the mitapivat and placebo arms, and there were no discontinuations of study treatment due to AEs. We plan to present a more detailed analysis of the Phase III ACTIVATE-KidsT data at an upcoming medical meeting. We hope that this study will be the first of several pediatric studies to make a positive impact in the lives of children facing rare hemolytic anemia, including thalassemia and sickle cell disease.

Turning to our progress in thalassemia, an overview of the data from the Phase III ENERGIZE study were presented in a plenary session at the EHA meeting in June by Dr. Ali Taher from the American University of Beirut Medical Center; and in a poster detailing health-related quality of life and patient-reported outcome measures were presented by Dr. Kevin Kuo from the University of Toronto and in an investor webcast. Greater detail was provided on efficacy and safety.

Importantly, patients treated with mitapivat experienced improvements on multiple health-related quality of life measures, including fatigue and walking capacity. In addition, last month we were very pleased to announce positive top line data from the Phase III ENERGIZE-T study of mitapivat in transfusion-dependent thalassemia, which positions mitapivat as the first oral disease-modifying therapy to demonstrate efficacy in transfusion-dependent alpha- and beta-thalassemia.

Let me now take a moment to review the design and the results of that study. There is a 48-week double-blind period followed by an open-label extension period. A total of 258 patients were enrolled, with patients randomized 2:1 to either 100 mg mitapivat twice daily or placebo. The study met its primary endpoints of transfusion reduction response, defined as an equal or more than 50% 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.

30.4% of patients achieved the primary endpoint, compared to 12.6% of patients in the placebo arm. The difference was highly statistically significant, with a p-value of 0.0003. Treatment with mitapivat also demonstrated statistically significant reductions in additional measures of transfusion reduction response compared to placebo, as assessed by the 3 key secondary endpoints. An equal or more than 50% reduction in transfused red blood cell units in any consecutive 24-week period through week 48 compared with baseline, an equal or more than 33% reduction in transfused red blood cell units from week 13 through week 48 compared with baseline, and an equal or more than 50% reduction in transfused red blood cell units from week 13 through week 48 compared with baseline.

Moreover, 9.9% of patients in the mitapivat arm achieved the secondary endpoint of transfusion independence, defined as remaining transfusion-free for equal or more than 8 consecutive weeks through week 48 compared to 1.1% in the placebo arm.

Finally, during the 48-week double-blind period, incidence of adverse events were similar between mitapivat and placebo arm with 5.8% of the patients in the mitapivat arm experiencing an AE that led to discontinuation, compared to 1.2% of patients in the placebo arm. We look forward to presenting a more detailed analysis of these data at an upcoming medical meeting.

Taken together, the data from ENERGIZE and ENERGIZE-T strongly underscore mitapivat's potential to become a foundational, convenient oral treatment option for all subtypes of thalassemia, alpha- and beta-thalassemia and transfusion-dependent and non-transfusion-dependent thalassemia. We are on track to file an sNDA that incorporates all data from both studies by the end of this year, seeking a label that covers people living with all subtypes of thalassemia.

As Brian mentioned, we are quite pleased to note that mitapivat has received a Breakthrough Medicine Designation by the SFDA, or the Saudi FDA. The breakthrough medicine program aims to facilitate and accelerate development and review of new drugs that address unmet medical need in the treatment of serious or life-threatening conditions. Mitapivat becomes one of the first products to receive the Breakthrough Medicine Designation, and we look forward to working with the regulators together with our new partner, NewBridge.

Turning to sickle cell disease. Enrollment in the Phase III portion of the RISE UP of mitapivat continues to progress, and we continue to be on track to complete enrollment by the end of this year. 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 anemias, we are confident in 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.

We look forward to reporting top line data from the Phase III portion of the RISE UP study next year and to the potential for mitapivat to address the high unmet need in this disease by improving anemia, reducing sickle cell pain crises, and making patients feel better by reducing their fatigue. Finally, we remain on track to deliver on all milestones across the rest of our advancing pipeline, including beginning enrollment of the Phase IIb study, evaluating higher doses of our novel PK activator, AG-946, now named tebapivat, in lower-risk MDS. We are eager to share more details as the trial gets underway soon.

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. Having just returned from the Cooley's Anemia Foundation Patient and Family Conference in Atlanta, we heard many powerful stories, emphasizing the debilitating impact thalassemia may have on patients and their families.

All forms of thalassemia bring high rates of serious morbidities, reduced quality of life, and a heightened risk of premature death. It is challenging for patients to navigate the disease because treatment options are limited and the burden of disease, as well as the associated cost of care, is significant. Based on the positive data we have generated in the ENERGIZE and ENERGIZE-T studies, we aim to transform the treatment of this disease and bring to market the first therapy approved for all thalassemia subtypes.

There are approximately 6,000 adults diagnosed with thalassemia in the U.S. Approximately 4,000 of whom are non-transfusion dependent. In the U.S., there are no oral therapies approved for patients living with thalassemia. And for those with non-transfusion-dependent disease, there are no approved therapies at all.

Our commercial organization is actively preparing to address this high unmet need with a potential U.S. launch of PYRUKYND in thalassemia next year. In addition to the consistent and compelling data we have generated in the mitapivat development program, we believe there are 3 key factors that have the potential to support adoption of PYRUKYND in thalassemia in the U.S.

First, driven by the availability of newborn screening and well-established ICD-10 codes, the diagnosis rate in thalassemia is high, with many patients diagnosed before adulthood. Second, both patients and providers are concentrated in a 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, since some of the Centers of Excellence were included in our clinical trials, some treating physicians already have first-hand experience with mitapivat.

Taken together, we believe we are well-positioned to provide a potential foundational treatment option for patients with thalassemia, regardless of subtype. As we continue to progress toward a potential launch in the U.S., our team is focused on 4 key areas of launch preparation. First, we continue to conduct extensive market research and claims data analysis to further refine our market insights and our physician targeting. Second, we commenced a new disease education campaign in May, designed for both patients and clinicians, highlighting the long-term complications and burden of disease across all thalassemia subtypes. I'll share a little more about this campaign in a moment. Third, we are executing a disciplined expansion of our commercial and medical teams to right-size the organization for a successful launch in this larger, but still rare, market. 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 look forward to the same strong outcome in thalassemia.

On Slide 24, we have provided some of the messaging that our team is using in our new disease state education campaigns for both patients and healthcare providers. With the objectives of highlighting the disease burden of thalassemia and encouraging disease monitoring and management, our team is reinforcing the messages listed, especially working to reset the perception that non-transfusion-dependent patients are at less risk.

Next is a graphic from our campaign. It highlights how we are communicating to physicians that the serious risk of morbidities can exist, regardless of thalassemia patients' transfusion history. The response has been very positive, with the images and messaging resonating with both patients and healthcare providers.

I mentioned that our team continues to deepen our market understanding. On this slide, you can see the insights from a recent market research that helped elucidate the top clinical characteristics healthcare providers will consider when prescribing PYRUKYND: hemoglobin levels, transfusion burden, fatigue, and iron overload.

Outside of 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. Today, we are pleased to announce that we have entered into a distribution agreement with NewBridge Pharmaceuticals to prepare for a potential commercialization of PYRUKYND in the GCC region. NewBridge, a leading specialty company headquartered in Dubai, will commercialize PYRUKYND in Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates. We are excited to join forces with NewBridge as we drive towards potential commercialization in the region.

As noted on Slide 27, Saudi Arabia accounts for the largest patient population in the GCC. We are quite proud of the team's efforts to successfully secure a Breakthrough Medicine Designation for mitapivat thalassemia, which was granted by the SFDA, Saudi FDA. As noted in the last bullet, the access path in individual GCC countries usually begins with a price set at the regulatory level, followed by access with health authorities, local institutions, the private sector, and national standards. These are key elements in the process which we look forward to navigating over time with our partner, NewBridge.

Let me now provide an update on the current launch of PYRUKYND in PK deficiency. In the second quarter of 2024, we generated $8.6 million in net PYRUKYND revenue, compared to $8.2 million in the first quarter of 2024. In the U.S., a total of 201 patients have completed a prescription enrollment form, including 13 in the second quarter of 2024, a 7% increase versus the prior quarter. This has translated into 128 net patients on therapy, a 7% increase versus the prior quarter. Patients on therapy continues to span from a growing and diverse prescriber base of 173 physicians, and represents a broad demographic and disease manifestation 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 that the capabilities will continue to strengthen through the current launch in PKD, including efficient targeting analytics, patient and physician awareness and education, and patient access, will provide a firm foundation from which to maximize potential future U.S. launches of mitapivat, including in thalassemia in 2025, and in sickle cell disease in 2026. Above all, we are inspired and energized by the potential to bring a new therapy to these underserved patient populations.

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

[Cecilia Jones, executive]

Thanks, Tsveta. Our second 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.

Second quarter 2024 net PYRUKYND revenue was $8.6 million, an increase of $1.9 million compared to the second 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. As we pivot our organization's focus to the thalassemia launch preparedness, we expect to see more muted growth going forward and quarter-over-quarter variability in PKD revenues.

Cost of sales for the quarter was $1.5 million. R&D expenses were $77.4 million for the second quarter, an increase of $8.5 million compared to the second quarter of 2023. The year-over-year increase was primarily attributable to an increase in costs associated with the TMPRSS6 program in-licensed from Alnylam last year. SG&A expenses were $35.5 million for the second quarter, an increase of $5.1 million compared to the same quarter in 2023. This was primarily attributable to an increase in commercial-related activities as we prepare for the potential approval of PYRUKYND in thalassemia.

As a reminder, this quarter, we announced that the company has agreed to sell the rights to its 15% royalty on potential U.S. net sales of Servier's vorasidenib to Royalty Pharma. Under the terms of the agreement, Agios will receive an upfront payment of $905 million upon approval of vorasidenib by the FDA, and Royalty Pharma will receive the entirety of the 15% royalty on annual U.S. net sales of vorasidenib up to $1 billion, and 12% royalty on annual U.S. net sales greater than $1 billion. Agios will retain a 3% royalty on annual U.S. net sales greater than $1 billion. In addition, we still retain the right to a potential $200 million milestone from Servier upon FDA approval of vorasidenib from the divestiture of our oncology business. So, altogether, Agios will receive a total of $1.1 billion in payments upon the potential FDA approval of vorasidenib.

As a reminder, the PDUFA action date has been set for August 20, 2024. We ended the quarter with cash, cash equivalents, and marketable securities of $645.3 million. We expect that this balance, together with anticipated product revenues, interest income, and payments upon FDA approval of vorasidenib, will provide a financial independence to prepare for potential PYRUKYND launches in thalassemia and sickle cell disease, and to 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 strong balance sheet will continue to 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, mitapivat has continued to deliver positive late-stage data readouts spanning 3 hemolytic anemias, and we're pleased to have now completed our first Phase III trial in a pediatric patient population. Based on this consistent and compelling data package and the demonstrated strength of the Agios team, we continue to believe that mitapivat is poised to become a first-in-class and best-in-class treatment option for multiple indications and to become a multibillion-dollar franchise.

Our focus is squarely on thalassemia, where we aim to file an sNDA by the end of this year and seek a label that covers people living with all subtypes of the disease. 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 comes from Eric Schmidt from Cantor Fitzgerald.

[Eric Schmidt, analyst]

Congrats on all the continued progress. Maybe I'll ask about the new development today, the NewBridge transaction. Can you give us a little bit more color on some of the economics there and what you hope to receive? And maybe also talk about the timing now that you have Breakthrough Designation in Saudi Arabia.

[Brian Goff, executive]

Thanks, Eric. And Tsveta worked really hard with quite a large team on this new arrangement with NewBridge and GCC. You know that that's our second most important market for thalassemia and the first most important outside the U.S. So I'm going to let Tsveta comment on that.

[Tsveta Milanova, executive]

No, that's wonderful. And we are really, really happy to announce the agreement with NewBridge because we've been working hard to select a partner with a very thorough and good experience in the region to represent us as Agios. And we are also very proud to announce that we actually received the Breakthrough Medicine Designation from the Saudi FDA, with Saudi Arabia being the biggest market in the region. And we look forward to work with NewBridge actually to utilize the Breakthrough Designation and submit for regulatory approval for thalassemia as soon as possible, and we'll be providing more information on that as we enter into the process.

When you think about numeration agreement that we have with them, they're full-service distributors, so they represent our deals across the board from regulatory approval and commercialization activities across the whole region, it's a very typical kind of agreement for this type of relationships, which is basically a revenue split yield. So there will be no upfront payment for us as Agios. And as we continue to basically progress with commercialization, there will be a revenue split as part of it.

When we look at the region, we are really, really excited about the potential of our product because not only that there is a high unmet medical need in the region, but we have conducted clinical studies in the region. So there is already a person experience with some of the key centers in KOL in the region, and we look forward to provide access to patients.

[Sarah Gheuens, executive]

And then Eric, to follow up on the question around timing of regulatory engagement, so we are, of course, very excited to keep on moving forward with the development of our program. And so in fact, we will be working as soon as we can with the regulators across the board.

[Brian Goff, executive]

And I'll just close by saying that, that breakthrough medicines designation in Saudi is pretty unusual. And so we've been pleased to have that as a recognition of, as Tsveta noted, just a profound unmet need in that region. So it's an important part of the puzzle for us as we get ready to expand our presence outside the U.S. and particularly focus on these high unmet need regions.

[Operator]

And our next question comes from Christopher Raymond from Piper Sandler.

[Christopher Raymond, analyst]

Just a couple from me. Just with vorasidenib's upcoming PDUFA, you guys -- as you noted in your press release, you're in line for pretty meaningful cash infusion. Brian, I know you've talked about M&A and I'd say your language has been relatively cautious, I guess, in the past. But this is a $1 billion-plus infusion of sort of changes things, I would guess, in terms of the size and scope of what you could do. Can you maybe talk about how you're viewing M&A now as a lever after the August 20 PDUFA? And then I have a follow-up question.

[Brian Goff, executive]

Yes, sure. And thanks a lot. Obviously, I just want to reiterate again, I'm very proud of the work that Cecilia did with the royalty monetization of vorasidenib. That's an important step. And as a side note, vorasidenib itself is a mark of excellence for Agios science. It's very important for patients. And of course, it adds to our potential balance sheet enhancement.

So I think you mentioned M&A, I'll just maybe take it up a step and just talk about capital allocation for us. And the focus is efficient use of capital, no matter what. This certainly puts us in a position of strength. Our top priority above all else is preparing for and delivering upon these really important launches that we had near term. And we're quite excited about the fact that with success, this could be back-to-back launches. Thalassemia, Tsveta and the team are preparing for next year. And as we noted in our comments, with sickle cell disease, the RISE UP trial is on track for complete enrollment by year end. That points towards data readout next year and then, again, the possibility for a back-to-back launch. So that's the #1 priority.

Secondly, we continue to make great progress on advancing our own internal pipeline. And of course, that will use some of the capital. A great example is MDS. And we're looking forward to commencing on the Phase IIb study for low-risk MDS. That's a market that is growing beautifully, and we're very excited about that potential. And that's, by the way, with tebapivat, which we were pleased to announce today, as our INN for what was formerly known as AG-946.

And then to your point, Chris, about business development more broadly, it's always a focus. That said, we're very disciplined because we have no shortage of internal organic opportunities as well. And Cecilia and the team do a great job of making sure that our analysis of what creates the most value-enhancing opportunity goes through a rigorous and very competitive process. And BD, all of that is certainly in our sights. But again, great organic opportunities as well.

[Christopher Raymond, analyst]

Okay. Great. And then maybe just a quick follow-up. Just on sickle cell and the opportunity, we've had some feedback from KOLs that not all patients -- sickle cell patients experienced VOCs. Maybe just talk about your view around VOCs as an endpoint and the applicability for a broad population.

[Brian Goff, executive]

Yes, that's a great one for Sarah.

[Sarah Gheuens, executive]

Thank you. You're right. Not all patients experienced VOCs. And as you know, our intent is to deliver a product that can treat all aspects of sickle cell disease. So hemolytic anemia and sickle cell pain crises. We do -- as a principle across our different programs, we believe, based on the mechanism of action of our drug, the drug can work across the whole spectrum of disease, so a range of hemoglobin levels and a range of sickle cell pain crises.

Now from a clinical trial perspective, if you want to be able to measure a treatment effect, you need to enroll a patient population that has enough of the event ongoing to be able to measure that reduction. So that is why our clinical trial from an endpoint perspective has the inclusion criteria of sickle cell pain crises 2 or more. But I mean, just to be able to measure that treatment, the thing that our anticipation is that it can work for no matter how many sickle cell pain crises, you have including just 1 or 0. Unfortunately, that patient population can't enroll into the trial because we would not be able to measure a treatment effect in that patient population over the course of the year. Again, the drug is meant to address all aspects of sickle cell disease and our intent would therefore be based on the data we have generated across the program, including all of our clinical trials to go for a label that can treat sickle cell disease after regulatory review.

[Brian Goff, executive]

And to that point, Sarah, maybe you want to comment too on fatigue, which we try really hard not to oversimplify these diseases, especially sickle cell disease is so complex, in sickle cell pain crises, VOCs is one aspect, but fatigue is another very profound need.

[Sarah Gheuens, executive]

Right. So I just mentioned the primary end point, right, the hemoglobin primary endpoint of hemoglobin and sickle cell pain crisis reduction of the other primary endpoint to be able to measure a hemolytic anemia and VOC impact. As you know, that's supported by a bunch of other secondary endpoints, of which one is indeed focused on fatigue because that's what we hear from patients and from physicians that fatigue is very, very, very impactful and burdensome to the patient population. And that's typical for all of our designs. We really try to incorporate patient feedback and therefore, have incorporated fatigue as the main secondary endpoint.

As you know, we've just announced the thalassemia trial data, ENERGIZE, in which we did meet our key secondary endpoint for the first time of -- on the patient reported Alco that measure fatigue. So we are very hopeful for the rise of the study as well.

[Operator]

Our next question comes from Gregory Renza from RBC Capital Markets.

[Gregory Renza, analyst]

Good morning, Brian and team. Congrats as always on the continued progress. Maybe Brian, I'll just start with ACTIVATE-KidsT perhaps for Sarah. Sarah, can you just help us understand maybe the statistical assumptions? It certainly seems to us that treatment effect is clinically meaningful. The results largely consistent with the adult studies. Was the study underpowered? Was there a placebo behavior that maybe was consistent and consistent with historical transfusion rates? Any added color you have would be great. And then I have a follow-up.

[Sarah Gheuens, executive]

Sure. Thanks for the question. So ACTIVATE-KidsT, we really try to design a study that is appropriate for an ultra-rare disease population, and therefore, chose to really leverage the adult data we have generated, to get to a sample size that would be appropriate for this state of development and provide us with the adequate data. So we have to use a pretty complex statistical methodology to look at the primary endpoint of transfusion reduction. As mentioned, it's pretty complex because it depends on the amount of data you borrow from the adult study. And that gives some specific weights that you leverage to look at your pediatric data. And we can't say that across the board we see a treatment effect. So that's why we were very specific in the press release around our low or moderate weight borrowing of the adult study data because the data -- while we see positive loss ratios, the confidence intervals around that to include 1. So that's why we are very mindful of that.

To your point, the data that we have observed, the fact that there are 6 patients who became transfusion-free, so remember, this is a regularly transfused patient population, meaning they have a lot of transfusions coming into the trial, now these patients become transfusion-free. That is a clear demonstration of a treatment effect in that specific patient population. And if you're 1 of those 6 kids, that is a very meaningful difference for that specific person and their family because this has also obviously an impact to the family.

So that's why we are very excited about the results actually because we do feel like there is a meaningful story to be told out of this study. The main goal, of course, of this study, which we also can't -- which we are very happy about is the safety assessment, right? This is our first pediatric clinical trial after completing an adult program and get to an indication statement there. So this is our first endeavor to really expand the age range of that patient population. And so from that perspective, we do feel the safety data is very important, the efficacy data that we have generated is very encouraging, and we're very excited about the next steps in the development.

[Gregory Renza, analyst]

That's helpful. And just one other question. Just on thalassemia, and it's helpful to have Tsveta walk through some of the messaging as well as some of the characteristics that doctors could value. Just wondering if you had any thoughts on maybe real-world usage patterns assuming all goes as planned and the approval comes comes through. When it comes to the patients maybe staying on the drug longer term, any expectations or thoughts on patients perhaps with less hemoglobin improvement benefit, but maybe more meaningful quality of life improvements or staying on the drug? And if you have any thoughts on what level of hemoglobin improvement we would anticipate for thal patients to stay on the drug longer term?

[Brian Goff, executive]

There's a lot in there, Greg. And so maybe we'll just focus on the crux of your question that I heard was focused on the unmet need. And I think Tsveta could certainly put some color on that because we just returned from -- she noted in her prepared comments, The Cooley's Anemia Foundation Meeting, which is the annual meeting for thalassemia patients in the U.S. It's a pretty inspiring venue to be in and certainly brings home the range of unmet need that exists keeping in mind these are the engage patients. These are the ones that are actually skewed towards transfusion dependency and attend meetings like that.

But Tsveta has a lot of insights that we're continuing to build upon.

[Tsveta Milanova, executive]

Absolutely. And I'll start and then maybe I can also transfer to Sarah to talk a little bit kind of the broad applicability of our mechanism of action to across the hemolytic anemia being thalassemia. But absolutely, Brian and I had the opportunity to attend The Cooley's Anemia Foundation Patient and Family Conference, and it was truly, truly inspiring to have the opportunity to connect with many patients and treating physicians as well, listen and learn about the patient journey and the stories there, and very importantly, get excitement and the enthusiasm of both of the patients and the clinical community about potential new innovative therapies coming to the thalassemia space, including the potential Mitapivat as an approved product for that indication in the U.S.

Of course, this is the most engaged and educated audience, and it was great to get their feedback. And Greg, as you mentioned, we studied very clearly from the physician community and the market research that they'll consider all the relevant endpoints that we measure in our clinical trials as patient characteristics when making a treatment decision being hemoglobin level being transfusion burden, being iron overload, and of course, fatigue. And Sarah talked about the importance of fatigue in thalassemia and sickle cell disease.

As a commercial preparation, we are actually looking to reach a lot broader audience, both from the physician and patient space, and we are actively educating on the disease, the importance of actually improving hemoglobin levels and hemolysis given that hemolysis truly linked to developing disease complications and can lead to increased morbidity and mortality in that patient population. You asked a little bit about kind of the initial patient segment that will probably -- we'll focus on at launch and how we can expand that over time. When you think about the feedback that we got from the clinicians on the patient characteristics, they all look to prescribe. And when you think about which are the patients that are more likely to have regular business and interactions with the healthcare system, these will be the transfusion-dependent patients, given that they are regularly going and seeing their clinicians when they're being transfused, as well as patients who are more symptomatic, either have comorbidities linked to the disease as well as lower hemoglobin levels and fatigue. We would expect these patients probably to hear and be considered for Mitapivat dives in the initial stages of the launch. And as we look to educate product in clinical and patient community, we'll look to expand that into a broader patient population.

And now I'll hand it over to Sarah to talk about the importance of Mitapivat's mechanism of action and treating the totality of thalassemia.

[Sarah Gheuens, executive]

Thanks, Tsveta. So I would like to come back to the hemoglobin cutoffs in the clinical trials. As you know, we have the clinical trial endpoint of 1 gram per deciliter or more that we look at. But to your point, Greg, there are patients who may not reach that bar of becoming a responder in the clinical trial, but still they experience some benefit, and we have seen in our PKD patient population. We also see that in the thalassemia patient population. We highlighted at [Indiscernible] Dr. Taher showed a waterfall plot showing how the hemoglobin distribution in the patient population exposed to Mitapivat versus exposed to placebo looks like. You could see a very similar figure in the thalassemia patient population as what we have shown before in the pyruvate kinase deficiency patient population.

So there is definitely people who are improving some of their hemoglobin volumes, but they not reach the clinical trial endpoint, which is also one of the reasons why to setup points that hemolysis component is important, how patients feel is important. So this is why we allow patients and physicians to decide at the end of a clinical trial to still roll over in an open-label extension, even if they don't need the clinical trials are.

[Operator]

And one moment for our next question. And our next question comes from Divya Rao from TD Cowen.

[Divya Rao, analyst]

Congrats on the quarter. This is Divya on for Mark. I had a question on the ACTIVATE-KidsT. Looking at the AEs in the trial, could you comment on if there are any changes in sex hormone levels in the Mitapivat arm versus placebo? And then I have a follow-up.

[Sarah Gheuens, executive]

Thanks for the question. So we have not gone into deeper detail yet on all the safety beyond what we actually put out in the press release. So we look forward to doing that at an upcoming medical meeting.

[Divya Rao, analyst]

And then on AG-946, I was curious when you would -- when we could expect to see the Phase IIa data. And if it would be at a medical meeting or if that's...

[Brian Goff, executive]

First, Divya, we have to practice saying tebapivat because [Indiscernible] And we're going to try to do the same because 946 is burned in our heads, but Sarah [Indiscernible]

[Sarah Gheuens, executive]

Honestly, it's -- the numbers are still burned in my head as well. So apologies if I switch. But yes, so as mentioned, our current milestone and focus is the Phase IIb. So the team is very, very focused on that. So we will declare later when we presented IIa data at an appropriate time, but it will be at an upcoming medical event.

[Brian Goff, executive]

And I just want to reemphasize real quick that again, for MDS, and we'll learn as we proceed through the clinical trial program here, but this is a very compelling market for us. We certainly took note of -- the Reblozyl recently reported sales data that shows now a run rate in excess of $1.6 billion annualized. There is a very high unmet need in this population. Certainly, as is the case in all the diseases we pursue, there's room for multiple mechanisms of action. And if we're successful, this would be not only novel PK activation, but in a pill form, which would be very significant for patients.

[Operator]

And one moment for our next question. And our next question comes from Salveen Richter from Goldman Sachs.

[Unknown Analyst]

This is [ Lydia] for Salveen. Just another on thalassemia. How does the full Phase III ENERGIZE-T data that's coming at a medical meeting later this year, could you just frame expectations for the data in terms of any additional insights or data points that we could expect to be implement in terms of the clinical meaningfulness?

[Sarah Gheuens, executive]

So yes, we -- in our press release, we highlighted the -- because around the primary endpoint and one of the secondary endpoints were transfusion-independent. So obviously, we will highlight that again because we're very, very happy with that. As mentioned, we also met all key secondary endpoints, and we will be presenting the [Indiscernible] data as well and then, of course, safety as well. So it's going to be a typical intent to treat analysis presentation in line with how we designed and ran the clinical trial and have done the prespecified analysis.

We're very pleased with the results. In the key secondary endpoints you may see that we actually have a very long interval in which we measure a transfusion reduction for the first time. And so are, of course, again, very happy with the results that, that trial generated. The 2 trials have now completed and have their data read out. So we are very eager to move forward in the development and regulatory engagement and are looking forward to really have to review start this.

[Operator]

And one moment for our next question. And our next question comes from Tessa Romero from J.P. Morgan.

[Tessa Romero, analyst]

On the regulatory side in the U.S. for thalassemia, how should we think about the gating factors at this point for your submission of the sNDA? And is the base case here a standard or priority review?

And then our second question is just a follow-up on the arrangement with NewBridge. How should we think about the soonest we could start to see revenues here? And how many patients have thalassemia specifically in the Saudi region?

[Brian Goff, executive]

Sarah, you want to start with regulatory pathway?

[Sarah Gheuens, executive]

Yes. So we're very eager to work together with the FDA and submit the package for their review and assessment. So we're doing a typical process really. We don't comment on when or how, those are milestones for later. So I think we're just pleased with the progress our team is making and are just very excited to get everything going.

[Brian Goff, executive]

And then new Cecilia, sorry Tsveta, NewBridge GCC?

[Tsveta Milanova, executive]

The same thing with GCC, as we mentioned, we're super-excited about having signed agreement with NewBridge to take on the next steps of preparing for submission and potential commercialization given the GCC is the second most important region for us after the U.S. When it comes to submission and approval timelines, we'll start working with NewBridge. We haven't provided the specific timelines on that. It is -- there are about 70,000 patients with thalassemia in the region as we start working with NewBridge to deepen our market understanding. We might be able to provide more information, but not in this stage.

[Brian Goff, executive]

And clearly, Saudi Arabia is the largest component of that. That part is very clear. And do you want to just make one comment on access pathways in the region?

[Tsveta Milanova, executive]

Absolutely. So when we think about the GCC region, the best way to think about it is probably closer to the European kind of ways of assessing pricing and reimbursement. Submission getting to pricing and reimbursement agreement and uptake. The process starts with the submission at the regulatory level where you actually obtain a price at the national level. And then depending on the market, there are numerous steps after that to actually get formulary approval and agreement with the health institutions, other local hospitals in the private market. And over time, we are expecting to see tenders in the different markets, and we look forward to working with NewBridge to navigate all these key steps to patient access and speed the process as quickly as we can.

[Brian Goff, executive]

So Tess, we're excited about that arrangement. But just to come back to, by far, our #1 priority is the U.S. And again, we're thrilled to have the opportunity. And Tsveta is working very assertively with the commercial team to build out our commercial prowess in rare diseases, building on the momentum we've had in PKD and moving into thalassemia and hopefully beyond sickle cell as well.

[Operator]

And one moment for our next question. And our next question comes from Alec Stranahan from Bank of America.

[Alec Stranahan, analyst]

Just a couple from us. First, one follow-up on the sNDA submission and just sort of framing the data that will be going into that. Is the full data we should expect by the end of this year, kind of the complete picture of what the FDA will be reviewing? And anything incremental in efficacy from that update or more just sort of expanding on the safety and and the secondaries?

And then one question on the PK study in the non-transfusion setting next year. Any read-throughs to be made from the data today to that study, obviously, different primary end points and different patient population?

[Brian Goff, executive]

Sure. Thanks, Alec. So we'll take those in sequence. And Sarah, maybe the first one you could just comment on our planned package of data. And secondly, we'll talk about pediatrics.

[Sarah Gheuens, executive]

So of course, now the program, as mentioned, the 2 randomized clinical trials have completed, have been locked and we have the data. So we're very excited to put that together. We are really doing our -- the standard type of work that we would normally be doing for submissions that follow standard cuts timelines and updates that we need to do and are very eager to work with the regulators and get that process started. There's always questions back and forth. So there -- I mean, we're just going to go through the motion.

And in regards to the ACTIVATE-KidsT endpoints, so we are very pleased with the data that was generated in this clinical trial, both from a safety and an efficacy.

[Brian Goff, executive]

Yes. And then thoughts on the link or the read-through as it would be called to ACTIVATE-Kids non-transfusion-dependent patients?

[Sarah Gheuens, executive]

So again, it's a similar methodology applied for ACTIVATE-Kids. It's non-regularly-transfused patient population that were blinded. So we are very eager to get to the next point, and then we'll get that data package. We -- in the ACTIVATE-KidsT trial, we are very pleased because the transfusion-free response truly highlights the mechanism of that action of Mitapivat is applicable to kids as well. And so now we're hoping that, that also translates into the other trial.

[Operator]

And I am showing no further questions.

I would now like to turn the call back over to Brian Goff, CEO of Agios, for closing remarks.

[Brian Goff, executive]

Thanks, Justin. And so thanks a lot, everybody, for the great questions and for participating in today's call. This is clearly a very exciting time at Agios. And just thinking of the year so far to date, it's been a little bit breathless in the best way possible with continued delivery on our milestones and maybe more importantly, a lot still to come that we're very much looking forward to. So we have strong conviction that we're poised to deliver transformative new therapies for patients and ultimately to also create significant long-term value to shareholders.

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

[Operator]

This concludes today's conference call. Thank you for participating. You may now disconnect.