Good morning, and welcome to Agios' Second Quarter 2024 Conference Call. [Operator Instructions]. Please be advised that today's call is being recorded at Agios' request. I would now like to turn the call over to Chris Taylor, Vice President, Investor Relations and Corporate Communications for Agios..

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, 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.

With that, I'm pleased to turn the call over to Brian..

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 3 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 3 study to demonstrate efficacy of an oral disease-modifying treatment for transfusion-dependent alpha and beta-thalassemia.

Second, data from the positive Phase 3 ENERGIZE study of mitapivat in adults with alpha or beta thalassemia, who are not regularly transfused, were presented by leading KOLs in two 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 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.

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 3 ACTIVATE-kids T 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 3 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 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 two 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..

Thanks, Brian. This morning, we were very pleased to announce top-line data from the Phase 3 ACTIVATE-kids T study of mitapivat in children with CK deficiency who are regularly transfused, which is the first Phase 3 study to report data in this population. 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 the second study and we'll review all available data from both the ACTIVATE-kids T and ACTIVATE-kids studies.

Turning now to the data from ACTIVATE-kids T reported to date. As this first slide depicts, our pediatric PK deficiency program includes two Phase 3 studies evaluating regularly transfused and not regularly transfused pediatric patients with Pyruvate Kinase deficiency in ACTIVATE-kids T 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-kids T trial.

A total of 49 patients were enrolled in the study with patients randomized two to one to either mitapivat five 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 pre-specified statistical criterion for the primary endpoint in ACTIVATE-kids-T was not met using low or moderate borrowing of data from the ACTIVATE-kids study in results.

The results were clinically meaningful as transfusion reduction response and normal hemoglobin response to key secondary end point study are only observed in patients in 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 nine through 32 of the double-blind period normalized by weight and actual study drug duration compared with the historical transfusion volume standardized by weight into 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 endpoints of transfusion-free response and normal hemoglobin response, which were measured from week nine through week 32 of the double-blind period.

Six patients, nearly 20% in the mitapivat arm compared to zero in the placebo arm had a transfusion-free response with no red blood cell transfusions and four patients in the mitapivat arm compared to zero in the placebo arm, achieved a normal hemoglobin response.

Defined as hemoglobin concentrations within normal limits at least once, eight 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 3 ACTIVATE-kids T 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 3 ENERGIZE study were presented in a plenary session at the EHA meeting in June by Dr. Ali Taher from the American University of Bayoumis 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 3 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 two to one to either 100 milligrams with 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 two 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 endpoints 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 three key secondary endpoints.

An equal or more than 50% reduction in transfused 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 eight 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 was 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 sub-types 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 3 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 2 portion of the RISE UP study as well as the positive data we have generated in other hemolytic anemia, 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 3 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 2b study of evaluating higher doses of our Novel PK activator AG-946 now named the Tebapiva 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 Cecilia..

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 higher 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 three key factors that have the potential to support adoption of cytokines in thalassemia in the U.S.

First, driven by the availability of newborn screening and well-established ICD-10 code, 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 a 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 firsthand experience with mitapivat. Taken together, we believe we are well positioned to provide a potential foundational treatment option for patients with thalassemia regardless of sub-type.

As we continue to progress towards a potential launch in the U.S. Our team is focused on four key areas of launch preparation. First, we continue to conduct extensive market research and claim 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 the leukemia sub-types. 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 objective 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 the leukemia patient's transfusion history with content being 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 to 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 effort to successfully secure a breakthrough medicine designation for mitapivat in thalassemia, which was granted by the SFDA, Saudi FDA.

As noted in the last bullet, the access path in individual DTC 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 BID 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 represent 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 we 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..

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 favor 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 cost associated with the TMPRSS6 program in license from siRNA 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 and 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 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.

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..

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 three hemolytic anemias and we're pleased to have now completed our first Phase 3 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 sub-types 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 Instructions]. Our first question comes from Eric Schmidt from Cantor Fitzgerald. Your line is now open..

Thanks for taking my question and 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? Thanks..

Thanks, Eric. 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..

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.

We are also very proud to announce that we actually received the breakthrough medicines 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.

We'll be providing more information on that, as we enter into the process. When you think about the new operations agreement that we have with them, they are full service distributor. They will represent Agios 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 deal. There'll be no upfront payments for us as Agios. As we continue to basically progress this commercialization, there'll 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.

There is already a firsthand experience with some of the key centers and care wealthy in the region and we look forward to provide access to patients. And then, Eric, to follow-up on the question around timing of regulatory engagement, we are of course very excited to keep on moving forward with the development of our program.

And so, in part, we will be working as soon as we can with the regulators across the board..

I'll just close by saying that breakthrough medicines designation in Saudi is pretty unusual. And so, we've been pleased to have that as a recognition of, as Sarah noted, just a profound unmet need in that region. 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..

Our next question comes from Christopher Raymond from Piper Sandler. Your line is now open..

Thanks. 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 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..

Yes, sure. 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. 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. 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 have near-term. 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.

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. That's the number one 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 MBS and we're looking forward to commencing on the Phase 2b study for low risk MBS. 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.

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 sites, but again, great organic opportunities as well..

Okay, great. And then, maybe just a quick follow-up. On sickle cell and the opportunity, we've had some feedback from KOLs that not all sickle cell patients experience VOCs.

Maybe just talk about your view around VOCs as an endpoint and the applicability for a broad population?.

Yes, that's a great one for Sarah..

Yes. Thank you. You're right. Not all patients experience VOCs. 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. 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. That is why our clinical trial from an endpoint perspective has the inclusion criteria of sickle cell pain crisis two or more.

But I mean, just to be able to measure that treatment effect, but our expectation is that, it can work for no matter how many sickle cell pain crises you have, including just one or zero.

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 a 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 in all of our clinical trials to go for, a label that can treat sickle cell disease after a regulatory review..

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 and sickle cell pain crises, VOCs is one aspect, but Fatigue is another very profound need..

I just mentioned the primary endpoints, right, the hemoglobin primary endpoint of hemoglobin and sickle cell pain crisis reduction of the other primary endpoints to be able to measure hemolytic anemia and VOC impact.

As you know, that's like 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 a very, very, very impactful and burdensome to the patient population and as typical for all of our designs, we really try to incorporate patient feedback and therefore have incorporated Fatigue as a main secondary endpoint.

We've just announced the thalassemia trial data Energize in which we did meet our key secondary endpoint for the first time on a patient reported outcome that measures Fatigue. We are very hopeful for the RISE UP study as well..

One moment for our next question. And our next question comes from Gregory Renza from RBC Capital Markets. Your line is now open..

Great. Good morning, Brian and team. Congrats as always on the continued progress. Thanks for taking my questions. Maybe, Brian, I'll just start with, ACTIVATE-kids T perhaps for Sarah.

Sarah, could you just help us understand maybe the statistical assumptions? Certainly, seems to us that that PYRUKYND 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 or inconsistent with historical transfusion rates? Any added color you have would be great. And then I have a follow-up. Thank you..

Sure. Thanks for the question. ACTIVATE-kids T, we really tried to design a study that is appropriate for an ultrarare disease population and therefore it shows to really leverage the adult data we have generated to get to a sample size that would be appropriate for this stage of development and provide us with adequate data.

We have to use 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 them specific weights that you leverage to look at your pediatric data.

We can't say that, across the board, we see a treatment effect. 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 odds ratios, the confidence intervals around that do include one. That's why we are very mindful of that.

To your point, the data that we have observed, the fact that there are six patients, who became transfusion free, 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. If you're one of those six kids, that is a very meaningful difference for that specific person and their family, because this has also obviously an impact to the family.

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.

This is our first pediatric clinical trial after completing an adult program and get to an indication statement there. This is our first endeavor to really expand the age range of that patient population. From that perspective, we do feel the safety data is very important. The efficacy data that we have generated is very encouraging.

And so, we're very excited about the next steps in the development..

That's helpful. Thank you. And just one other question, just on thalassemia. It's helpful to have sort of 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 assume all goes as planned and the approval 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 that patients to stay on the drug longer-term? Thanks again, Brian and team..

There's a lot in there, Greg. Maybe we'll just focus on the crux of your question that I heard was focused on the unmet need. 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 engaged 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..

Absolutely. 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. Absolutely, Brian and I had the opportunity to attend the Cooley's Anemia Foundation Patient and Family Conference.

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 journeys and the stories there, and very importantly get the excitement and the enthusiasm of both the patient and the clinical community, about potential new innovative therapies coming to the thalassemia space, including the potential of 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.

Greg, as you mentioned, we've heard it very clearly from -- the physician community and the market research that they'll consider all of the relevant endpoints that we measure in our clinical trials, as patients' characteristics when making a treatment decision being hemoglobin level, being transfusion burden, being iron overload and of course fatigue.

Sarah talked about the importance of fatigue both 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 is truly linked to developing disease complications and leads to increased morbidity and mortality in that patient population.

You asked a little bit about kind of the initial patient segments that 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's characteristics, they'll look to prescribe and when you think about, which are the patients that are more likely to have regular visits and interactions with the healthcare system, this 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 makeup -- in the initial stages of the launch.

As we look to educate product clinical and patient community, we'll look to expand that into a broader patient population. Now I'll hand it over to Sarah to talk about the importance of mitapivat’s mechanism of action in treating the totality of thalassemia..

Thanks, Tsveta. 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 this leader or more that we look at.

But to your point, Grace, there are patients who may not reach that bar of becoming a responder in the clinical trial, but still may experience some benefit that we have seen in our PKD patient population. We also see that in the thalassemia patient population. We highlighted at Dr.

Tahir showed a waterfall plot showing how the hemoglobin distribution in the patient population exposed to mitapivat versus exposed to placebo looks like and 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.

There is definitely people who are improving some of their hemoglobin values, but they not reach that clinical trial endpoint, which is also one of the reasons why to set up points, the hemolysis component is important, how patients feel is important.

This is why we allow patients and physicians to decide at the end of a clinical trial to still roll over in the open label extension even if they don't meet the clinical trial bar..

One moment for our next question. Our next question comes from Divya Rao from TD Cowen. Your line is now open..

Hi, guys. Congrats on the quarter. I had a question on the ACTIVATE-kids T. 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 the placebo? And then I have a follow-up..

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

Okay. That's helpful. And then, on AG-946, I was curious when we could expect to see the Phase 2A data. And if it would be at a medical meeting..

First Divya, we have to practice saying mitapivat because that's ivat. We're going to try to do the same because 946 is burned into our heads, but Sarah, you're going to comment on that..

The numbers are still burning in my head as well, so apologies if I switch. But yes, as mentioned, our current milestone and focus is the Phase 2b. The team is very, very focused on that. We will declare later when we present the 2a data at an appropriate time, but it will be at an upcoming medical meeting..

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 Revlisol recently reported sales data that shows now a run rate in excess of $1.6 billion annualized.

There is 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. If we're successful, this would be not only novel PK activation, but in a pill form, which would be very significant for patients..

Our next question comes from Salveen Richter from Goldman Sachs. Your line is now open..

Hi. This is Lydia on for Salveen. Thanks so much for taking our question. Just another on thalassemia. Ahead of the full Phase 3 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 glean from it in terms of the clinical meaningfulness? Thanks so much..

Yes. In our press release, we highlighted the primary details around the primary endpoints and one of the secondary endpoints from transfusion independence. So, we will have that again because we are very happy with that. As mentioned we also met all three settings very end points and we will be presenting the data on that as well.

And then, of and we will be presenting the data on data as well, and then of course safety as well. 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 pre-specified analyses. 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 transfusion reduction for the first time. And so, we are of course again very happy with the results that that trial generated. The two trials have now completed and have their data read out.

We are very eager to move forward in the development and the regulatory engagement and are looking forward to really have the review started..

Thank you. One moment for our next question. And our next question comes from Tessa Romero from JPMorgan. Your line is now open..

Hi. Good morning, Brian and team. Thanks for taking our question. 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? 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? Thanks..

Sarah, you want to start with regulatory pathway?.

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

And then, Tsveta, NewBridge, anything?.

The same thing with GCC. As we've 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 that GCC is the second most important region for us after the U.S.

When it comes to submissions and approval timelines, we'll start working with NewBridge. We haven't provided the specific timelines on that. There are about 70,000 patients with thalassemia in the region. As we start working with the NewBridge to deepen our market understanding, we might be able to provide more information, but not in this stage..

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?.

Absolutely. When we think about the GCC region, the best way to think about it is probably closer to the European kind of ways assessing pricing and reimbursement submission, getting to a 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 out there that you actually get formulary approval and agreements with the health institutions, other local hospitals and other private markets, and over time we are expected to see tenders in the different markets and we look forward to working with NewBridge to navigate all of these key steps to patient access and speed the process as quickly as we can..

We're excited about that arrangement, but just to come back to by far our number one priority is the U.S.

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..

Thank you. One moment for our next question. Our next question comes from Alec Stranahan from Bank of America. Your line is now open..

Thanks for taking our questions. 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 on efficacy from that update, or more just sort of expanding on the safety 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 endpoints and different patient population? Thanks..

Sure. Thanks, Alex. We'll take those in sequence. Sarah, maybe the first one you can just comment on our planned package of data. Secondly, we'll talk about pediatrics..

Of course, now the program as mentioned the two randomized clinical trials have completed, have been locked and we have the data. We're very excited to put that together.

We are really doing the standard type of work that we would normally be doing for a submission that follows 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 is always questions back and forth. There, I mean, we're just going to go through the motion.

In regards to the ACTIVATE-kids T endpoint, we are very pleased with the data that was generated in this clinical trial, both from a safety and efficacy..

Yes.

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

Again, it's a similar methodology applied for ACTIVATE-kids non-regularly transfused patient population and we're blinded. We are very eager to get to the next point and then we'll get that data package.

We, in the ACTIVATE-kids T trial, we are very pleased because the transfusion free response truly highlights that the mechanism of action of mitapivat is applicable to kids as well. And so, now we're hoping that that also translates into the other trial..

Thank you..

I'm showing no further questions. I would now like to turn the call back over to Brian Goff, CEO Agios, for closing remarks..

Thanks, Justin. Thanks a lot everybody for the great questions and for participating in today's call. This is clearly a very exciting time at Agios.

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.

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. Thanks again and we look forward to speaking with you again soon..

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