Q4 2023 Agios Pharmaceuticals Inc Earnings Call
Participants
Christopher Taylor; Vice President, Investor Relations and Corporate Communications; Agios Pharmaceuticals Inc
Brian Goff; Executive Vice President, President - Hematology; Agios Pharmaceuticals Inc
Sarah Gheuens; Head - Research and Development, Chief Medical Officer; Agios Pharmaceuticals Inc
Tsveta Milanova; Chief Commercial Officer; Agios Pharmaceuticals Inc
Cecilia Jones; Chief Financial Officer; Agios Pharmaceuticals Inc
Eric Schmidt; Analyst; Cantor Fitzgerald
Chris Raymond; Analyst; Piper Sandler Companies
Danielle Brill; Analyst; Raymond James
Gregory Renza; Analyst; RBC Capital Markets
Tess Romero; Analyst; JPMorgan
Greg Harrison; Analyst; BofA Global Research
Divya Rao; Analyst; TD Cowen
Presentation
Operator
Good morning and welcome to Agios' Fourth Quarter 2023 conference call. At this time, all participants are in a listen only mode. There'll be a question and answer session at the end. Please be advised that this call is being recorded our deals request.
I would now like to turn the call over to Chris Taylor, Vice President, Investor Relations and Corporate Communications for Agios. Please go ahead.
Christopher Taylor
Thank you, operator. Good morning, everyone, and welcome to Agios' conference call and webcast to discuss fourth quarter and full year 2023 financial results. And recent business highlights. You can access slides for today's call by going to the Investors section of our website at Agios.com. On today's call, I'm joined by our Chief Executive Officer, Brian Goff, Dr. Sarah Hewitt's, Chief Medical Officer and Head of Research and Development Center melanoma, 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 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.
With that, I'll turn the call over to Bryan.
Brian Goff
Thanks, Chris, and 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. Driven by this goal, we continued to generate consistent and compelling data across our industry-leading PK activator franchise and with seamless cross-functional collaboration of the Agios team, we made remarkable progress advancing this mission in 2023. Highlighting this progress, we reported three key data readouts in the last 12 months. In June, we reported positive top line data from the Phase two portion of the rise up study of mitapivat, our lead PK activator in sickle cell disease, followed by the full data set in December at ASH, despite the field's recent progress in sickle cell disease, there are no novel oral therapies that improve that both improve anemia and reduce sickle cell pain crises, and that is precisely what we aim to deliver with mitapivat.
In November, we reported positive data from the open-label Phase IIa study of our other PKR activator, AG nine four six in lower risk MDS with 40% of patients achieving the transfusion independence endpoint. And just last month, we reported positive data from the Phase three energize study of mitapivat in non-transfusion dependent thalassemia. As a reminder, non-transfusion dependent or NTD. thalassemia accounts for approximately two thirds of thalassemia in the US and has no FDA approved treatment option despite not requiring regular transfusions and TD. thalassemia patients experienced significant impact on quality of life, a wide range of serious morbidities and an elevated risk of premature death together, the consistency of data generated across the mitapivat development program bolsters our conviction in the probability of success of our ongoing studies, including two additional Phase three readouts we expect by the end of this year. And this data highlights the potential of our PKR activators to transform the course of multiple hematologic diseases. Sarah will provide more detail on our advancements and upcoming milestones across our pipeline in just a few minutes. Importantly, we believe our PK activation pipeline is well positioned with multiple near-term catalysts to become a multi-billion dollar franchise and deliver significant value in parallel with advancing the late-stage mitapivat development program across multiple indications. Our commercial organization is laser focused on building the infrastructure established through our current launch in PK deficiency to prepare for potential U.S. launches of mitapivat in thalassemia in 2025 and in sickle cell disease in 2026.
With that, I will provide greater detail on the commercial opportunities for mitapivat in thalassemia as well as an update on our current launch in PK deficiency.
And just a bit. Finally, as you'll hear from Cecilia, we ended 2023 with a strong cash position with approximately 806 million in cash and investments on the balance sheet. In addition, we continue to track surveys progress towards the potential FDA approval of where aside nib, given our retained economics for both milestone and royalties. This is truly an exciting time at Agios with four additional Phase three readouts and two potential launches expected on the horizon. We look forward to multiple opportunities to drive significant near term value creation for patients, caregivers and shareholders.
With that, I'll now turn the call over to Sarah.
Sarah Gheuens
Thanks, Brian. In 2023, our research and development organization made tremendous progress advancing our PKR activator development program, led by topping up the industry's most advanced PK activator now with over eight years of clinical experience. The consistent and compelling data we have generated to date in PK deficiency, CELsignia and sickle cell disease continue to derisk our ongoing development program and highlight the potential for this molecule to transform patients' function in quality of life. We are also enthusiastic about the potential for the rest of our growing pipeline, and we are pleased to note that we remain on track to deliver on our milestones, including enrolling the first patients in the Phase IIb trial for A. nine 46 in lower-risk MDS and for the Phase one trial for HT. one A. one, the compound name for our PH stabilizer for phenylketonuria, reading our top line data for the Phase three activated T study in regularly transfused pediatric patients with PK deficiency and completing enrollment of the Phase three activity study in pediatric patients with CKD.
Turning to sickle cell disease, we were pleased to present detailed positive results from the Phase two portion of the Phase two three right study of mitapivat at ASH. In December, the study achieved its primary endpoint of hemoglobin response and in addition, an improvement in annualized rate of sickle cell pain crises was observed, and we have been delighted by the enthusiasm of the investigators. We continue to advance enrollment in the Phase three portion of this study and remain on track to complete enrollment by the end of this year. While the treatment landscape in sickle cell disease continues to evolve, there remains an urgent and unmet need for convenient, novel oral treatment options that address both anemia and sickle cell pain crises. And we believe firmly in the top of potential to deliver a best-in-class option for patients suffering from this devastating disease.
And finally, on thalassemia, I'll take a moment to highlight a few key elements of our program and the positive top-line Phase three data we reported last month in non-transfusion dependent thalassemia. As a reminder, the Phase three program of PI3-kinase delta senior and completing two Phase three randomized placebo-controlled trials. It was designed to deliver data across all populations of sound senior, such as Alpha and beta-thalassemia and populations with different transfusion. Both trials enroll patients with alpha or beta thalassemia, but involve different populations as it relates to transfusion, we want to highlight that energize is the first clinical program that included patients who are not regularly transfused and alpha thalassemia patients. As Brian mentioned, there are no FDA approved treatments for non-transfusion dependent thalassemia, which represents approximately two thirds of total thalassemia patients in the US. These patients suffer from a poor quality of life, a high rate of serious morbidities, including thrombosis and premature death. We were therefore very pleased to be able to announce positive results from the energize study. As a reminder, the NHI. study enrolled a total of 194 patients with either alpha or beta non-transfusion dependent thalassemia randomized 2 to 1 to 100 milligrams and above or placebo twice daily speed of enrollment and the actual number of patients enrolled in the study as well as a high completion and rollover rate supports the idea that people who are not regularly transfused were motivated to take action and speaks to the unmet need for this population. The primary endpoint of this study was hemoglobin response rate, defined as an increase of at least one gram per deciliter in average hemoglobin concentration from week 12 to week 24 compared to date. Key secondary endpoints of this study were changed from baseline in average Facet fatigue score and change from baseline in average hemoglobin concentrations. Also both assessed from week 12 to 24 on the primary endpoint treatment with mitapivat demonstrated a highly statistically significant results with 42.3% of patients in the treatment arm, achieving a hemoglobin response versus 1.6% of patients in the placebo arm in line with mitapivat novel mechanism of action, which focuses on overall red blood cell health and the data generated with mitapivat across additional disease areas. The beneficial effects of mitapivat in this study extended beyond hemoglobin alone, specifically treatment with 100 milligrams mitapivat resulted in statistically significant improvements in both key secondary endpoints, including a change from baseline in average Facet fatigue score, an important patient-reported measure of how patients feel and function. Importantly, across the primary and secondary endpoints, all prespecified subgroup analyses favored status as compared to placebo, suggesting that no single subgroup was responsible for driving the results which supports our plan to file for a broad label covering all CELsignia tests. It is therefore the first drug that not only improves hemoglobin but actually makes people without seeing at fields that are consistent with what we observed in patients with PKD and what we hope to be able to deliver for patients with sickle cell disease as well.
Complementing the near term benefit of thalassemia patients reporting that they had less fatigue and felt better in the near term conditions in the trial and other care.
Well, appreciate the potential longer-term benefits of reducing markers of hemolysis and the longer term potential to reduce serious morbidities. We are very much looking forward to presenting the full data set at a medical meeting beyond the excitement we have for the enterprise data itself, the readout of the energize trials also gives us further confidence towards the readout of energize. The CELsignia is a hemolytic anemia, irrespective of whether a patient is in need of transfusions or not. In addition, the mechanism of action of and it's something that is not dependent on the need for transfusions. We have already demonstrated and improvements in hemolytic anemia in the energize trials. With a positive change in hemoglobin, we are now waiting to see the improvement in domestic anemia can also be documented via a reduction in transfusions in our Chesapeake. As a reminder, the primary endpoint of energize T is transfusion reduction response, defined as a 50% or greater 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 periods through week 48 compared to baseline like the energized study in non-transfusion dependent thalassemia. The design of the interchange fee trial enables us to demonstrate clinical meaningfulness in a variety of ways, see a reduction in transfusion burden, which also includes transfusion metrics in line with that other studies have used. We designed this study incorporating learnings from prior studies and agency feedback and believe a dynamic assessment period is important as patients on static in your disease. We look forward to the readout of this study by midyear and plan a single regulatory filing to the FDA and compacting data from both energized and energized team by the end of this year, seeking a label that will enable people living with balancing access to a convenient and differentiated oral treatment option. Overall, I'm very proud of the tremendous progress made by our R&D organization in 2023 and look forward to continuing this momentum in 2024.
With that, I will now turn the call over to Satya.
Tsveta Milanova
Thanks, Aram. Felicia remains an area of high unmet need with few treatment options. The burden of disease on the patients is significant regardless of their transfusion need. Celsignia patients experienced increased mortality compared to the general population and can be significantly worse in non regularly transfused than those who are regularly transfused. Patients in Europe have high rates of morbidity and increased complications as they age adult patients with non-transfusion dependent thalassemia may actually have similar or worse quality of life compared to transfusion dependent patients. Of course, this burden of disease correlates So increased health healthcare costs to address this unmet need and galvanized by the positive data from the Phase three energize study of mesothelioma. Our commercial organization is actively preparing for a potential launch in thalassemia next year, beginning with the U.S. In the U.S., there are approximately 6,000 diagnosed adult patients with the leukemia. Approximately 4,000 of these patients are non-transfusion dependent and have no available treatment options today. The remaining 20 patients are transfusion dependent and have no oral treatment option. Our goal with mitapivat is to address the unmet need of all adults living with California and become the first therapy approved for all subtypes of the disease. In addition to the data we are generating through them with the pivotal clinical development program. There are three key factors we believe have the potential to support adoption of mitapivat on multiple leukemia patients in the U.S. First, there is strong alignment between where in the US. These patients reside and where they receive treatments.
The map on slide 26, patient prevalence overlaid with the arduous clinical trial site and for Centers of Excellence represented by the gold bars. Second, the diagnosis rate is high, driven by the availability of newborn screening and well-established ICD-10 codes. Many patients are diagnosed before adulthood.
And finally, as shown on slide 21, there is concentration of patients and providers at selected centers. Approximately 50% of all diagnosed patients are treated at fewer than 150 affiliated hematology oncology practices in the U.S. providing a clear focus for our initial launch. Given these market dynamics and final time target product profile, we believe we are well positioned to provide a potential foundational treatment option for patients with pellet premia regardless of subtype. Therefore, our team is focused on four core areas of U.S. launch preparation for building on the foundational work we have already done we continue to deepen the sophistication of our market understanding. We are conducting extensive market research and claims data analysis to inform HCP targeting field force sizing and deployment for launch second we'll be rolling out a disease education campaign for both patients and clinicians, highlighting the long-term complications and burden of disease across all CELsignia subtypes. Our disease education engagement will also work to correct the historical misperception that non-transfusion dependent patients are less likely to experience the debilitating long-term effects of the leukemia. To support these initiatives, we are establishing capabilities to enable execution of our educational efforts across personnel and non-personnel channel sorry, we'll continue to strengthen our commercial capabilities by expanding our sales team in anticipation of the thalassemia launch, rightsizing the team for a broader rare disease.
And lastly, in parallel with those efforts, we are preparing our market access team to engage with payers on disease state education in advance of the potential launch in thalassemia next year. Our team has obtained success in market access for PK deficiency, and we look forward to watching them pave the way in thalassemia, too, in addition to the well-established USD premium market. There are approximately 13,000 patients in the EU5 and approximately 70,000 for leukemia patients in the Gulf region. We aim to maximize the potential of these additional markets through coordinated regulatory filing, which we intend to pursue with partners. Taken together, we believe the potential launch of mitapivat in thalassemia represents a significant opportunity for IGO and a step forward as we prepare for potential back-to-back launches with sickle cell disease in 2023.
Now let me provide an update on the current launch of vital signs in PK deficiency. In the fourth quarter of 2023, we generated $7.1 million in net BioTime revenue compared to $7.4 million in the prior quarter. A total of 178 patients have completed a prescription enrollment form, including 18 in the fourth quarter of 2023, an 11% increase versus the third quarter this translated into net 109 patients on therapy, a 9% increase versus the third quarter. Patients on therapy continues to spend from a growing and diverse prescriber base of 154 physicians and represents a broader demographic and disease manifestation range that is consistent with the adult PK deficiency population. 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. The capabilities we continue to build and expand through the current launch, including efficient targeting analytics, patient awareness and education and patient access will provide a firm foundation from which we can maximize the potential U.S. launches in thalassemia in 2025 and in sickle cell disease in 2026 as we advance through this catalyst-rich period of Phase three data readout for mitapivat, we look forward to dramatically expanding the number of patients we serve.
With that, I'll turn the call over to Cecilia.
Cecilia Jones
Thanks, Meta. Our fourth quarter 2023 financial results can be found in the press release we issued this morning and more detail will be included in our 10 K, which will be filed later today.
Let me now take a moment to provide some context and highlight a few key points full year 2020 to be net Biocon revenue was $26.8 million compared with $11.7 million in Biocon revenue for 2020 to Q4 2023 net Paracon revenue was $7.1 million, a 4% reduction compared to the third quarter. The reduction was driven by lower number of weeks on hand of inventory compared to where we ended Q3, partially offset by favorability in gross-to-net adjustments. As a reminder, we anticipate low levels of inventory at any given time, given our limited distribution network, which consists of one specialty pharmacy and one specialty distributor, consistent with other rare disease launches. Gross to net is expected to be in the 10% to 20% range on an annual basis based on our learnings to date, given the ultra rare nature of the disease and the long lead times associated with initiating patients on therapy, we continue to expect slow and steady growth and quarter to quarter variability in 2024, similar to what we saw in 2023. Cost of sales for the fourth quarter was $0.6 million R&D expenses were $77 million for the fourth quarter and $296 million for the full year 2023, an increase of $16 million compared to the full year 2022. These changes reflect an increase in development costs for mitapivat and the upfront payments associated with a license agreement with Alnylam offset by a reduction in expenses associated with the evolution of our research organization and the sale of our oncology business to Servier.
Sg&a expenses were $35 million for the fourth quarter and $120 million for the full year 2023, a decrease of $2 million compared to the full year 2022. As a reminder, as part of the divestiture of our oncology business to Servier, we retain rights to a potential $200 million milestone upon FDA approval of Veracyte and if and 15% royalties on potential U.S. net sales, certainly publicly communicated plans to file for approval before the end of 2023. So we are eager to track their progress. We ended the year with cash, cash equivalents and marketable securities of approximately $806 million. We expect that this balance, together with anticipated product revenue, interest income on the potential for aside any milestone would enable the Company to fund our operating expenses and capital expenditures through several value-creating milestones and at least into 2026. This guidance does not include cash inflows that could extend our runway beyond 2026, including the potential royalties or royalty monetization from Veracyte and at commercializing mitapivat outside of the US through one or more partnerships or other potential strategic business or financial agreements. 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 Fiberxon as we move toward additional potential value-creating milestones in the near term. I am confident that our strong balance sheet will enable us to execute from a position of strength as we continue to pursue ways to create shareholder value.
I will now turn the call back over to Brian for his closing remarks.
Brian Goff
I think Cecilia, as we turn the page on a highly productive 2023. We're focused on executing across the additional four Phase three readouts for mitapivat that we expect over the next two years, beginning with the Phase three energize T. study in transfusion dependent thalassemia in the middle of this year. As we continue to stack successes, positive data readouts for mitapivat, we are only growing more confident in the probability of success ahead. We're well positioned with a differentiated mechanism of action that improves red blood cell health beyond hemoglobin increase and allows us to pursue large commercial opportunities with substantial value and the potential for two additional first-in-class and best-in-class indications for pirate time as we build a multi-billion dollar franchise in PKR activation as we continue to take steps toward realizing our vision of becoming a leading rare disease company. We will continue to strive to be responsible stewards of our balance sheet and evaluate meaningful opportunities for value creation and 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 will now open the call for questions.
Question and Answer Session
Operator
Thank you to ask a question, you'll need to press star one one on your telephones. To withdraw your question, please press star one again. Please wait for your name to be announced, we ask that you please limit your questions to one and one follow up. Please standby while we compile the Q&A roster. One moment for our first question, please. Our first question comes from the line of Eric Schmidt with Cantor Fitzgerald. Your line is now open.
Eric Schmidt
Look, thanks for the question and congrats on all the recent development successes. I guess maybe one for Sarah, given the next milestone, next milestone at least might be the energize key study for mitapivat in transfusion dependent patients. Can you give us a little bit of a preview here or set up with regard to the primary endpoint, I know you're looking at transfusion reductions in a slightly different way than what we've been accustomed to seeing with the luspatercept data. So how might that primary endpoint definition changed the way we view the data and what might the hurdle be?
Brian Goff
Great. Thanks, Eric. Thanks a lot for the question. And I just before Serco's, I just wanted to welcome you back to our geos earnings calls. So sorry, do you want to get started?
Sarah Gheuens
Sure. Thanks. Thanks for the question. Saying the dark endpoint. The primary endpoint has a different definition and the primary endpoint that was better suited to use in the sense that we are looking at a 50% reduction in any 12 week period rolling period, basically over the 48 weeks and patients are assessed, which we believe is a more on appropriate measure to assess a patient in the context of a dynamic disease over a longer stretch of time in which reflects better the real-world experience of patients may have some. We do have a similar endpoints like the spot as the primary endpoint in our secondary endpoints.
In regarding to the hurdles, it is it is a different end point. Indeed, the hurdle is not necessarily different in the sense that you have multiple assessments periods versus a fixed period in time. The bar of 50%, of course, is higher than 33%. But like I said, because it's every any 12 week periods, you have more shots on goal to speak. This was an endpoint that was better set also had in their assessment and in their review. But as it was not a prespecified like primary or secondary analysis that did not make it into the label.
Eric Schmidt
Thank you very much.
Brian Goff
Thank you.
Operator
Thank you. One moment for our next question, please. Our next question comes from the line of Chris Raymond with Piper Sandler. Your line is now open.
Chris Raymond
Thanks. And maybe just a question on energize data that we got last months, we've gotten a few questions around from investors around that sort of the transition from the Phase two data. This to the Phase three data, there was a degradation in the hemoglobin response, but you measured these effects over different time points. I know you guys had said that there was no waning of efficacy over time, but maybe just square this difference that you saw and I've got a follow-up.
Sarah Gheuens
Sure. Thanks for the question. So the primary endpoint that we used in Phase two was indeed different than the endpoint that we used in the Phase three, meaning that for the Phase two, we just looked at patients meeting the hemoglobin response at a single time point for the Phase three, we incorporated the duration in that endpoint over a longer stretch of time and measured at a later time point because it's a chronic disease. So them and from a safety perspective, you're truly looking for maintenance over a longer duration of time. So we averaged hemoglobin over 12 weeks versus that just single time point, which is much easier to reach as a bar.
In regards to the waning, we don't see waning of our hemoglobin response of mitapivat in this trial behave very similarly to how it behaves in PKD. So once patients show a response, they tend to maintain that response over time. There's always a little bit of fluctuation on that hemoglobin over time. But overall, it's Steve of positive and aligned kind of stays horizontal in comparison to their baseline. So we feel very confident with the results that we have observed and energized. In addition, it's more than hemoglobin alone that we observed. We really saw an improvement on the Facet fatigue there as well, which we believe is extremely meaningful because now we are adding to the hemoglobin plus story here. Some of the things that we've observed in PKD now also have been observed in the non-transfusion dependent thalassemia population, and that continues to add to this consistent and compelling data story that we are continuing to generate.
Chris Raymond
Okay, thanks. And then maybe just a follow-up to Eric's question on the success bogey of energized T. And I know it's you're talking but different measures is kind of an apples to apples comparison that was Pat or SAP, but some and just as you're thinking about the obvious difference in mitapivat is oral versus luspatercept, which is not just maybe talk in generalities, how you see these these two compounds sort of coexisting commercially?
Sarah Gheuens
Sure. So if we think about the non-transfusion dependent thalassemia patient population that currently have no therapy available so that he may talk about it. And with if we get it through, the next stages of development would be the therapy, then it would be available for non-transfusion dependent patient populations and is all the which is a huge benefit specifically for that population because patients aren't going to clinic as frequently. And if you have and it's a drug that requires frequent clinic visits and adds to the burden of disease. Typically for the transfusion dependent patient population, there is indeed a subcutaneous luspatercept available for transfusion-dependent beta thalassemia patients. Our program has studied all genotypes of balanced senior.
So that's one difference. The oral route of administration here is very relevant because it allows for almost a seamless incorporation into a transfusion scheduled amortizations may have versus requiring more visits on top of the transfusions scheduling. In that sense, it's also important to understand there's a very different mechanism of action between those two products on which you know, this person did stimulate red blood cell stimulator, while we're talking about, it's about trying to improve red blood cell health overall. And so we do see from that perspective there, they're vastly different
Brian Goff
And Chris, I mean that last point is the one that I would just emphasize is that I know folks are trying to make comparisons, but in so many ways, they're incomparable because of the profound difference in the mechanisms. And you'll hear a lot from us because we continue to be emboldened by this by the data that we see very consistently that the benefits of power of pyruvate kinase activation really do go beyond hemoglobin. So we'll await the data. Fortunately, we don't have to wait that long. Energize T is coming midyear, but I think above oral and the other dimensions, hemoglobin and the like, that's really the big headline for this mechanism is it's ultimately about red blood cell health.
Operator
Thank you. One moment for our next question. Our next question comes from the line of Danielle Brill with Raymond James. Your line is now open.
Danielle Brill
Hi, guys. Good morning. Thanks so much for the questions. Unusual. We have a question on powering assumptions for aggregate, key on, like Chris said, we know it's not apples to apples, but when you look at this pattern that their mean hemoglobin increase was about 1.5 grams and they achieved I think, around a 40% response rate. And on your primary endpoint with this context, what are your internal expectation for how mitapivat will perform? And I also have a follow-up.
Sarah Gheuens
Thanks for the question. So in regards to our powering assumptions, we haven't spoken about these, but we have, of course, studied all of the programs in front of us, which includes our own internal programs in which we took a very similar development approach for thalassemia as we had for PKD in regards to the hemoglobin increase that you mentioned. So we don't have from a transfusion dependent perspective, we don't believe you necessarily need to increase hemoglobin on top of making trends to impact people reduce their transfusions. This is truly a different approach because people when they get transfused, their hemoglobin goes down over time. So what we are trying to do here is basically avoiding that people their hemoglobin decreases back to a transfusion trigger, which then would trigger a transfusion. And it comes down again to that different mechanism of action, if you're like stimulating out red blood cells, ultimately your or you're going to increase the hemoglobin versus what we are trying to do about keeping the red blood cells happier and healthier, thereby reducing hemolysis is a completely different way of actually trying to avoid transfusions.
Danielle Brill
Thanks. That's helpful. And that actually on a perfect segue for my follow-up. Do you have data on Avon, the potential of mitapivat for extending the half-life of healthy red blood cells.
Sarah Gheuens
So we in the context of you mean healthy volunteers, red blood cells
Danielle Brill
or likely extending the lifespan of transfused blood.
Sarah Gheuens
So yes, so this is something that is extremely difficult to come to measure in the context of a transfusion setting as everything is kind of mixed. So it would require very, very calm, unique experience to be able to tease apart those types of red blood cells that are available. So we're not planning on doing that right now for our transfusion dependent patients.
Danielle Brill
Got it. Thanks. And thanks again for the questions.
Operator
Thank you.
And our next question comes from the line of Gregory Renza with RBC Capital Markets. Your line is now open.
Gregory Renza
Hey, good morning, Brian and team. Congrats on all the progress and thanks for taking my questions. Brian, you certainly speak to the multibillion dollar opportunity available with the PK activation and your portfolio. Just curious if you could then maybe just elaborate a little bit on that, maybe provide some of that inputs or assumptions that you using to get to that characteristic, whether it's with respect to mitapivat and the ramp of indications or the broader portfolio? And maybe I'll just layer in my second question and with respect to the landscape in PKR activation, perhaps have you. And Sarah can just read a little bit about maybe the differences with mitapivat versus others, especially have a pivotal test. Certainly, you've mentioned I believe you have the body of data. But when you think about some of the nuances upon PK activation or evidence of selectivity, maybe just help us understand the differences between mitapivat and the landscape. Thanks so much.
Brian Goff
Yes. Thanks, Greg. So I'll get started on your first question about the multi-billion dollar opportunity or opportunities that I referenced in my prepared comments that really comes from the fact that we're rapidly progressing in our pipeline, moving from clear ultra rare with PKD. into successively larger prevalent diseases. Some of those diseases, I think are a well characterized in terms of opportunity, sickle cell, for sure. There's been a lot of interest in a lot of therapeutic development focus. And here we're talking about moving from 3 to 8,000 patients across the U.S. and EU five in the case of PKD., jumping to just in the U.S. alone, 100,000 patients with sickle cell disease. But it's more than that. I mean, as we've already discussed this morning, we had this really exciting opportunity relatively near term with a potential launch next year in thalassemia, which is a prevalence step up in the case of the U.S. from PKD sickle cell I just mentioned. And then even after that, with our other PKR activator AG nine four six moving into low risk MDS. The great news about all this is we're moving in the right direction in terms of prevalence, and that is allowing us to enter into very compelling commercial opportunities and it also allows us to navigate through the appropriate pricing dynamics as we go forward. But we are very excited, most importantly, with the fact that as we advance our pipeline and as we've already noted, we have two back-to-back launch potentials with calcemia next year, followed by sickle cell disease in 2026. And then sorry, you want to pick up with the next question.
Sarah Gheuens
Sure. So in regard PKR2 activation and the differences between mitapivat and some other PKR activator. So we indeed probably stimulate T K a different ticket item enzymes amongst which the PKR., which is important for the red blood cell. But then also Pecem two is important, and we understand more and more of the relevance that the relevance of this specific IDO enzyme in the context of the diseases that we are studying. And as you know, calcemia sickle-cell disease MDS, there is different components to these diseases in which stimulation of Pecem two may be relevant as it is expressed in immature red blood cells. It is expressed in other tissues that are also touched by these diseases. We are planning to further study this clinically as well as specifically in sickle cell disease in the kidney. As we know, kidney is such an important organ in the context of sickle cell disease and many patients suffer from kidney disease. And we believe that Pecem two may have an added advantage there in regards to how that compares to other PK activator, specifically about what if that is some day, this is the drug that home, it's to be format drug. They always spoke about being a PKR, selective agents in regards to how they translate into other enzymes and enzymes. They have not spoken about that. It just highlights that there's selectivity message.
Operator
Thank you. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open as for the on for Salveen.
Thanks so much for taking your question on just one on sickle cell, could you just discuss where you see power kind of fitting into the current commercial landscape just broadly? And then can you also speak to the commercial or the enrollment progression and any physician feedback you've gotten so far. Thanks so much.
Brian Goff
Sure. And maybe I will just start and then quickly turn it over to Satya and then Sarah can pick up on the enrollment aspects. I mean, the fundamental premise of what we're driving towards with sickle cell disease is we believe that mitapivat pilocarpine has the potential to be what we refer to as foundational therapy. This is a very different mechanism of action. As we've talked about very unique from currently available options. We're increasingly convinced that the benefits on making the red blood cells healthier, really position it as such and then the fact that this is an oral treatment only adds to that potential. But I'll let Steve speak a little bit more about not just how we're thinking about sickle cell disease, but the bridge as we go from PKD. two energy to Dallas, Caemi and then the sickle cell.
Tsveta Milanova
Thanks, Brian. I'll start with sickle cell disease for us. But as you said, we have a very important milestone with the policymakers launch ahead of that, which we believe will be an important point from growing the commercial capabilities, executing on the telephony launch and after that, capitalizing on our sickle cell disease.
When we think about sickle cell disease, Brian mentioned that and I mentioned that already the prevalence of the disease is 100,000 patients in the U.S., which is a significant step up from where we are today with PK deficiency is a disease where patients are diagnosed and the burden of disease is well-characterized at the moment. The adult patient population with sickle cell disease has very limited treatment options available. They are either improving hemoglobin levels, which is the case a brighter for our improving DUCs. And based on the Phase two data and the target product profile we have for by recurrent for loans, we believe that we'll be very well-positioned with fiber kind to provide a treatment option, which will bring benefits to physicians, patients and ultimately payers as well by improving hemoglobin, reducing VOCs and ultimately improving the way our patients feel and function. And that's going to be at a unique value proposition if we were to deliver on that profile.
So we are very excited about that opportunity to come. But before we get to sickle cell disease, we are very excited to progress with our launch preparation for thalassemia as well. Afterwards, though the results from the energize R&D during the year we have definitely our press the button and are actively preparing fertility near launch to come in 2025, Senor to sickle cell disease. I think the policymakers launch will be a meaningfully differentiated in terms of market characteristics that compare to PKD. And that will position us well for adoption of fire behind assuming approval in 2025, including again, these patients are diagnosed. It's 6,000 diagnosed patients in the U.S. with the leukemia and well-established ICD-10 codes, a stronger concentration of the prescriber base. And all of these elements gives us confidence on our ability to commercialize the product and drive adoption at launch and similar to sickle cell disease. There's a better understanding of the thalassemia unmet need across both the transfusion dependence and also the non-transfusion dependent patients as well. So we are gearing up and getting ready to commercial organization to go launch into lithium in 2025, potentially followed by back-to-back launches in sickle cell disease in 20.
Brian Goff
Yes. And so I was just going to say that's great set. And I think everybody consents or excitement about what we have in front of us. And I was just going to ask Sarah to make a comment about the progress with rise up Phase three for sickle cell factory
Sarah Gheuens
because we are equally excited to move towards those launches. So we are heavily focused on our Phase three enrollment. Of course, right now, the the trial is progressing as we are anticipating. There's a lot of enthusiasm, both within our teams and of course, on the by the investigators as well. And so everything is on track to deliver to the milestone that we have set out for this year.
Thank you so much.
Operator
Thank you very much. Question comes from the line of Tessa Romero with JPMorgan. Your line is now open.
Tess Romero
Great. Good morning, Brian and team. Thank you for taking our question, so we can give a little bit to commercial PKD. And do you still think that PKD could be a 200 to 150 million peak opportunity here in the US? And if so, how long do you think it could take you to get there? And then my second question is, and we know that you're moving 89, 46 forward in lower-risk MDS, but we were curious and have you formally de-prioritized the program in sickle cell disease as we hadn't heard anything on this in a while? And can you confirm if that's the case or not? And thanks so much for taking your questions.
Brian Goff
Thanks a lot has actually the second question. We can handle that very quickly, which is no. And we have not de-prioritized anything with AG. nine or six. I think we're inspired by the potential. And at the right time, we'll provide updates about the progress, not just in our pursuit of low risk MDS, but also where we stand with respect to sickle cell disease.
Cecilia, do you want to comment on the first one we have today and
Cecilia Jones
thanks for the question. So we definitely remain excited about the opportunity and PKD., and we continue to expect those peak sales of $200 million to $225 million for the U.S. We continue to make progress each quarter and we're learning and I said I said it is helping also fit those capabilities for our launch, and we think it's going to be slow and steady, continuing to see the trends we've seen in 2023 for the next few years. But we do stick around maintain our peak of $220 million to $225 million , the
Brian Goff
I mean with PKD., and we've talked about this previously, but the in the deep commercial experience, the books that I have across multiple rare disease launches. This one-stop, it's a challenge. It is ultra rare. It's diagnostically intensive. There's long lead times for patients. So slow and steady is the right phrase. What we're continued to be inspired by each quarter is that persistency, which is something we saw relatively early with the launch of Paracon and PKD. that is a really important feature as we think about chronic rare disease launches to come that are in our sights. And so we'll we'll take the slow and steady path, and we're going to continue to expect that going forward. But the way pirate kind is performing is what we believe really puts us in a position of strength as we approach energize sorry, kissing energized as we approach our senior as well as sickle cell beyond that.
Tess Romero
Okay, thanks so much for taking our questions, Youbet's.
Brian Goff
Thanks a lot.
Operator
Thank you. Our next question comes from the line of Greg Harrison with Bank of America. Your line is now open.
Greg Harrison
Good morning and thanks for taking the question. I also just wanted to follow-up on AG. nine four six, how are you thinking just generally in development of about development and potentially overlapping indications with mitapivat if there could be improvement? And for example, in sickle cell, like you've discussed or or even calcemia? And what would you need to see from nine, four, six in order to make that decision?
Brian Goff
Yes, I'll start and then Sarah can jump in. First of all, Greg, I hope we're in that position where we have multiple indications just as we have right now with the PyroCarbon, one of the key advantages of it geos that having a really a leading PK activation franchises. We have not one but two products that we're developing and that allows us to have different economics, different pricing dynamics across the indications and between the products. I think there's a wide enough space for us right now, given where we are in the development program with AG. nine, four six that we can tailor the appropriate target product profiles, whether it's for sickle cell disease or for low-risk MDS.
In the case of lower-risk MDS, as I think folks know, we just reported out last year very encouraging proof of concept from our Phase IIa study. And we're in the process right now of making enhancements in the design so we can pursue Phase IIb. I feel very good about the work the team has done, and that will be the next step. And as I mentioned before, at the right time, we'll also report out the progress on sickle cell disease, anything you want to answer and just high level?
Sarah Gheuens
I think what you can express expect from development is that we always strive to design our trials to meet multiple stakeholders their needs, meaning we take our target product profile very seriously. So that is something that for nine for six, it's the same. We take very seriously and we incorporate we will be incorporating patient voice into regular regulatory feedback, obviously as well.
Brian Goff
We are a great example of that is in the case of sickle cell disease, a point that we're very proud of that. Our geos is we have deeply involved the community. In fact, Sara and I attended the conference last year where we won an award from the community about how carefully and thoughtfully. We involved sickle cell disease warriors and caregivers in how we think about designing the trials recruiting for the trials and ultimately what the commercial profile should look like and we'll do the same thing with AG. nine four six.
Greg Harrison
Great. Thanks for taking the questions.
Brian Goff
You've got. Great. Thanks.
Operator
Thank you. And our last question will come from the line of David Round with TD Cowen. Your line is now open.
Divya Rao
Hi, guys. This is David on for Mark. Thanks for taking my questions. I have to kind of follow-up question one on Erik's question earlier was the difference in the primary endpoint between mitapivat and powder sets for the transfusion dependent patients, something that was recommended to you by regulatory authorities or was it more of an internal choice? And then my second question is turning to the design of the Phase IIb in MDS. And do you plan to test multiple dose levels of 89 for six? And any color on the enrollment criteria versus what regulatory hot in the COMMANDS trial would be would be great. Thank you.
Sarah Gheuens
Thank you. Thanks, Dhivya. So in regards to the first question, primary endpoint, yes, indeed, we do, as I just mentioned on the previous question as well, we do our development in collaboration with regularly with regulators. So we take feedback from the regulators very seriously and tried to come. It really incorporate the feedback as best as we can. And so that's how we ended up settling for the 50% endpoints in a rolling 12 week period interval, which we indeed truly believe is a more dynamic endpoint and really reflects the real-world experience of a patient. So this is where it's always very good and we're always very grateful to be able to have those conversations because I do think incorporating feedback from multiple stakeholders always leads to better design choice. So and so that's that on the primary endpoint.
And then in regards to your question for MDS Phase IIb, yes, the Phase IIb is indeed on in our multiple doses that we are testing, we are going to test higher doses than we originally anticipated just because we have learned from our Phase two A. that MDS patients overall have lower exposure to same amount of drug than other other patient populations and healthy volunteers. So we are incorporating those learnings into our Phase IIb.
And in regards to our inclusion criteria, we have not come and we haven't presented the trialing progress post or anything like that yet, but you can expect this population to be relatively similar to how our population was in the Phase two A. However, we will be focusing on transfusion patients with transfusion burden. It will also be a broad broad MDS population just like we allowed in the IIa and we are not excluding perceived population like specific mutations or things like that.
Divya Rao
Thank you.
Operator
Thank you. I would now like to hand the conference back over to Mr. Brian Goff for closing remarks.
Brian Goff
All right. Thanks a lot, Norma, and thank you very much, everyone, for participating in today's call. Very good questions, which we very much appreciate. As you heard today, our team is great conviction in our potential to deliver transformative new therapies to patients and significant long-term value to shareholders. And we really look forward to speaking with all of you again, soon. So thanks a lot.
Operator
This concludes today's conference call. Thank you for your participation. You may now disconnect, and everyone have a wonderful day.
