Agios Pharmaceuticals (NASDAQ:AGIO) Q2 2026 Earnings Call

0:00 Good morning, and welcome to Agios Pharmaceuticals Second Quarter twenty twenty six Conference Call. At this time, all participants are in a listen only mode. There will be a question and answer session at the end. Please be advised that this call is being recorded at AGIO's request. I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at AGIO's. Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals' second quarter

0:30 twenty twenty six financial results and business highlights. You can access the slides for today's call by going to the Investors section of our website, agios.com. Please note we'll be making certain forward looking statements today. Actual events and results could differ materially from those expressed or implied by any forward looking statements because 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. On the call with me today from Agios are Brian Goss, Chief Executive Officer Cecilia Jones, Chief Financial Officer Svetta Milanova, Chief Commercial Officer and Doctor. Sarah Huens, Chief Medical Officer and Head of Research and Development. Following prepared remarks, we will open the call for questions.

1:17 With that, I am pleased to turn the call over to Brian. Thanks, Morgan. Good morning, everyone, and thank you for joining us. Before we review our second quarter results, I'd like to take a step back and highlight the strong position from which Agios is executing as we continue advancing toward our goal of building a multi billion dollar rare disease business. We are executing against multiple drivers of value creation, including the launch of ACVESNI in thalassemia, the potential expansion of mitapivat into sickle cell disease, and a pipeline that continues to grow through both internal innovation and disciplined business development.

1:58 During the quarter we further strengthened our portfolio with the addition of sevedoclonus, a next generation highly selective oral SIC inhibitor that expands our rare hematology franchise into immune thrombocytopenia or ITP. We also advanced AG-two thirty six into an operationally seamless phase twothree program in polycythemia vera, adding another potential growth driver within hematology. Beyond hematology AG-one hundred eighty one continues to progress and we expect phase 1b proof of mechanism data in phenylketonuria patients in the second half of the year. We also continue to apply a disciplined approach to portfolio management, making focused investment decisions and directing resources toward opportunities with the greatest potential to create value for patients and shareholders.

2:57 As you'll hear throughout today's call, our progress this quarter reflects the strength of that strategy, combining commercial execution, pipeline advancement, disciplined capital allocation and strategic business development to position Agios for sustainable long term growth. Turning to our second quarter highlights on the next slide, we delivered a quarter marked by strong commercial performance, meaningful pipeline progress, and continued portfolio discipline. First, we delivered sustained commercial momentum with $44,700,000 in total net revenue, including $40,900,000 in The US and four forty two cumulative ACBESMI prescriptions for REMS certified physicians.

3:49 Second, we further diversified our pipeline through the in licensing of sevedoplinib, a next generation highly selective oral SIC inhibitor for ITP, progressing toward Phase III and strengthening our rare hematology pipeline. Third, we advanced mitapivat toward a potential new indication in sickle cell disease. During the quarter we received FDA acceptance of our sNDA with priority review and were assigned a PDUFA goal date of November 1, bringing us one step closer to delivering a first in class medicine in an area of significant unmet need. And finally we ended the quarter with approximately $1,000,000,000 in cash, cash equivalents and marketable securities providing financial flexibility to support both commercial growth and pipeline progression.

4:44 Overall, we entered the second half of twenty twenty six with strong commercial delivery, a more diversified pipeline, an important near term regulatory catalyst and the capital position to execute on our strategy. With that, please advance to the next slide and I'll turn the call over to Cecilia to discuss financials. Thank you, Brian. Next slide, please. Turning to our second quarter financial results. Total Mucapivas net revenue was $44,700,000 including $40,900,000 in The U. S. And $3,800,000 outside The U. S. Of sales for the quarter was $3,000,000 and research and development expense was $100,800,000 compared to $91,900,000 in the second quarter of twenty twenty five, primarily due to an increase in process

5:39 research and development of $15,000,000 driven by the twenty five million dollars upfront payment associated with the agreement of OXXOJAN. Selling, general and administrative expense was $61,500,000 compared to $45,900,000 in the prior year period, reflecting an increase in commercial related activities as we execute our launch of Agios Pharmaceuticals. Net loss for the second quarter of twenty twenty six was $100,700,000 compared to a net loss of $112,000,000 for the second quarter of twenty twenty five. We ended the quarter with approximately BRL 1,000,000,000 in cash, cash equivalents and marketable securities, which we believe provides financial flexibility to support commercial execution, advancement of our pipeline and continued investment opportunities to create long term value.

6:34 Turning to our outlook for 2026. We continue to expect approximately 45,000,000 to $50,000,000 from PK deficiency revenues in The U. Full year operating expenses are expected to remain approximately flat versus 2025, excluding the $25,000,000 upfront payment associated with the sebidopanetin licensing transaction recognized in the second quarter and include investments to prepare for a potential sickle cell disease launch aligned with our November 1 PDUFA date. Our priorities for the remainder of the year remains clear: driving the ADVASTA launch, preparing for a potential sickle cell disease approval, advancing our pipeline and maintaining financial discipline.

7:21 Please advance to the next slide, and I'll turn it over to Sarek to cover commercial highlights and our VetME U. S. Thalassemia launch program. Thanks, Cecilia. Next slide please. With six months of launch experience now behind us, we are encouraged by the underlying drivers of performance. What we have seen so far continues to reinforce our confidence in the long term Afrezza opportunity in thalassemia. Importantly, the strong execution across our commercial and patient focused organizations further strengthens our confidence in future launch opportunities. In The US, performance reflected continued growth in thalassemia demand and solid commercial execution.

8:11 Net revenue in the quarter reflected approximately $5,000,000 of one time benefits related to stocking in thalassemia, along with modest gross to net favorability. We continue to expect gross to net within our previously guided 10% to 20% range, with quarter to quarter variability.

8:35 Outside The US, we delivered $3,800,000 in net sales, reflecting anticipated demand for thalassemia in Europe following approval and continued consistent early demand for thalassemia in The GCC. As we have seen consistently across rare disease launches, the shape of new patient starts naturally moderates as adoption broadens beyond the earliest wave of highly motivated patients and prescribers. We continue to expect quarter to quarter revenue variability, reflecting order timing, inventory movements and gross to net dynamics. Next slide, please. I'm very pleased with the continued U. S.

9:24 Launch performance of ATFESNI. During the second quarter, we generated an additional 200 prescriptions from RENT certified physicians, bringing cumulative prescriptions to four forty two as of June 30. As a reminder, this metric captures unique prescriptions for patients with completed SPARS forms from REMS certified physicians and serves as an early indicator of underlying demand. Importantly, the underlying launch dynamics remain healthy, While demand continued to come from highly motivated patients, we saw a growing proportion of non transfusion dependent patients in the second quarter, a profile consistent with the therapy moving beyond the earliest, most motivated cohort of transfusion dependent patients.

10:24 We continue to see strong conversion from prescription to treatment initiation. Time to start is naturally trending towards our anticipated ten to twelve week range as adoption broadens across the MGDT population where treatment decisions often involve more deliberate clinical discussions and patients may have less frequent interactions with the healthcare system. Access continues to strengthen and we now have approximately seventy five percent of the Latineal lives covered under payer policies. Additionally, physician rent certification continues to progress in steps with prescribing activity and is not a barrier to patient access.

11:15 As the launch matures, prescriptions with completed start forms become a less informative measure of performance, whereas revenue increasingly reflects both new patient starts and persistence on therapy. For that reason, in anticipation of a potential FDA approval for mitapivat in sickle cell disease, we plan to discontinue reporting prescriptions from REMS certified physicians after the third quarter and transition to revenue as our primary measure of commercial performance. Upon a potential sickle cell disease approval, we will assess the most meaningful metrics to communicate the progress and outlook of the broader mitapivat structure.

12:05 Next slide, please. I wanted to take a few moments to highlight thalassemia launch considerations in the second half of this year. The first half reflected a distinct initial phase of the launch. The first quarter benefited from a strong pre launch anticipation and momentum built in the period leading to approval following the more than three month PDUFA delay. Second quarter demand continues to reflect adoption from highly motivated patients and prescribers, with time to treatment initiation beginning to approach our anticipated ten to twelve week average at launch maturity.

12:51 Looking ahead, we expect the shape of the launch to naturally evolve. Adoption is expanding into a broader, non transfusion dependent population, where patients are typically seen less frequently and treatment decisions may take more time. As the patient mix continues to shift towards non transfusion dependent patients, we expect time to treatment initiation to move well within the ten-twelve week range we consistently discussed. We are also mindful that the first cohort of patients who initiated therapy in the earliest months of launch is approaching six months of treatment, a natural point at which physicians assess clinical response.

13:42 This is an important part of the treatment journey, and it is the period during which we will begin to build a broader, real world understanding of how physicians and patients evaluate response and integrate misapivas into long term care. Taken together, these dynamics reinforce that Agfetimi is delivering a healthy launch that is successfully progressing beyond the initial wave of adoption and into a broader expansion phase. As we move through the second half of the first launch year, our focus remains on expanding reach across the Telochaemia community, expanding adoption in the non transfusion dependent segment, while continuing to add new prescribers.

14:36 We remain highly confident in the long term opportunity for Afesmi and in our ability to build a durable growing thalassaemia franchise over time.

14:49 Please move to the next slide. We are actively preparing for a potential sickle cell disease launch in The US and are encouraged by both the commercial opportunity and the unmet need we see in this community. Our initial launch focus is on approximately twenty five thousand patients who are actively treated or in need of therapy today. We believe that population alone represents a meaningful opportunity for mitapivat, with potential to expand beyond the initial segment over time. Importantly, we are leveraging the capabilities, relationships and insights we have developed through the thirteen year launch, while continuing to invest in market access, education and community engagement activities ahead of the PDUFA goal date.

15:45 Spending FDA approval, we believe these efforts position us well to support a successful launch and to deliver Mycaptiva to patients in need of innovative treatment options. Please move to the next slide. And with that, I will hand the call over to Sarah to cover key R and D highlights from the quarter. Thank you, Sveta. Turning to our pipeline on the next slide. Following recent portfolio prioritization decisions, we remain focused on advancing a diversified rare hematology portfolio with opportunities across multiple stages of development. Misapivat continues to anchor the portfolio with approved indications in pyruvate kinase deficiency and thalassemia and a potential accelerated approval in sickle cell disease later this year.

16:34 During the first half of this year, we achieved an important milestone with thalassemia approvals in Europe and The UAE, completing regulatory approvals across all four priority launches geographically following prior approvals in The US and KSA. Since first quarter results, we filed and received acceptance in The US for the mitapivat sNDA in sickle cell disease with priority review and PDUFA goal date of November 1. We remain committed to bringing mitapivat to patients with sickle cell disease and recently dosed the first patients in Reignite, our phase three confirmatory trial, an important milestone in advancing the program. We also strengthened the pipeline during the quarter through the in licensing of sebideoclonib, a next generation six inhibitor that expands our reach within rare hematology and adds a compelling opportunity in immune thrombocytopenia.

17:27 Beyond metacibat and cepidoplinib, we continue to invest in future growth drivers, including AG236 in polycythemia vera and AG181 in phenylketonuria. Taken together, we believe the pipeline reflects a focused allocation of capital and resources towards programs where we see the greatest potential to create long term value for patients and shareholders. Please move to the next slide. As we discussed when we announced the in licensing of sepidoflunib, our interest in the program is grounded in its potential to address some of the limitations that have historically constrained the SYK inhibitor class. Sepidoplinib was designed to optimize both selectivity and pharmacokinetics, supported sustained target inhibition while maintaining a tolerability profile suitable for chronic use.

18:15 The clinical data generated to date are encouraging and support this design rationale, demonstrating dose dependent activity, no dose limiting toxicities through phase two, and evidence of durable platelet responses. Taken together, these data support a rationale for advancing sebideoclonib as a next generation highly selective SIC inhibitor. We're looking forward to engaging with the FDA in the coming months to align on progression to phase three. Next slide, please. At EHA in June, we were pleased to share a broad body of data across both thalassemia and sickle cell disease that continues to strengthen our confidence in mitapivat. Across the portfolio, we have 10 aspects accepted, including the RIZOX Phase three study, which was selected for the EHA oral plenary session.

19:03 In sickle cell disease, RIZOX demonstrated hemoglobin responses consistent with the mechanism of PK activation with hemoglobin responders experiencing clinically meaningful improvement in sickle cell pain crisis related endpoints and fatigue. At EHA, we presented new data showing clinically meaningful reductions in transfusion burden and red blood cell units transfused across the total trial population exceeding historical experience with hyperoxiduria. Importantly, outcomes from the subgroup of patients with at least one transfusion in the fifty two weeks prior to enrollment directly informed the treatment effect and firing assumptions for the ongoing Re IGNITE confirmatory trial supporting accelerated approval. We also presented additional patients reported outcomes data showing clinically meaningful improvements in how hemoglobin responders feel and function, including reductions in physical pain.

19:56 In addition, fifty six week follow-up data from the SATISFY Phase two investigator sponsored trial in related membronopathies showed robust hemoglobin response rates and mean hemoglobin improvement, as well as suggesting decreased iron burden. In non transfusion dependent thalassemia, we shared open label extension data showing that sixty percent of patients continuing on misapetab met criteria for hemoglobin response, and sixty percent of patients who switched onto mitapatop in the open label extension achieved hemoglobin response. Additionally, subgroup analyses indicate high hemoglobin response rates for non transfusion dependent patients with high baseline hemoglobin levels, indicating that less severely anemic MTD patients achieved improvements in hemoglobin levels and fatigue.

20:44 These data were received very favorably by the thalassemia community and reinforced the value of nisapitab in non transfusion dependent patients, which comprise the majority of the diagnosed adult patients in The US.

20:56 Taken together, these data reinforce the consistency of nisapivat's profile across indications and further strengthen our confidence in the long term potential of nisapivat in hemolytic anemia. While we continue to advance and expand the mitapivat opportunity, we're also focused on building the next generation of potential growth drivers within rare hematology. AG-two thirty six is an important example of that strategy. Next slide, please. Following encouraging Phase I data, we're advancing AG-two thirty six into an operationally seamless Phase IIIII development program in polycythemia vera. What continues to differentiate AG-two thirty six is its potential profile within evolving treatment landscape. The molecule demonstrated hepcidin induction through day 57 and favorable effects on iron parameters in extended follow-up, supporting the potential for an every six month dosing regimen without titration.

21:53 The Phase two portion of the study is designed to identify the optimal therapeutic window across multiple dose levels while enabling efficient progression into the registrational portion of the program. More broadly, the seamless Phase twothree strategy reflects our commitment to disciplined execution while advancing development as efficiently as possible with Phase two initiation planned for the second half of twenty twenty six. We believe AG-two thirty six has the potential to further diversify our rare hematology leadership and contribute to our long term growth beyond mitapivat. With that, please move to the next slide, and I will hand the call back to Brian for closing remarks. Thank you, Sarah. Next slide, please. As we look across the business, we continue to make meaningful progress against the strategic priorities we established for 2026.

22:45 We're building commercial momentum with ACBESTIAN thalassemia, reaching four forty two cumulative prescriptions as of June 30. We're advancing mitapivat toward a potential approval in sickle cell disease, which represents an important opportunity to expand our PK activation franchise and a potential next growth driver for the company.

23:08 We're also advancing AG-two thirty six, our siRNA TMPRSS6 inhibitor for polycythemia vera into an operationally seamless phase twothree program expected to begin in the second half of this year. And during the quarter, we further diversified our portfolio through the addition of sevedoplinib, a next generation highly selective SYK inhibitor in ITP progressing toward phase three.

23:34 Importantly, our progress this year reflects both execution and discipline. We're investing behind the opportunities where we believe Agios can have the greatest impact for patients and create the strongest long term value for shareholders. Next slide. Taken together we entered the second half of the year with a growing commercial foundation, a meaningful near term regulatory catalyst, and an increasingly diversified pipeline and the financial strength to execute on our strategy. Next slide please.

24:10 Today Agios is anchored by a growing commercial business and supported by a pipeline spanning multiple development stages and disease areas. Across the portfolio, we are pursuing opportunities where differentiated biology, meaningful patient unmet need, and disciplined execution can support durable long term growth. Collectively, these opportunities represent rare disease markets estimated at more than $10,000,000,000 in two thousand and thirty. Before we open the call for questions, I'd like to thank the entire Agios team for their unwavering commitment to patients and their continued dedication to executing on our strategy. Their passion, resilience, and focus have been instrumental in the progress we've made this year.

24:58 And with that, thank you all for joining us today. Operator, we're ready to begin the question and answer session. Thank you.

25:24 Our first question comes from the line of Alex Stranahan with Bank of America. Congrats on the really strong quarter here. Two questions from me. First, on time on treatment in the commercial setting, do you think the ENERGIZE studies are a good barometer here? Just trying to think about how the dynamic of patients potentially coming off therapy could play into second half sales? And then

25:56 when you look at the time on treatment, did this change at all between 1Q to 2Q? Did it move closer or further away from that ten to twelve week average range that you're setting out? And I guess, are you starting to see any repeat prescriptions under the REMS program at this point? Thank you. Thanks, Alex. So two parter. Sveta, you can take the first one. Actually, you'll take both of these. Time on treatment and ENERGIZE analogue. And then the second one, think, Alec, you're asking about

26:25 not time on treatment, but time to treatment from the demand to initiation. So, Sveti, do want to take that? Absolutely. We are very pleased with the strong initial start of the launch, Alex. And as we mentioned, we have in total four forty two prescriptions from REMS certified physicians for the first two quarters of the launch. As we look ahead in the first couple of quarters, we benefited from faster than anticipated time to treatment initiation. So it was faster than the ten to twelve weeks,

26:59 that we have prescriptions coming from highly motivated patients and physicians. Keeping that in mind, we'll start kind of the natural to reach the natural point of the six months at which physicians and patients are going to evaluate benefits for the product and continuation rate, but that's going to be more in the second half of the year, and we will monitor that closely. Currently, we see from the market is a very kind of strong

27:28 feedback and a positive feedback from the community. So, we expect continuation rates to be in line with the ENERGIZE study.

27:38 And, know, we'll continue to monitor that, but the product performance is very strong in the market. When it comes to time to treatment initiation, we start seeing that as we penetrate into the entity settings to move closer and closer to what we initially expected, the ten to twelve week range, And as we move into the second half of the year, we will continue to monitor that, but we expect to be well within the ten to twelve weeks, given the strong penetration in the NTT setting.

28:12 And your third question was around repeat prescriptions for the REMS. When we look at that, of course, we have patients who have been on therapy for multiple months. So we do start seeing the repeat prescriptions and patients and physicians are going through the ramp process very, very smoothly. Thank

28:32 you. Thank you. Our next question comes from the line of Andrew Berens with Leerink. Your line is open. Hi, thanks and congrats on the strong execution. I guess I just want to expand a little bit on the persistence rate since it's so important going forward. Is there anything that you can tell us about maybe the expanded access program at all?

29:01 What the experience will be like for these patients in the real world?

29:05 And then the other thing that's obviously very important is going to be a sickle cell label, whether it's on a Kesni or pyruvate kinase. What factors will go into that? And is there anything you can tell us in these early days ahead of the November 1 PDUFA that you give us confidence that you won't have a REMS or have to potentially reduce the pricing

29:31 for a COBESMY and thalassemia? Thanks. Thanks, Andy. And I will just say again, and thanks for the comments about the strong quarter. I am really pleased and proud with the continued execution from Sveta and the team. I think on the persistency, Andy, maybe we'll start with Sarah just reflecting on the clinical trial, the open label extensions and what we saw, because it still is early days for us to quantify persistence, but we always look at the trials and OLEs as a proxy. Yes, thanks, Brian. And I think, Andy here,

30:05 can really look at the open label data that we presented at EHA, recently as well. So as you know, we have very high continuation rates for people who finish the clinical trials and then go into the open label extension. And now we have the benefit of being able to have followed them for a period of time post randomized controlled trial. Where you see there is a good maintenance of response. So patients do continue on the drug.

30:32 And you see that maintenance of hemoglobin, the maintenance of anti hemolytic response and people good. Another point there, what was exciting to see at the EHA dataset was that people with higher hemoglobin also had good response to the treatment, which is important, of course, as we continue to expand the patients we capture in the launch for the non transfusion dependent patients. And so, yes, so I think the clinical trial data is actually the best way to look at that question right now. And yes, I just

31:06 wanted to add that we I've been spending a lot of time with clinicians in the field, had the opportunity to hear their feedback on the data. And as we enter into the second half of the year, and we start experiencing kind of the real world evaluation of persistency, I'm very confident that, you know, we'll see the repetition of what we see in the clinical trials in terms of continuation rates for six months. And then in regards oh, sorry. I was going to ask, can you give us a number, a percentage that you saw in the open label extension study of patients who stayed on? So for ENERGIZE, we had like an over ninety percent continuation from the clinical trial in regards yeah, and then of course, it always, you know, as time continues, clinical trials are burned, so it drops a little bit. It's very, very good persistence, for PKD, for thalassemia, sickle for cell disease in the clinical trial.

32:09 What was interesting there is also the response rate with longer exposure, which it's important for thalassemia from in the early forty percent.

32:19 We had some non responders convert into responders, so we got to a sixty percent response rate there. So the clinical trial data is very good. And we know obviously that's an important metric for us going forward,

32:38 we're still early days. This is our second full quarter of launch, which in a way matches the period of time for the ENERGIZE trial. So we'll continue to monitor and of course implement appropriate patient services support to help patients continue on therapy. And Andy, maybe you can just repeat the second part of your question. Yeah, just I mean, obviously, I don't think anyone expects sickle cell pricing to be as resilient as thalassemia or PKD. So it really depends on whether you get sickle cell out of tech, Besni or pyrucine. What do you think is going to drive that decision and any insights now that we're several months away from the PDUFA about which brand sickle cell may be added to if approved?

33:28 Yeah. So the PDUFA is indeed November 1 priority review, so we're very excited about that. We have not further discussed which brand name is going to be used. But as you know, the clinical trial data looks very good. We did not have the hepatocellular injury observed in the sickle cell disease patients. So therefore, it may not warrant the REMS. Either way, our teams are ready to execute a launch with or without the REMS. So more to come.

33:58 Absolutely. And as always, we'll provide more specifics at the time of launch once we have the label. We'll price the product for that indication and across the portfolio to maximize the opportunity based on the clinical data and of course, the market environment at the time. I must say we are in a very strong position given that it's our third indication. There is a very high unmet need in sickle cell disease.

34:27 And we do have a very strong market access team. I'm very proud of the progress they made in thalassemia with the payer policies, and we'll continue to learn and build from here. Great. Well, thanks for answering the questions, and congrats again on the strong quarter. It looks like it's going to continue. Thanks, Sandy. Please stand by for our next question. Our next question comes from the line of Gregory Renza with Truist Securities. Your line is open. Hi, team. This is Supat on for Greg. Congrats. Let me add the congrats to the team too on an excellent quarter. So my question is two parts as well, if I may. So as we enter the second half of twenty twenty six and we move beyond the initial wave of highly motivated transfusion dependent patients, how should we think about the run rate of new patient starts, particularly in

35:23 the broader non transfusion dependent population? And the second part is, where are you at in terms of growth? I know it's favorable this quarter. Where are you at within the range of the ten percent to twenty percent

35:37 expected target? Now you're at seventy five percent of cover life. Thanks and congrats again. Thanks, Supawat. Svetta, maybe you can start with and I think you said it the right way, as we extend further into the broader reach in the NTD population. Stadia, you want to take that and then we'll do gross to net

35:56 separately? Absolutely. I'm very pleased with the progress so far. We are really seeing a very healthy start of the launch, both from penetration into the community setting where the majority of prescribers are, as well as the penetration in the entity setting, which is the bigger commercial opportunity. As we mentioned in the second quarter, we added 200 prescriptions from REMS certified physicians.

36:26 As we move into the second half of the year, prescriptions growth and revenue growth are not going to be directly correlated on a perfect basis, given that we're moving into the more mature phase of the launch. And the revenues really also depends on time to treatment initiation, the ramp on boarding and persistency as we've discussed.

36:51 Moving ahead, as we move into the NGVT setting, we expect the time to treatment initiation to move well into the ten to twelve weeks, Given the fact that these patients have less frequent visits to the healthcare professionals, and they'll need to go through the insurance verification, as well as the REMS process as well. But we are really, really encouraged by the rate of patient adoptions, the progress that we are making, the way the patients are converting and staying on therapy at this part of the launch, and most importantly, the really positive feedback from what I'm hearing from the clinicians on the product profile in the real world. Great. And then, Supawat, I think the second part of your question was around the 10 to 20% guidance that we've given on gross to net.

37:45 Cecilia, do you want to comment here? Yes. So we expect that to continue to be in that range of 10 to 20% as we guided before. There's always some quarter over quarter variability, but on aggregate, that's a range we still expect to see. Thank you. Please stand by for our next question. Our next question comes from the line of Mark Fram with TD Cowen. Your line is open. Hi, thanks for taking my questions. And completely get the kind of pushes and pulls on turning a TRx into actual revenue and of course there will be some drop off patients on kind of back end starting in the second half. But do you view that kind of 200 patients at the top of the funnel as now kind of a sustainable rate or does that still reflect a little bit of that bolus that you kind of talked about for Q1 of the backlog of REMS certifications and kind of the highly, highly motivated patients?

38:50 Yeah, maybe I'll start and I'm going to turn it over to Sveta. I think Mark, a good way to think about a comment we've made several times in terms of engaged patients, engaged clinicians, is that's a gradient. And we know that we're still on the front end of that gradient. We instead of just commenting on it too, as we move further into the NTD population, by definition, these patients tend to have less frequency of clinical interactions. And so that's essentially the dynamic that we're up against. Sveta, what would you add? Yeah, no, absolutely. And as I also mentioned in my prepared remarks, looking into entering a new phase of the launch in the second quarter, we expect prescription growth and the revenue growth not to correlate directly in every single quarter due to the time statement initiation, the patient conversion rate persistency and kind of inter quarter ordering variability.

39:55 That's why we will actually move away from this initial indicator of demand after the third quarter, which is prescriptions to something that we believe is more reflective of the underlying health of the business, which is going to be. Revenue when you think about how the first, how is going to transition into the next phase of the launch, which is the second house in the first house in Q1 and partially in Q2, we really benefited from this earlier doctor, highly motivated patients and physicians, the delay in the PDUFA, which created the anticipation of the launch in the for the launch and patients and physicians were ready to start as quickly as possible. As we move into the second part of the launch, what I'm looking for is really the underlying dynamics of the launch, which allow us to further penetrate into the community setting a very strong adoption into the entity setting across alpha and beta thalassemia patients and moving into that more steady state of twelve week treatment initiation.

40:56 So we are very encouraged of the way the launch is going and the way the team is executing. Okay, that's all helpful. Then maybe just on the other end of the funnel and the discontinuation rate. Do you do you view these initial kind of very highly motivated patients and clinicians that are using that were starting therapy Q1 and early Q2. Are those patients you think more likely to stay on drug because of that motivation or are they perhaps the very hard to treat patients and maybe they'll have a somewhat higher discontinuation rate than kind of the long term number might end up being. As we progress into the next phase of the launch, we'll provide more color onto onto what we see in the real world. My suggestion for now and what are we hearing from the clinicians is that the core period in the clinical trials is a is a very good proxy for continuation and we'll continue to learn more.

41:54 I'm very pleased with the payer policies that have been issued. They really allow a lot of flexibility for patients and physicians to make informed treatment choices on continuation. The policies are really managing for managing patients to clinical trial criteria or better. So, let's use for now that the clinical trial is a proxy. Okay. Thanks. Thanks, Mark. Thank you. Our next question comes from the line of Samantha with Citi. Your line is open. Hi, good morning. Thanks very much for taking the question and let me add my congrats on the strong quarter. I'm wondering if you could just speak a little bit more to the dynamics of the clinical evaluation after six months of treatment that you were speaking on in your prepared remarks. What are physicians viewing as acceptable clinical bar for continuing treatment?

42:47 And is this six month clinical mark, is that pretty strict or is there some flexibility where it could vary when a physician would be looking to assess the clinical progress for a patient. And I have a follow-up. Thanks, Ed, and this is another good one for Svetta, and also where we have important learnings from our experience already with PKD now over many years in terms of evaluation. Absolutely. So, there is a variability of how patients and physicians define benefit, and I'm going to use the word benefit because it quite often goes beyond what is defined as the primary endpoint in the clinical trials. Of course, for transfusion dependent patients, both patients and physicians will look at transfusion reductions, both in terms of ability to expand the time between transfusions as well as reducing the amount blood and both of these aspects are important.

43:46 What do we hear from physicians? And I had the opportunity to meet both with patients and physicians as recently as the police anemia Foundation meeting is they really do that on a patient by patient basis. A majority of them mentioned the six months, both driven by the fact that our clinical trials were within that timeframe, but it's also a natural opportunity for them to evaluate initial benefits. And they'll make decisions based on that. Transfusion reduction in the CBT patients will be important. They are not necessarily going to stick to what was defined as a 50% reduction in the clinical studies going to be on an individual patient basis, and if they want to continue on therapy as well, and how they feel between the transfusions is also important.

44:35 On the NTT setting, they're going to look on improvement in hemoglobin. The one gram per deciliter is not like a hard yes or no. They'll also look at the improvement in parameters. And very importantly, in the entity setting is how patients feel the reduction in fatigue is a key driver both for patients and physicians to continue on therapy, irrespective of actual level of hemoglobin improvement. So, we are very encouraged from what we hear from our customers and look forward to learning more in the second half of the year. Great. Thanks very much. And then just a second question about the evolution of the prescriber base. Are you seeing physicians write scripts for multiple patients that they manage?

45:23 I'm wondering if there's any sort of, I guess, dynamic that you could share that you've seen over the first, two quarters of launch. Thanks very much. Absolutely. When I look at our prescriber base, the most important thing for me is to look for breadth of prescribing because the leukemia majority of the patients are managing the community and we don't have that much breath across the therapy area. And I see a very, very. Strong breath of prescribing across the country from from different clinicians. So, I'm very pleased with the healthy start of the launch. We do have a small number of key opinion leaders who have written for more than one patient, and we continue to see prescriptions coming from these prescribers.

46:12 And we expect that to continue that they do have a stable patient base, but really our opportunity is to continue to penetrate the community setting. Thanks very much. Thank you. Please stand by for our next question. Our next question comes from the line of Eric Schmidt with Cantor. Your line is open. Thanks, Mike. Congrats on all the progress as well. And unfortunately, another question for Svetta. She seems like she's on the hot seat today. So I just want to be clear about what's in the four forty two cumulative prescriptions that you're reporting. You know, historically, I think you've said those are for individual patients mapped to individual start forms and wouldn't include refills or anything like that. Is still the case? Absolutely.

47:03 They are unique patient prescriptions in a way that's kind of equivalent of a start form, and it's written by a REMS certified physician. And I assume, Sveta, you have some insight into how many refills have also been written thus far? So, yeah, the refill rates continue as patients reach their second and third month of therapy. So, the refills are continuing according to plan. So, depending on the patients that have started and are progressing to the rent, The refills are coming in. We are not providing a specific kind of brief field dynamics and total patients on therapy. And as I said, moving forward, we'll move away. From start forms and really start focusing on revenue more because it takes into account all of these dynamics that you're asking about, Eric, new patients start trying to treatment initiation, three fields and continuation.

48:01 Okay, you anticipated all of my questions. I've just got one left, which is conversion of patients from start forms to therapy. Do you have a sense of whether there have been many or any patients who have dropped out of the queue as they await therapy? Thanks. We have a very positive payer policies and we have no market access kind of hurdles for now at the beginning of the launch. I'm very pleased with that. Our fuel rate, which is basically prescriptions to patients starting on therapy is very high and it's very much in line with other rare diseases. Nothing unanticipated there. So I'm very pleased with that very high conversion rate. Yeah, and Eric, I'll just add that this is again where our PKD experience, smaller scale, but the experience really comes into play because it's usually a time element, not necessarily a loss element in the translation from a start form to a patient starting on therapy.

49:03 And again, we know with these NTD patients, as we move deeper into that penetration, it could take longer, which is why the translational aspect of going from a start form to revenue gets harder and harder from your perspective. Great. Thanks and congrats again. Thanks a lot. Our next question comes from the line of Emily Bodnar with H. C. Wainwright. Your line is open. Hi, good morning. Thanks for taking the questions and congrats also on the positive quarter. Ask on Europe sales for thalassemia. Were any of the 2Q revenues driven by Europe specifically? And how do you kind of think about ex U. S. Revenue growth for the remainder of the year?

49:49 And maybe secondly, with the sickle cell disease PDUFA coming in November, are you expecting to launch by year end? And should we be expecting any kind of initial revenues for the fourth quarter? Thanks, Emily. Cecilia can comment on the European question, and then we can come back to the question about sickle cell. Yeah. So, Emily, the ex US revenue so far this quarter is a combination of the continued demand in DCC as we have early access there, as well as anticipated demand for thalassemia in Europe following the approval in May. I'd say the vast majority of our revenues are still expected to come from The U.

50:36 S. For the upcoming quarters as we're still kind of ramping up the other regions, early access for both. So, we don't expect either one to be material contributors. And then the other question on sickle, again, the PDUFA date being November, it wouldn't be a material contribution to our full year revenues for 2026. And I will just add, Emily, we were enthusiastic about opportunity of a priority review in November 1, PDUFA for sickle cell, and none of you will know this, but we're actually at a pretty important sickle cell KOL and community physician meeting. So the reason I bring that up is I'm really proud of the work that Sped and the team are doing to get ready for that launch, and we're certainly looking to amortize as much as we can from the progress we're making in thalassemia towards that launch as well.

51:33 Thank you. Thank you. Please stand by for our next question. Ladies and gentlemen, due to the interest of time, we ask that you limit yourself to one question, please. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is open. Good morning. This is Lydia on for Salveen. Thanks so much for taking our question and congrats on the progress. Could you just speak broadly to the current breakout between transfusion and non transfusion dependent patients and when you anticipate the non transfusion population to make up a majority of patients on treatment? And then as a quick follow-up, once you reach that ten to twelve week range, do you expect that to sort of be the run rate going forward? Thanks so much. Sure. Thanks, Leah. Stella? Absolutely.

52:20 What we're seeing now is a growing proportion of the NGDT segment as we've always said and as an anticipated. In the first quarter, and partly in the second quarter, a significant proportion of the patients were the patients, given they have a more frequent interactions with the healthcare system and are in generally the more engaged patient population. We've seen a significant growth of the NTD patients in the second quarter. We expect that to continue. And if you look at our breakdown of our initial launch focus, we have about 4,000 patients that we are initially targeting and about fifty percent of them are the patients that will continue to penetrate that segment.

53:07 We expect the ten to twelve week average time to take on initiations to stabilize and remain constant over time. Thank you. Please stand by for our next question. Our next question comes from the line of Tess Romero with JPMorgan. Your line is open. Hi, Brian and team. Thanks so much for taking our question. So as a matter of quick housekeeping, can you just remind us what is the right way to think about the LOE for mitapivat? And then second, to double click here, what is the right way to think about how cumulative scripts for AgVesni should evolve from end of 2Q to end of 3Q?

53:54 And then when might you be in a position to guide to revenues if script count will no longer be reported after 3Q? Thank you. Okay, thanks, Tess. First one will be quick. Mitapivat, you can think of LOE as 2,035 of composition of matter plus extensions and there are additional potential for patent extensions beyond that. The second one, which of course for where we go from 2Q to 3Q will be directional. We're not giving specific guidance, but qualitatively, Sveta, I think this will be similar to earlier comments you've made about further penetration. Absolutely. As we look into the second half of the year, we're looking forward to continue to penetrate the entity segment.

54:45 And as we know, these patients have less frequent visits to the healthcare providers. With that in mind, we also anticipate time to treatment initiations to move into the ten to twelve week range, which will be a key dynamic of the quarter as well. We are reaching this important six month point of treatment benefit evaluation. And that's one of the main reasons we'll start transitioning beyond Q3 into actually providing revenues rather than continued prescriptions. Very importantly, have an important date November 1 with the addition of the sickle cell disease launch. And once we have, hopefully that launch, launch will provide more information of how we can characterize the evolution of the mitapivat franchise across indications, but, we will do that at the time of launch.

55:38 And Cecilia, Tess snuck in a third question about, guidance and when, so do you want to comment on that one? Yeah, yeah. So, Tess, as Svelda mentioned, also with sickle cell coming on board upon potential approval in November, we look into the appropriate time to provide guidance for the franchise going forward. Good. Thank you. Thank you. Thank you. And our final question comes from the line of Luca Issy with RBC Capital Markets. Your line is open. Hi, team. This is Shelby on for Luca, and thanks for taking our question. Maybe on the commercial preparation for a potential launch in sickle cell. I believe this has a higher Medicaid mix versus thalassemia and PKD.

56:27 So one, is that correct? And two, how are you thinking about gross to net dynamics and net revenue per patient in sickle cell relative to your other existing commercial products? And also, does the Novo competitive dynamic factor into your pricing approach at all? Any color there much appreciated. Absolutely. We'll provide definitely more specifics on pricing at the time of approval and that's going to be driven by the label and the competitive environment at the time. And we'll continue to observe that moving forward. Of course, the sickle cell disease population has a higher Medicaid proportion and that by definition has a mandatory rebate of twenty three percent, which will which will drive the the gross to make to to a higher level compared to PKP and thalassemia.

57:22 But I can tell you we are super excited about the PDUFA date, and the team is ready for launch. Thank you. Ladies and gentlemen, at this time, I would like to turn the call back over to Brian Goff for closing remarks. Thanks everyone for your questions and for joining us today. Sveta was in the hot seat today, which we quite enjoy, so thanks a lot for that. To close, we're really pleased with the progress we made in the second quarter that includes delivering on continued acvesmine launch momentum, advancing mitapivat toward a potential sickle cell disease approval as we just discussed, strengthening our pipeline with sevedoplimab and AG-two thirty six and maintaining the financial flexibility to execute.

58:09 So ultimately, we enter the second half of the year focused, disciplined and confident in our ability to build long term value for both patients and shareholders. So thanks a lot and we look forward to speaking with you all soon. Ladies and gentlemen, that concludes today's conference call. Thank you for your participation. You may now disconnect.