Agios Pharmaceuticals, Inc.

Good morning, and welcome to RGO's Pharmaceuticals Second Quarter 2026 Conference Call. At this time, all participants are in listen-only mode. There will be a question and answer session at the end. Please be advised that this call is being recorded at RGO's request. I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at RGO's. Thank you, operator.

Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals' second quarter 2026 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 Goff, Chief Executive Officer, Cecilia Jones, Chief Financial Officer, Sveta Milanova, Chief Commercial Officer, and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development. Following prepared remarks, we will open the call for questions. 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 Akvesme and thalassemia, the potential expansion of midipivet into sickle cell disease, and a pipeline that continues to grow through both internal innovation and disciplined business development. During the quarter, we further strengthened our portfolio with the addition of sevadoclinib, a next generation, highly selective oral stick inhibitor that expands our rare hematology franchise into immune thrombocytopenia, or ITP. We also advanced AG236, into an operationally seamless Phase 2-3 program in polycythemia vera, adding another potential growth driver within hematology. Beyond hematology, AG1A1 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. 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 RGOs 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 $44.7 million in total net revenue, including $40.9 million in the U.S. and 442 cumulative Akvesme prescriptions for REM-certified physicians. Second, we further diversified our pipeline through the in-licensing of sevadoplinib, a next-generation highly-selective oral sick inhibitor for ITP, progressing toward Phase III and strengthening our rare hematology pipeline. Third, we advanced Minipivet 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 Purdue faculty of November 1st, 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 billion in cash, cash equivalents, and marketable securities. providing financial flexibility to support both commercial growth and pipeline progression. Overall, we entered the second half of 2026 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 net revenue was $44.7 million, including $40.9 million in the US and $3.8 million outside the US. Cost of stays for the quarter was $3 million, and research and development expense was $100.8 million, compared to $91.9 million in the second quarter of 2025. Primarily due to an increase in in-process research and development of $15 million, driven by the $25 million upfront payments associated with the agreement to offer them. Setting general and administrative expense was $61.5 million, compared to $45.9 million in the prior year period, reflecting an increase in commercial-related activities that we executed a launch of at West Main in 2017. Net loss for the second quarter of 2026 was $107 million, compared to a net loss of $112 million for the second quarter of 2025. We ended the quarter with approximately $1 billion in cash, cash equivalents, and marketable securities, which we believe provides financial flexibility to support commercial execution, advancement of our pipeline, and continued investment in opportunities to create long-term value. Turning to our outlook for 2026, we continue to expect approximately $45 to $50 million from decay deficiency revenues in the U.S. Full-year operating expenses are expected to remain approximately flat versus 2025, excluding the $25 million upfront payments associated with the SEBI-DOC-NASCIN licensing transactions recognized in the second quarter, and include investments to prepare for a potential sickle cell disease launch aligned with our November 1st producer date. Our priorities for the remainder of the year remain clear. Driving the investment launch, preparing for a potential sickle cell disease approval, advancing our pipeline and maintaining financial discipline. Please advance to the next slide and I'll turn it over to Sarah to cover commercial highlights and our VETME U.S. Celestinia Launch Program.

Thanks, Cecilia. Next slide, please. With six months of launch experience now behind us, we're encouraged by the underlying drivers of performance. What we have seen so far continues to reinforce our confidence in the long-term opportunity in thalassemia. Importantly, the strong execution across our commercial and patient-focused organizations further strengthen our confidence in future launch opportunities. In the U.S., performance reflected continued growth in thalassemia demand and solid commercial execution. Net revenue in the quarter reflected approximately $5 million of one-time benefits related to stocking in thalassemia, along with modest growth to net favorability. We continue to expect growth to net within our previously guided 10-20% range with quarter-to-quarter variability. Outside the US, we delivered $3.8 million 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 movement, and growth to net dynamics. Next slide, please. I'm very pleased with the continued U.S. launch performance of Aspesne. During the second quarter, we generated an additional 200 prescriptions from REN-certified physicians, bringing cumulative prescriptions to 442 as of June 30th. As a reminder, this metric captures unique prescriptions for patients with completely sparse forms from Rand Certified Physicians and served as an early indicator of underlying demands. Importantly, the underlying launch dynamics remained healthy. While demands 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 cohorts of transfusion-dependent patients. We continue to see strong conversions from prescription to treatment initiation. Time to start is naturally trending toward our anticipated 10 to 12 week range as adoption broadens across the NGDP 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 75% of the Latina lives covered under payer policies. Additionally, physician rent certification continues to progress in steps with prescribing activity, and it's not a barrier to patient access. As the launch matures, Prescriptions with completed STARS forms become a less informative measure of performance, whereas revenue increasingly reflects both new patient STARS and participants on therapy. For that reason, in anticipation of a potential FDA approval for mitopivas in sickle cell disease, we plan to discontinue reporting prescriptions from REM-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 Mitaviva's franchise. Next slide, please. I wanted to take a few moments to highlight the Leukemia 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 10 to 12 week average at launch maturity. 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 We are also mindful that the first cohort of patients who initiate the therapy in the earliest month of launch is approaching six months of treatment, a natural point at which physicians assess clinical response. 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 misopivus into long-term care. Taken together, these dynamics reinforce that AccessMe 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 thalassemia community, expanding adoption in the non-transfusion-dependent segment while continuing to add new prescribers. We remain highly confident in the long-term opportunity for Acvesme and in our ability to build a durable, growing thalassemia franchise over time. Please move to the next slide. We are actively preparing for a potential sickle cell disease launch in the U.S. and are encouraged by both the commercial opportunity and the unmet need we see in this community. Our initial launch focus is on approximately 25,000 patients who are actively treated or in need of therapy today. We believe that population alone represents a meaningful opportunity for Metapiva, with potential to expand beyond the initial segment over time. Importantly, we are leveraging the capabilities, relationships, and insights we have developed through the 13-year launch while continuing to invest in market access, education, and community engagement activities ahead of the PADUFA call date. Pending FDA approval, we believe this effort positioned us well to support a successful launch and to deliver MiCAPIVA 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&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. Mixtapebot continues to anchor the portfolio with approved indications in Firebase Chinese efficiency and thalassemia and a potential accelerated approval in sickle cell disease later this year. During the first half of this year, we achieved an important milestone with Palestinian approvals in Europe and the UAE, completing regulatory approvals across all four priority launch geographies following prior approvals in the U.S. and KSA. Since first quarter results, we filed and received acceptance in the U.S. for the Mitzapibat SNDA in sickle cell disease with priority review and the PDUFA goal date of November 1st. We remain committed to bringing Metapipax to patients with sickle cell disease and recently dosed the first patients in Reignite, our Phase III confirmatory trial, an important milestone in advancing the program. We also strengthened the pipeline during the quarter through the in-licensing of stevidoplinib, a next-generation stick inhibitor that expands our reach within rare hematology and adds a compelling opportunity in immune thrombocytopenia. Beyond Metapidot and Cepidoplinib, we continue to invest in future growth drivers, including AG236 in Polycythinia 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 Cepidoplinib, our interest in the program is grounded in its potential to address some of the limitations that have historically constrained the stick inhibitor class. Cepidoplinib was designed to optimize both selectivity and pharmacokinetics, support the sustained target inhibition while maintaining a vulnerability profile suitable for chronic use. The clinical data generated to date are encouraging and support this design rationale Demonstrating dose-dependent activity, no dose-limiting toxicity through Phase 2, and evidence of durable platelet responses. Taken together, these data support a rationale for advancing cebidoplonib as a next-generation highly selective stick inhibitor. We're looking forward to engaging with the FDA in the coming months to align on progression to Phase 3. 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 metastasis. Across the portfolio, we have 10 aspects accepted, including the RISE-UP phase 3 study, which was selected for the EHA oral plenary session. In sickle cell disease, RISE-UP demonstrated hemoglobin responses consistent with the mechanism of PK activation, with hemoglobin responders experiencing clinically meaningful improvements in sickle cell pain crisis-related endpoints and fatigue. At eHow, 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 hydroxyurea. Importantly, outcomes from the subgroup of patients with at least one transfusion in the 52 weeks prior to enrollment directly informed the treatment effect and firing assumptions for the ongoing reignite confirmatory trial, supporting accelerated approval. We also presented additional patient-reported outcomes data showing clinically meaningful improvements in how hemoglobin responders feel and function, including reductions in physical state. In addition, 66-week follow-up data from the Satisfy Phase II investigator-sponsored trial in related mammography show 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 60% of patients continuing on Misafikov met criteria for hemoglobin response and 60% of patients who switched onto Misafikov 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 NPD patients achieve improvements in hemoglobin levels and fatigue. These data were received very favorably by the Thalassemia community and reinforced the value of Misapidop in non-transfusion-dependent patients, which comprise the majority of the item of adult patients in the U.S. Taken together, these data reinforce the consistency of Misapivac's profile across indications and further strengthen our confidence in the long-term potential of Misapivac in hemolytic anemia. While we continue to advance and expand the Misapivac opportunity, we're also focused on building the next generation of potential growth drivers within rare hematology. H.E.236 is an important example of that strategy. Next slide, please. Following encouraging Phase I data, we're advancing HE236 into an operationally seamless Phase II-III development program in polycythemia vera. What continues to differentiate HE236 is its potential profile with an evolving treatment landscape. The molecules demonstrated have site and 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 saturation. The Phase 2 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 2-3 strategy reflects our commitment to disciplined execution while advancing development as efficiently as possible with Phase 2 initiation planned for the second half of 2023. We believe AG-236 has the potential to further diversify our rare hematology leadership and contribute to our long-term growth beyond Mississauga. 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. We're building commercial momentum with Akbesby and Thalassemia, reaching 442 cumulative prescriptions as of June 30th. We're advancing Mitipivac 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. We're also advancing AG236, our siRNA-Tempr-6 inhibitor for polycythemia vera, into an operationally seamless Phase 2-3 program expected to begin in the second half of this year. And during the quarter, we further diversified our portfolio through the addition of sevadoplinib, a next-generation highly selective sick inhibitor in ITP progressing toward Phase 3. 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 enter 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. 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 billion in 2030. 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. And with that, thank you all for joining us today. Operator, we're ready to begin the question and answer session.

Thank you. Ladies and gentlemen, to ask the question, please press Start 11 on your telephone, then wait for your name to be announced. To withdraw your question, please press Start 11 again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Alex Stranahan with Bank of America. Your line is open.

Hey, guys. Thanks for taking my questions, and congrats on the really strong quarter here. Two questions from me. First, on time on treatment in the commercial setting, do you think the energized 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, you know, 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 10 to 12 weeks? 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, Alec. So two-parter. So Sveta, you can take the first one. Actually, you'll take both of these on time on treatment and energized as an analog. And then the second one, I think, Alec, you're asking about not time on treatment, but time to treatment from the demand to initiation. So Sveta, you want to take that?

Absolutely, we are very pleased with the strong initial start of the Cresme launch, Alec, and as we mentioned, we have in total 442 prescriptions from REM-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 10th to 12th weeks. We've given 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 continuations rate. But that's going to be more in the second half of the year, and we'll monitor that closely. Currently, what we see from the market is a very kind of strong feedback and a positive feedback from the community. So we expect continuation rates to be in line with the Energize study. And 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 NTDT settings to move closer and closer to what we initially expected, the 10 to 12 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 10 to 12 weeks, given the strong penetration in the NTDT settings. 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 REMS process very, very smoothly.

Thank you.

Thank you. Our next question comes from the line of Andrew Behrens with Levering. 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? What the experience will be like for these patients in the real world? And then the other thing that's obviously very important is going to be a sickle cell label, whether it's on a kesme or a pyrotine. What factors will go into that? And is there anything you can tell us in these early days ahead of the November 1st to do for that? Even as confidence that you won't have a REMS or have to potentially reduce the pricing for a kesme and thalassemia? Thanks.

Thanks, Andy. And I will just say again, and thanks for the comments about this front quarter, I am really pleased and proud with the continued execution from Svet 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 we can really look at the open label data that we presented at IHA 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 control trial. What you see there is a good maintenance of response, so patients do continue on the drug. and you see that maintenance of hemoglobin, the maintenance of anti-hemolytic response in people feeling good. Another point there, what was exciting to see at the e-hub 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. I think the clinical trial data is actually the best I've been spending a lot of time with clinicians in the field, had the opportunity to hear their feedback on the EFA 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.

In any regard... Can you give us... 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 90% continuation from the clinical trial. And then, of course, it always, you know, as time continues, clinical trials are burdensome. It drops a little, but it's very, very good persistence, both for PKD, for thalassemia, for sickle cell disease in the clinical trial. What was interesting there is also the response rates. with longer exposure, which is important for thalassemia. In the early 40%, we had some non-responders convert into responders, so we got to a 60% response rate there. So the clinical trial data is very good.

And we know, obviously, that's an important metric for us going forward. But we're still early days. This is our second full quarter of launch, which in a way matches the period of time for the energized 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 a sickle cell out of TechBesme or Pyrekind. 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?

Yeah, so the PDUFA is indeed November 1st 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 looked very good. We did not have the hepatocellular injury observed in the sickle cell disease patients, so therefore it may not warrant a REM. Either way, our teams are ready to execute a launch with or without a REM, so more to come.

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. 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.

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 support 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 2026 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 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 10% to 20% expected target? Now you're at 75% of cover life. Thanks and congrats again.

Thanks, Supawatt. So, Sveta, 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 study, you want to take that and then we'll do gross to net 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 NTT setting, which is the bigger commercial opportunity. As we mentioned, in the second quarter, we added 200 prescriptions from RAM certified physicians. physicians. As we move into the second half of the year, prescriptions growth and revenue growth are not going to be directly correlated, you know, on a perfect basis, given that we're moving into the more mature phase of the launch. And revenues really also depend on time to treatment initiations, ramps on boarding, and persistency, as we've discussed. Moving ahead, as we move into the NDVT setting, we expect the time to treatment initiation to move well into the 10 to 12 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 adoption, 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. Cecilia, you want to comment here?

Yeah, so we expect that to continue to be in that range of 10 to 20% as we've 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 Frim with TD Cohen. Your line is open.

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 the back end starting in the second half. But do you view that 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, you know, the backlog of REM certifications and kind of the highly, highly motivated patients?

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. As we, and Sveta just commented 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 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. That's why we'll 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 house 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 Early adopters, highly motivated patients and physicians, the delay in the PDUFA, which created the anticipation of the launch, 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 settings, a very strong adoption into the NPDT setting across alpha and beta thalassemia patients, and moving into that more steady state of 10 to 12 weeks treatment initiation. So we are very encouraged of the way the launch is going and the way the team is executing.

Okay, that's all helpful. And then maybe just on the other end of the funnel and just continuation rate, do you view these initial kind of very highly motivated patients and clinicians that are using, you know, that were starting therapy in, you know, 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 what we see in the real world. My suggestion for now and what we're hearing from the clinicians is that the core period in the clinical trials is a very good proxy for continuation and we'll continue to learn more. 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 treatments Thank you. Our next question comes from the line of Samantha Simincow with Citi. Your line is open. Hi, good morning. Thanks very much for taking the question and let me on 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? 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 Sveta 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 of transfused blood, and both of these aspects are important. What we hear from physicians, and I had the opportunity to meet both with patients and physicians recently at the Kulit Anemia Conference, Our 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 benefit. and they'll make decisions based on that. Transfusion reduction in the CDT patients will be important. They are not necessarily going to stick to what was defined as a 50% reduction in the clinical studies. It's 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. On the NTDT 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 hemolytic parameters and very importantly in the NTDT setting is how patients feel. The reduction in fatigue is a key driver both for patients and physicians to continue on therapy irrespective of the 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? 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 leucemia majority of the patients are managing the community and we don't have that much breadth across the therapy area. And I see a very, very strong breadth of prescribing across the country 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. And we expect that to continue. They do have a stable patient base, but really our opportunity is to continue to penetrate the community settings.

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 Sveta. She seems like she's on the hot seat today. So I just want to be clear about what's in the 442 cumulative prescriptions that you're reporting. 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 that still the case?

Absolutely. They are unique patient prescriptions. In a way, that's kind of the equivalent of a start form, and it's written by a REM-certified physician.

And I assume, Sveta, you have some insight into how many refills have also been written thus far?

So, yeah, the refill rate continues as patients reach their second and third month of therapy. So the refills are continuing according to plan. So depending on, you know, the patients that have started and are progressing to the ramps, the refills are coming in. We are not providing a specific kind of refill dynamics and total patients on therapy. And as I said, moving forward, we'll move away from StartForms and really start focusing on revenue more because it takes into account all of these dynamics that you're asking about, Eric. New patient starts, time to treatment, initiation, three fields, and continuation.

Okay, you anticipated all of my questions. I've just got one left, which is conversion of patients from StartForms 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. and 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. And again, we know with these and other NTD patients as we move deeper into that penetration. It could take longer, which is why the translational aspect of going from a stark 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 Botnar with HC Wainwright. Your line is open.

Hi, good morning. Thanks for your question. All up on Europe sales for Thalassemia, were any of the 2Q revenues driven by Europe specifically? And how do you kind of think about ex-US revenue growth for the remainder of the year? 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-U.S. revenue so far is quoted as a combination of the consistent continued demand in GCC, as we have like 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.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 sickles, again, given the PDUFA date being November, it wouldn't be a material contribution to our folio revenues for 2026.

I will just add, Emily, we're enthusiastic about the opportunity of a priority review in November 1st, 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 Sveta 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.

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 10- to 12-week range, do you expect that to sort of be the run rate going forward? Thanks so much.

Sure. Thanks, Lydia. Set up?

Absolutely. What we're seeing now is a growing proportion of the anti-DDT segment, as we've always said and as anticipated in the first quarter and partly in the second quarter, a significant proportion of the patients were the TDD patients, even they have 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 50% of them are the NTDC patients. So we'll continue to penetrate that segment. And we expect the 10 to 12-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 JP Morgan. 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 mid to pivot? And then second, to double click here, What is the right way to think about how cumulative scripts for Agvesney should evolve from end of 2Q to end of 3Q? 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. You could think of LOE as 2035 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 NTDT segment. And as we know, these patients have less frequent visits to the healthcare providers. And with that in mind, we also anticipate time to treatment initiations to move into the 10 to 12 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 continuous prescriptions. Very importantly, we have an important date, November 1st, with the addition of the sickle cell disease launch, and once we have hopefully that launch, launch will provide more information of how we We can characterize the evolution of the MetaPIVA franchise across indications, but we'll do that at the time of launch.

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 Sarah mentioned, also with SecoSol 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. 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 23% which will drive the growth tonight to a higher level compared to PKP and calisthenics. 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.

All right. 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. We're really pleased with the progress we made in the second quarter. That includes delivering on continued Akvesmin launch momentum, advancing midiPIVAT toward a potential sickle cell disease approval, as we just discussed, strengthening our pipeline with sevadoplinib and AG236, and maintaining the financial flexibility to execute. 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.