Good morning and welcome to Agios Second Quarter 2022 Conference Call. At this time, all participants are in a listen-only mode. There will be a question-and-answer session at the end of the call. Please be advised that this call is being recorded at Agios' request. I would now like to turn the conference over to Holly Manning, Senior Director of Investor Relations. Please go ahead.

Thank you, operator. Good morning, everyone, and welcome to Agios' second quarter 2022 conference call. You can access slides for today's call by going to the Investors Section of our website, agios.com. With me on the call today with prepared remarks are Dr. Jackie Fouse, our Chief Executive Officer; Dr. Sarah Gheuens, our Chief Medical Officer and Head of Research and Development; Richard Poddar, our Chief Commercial Officer; and Jonathan Biller, our Chief Financial Officer and Head of Corporate Affairs. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. With that, I will turn the call over to Jackie.

Thanks, Holly. Good morning, everyone, and thanks for joining our second quarter 2022 results call. The first half of 2022 has been remarkably productive across all facets of our business. I've continued to be impressed by the focused execution of the Agios team and their connection to each other and our vision of making an impact on the lives of patients. In February, our world-class commercial organization launched our first genetically defined disease medicine, PYRUKYND, which is the first FDA-approved therapy to treat pyruvate kinase deficiency and the first-ever approved PK activator. Today, we report impressive commercial performance for our first full quarter of launch, which Richard will cover in more detail. Our exceptional clinical team initiated two pediatric PK deficiency pivotal studies, as well as a sickle cell disease cohort of the AG-946 Phase 1 trial, all while operationalizing the AG-946 MDS study and continuing to advance site activation and patient enrollment across three pivotal studies of PYRUKYND in thalassemia and sickle cell disease. In May, we made the tough decision to evolve our research organization, which has led to the ongoing integration of our R&D teams and enhanced our research focus and business development activities. And in June, we had a robust presence at the European Hematological Association Meeting in Vienna with broad preclinical, translational, and clinical updates across the programs. Sarah will review our preclinical and clinical programs momentarily. A highlight for me occurred a few weeks ago when Agios employees came together for our first company offsite since the start of the pandemic two and a half years ago. It was an incredible reminder of the expansive talent we have at Agios and the interconnected culture that continues to thrive through the dynamic evolution of the business. Turning to slide five. A few weeks ago, we announced that as of Monday, August 8, I will transition to the role of Chair of the Board of Directors and Brian Goff will become the new Chief Executive Officer of Agios. Brian has vast experience in hematology, rare diseases and commercial and operational leadership cultivated over the course of 30 years at global biopharmaceutical companies. I strongly believe he is the right leader to guide Agios through its next chapter. As I reflect on my time as CEO, I'm proud of the bold strategic decisions that we made as a team, our resiliency in the face of a global pandemic and the individual lives that we have touched through the medicines we've created. My confidence in the Agios team and its ability to make a positive impact on the world remains steadfast, and it's for that reason that I'm so excited to continue to play a role in that mission as Chair of our Board. Starting Monday, I will be focused on helping Brian orchestrate a smooth transition into his role as CEO, serving as a founding Board member and point of reference, while also giving him space to learn and make decisions. I also look forward to working with my colleagues on our Board to fully leverage and evolve our collective Board skill set so that we can continue to be a great resource for Agios and the management team, as we move into a bright future as a rare and genetically defined diseases-focused company. Standing here today, Agios is operating from a position of immense strength with a first-in-class commercial launch, five pivotal trials underway, multiple early-stage clinical studies planned or underway, a promising preclinical pipeline and an enviable balance sheet that provides significant optionality for the future growth of the business. I look forward to continuing to be part of this amazing team, and I thank each of you for your support of Agios now and in the future. With that, I'll turn it over to Sarah.

Thanks, Jackie. Back in May, we announced the evolution of our research organization to focus our people and resources on existing validated preclinical programs and shift that pipeline group strategy to in-licensing and/or acquiring well-characterized high-potential assets. This approach enabled us to retain a strong internal research team focused on moving our most promising internal programs forward, while also pursuing opportunities that complement our scientific expertise in cellular metabolism and growing clinical and commercial capabilities. With this evolution, I'm excited to step into my new role as Head of Research and Development. It is my focus and priority to seamlessly integrate our research and development functions in a way that increases the coordination and efficiency of the organization and deepens the impact of patient insights on R&D decision-making. As shown on slide eight, we have a fully built research and development organization encompassing all functions needed to drive our preclinical and clinical programs forward and we have an incredible amount of talent across each of these functions. It has been truly gratifying to see the way this new structure has already had a positive impact on communication and collaboration within the R&D organization. Turning to slide nine. While our research leaders are focused on helping us thoughtfully evaluate the underlying science and fit of potential business development opportunities, they are also hard at work advancing our internally discovered preclinical programs. As shown on slide 10, our earliest program is a branched chain amino acids aminotransferase 2 inhibitor known as BCAA2 for the treatment of propionic acidemia called PA and methylmalonic acidemia also known as MMA. These acidemias are a group of inherited inborn errors of metabolism in which the body cannot break down branched-chain amino acids, leading to a toxic accumulation. BCAT2 inhibition may reduce the formation of these metabolites, which has the potential to enable patients to have fewer dietary and other restrictions and improve their quality of life. Our BCAT2 inhibitor is currently in late lead optimization. Turning to slide 11. Our most advanced preclinical program is the phenylalanine hydroxylate, or PAH, stabilizer for the treatment of phenylketonuria known as PKU. PKU is a rare inherited lifelong disease that causes phenylalanine to accumulate. Normalizing plasma phenylalanine concentrations may allow patients to increase natural protein intake, normalizing their diet and improving their quality of life. The program is approaching the development candidate milestone, and we expect to achieve an IND next year. As you can see on slide 12, on the clinical side, we have broad clinical development programs for both our PK activators, PYRUKYND and AG-946. Turning to slide 13. AG-946 is our novel PKR activator, currently being evaluated in a Phase 1 study with healthy volunteers in a sickle cell disease component. We have completed a single ascending and multiple ascending dose healthy volunteer cohorts and hope to present these data at the ASH Annual Meeting later this year. We recently initiated the sickle cell disease part of the study in order to obtain data for this molecule in a hemolytic anemia. In addition, we believe PK activation has the potential to improve red blood cell health in both intermediate myelodysplastic syndrome, or MDS, where there is a significant unmet need. As shown on slide 14, we are working through operationalizing the 2a parts of our AG-946 Phase 2a/2b study in MDS. The Phase 2a component of the study is an open-label proof-of-concept study of one dose level of AG-946 in patients with lower-risk MDS. The study will enroll 20 patients who will receive AG-946 once daily for the 16-week core period. Patients who complete the core period will be eligible to continue in an extension period. The primary endpoints for the study are hemoglobin response defined as equal or more than 1.5 grams per deciliter increase from baseline in the average hemoglobin concentration from week eight through week 16 and transfusion independence defined as transfusion-free for equal or more than eight consecutive weeks during the core period in patients with both transfusion burden only. Secondary endpoints include safety, additional measures of anemia and PK and PD biomarkers. We look forward to initiating the trial by the end of the year. Turning to slide 16 for our most advanced PK activator, mitapivat, known commercially as PYRUKYND, our clinical focus is to transform the course of hemolytic anemia by increasing red blood cell energy, health, and longevity, and we are well-positioned to be the first company to do this across three distinct hemolytic anemias. As shown on slide 16, we are exploring PYRUKYND in an operationally seamless Phase 2/3 study known as RISE UP in adults with sickle cell disease, with the goal of being the first potential oral agents to improve anemia, reduce VOCs and improve quality of life by increasing methemoglobin resulting in reduced pain and fatigue. The Phase 2 portion will randomize 69 patients 1:1:1 to 50-milligram mitapivat twice daily 100-milligram mitapivat twice daily or matched placebo. The primary endpoints are hemoglobin response defined as equal or more than one-gram per deciliter increase in average hemoglobin concentration from week 10 through week 12 compared to baseline and safety. Our goal is to complete enrollment in the Phase 2 portion by the end of this year. Upon completion of the double-blind portion of the Phase 2, we will evaluate the totality of the data before triggering the start of the Phase 3. The outcome of the primary endpoint is the first step. Then we will take into account changes in markers of hemolysis, the rate of sickle cell pain crisis, patient-reported symptoms, and other secondary endpoints. With Phase 2 success, these data will also allow us to make a determination on the dosing paradigm for the Phase 3 portion in the protocol. As an operationally seamless study, we have the ability to increase the speed at which we can transition from one phase to the next, as well as assess the need for modifications to the Phase 3 based on the outcome of the Phase 2 without impact on statistical and regulatory aspects of the trial. Moving to thalassemia on slide 18. We are very excited to have the potential to establish PYRUKYND as the first oral therapy to improve hemolytic anemia and ineffective erythropoiesis across data and alpha thalassemia as well as transfusion-dependent and transfusion-independent thalassemia. At the end of last year, we initiated our two global placebo-controlled pivotal trials of PYRUKYND, ENERGIZE and ENERGIZE-T. As a reminder, ENERGIZE will evaluate 171 patients randomized 2:1 to 100 milligrams of mitapivat twice daily or placebo in both alpha and beta thalassemia patients who are not regularly transfused. The primary endpoint of hemoglobin response is defined as an equal or more than 1-gram per deciliter increase in average hemoglobin concentration from week 12 to week 24 compared with baseline. ENERGIZE-T will evaluate 240 patients randomized 2:1 to 100 milligrams of mitapivat twice daily or placebo in both alpha and beta thalassemia patients who are regularly transfused, defined as six to 20 red blood cell unit transfused during the 24 weeks prior to randomization. The primary endpoint is transfusion reduction response defined as a 60% or greater reduction in transfused red blood cell units with a reduction of equal or more than two units of transfused red blood cells in any consecutive 12-week period through week 48 compared with baseline. Our team is focused on continuing global site activation and patient enrollment efforts in order to enroll a meaningful portion of patients in both studies by the end of the year. Finally, in February, PYRUKYND became the first FDA-approved therapy for pyruvate kinase deficiency and we continue our efforts to expand the utility of this medicine to all PK deficiency patients. In June, we initiated two studies of PYRUKYND in pediatric PK deficiency patients, ages one up to 18, as shown on slide 19. ACTIVATE-Kids will randomize 30, not regularly transfused patients 2:1 to either PYRUKYND or placebo and evaluate hemoglobin response over the 12-week course period. ACTIVATE-KidsT will randomize 45 regularly transfused patients 2:1 to either PYRUKYND or placebo and evaluate transfusion reduction over the 24-week core period. In parallel, our marketing authorization application for PYRUKYND in adult PK deficiency remains under review in the EU, and we remain on track to receive a decision from the EMA by year-end. In summary, as shown on slide 20, we are pleased with the progress made against our 2022 key milestones this quarter across all programs. With that, I will now turn the call over to Richa, our Chief Commercial Officer.

Thank you, Sarah. In the second quarter, which represented the first full quarter of the PYRUKYND launch, we generated net U.S. sales of $3.1 million. As we've said before, our commercial launch strategy outlined on slide 22 aims to connect with providers and facilitate access to appropriate disease and product information for the patient. Our focus is on ensuring, first, that the approximately 1,500 to 4,000 PK deficiency patients in the U.S. are accurately diagnosed through efforts like Anemia ID; second, physicians understand the urgency to prescribe to eligible patients and advocate for treatment; and finally, patients connect to myAgios support services to optimize disease understanding, ensure access and drive long-term medication adherence. With our first full quarter under our belt, we are encouraged by the early launch metrics as well as the meaningful feedback we have received from patients and physicians. I'll start with what we view as the key metrics we have observed so far as outlined on slide 23. As of June 30, our team of hemolytic anemia specialists has continued to engage with customers and have been successful in driving scripts as there are now a total of 52 unique patients with completed PYRUKYND prescription enrollment forms. This has converted to 37 total patients on PYRUKYND, which includes those with new prescriptions and those continuing treatment. Importantly, at this early stage of launch, these patients are coming from a unique prescriber base of 50 physicians diversified across the country, validating our view that the majority of patients are treated in the community versus academic medical centers or centers of excellence. The breadth of prescribing across states and practices indicates early launch health. As we saw in the first quarter, patients coming on therapy represent a range of demographics and disease characteristics very representative of the adult PKD patient population. These include splenectomized and non-splenectomized patients, patients that are regularly and not regularly transfused, young and old patients, and patients that have a range of various levels of hemoglobin. In terms of payer dynamics, our national account directors continue to have positive interactions with payers to date. As we saw in Q1, the majority of scripts have been approved through the medical exception process as payer policies are developed. Payer policies are starting to be developed with a few in place aligned to indication statement or the clinical trial eligibility criteria. Turning to slide 24. We are pleased with the continued interest in our Anemia ID kit, which is a free genetic testing program designed to drive an accurate diagnosis for patients with a general diagnosis of hemolytic anemia of unknown etiology. More than 4,200 kits have been ordered, a 20% increase since Q1. Consistent with last quarter, approximately 25% of kits have been completed and the PK deficiency positivity rate for those completed tests remains in the mid-single-digit percentages. Of the positive tests, they are split evenly between pediatric and adult patients. Looking to the second half of the year, there are several factors to consider as we continue to evaluate early launch trends. First, our label suggests patients continue on treatment for six months, at which point an assessment of response can be made. Based on our clinical trial experience, we believe approximately 40% to 45% of patients will be considered responders based on hemoglobin levels, markers of hemolysis, and individual assessment of function. As we reach the six-month mark of launch, we will start to see the non-responding patients come off therapy. For the patients who stay on therapy, we will be able to make better assessments of adherence and persistence. Second, as we said prior to launch, it will take approximately a year to achieve optimal payer coverage. We will continue to track payer policies as they are developed, including the criteria for initial coverage, which could be based on clinical trial eligibility. The exclusions for which are noted in the second right-hand box on slide 25, and not the indication statement, as well as how the individual payers define response as part of the reauthorization process. And finally, it is important for us to remember that PK deficiency is a rare chronic condition, which is poorly understood. Our efforts around disease education and encouraging accurate diagnosis continue to be paramount to ensuring long-term success. The commercial team is laser-focused on these initiatives, given that PK deficiency is a disease that requires multiple interactions to both educate on the disease to create urgency and also ensure accurate diagnosis. We are very encouraged with these early launch successes and the positive experiences we are creating with the broader PK deficiency community. We have built a passionate commercial organization with significant rare disease experience that is fully capable of executing our strategy and be excited and grateful for the impact we are making on the lives of PK deficiency patients. Importantly, what we are seeing from this launch is that our commercial strategy, our knowledge base, and the connections we are making are setting us up for success as we continue to expand the applicability of PYRUKYND to all eligible PK deficiency patients, as well as, in the longer term, other genetically defined diseases. With that, I'll now turn it over to Jonathan to review second quarter financials.

Thanks, Richa. Our second quarter 2022 financial results can be found in the press release we issued this morning, which I will summarize. More detail will be included in our 10-Q filing later today. Turning to slide 28. As Richa shared, PYRUKYND revenue for the second quarter was $3.1 million. In addition, we recognized revenue of $2.5 million in the quarter with respect to an upfront payment associated with the licensing of intellectual property for our Friedreich’s Ataxia preclinical program, which we had discontinued in 2020. Cost of sales for the quarter was $435,000. Turning to operating expense. Research and development for the second quarter was $74.5 million, an increase of $12.5 million compared to the second quarter of 2021. The year-over-year increase in R&D was driven primarily by increased headcount and workforce-related expenses, planned increased activity associated with the PAH preclinical program, start-up costs for the AG-946 Phase 2a MDS study, increased spend for the AG-946 Phase 1 trial, and start-up costs for the PYRUKYND pivotal studies in sickle cell disease and pediatric PK deficiency. Selling, general, and administrative expenses were $28.3 million for the second quarter, representing a $1 million decrease over the second quarter 2021. The decrease in SG&A expense was primarily due to the completion of the reimbursable transition-related services provided to Servier related to the sale of the oncology business, which concluded in the first quarter of 2022. TIBSOVO royalty revenue, which is recorded under royalty income and gain on the sale of the oncology business on our income statement, was $2.7 million. We ended the quarter with cash, cash equivalents, and marketable securities of approximately $1.1 billion. With this cash balance, we expect to be able to execute our current operating plan through major catalysts and to cash flow positivity without the need to raise additional equity. With that, operator, please open the line for questions.

Thank you. Our first question comes from Marc Frahm with Cowen. Your line is open.

Yes. Thanks for taking the question and congrats on the quarter. Maybe this is for Richa. Can you speak to the kind of full-time that you're seeing on those 52 start forms that have come in versus the 37 patients on drug? And how do you expect that trajectory to kind of change through the rest of the year?

Yeah. Marc, thanks for the question. So, we are encouraged, as we said, with the trends that we are seeing in regard to both getting patients on the drug and also getting access to the drug. So, we expect those to convert over time. It's taking about four to eight weeks at this point for patients to get on therapy, given that we are still transitioning through the medical exception process and as payer policies are being developed. As we've said in the past, slow and steady is the way that we anticipate this launch, including the second half. I think two things to keep in mind here: the patients are still titrating through their therapy. So, according to our label, we have the six-month assessment, where the assessment of response will be made for the patient. And depending on that, at least from our clinical sense, we know it's about 40% to 45% of patients expected to respond. We had some patients drop-off, and then as the payer policies and the authorization develop, we will know more as well in terms of what that second half looks like. So, those are the two things just to take into consideration as we go into the second half, but we are very encouraged with this early launch trend in terms of both diversity of patients who are getting prescribed drugs as well as the breadth of prescribing across the country.

Okay. That's helpful. And then, I know the authorization new regiment criteria process is pretty early, but the early feedback that you're getting on the reauthorization process, how strictly are you seeing those plans adhere to the response criteria in the trial versus being open to maybe a broader interpretation of what a response looks like?

So, I think it's really this is a rare disease, right? So, I think here's the conversation between the division and the plans, as well as our continued engagement with the payers, which we have continued to do and will continue to do as those reauthorization and utilization management criteria develop is going to be very important. So, those interactions thus far have been positive. Still too early to comment, like I said, but it continues to trend in the direction we hope it would.

Our next question comes from Gregory Renza with RBC. Your line is open.

This is Greg. Thank you for taking our questions and congratulations on the quarter. I have a follow-up question regarding the patients on PYRUKYND. Among the 37 patients, how many were newly added this quarter? What are your expectations for NRx growth in the second half? What headwinds and tailwinds should we consider? Additionally, regarding the diagnostic kit, Anemia ID, is the positivity rate influenced by prevalence, or are there other factors affecting it? How do you envision that rate evolving in the long term? Thank you.

Sure. So, I'll answer the Anemia ID question first. So, just we reported the positivity rate because we believe that we are at the point where it's pretty steady and has been pretty steady for a while. As a reminder, Anemia ID is not designed for PK deficiency specifically, right? We designed it with the needs of our physician and healthcare professional base as well as what we knew was needed to improve diagnosis for hemolytic anemia period. So, designed to test for hemolytic anemia of unknown etiology and to aid healthcare professionals to understand what the underlying cause is for the hemolytic anemia as opposed to being specific to PK deficiencies. So, as of this minute, we don't have any information to suggest that we would expect any upward mobility in the positivity rate associated with PKD specifically. So that's on Anemia ID. To your question on NRx versus TRx, again, it's really early to comment. I think what is important is that we are seeing slow and steady growth as we anticipated. We are seeing patients across a wide variety of demographics. We are not seeing patients off very specific kinds being prescribed; we're seeing across hemoglobin levels, across disease characteristics base representative of the adult PKD population, which is encouraging and across the country. This is a rare disease, chronic in nature that is not concentrated in any centers of excellence, so you would expect that result with the disease in general. Again, as a reminder, as I said earlier as well, this is our first full quarter. So, still really very early. We need to see what happens with the six-month assessment where the real-world efficacy looks like, which is going to take a long time for us to figure out. But in a clinical trial, it was 40% to 45%. And then we also have to see how the payer policies in terms of reauthorization and utilization management criteria that get shaped up, which will influence that as well. So, we have more sense of trends more like what we have fully as opposed to just a couple of quarters, but it's heading in the right direction, which is encouraging.

We have a question from Andrew Berens with SVB Leerink. Your line is open.

Hi. Congrats on the launch progress and thanks for giving color on the addressable market. I was wondering if you could also give us some color on the genotypes of the PKD patients that are on commercial PYRUKYND? And then, one on the thalassemia opportunity. Any thoughts on the transfusion-independent opportunity now that Bristol has stopped their program in that cohort?

In terms of genotype, a PK deficiency diagnosis can be established through enzyme testing or genetic testing. We don't always have genotype information for all of our PYRUKYND patients, but we are not currently seeing physicians limiting prescriptions based on genotype. Our product label is fairly broad, allowing for prescriptions to adult PKD patients aged 18 and above, which is reflected in our prescription trends. Regarding thalassemia, it is encouraging that we are beginning to see positive experiences with PKD, as the same physician and healthcare professional base will also be involved in thalassemia treatment. The more experience they accumulate with our drug, the better prepared we will be for an approval in the thalassemia space. Our program aims to address both alpha and both forms of thalassemia. We recognize that only a small percentage of the transfusion-dependent beta thalassemia patient population is currently served by luspatercept, and many patients are non-responders. There is a need for a convenient oral therapy. Physicians have expressed significant value in our clinical program, which considers the totality of data, including benefits across a wide range of functions. We see consistent benefits in our proof-of-concept data across all three hemolytic anemias, which we believe positions us well overall. We are optimistic about what we are observing, and Sarah can provide more details on the thalassemia clinical development plan.

Thank you, Richa. From the clinical development perspective, we are optimistic and on track with our thalassemia program. We do not view the recent decision as affecting our program or our chances of success. We have always intended to provide a comprehensive data package for the transfusion non-regularly transfused population, as Richa mentioned earlier. Additionally, our mechanisms of action are quite distinct. While both drugs raise hemoglobin levels, the differences in how they work, along with the data we've been collecting from our various clinical programs, including early indications of an impact on iron overload, reinforce our confidence in our programs and we are proceeding with the same level of confidence in our chances of success.

Great. Thanks. Thanks for that. Maybe a question for Jackie on VOC. You guys aren't considering acquiring GBT? Are you? Or just that's a joke? Thanks for taking the question. Appreciate it.

How about if I laugh in response to that.

Our next question comes from Mark Breidenbach with Oppenheimer. Your line is open.

This is Jaclyn in for Mark from Oppenheimer. Congrats on the quarter and thanks for taking our question. The first one is how many new scripts? What was the monthly retention rate in 2Q? And have you seen any prescription abatement due to payer-related issues?

I didn't catch the beginning of your question, but I can address the second part and come back to the first. You mentioned something about abatement. We haven't observed that patients prescribed the drug are reluctant to start therapy. We enroll patients into our myAgios high-touch support program after they are prescribed the treatment, which helps them initiate and maintain their therapy. Anecdotally, we have seen some patients delay starting therapy due to personal events like weddings or holidays, but there's no significant trend at this early stage. I'm not sure what your initial question was, so if you could repeat that, I would appreciate it.

Yeah. So, how many new scripts? And what was the monthly retention rate for the second quarter?

So, we haven't provided specifics on like this new scripts. What we have said is we have 52 prescriptions, and 37 of those have been filled, which includes both those patients that have initiated in this quarter as well as those that are continuing on from the previous quarter.

Okay. Thanks. And my other question is on the RISE UP trial. With the enrollment in the Phase 2 portion of the RISE UP study to complete by year-end. Can we expect a dose selection decision in the first half of 2023? And what initial data from the trial solely focused on the safety and hemoglobin response, or could we see some of the secondary endpoint data as well?

Hi, this is Sarah. You won't see data in the first quarter of 2023 because the Phase 2 trial has a follow-up period of 12 weeks. All patients need to complete that, undergo their safety follow-up, and then we need to conduct the database lock and review the data. Therefore, it's not feasible for that to occur in Q1. Regarding the data you will see, we are collecting more than just hemoglobin response and safety in that Phase 2 trial as we plan to gather all the data, and I've detailed the secondary endpoints in our presentation. We will analyze all the data to guide our go/no-go decisions for Phase 3, and there are predefined criteria for dose selection as well. Our focus will be on transitioning from Phase 2 to Phase 3, but we will present the data we have at an upcoming medical conference when it's ready, likely towards the end of the year.

Great. That’s helpful. Thank you so much and congrats again on the quarter.

Thank you.

We have a question from Salveen Richter with Goldman Sachs. Your line is open.

Thank you for taking my question. Could you elaborate on the launch trajectory of PYRUKYND in PKD? Are you planning to maintain current efforts to identify patients, or are you implementing new strategies for patient identification? How many patients who test positive with the Anemia ID test actually proceed to PYRUKYND treatment? Additionally, regarding PKD and sickle cell, what is your perspective on the market opportunity and which patient groups do you believe are most suitable for PYRUKYND? Thank you.

I'll begin by discussing Anemia ID and then address other points. It's crucial to note that, from a compliance perspective, we cannot ascertain which physician a PKD patient is associated with. Therefore, it's essential to promote disease awareness and enhance diagnosis over time. Anemia ID is not solely focused on pyruvate kinase deficiency but is designed to address the needs of the community by assisting in the differential diagnosis of unexplained hemolytic anemia, which highlights the value of the test and its usage. We observe ongoing growth in the test's adoption, as the community recognizes its utility in making differential diagnoses to tailor treatments based on the specific type of hemolytic anemia present. For at least one form, pyruvate kinase deficiency, we do have a treatment option available. Regarding diagnosis, it's important to emphasize that pyruvate kinase deficiency is a rare chronic condition dispersed across the country and not confined to specialized centers. Most cases are managed within community settings. Our initiatives, designed with a comprehensive understanding of the disease, focus on raising awareness, educating about the disease's burden, and collaborating closely with our medical partners to disseminate knowledge about the disease to the broader community. Maintaining and enhancing diagnosis efforts will be pivotal in this area, especially for rare diseases. We are witnessing steady progress in diagnosing patients and ensuring that eligible individuals receive treatment, which remains our continuous focus. Now, concerning sickle cell, I will have Sarah provide specific comments on the Phase 3 trial design, which will transition us into discussing how we plan to differentiate our product in that market. Sarah, would you like to discuss RISE UP?

Sure. The Phase 3 RISE UP trial is designed to be operationally seamless, building on what we established in Phase 2. This design gives us a lot of flexibility, allowing us to start bringing sites on board early and prepare them for enrollment quickly. It also enables us to analyze the Phase 2 data and make any necessary adjustments without affecting the trial's statistical or regulatory aspects. For Phase 3, we have two primary endpoints: the hemoglobin response and the analyzed sickle cell pain crisis endpoint. If we meet one or both of these, we can proceed to secondary endpoint testing, which will provide us with comprehensive data necessary to present a meaningful narrative for patients, physicians, and regulators. This approach is consistent with our other trials. The advantage of the RISE UP trial is that it allows us to address both anemia and vaso-occlusive crises, which are crucial in the context of sickle cell disease. We are optimistic that the results will support advancing treatment for sickle cell disease as a whole.

And the one thing I would add to everything that Sarah just said, right, we've designed the clinical studies and are thinking about how we differentiate based on input from what the community has told us, the broader sickle cell community physicians and patients to understand what the needs are and then design the study accordingly. As far as the commercialization is concerned, it depends on the totality of the data before we make any determination around that, but we're designing the study to ensure that we are set up for success.

Thank you.

We have a question from Danielle Brill with Raymond James. Your line is open.

Hi. Good morning. Thanks for so much for the question. I guess a follow-up to a couple of prior, maybe I'll just ask another way. Given your expectations on potential discontinuations at the six-month mark, I'm just wondering if there was a bolus of patients added in 1Q that might impact growth in 3Q? I guess if you could provide some more color on how we should be thinking about sequential revenue growth, that would be great? Thank you.

We currently have 52 patients prescribed PYRUKYND, with a prescription fulfillment time of four to eight weeks. Right now, 37 patients are on therapy, including those who have just started and those who are refilling their prescriptions. They are currently adjusting their dosages. At this time, we’re not going into more specifics. This is our first full quarter since launch, and we have much to learn. We are already gathering insights on what strategies are effective and how both physicians and patients are responding. This will be an ongoing learning process, so it’s too early to make further comments.

And I think we can also just remind everybody there was no bolus of patients in Q1. Majority of patients actually joined in Q2. And so, I think what we're starting to see is we've always talked about this being a slow and steady launch and building this market, and the terrific work of our commercial team is starting to pay off as we're gaining that traction with disease awareness and diagnosis and getting patients on. And I think it's going to continue to be a steady progression, but no bolus back in Q1.

Understood. Thank you.

We have a question from Greg Harrison with Bank of America. Your line is open.

This is Mary on for Greg. Thanks for taking our question. You mentioned that the awareness and the diagnostics of PKD could increase with the awareness of the treatment such as PYRUKYND. Maybe have you been seeing this increase? How are you planning to quantify this? And maybe how long would you expect this increase to take? Thank you.

When considering the advantage, it's important to note that we are dealing with a rare, chronic disease that isn't primarily addressed in specialized centers. It will require considerable effort and time before we can identify specific trends in disease awareness. We've mentioned a leading indicator earlier in this call. We are seeing a significant number of adult PKD patients starting therapy, and this is happening nationwide. This indicates that our awareness initiatives are effective, as both healthcare professionals and patients across the country are engaging with the treatment. Additionally, we are observing gradual growth in the use of our Anemia ID kits, which are crucial for diagnosing unexplained hemolytic anemia and are intended to enhance diagnostic capabilities over time. Both of these developments will contribute positively in the long run. Currently, we estimate that 30% of PKD patients are diagnosed, and we anticipate that this figure could rise to about 70% at its peak, which we expect will take approximately five to seven years. Given the nature of the disease and its widespread distribution, it will take some time before we can provide any specific figures. However, we are seeing trends moving in a positive direction.

Great. Thank you.

There's no other questions in the queue. I'd like to turn the call back for management for any closing remarks.

Thank you, operator, and thank you, everyone for the questions this morning. As always, I would like to wrap up thanking my Agios colleagues for their dedication and passion for making a difference for patients. I also want to thank all of the patients, caregivers, and physicians who partner with us in so many ways and especially those participating in our clinical trials across indications. Our connections across our stakeholders and our collective efforts fuel our ongoing innovation and impact for people with genetically defined diseases. I also need to take just a second and memorialize this moment as my last quarterly results call for Agios in the CEO role and just express again my gratitude to our terrific team for everything that they're doing. It's amazing to have such a great quarter with our first full quarter of launch for PYRUKYND in PKD in adults in the U.S. And there are just so many things that are amazing about this moment. And I'm very grateful for Brian joining the team as I view this as being an additive thing for Agios as he comes in as the new CEO with a terrific skill set to bring into our team, and as I transition into the role of Chair of the Board, remain part of the team. So, with that, I look forward to all of your ongoing support. Thank you for your support in the past and looking forward to a terrific future and many good quarters to come for Agios. Thanks very much for joining us today. You may now disconnect.

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