Ladies and gentlemen, please stand by your conference call will begin momentarily. Once again, ladies and gentlemen, please stay on the line. Good morning, and welcome to the Agios First Quarter 2022 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 Agios request. I would now like to turn the call over to Holly Manning, Senior Director of Investor Relations.

Thank you, Operator. Good morning, everyone. And welcome to Agios's First 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, Richa Poddar, our Chief Commercial Officer, Jonathan Biller, our Chief Financial Officer and Head of Corporate Affairs, and Dr. Bruce Car, our Chief Scientific Officer who will join for Q&A. 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 thank you for joining our first quarter 2022 results call. The first quarter of 2022 was a milestone moment for Agios, as we received the U.S. FDA approval for PYRUKYND, a first-in-class PK activator and the first and only approved disease modifying treatment for adults living with pyruvate kinase deficiency. From the scientists to first hypothesize the potential utility of PK activation, to the chemist who designed our molecule, to the clinical trial coordinators who helped enroll our trials, people across our organization, both past and present, has played a role in this important milestone. In addition, a tremendous number of people outside our organization were instrumental to this effort. Investigators, patients, caregivers, and advocates, all of whom have provided critical insights at every step of the way. Our connection to patients battling this rare, debilitating, lifelong hemolytic anemia, along with the promise of what we can deliver to their treatment options, is the reason we come to work every day. And our connections with patients, healthcare providers, partners, and each other, or how we transformed this idea into a medicine. Looking ahead, we are highly motivated to execute the U.S. Adult PK deficiency launch to the best of our ability. And we continue to believe PK activation has brought potential beyond PK deficiency. A huge focus for our team this year is executing on our aggressive clinical development plan spanning thalassemia, sickle cell disease, pediatric PK deficiency and MDS which Sarah will cover in more detail. I'm also pleased to share that we recently published our 2022 environmental, social, and governance report. In 2020, we published our first ESG report with the intent of disclosing relevant ESG initiatives and metrics from across the company that are aligned not only with our values and our culture but also with the United Nations ' sustainable development goals and the standards for the biotechnology and pharmaceuticals industries set by the Sustainability Accounting Standards Board. Since that time, our ESG program has grown and evolved as we continue to prioritize our commitments to the patients we serve, our employees, our communities, and world and business, ethics, and values. We support an advanced range of the ESG initiatives and encourage you to have a look at our report which is available on our website, agios.com under the corporate social responsibility section. A huge thank you to the cross-functional ESG working group for bringing this year's report to life. To wrap up, our commercial team is enthusiastically in the trenches with our U.S. adult PK deficiency launch, and Richa will update you on those details. Our clinical team is actively enrolling thalassemia and sickle cell patients in those pivotal programs, and Sarah will update you on those. And all our other functional teams are working hard to support the achievement of our 2022 corporate objectives and our strategic vision. With that, I'll now turn it over to Sarah.

Thanks, Jackie. The clinical team has been working extremely hard to execute on our ambitious clinical development plans for 2022. I'll start with pyruvate kinase deficiency where we are proud to be the first company to create a treatment for this rare lifelong hemolytic anemia. 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 addition, our team is actively working through startup activities for two pivotal trials in pediatric PK deficiency patients. We expect these trials to initiate in mid-2022. I'm also pleased to share that data from the core periods of the activate study of PYRUKYND in adults with PK deficiency who do not receive regular transfusion were published on April 14, 2022 in the New England Journal of Medicine. This trial and the ACTIVATE-kids study in PK deficiency patients who are regularly transfused supported the recent U.S. FDA approval of PYRUKYND and continues to generate important data in the extension study about the long term impact of treatments. At the EHA meeting in June, we'll share new PRO data from ACTIVATE, data demonstrating the normalization of hemoglobin levels with long-term treatment of PYRUKYND and additional comorbidities and complications data from the peak registry. Beyond PK deficiency, we believe PK activation has the potential to play an important role in the treatment of thalassemia and sickle cell disease. At the end of last year, we initiated our two global placebo-controlled, pivotal trials of cytokines in T halassemia, ENERGIZE and ENERGIZE-T. As a reminder, ENERGIZE will evaluate 171 patients randomized 2-to-1 to 100 milligrams of metapeva 5 daily for placebo, in both alpha and beta-thalassemia patients, who are not regularly transfused. The primary endpoint is hemoglobin response defined…

Thank you, Sarah. I'm pleased to provide the first quarterly pipeline launch update, where we generated net U.S. sales up $842,000 for the close decrease of launch following approval on February 17th. As we've said before, our commercial launch strategy focuses on connecting with the patients and educating the provider to ensure: First, the patients are accurately diagnosed through [Indiscernible] IV. Second, provisions to understand the urgency to describe an eligible patient’s advocate for treatments, and finally, patients connect to myAgios Support Services to optimize disease understanding in short access, and drive long-term medication endurance. Having been in the field for the last couple of months, our conversations with patients, physicians, and caregivers, continue to underscore the value that we believe BioTime brings to patients living with the disease. And then, [Indiscernible] we have an opportunity to make a goal difference in the likes of these patients with a first-in-class disease-modifying therapy. We have gained important insights in the early days of launch, to help further reinforce that our commercial launch strategy of assets. Since our launching mid-February through the end of the quarter, our team of hemolytic anemia specialists, have had more than 1,100 customer interactions, raising awareness of [Indiscernible] and educating physicians on how this first-in-class PKR activator can be used to benefit the indulged patients with PK deficiency. This positive engagement has been successful in driving scripts for those previously identified features. Our high such Patient Support program, myAgios, has effectively engaged with patients and physicians to begin disease and drug education as well as navigate reimbursement challenges to ensure access and minimize abandonment. In addition, a high priority for us is to drive the [Indiscernible] of PYRUKYND among the patient community. So we have been focused and generating the [Indiscernible] through social media pushes, word of…

Thanks, Richa. Our first 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. As Richa shared, PYRUKYND revenue for the first quarter was $832,000. Cost of sales for the quarter was $339,000. Turning to operating expenses. Research and development for the first quarter was $70.1 million, an increase of $12.5 million compared to the first quarter of 2021. The year-over-year increase in R&D was driven primarily by startup cost for the PYRUKYND pivotal studies in thalassemia and sickle cell disease, and planned increases in preclinical activities, offset by close outs of the ACTIVATE and ACTIVATE-T studies. Selling, General & Administrative expenses were $31.5 million for the first quarter, representing a $2 million decrease over the first quarter 2021. The decrease in SG&A expense was primarily due to lower workforce related spend. TIBSOVO royalty revenue, which is recorded under royalty income from gain on sale of oncology business on our income statement was $2.7 million. We ended the quarter with cash, cash equivalents and marketable securities of approximately $1.2 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. In the current environment, we are grateful for our strong balance sheet, but also mindful to maintain this advantage and ensure the capital necessary to execute on the promising clinical programs and retain flexibility for business development. Consequently, as we begin our annual long-range planning process, a process we kick off in the early spring of each year, to continue to be laser-focused on capital allocation to only our highest priorities, as well as continuing to proactively manage our expense base. With that, Operator, please open the line for questions.

[Operators Instructions]. Our first question comes from Anupam Rama with JPMorgan.

Hey guys, thanks for taking the question. What are you seeing on the reimbursement from for PYRUKYND? And what are you seeing in terms of time to [Indiscernible] into getting onto therapy? And then, what's the phenotype of the initial patients going on therapy in terms of severity, transfusion independence and other things like that? Thanks so much.

Thanks for the question Anupam. So income reinvestment are the conversations with the [Indiscernible] are way positive. And from a reimbursement standpoint as expected, majority [Indiscernible] have been through the medical exception process, we expect that to continue in the second quarter as well, until the payer policies are developed. So overall, I would say, on track and bringing back [Indiscernible] as we expected. Payer policies are still being developed across the board, so it really too early to comment on the specifics of the prior authorization [Indiscernible] management criteria, but we should have details of that in the next few quarters. So stay tuned for more updates on that front. In terms of your question around patient types of very reminiscent of what we would expect against the overall down to PKD patient populations. We are not seeing that there is a high utilization in any specific kind of PKD patient. But what we're seeing, as expected, given the paucity of treatment options and the huge unmet medical need and this being the first approved therapy. We're getting used across a variety of different types of patients, so both are not regularly transfused patients. The regularly transfused patients, are patients that are young, patients that are old, patients that have very different types of symptoms or very representative of the overall patient population.

Thanks so much for taking my questions.

Our next question comes from Marc Frahm with Cowen and Company.

Thanks for taking my questions and congrats on the early launch. Just -- was there any impact from stocking in the quarter or is this -- the 800,000 really true demand in the few weeks that you had in the quarter post approval? And then looking more broadly over the last three months, did you see an initial bolus of demand coming through in terms of start forms or have the start forms really steadily built through the past three years and months since approval?

Yes. So I'll address the second question first. So in terms of the overall dynamics, no bolus, it is as we expected. When patients are showing up, if they have appointments in the positions, they're getting on prior be walking through, they getting connected to the myAgios Patient Support Program, and then navigating to the access portion of it. So a very, very consistent without all the expectations. So no, like everyone's [Indiscernible] to get to the drug base, and [Indiscernible] what we expected just given the nature of the disease. And you'll continue to see the ongoing impact of the pandemic. And knowing that this is a rare chronic condition, you still see prioritization happening in terms of not sufficient to be calling the patients that are waiting for the appointments, and stops to be constantly educating on disease and getting both patients [Indiscernible] a bit about the diseases, whether it's -- they'll be able [Indiscernible] the therapy. So that's [Indiscernible] consistent with expectations. With regards to your question [Indiscernible] could cause of that is represented to be do book sales based on the orders that we get for our distribution partners. So there is going to be fluctuations against first quarter or the quarter. So once we have that sense of like overall [Indiscernible] dynamics will pay out. We should be able to give you a better guidance. But for now, that is represented above. It's a mix. You take some time to get [Indiscernible] and then get [Indiscernible] as well, but this is booked based on orders from distribution partners.

Okay. Thanks and [Indiscernible] and then to some [Indiscernible] what are the adverse event findings that supported the determination of the maximally tolerated dose?

Sure. So we -- as expected in a phase, well, we basically pushed up the dose as far as we can go and we did identify a dose limiting toxicity under the form of thrombocytopenia which was not associated with any other clinical adverse event and which was very monitorable and manageable because everything returned back to baseline when drug was discontinued. And so we also were able, on that data, to actually identify the doses because we had already reached the pharmacodynamics effects we wanted to observe. So we were able to determine a safe dose for sickle cell disease patients and MDS patients that did not have these events. And so we're very excited about it, the operationalizing components of both the sickle cell disease component of the Phase 1 and MDS are well on track.

Okay. Thank you.

Our next question comes from Greg Harrison with Bank of America.

Good morning. Thanks for taking our question. Are you able to talk about how many patients have started PYRUKYND therapy? And what can we expect to see throughout the early launch in terms of metrics like patient starts, discontinuations, duration of therapy, and things like that?

So we are not giving specifics yet, Greg, on the patients that have started. It's still very, very early days of launch trade and it is [Indiscernible] chronic condition. So what we wanted to do is, in order for us to be able to help you more appropriately, we want to look at the trends over time and give you a better of sense once we have a sense of what those trends look like. Right now, as we said, this was -- most of the approval to prepare a process, to the medical exception process of that is taking a while, because we want to make sure that, accurate payer policies get developed and patients have access longer term. So our strategy is working. We are seeing now and we have continued that positive interactions, that is enthusiasm has the anticipated from the patient community and from the physician community for this entire be. [Indiscernible] for more updates in future quarters. It's just too early to tell.

Got it, thanks. And then --

Sorry, it's Jackie. I was just going to -- we're seeing a nice steady flow and things going the way that we expected they would go, just as Richa said. So scripts are being written, we're actually already seeing refills. So this -- I think shows a nice dynamic, because we're only, what, in the second full or moving into the third full month of the launch. Also just remind everybody that, we're using one specialty pharmacy. So this is not a situation where you've got massive distribution network that you're filling a pipeline for someone. Just to be clear and sorry, I didn't mean to interrupt you.

Thanks. That's helpful. The other question I had was whether you -- I know it's very early, but if there's been any noticeable increase in disease awareness? And what do you expect to be the impact on diagnosis rates as people become more aware that there is a treatment available?

So I would say on the disease awareness, it's trending into right direction. We have updates as we collect data overtime because, you know, it's already been first quarter of full launch. When regards to diagnosis rate that's something that takes years to track, right. So you would not expect us to provide updates on that necessarily on a quarterly basis. The one thing I will say about that is our efforts around any idea particularly important and the reason why we keep -- we're very encouraged by the interest we see in that program. Because that is one avenue we have available to us to really help both with our efforts and on disease education, but also to ensure accurate diagnosis which will enable [Indiscernible] improvement in the diagnosis rate. So that we've continued to see steady growth and steady interest, so that's exciting for us. And that being continue to remain our focus.

Great, thanks again.

Our next question comes from Mark Breidenbach with Oppenheimer.

Hey. Good morning, guys. Thanks for taking the questions and congrats on the launch. Just a quick couple of quick ones for me. Can we expect cost of sales as a percentage of revenue to come down a little bit in future quarters? I guess I'm wondering where you're seeing that might stabilize to. And just with respect to SG&A for the quarter which was pretty flat versus the previous quarter, does that kind of imply that all the commercial infrastructure and all the hirings that needed to be done to support PYRUKYND launch had to have been completed at this point? Thanks for taking the questions.

Hi Mark, this is Jonathan. I will take your questions in order. So cost of goods, yes. You'll see that as volumes go up, you'll see cost of goods come down, because we have a fixed costs that become more leveragable, as demand picks up and the launch progresses. So that number will come down and it's a small molecule. So you'll see ultimately, similar to like what we had with TIBSOVO, for you should see become very healthy gross margins. And on SG&A, yes. We've been -- we worked hard last year and we're still working to make sure that we have the right cost base to run our business efficiently and allocate our capital to the highest priorities, which are the launch and what we're very excited about, clinical development across Dallas senior sickle cell and MDS. And Richa had her team on board really by about the middle of last year. And so, that is the run rate you'll see. And I think, overall on OpEx generally, you should see pretty consistent numbers through this year. We're not it's -- you're not going to be seeing numbers going up. It will be a -- there's always a little bit of fluctuation quarter-to-quarter, but it should be pretty flat or maybe even some quarters could even come down a little bit. So it's a very good indication, I think, of where you can kind of model going forward.

Thank you so much.

Our next question comes from Salveen Richter with Goldman Sachs.

Hi, thanks. This is Matt on for Salveen. Could you please provide some color on where you stand in the patients enrolled in the Phase 2 portion of RISE UP, ENERGIZE and ENERGIZE-T. And then separately when can we expect to look forward to any clinical catalysts from Agios source to academic collaborators this year? Thanks a lot.

Sure, so well, for both our ENERGIZE, ENERGIZE-T and RISE UP studies, we're very happy that we've enrolled first patients and then we're focused on really global site activation and realizations in those strides. We don't provide specifics on each enrollment number as we go along, but we are on track to meet our milestones as we had outlined before. And so I'm very excited about to work that's going on there. And then the second part of the questions I didn't hear.

Yeah, the second part of the question.

Can you repeat the second part of the question, please? Sorry.

Data.

Oh, the data catalyst, yes. Right now, the execution thesis is ongoing. The Phase 3 ENERGIZE and ENERGIZE-T are blinded and there's no interim plans, so there's no immediate data catalyst coming from there. A big one for us is going to be the Phase 2 study of RISE UP which is for next year. And then we have of course -- we have multiple based up presentations outlining data from across our programs that we're super excited about our single abstract will drop next week actually, so we're very excited about that.

Great, thank you.

Our next question comes from Andrew Berens with SVB Securities. Andrew, your line is open, you can ask your question.

Can you hear me? Great. Congrats and thanks for taking the question. I was just wondering a few on the launch. Do you know how many scripts were written that generated the $800,000 in sales? And then I wanted to get some color on the addressable market that you highlighted in the prepared remarks. I think you said up to 4,000 patients in the U.S. In the past, you've talked about a registry of identified patients that are around 1,100 to 1,200 patients. So these 4,000 patients, have they've been identified or is it a hypothetical calculated prevalence. And then one on 946. How [Indiscernible] did the platelets go at maximum tolerated dose, and do you know the [Indiscernible] over the [Indiscernible] beside the penia. I don't think we've seen it with any of the other PKR drugs that I'm aware of. And is it off-target or on-target.

Okay so with regards to your question around [Indiscernible], we're not providing specifics on that. The agency will tell you what it feels to distributors. That being said, over time, they will translate the reason why they has those sales is because there is patient demand and those are translating overtime into patient script. So once they have better sense of the overall trends, we would provide information on that on an honorably basis. So stay tuned for more updates on that as we learn more. But there's some inventory dynamics again, obviously. Too early to say, but as Jackie, also pointed out, we only have one distributor so you don't have massive swings in inventory that are happening. It is reflective overall patient demand. It will just take time for us to see that point through but now it's booked to be starting from an accounting standpoint both based on the fields to distributor. That's your first question. Second question around the overall prevalent in PK deficiency. As we mentioned in previous calls. Over all because it is a rare disease, it's poorly understood, not well characterized, under chronic condition. We have to work with five meters with a broader patient community because we already have to understand what the theoretical prevalence might be in this disease. And we've taken and triangulated data from a lot of different sources, which gives us confidence that the peak potential for pyruvate kinase deficiency is in that range of 1500 to 4000. For the purposes of the U.S. we usually say peak, we should consider them a point of that rate, somewhere in that 3,000 and we feel pretty good about that number from a [Indiscernible] with covenant standpoint. That doesn't mean we've identified those many patients being said before that the diagnosis rate is about 40% at this point and our efforts, both pre -launch and they continue forever in this disease space have been focused on improving disease commonality and also driving up that diagnosis rate to efforts [Indiscernible] and I can give me IT.

And we've said in the past as well, there, we believe that it's -- there's a like number of patients in Europe also. So I think it's or has talked about 3,000 to 8,000 between the U.S. and Europe and about -- it's about half and half in each geography with 3,000 in the U.S. as Richa said being kind of at the midpoint of that [Indiscernible]. But only 30% of guidance today.

And what would be the phenotype of these patients? Are they patients that are getting transfusions? What is the cutoff that you're using?

[Indiscernible] cutoff, this is basically everyone, right? Everyone that we believe has pyruvate kinase deficiency based on our work with the broader PK deficiency community. Within that, you have about 80% of patients that I doubt so there's no reason for us to believe that the adult PKD patients’ combination is different than your average population in the United States with represented of back-to-back split is 80% adults which is where we have our label. As you may have heard from us before, we are evaluating and planning on initiating studies in the pediatric population which will enable us to address the entirety of the PK deficiency population. But for now, we have an approval and what the commercial team is focused on is the adult PK deficiency which is represented by 80%. So overall, just that's the [Indiscernible] that focuses around disease education and driving [Indiscernible] of the approval of therapies, so both of those activities are ongoing right now.

And then in regards to questions around 946. So it's a stage one study that we really pushed sub the dose for the events that we observed with that adult that we're not planning to use. So in regards to what is the possible hypothesis we've been thinking about, but then because these are doses that we're not going to use, we're not going to further explore that, especially because the event is very monetizable and manageable, and the physicians that are actually working on the diseases that we're exploring are comfortable managing things like this as well. So we have not observed thrombocytopenia in the context of PYRUKYND, for instance, and so you will not see that reflected in our label. And in regards to 946, as mentioned, the doses that we selected are lower than the doses at when this was observed, and we're on track to initiate those studies.

Okay, thanks for answering all the questions and congrats again, on the early launch.

Our next question comes from Danielle Brill with Raymond James.

Hey guys. This is Alex on for Danielle. Thanks for taking our question. A question on anemia ID, and you said that 3,500 kids, have all of those kids been filled, like a -- are those just ordered or if it's actually been processed? And do you have the type of information available to say, how many of those identified patients in the hit rate had a prescription written, started treatment? And then, a detail on 946, can you reveal the maximum tolerated dose in the healthies and / or the doses chosen for the SCD cohort? Thanks.

With regards to AnemiaID, as we've mentioned, its 3,500 kits ordered but on a quarter completed. Physicians may be ordering the kits and knowing that they have patients that will come to their practice in the future. And so not all of them have been completed. And as we also said in our remarks, this is about mid-single digits in terms of the positivity rate, which again is based within our expectations, because we have -- knowing that AnemiaID is designed for hemolytic anemia, a known titolo genetics, it's not specific to PK deficiency. We were expecting the range to be in that side of mid-single-digit range. It's not the expected there either. What we are encouraged about is for the physician fee. This has good at patients. And the fact that we're continuing to see strong interest in the program and utilization. In terms of the direct conversion of the AnemiaID patient found into like a script, that process takes a little bit of time. You find a patient then have to find where the physician that has the patient and then the physician has to call the patient in, the patient has to be willing to go in and on of that. We've been following that and keeping track of all the patients we found through the program and ensuring that we are connecting to the physician's knowing that we have followed up with the patient. And then those conversations resulted in a script, but you can just dread, it takes time before that happens.

In regards to your question, regarding the dose assistance, we will disclose all of the details around our healthy volunteer to spending on an upcoming medical meeting. What I can tell you around the dose selected for sickle cell disease and MDS is that, for sickle cell disease, the protocol was already written and for MDS actually, as well. And we did not change any of our dose selection criteria based on the events observed.

Okay, great, thank you.

And I'm not showing any further request time. I'd like to turn the call over to Jackie for any closing remarks.

Thank you, Operator. And thank you, everyone for the questions this morning. As always, I would also like to thank my Agios colleagues for their dedication and passion for making a difference for patients. I also would like to thank all patients, caregivers and physicians who partner with us in so many ways. And especially, those participating in our clinical trials across all indications. Our connections across all of our stakeholders and our collective efforts together, fuel ongoing innovation and impact for people with genetically defined diseases. Thank you for joining us this morning. You may now disconnect.

Ladies and gentlemen, that concludes today's presentation. You may now disconnect. Have a wonderful day.