Good morning, and welcome to Agios’ Second Quarter 2023 Conference Call. At this time, all participants are in a listen-only mode. There will be a question-and-answer session at the end. Please be advised that this call is being recorded at Agios’ request. I would now like to turn the call over to Chris Taylor, Vice President, Investor Relations & Corporate Communications for Agios.

Thank you, operator. Good morning, everyone, and welcome to Agios second quarter 2023 conference call. You can access slides for today’s call by going to the Investors section of our website, agios.com. On today’s call, I’m joined by our Chief Executive Officer, Brian Goff; Dr. Sarah Gheuens, our Chief Medical Officer and Head of Research and Development; Tsveta Milanova, our Chief Commercial Officer; and Cecilia Jones, Chief Financial Officer. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements, actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of 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. And with that, I will turn the call over to Brian.

Thanks, Chris. Good morning, everyone, and thank you for joining us. Agios is focused on delivering transformative therapies for patients living with rare diseases, and in particular we are the pioneering leader in PK activation focused on hematologic diseases. In the second quarter, we made significant progress advancing our industry leading pipeline of PK activators, targeting hematologic diseases that share a common underlying pathophysiology. With each step forward each data readout the probability of success for the platform has strengthened, and we are excited to share our updates with you today. As we articulated at the beginning of this year, we are prioritizing potential business development opportunities based on five key criteria, rare disease focus, transformative for patients, and identified regulatory pathway, potential to de-risk early and a clear path to value creation. Earlier this morning, we were very pleased to announce a license agreement with Alnylam Pharmaceuticals, the leading RNAi therapeutics company that is highly aligned with these five criteria. Under this agreement, Agios will acquire the rights to develop and commercialize Alnylam novel preclinical siRNA for the potential treatment of Polycythemia Vera or PV. PV is a rare and potentially fatal hematologic disease that affects approximately 100,000 patients in the U.S. and for which phlebotomy is the standard of care. Our goal is to address the high unmet need in PV by delivering a convenient disease modifying treatment option that reduces or eliminates the need for phlebotomy. This agreement is therefore aligned not only with our business development strategy, but also our core scientific expertise and clinical and commercial capabilities in rare hematology. We look forward to initiating IND enabling studies later this year. Sarah will provide more detail on the siRNA development candidate in just a few minutes. Also, this quarter we announced positive results from the…

Thanks, Brian. Sickle cell disease is a serious, potentially fatal hematologic disease that affects approximately 120,000 to 135,000 patients in the U.S. and EU5. Today, there are no novel oral treatment options that both improve anemia and reduce sickle cell pain crisis, and that is what we aim to deliver for these patients. Turning to the top line data of the RISE UP Phase 2 study treatment with Mitapivat demonstrated a statistically significant increase in hemoglobin response rate compared to placebo. Hemoglobin response was defined as an increase of one gram per deciliter or more in average hemoglobin concentrations from week 10 through week 12 compared with baseline. 46.2% of patients in the 60 milligram BID Mitapivat arm and 60% of patients in the 100 milligram BID Mitapivat arm achieved the hemoglobin response compared to 3.7% of patients in the placebo arm. These increases in hemoglobin response were accompanied by improvements in markers of hemolysis and erythropoiesis, as well as numerical reductions in the analyzed rate of sickle cell pain crisis for this 12 week study. Specifically, patients in the placebo arm experienced an analyzed rate of sickle cell pain crisis of 1.71 compared to 0.83 in the 50 milligram arm and 0.51 in the 100 milligram treatment arm. The safety profile for Mitapivat observed in the study was generally consistent with previously reported data for Mitapivat in other studies of sickle cell disease and other hemolytic anemia. And there were no adverse events leading to discontinuation in any study arm. And finally, of the 79 patients enrolled in the study, 73 continued in the Phase 2 open-label extension. These data further underscore the potential of Mitapivat to address the high unmet need of patients with sickle cell disease by delivering a novel oral treatment option that both improves anemia…

Thank you, Sarah. Our commercial organization remains focused on maximizing the opportunity in the current launch in PK deficiency by executing on our strategy across all phases of the patient journey. The capabilities we are building today on disease awareness and education, access and initiation, and adherence and persistency will also serve as a foundation to fully realize the potential of anticipated future launches in Thalassemia sickle cell disease and low risk MDS. Our market research data continue to indicate that nearly 100% of our target healthcare providers are likely to recommend PYRUKYND to their adult patients with PK deficiency. For clinicians, key drivers of these recommendations include improvements in hemoglobin level, reduction in transfusion frequency, and a positive impact on long-term disease complications. To better understand the treatment experience on PYRUKYND, we recently conducted interviews with a sample of patients or their caregivers. Most patients reported positive experiences including improvement in hemoglobin and in energy levels, reduction in fatigue and decreased transfusion burden. Importantly, this feedback from both patients and clinicians is consistent with the strong persistency of treatment use we observe in the real world after the initial payer reauthorization. Moreover, discontinuations remain low and reauthorizations have not been a barrier. In the second quarter of 2023, we generated $6.7 million in net PYRUKYND revenue. A 20% increase over Q1 this year, a total of 147 patients have now completed a prescription enrollment form or PEF, including 20 in the second quarter of 2023, a 16% increase versus the first quarter of 2023. This has translated into net 99 patients on therapy, an 11% increase of over last quarter. Patients on therapy continue to stem from a growing and the reverse provider base of 130 physicians and represent a broad demographic and disease manifestation range that is consistent…

Thanks, Tsveta. Our second quarter 2023 financial results can be found in the press release we issued this morning and more detail will be included in our 10-Q which will be filed later today. I would like to take a moment to provide some context and highlight a few points. Second quarter 2023 net PYRUKYND revenue was $6.7 million, an increase of $1.1 million compared to Q1, 2023. As PYRUKYND is the first therapy for this ultra rare adult PKD patient population we continue to gather data and insights on the launch trajectory and will therefore not be providing guidance at this time, but we continue to expect a slow and steady trajectory to peak. Consistent with other rare disease launches, growth to net is expected to be in the 10% to 20% range on an annual basis. Cost of sales for the quarter was $1.1 million. Moving to expenses on the balance sheet, R&D expenses were $68.9 million for the second quarter, a decrease of $5.6 million compared to the second quarter of 2022. This decrease was primarily driven by a decrease in workforce related expenses as a result of reduced headcount related to the evolution of a research organization. SG&A expenses were $30.4 million for the second quarter, an increase of $2.1 million compared to the second quarter of 2022. That was primarily driven by an increase in stock-based compensation expense. As a reminder, TIBSOVO Royalty has ceased given the sale of a right to 5% royalties on U.S. net sales of TIBSOVO to Sagard in October, 2022, and as part of the divestiture of our oncology business to Servier, we retain rights to a potential $200 million milestone upon FDA approval of Vorasidenib and 15% royalties on potential U.S. net sales. We ended the quarter with cash,…

Thanks, Cecilia. This was a tremendous quarter at Agios. We announced positive Phase 2 data in sickle cell disease, completed enrollment in three clinical studies in licensed, a compelling external program that has the potential to transform the course of a rare hematologic disease with profound unmet need, and we continue to strengthen our commercial capabilities to support future launches. The data we continue to generate across our industry leading pipeline of PK activators remain consistent and compelling, and we continue to make meaningful progress towards our vision for Agios, which is to develop an established hematology franchise with approval spanning three hemolytic anemias and an expanded portfolio fueled by business development and advancement of our internal pipeline that is aligned with our core expertise and rare disease. As always, we will continue to strive to be responsible stewards of our balance sheet and evaluate meaningful opportunities for value creation. Finally, I would like to thank all of our employees for their hard work and dedication to our mission of transforming the lives of patients living with rare diseases and all of our partners, including the physicians, patients, caregivers and participants in our clinical development programs. With that, we will open the call for questions.

To start off, curious what factors led you to the decision to license the PV treatment from Alnylam and is this a model for future BD in terms of development stage, and having the potential where you could add your own expertise and value and then would you expect this asset to be broadly applicable across PV patients, or would it be more focused on the specific patient population?

Yes, it has been a great quarter and I’m happy to provide some comments around the deal that we announced this morning. Polycythemia Vera is a large market. We believe it is ripe for disruption and growth. And as I noted in my comments, you know, if you just think about the standard of care, it is phlebotomy and to us, that is just a great opportunity to do what we do best, which is reinvent the way that these rare diseases are treated and bring potential disease modifying therapies to these patients. So we are really excited about this particular ten per six assets from Alnylam. It fits really well with our discipline BD criteria, builds on our core capabilities and that is across our scientific expertise, our development capabilities, our commercial capabilities. And if you think about the BD criteria that we have talked about so many times, it checks all the boxes. So this is a rare disease. It is transformational potential for patients. We see an opportunity for early de-risking, which we have talked about a lot as a sweet spot for us. We believe there is a clear regulatory pathway. And ultimately this will be value creating is our strong belief because it comes from the Alnylam, you know, world-class RNAi platform. We also have strong conviction in the probability of success from the data generated to date. So we are excited about this. I guess to your question of where we go from here for clinical development, I think, and I will ask Sarah if she wants to make a comment. But it is a little too early for us to define the target product profile specifically. We have many options. We will be looking at efficacy dimensions, speed of action, for the product itself, for patients, safety profile, and of course convenience. And all of those are in play. But given the stage of development, we are just going to pause and bring the asset in, really look at it deeply for what, where we can put our development expertise in motion and then we will provide updates accordingly. And then the last thing I will just say to your point about is this a theme of the types of BD deals and so forth going forward. We retain optionality for a range of different BD deals. This one in particular really, as I mentioned, checked all the boxes and so we were eager to bring it in, but we will retain our disciplined BD criteria going forward. Sarah, anything you wanted to add?

Only to say that, you know, we are very excited about this. Of course, once we move forward with the program and have more details on our clinical development program. We will always be shooting to deliver value for patients and make a meaningful change with the development program, and you can expect execution on the program as well.

And we are excited to do that.

Our next question will come to the line of Gregory Renza from RBC Capital Markets.

Maybe just a couple quick ones for me, just following up on the in license on my own asset, maybe it would be helpful just to hear your thoughts and Sarah just, just on the preclinical data today certainly, others exploring manipulation of TMPRSS6. And just curious, how you think this asset can potentially differentiate or sets up well when you survey the available data to-date. And then secondly, great to see the dose selection for the Phase 3 and sickle. Just curious, just the rationale as you looked at the body of data over the last several weeks since the top line and made the step for 100 mg, thanks so much and congrats again.

Thanks a lot Greg. And I’m going to send this over to Sarah then for both questions.

Yes, thank you. So around the preclinical data, it has demonstrated in Vevo proof-of-concept in non-human primates with a safety profile that was very favorable and very good knockdown of the target observed. So we feel very confident about that. And as we mentioned earlier, we are very eager to get going on the IND enabling studies and the CDP, and provide more detail on that as we progress with that. I think for us, yes, there are others that are also looking at this target. To Brian’s point, this is a very big market. There is going to be differentiation around efficacy, safety, mode of administration, and also frequency of administration. So we believe that our CDP will be able to deliver on what the market needs. And yes, again, very excited to get going on this. For your second question around Phase 3 dose selection for sickle cell disease, obviously, we are very excited about the data of the Phase 2, and we are very fortunate to have both doses show benefit risk. Profile that was favorable. We have pre-specified criteria in the protocol and the team had time to now look at all of the data. So we followed that framework and selected the 100 milligrams. We have not disclosed further details on the data. We mentioned that we have submitted the abstract to ASH, and so are now awaiting the outcome of that. And then we are hopeful to be able to provide all that detail at that conference.

And Greg, maybe I will just tag on too and say, I always love to take the opportunity to speak with pride about Sarah and her entire R&D team. This is just a great example of the excellence operationally that we have and the efficiency of the design of the RISE UP Phase 2/3 trial and the fact that we were prepared for both doses. We were thrilled to see that both doses were effective. And now that we have the 100 milligram dose, the fact that we can proceed in the fourth quarter with the first patient dosed in the Phase 3 trial, I think is again, just a mark of excellence and a real point of pride for the organization.

Our next question comes line of Divya Rao from TD Cowen.

Just two from us. We are just curious, what do you define or how do you define success in the MDS trial? I know that there are other, you know, several mechanisms that are being tested in this space. Do you view those as competitive or do you see those more as opportunities maybe to build combinations with AG-946. And then I have a follow-up.

Yep. Thanks Divya. I will just start by saying, as is the case with all the disease areas that we are focused on, we have a very different mechanism of action with pyruvate kinase activation. And of course, you know, the question for low risk MDS, this is with our other PK activator AG-946, and I know Sarah will be eager to talk about what we are awaiting in terms of the Phase 2a data.

So, yes, thanks for the question. So I think for the MDS program, one, I want to highlight here again that the team has done an amazing job on enrollment of that Phase 2a program. I think it also highlights the enthusiasm of the investigators for this mechanism of action for MDS patients. We have not declared our framework for MDS to define success, but it is a Phase 2a. So we are indeed looking for a signal of efficacy and favorable safety and then our setup if that is there, then we are set up to move fast into a Phase 2b in which we will do a proper dose finding. It is indeed a market that is evolving, and it is, I think it speaks to that this is also a market that is ripe for a change. And we do believe that with this very differentiated mechanism of action, which is not being currently studied by, or not assessed far advanced by others, that we really are set up for success there as well. And then I think what cannot be underestimated is that ours is also an oral therapy, which provides a convenience of use for a patient population that is typically an older patient population.

That is really helpful. And then just a quick question on the sickle cell program, could you remind us on if you just closed the powering assumptions for the Phase 3 trial and then have you discussed the 100 milligram dose with the FDA or is that just mostly based on internal discussion and analysis of the data?

So for the sickle cell disease program, the 100 milligram dose, so right now, this is the internal framework that we have applied and all of the data that have assessed, we are very excited about an end of Phase 2 meeting with the FDA. We always look forward to our, the constructive dialogue that we have together. And, you know, it is always great because I do feel like we are all wanting the same thing, right. For across all of our programs we are really shooting to deliver medications that have a favorable benefit risk and can provide change to patients. So we are always very pleased with the constructive dialogue that we have. In regards to the powering assumptions. So obviously the Phase 3 is much bigger sample size than the Phase 2. So there is two endpoints there for the primary endpoint, the hemoglobin endpoint we use in leverage our internal data, for all of the statistical underpinnings. And then for the VOC obviously we have been looking at other programs to make powering assumptions there and are looking to make a meaningful change on VOCs for patients.

Our next question comes from the line of Salveen Richter from Goldman Sachs.

This is [indiscernible] for Salveen. Just one question from us on the licensing agreement with Alnylam. Given the novelty of the siRNA modality for Agios, what gives you confidence in the clinical development process?

So, thanks for the question. So I think it gives us confidence, because we do have internal expertise that have worked on this modality, but also many other modalities. So it is not like while this is a new compound or modality for Agios, it is not a new compound for Agios employees. And so we are looking forward to putting that internal knowledge to work. And I do think in the context of endpoint patient populations, all of that, it is straight into our wheelhouse of hematology drug development. And so, we are looking forward to putting those skills to work there as well.

Our next question will come from the line of Andy Berens from Leerink.

My questions are also on the MDS program. I was wondering if you could give us some overview of how you see the PKR class in MDS. I think, luspatercept is actually doing pretty well in that indication with sales over 700 million in a subpopulation. Can you give us the physiological rationale for the PKR class in MDS, as well as how you see it potentially being used relative to the EPO agents? And lastly, I know it is early, but how do you think the usage of EPO agents in that disease hypothetically impacts pricing power?

Yes. So Andy, thanks a lot for the question. I will just start by reinforcing what you just said. We find it a very attractive opportunity, based on the current incumbents and the progress that they’re making. The patient population, as we had on one of our slides, we identify as 75,000 to 80,000 patients across the U.S. and EU5. It is another disease that is ripe for disruption and coming in with PK activation, a very different mechanism of action. And as Sarah has noted a couple times already, on top of all that as an oral small molecule, we think has significant potential to be differentiated. But of course, we are going to be guided by the 2A data. You want to comment further, Sarah?

Well, just on the part of the rationale why we believe PK activation may work in MDS, it is truly there are similarities between MDS and Thalassemia that and we obviously have now progressed in Thalassemia quite well. So that is one piece. The glycolytic pathway is impacted in MDS patients at multiple levels, which we believe we can influence as well. There is hexokinase to PYRUKYND ratio disruptions. There is also a fact that MDS patients often have an acquired PK deficiency. So there is a multitude of reasons why we believe PK activation may provide benefit. We have published data on this at EHA, at ASH, and hopefully more to come at Ash. So we are very excited about, you know, the evidence that we continue to build in this disease.

And Andy, I will just, one other comment I will add is our team goes deep across many potential therapeutic areas that we are focused on. And, you know, sitting with us today, we have Tsveta Milanova, our Chief Commercial Officer who actually has been very involved in this space. And so it is early, of course, we are looking at Phase 2a data, but beyond that, Tsveta will be able to add a lot of insight and expertise in not just the commercial profile of the product, but also as you asked about, you know, pricing down the line and how we maximize the value creation. So we feel like we are really well prepared and cannot wait for this upcoming milestone by year end.

Our next question comes from Tess Romero of JP Morgan.

I thought I would ask a commercial one today, for PYRUKYND as you grow patients on drug, just trying to get a sense of how you think about trajectory of new patient adds here. It sounds like the drop off is pretty low. And do you think this run rate of 10 or so sequential net patients adds, like you’ve seen in the last couple quarters, is the right way to think about the launch going forward versus something maybe more accelerated given some of the initiatives on analytics, et cetera?

Yes, thanks. So Tsveta is thrilled to have a question about commercial, so I’m going to let her comment.

Hi Tess, good morning. So, as you said, we continue to make progress on the launch. Most importantly, we continue to see the strength of the PYRUKYND profile in the real world, especially when it comes to persistency, the positive provider feedback and the payer support. At the same time, we also know that PKD is an ultra rare disease. And as we said through our opening remarks, we would expect to continue to see slow and steady uptake. We will expect to see some variability quarter-over-quarter. But our efforts continue to be laser focused on identifying the right providers, providers who are likely to have patients with PK deficiency and patients who are appropriate for PYRUKYND either today or potentially in the future. And this is where our efforts in data and analytics continue to support our team as we continue to execute in the field. Very importantly, all the capabilities we are building today serve as a very good foundation for us as we continue to look into the future and potential future indications, expungement for PYRUKUND such as Thalassemia as well.

Yes, I mean the only thing I will just add, Tess, is that this is a very unique kind of launch. It is pretty far on the ultra rare spectrum. And we are building learnings from it. But I would look at it as slow and steady growth and we always caution to just be a little bit careful over quarter-over-quarter because it will be lumpy for quite some time. But we are very proud of the progress that Tsveta and the team continue to make.

Great. And if I can just squeeze in a commercial follow-up there, you know, given these dynamics, how do you think about providing longer term PYRUKYND guidance. Is that something you feel like you may be in a position to do as we kind of exit 2023 and get into next year?

Sure. Thanks. Cecilia, you want to take?

Yes, I can take that. So, you know, as we mentioned before this is for a ultra rare first therapy and we continue to learn data and insights. At this point, we are not going to give guidance. There will come a point, we will continue to evaluate when it is the right time to do that.

Yes, our anchor point, as we have talked about peak sales, 200 million to 225 million in the U.S., that is where we feel confident. We want to get more quarters under our belt until we give guidance on the revenue for PKD. And of course, the bigger picture for us anyway, is that we are approaching the readout of the Thalassemia data. That is a meaningfully larger launch that has potential in 2025. And we may be in a scenario we start to look at the collective guidance of multiple launches.

Our question comes from Danielle Brill of Raymond James.

I also have a question on the in license asset. So I know there are also antibodies targeting TMPRSS6 in development. I was wondering if you could elaborate on why you think siRNA maybe a superior modality in this indication. Is it just a more convenient dosing regimen or do you think there might be an efficacy advantage as well? Thank you.

Well, so thanks a lot Danielle, for the question. We think there are, as I noted earlier, potentially multiple opportunities for differentiation. TMPRSS6, we feel is now a well-established pathway. I mean, very simply the 90% knockdown of TMPRSS6 has an uplift effect on hepcidin, which decreases iron, which ultimately lowers the red blood cell production. That thread through that mechanism, we feel through all of our diligence, very confident in, and as I said, I think there will be opportunities for efficacy, safety of course will be -- that is one, when you look at some of the current opportunities therapeutically for patients, there is plenty of room for improvement. And then it could wind up also being a meaningful convenience opportunity because siRNA classically and particularly from the Alnylam platform, has proven that, that is a mechanism that has delivered benefit to patients with lower interval of treatment. But we are going to look at all of that very early, and we will start our IND enabling studies this year, and then we will report out our progress accordingly.

Thank you. And we are showing no additional questions, so we will turn the call back to Brian Goff for a final comment.

Alright, well thank you all very much for participating in today’s call, and of course for your continued interest in Agios. As you heard this morning, we are really energized by the tremendous progress we continue to make across our portfolio. We are confident in our potential to deliver significant long-term value for both patients and shareholders. So thank you very much again, and we look forward to speaking with you soon.

This concludes today’s conference call. Thank you for participating. You may now disconnect. Everyone have a great day.