Agios Pharmaceuticals, Inc. (AGIO) Earnings Call Transcript & Summary

Good morning and welcome to then Agios' webcast and conference call. [Operator Instructions] Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Agios' Chief Financial Officer, Cecilia Jones.

Thank you, operator. Good morning, everyone, and welcome to Agios' webcast to announce top line results from the Phase II RISE UP Study of mitapivat in patients with sickle cell disease. You can access slides for today's call by going to the Investors section of our website, agios.com. On today's call, I am joined by our Chief Executive Officer, Brian Goff; Dr. Sarah Gheuens, our Chief Medical Officer and Head of Research and Development; Dr. Ahmar Zaidi, Agios' Medical Director, Clinical Development and Research; and Tsveta Milanova, our Chief Commercial Officer. Before we get started, I would like to remind everyone that some of our statements -- we make 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 Brian.

Thanks, Cecilia, and good morning, everyone, and thank you for joining us for this call today. Today is an exciting day at Agios as we continue our pursuit to reinvent how rare diseases are treated, continuing on the path of our success developing the first disease-modifying treatment for adult patients with PKD, achieving full enrollment of our broad Phase III trials in thalassemia and today's focus, our RISE UP Study in sickle cell disease. Sickle cell disease is a serious and historically underserved hematologic disease that affects approximately 120,000 to 135,000 patients in the U.S. and the EU5 and for which there are no novel oral therapies that improve anemia and reduce sickle cell pain crises or fatigue. As you may have seen in our news release this morning, we are pleased to announce positive results from the Phase II portion of the operationally seamless Phase II/III RISE UP Study of mitapivat in sickle cell disease. With these results, we are now in a position to move efficiently into Phase III by leveraging the existing clinical trial sites infrastructure. This is yet another data set in the first placebo-controlled data in sickle cell disease that demonstrates continued consistency of results across the therapeutic areas we're exploring. Ahmar and Sarah are here to walk us through the data, so I will not preempt their commentary. I will note that we are delighted to share with you the top-level readout of the Phase II study to provide clarity into our decision to move forward as our team looks forward to presenting this in more detail at a medical conference as soon as possible. On a personal note, I certainly do want to extend sincere thanks to all of those involved in this study; the site coordinators, clinical partners and the extensive team at Agios and especially each and every patient who participated or tried to participate. At Agios, we like to say that our success is based on connections, and that is never more apparent than at an important data readout like today. Now I am very pleased to introduce Ahmar Zaidi, Agios’ Medical Director and sickle cell disease clinician and thought leader to walk us through the data readout. Ahmar?

Thanks so much, Brian. Similar to what Brian had just mentioned about sickle cell disease, I want to frame our conversation by just spending a little bit more time talking about sickle cell disease as an underserved indication with a significant unmet need. It's estimated that there are approximately 100,000 individuals in the U.S. and almost 300 million worldwide living with sickle cell disease. But this likely represents an underestimate due to lack of rigorous surveillance programs and variable newborn screening activity. Sickle cell disease, by its nature, is a catastrophic hemolytic anemia that results in premature mortality. The anemia is driven by the hemoglobin S mutation that results in formation of polymers that change the structure, function and overall survival of the red blood cell. There are a tremendous amount of clinical complications of sickle cell disease that include, but are not limited to, anemia, vaso-occlusive crisis, acute chest syndrome and acute and chronic end organ damage. Mitapivat is an oral small molecule allosteric activator of pyruvate kinase with the potential to optimize RBC metabolism. The energy-generating process in the red blood cell known as glycolysis is key to allow the red blood cell to carry out its cellular functions and allow it to remain healthy and [ deformable ]. The final step in this energy-generating process is driven by the enzyme pyruvate kinase. In sickle cell disease, it has been observed that this enzyme functions suboptimally. Mitapivat activates pyruvate kinase, which in turn generates more expendable energy for the red blood cell to use. As the entire energy-generating process becomes more efficient unexpected reduction in 2,3-DPG provides an anti-sickling effect by modulating oxygen affinity of hemoglobin. This bimodal mechanism of action is what makes mitapivat a potentially powerful drug in sickle cell disease. RISE UP is a Phase II/III operationally seamless trial of mitapivat in sickle cell disease that allows for speed and flexibility of our clinical program. The Phase II study has a 1:1:1 randomization to mitapivat at 50 milligrams BID, mitapivat 100 milligrams BID and matched placebo, intending to randomize 69 patients. The double-blind period was 12 weeks with a primary endpoint of safety and increase in average hemoglobin of 1 gram per deciliter or more from week 10 to 12 compared to baseline. Secondary end points were related to markers of hemolysis and annualized sickle cell pain crises. Following Phase II, patients were eligible to enroll in a 2016 week open-label extension. I'm very pleased to say that the Phase II portion of the RISE UP study has achieved its primary endpoint of hemoglobin response for both 50- and 100-milligram doses. The RISE UP Phase II study enrolled 79 patients in all with 27 patients on placebo and 26 patients in each of the 50-milligram and 100-milligram treatment arms. The enrollment in each arm was balanced geographically and demographically as well as across major clinical characteristics of patients with sickle cell disease. Treatment with mitapivat demonstrated statistically significant hemoglobin response rates compared to placebo. The results for the secondary endpoints showed a trend in sickle cell pain crises reduction at both doses as well as improvement in markers of hemolysis and erythropoiesis at both doses. The safety profile for mitapivat observed in the study was generally consistent with previously reported data in other studies of sickle cell disease and other hemolytic anemias. Very importantly, there were no AEs that led to discontinuation of mitapivat. I'm also very pleased to report that of the 79 enrolled patients 73 continued into the Phase II open-label extension period. On this slide, we see that treatment with mitapivat demonstrated a highly statistically significant increase in hemoglobin response rate compared to placebo. Diving in deeper we see that there were 12 responders out of 26 patients in the 50-milligram BID treatment arm, which is a 46.2% response rate, and 13 responders out of 26 patients in the 100-milligram treatment arm, which is a 50% response rate. This is compared to a 3.7% response rate in the placebo arm. Moving to annualized rates of sickle cell pain crises. Both mitapivat arms were lower compared to patients in the placebo arm. The annualized rate of sickle cell pain crisis in the Phase II RISE UP trial was 1.71 compared to 0.83 in the 50-milligram arm and 0.51 in the 100-milligram arm. Further data will be presented at an upcoming medical conference. With that said, I will now turn the call over to Sarah, who will review the structure of the Phase III portion of the study and share a perspective on dramatic unmet need for patients living with this disease.

Thanks, Ahmar, and a very special thank you to you and to the entire RISE UP team to get us to the point that we can discuss the data here today. So based on the data reported to date, Agios plans to proceed with the Phase III portion of the RISE UP study. It's an operationally seamless Phase II/III study design that allows us to leverage and create efficiencies in the start and conduct of the Phase III portion of the RISE UP study, with a goal of enrolling the first patient in Q4 of this year, recording the Phase III data in 2025 and potentially receiving U.S. approval in 2026. Given the promising data for both mitapivat dose armed, as Ahmar explained, the company will continue to analyze the study data over the coming weeks to select the dose for Phase III. So here is an overview of the study design. So the Phase II portion has now completed, moving on to the Phase III portion, and the Phase III is designed to evaluate a number of endpoints. And that will be central to have patients with sickle cell disease feel and function, and it will include a 52-week placebo-controlled period in which patients will be randomized 2:1 to either mitapivat or placebo twice daily. The primary endpoints are hemoglobin response, defined as an increase of at least 1 gram per deciliter from baseline to week 52 as well as the annualized rate of sickle cell pain crises. Key secondary end points will include change from baseline in hemoglobin and measures of hemolysis as well as measures of patient-reported outcomes, including measures of fatigue, pain and quality of life and the frequency of hospitalizations for sickle cell pain crises. So participants who have completed the Phase II are now in an open-label extension, as Ahmar explained, but participants who will enroll in the Phase III will also have an option to transition into an open-label study at the end of completing the RCT portion for 216 weeks. We are pleased with the enrollment in the open-label study that we have currently observed to date in our open-label study. We do believe that, that speaks to an unmet need and to patients truly wanting to participate here. When we complete the Phase III study, we are hoping to be able to deliver a novel oral therapy that improves anemia and reduces sickle cell pain crises. As Brian and Ahmar mentioned, 120,000 to 135,000 patients across the U.S. and EU5 are living with sickle cell disease, and there is an additional significant opportunity outside of these regions. The therapy at the end of the Phase III based on the endpoints highlighted on the previous slides, hopefully will deliver a novel oral therapy that can improve anemia, reduce VOCs and that is supported by the largest body of clinical evidence. The RISE UP study is an innovative seamless Phase II/III trial developed with community input. It is a global trial, and we have a global approach to clinical development across our programs. And we do believe that part of the success of the RISE UP trial to date is the connections with the sickle cell disease patient community and the physician community. The target profile, you can find on the right of the slide. So we hope to deliver chronic therapy, oral and improvement of these 3 different components of the disease. Safety profile consistent with prior clinical experience. With that, I will turn the call back over to Brian.

Well, thanks a lot, Ahmar and Sarah, Excellent job, really good for reviewing the Phase II results and for reinforcing the critical unmet patient needs that we're working so urgently to address. Thanks to both of you as well and your teams once again delivering on a key clinical readout for Agios. We couldn't be more proud of our team, and we are really grateful for all of our connections in the clinical and sickle cell patient community. Now before we move to Q&A, I wanted to close with a couple of quick slides. First, just a quick reminder of the diverse pipeline of commercial and clinical candidates that we're advancing in Agios. And if we go to the next slide, I just wanted to show how momentum has been building throughout 2023. In addition to today's tremendous news, we also recently announced that we have completed enrollment in our Phase III ENERGIZE and ENERGIZE-T clinical studies of PYRUKYND in thalassemia, and this puts us on track for 2 data readouts next year. And just a week ago, we announced that we had completed enrollment in our Phase IIa study of AG-946. This is our other PK activator in lower-risk MDS and it's a milestone that we had been targeting for year-end. This now puts us in a position to report out initial data by year-end, which is ahead of our prior target of 2024. Finally, looking forward to what we expect to be a catalyst-rich next few years. We anticipate readouts from the Phase III studies of PYRUKYND in thalassemia in 2024 and readouts from the Phase III studies of PYRUKYND in sickle cell disease and pediatric PK deficiency in 2025. And again, I'll just note that accelerated completion of enrollment for AG-946, as we announced a couple of weeks ago, allows us to pull into this year the data readout for that Phase IIa study. Now, one item that does not appear on the slide but has begun to receive more visibility in recent weeks is the potential milestone payment for vorasidenib. As part of the divestiture of our oncology business to Servier, we retained the rights to a potential $200 million milestone upon FDA approval as well as royalties on U.S. net sales. So we were pleased to read in the media interviews from ASCO that Servier, their team has projected a potential launch in the second half of next year. These data underscore Agios' strong track record in the discovery and development of therapeutics for disease areas with high unmet need, and we are quite eager to monitor Servier's progress. Based on today's data, we're very excited about the potential for 2 PYRUKYND potential launches by 2026. And with that, I will now turn it back to Catherine, our operator, to open the line for questions. Catherine?

[Operator Instructions] Our first question comes from Gregory Renza with RBC Capital Markets.

Brian and team, congrats on the data today. Maybe I'll just start maybe for Ahmar and for Sarah. Just to help us understand at this time point and with at least the data that you're showing today just help put this into context with respect to how you're viewing mitapivat against other orals out there, other treatments and the standard of care, certainly, some detail that I respect that you're withholding into a larger medical conference, but any context you have there? Maybe a second question is just how that the VOCs at least the pain crisis in context, certainly a big focus and great to see the trend but how you see that sort of playing out as you look at this versus placebo? And then last question, Brian, for you. What inputs are you looking at in order to select that dose? And when would we be able to see the rationale there?

Yes. Thanks a lot, Greg. We're thrilled about today's data. And Sarah, you want to start?

Sure. No, we're indeed absolutely thrilled about the data that the RISE UP study has generated for mitapivat. This is the first randomized controlled trial for a PK activator that has a substantial sample size. And so we are very pleased, as you can see in the press release that we have a very good hemoglobin response rate across the 2 doses that is accompanied by improvements in hemolysis and ineffective erythropoiesis that we also have our -- the VOC data that we were able to present in more detail. So we do believe that the data that has been generated to date in the Phase II sets us up really for the Phase III to hopefully deliver to the target product profile, which would be first novel oral therapy that allows us to deliver to different aspects of sickle cell disease with an improvement in hemolytic anemia and improvement in sickle cell pain crisis and how patients feel and function. And in that sense, that is a profile that is currently not available to date really with any of the therapy. So we're very excited. Ahmar, anything to add?

No, that's right. I'll just add to that and say there's certainly unmet need amongst patients for therapies that are acceptable, tolerable and target different pathways within sickle cell disease. So again, just echoing that we're very, very proud and happy with the data we have at hand.

And Greg, I'll just add on your -- the question of the dose that the mission for us -- I mean, we're in a, I would say, a very interesting and high-quality position that both doses were effective, as you heard from Sarah and Ahmar in terms of achieving the clinical endpoints. So now we will proceed with just making sure that we navigate through the further analysis to exactly, as Sarah said, make sure that we give patients the best opportunity at the finish line of Phase III to achieve improvements in hemolytic anemia and sickle cell pain crises in feel and function. And that's what we've been shooting for the whole way through. And this data just gives us further conviction that mitapivat really delivers and has continued to do so consistently across all the diseases that we've been assessing.

Our next question comes from Salveen Richter from Goldman.

This is Anoumid on for Salveen. Congratulations on the data. Just 2 questions from us. So what are the remaining next steps in order to initiate the Phase III trial? And in your view, what could success look like in that trial based on the data that you've seen, you've presented today?

So this is Sarah. So I think right now, the team is already immediately focused and have been focused on getting the Phase III up and running. And I think we're making very good progress. There's a lot of logistics that goes into something like this. But we are absolutely on track to deliver towards the first patient in Q4 by the end of this year. In regards to what we are hoping to deliver on is truly that trifecta that we have explained earlier, we do not make a change to the endpoint of the Phase III. So we will be still looking at the hemoglobin response rate and at reduction in the sickle cell pain crisis as we had outlined before, and we're very, very eager to move forward.

We have a question from Greg Harrison with Bank of America.

Congrats on the update. Have you done any sensitivity analysis to look at what the responder rates would be at thresholds of maybe 1.5 or 2? And are you able to talk about the mean hemoglobin increase that you saw?

So the team is working through the full analysis right now. This was really our first look that we want -- we were very eager to announce with all of you. We will not be providing additional data at this point in time because we really do want to present this data set at a medical meeting. So more to come.

Got it. And then what length of follow-up do you think is needed to see a static response in VOCs? And how is the Phase III portion powered to detect VOC reduction over 1 year?

So the -- so this is where we do believe that a Phase III needs to be year-long to be able to meaningfully measure a reduction in sickle cell pain crisis. So we will not be shortening our clinical trial but are going to continue with the plan as we have laid out. We also did not make any changes to the projected sample size right now for Phase III based on our Phase II results. So I think we're perfectly on track with the way we have designed a trial and again, very eager to get going.

Our next question comes from Tess Romero with JPM.

So first one is on, you mentioned improvements in markers of hemolysis and erythropoiesis across doses. What about patient reported fatigue, which I think was being evaluated as well? Second question is just maybe asked a different way than some of the prior questions here is, how did you actually interpret the annualized rates of sickle cell pain crises result at the 12-week time point? And how did this come in relative to your expectations? And also curious, how did the baseline VOC rate come in? It seems a little bit low, maybe to us.

We will -- as we mentioned, like we've looked at a bunch of different endpoints across the board and are very pleased with the results observed across to do both those arms. We will not be providing more detail at this point on additional endpoints beyond the hemoglobin response and the VOC rate, which we believe that the community would have the most interest in. And so we will be providing more detail at an upcoming medical meeting across our different -- across the different secondary end points. In regards to the VOC rate, we actually do believe that our baseline demographics represented the number that we wanted to see. You have to keep in mind indeed that this is a 12-week study. So the analysis is based on the patients who actually did have a sickle cell pain crisis within that 12-week period. And that is, in our view, what also explains this number. We are very pleased, though, with the results that we actually are able to see such a reduction within a 12-week time period, which is, by the way, also consistent with the data set that Dr. van Beers has generated and published on.

Our next question comes from Chris Raymond with Piper Sandler.

Congrats from us as well. Just 2 questions. I guess, you look at results here in RISE UP at 12 weeks. The Oxbryta measure was at 24 weeks. I'm just kind of curious if you could talk to any trends maybe you saw at 12 weeks? That is like should we expect responses maybe to deepen over time? And I know there's an open-label extension phase to the study. Maybe talk about how we might get data cuts before we start to see any indication from the Phase III? And then on the VOC rate here, I'm getting some questions from investors. The placebo rate was, I think, decently lower than what was seen with Oxbryta's placebo arm. Just maybe curious you can talk about how these patients in your trial compared to the broader sickle cell population?

Sure. So in regards to the broader sickle cell disease population, that Ahmar mentioned, we do believe that our baseline characteristics are representative of a sickle cell disease trial and also they were representative of the inclusion criteria that we have set forth within our clinical trial. We always mentioned that 12 weeks was a short duration trial, and so there is a limitation to the analysis of the amount of patients that you observe that have a sickle cell pain crisis within that period of time and then the extrapolation to a year's worth of data. But we do see a very, very good and positive trends there, which we believe is very promising also based on the variability that we observed within the data. So more to come on that at an upcoming medical meeting. And then in regards to the open-label extension trial, we actually have not disclosed when we will be taking data cuts or when we will be announcing further data of that. So more to come on that as well.

We have a question from Danielle Brill from Raymond James.

This is Alex on for Danielle. Just a question on the safety profile. So given the trial design, how confident are you with respect to rebound VOC upon drug cessation? And what steps, if necessary, do you think you'll need to take to achieve confidence in this rebound VOC risk? And then additionally, just curious if you could comment on the drug compliance in the trial and also in the OLE?

So as you -- Ahmar presented, we had a big chunk of people who elected to enroll into the open-label extension study. So the data set of people who discontinued is small. We do not have to date any safety trends and that remains consistent with our previous messaging around rebound VOC. We still believe that if you have to take a drug to be able to experience benefits for sickle cell disease, just like what you would need to do it for epilepsy or asthma or any other chronic condition that is meant to target the symptoms and signs of that condition. But so far, no change to our safety profile. And in regards to your question around compliance, the announcement that we have done is an intent to treat analysis. So meaning that everybody seemed to have taken the therapy. We have not reported out on compliance at this point and nor for the open label. More data to come on that at later medical meetings.

Our next question comes from Divya Rao from TD Cowen.

This is Divya on for Mark. Let me also add my congratulations on the data. I just had a question on the VOC rate. Could you comment on the rate of pain crises going into the OLE? Or is that something that we can expect at a later medical meeting? And then I have a follow-up.

Yes. So we have not. We just have been discussing the RCT data in our press release with those 2 data points. So the open-label clinical trial data set, we have not incorporated into this data set. We truly are looking at this as the RCT portion of the trial. I want to make sure that we are able to compare the placebo group to the 50-milligram group and the placebo group to the 100-milligram group with the same observation length. And we will be looking at open-label extension study trial data for presentation at a later medical meeting and outside of this RCT.

That's helpful. And then just based on your analysis, is there any sign that there's maybe a degree of hemoglobin benefit that someone achieved and how that correlates with the rate of VOCs that they experienced?

Can you repeat the question?

Yes. Just based on your analysis, is there any sign that maybe the degree of hemoglobin benefit that a patient achieves is correlated at all with the rate of pain crises they experienced?

So we will not be talking about that type of data right now. Sorry to disappoint, I feel like I'm saying that quite a bit on this call, but we'll be discussing more at medical meetings.

Yes. And maybe I'll just add, too, and hopefully, everyone appreciates this that we had communicated that as soon as we get our top line data, we would be eager to report out enough data that gives our stakeholders clarity on the disposition of our decision whether or not to go forward. I hope you hear the conviction that we have that between the hemoglobin data that we reported out across both doses and the trends in VOCs, we feel very strongly that this is a profile that is worth carrying forward and we're enthusiastic to do that. We knew that there would be a lot of additional questions. And as we get additional data, and we approach publishing that as well as presenting it at a medical meeting will be super eager to discuss that in more depth.

We have a question from Andy Berens from SVB Securities.

Congrats on the data and the decision to go forward. Sorry if you addressed it, but I did dial in late. How did you define vaso-occlusive crisis in the trial? How did pain crisis deliver in the 3 arms of the trial that did not rise to this definition of a VOC? And then remind me, are you planning to have a PRO in the pivotal program?

Yes, this is Ahmar. Thanks for the question. So the definition of sickle cell pain crises was essentially a patient that required a visit to a medical facility or a medical contact in conjunction with having to take a medication for their pain, whether that was an NSAID or opioid. We also had subtypes within those pain crisis of acute chest syndrome, sequestration of hepatic nature or splenic nature as well as priapism. And I think the second question was related to PROs going into Phase III. And certainly, our intention is to continue to try to capture feel and function of patients through their exposure to mitapivat in the Phase II looking forward to that.

Okay. And then just if a patient didn't go into the hospital but reported pain, how do those differ in the 3 arms of the trial if they were not actually admitted to a facility?

Yes. So we'll be analyzing that data. That data at this point is not available in our first look. But certainly, the team is working hard to sort of parse out the nuances around pain through the Phase II, so stay tuned.

And then one other thing to add is that we had an adjudication committee for our efficacy events.

Okay. Thanks, and congrats again.

And I'm showing no further questions at this time. I'd like to turn the call back over to Brian Goff for any closing comments.

All right. Thanks a lot, Catherine. Well, thank you so much, everyone, for joining us to learn more about our exciting new data in sickle cell disease. And as always, thanks for your continued support. We're going to look forward to sharing more about the data as we can. With that, have a great rest of the day. Thanks again.

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