Earnings Call Transcript - AGIO Q2 2025

Morgan Sanford, Vice President of Investor Relations

Thank you, operator. Good morning, everyone. I'm Morgan Sanford, Vice President of Investor Relations at Agios. Thank you for joining us to discuss Agios Pharmaceuticals Second Quarter 2025 Financial Results and Business Highlights. You can access the slides for today's call by going to the Investors section of our website, agios.com. Please move to the next slide. Today, we'll be making certain forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements. Because of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. Next slide, please. On the call with me today from Agios are Brian Goff, Chief Executive Officer; Cecilia Jones, Chief Financial Officer; Tsveta Milanova, Chief Commercial Officer; and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development. Following prepared remarks, we will open the call for questions. With that, please move to the next slide, and I am pleased to turn the call over to Brian.

Brian M. Goff, CEO

Thanks, Morgan. Good morning, everyone, and thank you for joining us on today's call. Next slide, please. 2025 is shaping up to be a breakout year for Agios, and we believe we have a clear path to deliver sustainable growth and unlock long-term shareholder value. First, we have a derisked multibillion-dollar opportunity with our first-in-class PK activator, PYRUKYND. Second, momentum is building as we approach multiple near-term high-value catalysts. We hope to add thalassemia as the second approved indication for PYRUKYND in the U.S., pending FDA approval, and we are now less than 40 days from our September 7 PDUFA goal date. We expect to read out the RISE UP Phase III trial for PYRUKYND in sickle cell disease before the end of the year and early next year, anticipate Phase IIb data for tebapivat, our more potent PK activator in patients with anemia due to lower-risk myelodysplastic syndromes. And third, we are well-capitalized to develop and launch PYRUKYND in thalassemia and sickle cell disease and to continue to advance our existing development programs, as well as look opportunistically to expand our pipeline through internal efforts and business development activities. Please move to the next slide. In the second quarter, we reported $12.5 million in net revenue, reflecting the strong value proposition of PYRUKYND. We entered into an agreement with Avanzanite Bioscience to commercialize and distribute PYRUKYND in Europe. This is a capital-efficient deal, allowing us to focus our investment on commercial launches in the U.S. We exited the second quarter with approximately $1.3 billion in cash, cash equivalents, and marketable securities and intend to be disciplined in our investment behind the commercial build-out of PYRUKYND and advancement of our pipeline. In the second quarter, we dosed the first patient in the Phase II trial of tebapivat in sickle cell disease and received IND clearance for AG-236, our siRNA targeting TEMPRSS6 intended for the treatment of polycythemia vera. We are at an important turning point in our growth story. Near-term, we have the potential to transform the treatment of thalassemia and sickle cell disease with PYRUKYND. And beyond, we have the opportunity to deliver additional medicines to rare disease patients waiting and in urgent need of innovative treatment options. Please move to the next slide, and I'll turn the call over to Cecilia to provide additional commentary on our second quarter performance and the future trajectory for PYRUKYND.

Cecilia Jones, CFO

Thank you, Brian. Next slide, please. Our second quarter 2025 financial results can be found in the press release issued earlier this morning, and additional details can be found in our 10-Q, which will be filed later today. Let me now take a moment to provide some context and highlight a few key points. Second quarter net PYRUKYND revenue was $12.5 million, an increase of 45% compared to $8.6 million in the second quarter of 2024 and an increase of 44% compared to $8.7 million in the first quarter of 2025. Sequential net revenue growth reflects continued commercial execution in PKD, as well as an extra week of ordering in the second quarter and an increase in the number of units processed directly by the specialty pharmacy. In the second half of the year, we expect continued quarter-on-quarter variability in net revenues due to ordering patterns. Pending approval for thalassemia in the U.S., we expect softer PKD demand as the sales force transitions promotional focus to thalassemia. We still anticipate the fourth quarter to reflect partial demand for thalassemia given the timing of a PDUFA goal date due to the expected time to convert patient enrollment forms to treatment initiations. Taken together, on a full year basis across indications, we expect net revenues in 2025 to show modest growth compared to 2024. Cost of sales for the quarter was $1.7 million. R&D expenses were $91.9 million, an increase of $14.5 million compared to the second quarter of 2024. This increase was primarily driven by a $10 million milestone payment to our partner, Alnylam, related to the development of AG-236. SG&A expenses were $45.9 million in the second quarter, an increase of $10.4 million compared to the prior year, driven by continued investment ahead of the potential commercial launch of PYRUKYND for the treatment of thalassemia. We ended the second quarter with cash, cash equivalents, and marketable securities of approximately $1.3 billion. Next slide, please. Our strong balance sheet supports our focused capital allocation strategy, allowing us to invest in our next wave of growth and pipeline delivery. First, we have executed a capital-efficient commercial build-out, prioritizing investment in potential U.S. launches, which present the largest commercial opportunity. Last year, we announced our partnership with NewBridge Pharmaceuticals to commercialize PYRUKYND in the GCC. And last month, we entered into an agreement with Avanzanite Bioscience to commercialize and distribute PYRUKYND in Europe. Both agreements are structured as revenue-sharing arrangements that favor Agios over the long term. We will record our share of ex-U.S. sales as net revenues. Second, we are strategically investing in our pipeline to advance our early and mid-stage clinical programs. Third, we will opportunistically look for ways to expand our pipeline through internal efforts or externally sourced assets. In closing, I am confident that our balance sheet will enable us to continue to execute from a position of strength.

Tsveta Milanova, Chief Commercial Officer

Thank you, Cecilia. Next slide, please. Net revenue growth in the second quarter reflects strong execution by our commercial team. However, we continue to anticipate quarter-on-quarter variability due to ordering and inventory dynamics typical for rare disease medicines. As of the second quarter, 248 patients completed prescription enrollment forms, up 6% from the first quarter of 2025. 142 patients are now on active PYRUKYND treatment, an increase of 4% on a sequential basis. Please move to the next slide. With less than 40 days to our PDUFA goal date, our commercial team is fully prepared for a launch in thalassemia, pending FDA approval. We believe in PYRUKYND's strong clinical profile shown across 2 Phase III studies, ENERGIZE in non-transfusion-dependent patients and ENERGIZE-T in transfusion-dependent patients. As shown on this slide, data generated across this robust clinical program means upon potential approval, we are set to deliver a series of firsts in the treatment of thalassemia in the U.S., all of which are profoundly meaningful to thalassemia patients. Next slide, please. We are confident in our ability to deliver on the U.S. launch of PYRUKYND in thalassemia, pending FDA approval for several reasons. First, thalassemia is well diagnosed due to widespread prevalence of newborn patient screening in the U.S. In addition, given the availability of claims data and ICD-10 codes, these patients have an established record of engagement with healthcare services. Second, the burden of disease is high, meaning symptomatic patients are actively managed and the associated cost of care is significant. Despite this, treatment options are limited, especially for patients with non-transfusion-dependent disease, and most patients still rely on supportive therapy. Third, this is a community with a high level of engagement across key thought leaders and robust patient advocacy representation. Just this month, we attended the first Thalassemia International Federation Pan-American Conference, where we engaged in meaningful conversations with patients and physicians that reinforce our understanding of their needs. Lastly, robust preparedness supports our ability to deliver a successful launch. Our disease state education is tailored to address the diverse multicultural aspects of thalassemia, and we have leveraged our connections with thought leaders to provide additional disease education for community-based physicians. Last year, we doubled our sales force to approximately 40 employees and have focused our launch planning on known treatment centers. Initial conversations with payers have been encouraging, reinforced by the compelling benefit-risk profile of PYRUKYND.

Sarah Gheuens, Chief Medical Officer and Head of Research and Development

Thank you, Tsveta. Next slide, please. PYRUKYND, our first-in-class PK activator, has demonstrated consistent, meaningful clinical data across multiple hemolytic anemias, reinforcing the strength of its differentiated mechanism of action as an allosteric activator of both PKR and PKM2 and the broad applicability of this unique mechanism. In pyruvate kinase deficiency, our first approved indication, treatment with PYRUKYND resulted in statistically significant improvements across multiple endpoints, highlighting improved hemoglobin levels, reduced hemolysis, and improved patient-reported outcomes. At the end of last year, we submitted a supplemental NDA for PYRUKYND for the treatment of alpha or beta thalassemia, regardless of transfusion burden. In our Phase III ENERGIZE and ENERGIZE-T studies, we showed statistically significant improvements on measures of anemia, including hemoglobin levels, transfusion reduction, and reduction in fatigue. We continue to partner with global health authorities on our regulatory filings and work towards our PDUFA goal date in the U.S. In sickle cell disease, we have reported compelling Phase II data from the operationally seamless RISE UP Phase II/III trial in 2023 and are on track to deliver top-line results from the Phase III trial by the end of the year.

Brian M. Goff, CEO

Thank you, Sarah. Next slide, please. In the second quarter, we made strong progress against our 2025 priorities. We achieved important milestones to advance tebapivat and AG-236, 2 assets with the potential to expand our reach into new rare disease indications. We believe 2025 will be a breakout year for Agios as we make strides towards the potential launch of PYRUKYND in thalassemia in the U.S., Phase III RISE UP readout in sickle cell disease, and continued advancement of our mid and early-stage pipeline. In closing, Agios has the necessary ingredients to deliver innovative medicines to rare disease patients in need, driving sustainable growth and unlocking long-term shareholder value. At our core, we are fueled by our connections with the rare disease communities we serve, enabling us to deliver clinical benefits that matter to patients with a tailored commercial model to best meet patients where they are. Importantly, we're on our way to building a diversified rare disease portfolio. We are rapidly advancing a best-in-class PK activator franchise, with potential across 4 indications, and we look forward to providing future updates on our early-stage pipeline with the opportunity to accelerate our growth outside of hematology.

Unidentified Analyst, Analyst

This is Imogen on for Eric. I think in the past, you've said that you would update investors on any change to mitapivat safety profile, including any cases of liver toxicity outside of thalassemia. Is there anything new that you have to report there?

Brian M. Goff, CEO

It's Brian. Thanks a lot for the question. I'll have Sarah comment on that first one with respect to any updates in the safety profile.

Sarah Gheuens, Chief Medical Officer and Head of Research and Development

So no updates to the safety profile. That's it really.

Unidentified Analyst, Analyst

Okay. Great. And then one quick follow-up. On the GCC approval date, is there any more color you could share on that? Are you expecting it maybe just after the U.S. approval?

Brian M. Goff, CEO

I want to reflect on what we announced in December of last year. I'm really proud that the team has submitted our application simultaneously across four different regions. Currently, we are actively discussing matters in all four regions, and we look forward to providing updates on the status of those reviews. Additionally, I want to mention that Tsveta and her team are ready from a commercialization perspective.

Marc Alan Frahm, Analyst

Maybe just with the thal review ongoing, are you able to comment on if you're maybe in labeling discussions yet? And obviously, safety information is going to need to be at least somewhat updated just to account for the fact that thalassemia is now hopefully going to become an approved indication. So, what's the latest thoughts on kind of how you're anticipating that part of the label to read? And then I'll probably have a follow-up question.

Brian M. Goff, CEO

Yes. Thanks, Marc. So, Sarah can start.

Sarah Gheuens, Chief Medical Officer and Head of Research and Development

Sure. Thanks, Marc. So well, maybe just to recap. But as you know, we've submitted to, as Brian just mentioned, 4 different regions for the indication of thalassemia based on our 2 well-controlled trials that met the primary and key secondary endpoints in both. So that's the benefit part. You mentioned on the risk side, we have, of course, the hepatocellular injury, which you can already see reflected in the PKD label that was based on the thalassemia observations. And so, we do, at minimum, anticipate there the update in the PKD label to reflect the indication statement and the dose to be changed to thalassemia and 100 milligrams BID. But the process and the review are, of course, ongoing and the FDA only provides you an end date of the complete review. So, the final label, that's what we will know at the PDUFA date.

Cecilia Jones, CFO

Thanks, Mike. Yes, from a financial perspective, we do expect to see a little bit more growth on the SG&A side for thalassemia. You're right, we built the bulk of the infrastructure with the sales teams and customer-facing teams starting last year after the trials read out, but we do have some launch-related expenses that would obviously only happen upon approval. So, we do see some more coming potentially after that.

Tsveta Milanova, Chief Commercial Officer

Yes, absolutely. The team is ready for a potential launch in thalassemia. As Cecilia mentioned, we deployed the field-facing organization late last year, which includes about 40 people in the sales organization and a cross-functional team that serves different customers. We are excited about the potential to provide PYRUKYND in thalassemia, pending FDA approval in the U.S., and we look forward to giving updates when possible.

Salveen Jaswal Richter, Analyst

As you look to the upcoming PDUFA here for thal and focus on the launch, could you just help us understand the initial target patient population that you'll be addressing or just be targeting here initially?

Brian M. Goff, CEO

Yes. Thanks a lot, Salveen. And again, I'll turn that one over to Tsveta.

Tsveta Milanova, Chief Commercial Officer

Absolutely. So, from a commercial perspective, thalassemia is really an attractive indication for us to potentially launch next. And the reason for that is that the patients with thalassemia are actually diagnosed and well known to the healthcare system in the U.S. There is a great database based on the ICD-10 code in the U.S., which we have been able to validate through our interactions with healthcare professionals. And that gave us a lot of clarity, not only where patients are currently being managed, but also what patients we should prioritize and focus on at launch. When you think about which patients are really the most appropriate for our initial launch target, these are about 4,000 patients out of the 6,000 diagnosed adult patients in the U.S. And the way we prioritize these patients is based on their symptomology, the fact that they are engaged with the healthcare system, and they potentially will require additional management and treatment. And in this group of patients, you see both transfusion-dependent patients who might be looking to reduce their transfusion burden, as well as non-transfusion-dependent patients who are symptomatic, they're experiencing fatigue and other complications of the disease, and both the patient and the physician might be looking for additional management and treatment. As I said, the team is very well prepared for the launch, and we have the opportunity to actually engage with these accounts in advance of the launch. Very importantly for us, it's important to remember and recognize that thalassemia is a disease with high unmet need. About 2/3 of the patients have no available treatment in the U.S. And that unmet need was really reinforced through our interactions with both patients and physicians earlier in the month where we had the opportunity to attend the Thalassemia International Federation Pan American conference, which gave us a lot of energy and excitement about the potential launch in the future.

Cecilia Jones, CFO

Yes. Thanks, Brian. So given the expected goal of PDUFA in September and the time it takes between a PF and patients initiating treatment from a revenue perspective for this year, 2025, we don't expect thalassemia revenues to be material.

Emily Claudia Bodnar, Analyst

I guess for the first one, maybe if you could talk about the pediatric opportunity for thalassemia and if you have any timing for potential FDA filing there? And then just maybe if you could confirm that you haven't had any changes to either access or, I guess, tone of speaking to the FDA in kind of recent weeks given some of the news going on there.

Brian M. Goff, CEO

Sure, thanks, Emily. Tsveta can start by discussing the commercial aspects of pediatric thalassemia, and then Sarah can provide insights on the trials and the future pathway.

Tsveta Milanova, Chief Commercial Officer

Certainly. There are approximately 8,000 thalassemia patients in the U.S., with around 6,000 diagnosed. This leaves about 2,000 pediatric patients. Thalassemia is a genetic disorder typically diagnosed at birth, and since newborn screening is available, the diagnosis rate is quite high. There is a significant unmet need, and we see an opportunity to add value for pediatric patients. Now, I'll turn it over to Sarah.

Sarah Gheuens, Chief Medical Officer and Head of Research and Development

We are approaching pediatric development by first assessing the benefit-risk profile in adults, which we have now established. Our plan for the thalassemia indication is to proceed in the same manner as we did for the pyruvate kinase deficiency indication, expanding our efforts by conducting trials in the pediatric patient population. Once that data is collected, we will submit it to regulators for their review.

Brian M. Goff, CEO

And I think, Emily, if I heard the second part of your question was about FDA interactions. Of course, we're not going to talk about specifics, but anything you want to add, Sarah, about our engagement?

Sarah Gheuens, Chief Medical Officer and Head of Research and Development

We take pride in our collaborative relationships with all of the regulators we engage with. Despite the disruptions reported in the news, we have not faced significant issues in our interactions with the FDA, and our engagement with them remains collaborative.

Unidentified Analyst, Analyst

This is Matthew on for Alec. Maybe first from us. I know the initial focus of the launch is on higher frequency of visit patients. Curious for those outside the initial focus, what the key points of education are to drive uptake and whether that differs U.S. versus ex U.S.? And then maybe a second question on the early-stage pipeline. Curious if there's been any change to your development plans in PKU after the approval of PTC's second.

Brian M. Goff, CEO

Okay. So, thanks, Matthew. So Tsveta can start on the question about beyond the initial higher frequency clinical touch points, what does segmentation look like?

Tsveta Milanova, Chief Commercial Officer

Absolutely. So, as we said, our priority segments are patients that are transfusion-dependent or non-transfusion-dependent patients that require additional management because of their symptoms of the disease. When we look beyond that patient segment, we'll continue to expand into the non-transfusion-dependent patients who might be experiencing symptoms but might not be ready to initiate therapy immediately. It's also important for us to remember that as patients age, the burden of their disease increases, so they might be actually developing complications of the disease as well. The key educational elements there will continue to remain the same. We know that the unmet need in thalassemia is well characterized. But it is also an evolving field and additional data on unmet need, especially in the non-transfusion-dependent patients is emerging. So, a lot of our educational efforts are actually disseminating that additional information and continuing to engage both with patients and physicians. We are also stressing the importance of continuous monitoring for those patients given the long-term disease complications and the pathophysiology of the disease, which is an important element for us. So, once we are ready to expand, we'll have more engaged both patients and the physician community on that front. They will be consistent in the U.S. and ex U.S., of course. Our priority and segmentation across the globe will remain quite consistent. However, ex U.S. will need to deal with different market access dynamics and patient access, which we'll address with our partners appropriately on a country-by-country basis.

Brian M. Goff, CEO

To emphasize Tsveta's point about markets outside the U.S., we are very clear on our geographic priorities. The U.S. is our top priority, which is why Tsveta and the team have structured our direct commercialization strategy. We are proud of the partnerships we have established, and I want to highlight our recent updates this morning with Avanzanite Biosciences in Europe and NewBridge in the GCC. This approach is very capital-efficient and relies on localized expertise in those regions. Regarding the second question about PKU, I will have Sarah address that.

Sarah Gheuens, Chief Medical Officer and Head of Research and Development

Yes, we have not changed anything based on the recent approval. We are very excited about the ability to monitor what happens and learn from the developments as they progress. However, the core principles of our program remain the same because we have a drug that is a phenylalanine hydroxylase stabilizer, which represents a completely novel mechanism of action. This oral therapy has the potential to offer another treatment option to patients who still have significant needs despite this recent approval. There will continue to be a strong demand for additional options, as some patients may not respond to existing therapies, and there are concerns such as potential anaphylaxis with treatments like Palynziq. The gap in available options is evident in the current label of the new drug, which indicates that there will be individuals who do not respond to this therapy and will require alternatives.

Unidentified Analyst, Analyst

Our next question is going to come from the line of Andrew Berens with Leerink Partners. Congrats on all the progress. This is a follow-up to Marc's earlier question. Has anything changed in the sickle cell trial protocol since you identified risks in liver injury at ASH 2024? Interested in whether the consent forms and the monitoring requirements have changed.

Sarah Gheuens, Chief Medical Officer and Head of Research and Development

Yes. Okay. So, in regards to the sickle cell disease protocol, we've announced in the past that when we identified this risk in the thalassemia program that we had aligned all of our protocols to have monthly monitoring for the first 6 months, so including our open-label extension trial. So, for the sickle cell disease protocol, we aligned the open-label extension study to match what happens in the first part of the randomized controlled trial because obviously, placebo patients get exposed for the first time in the open-label extension study. So, we made sure that they have the same type of monitoring. And so that is effectively reflected in the protocols, and we did update those informed consents as well, obviously. And in regards to your next question around the dosing differences between the sickle cell disease Phase II and the MDS Phase IIb. You are right, we are exploring lower doses within the sickle cell disease Phase II, and that is because the sickle cell disease patients, their metabolism matches the healthy volunteer metabolism that was observed in the Phase I. A reminder that we have sickle cell disease patients included in that trial as well. So, we have that. But then in the MDS trial in the IIa, we observed that the MDS patients metabolize the drug faster. So, we adapted the doses appropriately. And so that's what you'll see that we are exploring different doses between sickle cell disease and MDS.

Unidentified Analyst, Analyst

Our next question is going to come from the line of Tess Romero with JPMorgan.

Tessa Thomas Romero, Analyst

So, to double-click back on a few of the earlier questions on the call, is it still reasonable to assume that the potential risk of hepatocellular injury will sit in the warnings and precautions section of the label as is currently reflected today? And relatedly, when do you expect to present your open-label extension data that you have collected in this population that may be of interest to physicians and institutions as they begin to prescribe in thalassemia?

Brian M. Goff, CEO

Sure. Thanks. Sarah can take both of those. I'll just say on the open-label extension, we're also interested in the data, of course, but we're going to do things sequentially. But go ahead.

Sarah Gheuens, Chief Medical Officer and Head of Research and Development

Yes, I can start by mentioning the open-label extension. We will publish data from the open-label extensions as we typically do, similar to what we've done for PKD. Right now, our focus is on ongoing reviews, prioritizing the efforts of our teams in that area over additional publications on the extension data. However, those publications will come in due time. We understand the interest in this information. Regarding your question about HCI and its position in the label, Brian touched on this earlier. We are actively engaging with the agency, and the benefit-risk review is still in progress. Currently, what is included in the PKD label reflects what we have found in our program. The relevant language concerning another condition and higher dosage is in the warning and precautions section of the PKD label and will need to be updated when the final label for thalassemia is established. We do not comment on ongoing review processes with the agency regarding what specific changes might occur. As you know, our PDUFA date is September 7, at which point we expect the procedure to be finalized, and we will have the final label to discuss further.

Unidentified Analyst, Analyst

And our final question is going to come from the line of Greg Harrison with Scotiabank.

Theresa, Analyst

I would like to inquire about the initial launch focus for thalassemia, particularly regarding the prescriber base and how you plan to manage any differences in care between academic centers and community hematologists.

Brian M. Goff, CEO

Yes. Thanks, Theresa. Sarah can reiterate a few of the points we talked about earlier in terms of in the U.S., the 4,000 patients that are in our addressable target and add a little bit more on community versus academic.

Sarah Gheuens, Chief Medical Officer and Head of Research and Development

Absolutely. So, Theresa, as I mentioned, in the U.S., we really benefit from the fact that the thalassemia patients are diagnosed, and they are well-established ICD-10 codes. So we have a lot of clarity of where these patients are currently being treated and managed. In addition to that, the team has been really focused on a very robust launch preparations where we had the opportunity to connect with the prescriber base and profile the accounts and really prioritize them appropriately based on the patients that they have and their potential willingness to manage these patients further. Of course, the majority of the transfusion-dependent patients are actually within the academic centers where you will see a little bit more penetration in the transfusion-dependent setting. However, there is a very high unmet need in the non-transfusion-dependent patients, and that need is very well characterized and understood even though some of these patients are managed in the community, we've been able to actually engage with those prescribers, identify where these patients are managed, provide disease education and prioritize those accounts so we can pull them through launch as well at the beginning of the launch.

Brian M. Goff, CEO

Okay. Thanks, Michelle, and thank you very much, everyone, for participating in today's call. As you know, we're halfway through yet another busy year. It's a very exciting time at Agios, and we truly believe that we are poised to deliver transformative new therapies for patients and to create significant long-term value to shareholders. So, thanks again, and we look forward to speaking with you again soon.

Operator, Operator

This concludes today's conference call. Thank you for participating, and you may now disconnect. Everyone, have a great day.