Agios Pharmaceuticals, Inc. (NASDAQ:AGIO) Q4 2023 Earnings Call Transcript

Agios Pharmaceuticals, Inc. (NASDAQ:AGIO) Q4 2023 Earnings Call Transcript February 15, 2024

Agios Pharmaceuticals, Inc. isn’t one of the 30 most popular stocks among hedge funds at the end of the third quarter (see the details here).

Operator: Good morning. And welcome to the Agios Fourth Quarter 2023 Earnings Conference Call. At this time, all participants are in a listen-only mode. [Operator Instructions] 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 and Corporate Communications for Agios. Please go ahead.

Chris Taylor: Thank you, operator. Good morning, everyone and welcome to Agios’ conference call and webcast to discuss fourth quarter and full year 2023 financial results and recent business highlights. 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, 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 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’ll turn the call over to Brian.

Brian Goff: Thanks Chris, and good morning, everyone, and thank you for joining us. Our mission at Agios is to develop and deliver transformative medicines that elevate and extend the lives of patients living with rare diseases. Driven by this goal, we continue to generate consistent and compelling data across our industry-leading PK Activator franchise. And with seamless cross-functional collaboration of the Agios team, we made remarkable progress advancing this mission in 2023. Highlighting this progress, we reported three key data readouts in the last 12 months. In June, we reported positive top-line data from the Phase 2 Portion of the RISE UP Study at mitapivat, our lead PK Activator in sickle cell disease, followed by the full data set in December at ASH.

Despite the field’s recent progress in sickle cell disease, there are no novel oral therapies that both improve anemia and reduce sickle cell pain crises, and that is precisely what we aim to deliver with mitapivat. In November, we reported positive data from the open-label Phase 2a way study of our other PK Activator, AG-946, in lower-risk MDS, with 40% of patients achieving the transfusion independence endpoint. And just last month, we reported positive data from the Phase 3 ENERGIZE study of mitapivat in non-transfusion-dependent thalassemia. As a reminder, non-transfusion-dependent, or NTD, thalassemia accounts for approximately two-thirds of thalassemia in the U.S., and has no FDA-approved treatment option. Despite not requiring regular transfusions, NTD-thalassemia patients experience significant impact on quality of life, a wide range of serious morbidities, and an elevated risk of premature death.

Together, the consistency of data generated across the mitapivat development program bolsters our conviction in the probability of success of our ongoing studies, including two additional Phase 3 readouts we expect by the end of this year, and this data highlights the potential of our PK activators to transform the course of multiple hematologic diseases. Sarah will provide more detail on our advancements and upcoming milestones across our pipeline in just a few minutes. Importantly, we believe our PK activation pipeline is well positioned with multiple near-term catalysts to become a multi-billion dollar franchise and deliver significant value. In parallel with advancing the late-stage mitapivat development program across multiple indications, our commercial organization is laser focused on building the infrastructure established through our current launch in PK deficiency to prepare for potential U.S. launches of mitapivat in thalassemia in 2025 and in sickle cell disease in 2026.

Tsveta will provide greater detail on the commercial opportunities for mitapivat in thalassemia, as well as an update on our current launch in PK deficiency in just a bit. Finally, as you’ll hear from Cecilia, we ended 2023 with a strong cash position with approximately $806 million in cash and investments on the balance sheet. In addition, we continue to track Servier’s progress towards the potential FDA approval of vorasidenib given our retained economics for both a milestone and royalties. This is truly an exciting time at Agios with four additional Phase 3 readouts and two potential launches expected on the horizon. We look forward to multiple opportunities to drive significant near-term value creation for patients, caregivers, and shareholders.

With that, I’ll now turn the call over to Sarah.

Sarah Gheuens : Thanks, Brian. In 2023, our research and development organization made tremendous progress advancing our PK activator development program. Led by mitapivat, the industry’s most advanced PK activator, now with over eight years of clinical experience, the consistent and compelling data we have generated to date in PK deficiency, thalassemia and sickle cell disease to continue to de-risk our ongoing development program and highlight the potential for this molecule to transform patient’s function and quality of life. We are also enthusiastic about the potential for the rest of our growing pipeline, and we are pleased to note that we remain on track to deliver on our milestones, including, enrolling the first patients in the Phase 2b trial for AG-946 in lower risk MDS, and for the Phase 1 trial for AG-181, the compounds named for our PAH stabilizer for phenylketonuria.

Reading our top line data for the Phase 3 ACTIVATE kids-T study in regularly transduced pediatrics patients with TK deficiency, and completing enrollment of the Phase 3 ACTIVATE kids-T study in pediatric patients with TKB. Turning to sickle cell disease, we were pleased to present detailed positive results from the Phase 2 Portion of the Phase 2/3 RISE UP Study mitapivat at ASH in December. The study achieved its primary endpoint of hemoglobin response, and in addition, an improvement in analyzed rates of sickle cell pain crises was observed. And we have been delighted by the enthusiasm of the investigators. We continue to advance enrollment in the Phase 3 portion of this study and remain on track to complete enrollment by the end of this year.

While the treatment landscape in sickle cell disease continues to evolve, there remains an urgent and unmet need for convenient novel oral treatment options that address both anemia and sickle cell pain crises. And we believe firmly in mitapivat’s potential to deliver a best-in-class option for patients suffering from this devastating disease. And finally, on thalassemia, I’ll take a moment to highlight a few key elements of our program, and the positive top-line Phase 3 data we reported last month in non-transfusion-dependent thalassemia. As a reminder, the Phase 3 program of PYRUKYND in thalassemia, and compacting two Phase 3 randomized placebo-controlled trials, was designed to deliver data across all sub-populations of thalassemia, such as alpha-and beta-thalassemia and populations with different transfusion needs.

Both trials enrolled patients with alpha or beta-thalassemia, but enrolled different populations as it relates to transfusion needs. We want to highlight that ENERGIZE is the first clinical program that included patients who were not regularly transfused and alpha-thalassemia patients. As Brian mentioned, there are no FDA-approved treatments for non-transfusion-dependent thalassemia, which represents approximately two-thirds of total thalassemia patients in the U.S. These patients suffer from a poor quality of life, a high rate of serious morbidities, including thrombosis and premature death. We were therefore very pleased to be able to announce positive results from the ENERGIZE study. As a reminder, the ENERGIZE study enrolled a total of 194 patients with either alpha or beta non-transfusion-dependent thalassemia, randomized 2:1 to 100 milligrams mitapivat or placebo twice daily.

The speed of enrollment and the actual number of patients enrolled in this study, as well as the high completion and rollover rate, supports the idea that people who are not regularly transfused were motivated to take action and speak to the unmet need for this population. The primary endpoint of this study was hemoglobin response rate, defined as an increase of at least one gram per deciliter in average hemoglobin concentration from week 12 to week 24 compared to baseline. The key secondary endpoints of this study were change from baseline in average FACIT-Fatigue Score and change from baseline in average hemoglobin concentration, also both assessed from week 12 to 24. On the primary endpoints, treatment with mitapivat demonstrated a highly statistically significant result, with 42.3% of patients in the treatment arm achieving a hemoglobin response versus 1.6% of patients in the placebo arm.

In line with mitapivat’s novel mechanism of action, which focuses on overall red blood cell health, and the data generated with mitapivat across additional disease areas, the beneficial effects of mitapivat in this study extended beyond hemoglobin alone. Specifically, treatment with 100 milligrams mitapivat resulted in statistically significant improvements in both key secondary endpoints, including a change from baseline and average FACIT-Fatigue Score, an important patient-reported measure of how patients feel and function. Importantly, across the primary and secondary endpoints, all pre-specified subgroup analyses favored mitapivat compared to placebo, suggesting that no single subgroup was responsible for driving the results, which supports our plan to file for a broad label covering all thalassemia subtypes.

This is therefore the first drug that not only improves hemoglobin but actually makes people with thalassemia feel better, consistent with what we observe in patients with PKD and what we hope to be able to deliver for patients with sickle cell disease as well. Complementing the near-term benefits of thalassemia patients reporting that they had less fatigue and felt better in the near-term, clinicians in the trial and other KOLs appreciate the potential longer-term benefits of reducing markers of hemolysis and the longer-term potential to reduce serious morbidity. We are very much looking forward to presenting the full data set at a medical meeting. Beyond the excitement we have for the ENERGIZE data itself, the readout of the ENERGIZE trial also gives us further confidence towards the readout of ENERGIZE-T.

Thalassemia is a hemolytic anemia irrespective of whether a patient is in need of transfusions or not. In addition, the mechanism of action of mitapivat is not dependent on the need for transfusions. We have already demonstrated an improvement in hemolytic anemia in the ENERGIZE trial with a positive change in hemoglobin. We are now waiting to see if the improvement in hemolytic anemia can also be documented via a reduction in transfusions in ENERGIZE-T. As a reminder, the primary endpoint of ENERGIZE-T is transfusion reduction response, defined as a 50% or greater reduction in transfused red blood cell units with a reduction of equal or more than two units of transfused red blood cells in any consecutive 12-week period through week 48 compared to baseline.

Like the energized study in non-transfusion-dependent thalassemia, the design of the ENERGIZE-T trial enables us to demonstrate clinical meaningfulness in a variety of ways to see a reduction in transfusion burden, which also includes transfusion metrics in line with that other studies have used. We designed this study incorporating learning from prior studies and agency feedback and believe a dynamic assessment series is important as patients aren’t static in their disease. We look forward to the readout of this study by mid-year and plan a single regulatory filing to the FDA and compacting data from both ENERGIZE and ENERGIZE-T by the end of this year, seeking a label that will enable people living with thalassemia access to a convenient and differentiated oral treatment option.

Overall, I’m very proud of the tremendous progress made by our R&D organization in 2023 and look forward to continuing this momentum in 2024. With that, I will now turn the call over to Tsveta.

Tsveta Milanova: Thanks, Sarah. Thalassemia remains an area of high unmet needs with few treatment options. The burden of disease on the patient is significant regardless of their transfusion needs. Thalassemia patients experience increased mortality compared to the general population and can be significantly worse in non-regularly transfused than those who are regularly transfused. Patients endure high rates of morbidities and increase complications as they age. Adult patient with non-transfusion dependent thalassemia may actually have similar or worse quality of life compared to transfusion dependent patients. Of course, this burden of disease correlates to increased healthcare costs. To address this unmet need and galvanized by the positive data from the Phase 3 ENERGIZE study of mitapivat, our commercial organization is actively preparing for a potential launch in thalassemia next year, beginning with the US.

In the US, there are approximately 6, 000 diagnosed adult patients with thalassemia. Approximately 4, 000 of these patients you are non-transfusion dependent and have no available treatment options today. The remaining 2, 000 patients are transfusion dependent and have no oral treatment options. Our goal with mitapivat is to address the unmet needs of all adults living with a thalassemia and become the first therapy approved for all subtypes of the disease. In addition to the data we are generating through the mitapivat clinical development program, there are three key factors we believe have the potential to support adoption of mitapivat among the thalassemia patients in the US. First, there is strong alignment between where in the US these patients reside and where they receive treatment.

The [inaudible] slide 20 depicts patient prevalence overlaid with the Agios clinical trial site and or centers of excellence represented by the gold stars. Second, the diagnosis rate is high, driven by availability of newborn screening and well-established ITD-10 codes. Many patients are diagnosed before adulthood. And finally, as shown on slide 21, there is concentration of patients and providers at selected centers. Approximately 50% of all diagnosed patients are treated a fewer than 150 affiliated hematology oncology practices in the US, providing a clear focus for our initial launch. Given this market dynamic and PYRUKYND target product profile, we believe we are well positioned to provide a potential foundational treatment option for patients with thalassemia regardless of subtype.

Therefore, our team is focused on four core areas of US launch preparation. First, building on the foundational work we have already done, we continue to deepen the sophistication of our market understanding. We are conducting extensive market research and claims data analysis to inform ATP targeting, field force sizing, and deployment for launch. Second, we will be rolling out a disease education campaign for both patients and clinicians, highlighting the long-term complications and burden of disease across all thalassemia subtypes. Our disease education engagement will also work to correct the historic misperception that non-transfusion dependent patients are less likely to experience the debilitating long-term effects of thalassemia. To support these initiatives, we are establishing capabilities to enable execution of our educational efforts across personal and non-personal channels.

Third, we will continue to strengthen our commercial capabilities by expanding our sales team in anticipation of thalassemia launch, right-sizing the team for a broader rare disease. And lastly, in parallel with those efforts, we are preparing our market access team to engage with payers on disease safe education in advance of the potential launch of thalassemia next year. Our team has obtained success in market access for PTA deficiency, and we look forward to watching them pave the way in thalassemia too. In addition to the well-established US thalassemia market, there are approximately 13, 000 patients in the EU5 and approximately 70 ,000 thalassemia patients in the Gulf region. We aim to maximize the potential of this additional market through coordinated regulatory filings, which we intend to pursue with partners.

Taken together, we believe the potential launch of mitapivat in thalassemia represents a significant opportunity for Agios and a step forward as we prepare for potential back-to-back launches with sickle cell disease in 2023. Now, let me provide an update on the current launch of PYRUKYND and PK deficiency. In the fourth quarter of 2023, we generated $7.1 million in net PYRUKYND revenue, compared to $7.4 million in the prior quarter. A total of 178 patients have completed a prescription enrollment form, including 18 in the fourth quarter of 2023, an 11% increase versus the third quarter. This translated into net 109 patients on therapy, a 9% increase versus the third quarter. Patients on therapy continue to spend from a growing and diverse prescriber base of 164 physicians and represent a broader demographic and disease manifestation range that is consistent with the adult PK deficiency population.

We continue to be encouraged by the persistency of patients on treatment and remain focused on efficiently identifying providers likely to treat patients with PK deficiency. The capabilities we continue to build and expand through the current launch, including efficient targeting analytics, patient’s awareness and education and patient access will provide a firm foundation from which we can maximize the potential U.S. launches in thalassemia in 2025 and in sickle cell disease in 2026. As we advance through this catalyst-rich period of Phase 3 data readouts for mitapivat, we look forward to dramatically expanding the number of patients we serve. With that, I will turn the call over to Cecilia.

Cecilia Jones: Thanks, Tsveta. Our fourth quarter 2023 financial results can be found in the press release we issued this morning, and more detail will be included in our 10-K, which will be filed later today. Let me now take a moment to provide some context and highlight a few key points. Full year 2023 net PYRUKYND revenue was $26.8 million compared with $11.7 million in PYRUKYND revenue for 2022. Q4 2023 net PYRUKYND revenue was $7.1 million, a 4% reduction compared to the third quarter. The reduction was driven by lower number of weeks on hand of inventory compared to where we ended Q3, partially offset by favorability in gross-to-net adjustments. As a reminder, we anticipate low levels of inventory at any given time given our limited distribution network, which consists of one specialty pharmacy and one specialty distributor.

Consistent with other rare disease launches, gross-to-net is expected to be in the 10% to 20% range on an annual basis. Based on our learnings to date, given the ultra-rare nature of the disease and the long lead times associated with initiating patients on therapy, we continue to expect slow and steady growth and quarter-to-quarter variability in 2024, similar to what we saw in 2023. Cost of sales for the fourth quarter was $0.6 million. R&D expenses were $77 million for the fourth quarter and $296 million for the full year 2023, an increase of $16 million compared to the full year 2022. These changes reflect an increase in development costs for mitapivat and the upfront payments associated with the license agreement with Alnylam. Offset by a reduction in expenses associated with the evolution of our research organization and the sale of our oncology business to Servier.

SG&A expenses were $35 million for the fourth quarter and $120 million for the full year 2023, a decrease of $2 million compared to the full year 2022. As a reminder, 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 US net sales. Servier publicly communicated plans to file for approval before the end of 2023, so we are eager to track their progress. We ended the year with cash, cash equivalents and marketable securities of approximately $806 million. We expect that this balance together with anticipated product revenue, interest income, and the potential for vorasidenib milestone would enable the company to fund our operating expenses and capital expenditures through several value creating milestones and at least into 2026.

This guidance does not include cash inflows that could extend a runway beyond 2026, including the potential royalties or royalty monetization from vorasidenib, commercializing with a pivot outside of the US through one or more partnerships or other potential strategies business or financial agreements. We remain focused on creating shareholder value, including by proactively managing our cost base and deploying a disciplined cash allocation approach as we prepare to support potential future launches of PYRUKYND. As we move toward additional potential value creating milestones in the near term, I am confident that our strong balance sheet will enable us to execute from a position of strength as we continue to pursue ways to create shareholder value.

I will now turn the call back over to Brian for his closing remarks.

Brian Goff: Thanks Cecilia. As we turn the page on a highly productive 2023, we’re focused on executing across the additional four Phase 3 readouts for mitapivat that we expect over the next two years, beginning with the Phase 3 ENERGIZE-T study in transfusion dependent thalassemia in the middle of this year. As we continue to stack successive positive data readouts for mitapivat, we are only growing more confident in the probability of success ahead. We’re well positioned with the differentiated mechanism of action that improves red blood cell health beyond hemoglobin increase and allows us to pursue large commercial opportunities with substantial value and the potential for two additional first-in-class and best-in-class indication for PYRUKYND as we build a multibillion dollar franchise in PK activation.

As we continue to take steps toward realizing our vision of becoming a leading rare disease company, we will continue to strive to be responsible stewards of our balance sheet and evaluate meaningful opportunities for value creation. Finally, I’d like to thank all of our employees for their hard work and dedication to our mission of developing and delivering transformative medicines that elevate and extend the lives of patients living with rare diseases and all of our partners, including the patients, physicians, caregivers, and participants in our clinical development programs. With that, we will now open the call for questions.

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Q&A Session

Operator: [Operator Instructions] Our first question comes from the line of Eric Smith with Cantor Fitzgerald.

Unidentified Analyst : Thanks for the question and congrats on all the recent development successes. I guess maybe one for Sarah, given the next milestone, the next milestone, key milestone at least, might be the ENERGIZE-T study for mitapivat in transfusion dependent patients. Can you give us a little bit of a preview here or set up with regard to the primary endpoint? I know you’re looking at transfusion reductions in a slightly different way than what we’ve been accustomed to seeing with the Luspatercept data so how might that primary endpoint definition change the way we view the data and what might the hurdle be?

Brian Goff: Great. Eric, thanks a lot for the question. Before Sarah goes, I just want to welcome you back to Agios earnings call. So Sarah, do you want to get started?

Sarah Gheuens: Sure. Thanks for the question. So indeed, our endpoint, our primary endpoint, has a different definition than the primary endpoint that Luspatercept used in the sense that we are looking at a 50% reduction in any 12-week rolling period, basically, over the 48 weeks that patients are assessed, which we believe is a more appropriate measure to assess a patient in the context of a dynamic disease over a longer stretch of time and which reflects better the real -world experience a patient may have. We do have a similar endpoint like the Luspatercept primary endpoint in our secondary endpoint. In regarding to the hurdles, it is a different endpoint indeed. The hurdle is not necessarily different in the sense that you have multiple assessment periods versus a fixed period in time.

The bar of 50%, of course, is higher than 33%, but like I said, because it’s every, any 12-week period, you have more shot on goal as to speak. This was an endpoint that Luspatercept also had in their assessment and in their review, but as it was not a pre-specified, like, primary or secondary analysis, that did not make it into the label.

Operator: Our next question comes from the line of Chris Raymond with Piper Sandler.

Chris Raymond: Thanks. Maybe just a question on the ENERGIZE data that we got last month. We’ve gotten a few questions from investors around the sort of the transition from the Phase 2 data to the Phase 3 data. There was a degradation in the hemoglobin response, but you measured these effects over different time points. I know you guys had said that there was no waning of efficacy over time, but maybe just square this difference that you saw, and I’ve got to follow up.

Sarah Gheuens: Sure. Thanks for the question. So the primary endpoint that we used in the Phase 2 was indeed different than the endpoint that we used in the Phase 3, meaning that for the Phase 2, we just looked at patients meeting the hemoglobin response at a single time point, and for the Phase 3, we incorporated duration in that endpoint over a longer stretch of time and measured at a later time point because it’s a chronic disease. So then from a Phase 2 perspective, you’re truly looking for maintenance over a longer duration of time. So we averaged hemoglobin over 12 weeks versus that just single time point, which is much easier to reach as a bar. In regards to the waning, we don’t see waning of our hemoglobin response. So we talked about in this trial behaves very similarly to how it behaves in PKD.

So once patients show a response, they tend to maintain that response over time. There’s always a little bit of fluctuation on the hemoglobin over time, but overall it stays positive and the line kind of stays horizontal in comparison to their baseline. So we feel very confident with the results that we have observed in ENERGIZE. In addition, it’s more than hemoglobin alone that we observed. We really saw an improvement on the FACIT-Fatigue there as well, which we believe is extremely meaningful because now we are adding to the hemoglobin plus story here. The things that we’ve observed in PKD now also have been observed in the non-transfusion dependent thalassemia population, and that continues to add to this consistent and compelling data story that we are continuing to generate.

Chris Raymond: Okay. Thanks. And then maybe just a follow-up to Eric’s question on the success bogey of ENERGIZE-T. I know you’re talking about different measures that’s not an apples-to-apples comparison to Luspatercept, but just as you’re thinking about the obvious difference, admitted to that as oral versus Luspatercept, which is not, just maybe talk in generalities how you see these two compounds sort of coexisting commercially.

Sarah Gheuens: Sure. So if we think about the non-transfusion dependent thalassemia patient population, they currently have no therapy available. So that is, we talked about if we get it through the next stages of development, it would be the therapy that it would be available for non-transfusion dependent patient populations. And it’s oral, indeed, which is a huge benefit specifically for that population, because patients aren’t going to clinic as frequently. And if you have a drug that requires frequent clinic visits, it adds to the burden of disease typically. For the transfusion-dependent patient population, there is indeed a subcutaneous product that’s available for transfusion-dependent beta- thalassemia patients. Our program has studied all genotypes of thalassemia.

So that’s one difference. The oral rise of administration here is very relevant because it’s allowed for almost seamless incorporation into a transfusion schedule that a patient may have versus requiring more visits on top of the transfusion schedule. In that sense, it’s also important to understand there’s a very different mechanism of action between those two products, which — this product is a stimulus. And red blood cell stimuli while mitapivat is trying to improve red blood cell health overall, and so we do think from that perspective, they’re vastly different.