© Reuters.
Agios Prescribed drugs Inc. (AGIO) lately shared promising updates throughout its earnings name, highlighting vital progress in its scientific growth packages for mitapivat and AG-946, potential remedies for varied hematologic illnesses. The corporate reported optimistic knowledge from key research, together with the Part 3 ENERGIZE research for mitapivat in non-transfusion-dependent thalassemia, and is getting ready for potential product launches within the coming years. With a robust monetary place, marked by $806 million in money and investments on the finish of 2023, Agios is poised to advance its late-stage growth and deal with excessive unmet wants in illnesses like sickle cell and thalassemia.
Key Takeaways
- Agios Prescribed drugs reported optimistic outcomes from three key research for mitapivat and AG-946.
- The corporate is getting ready for potential launches of mitapivat for thalassemia in 2025 and sickle cell illness in 2026.
- Agios plans to submit a regulatory submitting for mitapivat with the FDA by the tip of the 12 months.
- The corporate goals to be the primary to have a remedy authorised for all subtypes of thalassemia, focusing on the US, EU5, and the Gulf area markets.
- Agios ended the 12 months with a robust monetary place, with $806 million in money and investments.
Firm Outlook
- Agios is specializing in educating sufferers and clinicians about thalassemia and mitapivat as a remedy choice.
- The corporate intends to create shareholder worth by managing prices and strategically allocating money for future product launches.
- Agios is optimistic concerning the business alternatives for its differentiated mechanism of motion and potential indications for PYRUKYND.
Bearish Highlights
- The corporate acknowledged the problem of measuring the lifespan extension of wholesome and transfused purple blood cells in a transfusion setting, which isn’t presently deliberate for research.
Bullish Highlights
- Agios is assured within the potential of mitapivat as a foundational remedy for sickle cell illness.
- The corporate is inspired by the persistency of PYRUKYND’s efficiency in PK deficiency.
- Agios received an award for its cautious involvement with the sickle cell illness group in designing and recruiting for scientific trials.
Misses
- There was no point out of particular challenges or setbacks within the growth course of through the earnings name.
Q&A Highlights
- The first endpoint for the ENERGIZE-T research was clarified as a 50% discount in transfusion burden over a 12-week interval.
- Agios mentioned the business coexistence of mitapivat and Luspatercept, noting the multibillion-dollar alternative in PK activation.
- Within the growth of AG-946, a number of dose ranges can be examined within the Part 2b trial for MDS, together with larger doses than initially anticipated.
Agios Prescribed drugs Inc. stays steadfast in its dedication to delivering new therapies for hematologic illnesses and creating worth for its shareholders. With a strategic deal with advancing its late-stage growth pipeline and getting ready for upcoming product launches, Agios is well-positioned within the biopharmaceutical market. The corporate’s monetary power and dedication to addressing unmet medical wants in illnesses like sickle cell and thalassemia underscore its potential for continued progress and innovation.
InvestingPro Insights
Agios Prescribed drugs Inc. (AGIO) has proven a outstanding income progress of 141.99% over the past twelve months as of Q1 2023, an indication of the corporate’s increasing operations and potential for future success. This progress is complemented by a robust monetary place, as the corporate holds more money than debt on its stability sheet, which might present a stable basis for its deliberate product launches and scientific growth packages.
InvestingPro Ideas spotlight that analysts are optimistic about AGIO’s gross sales progress within the present 12 months, which aligns with the corporate’s personal optimistic outlook and preparations for potential market entries. Nevertheless, it is price noting that AGIO is rapidly burning via money, and analysts don’t anticipate the corporate to be worthwhile this 12 months. With a present market capitalization of roughly $1.5 billion and a price-to-book ratio of 1.69, AGIO is buying and selling at a excessive income valuation a number of, which signifies excessive expectations from the market concerning the corporate’s progress prospects.
Furthermore, AGIO’s inventory has skilled sturdy returns over the past month and three months, with worth complete returns of twenty-two.15% and 20.5% respectively, reflecting investor confidence within the firm’s strategic course and scientific developments.
For buyers looking for a deeper dive into AGIO’s monetary well being and future prospects, InvestingPro presents extra insights and metrics. There are 10 extra InvestingPro Ideas out there, which might additional inform funding choices. readers can entry the following pointers at https://www.investing.com/professional/AGIO and use the coupon code PRONEWS24 to get a further 10% off a yearly or biyearly Professional and Professional+ subscription.
Full transcript – Agios Prescribed drugs (AGIO) This fall 2023:
Operator: Good morning. And welcome to the Agios Fourth Quarter 2023 Earnings Convention Name. Presently, all members are in a listen-only mode. [Operator Instructions] Please be suggested that this name is being recorded at Agios’ request. I’d now like to show the decision over to Chris Taylor, Vice President, Investor Relations and Company Communications for Agios. Please go forward.
Chris Taylor: Thanks, operator. Good morning, everybody and welcome to Agios’ convention name and webcast to debate fourth quarter and full 12 months 2023 monetary outcomes and up to date enterprise highlights. You may entry slides for at present’s name by going to the Buyers part of our web site, agios.com. On at present’s name, I’m joined by our Chief Government Officer, Brian Goff; Dr. Sarah Gheuens, Chief Medical Officer and Head of Analysis and Improvement; Tsveta Milanova, our Chief Business Officer; and Cecilia Jones, Chief Monetary Officer. Earlier than we get began, I want to remind everybody that among the statements we make on this name will embody forward-looking statements. Precise occasions and outcomes might differ materially from these expressed or implied by any forward-looking statements on account of varied dangers, uncertainties and different elements, together with these set forth in our most up-to-date filings with the SEC and some other future filings that we could make with the SEC. With that, I’ll flip the decision over to Brian.
Brian Goff: Thanks Chris, and good morning, everybody, and thanks for becoming a member of us. Our mission at Agios is to develop and ship transformative medicines that elevate and lengthen the lives of sufferers dwelling with uncommon illnesses. Pushed by this purpose, we proceed to generate constant and compelling knowledge throughout our industry-leading PK Activator franchise. And with seamless cross-functional collaboration of the Agios crew, we made outstanding progress advancing this mission in 2023. Highlighting this progress, we reported three key knowledge readouts within the final 12 months. In June, we reported optimistic top-line knowledge from the Part 2 Portion of the RISE UP Research at mitapivat, our lead PK Activator in sickle cell illness, adopted by the complete knowledge set in December at ASH. Regardless of the sphere’s latest progress in sickle cell illness, there aren’t any novel oral therapies that each enhance anemia and cut back sickle cell ache crises, and that’s exactly what we purpose to ship with mitapivat. In November, we reported optimistic knowledge from the open-label Part 2a manner research of our different PK Activator, AG-946, in lower-risk MDS, with 40% of sufferers reaching the transfusion independence endpoint. And simply final month, we reported optimistic knowledge from the Part 3 ENERGIZE research of mitapivat in non-transfusion-dependent thalassemia. As a reminder, non-transfusion-dependent, or NTD, thalassemia accounts for roughly two-thirds of thalassemia within the U.S., and has no FDA-approved remedy choice. Regardless of not requiring common transfusions, NTD-thalassemia sufferers expertise vital affect on high quality of life, a variety of great morbidities, and an elevated danger of untimely loss of life. Collectively, the consistency of knowledge generated throughout the mitapivat growth program bolsters our conviction within the chance of success of our ongoing research, together with two extra Part 3 readouts we anticipate by the tip of this 12 months, and this knowledge highlights the potential of our PK activators to rework the course of a number of hematologic illnesses. Sarah will present extra element on our developments and upcoming milestones throughout our pipeline in just some minutes. Importantly, we consider our PK activation pipeline is properly positioned with a number of near-term catalysts to turn out to be a multi-billion greenback franchise and ship vital worth. In parallel with advancing the late-stage mitapivat growth program throughout a number of indications, our business group is laser targeted on constructing the infrastructure established via our present launch in PK deficiency to arrange for potential U.S. launches of mitapivat in thalassemia in 2025 and in sickle cell illness in 2026. Tsveta will present better element on the business alternatives for mitapivat in thalassemia, in addition to an replace on our present launch in PK deficiency in only a bit. Lastly, as you may hear from Cecilia, we ended 2023 with a robust money place with roughly $806 million in money and investments on the stability sheet. As well as, we proceed to trace Servier’s progress in direction of the potential FDA approval of vorasidenib given our retained economics for each a milestone and royalties. That is actually an thrilling time at Agios with 4 extra Part 3 readouts and two potential launches anticipated on the horizon. We stay up for a number of alternatives to drive vital near-term worth creation for sufferers, caregivers, and shareholders. With that, I will now flip the decision over to Sarah.
Sarah Gheuens: Thanks, Brian. In 2023, our analysis and growth group made great progress advancing our PK activator growth program. Led by mitapivat, the {industry}’s most superior PK activator, now with over eight years of scientific expertise, the constant and compelling knowledge we’ve generated to this point in PK deficiency, thalassemia and sickle cell illness to proceed to de-risk our ongoing growth program and spotlight the potential for this molecule to rework affected person’s perform and high quality of life. We’re additionally enthusiastic concerning the potential for the remainder of our rising pipeline, and we’re happy to notice that we stay on observe to ship on our milestones, together with, enrolling the primary sufferers within the Part 2b trial for AG-946 in decrease danger MDS, and for the Part 1 trial for AG-181, the compounds named for our PAH stabilizer for phenylketonuria. Studying our high line knowledge for the Part 3 ACTIVATE kids-T research in repeatedly transduced pediatrics sufferers with TK deficiency, and finishing enrollment of the Part 3 ACTIVATE kids-T research in pediatric sufferers with TKB. Turning to sickle cell illness, we had been happy to current detailed optimistic outcomes from the Part 2 Portion of the Part 2/3 RISE UP Research mitapivat at ASH in December. The research achieved its main endpoint of hemoglobin response, and as well as, an enchancment in analyzed charges of sickle cell ache crises was noticed. And we’ve been delighted by the keenness of the investigators. We proceed to advance enrollment within the Part 3 portion of this research and stay on observe to finish enrollment by the tip of this 12 months. Whereas the remedy panorama in sickle cell illness continues to evolve, there stays an pressing and unmet want for handy novel oral remedy choices that deal with each anemia and sickle cell ache crises. And we consider firmly in mitapivat’s potential to ship a best-in-class choice for sufferers affected by this devastating illness. And eventually, on thalassemia, I will take a second to spotlight a couple of key parts of our program, and the optimistic top-line Part 3 knowledge we reported final month in non-transfusion-dependent thalassemia. As a reminder, the Part 3 program of PYRUKYND in thalassemia, and compacting two Part 3 randomized placebo-controlled trials, was designed to ship knowledge throughout all sub-populations of thalassemia, akin to alpha-and beta-thalassemia and populations with completely different transfusion wants. Each trials enrolled sufferers with alpha or beta-thalassemia, however enrolled completely different populations because it pertains to transfusion wants. We wish to spotlight that ENERGIZE is the primary scientific program that included sufferers who weren’t repeatedly transfused and alpha-thalassemia sufferers. As Brian talked about, there aren’t any FDA-approved remedies for non-transfusion-dependent thalassemia, which represents roughly two-thirds of complete thalassemia sufferers within the U.S. These sufferers endure from a poor high quality of life, a excessive price of great morbidities, together with thrombosis and untimely loss of life. We had been subsequently very happy to have the ability to announce optimistic outcomes from the ENERGIZE research. As a reminder, the ENERGIZE research enrolled a complete of 194 sufferers with both alpha or beta non-transfusion-dependent thalassemia, randomized 2:1 to 100 milligrams mitapivat or placebo twice day by day. The pace of enrollment and the precise variety of sufferers enrolled on this research, in addition to the excessive completion and rollover price, helps the concept that people who find themselves not repeatedly transfused had been motivated to take motion and converse to the unmet want for this inhabitants. The first endpoint of this research was hemoglobin response price, outlined as a rise of at the very least one gram per deciliter in common hemoglobin focus from week 12 to week 24 in comparison with baseline. The important thing secondary endpoints of this research had been change from baseline in common FACIT-Fatigue Rating and alter from baseline in common hemoglobin focus, additionally each assessed from week 12 to 24. On the first endpoints, remedy with mitapivat demonstrated a extremely statistically vital consequence, with 42.3% of sufferers within the remedy arm reaching a hemoglobin response versus 1.6% of sufferers within the placebo arm. In step with mitapivat’s novel mechanism of motion, which focuses on total purple blood cell well being, and the information generated with mitapivat throughout extra illness areas, the helpful results of mitapivat on this research prolonged past hemoglobin alone. Particularly, remedy with 100 milligrams mitapivat resulted in statistically vital enhancements in each key secondary endpoints, together with a change from baseline and common FACIT-Fatigue Rating, an essential patient-reported measure of how sufferers really feel and performance. Importantly, throughout the first and secondary endpoints, all pre-specified subgroup analyses favored mitapivat in comparison with placebo, suggesting that no single subgroup was answerable for driving the outcomes, which helps our plan to file for a broad label overlaying all thalassemia subtypes. That is subsequently the primary drug that not solely improves hemoglobin however really makes individuals with thalassemia really feel higher, per what we observe in sufferers with PKD and what we hope to have the ability to ship for sufferers with sickle cell illness as properly. Complementing the near-term advantages of thalassemia sufferers reporting that they’d much less fatigue and felt higher within the near-term, clinicians within the trial and different KOLs recognize the potential longer-term advantages of decreasing markers of hemolysis and the longer-term potential to scale back severe morbidity. We’re very a lot wanting ahead to presenting the complete knowledge set at a medical assembly. Past the thrill we’ve for the ENERGIZE knowledge itself, the readout of the ENERGIZE trial additionally offers us additional confidence in direction of the readout of ENERGIZE-T. Thalassemia is a hemolytic anemia regardless of whether or not a affected person is in want of transfusions or not. As well as, the mechanism of motion of mitapivat shouldn’t be depending on the necessity for transfusions. We’ve got already demonstrated an enchancment in hemolytic anemia within the ENERGIZE trial with a optimistic change in hemoglobin. We are actually ready to see if the development in hemolytic anemia can be documented through a discount in transfusions in ENERGIZE-T. As a reminder, the first endpoint of ENERGIZE-T is transfusion discount response, outlined as a 50% or better discount in transfused purple blood cell models with a discount of equal or greater than two models of transfused purple blood cells in any consecutive 12-week interval via week 48 in comparison with baseline. Just like the energized research in non-transfusion-dependent thalassemia, the design of the ENERGIZE-T trial allows us to exhibit scientific meaningfulness in quite a lot of methods to see a discount in transfusion burden, which additionally consists of transfusion metrics in keeping with that different research have used. We designed this research incorporating studying from prior research and company suggestions and consider a dynamic evaluation sequence is essential as sufferers aren’t static of their illness. We stay up for the readout of this research by mid-year and plan a single regulatory submitting to the FDA and compacting knowledge from each ENERGIZE and ENERGIZE-T by the tip of this 12 months, looking for a label that can allow individuals dwelling with thalassemia entry to a handy and differentiated oral remedy choice. Total, I am very happy with the great progress made by our R&D group in 2023 and stay up for persevering with this momentum in 2024. With that, I’ll now flip the decision over to Tsveta.
Tsveta Milanova: Thanks, Sarah. Thalassemia stays an space of excessive unmet wants with few remedy choices. The burden of illness on the affected person is critical no matter their transfusion wants. Thalassemia sufferers expertise elevated mortality in comparison with the final inhabitants and will be considerably worse in non-regularly transfused than those that are repeatedly transfused. Sufferers endure excessive charges of morbidities and improve problems as they age. Grownup affected person with non-transfusion dependent thalassemia may very well have comparable or worse high quality of life in comparison with transfusion dependent sufferers. In fact, this burden of illness correlates to elevated healthcare prices. To deal with this unmet want and galvanized by the optimistic knowledge from the Part 3 ENERGIZE research of mitapivat, our business group is actively getting ready for a possible launch in thalassemia subsequent 12 months, starting with the US. Within the US, there are roughly 6, 000 recognized grownup sufferers with thalassemia. Roughly 4, 000 of those sufferers you’re non-transfusion dependent and haven’t any out there remedy choices at present. The remaining 2, 000 sufferers are transfusion dependent and haven’t any oral remedy choices. Our purpose with mitapivat is to deal with the unmet wants of all adults dwelling with a thalassemia and turn out to be the primary remedy authorised for all subtypes of the illness. Along with the information we’re producing via the mitapivat scientific growth program, there are three key elements we consider have the potential to help adoption of mitapivat among the many thalassemia sufferers within the US. First, there may be sturdy alignment between the place within the US these sufferers reside and the place they obtain remedy. The [inaudible] slide 20 depicts affected person prevalence overlaid with the Agios scientific trial website and or facilities of excellence represented by the gold stars. Second, the analysis price is excessive, pushed by availability of new child screening and well-established ITD-10 codes. Many sufferers are recognized earlier than maturity. And eventually, as proven on slide 21, there may be focus of sufferers and suppliers at chosen facilities. Roughly 50% of all recognized sufferers are handled a fewer than 150 affiliated hematology oncology practices within the US, offering a transparent focus for our preliminary launch. Given this market dynamic and PYRUKYND goal product profile, we consider we’re properly positioned to supply a possible foundational remedy choice for sufferers with thalassemia no matter subtype. Subsequently, our crew is targeted on 4 core areas of US launch preparation. First, constructing on the foundational work we’ve already achieved, we proceed to deepen the sophistication of our market understanding. We’re conducting intensive market analysis and claims knowledge evaluation to tell ATP focusing on, discipline pressure sizing, and deployment for launch. Second, we can be rolling out a illness training marketing campaign for each sufferers and clinicians, highlighting the long-term problems and burden of illness throughout all thalassemia subtypes. Our illness training engagement can even work to appropriate the historic misperception that non-transfusion dependent sufferers are much less prone to expertise the debilitating long-term results of thalassemia. To help these initiatives, we’re establishing capabilities to allow execution of our instructional efforts throughout private and non-personal channels. Third, we’ll proceed to strengthen our business capabilities by increasing our gross sales crew in anticipation of thalassemia launch, right-sizing the crew for a broader uncommon illness. And lastly, in parallel with these efforts, we’re getting ready our market entry crew to have interaction with payers on illness secure training prematurely of the potential launch of thalassemia subsequent 12 months. Our crew has obtained success in market entry for PTA deficiency, and we stay up for watching them pave the best way in thalassemia too. Along with the well-established US thalassemia market, there are roughly 13, 000 sufferers within the EU5 and roughly 70 ,000 thalassemia sufferers within the Gulf area. We purpose to maximise the potential of this extra market via coordinated regulatory filings, which we intend to pursue with companions. Taken collectively, we consider the potential launch of mitapivat in thalassemia represents a major alternative for Agios and a step ahead as we put together for potential back-to-back launches with sickle cell illness in 2023. Now, let me present an replace on the present launch of PYRUKYND and PK deficiency. Within the fourth quarter of 2023, we generated $7.1 million in internet PYRUKYND income, in comparison with $7.4 million within the prior quarter. A complete of 178 sufferers have accomplished a prescription enrollment kind, together with 18 within the fourth quarter of 2023, an 11% improve versus the third quarter. This translated into internet 109 sufferers on remedy, a 9% improve versus the third quarter. Sufferers on remedy proceed to spend from a rising and numerous prescriber base of 164 physicians and characterize a broader demographic and illness manifestation vary that’s per the grownup PK deficiency inhabitants. We proceed to be inspired by the persistency of sufferers on remedy and stay targeted on effectively figuring out suppliers prone to deal with sufferers with PK deficiency. The capabilities we proceed to construct and increase via the present launch, together with environment friendly focusing on analytics, affected person’s consciousness and training and affected person entry will present a agency basis from which we will maximize the potential U.S. launches in thalassemia in 2025 and in sickle cell illness in 2026. As we advance via this catalyst-rich interval of Part 3 knowledge readouts for mitapivat, we stay up for dramatically increasing the variety of sufferers we serve. With that, I’ll flip the decision over to Cecilia.
Cecilia Jones: Thanks, Tsveta. Our fourth quarter 2023 monetary outcomes will be discovered within the press launch we issued this morning, and extra element can be included in our 10-Okay, which can be filed later at present. Let me now take a second to supply some context and spotlight a couple of key factors. Full 12 months 2023 internet PYRUKYND income was $26.8 million in contrast with $11.7 million in PYRUKYND income for 2022. This fall 2023 internet PYRUKYND income was $7.1 million, a 4% discount in comparison with the third quarter. The discount was pushed by decrease variety of weeks readily available of stock in comparison with the place we ended Q3, partially offset by favorability in gross-to-net changes. As a reminder, we anticipate low ranges of stock at any given time given our restricted distribution community, which consists of 1 specialty pharmacy and one specialty distributor. In keeping with different uncommon illness launches, gross-to-net is predicted to be within the 10% to twenty% vary on an annual foundation. Based mostly on our learnings to this point, given the ultra-rare nature of the illness and the lengthy lead instances related to initiating sufferers on remedy, we proceed to anticipate gradual and regular progress and quarter-to-quarter variability in 2024, just like what we noticed in 2023. Price of gross sales for the fourth quarter was $0.6 million. R&D bills had been $77 million for the fourth quarter and $296 million for the complete 12 months 2023, a rise of $16 million in comparison with the complete 12 months 2022. These modifications mirror a rise in growth prices for mitapivat and the upfront funds related to the license settlement with Alnylam. Offset by a discount in bills related to the evolution of our analysis group and the sale of our oncology enterprise to Servier. SG&A bills had been $35 million for the fourth quarter and $120 million for the complete 12 months 2023, a lower of $2 million in comparison with the complete 12 months 2022. As a reminder, as a part of the divestiture of our oncology enterprise to Servier, we retain rights to a possible $200 million milestone upon FDA approval of vorasidenib and 15% royalties on potential US internet gross sales. Servier publicly communicated plans to file for approval earlier than the tip of 2023, so we’re keen to trace their progress. We ended the 12 months with money, money equivalents and marketable securities of roughly $806 million. We anticipate that this stability along with anticipated product income, curiosity earnings, and the potential for vorasidenib milestone would allow the corporate to fund our working bills and capital expenditures via a number of worth creating milestones and at the very least into 2026. This steering doesn’t embody money inflows that would lengthen a runway past 2026, together with the potential royalties or royalty monetization from vorasidenib, commercializing with a pivot exterior of the US via a number of partnerships or different potential methods enterprise or monetary agreements. We stay targeted on creating shareholder worth, together with by proactively managing our price base and deploying a disciplined money allocation method as we put together to help potential future launches of PYRUKYND. As we transfer towards extra potential worth creating milestones within the close to time period, I’m assured that our sturdy stability sheet will allow us to execute from a place of power as we proceed to pursue methods to create shareholder worth. I’ll now flip the decision again over to Brian for his closing remarks.
Brian Goff: Thanks Cecilia. As we flip the web page on a extremely productive 2023, we’re targeted on executing throughout the extra 4 Part 3 readouts for mitapivat that we anticipate over the following two years, starting with the Part 3 ENERGIZE-T research in transfusion dependent thalassemia in the course of this 12 months. As we proceed to stack successive optimistic knowledge readouts for mitapivat, we’re solely rising extra assured within the chance of success forward. We’re properly positioned with the differentiated mechanism of motion that improves purple blood cell well being past hemoglobin improve and permits us to pursue massive business alternatives with substantial worth and the potential for 2 extra first-in-class and best-in-class indication for PYRUKYND as we construct a multibillion greenback franchise in PK activation. As we proceed to take steps towards realizing our imaginative and prescient of turning into a number one uncommon illness firm, we’ll proceed to attempt to be accountable stewards of our stability sheet and consider significant alternatives for worth creation. Lastly, I might wish to thank all of our workers for his or her onerous work and dedication to our mission of growing and delivering transformative medicines that elevate and lengthen the lives of sufferers dwelling with uncommon illnesses and all of our companions, together with the sufferers, physicians, caregivers, and members in our scientific growth packages. With that, we’ll now open the decision for questions.
Operator: [Operator Instructions] Our first query comes from the road of Eric Smith with Cantor Fitzgerald.
Unidentified Analyst: Thanks for the query and congrats on all of the latest growth successes. I suppose possibly one for Sarah, given the following milestone, the following milestone, key milestone at the very least, may be the ENERGIZE-T research for mitapivat in transfusion dependent sufferers. Are you able to give us a bit of little bit of a preview right here or arrange with regard to the first endpoint? I do know you are taking a look at transfusion reductions in a barely completely different manner than what we have been accustomed to seeing with the Luspatercept knowledge so how would possibly that main endpoint definition change the best way we view the information and what would possibly the hurdle be?
Brian Goff: Nice. Eric, thanks loads for the query. Earlier than Sarah goes, I simply wish to welcome you again to Agios earnings name. So Sarah, do you wish to get began?
Sarah Gheuens: Certain. Thanks for the query. So certainly, our endpoint, our main endpoint, has a distinct definition than the first endpoint that Luspatercept used within the sense that we’re taking a look at a 50% discount in any 12-week rolling interval, principally, over the 48 weeks that sufferers are assessed, which we consider is a extra acceptable measure to evaluate a affected person within the context of a dynamic illness over an extended stretch of time and which displays higher the true -world expertise a affected person could have. We do have an identical endpoint just like the Luspatercept main endpoint in our secondary endpoint. In concerning to the hurdles, it’s a completely different endpoint certainly. The hurdle shouldn’t be essentially completely different within the sense that you’ve got a number of evaluation durations versus a hard and fast interval in time. The bar of fifty%, in fact, is larger than 33%, however like I mentioned, as a result of it is each, any 12-week interval, you have got extra shot on purpose as to talk. This was an endpoint that Luspatercept additionally had of their evaluation and of their evaluate, however because it was not a pre-specified, like, main or secondary evaluation, that didn’t make it into the label.
Operator: Our subsequent query comes from the road of Chris Raymond with Piper Sandler.
Chris Raymond: Thanks. Possibly only a query on the ENERGIZE knowledge that we obtained final month. We have gotten a couple of questions from buyers across the kind of the transition from the Part 2 knowledge to the Part 3 knowledge. There was a degradation within the hemoglobin response, however you measured these results over completely different time factors. I do know you guys had mentioned that there was no waning of efficacy over time, however possibly simply sq. this distinction that you simply noticed, and I’ve obtained to observe up.
Sarah Gheuens: Certain. Thanks for the query. So the first endpoint that we used within the Part 2 was certainly completely different than the endpoint that we used within the Part 3, which means that for the Part 2, we simply checked out sufferers assembly the hemoglobin response at a single time level, and for the Part 3, we included length in that endpoint over an extended stretch of time and measured at a later time level as a result of it is a power illness. So then from a Part 2 perspective, you are actually on the lookout for upkeep over an extended length of time. So we averaged hemoglobin over 12 weeks versus that simply single time level, which is way simpler to succeed in as a bar. Regarding the waning, we do not see waning of our hemoglobin response. So we talked about on this trial behaves very equally to the way it behaves in PKD. So as soon as sufferers present a response, they have an inclination to keep up that response over time. There’s all the time a bit of little bit of fluctuation on the hemoglobin over time, however total it stays optimistic and the road form of stays horizontal compared to their baseline. So we really feel very assured with the outcomes that we’ve noticed in ENERGIZE. As well as, it is greater than hemoglobin alone that we noticed. We actually noticed an enchancment on the FACIT-Fatigue there as properly, which we consider is extraordinarily significant as a result of now we’re including to the hemoglobin plus story right here. The issues that we have noticed in PKD now even have been noticed within the non-transfusion dependent thalassemia inhabitants, and that continues so as to add to this constant and compelling knowledge story that we’re persevering with to generate.
Chris Raymond: Okay. Thanks. After which possibly only a follow-up to Eric’s query on the success bogey of ENERGIZE-T. I do know you are speaking about completely different measures that is not an apples-to-apples comparability to Luspatercept, however simply as you are fascinated with the plain distinction, admitted to that as oral versus Luspatercept, which isn’t, simply possibly speak in generalities the way you see these two compounds kind of coexisting commercially.
Sarah Gheuens: Certain. So if we take into consideration the non-transfusion dependent thalassemia affected person inhabitants, they presently haven’t any remedy out there. So that’s, we talked about if we get it via the following levels of growth, it could be the remedy that it could be out there for non-transfusion dependent affected person populations. And it is oral, certainly, which is a large profit particularly for that inhabitants, as a result of sufferers aren’t going to clinic as often. And when you have a drug that requires frequent clinic visits, it provides to the burden of illness usually. For the transfusion-dependent affected person inhabitants, there may be certainly a subcutaneous product that’s out there for transfusion-dependent beta- thalassemia sufferers. Our program has studied all genotypes of thalassemia. In order that’s one distinction. The oral rise of administration right here may be very related as a result of it is allowed for nearly seamless incorporation right into a transfusion schedule {that a} affected person could have versus requiring extra visits on high of the transfusion schedule. In that sense, it is also essential to grasp there is a very completely different mechanism of motion between these two merchandise, which — this product is a stimulus. And purple blood cell stimuli whereas mitapivat is attempting to enhance purple blood cell well being total, and so we do assume from that perspective, they’re vastly completely different.
Brian Goff: Sure, and Chris, I imply, that final level is the one which I’d simply emphasize, is that I do know of us are attempting to make comparisons, however in so some ways, they’re incomparable due to the profound distinction within the mechanisms. And you may hear loads from us as a result of we proceed to be emboldened by this, by the information that we see very constantly that the advantages of the of PYRUKYND kinase activation actually do transcend hemoglobin. So we’ll await the information. Happily, we do not have to attend that lengthy. ENERGIZE-T is coming mid-year. However I feel above oral and the opposite dimensions, hemoglobin and the like, that is actually the massive headline for this mechanism is, it is finally about purple blood cell well being.
Operator: Our subsequent query comes from the road of Danielle Brill with Raymond James.
Danielle Brill: Hello guys, good morning. Thanks a lot for the questions. I even have a query on powering assumptions for ENERGIZE-T. Like Chris mentioned, we all know it isn’t apples-to-apples. However whenever you take a look at Luspatercept, their imply hemoglobin improve is about 1.5 grams. They usually achieved, I feel, round a 40% response price in your main endpoint. With this context, what are your inside expectations for a way mitapivat will carry out? And I even have a follow-up.
Sarah Gheuens: Thanks for the query. So with regard to powering assumptions, we’ve not spoken about these, however we’ve, in fact, studied the entire packages in entrance of us, which incorporates our personal inside packages wherein we took a really comparable growth method for thalassemia as we’ve for PKD. Regarding the hemoglobin improve that you simply talked about, so we do not, from a transfusion dependent perspective, we do not consider you essentially want to extend hemoglobin on high of creating individuals cut back their transfusions. That is actually a distinct method as a result of individuals, after they get transfused, their hemoglobin goes down over time. So what we are attempting to do right here is principally avoiding that folks, their hemoglobin decreases again to a transfusion set off, which then would set off a transfusion. And it comes down once more to that completely different mechanism of motion. In case you are like stimulating out purple blood cells, finally, you are going to improve the hemoglobin versus what we’re attempting to do about retaining the purple blood cells happier and more healthy, thereby decreasing hemolysis. It is a fully completely different manner of truly attempting to keep away from transfusions.
Danielle Brill: Thanks, Sarah. That is useful. And that really is an ideal segway for my follow-up. Do you have got knowledge on the potential of mitapivat for extending the half -life of wholesome purple blood cells?
Sarah Gheuens: So we, within the context of, you imply, wholesome volunteers purple blood cells?
Danielle Brill: Or like, sure, extending the lifespan of transfused blood.
Sarah Gheuens: So, sure, so that is one thing that’s extraordinarily troublesome to measure within the context of a transfusion setting as every part is form of combined. So it could require a really, very distinctive experiment to have the ability to tease aside these sorts of purple blood cells which are out there, so we’re not planning on doing that proper now for transfusion-dependent sufferers.
Operator: And our subsequent query comes from the road of Gregory Renza with RBC Capital Markets.
Gregory Renza: Hey, good morning, Brian and crew. Congrats on all of the progress, and thanks for taking my questions. Brian, you actually converse to the multibillion greenback alternative out there with PK activation and your portfolio. I am simply curious in case you might possibly simply elaborate a bit of bit on that, possibly present among the inputs or assumptions that you simply’re utilizing to get to that attribute, whether or not it is with respect to mitapivat and the ramp of indications or the broader portfolio. And possibly I will simply layer in my second query, which with respect to the panorama in PK activation, maybe in case you and Sarah can simply riff a bit of bit about possibly the variations with mitapivat versus others, particularly etavopivat. Actually you’ve got talked about the lead. You have got the physique of knowledge, however when you concentrate on among the nuances on pan-PK activation and even selectivity, possibly simply assist us perceive the variations between mitapivat and the panorama. Thanks a lot.
Brian Goff: Sure, thanks, Greg. So I will get began in your first query concerning the multibillion greenback alternatives that I referenced in my ready feedback. That actually comes from the truth that we’re quickly progressing in our pipeline, shifting from clear ultra-rare with PKD into successively bigger prevalent illnesses. A few of these illnesses, I feel are properly characterised when it comes to alternative, sickle cell for positive, the place there’s been lot of curiosity and lots of therapeutic growth focus. And right here we’re speaking about shifting from 3, 000 to eight, 000 sufferers throughout the US in EU5 within the case of PKD, leaping to only within the US alone 100, 000 sufferers with sickle cell illness. Nevertheless it’s greater than that. I imply, as we have already mentioned this morning, we had this actually thrilling alternative comparatively close to time period with a possible launch subsequent 12 months in thalassemia which is a prevalent step up within the case of the US from PKD. Sickle cell, I simply talked about. After which even after that with our different PK activator, AG-946, shifting into low danger MDS. The nice information about all that is we’re shifting in the correct course when it comes to prevalence. And that’s permitting us to enter into very compelling business alternatives. And it additionally permits us to navigate via the suitable pricing dynamics as we go ahead. However we’re very excited, most significantly, with the truth that as we advance our pipeline and as we have already famous, we’ve two back-to-back launch potentials with thalassemia subsequent 12 months adopted by sickle cell illness in 2026. After which, Sarah, you wish to choose up with the following query?
Sarah Gheuens: Certain. So, with regard to PK activation and the variations between mitapivat and another PK activators, so we certainly, properly, whereas we stimulate PK, completely different PK isoenzymes amongst which the PKR, which is essential for the purple blood cell, however then additionally PKM2 is essential, then we perceive increasingly more the relevance of this particular isoenzyme within the context of the illnesses that we’re learning. And as you recognize, thalassemia, sickle cell illness, MDS, there may be completely different parts to those illnesses wherein stimulation of PKM-2 could also be related as it’s expressed in immature purple blood cells. It’s expressed in different tissues which are additionally touched by these illnesses. We’re planning to additional research this clinically as properly, particularly in sickle cell illness within the kidney. As we all know, kidney is such an essential organ within the context of sickle cell illness, and now many sufferers endure from kidney illness, and we consider that PKM-2 could have an added benefit there. With reference to how that compares to different PK activators, particularly at our Etavopivat that’s, they, that is the drug that was once Forma’s drug, they all the time spoke about being a PKR selective agent with regard to how they translate into different isoenzymes, they haven’t spoken about that. They’ve simply highlighted their selectivity message.
Operator: Our subsequent query comes from the road of Salveen Richter with Goldman Sachs.
Unidentified Analyst: Hello, that is Lydia on for Salveen. Thanks a lot for taking our query. Only one on sickle cell. May you simply talk about the place you see PYRUKYND becoming into the present business panorama simply broadly? After which are you able to additionally converse to the enrollment development and any doctor suggestions you’ve got gotten to this point? Thanks a lot.
Brian Goff: Certain. And possibly I’ll simply begin after which rapidly flip it over to Tsveta after which Sarah can choose up on the enrollment features. I imply, the basic premise of what we’re driving in direction of with sickle cell illness is we consider that mitapivat, PYRUKYND has the potential to be what we discuss with as foundational remedy. It is a very completely different mechanism of motion as we have talked about. Very distinctive from presently out there choices. We’re more and more satisfied that the advantages on making the purple blood cells more healthy actually place it as such. After which the truth that that is an oral remedy solely provides to that potential. However I will let Tsveta converse a bit of bit extra about not simply how we’re fascinated with sickle cell illness, however the bridge as we go from PKD to thalassemia after which the sickle cell.
Tsveta Milanova: Thanks, Brian. I will begin with sickle cell illness for us, however as you mentioned, we’ve an important milestone with the thalassemia launch forward of that, which we consider can be an essential level from rising the business capabilities executing on the thalassemia launch. And after that capitalizing on sickle cell illness. After we take into consideration sickle cell illness, Brian talked about that and Sarah talked about that already the prevalence of the illness is 100, 000 sufferers within the US, which is a major step up from the place we’re at present with PK deficiency. It is a illness the place sufferers are recognized and the burden of illness is properly characterised. In the mean time, the grownup affected person inhabitants with sickle cell illness has very restricted remedy choices out there. They’re both enhancing hemoglobin ranges, which is the case of a brighter or enhancing VOCs primarily based on the Part 2 knowledge and the goal product profile, we’ve for a PYRUKYND for launch. We consider that we’ll be very properly positioned with PYRUKYND to supply a remedy choice, which can convey advantages to physicians, sufferers, and finally, payers as properly by enhancing hemoglobin, decreasing VOCs, and finally enhancing the best way sufferers really feel and performance. And that is going to be a novel worth proposition if we had been to ship on that profile. So we’re very enthusiastic about that chance to come back. However earlier than we get to sickle cell illness, we are literally very excited to progress with our launch preparations for thalassemia as properly. After we noticed the outcomes from the ENERGIZE knowledge within the 12 months, we’ve undoubtedly pressed the button and are actively getting ready for thalassemia launch to come back in 2025. Much like sickle cell illness, I feel the thalassemia launch can be meaningfully differentiated when it comes to market traits in comparison with PKD and that can place us properly for adoption of PYRUKYND, assuming approval in 2025, together with once more, these sufferers are recognized, it is 6, 000 recognized sufferers within the US with thalassemia, and well-established ICD 10 personal, a stronger focus of the prescribed base and all of those parts offers us confidence on our capability to commercialize the product and drive adoption at launch. And just like sickle cell illness, there’s a higher understanding of the thalassemia unmet wants throughout each the transfusion dependent but in addition the non-transfusion dependent sufferers as properly. So we’re gearing up and on the brink of commercialization to go, launch in thalassemia in 2025 doubtlessly, adopted by again to again launch in sickle cell illness in 2026.
Brian Goff: After which, I used to be simply going to say that is nice, Tsveta. And I feel all people can sense of pleasure about what we’ve in entrance of us and I used to be simply going to ask Sarah to make a remark concerning the progress with RISE UP Part 3 for sickle cell.
Sarah Gheuens: Precisely as a result of we’re equally excited to maneuver in direction of these launches, so we’re closely targeted on our Part 3 enrollments in fact proper now. The trial is progressing as we’re anticipating, there’s lots of enthusiasm each inside our groups and naturally by the investigators as properly, and so every part is on observe to ship to the milestone that we’ve set out for this 12 months.
Operator: Our subsequent query comes from the road of Tess Romero with JP Morgan.
Tess Romero: Nice. Good morning, Brian and crew. Thanks for taking our query. So, switching gear a bit of bit to business PKD. Do you continue to assume that PKD might be a $200 million to $250 million peak alternative right here within the US? And if that’s the case, how lengthy do you assume it might take you to get there? After which my second query is, we all know that you simply’re shifting AG-946 ahead and decrease danger MDS. However we had been curious, have you ever formally deprioritized this system in sickle cell illness, as we hadn’t heard something on this shortly? Are you able to verify if that is the case or not? Thanks a lot for taking our query.
Brian Goff: Thanks loads, Tess. Really, the second query, we will deal with that in a short time, which is not any. And we’ve not deprioritized something with AG-946. I feel we’re impressed by the potential. And on the proper time, we’ll present updates concerning the progress, not simply in our pursuits of low danger MDS, but in addition the place we stand with respect to sickle cell illness. Cecilia, do you wish to touch upon the primary one?
Cecilia Jones: Yeas positive. Thanks, Tess, for the query. So we undoubtedly stay excited concerning the alternative in PKD, and we proceed to anticipate these peak gross sales at $200 million to $225 million for the US. We proceed to make progress every quarter, and we’re studying, and as Tsveta mentioned, that is serving to additionally construct these capabilities for that launch. We expect it may be gradual and regular, persevering with to see the developments we have seen in 2023 for the following few years. However we do nonetheless preserve our peak of $200 million to $225 million.
Brian Goff: Sure, I imply, with PKD, and we have talked about this beforehand, however within the deep business expertise that each Tsveta and I’ve throughout a number of uncommon illness instances, this one’s powerful. It is a problem. It’s extremely uncommon. It is diagnostically intensive. There are lengthy lead instances for sufferers. So gradual and regular is the correct phrase. What had been proceed to be impressed by every quarter is that persistency, which is one thing we noticed comparatively early with the launch of PYRUKYND and PKD, that may be a actually essential characteristic as we take into consideration power uncommon illness launch is to come back which are in our websites. And so we’ll take the gradual and regular path and we’ll proceed to anticipate that going ahead. However the best way PYRUKYND is performing is what we consider actually places us ready of power as we method ENERGIZE, sorry, preserve seeing ENERGIZE, as we method thalassemia in addition to sickle cell past that.
Operator: Our subsequent query comes from the road of Greg Harrison with Financial institution of America.
Greg Harrison: Hey, good morning. And thanks for taking the query. Additionally, simply needed to observe up on AG- 946. How are you considering simply usually in growth, about growth and doubtlessly overlapping indications with mitapivat that might be enchancment? For instance, in sickle cell, such as you mentioned, and even thalassemia. And what would it’s essential to see from 946 as a way to make that call?
Brian Goff: Sure, I will begin after which Sarah can leap in. To begin with, Greg, I hope we’re in that place the place we’ve a number of indications, simply as we’ve proper now with PYRUKYND. One of many key benefits of, at Agios, of getting actually a number one PK activation franchise is we’ve not one, however two merchandise that we’re growing. And that permits us to have completely different economics, completely different pricing dynamics throughout the indications in between the merchandise. I feel there is a extensive sufficient house for us proper now, given the place we’re within the growth program with AG-946 that we will tailor the suitable goal product profiles, whether or not it is for sickle cell illness or for low danger MDS. And within the case of low danger MDS, as I feel of us know, we simply reported out final 12 months very encouraging proof-of-concept from our Part 2a research. And we’re within the course of proper now of creating enhancements within the design so we will pursue Part 2b. I really feel superb concerning the work the crew has achieved and that’ll be the following step. And as I discussed earlier than, on the proper time, we’ll additionally report out the progress on sickle cell illness. Something you wish to add, Sarah?
Sarah Gheuens: Simply excessive degree, I feel what you possibly can anticipate from growth is that we all the time attempt to design our trials to fulfill a number of stakeholders, their wants, which means we take our goal product profile very severely. So that’s one thing that for 946 is identical. We take that very severely and we incorporate, we can be incorporating affected person voice and the regulatory suggestions clearly as properly.
Brian Goff: Sure, and an excellent instance of that’s within the case of sickle cell illness, a degree that we’re very happy with at Agios is we’ve deeply concerned the group. The truth is, Sarah and I attended the convention final 12 months the place we received an award from the group about how rigorously and thoughtfully, we concerned sickle cell illness warriors and caregivers in how we take into consideration designing the trials, recruiting for the trials, and finally what the business profile ought to seem like. And we’ll do the identical factor with AG-946.
Operator: And our final query will come from the road of Divya Rao with TD Cowen.
Divya Rao: Hello, guys. That is Divya on for Mark. Thanks for taking my questions. I’ve two form of follow-up questions. One on Eric’s query earlier, was the distinction within the main endpoint between mitapivat and Luspatercept for the transfusion-dependent affected person, one thing that was really useful to you by regulatory authorities, or was it extra of an inside alternative? After which my second query is popping to the design of the Part 2b and MDS. Do you propose to check a number of dose ranges of AG-946? And any coloration on the enrollment standards versus what [inaudible] may have within the command trial can be nice. Thanks.
Sarah Gheuens: Superior. Thanks. Thanks, Divya. So regarding the first query, main endpoint, sure, certainly we do, as I simply talked about on the earlier query as properly, we do our growth in collaboration with regulators. So we take suggestions from the regulators very severely and attempt to actually incorporate the suggestions as finest as we will. And in order that’s how we ended up settling for the 50% finish factors in a rolling 12 week interval interval, which we certainly actually consider is a extra dynamic endpoint and actually displays the true world expertise of a affected person. So that is the place it is all the time superb. And we’re all the time very grateful to have the ability to have these conversations as a result of I do assume incorporating suggestions from a number of stakeholders all the time results in higher design selections. In order that’s that on the first endpoint. After which with regard to your query for MDS Part 2b, sure, the Part 2b is certainly a number of doses that we’re testing. We’re going to check larger doses than we initially anticipated, simply because we’ve realized from our Part 2a that MDS sufferers total have decrease publicity to similar quantities of drug than different affected person populations and wholesome volunteers. So we’re incorporating these learnings into our Part 2b. And with regard to our inclusion standards, we’ve not — we’ve not offered a trial in progress put up or something like that but, however you possibly can anticipate the inhabitants to be comparatively just like how our inhabitants was within the Part 2a. Nevertheless, we can be specializing in transfusion, sufferers with transfusion burden. It would even be a broad MDS inhabitants, identical to we allowed within the 2a. We’re not excluding per se a inhabitants like particular mutations, issues like that.
Operator: I’d down like at hand the convention again over to Mr. Brian Goff for closing remarks.
A – Brian Goff: All proper. Thanks loads, Norma. And thanks very a lot, everybody, for collaborating in at present’s name. Excellent questions, which we very a lot recognize. As you heard at present, our crew has nice conviction in our potential to ship transformative new therapies to sufferers and vital long-term worth to shareholders. And we actually stay up for talking with all of you once more quickly. So thanks loads.
Operator: This concludes at present’s convention name. Thanks in your participation. Chances are you’ll now disconnect. Everybody have an exquisite day.
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