Thank you for taking time out of your busy schedules to join us today for Astellas R&D Day. I am Kato, Chief Communications and IR Officer, and I'll be serving as the moderator today. It is a pleasure to have you here. Following our presentation, we will move on to the Q&A session. The presentation will be based on the presentation materials available on our website. Simultaneous interpretation in Japanese and English will be provided throughout the event, including the Q&A session. Please note that we cannot guarantee the accuracy of the simultaneous interpretation. You can select your preferred language from the menu at the top of the Zoom screen. If you select the original language, you will be able to listen to the audio in the original language. Please note the following.
This material, our representations and answers and statements by representatives of the company in the Q&A session include forward-looking statements based on assumptions and beliefs in light of the information currently available and subject to significant risks and uncertainties. Actual financial results may differ materially depending on a number of factors. They contain information on pharmaceuticals, including the product under development, but it is not intended to make any representations or advertisement of these preparations. The data we are going to introduce today is based upon the contents presented at the Congress meeting. Let me introduce today's speakers. The presenters are Naoki Okamura, CEO. Tadaaki Taniguchi, CRDO, Chief R&D Officer. Now presentation is started.
Good morning, everyone. I am Okamura from Astellas Pharma. Thank you very much for taking the time to join us for this briefing today.
First of all, Astellas has a very clear vision. It is on the forefront of a healthcare change to turn innovative science into value for patients. At Astellas, we define this value in bold by placing the outcomes that are truly matter to patients in the numerator and the cost to the healthcare system of delivering those outcomes in the denominator. This approach serves as a guiding principle for decision-making across the entire company, including our R&D strategy. Please go to Page five. We adopt a research and development strategy known as the Focus Area Approach, with the goal of delivering meaningful outcomes in areas with high unmet medical needs. The Focus Area Approach consists of three core elements: biology, modality and technology, and disease. We begin by understanding the biology of the disease and its impact on patient lives.
Next, we select the optimal modality or technology that aligns with the characteristics of that biology and apply it to the patients who are most likely to benefit. When those three elements are firmly linked to form a solid triangle, we define this as our primary focus. By providing around the vertices of this triangle, we believe we can generate multiple valuable programs from a single scientific foundation. Page six. We concentrated our R&D resources on areas where we possess deep scientific expertise and have the highest potential to deliver value to patients. We currently have four primary focus: immuno-oncology, targeted protein degradation, blindness and regeneration, and genetic regulation. For each primary focus, we have designated flagship programs aiming at the proof of concept of POC judgment by the end of FY 2025 and have been advancing development with a high priority.
Of these, we have achieved a POC for three assets: ASP 2138, ASP 7317, and zitidagresib, previously referred to as ASP 3082. Page seven. By making disciplined decisions regarding our portfolio and accelerating high-quality science, we have driven the creation of tangible value for patients. As shown in the slide, we have made significant progress over the five-year period of our CSP 2021. First, we have accelerated our pipeline. Over the past five years, we have achieved 12 phase II first subject dose or FSD for new molecular entities and initiated one new phase III trial. We have certainly increased our speed and execution capabilities across the entire development process, including achieving a total of four POC from three assets. Next, we strengthened our portfolio discipline.
We decided to terminate 21 clinical stage programs, and as a result, we reallocated resources to assets with a higher expected value and lower risk. This has significantly improved the quality of our entire pipeline. We built a foundation for sustainable productivity. We transformed our R&D organization into a patient-centric end-to-end model, invested in key capabilities, and introduced new ways of working to achieve more consistent results. This series of achievements clearly demonstrates the strengths of our Focus Area Approach. This approach will also form the foundation of Astellas' R&D strategy in our next midterm business plan, scheduled to be released on 26 May . Page eight. We are implementing initiatives to overcome short-term challenges, including a loss of exclusivity of XTANDI and a return to growth.
First, we are focusing on maximizing the sales of our strategic brands to mitigate the impact of revenue decline following the loss of exclusivity of XTANDI and to pave the way for future growth. At the same time, we are focusing on accelerating development to build our pipeline to market as quickly as possible. Furthermore, by advancing these efforts and a robust operational efficiency and financial discipline, we are building a profitable business structure while addressing current challenges. Through these approaches, we will continue to invest in long-term growth while addressing short-term challenges, thereby maintaining and strengthening our momentum. Page nine. As part of this strategy, we have introduced a new end-to-end model along the patient axis and have been driving organizational transformation. Under this new operational model, we view research, development, commercialization, and lifecycle management as an integrated whole, consistently focusing on improving productivity and creating value.
By strengthening collaboration across functions, we are able to advance programs more efficiently from the early stages of drug discovery through late-stage development, enabling clearer and faster decision-making. Page 10. Through our disciplined strategy, we are building a robust pipeline. While focusing on the areas where we possess deep expertise, we are also leveraging the capabilities of external innovation partners to create meaningful value for patients. In each therapeutic area, we have built a deep pipeline, comprising not only our strategic brands already on the market and our primary focus flagship programs, but also follow-on programs, externally acquired programs, and even early-stage research programs that support next-generation innovation, thereby forming multiple franchises.
Good examples include the prostate cancer franchise, multi-modality therapies targeting Claudin 18.2, and the acquisition of IZERVAY, which is indicated for geographic atrophy in age-related macular degeneration, GA, in AMD, paving the way for retinal pigment epithelial cell-based therapies. These efforts have created a balanced and sustainable portfolio that reliably delivers short-term progress while continuously generating future innovation. Next, Taniguchi will provide a detailed explanation of our R&D initiatives. Taniguchi-san, please.
Good morning. I am Taniguchi, CRDO. I will now provide a detailed explanation of our R&D initiatives. For those living with serious diseases, science holds the potential to significantly transform their lives. However, many patients still have limited treatment options. Addressing these medical needs is a major driving force behind our R&D strategy. Next slide, please. Page 12. Astellas has a proven track record of continuously developing innovative medicines and delivering them to patients.
The innovative treatments developed by Astellas across multiple therapeutic areas are being used by patients in many countries around the world. Building on our experience accumulated to date, we continue to work toward expanding access to medicines and further improving treatment outcomes while broadening our focus to earlier and more extensive stages of disease. Page 13. In fact, our efforts to date have fundamentally transformed patients' expectations for treatment. In the oncology field, recent phase III study results have further solidified the position of PADCEV in urothelial cancer in EV-303 and EV-304 study.
Regarding XTANDI, the phase III EMBARK study demonstrated that it significantly delays disease progression in early stage prostate cancer. In gastric cancer combination data from ILLUSTRO study support its clinical potential with the checkpoint inhibitor. In ophthalmology, IZERVAY has demonstrated the ability to inhibit the progression of geographic atrophy, and in women's health, VEOZAH offers a new non-hormonal treatment option for vasomotor symptoms or VMS. This result demonstrate the ongoing success of Astellas R&D efforts in consistently translating innovation into value for patients across multiple disease areas. Page 14. I will explain PADCEV and enfortumab vedotin as an example. In February ASCO GU, we presented the latest data from EV-304 trial, the study targeting patients with cisplatin-eligible muscle-invasive bladder cancer or MIBC.
The perioperative enfortumab vedotin and pembrolizumab significantly improved the primary endpoint event-free survival, EFS, compared to neoadjuvant chemotherapy. In addition, significant improvements were observed in overall survival, OS, and pathological complete response, pCR. These results further confirm the benefits of PADCEV in the perioperative treatment of MIBC. Please go to the next slide.
Page 15. This slide illustrates progress across the full development spectrum. Our broad pipeline ranges from strategic brands that continue to expand their impact through life cycle management to a diverse range of early stage development programs that will contribute to future growth. By focusing on the life cycle management of strategic brands in areas such as oncology, ophthalmology, and women's health, we are maximizing value while further strengthening our leadership in each field.
At the same time, we are steadily building our pipeline that will underpin our future growth through our primary focus flagship program and several follow-on programs. Next slide, please. Page 16. In order to address the challenges ahead of us with XTANDI's loss of exclusivity, we need to build a resilient portfolio that will support our mid- to long-term growth. From 2024 to 2026, we fundamentally transformed our R&D organization and governance structure, and achieved productivity gains by strengthening the foundation necessary for sustained success. Building on this newly established foundation from 2027 to 2029, we will set clear priorities, generate more high quality development programs, and further enrich our pipeline. As a result, from 2030 to 2034, we will be able to significantly improve R&D productivity by accelerating the development of higher value products. Next slide, please.
Now, I would like to share more about transformation of our R&D organization. Next slide, please. Page 18. Since 2024, we have taken bold measures to increase productivity and efficiency in R&D, and these measures are already delivering tangible benefits. Regarding internal and external collaboration, by introducing end-to-end operation model and agile working practices mentioned by Okamura, we have reduced handover processes between departments, enabling teams to advance project more quickly. Furthermore, by collaborating with right partners, we have been able to create a broader range of values. Through initiative to accelerate the pipeline, we have shortened development cycle times and enhanced necessary capabilities. We are also actively investing in talent, striving to enhance the skills of R&D teams and expertise of early development stage.
In development, we have established a system capable of conducting our own research and or clinical trials, reducing costs, and accelerating clinical trial speed and quality improvement. I will explain the details later on. Furthermore, by actively promoting the use of data, including the proactive utilization of real world data and integration of R&D database and AI-driven simulation and modeling, we are working to speed up decision-making and strengthen evidence base. These initiatives form a cohesive strategy collectively and continuously improving speed, quality and efficiency of our R&D. Next slide, please. Page 19. I will explain how we prioritize our portfolio. We continuously review all programs from preclinical stage to life cycle management based on each probability of success and value.
For programs assessed as having both a low probability of success and low value located in the bottom left of the diagram, we make strategic decisions such as lowering their priority or stopping them. This allows us to allocate resources to promising programs in the bottom right, thereby accelerating their development. As development progresses, we expect the probability of success to increase, shifting those programs to the top right quadrant and enhancing the overall value of the pipeline. Next slide. Next slide, please. Page 20. We are reducing the time from clinical trial execution to submission and approval through transforming clinical operations.
Specifically, through in-house development of key capabilities ranging from protocol development and clinical trial conduct to data analysis and study reports preparation, we aim to strengthen direct communication with trial sites, thereby improving the quality of protocols, accelerating patient enrollment, and expediting data analysis and study report preparation. As a result of this transformation, in clinical trials, the achievement of milestones such as site selection and first dosing has been accelerated. In the regulatory submission process, the time from submission or acceptance has been significantly reduced. Furthermore, by improving the quality of our submission, we have shortened the time from submission to approval, and in FY 2025, we obtained eight approvals for our strategic brands in major markets.
Furthermore, these benefits is not just one time event, but can lead to ongoing improvement in our capabilities, such as strengthening relationship with our trial sites and physicians, conducting patient-centered trials, and AI-driven automation, as explained in the next slide. Next slide, please. Page 21. We are investing in cutting-edge technologies, including AI and robotics, to accelerate our digital transformation proactively. For example, in drug discovery research, we aim to accelerate the development of biopharmaceuticals and improve productivity, not only through NVIDIA's AI-powered supercomputing for small molecule drug design that has already been implemented, but also by introducing AI-enabled Protein Station for research automation. AI-driven gene therapy will lead to precise organ targeting, reduced toxicity, and enhanced treatment. These tools will help us test hypotheses faster and prioritize the strongest programs, accelerating research, reproducibility, and speed.
In development, leveraging Study Designer, Evinova's AI native platform will enable us to efficiently design more sophisticated patient-centric clinical trials in future. We aim to further improve trial efficiency through initiatives such as clinical trial monitoring using AI agents. Next slide, please. Page 22. We are driving cutting-edge research and building a long-term pipeline. Our research consolidated eight divisions to three centers of excellence, namely oncology research, cell and gene therapy research, and innovation labs. Cell and gene research and innovation labs, expecting they will be our core enablers for our mid-to-long term R&D strategy. By integrating expertise of each research center, we can develop optimum treatment based on the pioneering scientific findings while fully understanding patients' needs and their conditions. Furthermore, these centers act as hubs for collaboration in and outside of the company, leading cutting-edge science while working closely with partners in academia and biotech sector.
Next slide, please. Page 23. We are strategically building an ecosystem, strategic ecosystem in collaboration with a wide range of partners, incorporating outstanding external technologies and expertise through partnership with biotech companies such as Evopoint and Avert Biotechnology, as well as world-leading academia such as Mass General Brigham, MGB. We are combining our deep expertise in primary focus with cutting-edge external innovation to drive progress in R&D. As an example of a partnership with academia, Astellas is the only pharmaceutical company partnering with Mass General Brigham, MGB. Through close collaborative research program, we are building early-stage pipeline and translational medicine, accelerating the creation of new therapies in oncology, rare disease, and ophthalmology.
By sharing a long-term vision with our strategic partners and collaborating openly and flexibly, we are strengthening and accelerating innovation. Next slide, please. Page 24. We have built reliable manufacturing and supply capabilities to provide consistent support for R&D innovation from the early development through commercialization. We have established a global manufacturing and supply network with manufacturing sites in Japan, the U.S., Ireland, and China, and through strategic partnerships with CDMOs. We have made a strategic investment in our own manufacturing capabilities, including our cell and gene therapy manufacturing sites in the U.S., to ensure we are equipped to handle the diverse and complex modalities emerging from primary focus. By combining this manufacturing infrastructure with our regulatory expertise, we deliver high-quality manufacturing and supply at every scale throughout development. Next slide, please.
Next, I will outline the progress of our pipeline with each primary focus area. Next slide, please. Page 26. In our primary focus targeted at protein degradation, we are working to target proteins that have historically been considered undruggable with the ambition to transform treatment options for patients.
Our flagship asset, zitidagresib, is a potential first-in-class targeted protein degrader for solid tumors with KRAS G12D mutations, which had long been considered undruggable. KRAS G12D mutation is found in approximately 40% of PDAC, pancreatic ductal adenocarcinomas, and approximately 5% of NSCLC, non-small cell lung cancers. Alongside our flagship program, we are advancing a follow-on asset, ASP5834, pan-KRAS targeted protein degrader designed to address multiple KRAS alterations, reflecting the expandability of the program platform. The progression of both the flagship and follow-on asset illustrates how this platform can be expanded beyond a single target, supporting our ambition to extend to additional cancers and potentially other diseases over time. I will explain latest development status on zitidagresib using a few slides. Next slide, please.
Page 27, zitidagresib has achieved POC in pancreatic ductal adenocarcinoma, or PDAC, and non-small cell lung cancer, NSCLC, both of which have significant unmet medical needs, and is currently being developed in parallel across multiple cancer types. For PDAC, we have initiated enrolling patients in a phase III trial for first-line treatment, and primary analysis is anticipated in FY 2029. We have also achieved POC in NSCLC and are currently preparing to initiate a phase III study for second and later lines. Primary analysis for this is also anticipated in FY 2028.
In addition, data generation is in progress in other cancer types with KRAS G12D mutations. Regarding colorectal cancer, based on the clinical data available to date, we have decided not to pursue late-stage development. Page 28. I will now revisit the data on zitidagresib in PDAC that we presented at the ASCO GU meeting in January, as mentioned earlier. In our phase I study of KRAS G12D-positive PDAC, the combination of zitidagresib and modified FOLFIRINOX as first-line therapy demonstrated anti-tumor activity and a manageable safety profile. Among the 12 patients whose efficacy could be assessed, the objective response rate, ORR, was 58.3%, and the disease control rate, DCR, was 83.3%. Infusion reactions were reported in 72.2% of patients.
However, these were primarily low-grade, occurred mostly at the first dose, and were manageable with the standard supportive care. There were no treatment discontinuations due to these reactions. Based on these results, we have initiated patient enrollment for a phase III trial evaluating the combination of zitidagresib with a modified FOLFIRINOX or another NALIRIFOX as first-line therapy for PDAC patients. Page 29. Here, I present clinical data on zitidagresib in patients with advanced or metastatic NSCLC with KRAS G12D mutations. This data were presented at the European Lung Cancer Congress last week and simultaneously, on the same day, published in the New England Journal of Medicine.
In a cohort of 32 patients receiving second or third-line treatment, the ORR was 37.5%, and as shown in the figure on the right, the median progression-free survival, or PFS, was 11.2 months. No new safety signals were identified. Based on these results, we are preparing to initiate a phase III trial of zitidagresib monotherapy in advanced or metastatic NSCLC patients. Next slide, please. Page 30. Next, I will explain our primary focus on immuno-oncology. Immunotherapy has significantly advanced cancer treatment, but many patients still do not achieve sufficient efficacy, leaving a significant unmet medical needs. In this primary focus, we aim to achieve high therapeutic efficacy by leveraging diverse modalities that target both the immune system and the tumor microenvironment.
Specifically, we are utilizing next-generation platforms such as T-cell engagers, ADCs, and bispecific antibodies to achieve more effective and sustained treatment outcomes for difficult to treat cancers. I'll provide a detailed introduction to our flagship program, ASP2138, on the next slide. Next, please. Page 31. ASP2138 is a potential first-in-class bispecific antibody designed to activate T-cells and damage cancer cells by binding claudin 18.2-expressing cells to CD3-positive T-cells. Claudin 18.2 is expressed in gastric cancer and PDAC, which represent areas of high unmet medical needs. We have already achieved POC in gastric cancer and are preparing to initiate a phase III trial targeting first-line treatment for patients with low to moderate claudin 18.2 expression in gastric cancer who are not eligible for VYLOY. Primary analysis is anticipated in FY 2029. Next, please. Page 32.
Our partnership with Vir Biotechnology is an example of how we are leveraging insights gained in the prostate cancer field to connect our cancer immunotherapy with actual clinical development. Under this strategic partnership, we are advancing the development of VIR-5500, which targets a novel immune-mediated mechanism. VIR-5500 is designed to incorporate a proprietary masking technology that keeps the T-cell engager masked until it reaches the tumor microenvironment, thereby reducing its effect on normal cells and minimizing side effects. Currently, a phase I study is underway as a monotherapy. An initial anti-tumor activity and a favorable safety profile have been demonstrated in patients with metastatic castration-resistant prostate cancer, or mCRPC, with the treatment.
Findings shared at the ASCO GU show target engagement and immune activation with manageable safety at doses evaluated to date. It was announced in February. These results support the continuation of development and provide the crucial data to inform a future dose selection and development strategies. Next slide, please. Page 33. Under primary focus gene therapy, we aim to make AAV gene therapy, which modulates genetic causes of diseases, more accessible to more patients. Gene therapy holds the potential to treat and address genetic diseases at their source, for which many patients worldwide are eagerly awaiting new treatments. However, the development of gene therapy presents various challenges in terms of drug discovery, development, and manufacturing. To address this series of challenges, Astellas has been building internal expertise in R&D and manufacturing, while also collaborating with external partners to establish a platform.
Our flagship program is AT-845, an AAV gene replacement therapy for Pompe disease. The final POC decision is pending as we review additional analysis of data. Furthermore, we are advancing follow-on programs for neuromuscular and neurodegenerative diseases, and are also working on next generation approaches such as MTM1, a gene replacement for X-linked myotubular myopathy, XLMTM, using a novel AAV capsid. Next slide. Page 34. Next, we turn to primary focus blindness and regeneration. Here, we are addressing diseases that lead to irreversible vision loss and those representing a significant unmet need. Our flagship program, ASP7317, is a pluripotent stem cell-derived retinal pigment epithelial cell designed to replace damaged cells in patients with geographic atrophy secondary to age-related macular degeneration. We have now achieved proof of concept, POC, in patients with severe visual impairment, making a significant milestone.
Additional phase I-B safety and efficacy data are planned to be presented at the ARVO 2026 Association for Research in Vision and Ophthalmology in May. Details will be communicated there. Alongside ASP7317, we are also progressing ASP2020, a follow-on allogeneic cell therapy for Stargardt macular dystrophy, reflecting the broader applicability of this regenerative platform. Next slide, please. Now, I will use a few slides to explain direction of our research and development organization for sustaining long-term value creation. Next slide, please. Slide 36. We anticipate that the R&D transformation and pipeline progress outlined thus far will form the foundation for sustained growth throughout the 2020s until 2029. Looking ahead to the early 2030s, we aim to significantly improve productivity to reach the top tier of the industry, building a pipeline of high value-added products and accelerate R&D. Next, please. Page 37.
We outline our initiatives focused on growth in the 2030s. Firstly, accelerate the development of our flagship programs and our lifecycle management initiatives. Next, to expand the pipeline of follow-on programs, we will continuously improve program success rates and decision-making based on data and continuously improve entire R&D productivity. Furthermore, looking ahead, we aim to advance 10 NMEs into late development stage by 2034. Page 39. Astellas is undertaking a fundamental transformation of its R&D organization with the aim of raising R&D productivity to the top tier in the industry. We are strengthening our pipeline by pursuing higher quality science through an end-to-end operating model and prioritize investment in modalities and platform that differentiate our portfolio. Furthermore, by building a robust drug discovery platform, we will generate multiple high quality asset, thereby maximizing pipeline value and accelerate R&D.
We will continue to deliver sustainable growth and meaningful outcome for the patients and the value. This concludes my presentation. Thank you.
This is from us as a presentation. Now I would like to entertain questions. If you have questions, please use the Raise a Hand button at the bottom of the Zoom screen. If you are joining here with your smartphone, tap the Details, and you can find the Raise a Hand appeared. Please tap that. I'm going to call out the names, so if you hear your name, unmute yourself on your own screen and mention your name and your affiliate to start the question. Let's start. Thank you very much for waiting. First question is from Citigroup Securities, Yamaguchi-san, please.
Yamaguchi from Citi, can you hear me?
Yes, we can hear. Good morning.
Thank you. The confirmation 7317. In the past, the data of improving the visual acuity has been shown, and you've been saying a POC judgment, and this time you mentioned that a POC is achieved. This is very first time that you mentioned the POC is achieved. Is that understanding right?
Yes, you are right.
The second question. 3082. Lung cancer data is introduced. Cross-trial comparison does not have meaning, and there is no significance in early stage. However, with a simple comparison, ORR and DCR compared to Revolution, what is happening? How do you view about this? For the PDAC, the data was really good, but from your perspective, this comparison is, as has been expected, good, unfavorable. Would you make a comment?
Thank you very much. The data shown for CTD aggressive this time has been shown ORR is 37.5%. First of existing product therapy, in other words, comparison with the chemotherapy is the right way to be done. 37.5% of ORR compared to the chemotherapy, such as docetaxel, this response rate is extremely high. EFS, this time in median, it's open label. This might be just for reference, but 11.2 months. Docetaxel past data we refer to, it was around four months of the PFS reported. Compared to that, it's more than two-folds of PFS extension. That's the data we have. With this, we are getting into phase III. We are going to make appropriate study design for phase III. That's what we are planning currently.
Thank you very much.
Page 19. You showed a chart of the portfolio review, and especially one and two and three, you made a comment about those. It might be difficult for you to talk about the details, but this one, that is a strategic deprioritization. That means in the beginning you didn't expect that the situation was changed. What are the major reasons of this deprioritization from the beginning? Possible value is not really clear or the competitive superiority is lost. Could you share with us?
Thank you very much. Basically, these are including the very early stages, not even in the clinical stage. Target Product Profile are not necessarily completely fixed, and such kind of projects are included in here. Based upon that as an assumption or the condition, please listen to my explanation from here.
As you know, in a preclinical study, there are various things we have to prove, and we will go through the studies and there are things that this is okay, this is not okay at all, and although there are something in between. For those, we are going to do some additional studies to identify and make a decision if we can go for that or discontinue that. As has been Taniguchi repeatedly saying, the discipline is important here. If discipline is not strong enough, you try to hang on the project so that the project can survive as long as possible. This time, completely we review such discipline. If such and such factors are not satisfied, we should make a decision of discontinuation. We actually execute that approach.
For each project, the important factors are different, and that is different depending on the target disease. If the modality is new, we thought in the beginning it was really good, but once the development, the efficacy is not really expected. We have roughly six factors for the project evaluation. If five criteria out of those are not satisfied, rather than dragging the development on that, you make a bold decision to discontinue so that you can allocate the valuable asset to the more potential asset. That's described here. Did I answer your question?
You have done that for 2024 and that is going to be continued, so you expect a further improvement efficiency?
Yes, that's right.
Understood. Thank you very much.
Let's move on to the next. JP Morgan Securities, Wakao-san, please.
Thank you. JP Morgan, Wakao speaking. My first question is also about the zitidagresib. NSCLC PFS data is really good. So far, just like Taniguchi-san mentioned, it's not inhibition, but the degradation is suggesting the continuous efficacy. It happened, it was really surprising. This might be the same question, zitidagresib. How do you view about the possibility of being the best in class within NSCLC? I believe that it is clear it's going to be the first in class. For Revolution Medicines pan-KRAS, compared to that, assumingly it's good, but their PFS data is not available yet. Cannot make the head-to-head comparison. We would like to know how you view about that. Another question is about PDAC.
Second line, third line, OS 10.3 months data is available, published in New England Journal of Medicine. For this second line, third line comparator is not available in Revolution. How so? How do you evaluate this data? Compared to chemotherapy, it is superior, which is clear. But against the coming next generation types, how do you view it?
Thank you very much. Wakao-san is correct. In comparison to Revolution, we are paying close attention with interest. As you correctly mentioned, KRAS G12D is their target. For those pharmaceuticals, our data is not that much available, so head-to-head comparison is rather difficult. The pan-KRAS oral inhibitor, what is the situation vis-à-vis that is the area that we are paying attention to. The difference is, in particular in lung cancer, as we look at the data available on ORR, not much difference between the two. Versus chemotherapy, it's much better. According to the publicly available data of them, ORR are not big difference between the two. As for PFS, duration of the effect, their data is rather limited.
What is the situation in comparison to that? That is not so sure. Our hypothesis, that is KRAS G12D, to decomposing the KRAS protein itself is the strategy. Our hypothesis is being proven, meaning that the durability of the effect is maintained very significantly. That is our impression. Protein degrader and the KRAS suppressor or inhibitor, if you make comparison, people often talk about the following. As for inhibitor, the resistance occur. That is an issue, and how they are going to overcome them, it's something that we don't know. The different mutation of KRAS or different pathway may appear, that is regarded as a challenge. Versus our KRAS-targeted degrader, we degrade the protein themselves, so the refractoryness or resistance is less likely to occur in our modality.
Therefore, we are going to accumulate in particular phase III data moving forward. First and foremost, for non-small cell lung cancer, zitidagresib would have a potential to become our best in class. That is what we want to pay attention to. This is the first point, PDAC, and pancreatic ductal adenocarcinoma. In that cancer, there was no drug that reported to be efficacious in second line, third line, and zitidagresib and Revolution Medicines mutation inhibitor data were reported this time. More than expected, we got the feeling that it is more effective than we expected. In comparison to second line, third line, with the combination of chemotherapy, a higher efficacy is already shown.
In the pancreatic ductal cancer development strategy focusing on first line is likely to be a path or is the current path. So far in the pancreatic cancer, currently, as you know, other than chemotherapy, there is no medication which shows efficacy so far. It's very promising. Our compound is very promising, but given the current landscape, so combination of zitidagresib and chemotherapy could be the main line of first line of pancreatic cancer. With that in mind, we want to design the study and we want to conduct enrollment of the study though we have already started screening.
Thank you very much. That is very informative.
Second, on Page eight, in the midterm exploratory meeting, I believe you're going to explain more in detail, but after the extend the LOE, the growth you have strategic brands and the pipeline. As for your pipeline, the project range that you have highlighted this time will constitute the main body of the pipeline, and you often talked about discipline this time. Beyond FY 2027 onward, OP margin 30% is going to be sustainably generated. As we have the late stage subsequent development, are we able to maintain OP 30%? Thank you.
This is not the precise diagram. This is just an illustrative chart. With this assumption, I would like to explain, as Dr. Taniguchi mentioned, life cycle management of strategic brands is included in center in red.
The light pink pipeline in this chart, according to Dr. Taniguchi's explanation, are derived from primary focus or, depending on the situation, they are the ones that we may acquire or have already acquired from outside. Those constitute this pink pipeline. As you mentioned, from tomorrow, we will enter into FY 2026, and from FY 2026, those which we obtain POC will move into late stage developments. As you mentioned, there will be a high amount of R&D expenses that we will incur. Therefore, we have several meaning of discipline when we say discipline. One, even if things are advanced, we want to prioritize, and we inject our capital resources in the prioritized ones.
It is important to create new things one after another, but after you give it a try, if it doesn't work, we want to give it up, meaning that, we don't want to linger on for a long time. That is another meaning of discipline. We want to transform as advancement of science to value of patient. That is our vision, we don't want to sacrifice R&D. We want to improve work efficiency in other areas, we want to invest in R&D while securing profit. That is our mindset in building our next midterm plan or CSP. Depending on the situation, the.
We don't do this to reduce the ratio of R&D expense in sales, but depending on some project, we want to reduce the R&D expense so that we don't want to sacrifice our future growth. There is some room for us to consider that. That's all.
Fair copy. Margin 30%. That is continuously you are going to aim at. Is this understanding right?
So far, as has been mentioned, by 2027, FY 2027, we achieve 30%, and afterwards we are going to maintain that. That's what we currently are thinking.
Understood. Thank you very much.
Thank you. Next, VOV Securities. Minaga-san, please.
Thank you for giving me this opportunity. VOV Securities, Minaga is my name. I have two questions. First is about prioritization. In your company, there are several points of the evaluations, and based upon that, you prioritize your projects. I'm referring to Page six . There are four primary focus that you have, and the rearrangement of these primary focus, and also you're going to make major changes. That's the question that I have.
That's because we currently have some oncology update, and I believe you're progressing quite well. Therefore, are you going to focus more on oncology? Are you getting into the gene therapy? You are going to add additional primary focus here? That is the first question from me. Thank you.
Probably, as you know, this Focus Area Approach, we named it as a Focus Area Approach and officially communicate to you. That happened around 2015 or 2016. Considering from then, we see there are some changes in the primary focus as well. For example, we had primary focus, four of them at the very first. The antigen-specific immune modification, that is a primary focus that we had, and aiming at the allergy treatment. Certain specific modality is utilized there.
Based upon the clinical trials, we decided to discontinue that primary focus. This is a gene therapy that was not included primary focus, but rather a candidate. Now it is officially within this primary focus. Recently we have mitochondria. That is another primary focus, but we couldn't come up with the expected result or efficacy. That's why we discontinued that as well. The primary focus is not something that we continue to stick to those once decided, but rather from those primary focus, if expect multiple expected assets worth continuing available or not. Based upon that, we just make a decision about the primary focus. For each these four primary focus, I think there's still the expandability.
As Taniguchi explained, with referring to iLab, the science is getting newer and newer, and how we connect those with the drug is our work. The biology is sufficient and robust, and the modality is appropriate. Clinically it is proven. We have this triangle, and it's not just one. We come up with several items as a primary focus with pivoting around these triangles, and based upon that, we decide to prioritize, reprioritize, and so on. Thank you.
Next is about the specific project that is CLDN-aggressive PDAC first line, phase III studies started, I believe. The base treatment is FOLFIRINOX and also now NALIRIFOX. Those are quite intensive chemo.
Even with this chemo, the efficacy is achieved to a certain extent. The Revolution pan-KRAS, now the PAC gem is the comparator. Now, PAC gem base is probably easier comparator to see the efficacy. But here you pick up a G12D alone as mutation, meaning that you have a confidence in the efficacy. Do you think with the current approach, you can show the clear advantage in efficacy? Thank you.
PDAC. First line. As has been explained, the combination with the chemo is the center of our strategy. The selection of chemo is FOLFIRINOX or NALIRIFOX are selected because those are mainly utilized in the Western countries. Revolution phase III study, and if we look at NALIRIFOX nab-paclitaxel/gemcitabine chemo and monotherapy and combination with chemotherapy.
They have three arms within the study design. That's what we've heard. Fundamentally, there might be a bit of a difference because their product is a pan-KRAS and ours is targeting only KRAS G12D. That accounts for the G12D mutation that accounts for about 40% of the PDAC. That is our focus. And second, as has been explained already.
In the treatment of PDAC, the biggest issue is the continuation of, or sustainability of, the efficacy. Needless to say, the same time with the deep regression of the tumor, how long you can extend or sustain the efficacy, that is the key. Looking at the past PDAC study, in the beginning, initial phase, efficacy is higher seemingly. However, looking at the sustainability of the efficacy, meaning that there's no impact onto the extension of OS. Therefore, for PDAC, the continuation of efficacy, especially impacting on the OS, that is the most important key factor that we need to pursue to. Based upon that, we decided this study design. Revolution Medicines takes a different strategy. Therefore, ultimately, I think we can see if we make a head-to-head comparison.
Are there any other questions? Next question from Nomura Securities, Mr. Matsubara, please.
Matsubara from Nomura Securities. Thank you. 3082 is my question. Good results was shown. Congratulations. I would like to ask about adverse event with the administration, infusion-related reaction. 63% stopped the administration in a few cases. Transaminase or neutrophil reduction was observed. Will that be the hindrance of development? As for infusion, every time of the administration, infusion-related adverse events may have reduced. Can you comment on those?
As for adverse events, we are focusing very much, and as was asked earlier, the selection of combination therapy, the chemotherapy that we select, they are a very potent chemotherapy. Because of that, hematology-related adverse events, including nausea and vomiting, gastrointestinal AEs, are observed. However, as for zitidagresib, we showed you mono data earlier, but in practice, the major AE was not observed. ALT increase was shown in some of the cases, but there are not many cases that stopped administration as a result of ALT increase. As for first line PDAC treatment, first whether we are able to show effect or not counts, and will there be continuation of effect? These two keys are crucially important in pancreatic cancer treatment.
We also have to think about managing AE, so we have to strike a balance between the two. Chemotherapy-related adverse events or cytotoxic AEs, there are such AEs, but continuous treatment is possible in our regimen. For example, due to AE, if we are not able to administer continuous cytotoxic, that is not the case. We don't have such case.
ASP7317. POC was achieved. Congratulations for a launch. Development is smoothly underway. How do you differentiate with IZERVAY? A right type, IZERVAY, and a severe type, ASP7317. Can you tell us how you demarcate with IZERVAY and ASP7317?
Thank you. As for IZERVAY, as you know, C5 complement aptamer. In the past, GATHER1, GATHER2 study, I think you understand the situation. In the AMD, progression of geographic atrophy was inhibited. Such data was clearly shown. GA secondary to AMD, as condition deteriorates, and it doesn't improve, that is a condition. Stopping the progress of the disease is clinically very significant. That is the reason why we have developed IZERVAY. In comparison to IZERVAY, ASP7317, though the number of patients was very limited, we showed some data in the past. The maximum visual acuity was likely to be improved, so we saw such tendency. With a very different efficacy endpoint, we are going to assess the efficacy.
As for IZERVAY, second point, IZERVAY, suppression of the disease progression. When the visual acuity is impaired, it's rather difficult to use. The early to moderate patients would likely to receive IZERVAY moving forward as well. In comparison to that, as for ASP7317, it's a cell therapy. The patients for POC this time, the visual acuity degradation was very significant, meaning that the severe visual impairment the patients were the target for our POC assessment. We are going to go into phase III from now on. As for the target patients, those patients with advanced visual impairment, meaning severe geographic atrophy patients would likely to be enrolled. What would be the overlap between IZERVAY and ASP7317?
We don't see much overlap, meaning that so early or middle mild moderate visual impairment IZERVAY. But when the condition exacerbates with the 7317, improvement of visual impairment can be tried.
Thank you very much for your explanation in detail.
Next, UBS Securities Sakai-san, please.
UBS Sakai, thank you for your explanation. Going back to Page 19, two by two chart that you showed earlier. The portfolio management you strike balance between art and science, and it's always a challenge in this industry as I observe. Unless you get POC, I believe it is rather difficult to understand the value of the program because you never know until you see POC.
Practically, program value and the probability of success probability in order to improve the probability, what kind of measures do you take?
Horizontally, this is value. That means the value of when we make success. Usually, if it's early, it is costly beforehand, and the sales increase and profit increases that toward the far. With a discount, the value is lower, and with the probability of the success is multiplied. This is NPV with a success scenario. We are going to study what's going to happen to the future. If everything is successful, how high the value would be. Meaning the left bottom, even they make a success, we will not be able to expect a higher value.
That's why they should be deprioritized. Those are quadrants that we see, X equals something, Y equals something in terms of the program value. If you apply that to all the primary focus, then the oncology product go toward more right. If it is a rare disease, because the targeted patients are limited in number, no matter how successful you are, you cannot come closer to the right side near to the oncology. Just like Sakai-san you mentioned, it's the world of art, and if the primary focus that should be survived or are killed in for that decision making, and if you apply the universal ways of evaluation, all the value of the rare disease is going to be reduced. How to evaluate the primary focus?
Well, according to this, the something left is going to be discontinued, but the right side is going to be continued. For the primary focus, each of them are not necessarily evaluated in line with the exactly same access. That's the way we are working on currently.
Thank you very much.
One thing, some technical. Technically, that is already wholly explained by Okamura. Improve the probability of success and improve the program value. Those are important. As R&D, what should we do? First, the clear drawing of the target product profile. With having that, you can specify the value further. You can have a tangible view of the value. In order to achieve that, you design non-clinical and clinical studies.
As the result of that study is expected or assumed, and if the result is in line with that assumption, expectation or not, then you decide the priority of the programs. That's the approach we take in R&D, as it's been described in Page 18. Decision making based upon the data. We would like to foster a data-driven culture. We clarify the TTT, the drug we want to make in the very beginning. In order to achieve, realize that such and such data is necessary, that's why you design the non-clinical and clinical trial.
Of course, it's not always exactly a match the expectation we had, and so we have to consider about the achievability of that target. The criteria is clarified, then based upon that data is collected and then make the judgment. As Okamura mentioned, so that we can work in line with the strong discipline, we are trying to make the culture.
Thank you very much. Now 3082 protein degrader. The response of the duration, those are not really ringing a bell for me. For example, mechanism of the resistance. It's not inhibitor, but it's a degrader. Are there any change differences in terms of the biological perspective? Looking at the New England Journal of Medicine. Degrader probably is an NCE, KRAS G12D degradation is 70.6% or so. I don't think it's not the 100% of the degradation. How can we make a decision about this or make understanding about this?
Degrader resistance, a mechanism that is under the study these days. Not yet published, but there are some biological changes likely to cause the degradation is studied or changes studied to be understood. As soon as the data is ready to be published, we can share that. But as you know, inhibitor and the degrader, we have a stronger impression that these two are quite different, extremely different because. Also the resistance mechanisms are different. The way to overcome such resistance are also different that we assume.
In clinical trials, in an early clinical trial with the combination, such idea is applied for this development. Regarding the second question, that is KRAS G12D, to what extent it should be degraded to show, demonstrate the efficacy? Regarding that question, as you see, according to the data we shared with you this time, 70% to 75% protein degradation is observed in data. If that is sufficient or not, if we refer to the basic data, the suppression of KRAS pathway to that extent, because the tumor goes to the apoptosis, and such kind of data is available. This level of suppression or efficacy for the protein degradation, we believe that sufficient tumor suppression can be achieved. On top of that, it's sometimes difficult to achieve with the mono.
In order to accelerate the efficacy, the chemotherapy combination is used, and in line with that, KRAS is also suppressed. They have the add-on effect or the synergistic effect. That's the way it works, and the initial data shows that as well.
Last question, simply. This was not talked about ASP2998 Trop2 ADC. So dual payload is attached, was presented at the AACR. Can you explain differentiation point Trop2 is available in some numbers?
ASP2998, as you mentioned, at the end of April at the AACR. First, the non-clinical data is likely to be presented. ASP2998, targeting Trop2, so-called a dual payload ADC. That's ASP2998. What do we do with dual payload?
Topoisomerase-based payload. STING agonist is attached. So which we'll announce from now on. So as you are going to look at the AACR data, you will know, but targeting the existing Trop2 ADC, if we compare with that, what will be the result of ASP2998 will be presented to you.
If you look at the result of that, you will, I think, understand why we develop this ASP2998.
Thank you. That's all from me.
Thank you. Next, Morgan Stanley MUFG Securities. Muraoka-san, please.
Thank you. Morgan Stanley, Muraoka is my name. ASP7317. The maximum visual acuity improvement was obtained in severe patients. Golden Week, I'm very much looking forward to ARVO data. As a next step, what will be the next step? Is my question too early to ask? Koizumi-san said it's an extremely important success, so I thought you were able to skip significantly. But can you give us a color to what you said?
Muraoka-san, thank you for a good question.
It's very difficult for me to answer to that question, but what we can tell is that the POC study, based on the data, we nurture the culture for decision-making. Clear POC criteria is just determined in advance, and based on that predetermined criteria, we overcame. That is why we declared POC. This is the first point.
The second point, I would like you to look at the ARVO data first and foremost, so I hope you will have high expectation to that data. As for future development, with the FDA U.S., we have already started interaction, and through this interaction with FDA, what kind of development strategy can we set up that is being considered within the company? Not only in the U.S., but moving forward in Japan, also in Europe and in China. We will engage in worldwide development, most probably. We hope to engage in global development, hopefully.
Looking at the region and the countries, how will development be accepted in the early part of FY 2026?
We want to scrutinize those things.
Thank you. Phase Ib, you show data in small amount, but my impression is that it's taken time, significantly. The next step starts and when do you think we will be able to hear the answer for that? In 2028, 2029, phase III results will be available. Will this ASP7317, the next step update occur in the same timing, or do you think it will take a longer time?
As mentioned, next fiscal year, which will start the next tomorrow. First half of next fiscal year, we will complete the interaction with authorities. In the latter part of next fiscal year, we should be able to talk about development plan.
Understood.
At that time, a program will be updated. 3082. Colorectal cancer second line stoppage.
Can you share with us the background of this? Was that the simple reason? Or was that a different reason? What is the background of making decision to stopping?
Static aggressive colorectal cancer, as you know. KRAS G12D, the mutation is apparent in 15% of the colorectal cancer, and colorectal cancer is a big population. In parallel to lung cancer and PDAC. In phase I, we looked at the efficacy in CRC. Excuse me, colorectal cancer. It's here.
Unlike PDAC and small cell lung cancer, the situation of colorectal cancer is a little different, and as soon as we are ready for data, we are going to present. As of now, we have not shown efficacy that encourages us to go forward with colorectal cancer with 3082. Based on data, we made a decision.
Understood. Thank you very much. That's all from me.
Stop. Thank you very much. We have about six minutes and I would like to. Because a lot of people raising hands and I would like to ask a lot of people to ask questions. From here, we would like to ask you to ask just one question. Now, Sawada-san from JP Morgan Asset Management, please.
Can you hear me?
Yes, we can hear you.
One question is available. I would like to ask about the Claudin 18.2 and the peripheral of that which is not really mentioned within this meeting here today. The low expression of the Claudin 18.2 is the target for the development this time.
VYLOY ILUSTRO Cohort 4B results. That is really good data, but to put it in another way, ASP2138 development on a highly expressed patient is likely to be the similar result with the VYLOY. That's why you decided in this way or 4B result, how have you evaluated and how do you differentiate? Would you please mention something about here? Thank you very much.
Regarding VYLOY, last Cohort 4B came up with really good data. So Claudin highly expressed patients and also CPS also highly evaluated. That's highly expressed. That's the target of the development currently. ASP2138 as the first indication because our strategy to do the development for the higher unmet needs.
Claudin, because Claudin high expressed is already developed for VYLOY, there are patients not indicated for VYLOY. That is, mid- to low, low- to mid-expression that accounts for about a third of the gastric cancer patients. We thought it is a favorable way to go for the development. For the Claudin high expression, what should we do now to the future and also considering the IV administration for VYLOY and such characteristics it has, which is leading to the difficulty of management of the side effects. For this ASP2138, even with the highly expressed patients, the sufficient efficacy, safety, and also convenience are needed to be observed. When it comes to subcutaneous, that is useful.
Considering all the factors, we would like to consider if 2138 is needed to be developed for highly expressed patients as well.
Arno, thank you very much.
Next, Barker-san from Jefferies Securities.
Steve Barker speaking from Jefferies Securities. My question is about 2138 phase III study. Claudin 18.2 expression, the minimum threshold, how are you going to set that?
Thank you for the technical but important question. In particular, the middle expression is rather easy, but the Claudin, a low expression, what is the degree of that? I think that was your question. According to the phase I study that we have conducted, and detailed analysis of that was made. Pathologists and we consulted to identify a cutoff to determine low expression or zero expression to delineate between the two. Against this. Categorization of a low expression cutoff value was set up, and by using that, we plan to start phase III study. The details is described in protocol, but we refrain from informing of that yet.
Analysis per expression level will be possible, and do you have a plan to secure the power for that?
Yes. In our protocol, at the central level, the expression will be confirmed, and as for enrollment, as far as I'm informed, the site data will also be used, based on the confirmation of expression. In phase III, middle to low expression was observed to see effect and cutoff value was confirmed and will be confirmed, and then we will file submission.
Thank you. That's all from me.
Now in the interest of time, we would like to make the next question as the final question. Sanford C. Bernstein. Sogi-san, please.
Thank you. In development, AI usage is my question. On Page 21, you showed introduction of technology.
Study design platform is described on Page 21, and honestly, I'm surprised because in the area of development, of course, in the drug discovery also, but in development, the optimization of sites and acceleration of patient recruitment and patient management and as well as data management, of course. For the regulatory document preparation, it seems that AI is very useful in those areas.
As of now, what's shown on the slide is the approach that you are going to address at Astellas. As for cost and timeline, I believe there will be impact of AI. That's my view. How much cost saving as well as shortening of timeline would you like to achieve? In 2030 or 2035, as of that timing, what is your idea?
Thank you very much. Epinova AI Native Study Designer. That is quite interesting. There are AI agents and the data have a discussion of a platform on the design of the protocol, and that minutes is generated. That is quite interesting. That's why we put it in this slide. As we mentioned, for the development, usage of the AI is just a part of our day-to-day work, so I didn't explain about that. Two years ago and since then, protocol, informed consent, and all such clinical trial documentation translation into each country's language, that is quite cumbersome work. With using AI translation, we were able to accelerate the speed. For example, for the translation from Japanese to English, it took two months.
With using AI, it can be completed within just a couple of days. Of course, the final confirmation is going to be done by human. Technical language translated into easy to understand for the patients. Their large language model is utilized and that is completely utilized, but that's already part of our job. That's why I didn't focus on. CSR generation. Each team already use AI for generation of the report. General document creation is where that we use the AI, just our day-to-day work. AI agent is quite interesting, so this might be the response to the question of your second question. Toward the future cost reduction and also time reduction, we can extremely expecting on AI in the terms.
We are working on the confirmatory or validation work and after that, when we are ready, we would like to share what we would go.
Thank you very much.
Thank you very much for your participation and asking a lot of questions. Now time is up. With this, we would like to close this R&D day presentation. Thank you very much for your participation.