Thank you very much for joining our R&D meeting out of a very busy schedule. I'm delighted to serve as MC today. I'm Ikeda from Corporate Advocacy and Relations. Thank you for your time. You can join this meeting via Zoom webinar or live streaming. After our explanation, we will go into Q&A session. You can ask questions only through Zoom webinar. You cannot ask questions in our live streaming. Today, we have simultaneous interpreting between Japanese and English. If you're joining from Zoom webinar, from the Zoom screen menu, you can choose the language of your preference. We are going to explain based on the meeting materials posted on our website. Today's presenters are as follows: Representative Director, President and CEO, Kenji Yasukawa. Chief Scientific Officer, Yoshitsugu Shitaka. Head of Targeted Protein Degradation, Masahiko Hayakawa. During the Q&A session, Primary Focus Lead, Peter Sandor, is going to join. Simultaneous interpreting is available, including Q&A, but we cannot guarantee its accuracy. This material or presentation by representatives for the Company and their answers and statement in the Q&A session includes forward-looking statements based on assumptions and belief in light of the information currently available to management and subject to significant risk and uncertainties. Actual situation may differ materially depending on a number of factors. They contain information on pharmaceuticals, including compounds under development, but this information is not intended to make any representations or advertisement. We'd like to go into the presentation. Yasukawa-san, please. Good morning, everyone. I'm Yasukawa. It's in December. I'm quite sure that you are very busy. Thank you very much for your allocation of your time for our R&D meeting. Page 2 is a cautionary statement. As usual, I would like to skip reading it. Page 3. This is agenda for today. There are 3 parts. I am going to make a very simple introduction. The Hayakawa, the Head of Targeted Protein Degradation, is going to explain the bottom topic for today. Closing is done by Dr. Shitaka, Chief Scientific Officer. Page 5. I will explain why the Targeted Protein Degradation, a new primary focus, was selected as the primary focus along with its characteristics. As shown in the figure on the left, this primary focus focuses on the biology of proteolysis and utilizes protein degrader as a novel modality to target cancer caused by abnormal proteins. In selecting the primary focus, as you see on the right, the prescribed criteria has to be met. The first is scientific validity. We have established a technology platform for a new modality, protein degrader, from which we can continue to generate promising assets. We believe that this is quite rationale that we've selected this as our primary target or primary focus because we have such a ground. The second is the feasibility. By leveraging proficient capabilities for medicinal chemistry and manufacturing of small molecule cultivated over the years, as well as our development in oncology, we are able to move forward quickly and efficiently with the individual programs. Regarding the 3rd program, 3rd point of the program, the lead program ASP3082 entered the clinical trial phase this year, and multiple follow-on programs are under investigation in the research phase. These points were discussed at meetings such as Executive Committee and the Board of Directors, and the decision was made to make this the primary focus. We will continue to create programs from this platform on an ongoing basis and proactively invest resources to further accelerate development. From here, the lead of primary focus, Hayakawa, is going to talk about the details. Good morning, everyone. I'm Hayakawa, Head of Targeted Protein Degradation. I was involved in small molecule drug discovery research as a medicinal chemist for about 15 years since I joined the company. After that, I worked in planning for the research division and led the unit conducting research in protein degradation, and then I have been in my current position since this October. Page 8, please. This shows the key points that I would like to communicate with you. I will divide the presentation into four parts: the basics of the technology platform, ASP3082, the lead program, the capabilities we have, and the expandability of the Primary Focus. Slide 9, please. First, I would like to explain about the basics of the technology platform. Now page 10, please. Excuse me. This slide explains about the undruggable target. The left chart shows the difference between druggable target and undruggable target. Druggable targets have distinct binding sites suitable for inhibition by small molecule compounds, through which function can be controlled. On the other hand, undruggable targets are said to be difficult targets for small molecule drugs because their function cannot be sufficiently controlled simply by compound binding due to lack of apparent active site. It is estimated that about 80% of the proteins involved in disease are undruggable targets with shallow binding pockets. Shown to the right are a variety of undruggable targets. Because of the difficulty in accessing these targets, treatment options for diseases associated with these targets are limited. Slide 11, please. On page 11, we describe the mechanism of action of protein degrader, a new modality we use against undruggable targets in the cell. A protein degrader works by hijacking the body's natural protein and degradation process, the ubiquitin-proteasome system. As you see on the left, a protein degrader consists of a protein binder and E3 ligase binder. A linker connecting the two. Protein degrader is characterized by the fact that they exert their action by catalyzing the ubiquitination process, rather than by binding to the target protein and directly inhibiting its function, and thus do not require the strong binding affinity of conventional low molecular weight compounds. As you see the right half of the slide, the protein degrader brings the target protein and E3 ligase adjacent to where a ubiquitin marked for destruction tag is added to targeted protein. The target protein is subsequently degraded by the proteasome, an enzyme that selectively degrades ubiquitin-added proteins. Once catalyzed, the protein degrader is released and triggers this process again. This is assumed to allow the target degrader to remain in the cell and continue to degrade the target protein for an extended period of time. Through this mechanism, we believe that strong and sustained degradation effect on undruggable targets can be achieved. Slide 12, please. This slide shows the potential benefits of protein degraders over other modalities. Among the various modalities used against undruggable targets, protein degrader has 3 main advantages. The first is access to undruggable targets. As explained earlier, we believe that proteins that are difficult to target with conventional small molecule compounds can be targeted because they do not require deep pockets. The second is penetrating biological barriers. Since protein degraders are not very large in molecule size, they can penetrate cell brains and the blood-brain barrier, and they also have excellent penetration in solid tumors, where large molecules have difficulty to reach. Third is specificity. Protein degraders can selectively degrade their targets by forming a ternary complex with a target protein and E3 ligase, which may be advantageous in terms of efficacy and safety balance. With these advantages, we believe protein degraders are best suited among modalities to access undruggable targets in cells. Slide 13, please. We discussed the status of protein degrader development. In this figure, the programs that have entered the clinical phase are mapped based on the study phase and target classification. Moving from outside to the center of the circle, the phases are represented as phase 1 and phase 2. There are currently 2 programs in phase 2. These are targeting the estrogen receptor and androgen receptor in breast and prostate cancer, respectively. Several other programs are in phase 1. Although it is a program of another company, clinical trial data suggesting pharmacological effects have been reported at recent conferences, the usefulness of this modality itself is being demonstrated in clinical trials. ASP3082, which is currently under development by Astellas, is the world's first protein degrader for KRAS mutants to enter the clinical study and is expected to become a first-in-class drug. This is going to be explained further in the following slides. Next, please. Here is about the product potential of the lead programs, ASP3082. Slide 15, we discuss the KRAS mutation that is the target of ASP3082. RAS proteins are GTPases that regulate signaling pathways and other interactions. RAS mutations are one of the major oncogenic factors, KRAS, NRAS, and HRAS are most commonly involved. Especially the KRAS mutation frequency is known to be quite high. As shown in the figure on the right, KRAS is normally in inactive or off state, but becomes active or on during cell proliferation. Normal KRAS switches between these on and off states in conjunction with the cell proliferation, thus maintaining a proper cell proliferation. On the other hand, when mutations occur in KRAS, the active on state persists. This results in uncontrolled cell proliferation leading to cancer. As shown in the figure at the bottom right of the slide, there are multiple types of KRAS mutations, which are denoted as G12C and G12D. This means that the 12th G glycine is replaced by C, cysteine, or D, aspartic acid, in the amino acid sequence of the KRAS protein. On slide 16, we discuss the population of cancer patients with KRAS mutations. Approximately 1.8 million new cases of cancer are diagnosed annually in the United States. The 14.1% portion of this population shown in color in the upper left indicates that a cancer-causing target has been identified and that a therapeutic agent exists for this target. The 11.6% or approximately 210,000 people shown in pink are the patients with KRAS mutations. The light-colored area is the group of patients with a G12C mutation among KRAS mutations. For this mutation, small molecule inhibitors are now on the market. Therefore, validity of target KRAS mutations and suppressing their function has already been clinically proven. On the other hand, there are still no effective treatments for KRAS mutations other than G12C, and there is a huge medical needs. Page 17, please. In this slide, this describes the major types of KRAS mutations. There are a variety of known mutations in KRAS, but the most prominent are G12D, G12V, and G12C. The 12D mutation on the left side of the figure, the target of ASP3082, is reported to occur in 37% of pancreatic ductal adenocarcinomas, 12.5% of colorectal cancers, 8% of anaplastic endometrioid cancers, and 4.9% of lung adenocarcinomas, and can be targeted in many cancer patients. For the G12V mutation in the middle, there are a very large number of patient. As for the G12C mutation on the right, as shown in the previous slide, an inhibitor has already been launched. Although the overall number of patient is not as large as for G12D and G12V, some reports predict peak annual sales of more than JPY 200 billion. It is currently attracting a great deal of attention. On page 18, let me explain the difference between G12C and G12D mutations. In general, inhibiting KRAS is difficult because the pocket to which the inhibitor binds is shallow. As was mentioned before, for KRAS G12C mutation, a small molecule inhibitor has been launched already. In KRAS G12C mutation, a highly responsive cysteine residue exists. The drug can inhibit the KRAS function through strong binding here. Other mutations, including G12D, do not have such sites, it's challenging to create compounds which can inhibit the function by strong binding. To address this issue, we considered the targeted protein degrader approach and created ASP3082, a compound which specifically binds to KRAS G12D and E3 ligase and catalyzes the degradation. On page 19, I will explain the efficacy of ASP3082 by using animal model experimental data. Xenograft mice bearing human pancreatic cancer with KRAS G12D mutation were used to compare the anti-tumor efficacy of the conventional small molecule KRAS G12D inhibitor and the ASP3082 KRAS degrader. The small molecule inhibitor could suppress the tumor growth to a certain degree, its efficacy was not enough. ASP3082 demonstrate very strong anti-tumor efficacy and tumor regression was observed. Based on these results, it is expected that ASP3082 can demonstrate high clinical efficacy against cancer with KRAS G12D mutation, which was considered to be undruggable target. We presented more detailed non-clinical study data of ASP3082 at an academic society meeting in October. At that time, there was a great reaction. The profile of this compound is drawing strong interest from researchers around the world. Let me explain our drug discovery capabilities. On page 21, I will explain the history of related research Astellas has conducted by now. In the 2010s, we started our research aiming to generate conventional KRAS mutant inhibitors. It was technically difficult to create binders that bind specifically to KRAS mutants such as G12D, but we identified proprietary KRAS mutant binders based on Astellas' historical small molecule capabilities. Independently from this inhibitor research, we also started protein degrader research in the 2010s. Through this, we built various technologies for drug discovery using this modality. By combining these 2, we started a research on KRAS G12D degraders in 2020. Since then, as is shown on the slide, this has advanced at an unprecedented speed as a compound aiming to be a first-in-class product. In just 5 months after the start of our research, we identified ASP3082. Furthermore, after selecting ASP3082 as a new drug candidate, we achieved IND submission in just 1 year. On page 22, let me explain the capabilities we have developed in creating ASP3082. Until the creation of ASP3082, there were 2 major challenges. The first one was to bind the compound to POI, a protein target. The second was to enhance the efficacy so that we can achieve sufficient inhibition of function. It took quite a lot of time and efforts to create a compound which binds to KRAS G12D mutant. We were successful by leveraging our capabilities for small molecule synthesis, which we have been good at from before. On the other hand, even if a binder can be created, due to shallow binding pockets of targeted proteins, we couldn't achieve sufficient inhibitional function. By using protein degrader as a modality, we enhanced the efficacy successfully. The upper and lower parts of the diagram are the capabilities we have developed through this process. First, we have proprietary binder compounds against KRAS mutations. We can utilize capability technologies in chemistry synthesis to create binders for expansion to other targets. I will explain this later. Regarding the E3 binders, in addition to the one created by Astellas on its own, we also acquire next-generation technologies through partnering. At the bottom, you can find examples of the technologies we utilize in drug discovery for this modality. It's not just enough to create a targeted protein binder and E3 binder to be connected with a linker. It's important to optimize the structure, including the three parts. In addition to the conventional chemical synthesis, we can leverage robotics and AI algorithm. We also have state-of-the-art modeling technology and highly efficient molecular synthesis technologies as well. By combining these, we can create optimal targeted protein degraders quickly and efficiently. On page 23, let me explain the process to create ASP3082 as a specific example. The modeling system we use to generate ASP3082 is unique, as it's an integration of researchers' expertise and computer modeling. Usually, it takes multiple years to optimize for small molecule drug discovery, but only 5 months were required to identify ASP3082 successfully. As is shown in the diagram, we started optimization from hit compounds, and the 38th compound we synthesized was ASP3082. Given the fact that, in usual optimization process, synthesis of hundreds to 1,000 or even more compounds is necessary, we were able to create a new drug candidate very efficiently with less steps. By leveraging the capabilities we have accumulated, we think we can create new drug candidates in a short period of time in our follow-on programs and can expand our pipeline continuously. Last but not the least, I will explain the expandability of this primary focus. As is shown on page 25, various applications can be possible with regards to the targeted protein degradation technologies. By converting POI binders in line with different purposes, it will be possible to access various targets. Also, by modifying the design of E3 ligase binder and linker, we can aim to enhance the power of degradation and strengthen functions such as tissue specificity. In proceeding with this, we will not just depend on our own existing technologies, but we will also actively combine them with external capabilities. Next, page 26, let me explain the direction of our partnering. As I mentioned on the previous page, we are considering two directions, expandability to various target proteins and to strengthen functions by design modification of the entire modality. We are exploring partners actively in both. We already have partnership with FIMECS, which has synthesis platform for efficient protein degraders and cancer-specific E3 ligase binders. We would like to use their state-of-the-art technologies and aim to create next-generation protein degraders. We would like to expand partnering in the future, incorporate external capabilities, and further enhance our competitive edge. On page 27, I will explain our overall strategy for this primary focus. As the first phase, we will aim for the launch of KRAS-targeted protein degrader. In addition to ASP3082 targeting a G12D mutant, programs targeting other KRAS mutants are also ongoing. As the second wave, we will utilize both partnering and our own technologies to expand to oncology targets other than KRAS and promote the creation of next-generation protein degraders. As the third wave, we will aim for expansion to non-oncology targets, such as immunology and other target diseases. On page 28, let me explain the current pipeline. Regarding our lead program, ASP3082, phase 1 study, monotherapy dose escalation part is ongoing, with data readout expected in FY2023. For KRAS G12D mutations, we are studying a backup compound in parallel as well. The next program we are considering is pan-KRAS degrader, which is the third one from the top. Pan-KRAS means various KRAS mutants. We are discussing this as a compound with the potential to be applied to a broad range of patients. Our lead program is now in the IND preparation phase, aiming for IND submission in FY2023. We cannot disclose the details, but as the second wave, we are also working on cancer-related programs targeting non-KRAS proteins, including 2 collaboration programs with FIMECS. For non-cancer diseases in the third wave, we are conducting exploratory research. We are working to generate continuous programs broadly from initial stage of research to clinical stage in this primary focus as a whole. That's all from me. Lastly, Chief Scientific Officer Yoshitsugu Shitaka is going to explain from the viewpoint of our research, our new organization structure. Shitaka-san, please. Good morning, everyone. Shitaka, Chief Scientific Officer. At the end of our presentation today, as a background leading to the creation of this new Primary Focus, I'd like to explain the changes brought about by the new research organization structure we implemented in the last fiscal year. Page 30. By modifying the research organization structure in October last year, we changed the structure from functional lead hierarchical structure to objective-based, agile organization shown on the left. We created an agile organization by objective, such as immuno-oncology and Targeted Protein Degradation, assigned researchers with required expertise, and delegated authority. We wanted to change mainly the 3 things shown in the middle, namely the speed of decision-making, mentality, and behaviors of our researchers, and timely decision for investments. One year has passed since the reorganization. We are feeling the great effect as changes and improvements we wanted to realize are occurring in the research organization as a whole. First, our daily decision-making has become much faster. In a flat organization, researchers' original ideas and ambitious plans are being proposed and shared. In the ASP3082 creation process, breakthrough proposals and decisions were made on-site by those in the research labs rather than by top-down. Mindset change spills over from research to manufacturing and clinical development divisions as well, resulting in entry into clinical trial in a record time of just one year from the identification of a compound and a promotion of ASP3082. In my capacity, investment effects are much more visible in each objective, we can change the allocation of our investments in the agile organization in line with the performance, even during the middle of our fiscal year. In reality, we have checked the progress of our research on Targeted Protein Degradation at an appropriate timing, judged the potential, and expanded investments flexibly. As a result, as we presented earlier, ASP3082 achieved the world's first IND by targeting KRAS G12D. We were successful in creating multiple promising follow-on programs to accelerate the Primary Focus selection this time. In the R&D meeting last year, we told you that we are adopting a framework where an organization can grow or maybe shrunk according to its performance. The organization to execute Targeted Protein Degradation has grown from a small venture unit to a research engine to promote the Primary Focus. We will more significantly delegate authority and reinforce investments in this area so that we can further accelerate our research and generate programs continuously into the future. This concludes our presentation. Thank you very much. Thank you. This is all from us. We would like to entertain questions from your side. The questions are entertained only from the Zoom webinar, but not from the live streaming. You can ask questions either in Japanese or English. If you have any questions, please refer to the raise hand button that you can find at the bottom of the screen. From the smartphone, you can find the Details icon and tap it. You can find the Raise Your Hand icon. When your name is called upon, please unmute yourself. You mention your name and affiliates first to ask questions. This time, from overseas, our primary focus lead, Peter is attending here together with us. Sometimes the answer will be in English. For those in the Zoom, you can select original language as well. Depending on your necessity, please adjust your channel. Now let's start Q&A. Thank you very much for waiting. First, question is, Mr. Yamaguchi from Citigroup Securities, Citigroup Securities. Can you hear me? I'm Yamaguchi from Citigroup. Yes, we can hear you. Thank you. I have a couple of questions here. First of all, this research team or group, or the members of this research group, basically those are all internal people. Who are the members of this research group? Are they all internal members? Yes, that's right. They are all internal employees and the members, but of course, the external capability is utilized, so we have these double approaches. Thank you very much. Also the... you have three factors. This might be too simplified a way, but the binder to the target protein, E3, and in between you see the linker. E ach of them is, of course, important, but which one shows you the most difficulty? For making it a platform, of course, the left is going to be changed every time, but the right one, E3 linkers, they have to be always generated in a very different types. In order to expand this project, you have to go through such process each time. Thank you very much for asking your questions. Y ou point out is quite important. What is important is the components, that is about the left side, and also the right side that is connecting E3. And the binder. Both are very important components as I said. For each of them, sometimes it differs depending on the programs, but it is necessary to have such capabilities. What is the common capability? That is assembly, assemble all these components. But we have good at for modeling and expertise. We have those as a common platform that I can, we can use. Thank you very much. Lastly, for the future in this area, various companies are making their reports in this field. Competition is going to intensify into the future, and you're doing your development under such circumstances. Particularly the ASP3082, the initial asset. With the speed to reach the market, this is going to be very important for the expansion of the franchise into the future. Erbitux combination is used in phase 1 study. In pancreatic cancer, I think initially, in which tumor types are you going to use in the initial studies? What are your tumor type strategy? Competition is going to intensify. Regarding 3082, CRC is the initial target. Also, as you can see on page 17, higher onset pancreatic cancer, CRC, and ductal cancer, lung cancer, ovarian cancer, and also the uterine corpus cancer, we'd like to consider. Thank you very much. Thank you. Thank you. Next, Credit Suisse Securities, Mr. Sakai, please. Sakai from Credit Suisse. Thank you very much. This might be two simple question, but the phase 1, that is open label study with the 270 subjects, I think that's a relatively reasonable size. Looking at the ASP3082 alone, or this is the undruggable world. What's your focus or expectation about the probability of success that you had? ASP3082 probability of success is your question? Yes. Well, yes, it's a undruggable field, but the pathological involvement, we believe, this is the target with a high level of the evidence. We believe that this is quite gradable and gradation level is quite so high. We have a high probability of success hit set. I see. O f course internally you look toward the level of the success, right? For example, if you refer to page 28. Some information is undisclosed, regarding the sense of the speed, are you going to wait for the result of 3082? I believe you are working on backup program as well. Other than those, you mentioned you are going to put the resources further. In an earlier phase, are you shift toward a phase 1? Do you have such a plan? What's the to what level of the speed or sense of speed you apply for this? Well, without waiting for the result of 3082, we work for the follow-on projects one after another. ASP3082. The optimized study is finished, and after just 1 year, ASP3082 got into the clinical phase. That is the level of the speed we are thinking about for follow-on products because this field is quite competitive. Yasukawa speaking. Regarding the first question, let me make additional comment. Slide 12, if you refer to. There are three benefits described here. Biology, ubiquitination is introduced, and that is quite robust. Of course, compared to the ordinarily low molecular weight compounds, the molecular weight is larger. Production side, well, when we adapted this theme as Primary Focus, the middle one is the focus. If it's really penetrating to the tissue, although it resides within the vessel or before getting in the tissue, PK goes up or not. Those were part of the concerns that I had. Looking at the result of initial clinical trial, it was confirmed that it was absorbed and distributed systemically. The first hurdle that I thought it was the highest among this project, well, what we were able to overcome. Of course, we have a backup for the preparation. If phase 1 went much further, and we can learn about the level of the blood concentration, if that achieves to the targeted level. If the target level of the blood concentration is achieved, we would not think about the follow or we would not think about the backup. Thank you very, very much. On page 19, compared to inhibitors, was this published? What is the comparator? Hayakawa would like to explain. Here, as you pointed out, what is compared against what? Directly, yes, I understand your point. Inhibitors are used as a component to develop degraders. The left side, inhibitors. It would work as inhibitors. Also, the degraders were compared against inhibitors. As for the inhibitor part, 30 milligram oral BID almost to the limit it was dosed. Still, the tumor could not be controlled sufficiently. If we add the degrader function, tumor was almost cleared by injecting twice a week, very powerfully, tumor shrunk. That's the comparison here. Understood. Sorry to say this, you didn't expect a lot of efficacy here in this model to begin with. Going back to the history, originally, we were doing inhibitor research with a lot of focus initially. Compared to other companies, from the initial stage, we identified inhibitors. How we can optimize? Even if we optimize, tumor in vivo model did not demonstrate sufficient efficacy. We had such a long time in our research. We switched to degrader profile, we were able to accelerate. Understood. I have great expectations on you. Thank you very much indeed. Thank you very much. Next, JP Morgan's, Goitis. Mr. Wakao, please. Thank you very much. Wakao, JP Morgan. First question. This protein degraders are developed by other companies as well. Looking at the technologies, what's the difference of the technologies between other companies and yourself? Thank you. First of all, asset. KRAS, as you see on the screen, we have various types of the target possible, because we have such tools on our hands. Therefore, we can have a variety of the approaches that can work on others than KRAS as well. Three components assembly. That design is very special technology-based, so that is what we have a great confidence. The other parts that is expanding these days is E3 binder technology. On top of the ordinary binders, but also we have our original binders and from the FIMECS as well. They have a very interesting and new technology, so we would like to expand this further. That's the difference of us from others. Against the target, as you explained, you have to tune up. It's difficult to compare the technologies, just simply. Correct? We have these technologies, and it's difficult to make an apple-to-apple comparison. We have chemical drug discovery activities, and we accumulated our design and manufacturing capabilities. Our technologies can be said as something very good. Thank you very much. Secondly, on this page, in the end, the initial target is undruggable, but this time what you have is having a binding. The thinking behind here, it can bind, but it's not as much as to show inhibitory effect. E3 binder ubiquitin. That's why you have a degrader. Regarding the binding sites or binding barrier, the binding capability is not so high, but by having this, it's supplemented. How is it being bound? Thank you for the very important point. In the case of degrader, the binding can be very weak, which is enough. That's the difference compared to the usual small molecules. It's like a keyhole. It's like to insert a key to lock to inhibit the function with a small molecule. In the case of degraders, protein A to target degradation and ubiquitination, protein B, it can be close to each other. That's enough. In the case of a degrader, there can be just weak binding with each other. Binding is very different compared to the conventional ones in terms of the science. In line with that, well, if the specificity is low, it sounds like it binds various variable places and therefore E3. It is very important to show the specificity. In the first program, I just wonder the level of the specificity, and you mentioned there are various types. What is the current expansion reach? Thank you very much. For specificity, to put it in a simple, the specificity is said to be quite high, compared to the low molecule products and activator. As has been mentioned, deep lock with a key, that is a very limited interaction where you co-have to come up with the specificity. Within the body, there is the same type of the philosophy is applied for the key and the lock. That's why the specificity is very difficult to achieve. This time, the protein degrader, protein N and B are shaking each other and AB surface interface are contact in a wider area. Generally speaking, specificity is likely to be high. On top of that, as has been pointed out, this is quite important point. This E3 binder, this protein, there are more than 600 kinds within our body. For example, some are specific to cancers or specific to some tissue, they are known. We can make use of those of them to realize the required specificity or improve the value of the substance. Thank you. 1 additional comment. 3082 specificity. While proteomics is utilized, selectivity is very high, it degrades KRAS G12D alone. That's confirmed with the experiment. Next fiscal year, the initial part is going to complete for 3082. Are you going to show us the data next year, in the next fiscal year, Peter? What is the current status of a phase 1 study? Please explain, Peter. The current phase 1 study is in dose escalation. We expect the data out of the first phase in fiscal year 2023. This will guide us into the next step of the program to design and decide on which two more types to develop it further and how to expand the monotherapy and/or combination. We will decide at this point when and where to disclose the data. It will likely be disclosed at academic meetings or conferences. Thank you very much. Very clear. Thank you very much. That's all from me. Thank you very much. Next, Schroder Investment Management, Mr. Sato, please. Mrs. Sato, please excuse me, I'm Sato. There are a couple of questions. First of all, from the scratch, you started the research, and it's been only 2 years and 3 months to achieve the first inpatient. T his is unprecedented speed. Why would this modality, this speed was achieved? Is there any background that you can share with us for this quick achievement? Thank you. From the identification of compound IND, it took 1 year. This is very fast. This is the shortest, record short for us as well. We conducted several studies in a parallel manner. We took risks. That's one of the contributor for this. For optimization, as has been repeatedly mentioned. We have accumulated know-how for that. Also modeling. The accuracy for that is extremely high. The forecast, the prediction of the modeling achieved a very high accuracy level. That's another reason. Right. From the perspective of actual research field, as Shitaka mentioned a little while ago, agility is high and flat and objective-wise, the organization was established. That contributed a lot. The decision-making was quite quick. Within the organization the decision was made quickly and internal-external collaboration went in a speedy manner. That's why we were able to accelerate the speed from the research to R&D. Thank you very much. Yasukawa, let me make additional comment. On this page, 38 compound is what we achieved, what we wanted to have that thanks to the computer technology. One year from the ASP3082 discovery to IND. This is actually based upon my request. The molecule compounds are synthesis experience is so much accumulated internally. Things that what is done, then what is triggered. There is such a kind of a role internally. If you just follow that, we, yes, we can minimize the risk, but it would take a longer time. We shouldn't be in that way all the time. Once some promising thing is identified or when we have to win the competitor, we shouldn't think about only the low-risk approach. When we find something good, we have to take risks and several tests should go on in a parallel manner to achieve the IND in a shortest time. That's the request I've been placing to the research people, that was achieved with this ASP3082 team. This is a good precedent for us, same thing could be applied for the following, good compounds if those are identified. This brings the confidence to other teams as well, to the company as a whole as well. Thank you very much. Also the delegation of authority to people in the field by reorganization and taking risks to have programs in parallel, if that's the background, not just in this modality, but for others as well. Y ou can apply this to other areas as well. What do you think? Yes, your understanding is correct. There is a change in such a mindset for the entire research and also for the entire company. It's spreading now. This is going to be a very good precedent so that we can have a great sense of speed for the following programs as well. Thank you very much. ClinicalTrials.gov. I'm checking that. Once every 3 weeks, IV infusion. Once it's bound, it's going to be released and then go back to bind to the receptor. With 1 dosing, the efficacy is going to last for a long time with 1 dosing? Yes, you're right. Once a week, IV administration, but as you said, it's a protein degrader. KRAS mutant would be gone completely. It takes time to regenerate. The efficacy would be prolonged. The distribution of the drug in the tissue and cancer, it's superior compared to the conventional small molecules. That's why we can use this kind of a dosing regimen. Peter, when you wrote the protocol, how did you determine the dosing frequency? According to the data you have by now, once-a-week dosing seems to be good or not? What do you think? Anything you can share right now? It was designed based on the preclinical pharmacology, data. What we have seen so far confirms the preclinical experiments and expectations completely. Right now it seems that we are on the right, dosing schedule and frequency as well. Thank you very much. It says, the 21-day cycle. This is once a week administration, and after that you will have the drug holiday. That's the image of the administration cycle? Current, clinical study design. Thank you very much. Thank you very much. Phase 1 primary completion date, that is 2026th March. It's a bit far ahead, but the first part is planned to be completed in the next year. I think you have a bit of the leeway for your scheduling. Is there any background for that? Is there any reason for that? The study, the primary completion date describes the time when the, all the patients have been dosed and followed up for the predefined period. As we mentioned earlier, we expect to finish the dose escalation next fiscal year, and we will have safety information about the drug and then we will have the dose for the next phase of the clinical study. Our expectation is that we will start to see the first proof-of-concept type data in the fiscal year 2024/2025 timeframe. That's all from me. Thank you very much. Yes. Thank you very much. Next, Morgan Stanley MUFG Securities, Mr. Muraoka, please. Hello, I can hear you now. Thank you. Muraoka speaking. Listening to the presentations and discussions today, undruggable target. It can be used for undruggable target. I now understand it clearly, but the drugs you gave up because of the lack of efficacy or insufficient blood concentrations, you can renew such drugs. It's like a dream. Is it possible to take such a strategy? Yes, you're right. KRAS and others, there was a pipeline table. It's undisclosable, but in the background, you can find very well-known targets. In terms of the disease biology, these are targets with a high probability, but we couldn't produce. We would be able to produce. Once you're able to produce, it's going to be very efficacious. We'd like to address such targets. Puse. Thank you. Your partner, FIMECS, that's Takeda's spin-off company, right? This is my own imagination, within Takeda, these are not discovered. With our partnership with Astellas, the development is taking place in a very interesting manner. That's out of my imagination, is this understanding right? Well, I don't know if this project is not emerged in Takeda or not, but of course, it's a spin-off and FIMECS has a technology of RaPPIDS. This has a very synergistic effect with our project. We have a high expectation on the collaboration with them. Well, within Takeda, did you think that this is a good company and technology, but it was inaccessible, so the spin-off timing was most appropriate and optimal for you? Yes, we understood in that way. Thank you very much. My last question. I know this is deviating from today's theme, any comment on the success of Sobi Rexulti? Yes, Kaori speaking. Sobi Rexulti, as you know, it was originally something we purchased from a European venture. Before our purchase, they had a small size phase 2 study. A few years ago, there was an impairment loss. You may remember this. Initially, just with that phase 2, we wondered whether we can file for accelerated approval. That was the level of the results. It was a small size study, the study itself was mainly done in Eastern Europe. Just with that data, we thought we could not file a submission. If we want an accelerated submission, if that was possible after filing, after conditional approval, confirmatory study was to be conducted. That study is now being done as phase 3 study. Personally, phase two data, I think, i s going to be reproduced. That was my belief. We have such data exactly as I thought. These are the results we expected. There was no surprise about the results. That's the situation right now. The other one will be at the beginning of next year. It's an event-driven study. We are trying to count down in the final stage. Once we make a decision, we make the announcement. You were able to reproduce the results in the previous phase two, OS, PFS, hazard ratio 0.45. This was great. The results are kind of comparable. Regarding the study with already available results, yes. Understood. That's all from me. Thank you very much. The study results, once available, will be reported to you. Thank you very much. Mizuho Securities. Next, Mizuho Securities. Mr. Tsuzuki, please. Thank you very much. I'm Tsuzuki from Mizuho Securities. Can you hear me? Yes. Thank you for the presentation and explanation. This is quite interesting. I would like to ask you a question about the rate limiter for this degrader. You make the target, the protein linker and also E3 ligase. I think these three are important components. Out of these three, which is likely to be the highest bottleneck rate limiter? Of course, it differs depending on the project. Regarding this ASP3082, for the optimization of the linker, page 23, you have to go through the fine-tuning process or the identifying the target protein became the rate limiter. What was the rate limiting factor for this project, and what is likely to be the future rate limiting factor? This is the first question. Hayakawa speaking. That is a very important question. Thank you very much. KRAS G12D degrader case. Well, as it's been pointed out in my presentation, the left side, that is the original G12D binder. Making that took a longer time. The process afterwards, like assembly and so, the part of E3 binder, that match is quite well. Ultimate molecule establishment was considered based upon the, our design technology, it was accelerated. Just like you pointed out, it's case by case. For KRAS, currently, we have mostly the insufficient binder set. Therefore, in an accelerated manner, the degrader is likely to be established. Regarding assets other than KRAS, again, for a longer time, for the chemist or the small molecule binder research has been long ongoing, we can make use of that. W e will have other project designated as undruggable. In that case, it would work for them as soon as possible so that we can gain the new interesting asset. Thank you very much. One more question about the linker. If I'm wrong, please, correct me. E3 ubiquitin ligase. What is the residue in the protein is going to be important? On page 23, on the 1st to the 38, compound you created, lysine residue was a rate-limiting factor. You have a lot of assets in your pipeline, and you can solidify your know-how, and you can be faster for the future. I'd like to know more. Very, thank you for the very deep question. We don't know everything in science yet, but lysine residue ubiquitination is done in parallel as well. The speed of ubiquitination is very fast. That is repeated, and it goes into a proteasome degradation, and it turns in an irreversible fashion. We are assuming such a catalytic mechanism. I don't know how much I can say, but what's important is the target protein, POI and E3 ligase. They must be brought about to be adjacent, close to each other. 1 more question. Another is the selection of the binder. Those cannot be either a agonist or antagonist obtained by the major pharma, mega pharma. Mega pharma has the favorability in this project. Also you are thinking about the collaboration with the company with having the most optimized binder for the next project. L ogically, that will be the way. Thank you very much. It seems that you are covering our intention already. What you pointed out is quite right. Therefore, not specific to internal development, but we are always looking for the attractive partner. That is going to be quite important. Understood. Thank you. Thank you very much. Thank you very much. Next, J.P. Morgan Asset Management. Mr. Sawada, please. Yes. Can you hear me? Yes, we can hear you. I am from J.P. Morgan Asset Management. My name is Sawada. I have a few questions. First of all, to begin with E3 binder ubiquitin ligase. If you change the types of ubiquitin ligase, POI target protein could not be degraded well. Which ubiquitin ligase to be selected? Such know-how is already available in your hands? As for KRAS, I am sure you know this already, but depending on the targets, ubiquitin ligase, what would be degraded in ubiquitin ligase? There are still some things you don't know yet? Thank you for your question. We have not understood everything yet. Regarding KRAS E3 binder, what types should be the best to be combined? We have such information. With modeling, we can get some information to a certain degree, and also, tissue or disease specificity could be achieved with certain E3. Molecular design would tell us a certain information. We have to go through a trial-and-error process still. Understood. If that is the case, you mentioned that there are about 600 clients. They are always existing in our cells or depending on a cell. The ubiquitin ligase that it wants to adhere is sometimes not available. Thank you for the question. You are right. Depending on a cell, there are E3 available, E3 not available, so there is a localization taking place. There is a tissue you would like to degrade or the status of the pathological status you can degrade. I think that kind of approach will be available. Understood. When or where it is localized, that kind of information is now available? Yes. Including ourselves, bio venture, pharmas. Yes, we collect the data and strategically a reasonable combination is what we are always thinking about. If that is the case, this ubiquitin ligase that is targeting a certain cell, but the ubiquitin ligase is not available for a certain cell, but not available in other cells. Therefore, even with this technology, it's very difficult to target. If you work on in a creative manner, then the ubiquitin ligase that you would like to target exists within a cell in whatever shape it will be. Right. If you look at the, a certain cell and if you like to degrade a certain target, then some optimal one is available somewhere, so we can find something. Of course, the selection is important. Arnold. There is know-how and you have to explore well in this year, in this field. Is that going to be one important area? Yes, you're right. Understood. That's all from me. Thank you very much. Thank you very much. Next, Sanford C. Bernstein. Mr. Sogi, please. Ms. Sogi, thank you for the great presentation today. KRAS targeting is the topic I'd like to ask a question about. Amgen, in the presentation, there was a mention, Amgen's LUMAKRAS is already launched into the market. This summer, Phase 3 data was published as well. As a target, KRAS G12C mutation, so the target is different. As you said, target is NSCLC. It's different, but still the pharma industry and scientific community have great expectations to target KRAS. As a clinical data the efficacy was not achieved compared to what was expected. I think that's the overview. Reflecting this, LUMAKRAS sales and penetration in the market is not so fast in the actual market. KRAS target, I understand the differences, but based on this, why, LUMAKRAS has these results and for you, there can be a different clinical impact you may be assuming. I'd like to hear your view. Thank you for the question. That's something we carefully watch. As for LUMAKRAS, it's an inhibitor. First of all, we have to say it's an inhibitor. Ours is a degrader. In terms of efficacy, the target protein is eliminated or degraded, we can enjoy the benefit because of this. That's our expectations. On the other hand, can we realize those expectations? There are still some uncertainties. LUMAKRAS is faced with issues like resistance occurring in a variety of ways. We have full-on programs we'd like to refine and combination therapies. The strategy for that are going to be very important as well. Thank you very much. Thank you very much. We have a couple of people still waiting for asking questions. It's time. With this, we would like to close this meeting. Everyone, thank you very much for your attendance. This is the end of the translation service.