We will now start the R&D Day of Sosei Group. Thank you very much for taking time out of your busy schedule to attend this R&D Day today. I am Nomura, CFO, and I will serve as the moderator. Outside of this room, we have some retail investors participating online. Thank you very much to the individual investors also for participating. We have a camera at the back of the room. The camera will only shoot the stage, and you will not be in the photo. Our R&D, as Chris will explain later, this R&D Day is the first time in three years. COVID-related restriction is finally lifted, and we can now welcome foreign travelers too. We are having this for the first time in three years. Today's program, as already been informed, first, the business overview and then the R&D and pipeline update, and lastly, some in-house program. The presentation will be a little over one hour, followed by Q&A. We plan to end at 5:30. For Q&A session, we would like you to raise your hand, you in this room and also raise hand function for those of our online. Please state your name and affiliation before your question. For the online participants, you have Q&A button, so you can send chat your question to us anytime. We will take questions as much as time allows later. Today, we have three speakers who will speak in English. We have the simultaneous interpretation equipment on your table. Channel one is Japanese, channel two is English. Zoom participants, on the lower right, you have the globe mark, where you can choose your language. Please choose the language you like. If you do not choose anything, you will hear the speaker's original voice. The material, the screen is a bit small, but the material is posted on the IR section of our website. Please take a look. That is all for me. Thank you. Chris, the floor is yours. Thank you, Hiro. Good afternoon, everyone. It's great to be back in Japan. It's very nice to see all of your faces again. For those of you that haven't met me, my name is Chris Cargill. I'm the CEO of Sosei Group Corporation. Today, I'm joined by my fellow executives and scientific colleagues. We've got Matt Barnes, head of UK R&D Innovation. Rie Suzuki, who's a senior leader in our Translational Medicine team. Kieran Johnson, Chief Accounting Officer, and Hironoshin Nomura, our Chief Financial Officer. I'm going to begin with an overview of our short, mid, and kind of long-term objectives as we aim to build one of Japan's world-leading biotech businesses. Perfect. I'll begin with our vision. The vision is quite simple, taking Western innovation, fusing it with Japanese quality. Our mission or our call to action is to translate world-leading science into life-changing medicines. We are uniquely positioned to achieve this mission, and it starts with our Western innovation engine, which is located in Cambridge in the United Kingdom, in the biotech hub there. Our near to midterm focus is to ensure that our Western innovation platform remains world-leading. U.K. is renowned for its discovery research, and the U.K. biotech industry is well-formed with outstanding access to talent. We plan to be innovating at our Cambridge, U.K. hub for many, many years to come. Over the long term, we plan to bring these innovative medicines that we create in the U.K., together with medicines that we in-license from U.S. or EU partners, for quality development in Japan to benefit Japanese patients that are waiting. Our long-term vision is to leverage Japan's world-leading strength in quality across all aspects of manufacturing, clinical and disease knowledge, and medical and scientific engagement. It's Western innovation, Japanese quality, world-leading science, life-changing medicines. This is the vision at Sosei. Our employees globally know this slide very well because it's one that we use at our internal town hall meetings every quarter. In the middle of the slide, there are three guiding principles that drive excellence at Sosei. Being science-led, being patient-focused, and being program-centric or team-oriented. In addition to these principles, there are four clear and transparent objectives that we have to build a business that we can all be proud of. Firstly, number one, our near-term objective is to transform R&D to be both translational, medicine-led, or TM-led, and to be program-centric. Secondly, our midterm objective is to enhance the group structure and its operational efficiency. Thirdly, our long-term objective is to activate our Japan biotech business. Lastly, another long-term objective we have is to expand into new geographic markets. I'll now discuss these four objectives in more detail. I'll begin with the first objective, which is our near-term focus to transform R&D to be TM-led R&D. What do we mean when we say we want it to transform and be TM-led with R&D? Well, historically, the company's approach was to work on targets that were already clinically validated, attempt better chemistry, and hope that we would create best-in-class drugs of interest. In this approach, it still makes sense for selected programs and diseases. However, for us to create real value and to make a real difference to patients, we need to add novel first-in-class targets to our portfolio because this is what the industry is continuously searching for. Now, Matt will talk to this later, but at Sosei, we leverage external data, technologies, and innovation partners to bring critical information into the discovery cycle sooner. We do this to accelerate how we choose the right target for a specific disease, how we discover the right asset to modulate that target, and then to test the right therapeutic hypothesis to identify the patients that will benefit most. On this next slide, the diagram across the top, it shows the typical path for traditional drug discovery and development, and we know a lot about this. Typically, it takes longer than 10 years and more than U.S. billion dollars to bring a new drug to the global market. We know less than 10% of drugs discovered are successfully approved. The probability of success is extremely low. Yet despite these high levels of attrition, there's few companies in the industry that properly embrace these facts. There's too many companies that are focused on keeping programs alive for as long as possible, which is very unproductive and capital-intensive. On the bottom of this slide, what we're really trying to show here is how our TM-led approach will work. It helps us to gain critical information earlier in the drug discovery and development process, which enables us to accelerate faster or alternatively kill programs faster. The biggest problem in this industry is there's too many programs that should have been killed earlier, and they're not. Therefore, there's enormous amounts of capital that are wasted. Under this leadership group at Sosei, we will kill programs in the future if they don't meet our thresholds to continue. That's because killing programs earlier during the cheaper phases of drug development enables us to reinvest the capital in TM-led R&D programs that may have a markedly greater impact on patients out there that are waiting. This TM-led approach to testing the hypothesis allows us to be more productive, optimize our use of capital, and in doing so, create value by potentially enhancing the probability of technical success along the drug discovery journey. The left-hand side of this slide shows historically how we have built out our organizational capabilities. Clearly, over the next decade, as we build our TM capability, we expect TM to add significant value to our programs and therefore also directly contribute to corporate value growth. Partnering with big pharma and biotech companies for the major patient markets of the U.S. and the E.U. is going to remain a core part of our business model. We know that programs that are TM-led tend to attract much larger transaction economics, as evidenced on this slide by the upfront that we received from Neurocrine last year for a phase I- B asset. You can see on the right-hand side of this slide where we show the transacted value against the stage of the program at the time it was transacted. The TM-led approach that we are taking will see us take more programs into early clinical development. When we choose to partner them in the future, we expect to gain larger transaction economics like the Neurocrine transaction. We also know the challenges that many companies in the industry face, particularly those with research divisions. They operate in linear ways with groups that are typically designed around narrow scientific domains. These narrow scientific domains are led by functional heads, and the functional heads enforce strict process protocols that require team members to turn to them for all key decisions. The lack of end-to-end coordination drives waste, inefficiency, and declining levels of productivity. Furthermore, it takes longer with the timelines, which destroys the net present value for innovative programs. For these reasons that I've mentioned, and Matt will touch on this more later, we're transforming our R&D business to be 100% program-centric in its structure. This means all programs have leaders that are empowered to iterate quickly and make decisions without deference to functional reporting lines. End-to-end program teams across R&D have all of the internal and external subject matter e-experts that they need assigned to support those teams, and the program leaders are empowered and accountable for all decisions. The program-centric approach, we hope, will drive productivity gains. Now turning to the second objective, and this next objective is a midterm objective for the company, and it's focused on enhancing our group structure and its operational efficiency. On the left-hand side of this slide, this shows you all the usual functional lines that companies have internally in this industry. Most companies rely on legacy in-house infrastructure, which can lead to high fixed costs and an inability to flex or scale rapidly. As Sosei is a relatively small company, we plan to do things differently. Going forward, we will extensively leverage external organizations to manage our cost base that we can scale up or down flexibly as required. The right-hand side provides an example of some of the traditional core functions that we are prepared to virtualize as we grow in the future. This process has already started and we're implementing a more virtual approach to our TM-led capabilities. In April 2022, earlier this year, we partnered with Weatherden, a network of scientific and clinical development experts, so that we can flexibly tap into their resources as and when needed. You see the range of services that they can provide on this slide. To date, Weatherden team members have provided subject matter expertise on a flexible basis to four of our programs, which has enabled us to iterate faster and make better decisions faster. As we grow, the virtual approach will ensure that we do not create an unsustainable fixed cost base, which supports the quick win, fast fail approach that we have embraced. Now I want to turn to the third objective, and this is one of our long-term objectives, and this is really to activate our biotech business in Japan. Going forward, it is our intention to build a pipeline in Japan to benefit patients who are waiting. We plan to do this via three approaches. Firstly, for innovative programs that we discover in the U.K., we will, with selected programs, develop them in Japan for Japanese patients, and this is likely to start with an IBD program in the future. When we partner our innovative programs in the future with big pharma companies or biotech companies, we will seek to retain the territory rights for Japan at a minimum, so that we can develop them for Japan in Japanese patients. This is what we did last year with the Neurocrine transaction, where we retained rights for the M4 program. Lastly, we will seek to in-license or acquire late-stage innovative programs from U.S., European, or other partners and develop them in Japan for Japanese patients. This is part of our strategic growth plan to accelerate value creation. We are a Japanese company, and our long-term priority is to deliver innovative medicines to patients in Japan and globally via our partners. On this objective, I just wanted to touch on the fundamental drivers that support our thinking. For many years, the Japanese market has been an afterthought for U.S. biotech companies with their drug launches. This has meant that Japanese patients with unmet medical need either wait too long for innovative medicines to arrive in Japan, or sometimes they miss out altogether. As I mentioned on the previous slide, over the long term, we want to be at the forefront of investing in Japanese patients. We believe the market fundamentals have changed and now support activating a disruptive biotech player in this market. A couple of the key highlights. Japan is the second-largest pharma market globally, ex-China, and we expect it to remain very large. Japan has a large aging population driving sustained demand and ability to pay. Japan has a very strong regulatory environment that is aligned with FDA and EMA practices as well as broad-based reimbursement. It's a stable and pro-innovation market driven by innovative specialty drugs. Japan-based biotech competitors are relatively conservative, which creates an opportunity for a strong company like Sosei. Japan has become an attractive market of late for venture-backed businesses, which validates the existence of such investment opportunities. Long term, it is our plan in Japan to focus on underserved specialty therapeutic and disease areas. Long term, we will adopt a lean, rational development and commercial model in Japan. Long term, we will build a core in Japan with the ability to maximize value from across the broader APAC region. On my final slide, this is a nice segue. The last long-term objective is to expand the company into new geographies. We believe the most natural place for us to expand beyond Japan is Asia-Pacific, which we believe can be accessed efficiently without large levels of incremental investment. Overall, the Asia-Pacific ex-China market is approximately $70 billion, which is comparable to a major market like Germany when considered as a single block. On the left-hand side, of the nine APAC markets highlighted, four have pricing, market access, and clinical practice equivalent to the U.S. and the EU. We believe the barriers to entry are quite low. That concludes my presentation. Thank you for listening for now. I'll turn to Matt Barnes, who heads our U.K. R&D innovation business, to discuss our activities in the U.K. Thank you. Thank you, Chris. Good afternoon, everybody. I would now like to focus on providing an R&D update along with my colleague, Dr. Rie Suzuki. Initially, this will focus on an overview of our key events over the last six months, followed by an update on our R&D operations. Then a broad overview of our R&D portfolio and programs. Rie will then provide a more detailed update on two of our most advanced programs from our internal pipeline. Key events summary, last six months from March- September. This slide represents these key events. Starting at the top, in March, we announced our change in senior leadership to drive the company to its next stage of evolution. In April, we announced a strategic collaboration with Weatherden, as Chris has mentioned, which is a consulting group with significant expertise in clinical drug development and accelerating the translation of novel science into life-changing medicines for patients. To strengthen our translational medicine capabilities, I will discuss this later and establish a best practice approach. In addition, we further consolidated investment in our translational medicine capabilities through our expansion into a second facility in Cambridge at the Cory Building in May. This new facility houses all of our members in the translational medicine team under one roof. Also in May, to support our target identification and validation strategy, we announced a collaboration with a company called Kallyope, which I will talk about later. In June, our business development and some of our key members of our scientific leadership team, including myself, attended the bio-partnering meeting in San Diego to ensure continued and open dialogue with potential partners of the future. We also held our internal scientific advisory board meeting, chaired by our former head of U.K. R&D, Malc-Malcolm Weir. In July and August, we announced key collaborations with Cancer Research U.K. and AbbVie, and announced the acceptance of our IND for the M4 agonist with Neurocrine. In September, we were both proud and honored to receive an Informa Pharma Intelligence Award for our strategic collaboration with Neurocrine. In addition, our CEO, Chris Cargill, was awarded Executive of the Year. That brings us to today in October, where we're hosting this R&D Day. We've had an extremely busy and productive six months, and for many of the key events covered on this slide, I'll provide more detail in later slides. On to R&D operations update. This next set of slides really provides just some background to the company to refresh people's memories. We're a world-leading drug discovery company targeting G protein-coupled receptors. For those of you who are new to hearing about our company, we focus on G protein-coupled receptors, and we are the world leaders in drug discovery and early development. We apply our proprietary STAR technology and structure-based drug discovery platform to discover small molecule therapeutics that modulate G protein-coupled receptors or GPCRs. Our headquarters are here in Tokyo. However, our R&D center of excellence is located in Cambridge, U.K., and this is where the bulk of our employees are based. We are a science-led organization. 75% of our staff have a science background, the vast majority of those holding PhDs. Some other key items of note regarding our expertise include, we are prolific researchers and drug hunters in this area, having solved over 300 molecular structures to date from over 30 different GPCRs. We've published more than 180 scientific articles, including seven prestigious Nature papers, and we have over 500 global patents. We are highly skilled at working in collaboration with partners. We work with more than 15 major global pharma companies and biotech partners, resulting in significant revenues to date. We have over 40 active programs, both partnered and in-house, and have evolved this pipeline in recent years to specifically focus on three therapeutic areas: neurology, immunology, and GI. With an increasing focus on novel drug targets, which we believe is what potential partners want in the future. This next slide, the next two slides give us some background to this structure-based drug design or SBDD platform. The first of these slides describes our STAR platform. As GPCRs are membrane proteins, they are inherently unstable with low expression, which makes the protein very difficult to work with. To address this problem, we introduce stabilizing mutations into the protein to increase the thermostability and expression. This is what we call a stabilized receptor or STAR. We can use the STAR protein for a number of applications, and we've now successfully generated more than 70 GPCR STAR proteins. Our STAR technology underpins our structure-based platform, which we use as a powerful tool to support our drug discovery. Our scientists work closely together and can utilize this platform to generate new GPCR structures, identify hit compounds, and subsequently optimize these compounds in a highly efficient and productive manner. As a result, we've achieved more than 25 preclinical drug candidates molecules for our in-house and collaboration partners and projects. We are a company with world-leading, highly productive platform, but we do not intend to sit still. We want to continue to grow and evolve our platform and company. Since our change in leadership, to drive the company to its next stage of evolution, we have identified several areas to focus on to maintain our global leadership position and support the next generation of growth. For platform growth, we want to build on the strength of our industry-leading SBDD platform, drug discovery and early development position, and also lead the next wave of growth through expansion beyond GPCRs and adding new technology capabilities. For target biology, we wish to entrench target biology into all of our projects to provide a greater understanding of disease processes, which will allow us to define robust, testable hypotheses linking drug targets to cells, to mechanisms of action, to site of action, and ultimately to clinical efficacy. For translational medicine, we have now fully integrated our pre-clinical and clinical capabilities together to support this translational medicine approach, which is fit for purpose and best practice. As mentioned previously, this is now all under one roof. Being program-centric, Chris touched on this earlier. Since the beginning of 2022, we've adopted a program-centric approach, which really does empower and align team structures with aligned incentives. Programs are now accountable for their own R&D budget, risk management, and project plans. Functions exist to support these projects. Of course, the patients and the patient focus. We absolutely must keep patients as the focus of what we do on a day-to-day basis and continue to strive to deliver innovative quality drugs to patients faster. Recognizing that partnering some projects can deliver clinical validation earlier. Of course, underpinning all of our world-leading science is our aim for operational excellence and best practice. This means our aim is to be as efficient as possible with respect to all the resources that we have available, providing the appropriate resources to the right program at the right time to give our programs the best probability of success and return on investment. We've now employed project managers into an enterprise management office to provide more accurate information to senior management, to store data in a format that facilitates external communication faster. I would now like to focus in more detail on areas of platform growth. We're continually strengthening this area by adding new complementary technologies shown here in the slide are our existing STAR and SBDD technology. Also included are additions to this, namely cryo-EM, protein binder toolkit, chemogenomic GPCR library, DELS and DEL screening or DNA encoded library. I'll describe these in more detail in the next few slides. Firstly, Sosei Heptares has been an early adopter of cryo-EM with continued growth. Richard Henderson, our co-founder and scientific advisory board member, won the Nobel Prize in 2017 for developing this technology. We continue to expand our cryo-EM capabilities and now offering routine cryo-EM structures, structure determination to support our SBDD platform. To date, over 45 structures of more than 15 unique GPCRs have been determined by cryo-EM at Sosei Heptares in both agonist and antagonist conformation. The example provided is a GPCR from the family B of receptors, which are long-standing drug targets implicated in a range of diseases. Historically challenging structure determination, which is now approachable with cryo-EM. We've now actually determined multiple structures also of family A, family B, and family F receptors by both X-ray crystallography and cryo-EM to enable our structure-based drug discovery. Secondly is the development of our protein binder toolkit. Cryo-EM structure determination often benefits from the introduction of additional protein domains, which include domains fused to the STARs or introduced during expression or purification. Fusion partners, mini-G proteins, nanobodies, antibody fragments, have all been successfully used. Protein binders like this offer clear benefits in structure determination for other non-GPCR membrane protein classes. Establishing a more routine and robust platform in this area is included as part of the Cambridge site lab expansion plans. A third technology is DEL screening or DNA encoded library screening. DEL screening offers an alternative strategy for hit identification in early drug discovery, and involves chemical libraries of 15 billion to greater than 1 trillion compounds, access through partners to allow unprecedented levels of chemical diversity. The STAR proteins we generate, that I mentioned previously, can be panned with known two molecules to identify new binding sites, and we have now used more than 10 STAR proteins in this DEL screening format in both agonist and antagonist mode. Lastly, we have been assembling a bespoke chemogenomic GPCR library screen over the last few years, which we can use with wild type or non-STAR protein. This in-house library represents a 50,000 compound set, which is being very carefully curated using our proprietary GPCR structural chemogenomics and pharmacology knowledge. The library contains GPCR diversified ligand sets covering more than 390 GPCR ligand modality combinations, and more than 10 GPCR targets have been screened to date from a mixture of both internal and partner programs, with quite a lot of success. Pioneering future innovation. These core and additional technologies will of course be used to strengthen our platform in GPCRs. However, we are also exploring future innovations through the use of these technologies when applied to non-GPCR membrane protein targets, such as ion channels, transporters, integrins, and oral small molecule alternatives to biologics. We will look to collaborate with partners which have complementary technologies in this area. One current example of this is our collaboration with Metrion, which specializes in ion channel drug discovery. Ultimately, this future innovation concept will allow us to take a broader structure-based drug discovery approach to all membrane proteins, expanding our opportunities for new drug targets and future growth. Chris showed this slide earlier. So we previously identified what we think are the three big challenges in drug discovery and development: choosing the right target, discovering a therapeutic agent, and conducting the right patient studies. Our approach to these challenges will result in choosing the right drug target, developing the right asset to test the right therapeutic hypothesis, which will be driven by our individual programs. A further key area of focus is developing this project or program-centric approach throughout the organization. As mentioned previously, since the beginning of 2022, we've adopted a program-centric approach, which empowers and aligns team structures with aligned incentives. Programs are now accountable for their own budget, risk management, and project plans. The last slide is this focus on clear unmet medical need. We always need to be mindful of the patients and our overriding aim to deliver innovative quality drugs to patients faster. Our focus will be on areas of unmet medical need and a clear understanding of treatment paradigms, and target product profiles early will ensure we work on projects that have real potential clinical benefit. Now I will focus attention on our R&D portfolio and projects in this next section. This slide represents an overview of our current R&D portfolio or pipeline. With projects or programs phased by discovery, preclinical development, or clinical stage. The pipeline is also sectioned into partner programs listed in the top half of the slide, those programs where we co-develop in the middle of the slide, and our internal proprietary projects or programs at the bottom of the slide. I will now provide a brief update on the Neurocrine and Pfizer collaborations highlighted in this slide. Firstly, this slide relates to our novel muscarinic receptor agonist collaboration with Neurocrine Biosciences. As highlighted in their quarterly results presentation in August, Neurocrine has confirmed that it will initiate a placebo-controlled phase II study to investigate 568, formerly 878, the selective M4 agonist, as a potential new treatment for schizophrenia later this year. This clinical development milestone triggered a payment of $30 million to Sosei Heptares from Neurocrine. 568 represents the most advanced candidate under this multi-program collaboration, but also of note is the intention to initiate phase I studies on both a dual M1, M4 agonist and an M1 selective agonist in 2023. Sosei Heptares is working extremely closely and effectively with Neurocrine on this collaboration. I will now provide an update on Pfizer. Pfizer 532, a GLP-1 agonist which Pfizer recently presented at the EASD meeting in September. Please note this asset was discovered by Pfizer scientists during a research collaboration in which Pfizer accessed Sosei Heptares' proprietary technology to develop and enable structure-based drug discovery for GPCRs. The study was a phase I-B trial which included cohorts of participants with type 2 diabetes and obesity who received 532 or placebo once daily with a rapid titration over four to six weeks to achieve high doses. Early clinical data from this study presented by Pfizer suggests observed half-life of the molecule is supportive of once a day administration. In addition, a robust dose dependent declines in mean daily glucose were observed with once daily 532 in participants with type 2 diabetes. While longer duration of intervention is required to assess the effect of treatment on body weight, reductions were also observed with dosing with 532 for four to six weeks, with mean decreases from baseline of up to 5.5% in participants with type 2 diabetes and approximately 5.2% in participants with obesity. The safety and tolerability profile was found to be consistent with the GLP-1 class and MOA, with adverse events generally mild. Most common AEs were GI related. In summary, 532 offers a potential best-in-class small molecule against an already well-validated drug target, GLP-1, and has huge potential in indications such as type 2 diabetes and obesity. I will now provide a brief update on our multi-target collaborations. We've made excellent progress in our multi-target collaborations. I've already made reference to our collaboration with Pfizer which includes the aforementioned GLP-1 agonist, 532. This has been an incredibly productive collaboration and has provided three clinical stage assets since inception seven years ago. In addition, I would like to make reference to three other discovery-based collaborations with large pharma companies, Genentech, Takeda and AbbVie. These collaborations have been progressing extremely well over the last two to three years with early discovery milestones achieved with each partner. More specifically, in our Genentech collaboration, we've achieved five milestones since 2019 with targets for both small and large molecules. I would also like to draw your attention to the recent second collaboration with AbbVie, which I will cover briefly on the next slide. In August, we were proud to announce a multi-target collaboration with AbbVie to develop novel medicines targeting neurological diseases. This follows the 2020 agreement which was focused on inflammatory and autoimmune diseases. We received an upfront payment of $40 million and a further potential $40 million in near-term milestones. I will now focus on new target identification and validation collaboration partners. We started this initiative around 18 months ago and have presented this concept on previous occasions. However, just reminding the audience to the background as it's useful context to some of our collaborations we've recently started in this space. The aim of this initiative is to support the identification and validation of new GPCR drug targets across our core therapeutic areas, GI, immunology, immuno-oncology and neuroscience. To do this, we plan to establish strategic external relationships to leverage top-end external company omics platform and databases and validation capabilities to supplement these efforts. We believe that this would maximize our chances in identifying and validating hot or novel GPCR targets with direct links to disease and disease mechanisms. Together with our existing SBDD platform, this initiative would fuel our pipeline and generate higher value creation for the future. We've been extremely successful in prosecuting these strategic collaborations. Let's look at some of the partners in more detail. In addition to our first collaboration with InveniAI in 2021, we've also established two key partnerships in the last 10 months. Firstly, in January 2022, we signed a deal with a company called Verily to identify new GPCR drug targets and subsequently generate novel drug candidates in immune-mediated diseases. The research collaboration combines Verily's immune profiling capabilities and Sosei Heptares STAR platform SBDD. To identify GPCRs expressed in immune cells, enhance our understanding of their functional relevance, and prosecute them as potential drug targets in immune-mediated diseases. Secondly, in May 2022, we entered into a collaboration with Kallyope to identify and validate novel gastrointestinal GPCRs for drug discovery. This agreement will leverage our GPCR-diversified compound library and GPCR expertise with Kallyope's gut brain axis platform, which includes an organoid phenotypic screening approach. Novel GPCR drug targets emerging from this collaboration will provide new opportunities for potential therapeutic intervention in GI diseases. Lastly, I will focus on our four wholly-owned programs from our internal pipeline. For our internal pipeline, we're advancing these four wholly-owned programs. On the left is GPR52 agonist program, which is a novel GPCR which presents opportunities in schizophrenia and psychosis. Next is our H4 antagonist for atopic dermatitis. EP4 antagonist for immunosuppression in solid tumors. On the right-hand side are our EP4 agonist for IBD. We are extremely excited about these four internal programs as they offer opportunities across our key therapeutic areas of focus. They represent a mix of novel and validated drug targets, which allows for some mitigation of risk while providing a great opportunity for our translational medicine team to demonstrate the best practice approach we strive for. Advancing these internal programs into the clinic will ultimately provide Sosei Heptares with higher value creation. I will now hand over to Dr. Rie Suzuki, who will provide a more scientific detail on two of those programs you just saw, the EP4 antagonist and the EP4 agonist programs. Thank you. Thank you very much, Matt, and thank you very much, Chris. Good afternoon, everybody. Today, I'd like to take the opportunity to share with you information on two of our programs. Both targeting a GPCR for which we see exciting opportunities across multiple therapeutic indications, and this is the EP4 receptor. This represents a very good example of how we have leveraged a unique STAR platform and expertise in structure-based drug design to develop novel, high-quality drug candidates. You've heard from Matt, this is an exciting time as we start to see a number of our assets moving into clinical development. Among those, we'll be talking today about the EP4 receptor antagonist, which is being progressed for the treatment of cancer. In the second half of the presentation, we'll highlight our opportunities for a GI-restricted EP4 agonist, which is being positioned for inflammatory bowel disease. EP4 receptor plays a diverse role in regulating numerous aspects of physiological function, including immune cell regulation. The endogenous ligand is a mediator called prostaglandin E2, and this lipid is synthesized by the COX enzyme and is released at sites of inflammation. Now, in the case of cancer, what we know is that both the expression COX-2 and the PGE2 are elevated within the tumor, and this creates an immunosuppressive environment. It's one of the mechanisms that's exploited by cancer cells to escape our immune surveillance, allowing the tumor to grow and also proliferate. The project hypothesis here is that by blocking PGE2 signaling with an EP4 antagonist, we can restore immune surveillance. When given in combination with agents like our checkpoint inhibitors, this will result in robust antitumor activity. Now, if we turn to chronic inflammatory diseases like IBD, what we're after is the converse. Here we're looking to dampen down the excessive inflammation, restore homeostasis, and allow the damaged gut to heal. Now, given the unmet needs in both these disease areas, there is a good rationale to go after both an agonist and an antagonist approach. We've maximized our structural understanding of this receptor to design high-quality molecules for EP4. In the next session, we'll provide an overview of each of these programs, and the first will be the EP4 antagonist program for immuno-oncology. Cancer still remains the leading cause of death worldwide, and according to WHO, it accounts for roughly one in six deaths. Now, current treatments of cancer, this involves a combination strategy which includes surgery, radiotherapy and pharmacological approaches. In particular, immunotherapy, which harnesses the power of the immune system to attack tumors, has received a significant spotlight as a potential novel approach for the treatment of cancer. Now, this next slide here illustrates how patient survival has improved over the years with the introduction of immunotherapy agents. What we can see here is that the survival rate is improving, but even with checkpoint inhibitors like PD-1, benefits are only seen in subset of patients, and not everyone will respond. There's clearly room for improvement, and this once again emphasizes the need for improved anti-cancer therapies as well as better combination strategies. Why might EP4 represent a good target for cancer? The tumor microenvironment is a very active and dynamic environment. Within this complex environment, cancer cells have developed ways to evade immune response, allowing the tumors to proliferate, metastasize, and also develop a resistance to therapy. Crucial part of developing novel effective therapies, therefore relies on lifting the immunosuppression. One of the key contributors that drive this immunosuppression is PGE2 and COX-2, both of which are upregulated in the tumor microenvironment. We know that high PGE2 burden in the tumor links to poorer clinical outcomes. This highlights the opportunity for novel therapies like EP4 antagonists to restore immune homeostasis and drive an active anti-tumor response. Based on this strong biological rationale, the goal of Sosei Heptares' EP4 antagonist program was to identify a potent and selective antagonist molecule, which can be delivered orally once daily with a low dose. Now, using knowledge of the EP4 structure and through successful application of structure-based drug design, we've been able to make rapid advances in chemistry and this led to identification of a novel high-quality molecule, HTL0039732, which is now the lead molecule, moving into phase I clinical studies. On the right here, is a snapshot of the competitor landscape, and we can see that a number of EP4 antagonists are moving into early clinical phase development. Now, these are being explored either as a monotherapy or in combination with different IO mechanisms. Here's an overview of HTL0039732. We have a molecule that has high potency and selectivity. It also demonstrates excellent safety profile and ticks all the desired characteristics for a candidate drug molecule. On the right is the profile of HTL0039732 in an animal model where we're measuring the tumor growth over time. What we can see here in the red line is that the EP4 antagonist in combination with a PD-1 checkpoint inhibitor produce clear reductions in tumor volume. This data provides very strong promise for this novel combination approach for the treatment of cancer. To summarize, we successfully utilized the proprietary cell platform and structure-based drug design to develop high-potency EP4 antagonist HTL0039732. As many of you will know, back in July this year, we entered into a partnership with CRUK, Cancer Research U.K., to advance 39732 into phase I clinical trials. Now, through this partnership, we'll be exploring the potential of this drug to treat a wide range of cancers in combination with other immunotherapies. This really represents a very exciting time for our company, where we have the opportunity to move one step closer to bringing impactful medicines to patients in areas of unmet need. This aligns with our strong patient focus, which you'd heard from both Chris and Matt. Now with that, we'd like to share a short video clip from a medical advisor at Cancer Research U.K. Centre for Drug Development. Dr. Stefan Symeonides will share his perspectives on the future of novel immunotherapy agents, such as HTL-0039732, to help tackle the challenges in treating difficult cancers. Please take a moment to enjoy the video. Hello, my name is Dr. Stefan Symeonides. I'm a medical oncologist in Edinburgh, U.K., and work for Cancer Research U.K. Center for Drug Development. As the medical advisor for the EP4 antagonist, HTL0039732. CRUK is the world's largest charity funder of cancer research. We want to bring about a world where everyone can lead longer, better lives free from the fear of cancer. Our research has already helped save millions of lives, and it's our ambition that the one in two people who currently survive their cancer will increase to three in four by 2034. CRUK Centre for Drug Development is the world's only charity-funded drug development center. Our mission over the last 25 years has been to bring innovative, scientifically promising new cancer drugs to the clinic, collaborating closely with academia and industry. Over that time, over 140 potential new anti-cancer agents have been brought to trials with a current portfolio of 21 agents in preclinical development, phase I or phase II-A clinical trials. There is enormous potential for immunotherapy to treat cancer, as shown by the remarkable recent success of the PD-1 and PD-L1 checkpoint inhibitors. This has translated to more patients responding to treatment, more durable benefit, and increased long-term survival. However, sadly, still only the minority of patients benefit from the current immunotherapy options. Prostaglandin E2 has a number of actions, and in cancer, its EP4 receptor has been strongly linked with the immunosuppressive environment that allows cancer cells to evade the immune system. We need to release the immunosuppression for the immune system and immunotherapy drugs to be able to attack the tumor effectively. HTL0039732 is an oral, highly specific inhibitor of EP4. In the laboratory, it reverses prostaglandin-induced immunosuppressive changes, and it synergizes with immune checkpoint drugs to shrink tumors. In close collaboration with Sosei Heptares, CRUK is sponsoring and running the phase I/II- A clinical trial of HTL0039732, exploring a range of cancers where there are indications that EP4 may be important. Currently including gastroesophageal, head and neck, prostate, and microsatellite stable colorectal cancers. People with these cancer types have to date largely missed out on the remarkable advances in the field of immunotherapy. We're very happy to be partnering with Sosei Heptares to explore if HTL0039732 in combination with other immunotherapies might extend those exciting benefits to those underserved patient groups. We've had a close and really constructive collaboration with Sosei Heptares as we've developed our clinical plans. We're looking forward to continuing to work together in partnership to explore the exciting potential of HTL0039732 for patients with cancer. Thank you. Okay. In this next section, we'd like to now move on to the second program, which is an oral EP4 agonist for inflammatory bowel disease. Inflammatory bowel disease is a chronic relapsing disease of the gut, which can be broadly divided into two types: ulcerative colitis and Crohn's disease. Now, in both these disease states, patients typically cycle through episodes of active flare and remission, and the strategy of current therapies is largely focused on suppressing the overactive immune system. This can be associated with safety issues and can put patients at risk of serious infections and immunosuppression. Now, over the past decade, biologics have gained an important place in the treatment of IBD, but it's known that only 30% of patients maintain a good response. Effective control inflammation is absolutely critical, and when medications are no longer effective, complications may develop. For some unfortunate patients, this could lead to surgery to remove part of the affected bowel. Hence, the goal of therapy is to minimize these cycles of inflammation, and in a while, we'll explore why there's now a strong focus on trying to promote mucosal healing. This next slide illustrates some of the biologics that are widely used in IBD. Now, anti-TNF therapies such as Remicade and Humira, these have become the mainstay treatments for IBD. If you look across the various biologics, the response rate is generally around 20%-40%, and the challenge in the development of novel IBD therapy has been to find ways to break this efficacy ceiling. Now, in addition to this, one of the shortfalls of current treatment is the safety, and there's a high need for novel safe therapies that can transform this landscape. What are the key benefits of EP4 agonists in IBD? One of the key reasons why patients break out of remission and undergo repeated cycles of flare is due to the incomplete repair of the gut barrier, which forms the first line of defense. When the barrier is not healed, it allows bacteria and other antigens to enter the body and trigger strong inflammatory response. Current available therapies do not directly repair the barrier, and this is where an EP4 agonist could potentially fill the key gaps. This, therefore, offers a very promising approach to tackle inflammation and may complement existing IBD therapies to bring clinical benefits to patients. The benefits of EP4 agonist are supported by a small phase II clinical study conducted by Ono Pharmaceuticals, where Ono 4819 demonstrated early signals of efficacy in patients with mild to moderate ulcerative colitis. Now, in this study, there were improvements that could be detected within two weeks of treatment, once again highlighting the potential promise of this approach. The chemistry strategy for our EP4 program at Sosei Heptares is unique in that we've leveraged our strengths in structure-based drug design to design novel GI restricted compounds. Just to illustrate how our molecules differ from other literature molecules, I'm gonna turn your attention to this figure on the right, which illustrates a design property space that we were aiming to target. CAG-308, which is an EP4 agonist molecule developed by Kaken Pharmaceutical, is a high potency compound which is well absorbed following oral administration. These molecules generally sit on the top right-hand corner. The unique goal of our EP4 agonist program, it was to design molecules which act locally in the gut and display minimum systemic absorption. This represents a property space that, to our knowledge, has not been explored by many competitors. The design strategy was highly enabled by having a structural understanding of the receptor. Now, to illustrate how the profile Sosei Heptares EP4 agonist differs from previously developed EP4 agonist, this next slide here highlights a number of key differentiation areas. The first is the low permeability. Sosei Heptares EP4 agonist is designed to have limited absorption, which we believe will lead to an improved safety profile. Secondly, by reducing the amount of drug that's absorbed, we're able to deliver the drug to the most distal regions of the gut. This is beneficial for diseases like IBD, where inflammation is localized to distal colon. This next slide shows preclinical data that highlights the potent anti-inflammatory and barrier-promoting properties of this mechanism. Now overall, this data is consistent with the preclinical literature, where EP4 agonists have been shown to improve gut repair and supports the early efficacy observations reported in the phase II IBD study with Ono 4819. Just to conclude this section, we've developed a novel GI restricted EP4 agonist molecule, and this represents an exciting approach that has the potential to address areas that are not effectively managed by current treatments. With that now, we'd like to share another video clip, this time from a consultant gastroenterologist, Dr. Tim Raine at Cambridge University Hospitals. We asked the opinion from an IBD clinician's perspective on where the unmet needs are and what opportunities might exist for novel mucosal healing agents like EP4. Please take a moment to enjoy the clip. My name is Tim Raine. I'm a gastroenterologist working at Cambridge University Hospitals in the East of England, where I look after the IBD service and the IBD clinical trials program. It's my great pleasure to have been working with Sosei Heptares, and discussing with them a number of novel strategies that I know you have in the field of disease that I treat. It's a real privilege to look after patients with IBD, and the last few years have seen a real explosion of therapeutic options for this patient population. The reality is we still face something of a therapeutic ceiling. When we use new drugs that have come through from clinical trials programs, we know that many of these drugs are indeed more effective than placebo. I still can't look a patient in the eye and tell them that I'm gonna start them on a drug which is guaranteed to work or that will be highly likely to work and that won't cause them toxicities. We're constantly looking for new ways of understanding how we can best use new drugs and existing drugs to help our patients. The Sosei EP4 program, I've had some discussions about, I think it's a really interesting and novel strategy. So far, we've very much focused in on different ways of immunosuppressing individuals, and all of that has certain risks, as well as benefits associated with them. I'm really interested in novel strategies that can seek to go beyond just suppressing T- cell and macrophage function. I think the EP4 program potentially delivers that. Here's a strategy to really look at the mucosal surface, where the ulcer really begins, and see if we can do something to restore barrier function that we know is defective in these individuals. I look forward. To seeing how this program develops and many, many more interesting and fascinating conversations. I wish you all the best with your development program. Okay. We hope that this has provided a flavor of the exciting pipeline that's building at Sosei Heptares. As we heard today, Sosei Heptares' STAR platform continues to support our SBDD. This has successfully enabled the development of these two high-quality assets, which we hope to progress into the next stage of clinical development. With that, I'd like to conclude our presentation. We'd like to once again thank you for your kind attention, for joining the Sosei Heptares' R&D Day. Thank you. Thank you very much for your attention. We now end the presentation part, we will move now to the Q&A. After taking a look at the presentation, this is R&D Day, the information was very detailed, I think. I hope you could ask questions and clarify whatever questions you have. As I mentioned earlier, in this room, please raise your hand if you have any questions. I will point to you, and our staff will bring over the microphone. Please state your name and your affiliation first. The participants over the web, I'm starting to receive questions over chat already, and we will answer those questions too, as much as time allows. That's all from me. Any questions? Please raise your hand. Yes, a gentleman over there. Jefferies Securities, Mio Isani[Miora Isanin]. I have a few questions. First of all, in multiple pages you talked about translational medicine. This, I am very interested in this. In particular, quick win, fast fail, you will achieve that. I think that is the sweet point and that is the key point you said. You will increase the pipeline in a productive manner. I think that will be the requirement. Otherwise, after you fail fast, your pipeline will shrink. I felt that you have confidence that you can go with this. Am I understanding correctly? In order to realize high productivity, it is difficult to see this from an outside person. What are you realizing to realize this high productivity? Are there mega ventures and pharma companies in Japan and abroad? If there are good references or examples, best practices, I would like to know. Thank you very much. Thank you for the question. First question was about the translational research, quick win, fast fail. Your question is on this strategy and, if we do this, you may worry that the pipeline will taper off. That will not be the case. Any other benchmarking companies that you benchmark? We will answer this question first about the productivity of R&D. Matt will answer. Chris, could you start or? Sure. I'll go first and yeah, then Matt can follow up. I mean, look, we're in a very unique position at our company, relative to a normal biotech, which may be focused on developing one or maybe two programs. You know, today we've talked about some of our star programs. What we haven't talked about is, you know, the 10+ other programs that are in discovery and our ability to continuously create new programs. We can adopt a quick win, fast fail approach because we have no fear that we will run out of programs to discover and develop. If you think about what our specialization is, you know, we're very much focused on GPCRs. Only 30% of GPCRs have been drugged to date. There is a massive opportunity for us that certainly will span the next few decades for us to continue drugging GPCRs that we haven't drugged before. If we just talk about what we can do internally in the area of our specialization, there is zero fear that we will run out of potential programs to innovate with. What we haven't talked about is also, you know, the productivity of this platform and the economics that it generates gives us the opportunity to also search for programs that we can in-license from external partners and develop as well. It's for that reason that we can adopt quick win, fast fail, because we only want to be developing the very best programs that are going to make the biggest difference for patients. Not just every program that we can work on. That, you know, that's the thing that differentiates us a little bit. We don't have that fear of running out of things to work on. We've got more than enough programs as it is, but we can continuously, you know, generate more through our discovery engine. I'll let Matt talk a little bit about what we do in pre-discovery and discovery, which fuels our pipeline. Yeah. Thanks, Chris. Yeah, as Chris mentioned, so for me, it's not necessarily thinking about, you know, the fast fail, as such. It's actually more about asking the right question. I think if you ask the right question and the answer is, "Do not proceed," that's okay. It's a case of trying to identify what that question is early. In my presentation, I talked about robust testable hypotheses. It's about making sure we have these entrenched in our programs so that we know what that question is, so that we have a very clear answer whether it's a go or a no-go decision. From a sort of risk of the pipeline shrinking, I think if that happens, we are doing something significantly wrong. I think some of the things we've put in place recently that Chris highlighted is this pre-discovery phase, which is, I think is highlighted on the top left, if my Japanese is correct. It's where it says pre-discovery. We created pre-discovery phase maybe two or three years ago. The reason that we did this was to really provide a time and space for early exploratory projects to build confidence in targets. We use this phase and we're asking things like, you know, questions about the target validation. We're asking, can we generate hit compounds? Can we find hit compounds? Can we generate a structural biology position? We're putting all the building blocks in place before we push the button to move forward to discovery. The idea is that only programs we have confidence in, we move into discovery. I'd like to think that once those programs are moving forward, we've already weeded out the programs where maybe that question is wrong, but we've done that very, very early on. Thank you very much. If you have your next question, please. Yes, my second question. EP4 antagonist on page 49, you showed us this competitive landscape. It seems like you have other projects up and running too. On page 58, Ono and Kaken comparison, and you talked about potency and the selectivity, and it's highly potent, you showed us, highly effective. In the antagonist, what about the competition? How does competition look like? Thank you very much. The competition of the competitive drug in the antagonist. Matt will talk, and then Dr. Suzuki will also follow. Thank you. I'll start, and then maybe I will pass on to Rie. EP4 antagonist, this is more of a fast follower type approach. Many of these competitors, actually, if you look at the assets around those programs, they're actually repositioning of older molecules. They actually require significantly high human doses to achieve a good target occupancy. We think, we believe they haven't fully been optimized for an immuno-oncology application. However, they are very, very useful because they might give us some early clinical validation from a mechanism point of view, which gives us confidence moving forward with our best-in-class molecule, which is being designed specifically for this particular approach. I think the only difference, and Rie might talk about this, is the Ono BMS molecule, which I think is a good molecule, and there was a recent publication on this. I think it's yet to fully come out, but from the abstract, it looks like there is some confirmation of a pharmacodynamic effect in cancer patients. That really gives us some confidence that we're in the right space in terms of this mechanism. Thank you very much for your question. Yes, in terms of EP4 antagonist, yes, there are a number of competitors right now moving into the early clinical development, as you can see on this slide here. As Matt said, a number of these companies, we don't know fully the human dose. But for example, if we take an example like E7046, that one is going in at several hundred mg. Now, we believe with our molecule that in order to target IC90 coverage over 24 hours, we're able to go under 100 mg. So there's clearly an opportunity for at least a class-matching compound. We've been able to do this through the understanding of the EP4 structure. I think it's fair to say. There is a huge market in cancer. As we heard from the doctor as well, there are still cancers whereby patients don't actually gain adequate symptom relief or disease relief even with the introduction of new IO agents. There's a huge opportunity here to actually utilize our understanding of the biology to guide us on the right combination strategy with a variety of different IOs. I think that's what, you know, many companies are starting to see. We see that there's a tremendous opportunity here for probably more than one agent in this space. Yes, no, we believe that there's a huge opportunity that can make a difference to these patients for the EP4 antagonist. Just final point. On Rie's last point. PD-1 is a great example. Right, several billion dollars of sales across multiple PD-1 assets, and people are still making them. Right. If you get it right, it's a huge opportunity. Yeah. I wouldn't worry so much about the competition in this space. Thank you for the question. All right. Thank you. Thank you very much. The person at the right from my side and left from the venue. My name is Matsumura from Nomura Securities. Thank you very much for your explanation. I have two questions related to EP4. The first one is, in vivo trial, this was targeted for colon patients, but what were the situations for the others? Also, this is administered on day eight, but if there is infiltration and metastasis, and if the tumor is large, then if there is a heterogeneity, then what kind of efficacy would your drug have? I think I have to ask Matt and Rie to respond to these questions. Thank you. If I heard the question correctly, this is the EP4 antagonist program for cancer. The question was. The first question was about the in vivo data. You noticed very carefully that this was with colorectal tumor in vivo. That's correct. Rie, I think, can talk about this more, but we very much use the colorectal tumor preclinically as a proof of concept. We could go and do lots more preclinical studies on different tumor types, but I think we'd really prefer to do that in the clinic. That early clinical trial will, as was described, represent a number of different cancer indications. The second one, I think, was about some heterogeneity and metastasis. If I got the question correctly, I think, again, I think we would look to try to address that in early clinical studies. We do have, and we are working towards a biomarker signature. I think that might help address the heterogeneity that we might see in tumor types. That's something that we're currently working on as part of our clinical development plans. If we can identify a biomarker signal or signature which really allows us to stratify patients, cancer patients, that's going to really help address that point of heterogeneity. I'll now pass on to Rie. Thank you, Matt, and thank you very much for the question. Yes, in terms of what other cancer types, I think one of our strategies will be to go for cancer types where the PGE2 levels and COX-2 levels are highly upregulated. That includes cancer types such as the head and neck cancer, colorectal cancer certainly is another one. We do know also that the gastroesophageal cancer, sorry, I couldn't pronounce that very well, that is also high in PGE2 and COX-2 signatures. Here's an opportunity. If our hypothesis is that PGE2 and COX-2 drives this immunosuppression, the natural thing will be to choose cancers which have got these high signatures, and we can start to select patients or prioritize that in the first instance to go and test the hypothesis. That's exactly what we're planning to do. In our in vivo studies, I think what we can say is that we've seen remarkable efficacy in combination with PD-1s. I think you saw one of the slides. Hirasawa[Geisinger], I don't know whether you can show. Yes, this one here. The red line here shows the effect of our EP4 antagonist together with a PD-1 checkpoint inhibitor. What we can also tell you is that in animals which have been treated with this, if you rechallenge them once again with the CT26 tumor cells, these animals will reject the tumor. There's a very long-lasting kinda efficacy that you can demonstrate. Now we've switched the immune-tolerant phenotype to more in the tumor-aware phenotype. That's a really key important aspect of this mechanism. Thank you very much. Then I have a next question related to GLP-1 agonist. Our competitors are Chugai and Lilly and compared with OWL833, Hemoglobin A1c was a -1.77, and the weight change was 4.7 kg, not much difference from you, but is there any superiority in your products at the moment? I would like to ask Matt to respond to that question. Thank you for the question. This relates to Pfizer's GLP-1 532 asset. You mentioned or made some reference to some figures about HbA1c and body-weight reduction. I think, we are very encourage, I think, by the data, that Pfizer presents on 532 it shows some reports and changes in some of the endpoints were measured, one thing we have to bear in mind, which actually Pfizer did refer to when they made this presentation, is that this was four to six weeks study. So I think you have to be quite careful in comparing across other GLP-1 agonists and make sure you're comparing to a similar time of study. Certainly for things like body weight and HbA1c you would want to look at the effect on those endpoints in longer term studies. I think Pfizer included those endpoints as an early sign and I think we would be encouraged to see some effect. But we look forward to seeing that molecule in some longer term studies. Thank you. Thank you very much. Those are all my questions. Thank you for your questions. Next question, please. Yes, at the front, please. Thank you. Can I ask a question in English? Sure. This is Yamaguchi from Citigroup. I have one quick question, follow-up question on the PF-532. There is a discussion on the GI talks regarding to the quick titration because it's on the phase I-B. Pfizer said it's gonna be a more different titration on the phase II. Pharmacologically speaking, does it make sense? In a sense, do you believe that GI talks on the titration will be avoided on the phase II program on the 532? That's the first one. Yeah. Thanks for the question. I think that's almost a multi-million dollar question. I think the adverse events that were observed in that Pfizer study are very consistent with that mechanism. Pfizer's response to this question was that they would do a slower titration, and they believe that that would alleviate. They have lots of experience in doing trials with GLP-1 agonists. I'm sure that they have everything in hand. Yeah. I think we have to wait for the study. I think I'm sure absolutely Pfizer know what they're doing. Yeah. Second question on EP4 agonist. You show some good reference on the EP4 agonist, but you gave me some comparison between the Kaken product and Ono product as well. But it looks, correct me if I'm wrong. It looks like the situation is the same as the 5-ASA situation in the sense that they should be if it's kind of stay there at the gut and the longer as long as possible, then the drug works. In a sense that, is that product matter or it's more the formulation matters? Just stay there, like, using more like a long-acting drugs. I can start, and then I'll pass to Rie. Yeah. I think if you go to the next slide, Hiro. Yes. Yeah. On the left-hand side, I think that's really the best diagram, best scheme, I think, to show the concept. Those agents, the Ono and the KAG-308 molecules, they have oral absorption, they get into the bloodstream. They exert some efficacy, I think, which Rie did refer to. Of course, they also, if they're systemically absorbed, they also have this cardiovascular change. What we've done is we've used the chemistry and structural knowledge that we have around EP4 to add physical chemical properties to the molecule to restrict it to the GI and minimize the systemic absorption. The theory, the concept is you maintain the efficacy, but you reduce the cardiovascular events. Maybe I can add a little bit more. Yes. Ono 4819, that was given actually intravenously, so it is a systemic molecule. In KAG-308, once again, it is a different formula compound in a sense, as Matt said, it is systemically absorbed. The key difference that we see here is that if we think about the localization of EP4, we know these receptors are present in the epithelial cells. We know it is on the luminal side with all along the gut. That's one of the key site of action whereby these molecules are able to tighten the barrier essentially. We're maximizing the topical action of EP4 to be able to sort of go all the way down into the gut and to also essentially line the gut. In order to do so, we believe that our molecule has the right physical, chemical properties that allow us to, if you like, paint the gut all the way down to give us the maximal efficacy, as Matt said, in the absence of any systemic safety, one of which will be cardiovascular effect. That's our strategy. You target to be the same as level of but not 5-ASA, but more on biological level, which you're looking for at the moment. That's correct. Yes. That's right. Yes. Wow. I think that the biotech company will buy it if it works, right? They will be a potential buyer. There are several buyers who are really interested in those spaces. Yes. Indeed. Yes. You are going to tie up with in the future, right? We wanna take this into the clinic ourselves first and then look to partner once we've shown a proof of mechanism. Yeah. That's really what we want to do. It's great to know that there were people out there that would want something like this. Yeah. Thank you. Yeah. Thank you. Does anybody else have any questions? The person at the front. The man at the front, please. Thank you very much for the explanation. My name is Tsuzuki from Mizuho Securities. I have several simple questions about the translational medicine within your company. Specifically, what are the measures you're taking and what were useful? If you can give us the specific examples, that will be helpful. That's my first question. Thank you very much. I would like to ask Matt to respond to that question about the translational medicine. Yeah. Again, I will start maybe and then ask Rie to comment as well. Translational medicines is quite a broad term, I think that people use. I think you saw on one of my slides. It's one of our areas of focus, and it has been over the last six months. It means a number of things. Operationally, I would say that it's actually about trying to integrate pre-clinical and clinical disciplines. This is incredibly important because what you really need to do is have a genuine understanding and collaborative effort between both the pre-clinical and the clinical colleagues to make sure that the data that's generated pre-clinically actually informs some of the clinical studies that you might do in the future. It's really important those people work together. As I mentioned, we've actually got those. We've actually joined those people into one single department, and we've also put them in the same building under the same roof. They're actually now working alongside each other on a day-to-day basis. That's certainly one thing. I think from a scientific point of view, I think you saw Chris in one of his slides. He talked about us taking things into the clinic and building some more value into some of our assets. We want to really take things to a phase I-B, ideally a proof of mechanism in patients. Scientifically, I think there are aspects of translational medicine and clinical early clinical trial design and the use of biomarkers is an area really that we really need to focus on. We just touched on one example of that with our EP4 antagonist with CRUK. What we'd like to do is do the same with some of our other programs. Those four priority programs that we talked about, having a sort of biomarker or a patient stratification, that's all really under the umbrella of translational medicine. For me, there's an operational part joining together and a scientific part, which means really understanding how we're going to execute the studies and what the endpoints we're going to measure are. Rie, I'll ask you to comment as well. Thank you, Matt. Thank you very much for the question again. Yes, as I'm continuing from Matt's point, I think what I'll add maybe potentially is translational medicine. It starts from. It's a, I guess, a combination of translational sciences and translational or experimental medicine. What we're trying to do here is a lot of the preclinical studies that we run, we always have to think about how this might translate to man. A lot of the times we would be using in vivo models, but we need to understand, complement that with, for example, human cell assays to really make sure that the medicine that we're developing is not just for furry animals, but actually will be beneficial to man. I think you heard from Matt and Chris around you know making quick decisions in the clinic. One of the key things that we want to be doing when we go into our phase I studies is to confirm acute target engagement as well as our pharmacology. A big part of translational medicine is to really make sure that we bolt on these endpoints early. We think about how we're gonna be testing, what is the right target hypothesis, and how are we gonna test that in man. In addition to that, one step further will be who are we gonna treat? How do we identify the patients that will most respond to our therapies? These are the kind of building blocks that we're trying to embed as part of our translational plan in translational medicine. Thank you very much. I have one question. I'm not quite sure whether this will be answered from you since this is R&D, but I think your strength in a structure and amongst the one that you're working on with the structure first-in-class, how many do you have for first-in-class? How many first-in-class do you have amongst the ones which are not yet launched as the drugs? You have multiple partnerships with Pfizer, Genentech and Takeda and AbbVie. You have many of them. When as to the background for the increase, the others want to elucidate GPCR, but they cannot. They know to which diseases they can be efficacious. I think that they are partnering so that you can identify. Am I correct in my understanding, and is there capacity for further increase for partnership? Those are the areas of my interest. Yeah. I think I can understand the question. The first one about first in class versus best in class. You heard both myself and Chris talk about novel targets. When we talk about novel targets, we really are talking about first in class potential. I would say that I'm not going to give you a specific number about first in class versus best in class. I would say that we look to try to balance the risk in our pipeline by having both first in class opportunities, but also we do still include some best in class opportunities. The best in class opportunities absolutely have to have a differentiation strategy. We talked a little about this with our EP4 antagonist, where, you know, we would really like to identify something that's differentiated. We do try to balance the risk, and it is very much a program or project specific point. Remind me about the second question. It's for the multi-target collaboration. Some of those existing partnerships, Genentech, Takeda, AbbVie, they're all multi-target collaborations. They all have some differences, but also some similarities. There usually is some flexibility in those collaborations for the addition of extra targets. It really depends on the companies. Some companies will come to us and they will say, "We are interested in these two GPCRs, but we want you to potentially work on four or five or six. But we don't know what they are at the moment, so can we just keep the slot?" We have other companies that come to us and say, "We have four already that we really know and we want to do." It really depends on the company about the potential for expansion. Some, they kind of like to keep some slots available, but others already know what they want to do. I hope that answered the question for you. Sorry. Is it for new collaborations? Yes. I mentioned in our key events something about attending the BIO Partnering meeting in San Diego. We are still actively looking for collaborations with other pharma partners that are similar to those deals you mentioned, Takeda, AbbVie, Genentech, et cetera. I talked in one of my slides about operational excellence and about how important this is in terms of our EPMO project management team really providing the most accurate information about budget and headcount and where our people are working, which projects they're working on. I think with that increase in operational excellence, it really does allow us to forecast more accurately, and we can determine what our capacity is for additional collaborations, so we can do this in a more confident way. I think, yeah, we are still open to talking to companies about this. I would say now that we are in a position where companies now are actually approaching us rather than us approaching other companies. I think we've managed to gain a reputation, I think, for what we do to a point now where companies are actually coming to us to talk. Yeah. Thank you. I hope that answered that question. Thank you. Thank you very much. I have one last question. Now, you introduced us various platforms, but in the stock market, I think that there's much attention about the M&A and including go and n o-g o of the platforms. You have introduced many of them, but at this point in time, in this acquisition, do you have any differences in your ideas? This is the last point I would like to ask, and I think this is a question to Chris. Is there any relationship between the platform and M&A, and what is your basic view about M&A? Can you talk about that? Sure. Thank you for the question. Sosei Group is a company that's been built upon M&A. After listing in the early 2000s, the first transaction that the company did was the acquisition of Arakis in Cambridge, U.K., as well. What that brought us was our first pipeline. It brought us glycopyrrolate, which, you know, ultimately was commercialized in COPD products from Novartis, which brought us a revenue stream. That revenue stream was then utilized to acquire Heptares, which gave us a long-awaited capability to generate our own novel medicines. When we think about M&A going forward, it's always going to be a potential strategic option for the group. You know, we think M&A can be very useful when done correctly, and we never stop looking for opportunities. I've talked in the past that it is clearly part of our strategic plan. We had hoped during the COVID period that we may actually be able to find some interesting opportunities, but what we saw during COVID was actually the opposite. Hyperinflation in the valuation of biotech companies and a proliferation apply companies getting listed. Today, that is now somewhat reversing. Some opportunities could potentially appear in the future. Of course, we now find ourselves in a situation where the yen is weak versus the dollar, and therefore, you know, it could make a strategic transaction quite difficult in the current environment. These are all things that you can't control. One thing that I will confidently say is that we're an organization that likes M&A. We can do M&A, and if the right opportunity presents itself in a manner that it will help us with our strategic ambitions that we've talked about today, then we will pursue it. That could be anything from something small that bolts onto our platform to enhance our platform and our ability to innovate up to a product, for example, that might give us the opportunity to get closer to a point of commercialization. It really just depends on what's available. We're not spending 20 hours a day looking, but we do keep our eyes and ears close, and we attend industry conferences and, you know, it is something that we could do. It's probably not a high priority right now. Did I cover both questions? Yeah, you did. Cool. Thank you. Thank you very much. Any other questions from this room? Yes, in the front row, please. I would like to ask this question in English. This is Wei Ting Tan from Macquarie Group. Thank you very much for inviting to the R&D Day and for the presentation. I have a question about the translational medicine like approach. Like, you say that it helps to increase the value and also the success rate of the programs. And also, like congratulations, there are a number of like pre-clinical stage programs. I just wonder for this program, does that reduce the time to bring these pre-clinical programs to clinical stage? Thank you very much. Again, I think I might start and then hand over to Rie again. Yeah. I think the question there, you're talking about our translational medicine strategy, and particularly in reference to those four priority pre-clinical programs that we mentioned. I think the question is around, is this going to impact the time, the timelines, right? Yeah. We hope that it will not alter the timelines significantly. I think our plan really is that if we start early enough on our programs, it won't impact at that phase. That's the kind of concept. These particular programs are a bit later, and we are working quite hard to catch up on you know providing some of the enabling work around the translational medicine approach for those programs. I'm sure we will. Certainly for earlier programs, we're thinking about this translational medicine much earlier. I think in the future, I think it's going to get very smooth when we get to the point of transitioning into the clinic. I don't anticipate any changes to the timelines. Thank you. Rie, do you want to add anything? Thank you very much. Thank you very much. Any other questions? If not, we have many questions from the web, and we would like to now take up two questions. The first one is about strategy. You will be focusing on the development in Japan. In that case, the CEO of Heptares, for example, a global phase I including Japan. We did not see much of that until now, but am I correct to assume that this would increase in the future? This is the question to Chris. Thank you. The person online for that question. Yeah, that's correct. Obviously we have an early clinical or translational medicine capability in the U.K. For selected programs going forward, it is the intention to also include a Japanese subject or patient population alongside those trials. You could think about it in the sense of it being effectively a global clinical trial that includes Japanese subject or patient arm. Where we can do that, we will. It may not work for some programs. Some of our programs we've talked about today are kind of already ahead, and we may find ourselves, if we choose to go to Japan, having to go to Japan slightly after we've already done Western trials. Certainly going forward, the go-forward plan is we would do it concurrently if we can. Thank you. Thank you. Thank Thank you to the person who posted the question. Another question is about Pfizer GLP-1 agonist. A related question was asked earlier. Pfizer internally, there's a competition for the same target. The development is ongoing. Will yours be selected in the future? If yours will be selected, for yours to be selected, what is the prerequisite? What do you need to be selected? Question to Matt. I think I know that this is a difficult question to answer, but. Yeah. Yeah, I'd love to know the answer to this question. Anyway, yeah. I think what Pfizer have said, they're in a great position, right? They've got a validated target with biologics. And they've got, you know, the luxury of having two small molecules in clinical development. They're in a great position. They've been pretty clear in some of their investor presentations about what their intentions are. They see it, I think, as competition. Now they're not running at the same point, so 532 is running slightly behind danuglipron. But I think their intention, Pfizer, is to generate some additional clinical data with 532, and ultimately they'll end up comparing those two, and they'll choose one of those to move into phase III. There are some differences that we can see already. The pharmacokinetic profile, I mean, certainly 532 looks consistent with once a day. Danuglipron, I think, more twice a day. There are some differences, but it's still quite early. The honest answer is I cannot answer that question right now. This is totally in Pfizer's hands. From what they've told us, we believe that they will compare the data generated in additional clinical studies on both compounds and choose one to move forward into phase III. Thank you very much. I cannot say anything, but if I could add a little, this is exactly what Pfizer is saying. Pfizer's internal project, phase II-B to A for type 2 diabetes, they have the results on P. For obesity, the phase II-B will come before ours. Now, what Pfizer said is, they will wait for our project result and then decide on the compound. Like Matt said, the project is moving forward quickly, but they will wait for our result before drawing a conclusion. Just a small piece of additional information. I think we have time to take one last question from the floor. If you have any questions from the floor, the gentleman over there, please. Excuse me. This is a very basic question. There are four products you are developing in-house and they will be entering into a phase I next year. Are you going to look at the efficacy, not only safety? Will you be finishing all the data readout? If not, would it be possible to conclude an agreement? In other words, would it be possible to have some kind of revenue stream next fiscal year? Thank you for the question. This is a question to Matt. Thank you. Yeah, thanks for the question. That there are no simple question. Ask any question is okay. I think it is too early, I think, to answer your question specifically. Yes, we will initially be looking at the pharmacokinetics and the safety of all these particular molecules. If you look at the GPR52, the first half of 2023, this will be one of our first internal. We'll be looking. It's quite a novel target, we'll be looking at pharmacokinetics and safety mainly in those very initial studies. The only thing I would add, it's probably too soon to think about us then generating a data package with some efficacy or pharmacodynamics next year. It's probably too early. The only thing I would say is that for the EP4 antagonist, of course, slightly different in that, you know, we're gonna be going straight into patients in phase I because it's cancer. You know, if things go well, and we have some good endpoints that we might be able to measure, that will probably be the first program that we might start to see some evidence of efficacy there. Thank you for the question. I hope that answered your question. Thank you. Since it's time, thank you very much for joining for a long time, and we would like to conclude today's R&D program. Please, if you have the interpretation receiver, please make sure to leave them on the table. Thank you very much for your attendance today. With this, we would like to conclude R&D Day.