R&D Day 2019

Dec 19, 2019

Slides

Good morning, ladies and gentlemen. Welcome to Daishankyo R and D Day. Thank you for your participation today. My name is Junichi Onuma. I am the MSC today. Let me introduce presenters, our President and CEO, Sunao Manabe our Global R and D Head, Junichi Koga our Global Oncology R and D Head, In Q and A session, our Global Head of Oncology Development, Joe Gannon, will also answer the question. Okay. Now I hand it over to Manabe san. Good morning, ladies and gentlemen. My name is Snow Manabe, and I am the President and CEO of Daisankyo. I would like to thank you for your participation in Daishankyo's R and D Day. To begin with, I will explain the strength of Daishankyo's R and D and share some top line strategic direction. Following my presentation, Yuichi Koga, our global R and D head, will explain our R and D strategies and Anton Yvel, our global oncology R and D head, will provide an update on the status of R and D in the oncology area and our plans moving forward. First, I would like to talk about the emphasis I place on research and development at Daisankyo. I believe that the strength of our R and D comes from leveraging the combined science and technology capabilities from across our organization. There are three sources. The first source is our in house drug creation capabilities cultivated over many years. Since our foundation more than hundred years ago, Adaik Sunkyo has developed innovative pharmaceuticals as a drug discovery oriented company. Our capability to create new drugs has always been based on our in house science and technology. The second source is our culture of sharing know how and outcomes and refinement. I have a long career in our research center and was directly involved in the creation of in house discovery products. I know that there is a well established culture at our R and D operations which encourages individual researchers to share their know how and acquire outcomes. Based on this knowledge sharing, our researchers make improvement and refinement, which enhance our scientific and technological capabilities as an organization. The third source is the assessment capability for science. I am in constant contact with my colleagues at our R and D site. The ability to evaluate new science has become become even stronger based on continuous know how sharing and greater effort to refine acquired outcome. I place a lot of trust in them. By effectively leveraging our science and technology, Daisankyo is able to pursue innovation and continuously deliver new drugs, which makes a significant contribution to patients. DXD ADC assets such as DS-eight twenty one are the direct result of our focus on science and technology and our drive for innovation. The XD ADC is a new highly promising asset that we created based on science and technology that Sankyo and Daiichi cultivated prior to our integration. By leveraging highly promising assets, my mission as CEO is to deliver DXD ADC assets to as many patients and as quickly as possible. To fulfill my mission, I aim to enhance our global development and commercial capabilities. Specifically, I will prioritize enhancing our capabilities in The United States, which is the most important market for the growth of our oncology business. We will focus R and D investment in three ADCs, DES A2O1, DES ten sixty two and U340-two. In addition, we will newly invest 100,000,000,000 yen to prepare for greater anticipated demand for investigation of drugs and commercial products. By delivering ADC assets to as many patients and as quickly as possible, we aim to become the number one ADC company globally. This will ensure we realize our 2025 vision of becoming a global pharma innovator with a competitive advantage in oncology. Meanwhile, I believe that my mid to long term mission is to steer the company to create assets beyond DXD ADC to ensure sustainable growth. To create beyond DXD ADC assets, we will expand our drug creation technology platform by utilizing our competitive new modalities and technologies. We will identify competitive assets through our enhanced evaluation capability and by focusing management resources. Over the long term, we aim to deliver drugs for diseases that can make use of our new modalities, not limited to specific therapeutic area such as oncology. Delivering new drugs with significant contribution for patients by pursuing innovation is the key driver for growth. Under my leadership, Daisangkyo will pursue innovation based on advanced science and technology in three ways. Firstly, by acquiring the world's cutting edge science and technology necessary for global expansion through open innovation. And secondly, by acquiring the most innovative talent from around the world. And thirdly, by seizing the opportunities generated by digital revolution in areas such as AI and big data. Currently, we are focusing on our five year business plan ending in fiscal year twenty twenty. We are aiming to get closer to our 2025 vision of becoming a global pharma innovator with competitive advantage in oncology. We plan to develop and announce the next five year business plan in 2021. In parallel, we will renew our mid to long term vision for beyond 2025 to create a road map for sustainable growth. Thank you very much. Now I would like to hand over to Juichi Koga. Thank you, Manovis. I'm sorry, I broke my voice, but this is just a practice of this session. Thank you very much coming here. I try to deliver you our new strategy. Manabe san touched upon the middle term, long term vision toward 2025. But beforehand, such a good result based on three ADC result, we are working on new strategy. So let me summarize how we are going forward. Next slide please. Here, beforehand, what happened for our present product, our present development outcome as approval. This is what we show at 2017 as TransAlta Enterprise 2025 Vision and Specialty Medicine 2025 Vision, where we have an ADC franchise, AML franchise and the breakthrough science franchise for CE and also maintain the revenue and for future growth number two, fill up OSM. Then what happened is gizaritinib approval in Japan in cancer enterprise AML franchise, then pixiratinib approval in U. S. In specialty medicine, amiravirin approval in Japan, then Saxendo approval in Japan. That's a tremendous result for totally new drug approval. We have many other amendment or many other small approval, but these four are really good achievement this year. May I have the next slide? Having said that, we been getting excellent result in ADC, which was Madhav Hassan touched upon, then later on, Anton will touch upon. The potential of three ADC, DS8201, DS1062, U3A1402 are increasing a lot. Then we are pretty much sure that successful result on this development, how we can care of this product, the potential of this product or accelerate this product. So that's the kind of the discussion we have in R and D, global R and D setup. So three important pipelines are already pillar for us. So next slide, please. Then new R and D strategy. Another catchy phrase is three and alpha. Then of course, ADCs. We have many more ADCs based on our own technology or next generation after next generation technology. We have those. But now we are seeing three ADCs are so successful. These 08/1062, 1402 together with precision medicine science, which is based on biomarker analysis and so on. Those are kind of the asset we should focus on. Then others may not be a right expression. Beyond 2025, we should have a valued project in house. Although those are early asset, so why not potential to those? How we do that? So that is the kind of the difficulty. III and alpha is easy to say, but there are other specialty medicine pipeline together. But together mean nothing, something The timely and flexible resource allocation could be realized, then seamless collaboration among organization that will be realized. Then also less resource should be allocated for alpha, but we will work it out. So that is the kind of strategy we are taking. So next slide, please. I'm sorry, this is a very busy slide, but not only three oncology asset oncology asset or other than oncology specialty medicine asset, many of the assets are there. But other than three assets, three oncology asset, rather early stage, then maybe we need to reprioritize or maybe some of our delay or out license. We will do it, but still we have a good room, good resource to work it out. Next slide, please. So having said so that all asset other than free ADC is prioritized, right, whether or not there is a first in class drug can be or whether or not that's a best in class drug. Either way, we can change standard of care. So that is a measurement to analyze and prioritize our asset. Those are prioritization is going on. Then maybe we can show later next year. Next slide, please. Let me discuss about our science, our scientists, because recently, last couple of years, I I was frequently asked asked why Dai Sankyo changed such much? Well, why you can't find your own asset by by your own science? Basically, I have two answer last ten years or even before. One is the excellent junior scientist. Doctor. Japan custom that every year, new graduate we are hiring, master, PhD or even the postdoc we are hiring. Those we throw in to the laboratories and then transfer the laboratory and laboratory, then try to educate, learn our culture and learn other science. But also, we try to implant the mentality of resilience. That is the kind of thing we can be innovative product to realize because early research is not always straightforward. Many against the window there. So the mindset of resilience is a critical thing for us. That is one one of the, you know, I have to say, reason we can find our own, you know, asset, own innovative asset. But next is more strategical things. Can I have a next slide? Yes. We have working ADC, for example, even 1990s, but a small group of working. But last ten years, we established new modality research laboratory, our own laboratories, who focus on new modality other than small molecule. Together with technology research, we can make it. Also together with discovery research, what type of modality can be applicable. So that is the thing we can work on. That is why antibody peptide or protein mimic DNA, oligo, those technologies are born. Can I go next slide? So this is a similar slide on Malawi san already expressed. These modalities are already in our hand by our own technology. We can throw those technology, any of the asset discovery group find out that mode of action. So that is a strength, even messenger RNA or depict nanoparticle or antilodipinemic bispecific or even cell therapy or gene therapy. That's technology in our hand. So that is our strength. So these are two result two reasons we can find our own innovation in house. Also, we are in good position to evaluate external acetone. Next slide, please. Maybe I touch upon two slides about our V2 nanoparticle. Of course, this is too early to say, but we have a more advanced product, but I cannot show here. So that is why let me talk about the very early asset. Repeat nanoparticle, known everybody, but listen, we have our own chemistry. This original lithium lipid that will help us improve the profile of lipid nanoparticle. There are many other modality that by our own technology like HNN breached nucleotide technology by our own zone. But even repeat nanoparticle, we have our own technology to balance. So next slide, please. This is ADAS, MEDSiRNA technology. This is also our own technology to stabilize nucleic acid then utilize. Then maybe we can throw this in our own lipid nanoparticle, then we can deliver to by using our antibody technology or protein chemistry. So that's a kind of combination of our own internal asset to work with then to create our own new innovation. So this is just a small example. Then we can work out many of the assets, although it's more than a handful, but people are working on. Next slide, please. Yes. We are a Japan based company started. But as Manabe san mentioned about, we are now focusing how to build up the capability in U. S. But beforehand, of course, we are working in molecular science technology inside the company. Then we of course, we have been serving patients globally. But now even more, Then how we nourish those cultures, trust, brand, the best of East and West, then great unity, embrace our difference, and then appreciate disruptive mindset, then transparency and collaboration. Altogether this, we try to nourish our worldwide science and technology and serve patients globally. I think we can do it. So now let's introduce Antoine. He has plenty of slides to talk with. So please have a good time. Thank you. Thank you, Giannichi. So good morning. My name is Antoine Ver, for those of you who do not know. I'm happy because we will share a good amount of time and data together. And this will be evidence of our progresses towards becoming a globally recognized force in oncology. So expect a lot of slides and a lot of data. And actually, some of these data are new and have not been presented before except a couple of days in Tokyo, couple days ago in Tokyo. A quick reflection on the journey so far. After years of highly innovative research preparing for today's successes, as you remember, we launched Cancer Enterprise approximately three years ago, and that included capital investment of 300,000,000 to support the ADC manufacturing on the recognition even then that the manufacturing was probably the most critical factor in pushing forward the delivery of our ADC. We established ambitious 2025 target. We reassigned the majority of the R and D budget to cancer enterprise and we propelled ourselves at the forefront, the ADC strategy, a strategy which has been validated by the AstraZeneca collaboration. We are now on to what we call the three ADCs and ALPHA strategy, which is based on finally seeing the ADC technology bound to dominate for a while in oncology. We all know that TKIs were the dominant feature of the 2000 and immuno oncology is the dominant feature of the current finishing decade. Now it is probably the beginning of the ADC decade. Not that ADC is a new concept. It's actually quite the opposite. It was first brilliantly described in 1913, meaning really more than one hundred years ago, by Paul Ehrlich, a Nobel Prize winner. And then later on, the first construct combining methotrexate with the murine anti leukemia serum was administered to a patient in 1958 by George Matte, a brilliant French oncologist who I had the honor to have as a mentor when I started myself in medical school in 1975. And since then then, there has been few successes as shown here. So why now? The 1913 concept was brilliant. It's impressive to see on this cartoon to which extent Paul Ehrlich described all the components of an ADC. So breakthrough came with the creation of a DXD technology and the most important is a safe and effective delivery in a tumor of a bystander effect. So slide this slide we've seen multiple times. It doesn't hurt to remind ourselves that first and foremost, DXD is a highly technologically advanced smart chemotherapy platform where each of the seven components described here are equally critical to the unique activity and safety profile observed with our drug candidates. And we recently added a further twist to so called D4 DAR4 or D4 ANDREACH drug antibody ratio four, making the final drug product optimized for the best drug antibody ratio. This DAR4 has been used for ten sixty two and seven thousand three hundred to our five clinical candidates. It appears now that DXD is a very mature and portable technology, and our challenge is to have the right target coverage. We're currently aiming at approximately 10 targets, expanding to hematological disease and obviously maintaining the right development focus. Meanwhile, we are progressing our next generation of ADCs, and we are aiming at the clinical stage around twenty twenty two, twenty twenty three. I know this is a question that everybody asks, which is what is coming next. But before going next, let's go into DS-eight thousand February and one. So next slide will be next slides will be directly from this presentation made last week at San Antonio Breast Cancer Symposium during the opening presidential symposium, which was part of the official SABCS press program and published simultaneously in the New England Journal of Medicine. So data were extremely well received. I'm sure we are very familiar with this data. I will explain them, but emphasize one key aspect, ILD, which may have been misinterpreted by some. This pivotal study is the last part of the data that we submitted to FDA and PMDA to support the first approval of 8,201. Study enrolled women with HER2 centrally confirmed metastatic breast cancer resistant to or refractory to prior TDM1. Stable brand metastases were permitted at entry. This presentation focuses on all subjects treated at the recommended dose of five point four milligram per kilogram, I. E, a total of 184 subjects. So data cutoff for this data is 08/01/2019. Subjects were enrolled globally, approximately onethree in each of the three regions, North America, Asia and the European region. Ninety one point eight percent of women had visceral disease at entry and thirteen percent had brain metastases. As we anticipated, these subjects had exhausted all available treatment options and had received a median six prior lines of therapy for their metastatic breast cancer. One hundred percent have received trastuzumab and TDM-one and two third have received pertuzumab as well. Here is the primary endpoint, the RECIST confirmed response rate by independent central review. On an intent to treat analysis, a confirmed overall response rate is sixty point nine percent, and an impressive six percent of subjects achieved a complete response, a complete disappearance of all tumor. Ninety seven point three percent of subjects achieved disease control rate and only one point six percent of subjects had progression of disease as the best response. The duration of response measured from the time the response is first observed was fourteen point eight months. The time to observing first the response was six weeks, meaning the first scheduled CT scan. Here is the corresponding waterfall plot of the best change in tumor site. I'm sure you've seen this, but with brain metastases at entry, that's the third row. The effects observed across all subgroups are extremely consistent. Finally, the progression to survival and overall survival Kaplan Meier estimates are shown here. Since the overall response rate is greater than sixty percent, the PFS is logically the combination of the six weeks to observe the first response and the additional fourteen point eight months of duration of response. Hence the PFS of sixteen point four months. Of interest are two things. Number one, the median follow-up for this patient is still less than the estimated medians showing that the estimates may vary with additional follow-up. Second, the PFS in the twenty four subject with brain metastases was eighteen point one months, which appears no different from the other subject and this is a critical finding. On this slide, I showed by adverse event terms the frequency and severity of adverse events, grade one or two in light blue, dark blue for grade three and above. Stereo AEs were observed in twenty two point eight percent of subjects, which is remarkable given the long duration of treatment administered. Fifteen point two percent of subjects discontinued treatment for adverse event, a little more than half of these cases or eight point seven percent due to ILD. As we will show, the safe use campaign has led to slightly increase the frequency of reported ILD. Overall, it did not bring the drug discontinuation rate to anything above typical for a cancer drug. In particular, for subjects with grade one ILD fully recovering after temporary drug stop, DS-eight thousand two hundred and one treatment could restart. Left ventricular ejection fraction of LVEF was an important safety concern given the history of such toxicity with prior HER2 targeting therapies. Despite intensive monitoring for detecting any such LVEF toxicity, especially at the FDA's request, no drug related signal was observed with respect to cardiac toxicity. Now the ILD. Here we need to spend some time. Twenty five subjects reported adverse event adjudicated as drug related ILD by the ILD adjudication committee. The majority were Grade one and two, one was Grade three and four cases were fatal cases. All these fatal cases have been previously reported, in particular during the ASCO June twenty nineteen investor call. They occurred before the ILD Safe Use campaign was initiated. We will come back to this later today. How do these data compare? Obviously, on the left hand side is the Cleopatra regimen. It's a combination of dual HER2 suppression with trastuzumab and pertuzumab combined with docetaxel. This regimen is a firmly established gold standard for first line treatment of metastatic HER2 breast cancer and it provides a solid eighteen point five months progression free survival. On the right hand side is 8,201 after a median of six prior lines of treatment in the metastatic setting. So PFS at sixteen point four months is extremely impressive. So drug clearly warrants both bold and safe development attempts in the earlier line metastatic setting in early breast cancer as well as in other tumor types. So what have we seen so far? ADC started in 1913 and it took until now to really break through. So 2020s will be the ADC decade. The SAT-two zero one is, first and foremost, a massively advanced technology called breakthrough. It was designed to achieve breakthrough. It delivers unique practice changing evidence. Breast cancer doctors do not think ILD. This is why we do not shy away from discussing the importance of monitoring and actively screening and treating any suspicion of ILD. Now everybody talks about acceleration and expansion and that will be a critical point going forward. But I want to take a moment to recognize just what we, Daiichi Sankyo, have accomplished. The first subject dose in the first in human trial for DS-eight thousand two hundred and one was September 2015. The BLA submission took place in August 2019 in under four years. This is a remarkable speed in development in plan and delivered by Daichi Sankyo on its own. And this was coupled with a massive manufacturing scale up, thanks to delivering on the dot the benefit of a $300,000,000 CapEx triggered in July 2016 on the basis of my views and a handful of patient data. And now the cherry on the cake. Keytruda, a well established drug, is currently the second fastest U. S. Biologic ever. From first time in human to market in The U. S, it took four point five years for Keytruda. So the SA-eight two hundred one can possibly break this record. In order to maximize the project value of AD201 and allow us to support independently the rest of our portfolio, as you know, we signed a global development and commercialization agreement with AstraZeneca in March 2019. AstraZeneca has, of course, an extensive experience in global resources for oncology. We have sorry, we may receive up to $6,900,000,000 from AstraZeneca. We believe that the establishment of our oncology business will be accelerated through jointly designing and implementing various strategy with AstraZeneca. We believe that this collaboration will maximize the value of not only DS-eight thousand 201, it will also allow and help Daiichi Sankyo as we are independently developing our other ADCs as well as our other oncology project in the future. I will not read this slide, but it does provide concrete evidence of the immediate benefits of the AstraZeneca collaboration from a seamless collaboration as we were finishing the regulatory submissions and met all prior deadlines to an ambitious plan going forward. In In a nutshell, the benefit of the collaboration is to be able to be both bold in our development option as well as safe and secure, more traditional stepwise progression in development. In particular, we have updated the joint clinical development plan and added 26 new studies, which I will present only directionally. And very concretely, it is clear that Daiichi Sankyo AstraZeneca collaboration fully finances the DXD ADC's development. For 08/2001, this is at the speed and scale Daiichi Sankyo alone could not have supported, while we are also preserving Daiichi Sankyo's ability to progress the rest of our portfolio. Next fiscal 2020, we're planning to spend extending for DS8201 approximately 175% of the current spend for the current fiscal year only with Daiichi Sankyo part, one so 175 of what we're currently spending. For DS1062 and U31402, we're also planning to increase our spend by approximately 175% on these two assets. So on that basis, what is our obligation for DSAT-two zero one? It is clearly to transform the treatment for patients who have HER2 disease as they will be newly defined. For HER2 metastatic breast cancer, it is to establish 8,201 as a new standard of care in HER2 positive breast cancer and optimize the role of DS8201 in early breast cancer setting. For the HER2 low metastatic breast cancer, it is to redefine the breast cancer treatment paradigm. And finally, it is to expand leadership across other tumors. This slide is here to briefly explain what we mean by changing the breast cancer clinical paradigm. For twenty plus years, breast cancer has categorized at diagnosis with a status sticking throughout the entire disease and treatment history, just like you're stuck in a swimming lane. DSAT-two zero one, by offering a possible treatment intervention on the basis of a new marker, has a potential to break these lanes and shift how the disease is fought off and cared for. Concretely, we are planning to start 16 new studies in the next eighteen months distributed, as shown on this slide, between the plan for new standard of care in HER2 breast cancer, the redefinition of breast cancer treatment paradigm and the expansion beyond breast cancer. Here is a more traditional view of a directional clinical development plan now comprising 43 studies. As backup, you will find two charts, one for breast cancer and one for non breast cancer clinical development plan, which gives you placement of these studies relative to future standard of care in a group of seven countries, the G7 group of seven countries. A quick note to finish on the Alliance. We are here to transform treatment for patients with HER2 disease. Our obligation to patients is beyond what one company can achieve alone and we are very proud I'm very proud personally of this collaboration. Now moving on to the next ADCs. Here is ten sixty two, our Trop-two ADC and probably our second most interesting asset. I think you will agree. We are very proud of this DAR4 technology as it allowed us to more precisely create a better therapeutic window. The next few slides I will present rapidly as these are slides which were presented after the World Conference on Lung Cancer in September. Here's a Phase I first in human study design in non small cell not selected for Trop-two expression and after failing immuno oncology for greater than eighty five percent of subjects. The maximum tolerated dose was reached at eight milligram per kilogram and both the six and eight milligram per kilograms are now under expansion cohorts. This is a wonderful plot across all diseases, which we've all seen before. And a famous dose effect spider plot with a cutoff date of July 2019. And here is a slide summarizing safety as was observed last summer and presented at World Conference on Lung Cancer. I'll update the ILD in a moment. Now is the interesting part. Here are preliminary efficacy data up to November 1639, data which have not been presented before except forty eight hours or thirty six hours ago in Tokyo. With a total of approximately 60 subjects, we continue to see good and compelling tumor response with a dose effect and now with durability of response. What does it mean for Daiichi Sankyo? The S1062 continues to appear to be and have the characteristic of a drug to be. It maintains clear activity, dose effect, durability and tolerability with obviously ILD to watch. DXD portability is further established adding the technology of D4 and REACH DR4, and that technology is validated. Driven by the emergent non small cell lung cancer data, we believe the differentiation versus IMU132 appears highly credible. And we clearly see a fast to market path in The U. S. Emerging in non small cell lung cancer. So the non small cell development plan is fairly simple. As a Phase I expansion accrues and matures, a pivotal monotherapy Phase II study in non small without actionable mutation and after IO will be set up as soon as feasible, approximately 2020. This will lead to a randomized Phase III versus docetaxel plusminus ramucirumab aiming at a post approval commitment. Obviously, we still have to consult the FDA on this plan. In parallel, should the early result in EGFR mutant confirm themselves, a parallel track in EGFR mutant might be pursued. And finally, we'll start as soon as we can Phase I IO combination with key players, meaning pembro, nivo and durvalumab as enabling study for an eventual first line randomized study versus IO or IO chemo. Now on to U3-fourteen oh '2, our ErfriDXD ADC with a drug antibody ratio of eight. Here again, quickly reviewed at the slide of the Phase I study in EGFR mutant lung cancer failing TKIs. These data were presented also at the World Cancer Lung Conference The World Conference on Lung Cancer, sorry. Here's a waterfall plot and the interesting tumor control and response profile observed regardless of the underlying mechanism of resistance to the prior TKI based line of treatment. What does it mean for DaijiSanQ? U3-fourteen oh two appears active in non small cell lung cancer. Targeting U3-fourteen oh two may be a practical approach to treat EGFR mutant non small cell lung cancer, only fourteen out of eighty two subjects responding. And the disease control rate stayed high at eighty nine percent. So what have we learned? As I will show in the next slide, ERF re expression in breast cancer is more variable and heterogeneous than we anticipate. IHC detection, even if specific, might not be sensitive enough to best detect the breast cancer population most likely to benefit. We know the drug works. We just have to find how. So kinetics of the ERF3 receptor in breast cancer is clearly different from that of ERF2 in breast cancer and ERF3 in lung cancer. And I'll show you some data. Let me show you some data supporting these observations. First, based on fresh biopsies right before treatment in 43 subjects, the best overall response rate shows that all responses observed, which are in green color, are in the IHC high group on the left. However, IHC does not enrich much in responses, which are still only six out of 31 subjects in the IHC high. Second, on the left panel, we know now that HER free expression frequently varies in breast cancer over time. This is shown here comparing HER free expression level on archive biopsy testing, meaning initial biopsy and on the fresh pretreatment biopsy. This is an important finding that as unlike ER2, which is highly stable in breast cancer or ER3, which is also highly stable in EGFR mutant post TKI, ERF3 in breast cancer cannot be predicted based on archival sample. More importantly, on the right panel, you see that under treatment with U3-fourteen oh two in breast cancer, the level of ERF3 expression seems to consistently drop between immediately pretreatment and day forty two on treatment. Finally, these dynamic receptor expression changes are consistent with the observation we make regarding the payload Cmax. For fourteen oh two, as shown on the top left panel, the payload Cmax at cycle one appears double of that at cycle three at both four point eight and six point four milligram per kilogram. And this is higher exposure and different compared to DS8201 on the right hand panel. This is consistent with thrombocytopenia shown in the bottom panels, which is more pronounced during cycle one for U34002 and virtually inexistent for DS8201. We're beginning to see that in breast cancer, ERF3 receptor is not a typical receptor. It's highly variable over time, under treatment and it affects the kinetic or payload release. In lung cancer, experiments made at Dana Farber Cancer Institute by Pathogen show that unlike in breast cancer, there is a sustained internalization rate of U3 fourteen oh two in EGFR lung cancer. This is true for monotherapy in the black line and it further increases and is sustained in combination with orcimetinib in the red line. We are obviously actively discussing with AstraZeneca on how to further test this in human and test these hypotheses. So what does it mean for DIGIS NKU3-fourteen oh two? In lung cancer, EGFR mutant presents a clear monotherapy opportunity. ERF3 is consistently expressed and internalized post TKI and ERF3 is probably a likely passenger expression of EGFR TKI resistance. And the combination with osimetinib is also being pursued. In breast cancer, the bioreceptor dimerization, internalization, trafficking is substantially modified by yet unknown factors. Intensive translational research is now ongoing at the Memorial Sloan Kettering, at MD Anderson, with the Sortie Group in Europe and others as well as Gustave Roussie. This likely will create an eighteen to twenty four month delay to be able to select the subject with highly sensitive tumors. We know they exist. We just can't select them now on the basis of even a fresh biopsy IHC. Colorectal and prostate cancer Phase IIs are planned and progressing. We have initiated, as you know, a clinical trial with our fourth DXD ADC conjugate, DS7300, in collaboration with the Sarah Cannon Research Institute. The first in human Phase III study evaluating DS7300, B7H3 ADC, is in patients with advanced or unresectable or metastatic solid tumors. B7H3 is a protein which is overexpressed in various types of cancers. Again here, we have chosen construct. B7 H3 is a member of a B7 immune checkpoint family, including PD L1. The role of B7 H3 is actually currently unknown. The precise function is not elucidated. However, we know it is expressed at high level in multiple solid tumors with low expression in normal tissues. This particular DXD ADC was designed with the selective drug antibody ratio of four to mitigate any potential for toxicity. Here's a Phase I design, a fairly typical NAB. A number of tumor types are considered head and neck, esophageal, non small cell lung cancer, bladder, etcetera. We have a mandatory fresh biopsy at study entry, but no selection based expression. We're planning to expand in three prespecified tumor type squamous cell carcinoma of the head and neck, squamous esophageal and squamous non small cell lung cancer. This first in human Phase I dose escalation is ongoing with active site both in The U. S. And Japan. And here is the fifth ADC soon, very soon to enter the clinic as well. This one is a plain DARK-eight. GPR-twenty is highly specific for GIST and this will be tested with George Dimitry, obviously, at Dana Farber Cancer Institute. Here's again the study design. It's a typical design for our ADC first time in human studies. So expansion will be clearly in GIST. Now an update on the DXD ADC platform ILD experience. As you will recall, early in the current calendar year 2018 I'm sorry, 2019, we initiated for DS AT-two zero one a first phase investigator safe use campaign for the ILD detection and management. The goal was to drive ILD awareness, detection and management. With AstraZeneca, we created a comprehensive education for medical science liaisons. We developed tools for VMS cells to use in proactive, direct communication with treated physicians. We developed internal understanding and external communication plans. We directly targeted healthcare providers prioritizing investigators with patients under treatment. We ensured continuous education and top of mind status through numerous outlets, in person, online, etcetera. And we gave HCP tools to reduce ILD severity and improve management. Finally, we developed resources for patients themselves. We provided education of patients around the risk of ILD and the need to self monitor for symptoms. The purpose was to drive awareness and give patient tools to support detection and management. We are extremely pleased with the effect of this campaign. With respect to DS-eight 201, the critical finding is at the bottom of this slide. After the initial Phase I Safe Use campaign was initiated, the majority of the new cases were low grade, Grade one and Grade two, and only one subject was diagnosed with a Grade three ILD. No new grades four and five were reported program wide at a dose of five point four milligram per kilogram. Let me repeat. No new grade four or five was reported program wide at a treatment dose of five point four milligram per kilogram. Next slide. I'm sorry. You messed up. Just go back on the script, please. Good, thank you. For fourteen oh two I'm just confused. We're good. Sorry. Yes, other things on this slide. The adjudicated drug related any grade ILD for 8201 increased from eight point two percent to thirteen point five percent. And the new adjudicated related ILD events included two Grade one, seven Grade two and one Grade three. Discontinuation associated with TEA increased from eight point two percent to fifteen point two percent, mainly driven by the new event of low grade ILD. For fourteen oh two, of two zero five subjects treated, nine had adjudicated drug related ILDs with one case of grade five fatal outcome. For ten sixty two, of eighty eight subjects treated, four or four point five percent had adjudicated drug related ILD with one case of grade five. Daiichi Sankyo and AstraZeneca has convened an advisory board consisting of oncologists and radiologists in order to discuss the ILD management algorithm and their current inclusion and exclusion criteria. As a result, the management algorithm of ILD has been updated in consultation with the FDA, and a new phase of a safe use campaign has started across the ADC franchise. The algorithm is even more prescriptive with respect to how to manage the patient and we are assisting treating physician in how they manage the ILD risk for patients. The inclusion and exclusion criteria have been refined to exclude patients that could be at higher risk of developing ILD. Finally, the free and alpha strategy. Our clear focus now is on the ADC, as you may have sense. We nevertheless do not want to leave beyond our obligation to continue to discover great medicine and integrate great technology to produce a steady flow of first or best in class drug, as Kogosan just explained before me. Daiichin Sankyo is probably one of the best discovery machines and it is our pride and our duty to deliver the value stemming from our labs. To that effect, we keep critical attention on the potential of the alpha asset to contribute to a robust science and technology driven portfolio. We want to maximize the development of ADCs with breadth and depth expansion and fully leverage the value of our collaboration with AstraZeneca. Regarding ten sixty two and fourteen oh two, we aim at a swift and independent development of these next ADCs. To maximize value of development, we looked rigorously at every various opportunities for indication development and we applied strict prioritization. Illustrated here is evidence indication that could be pursued for October and 1402 combined, the top 17 indication of these 38 give approximately 90% of the value and require approximately 60% of clinical supply and not shown here, but approximately 55% of the R and D costs. On the graph, you see that on the y axis is a measure of value, which is approximately the first ten year value minus the development cost. And the x axis, you have a number of supplies needed. We used similar analysis for R and D spend complexity and we reached very consistent conclusions. Interestingly, the first two indications at the bottom of the graph, the non small cell lung cancer EGFR wild type post immuno oncology second line for October and the first line for October, both of these indications represent approximately 50% of the total value. So our prioritization is extremely clear. What is the free and alpha strategy? Gregassen briefly explained that. In my word, this is to deliver the full value of a free ADC and to ensure longer term performance that will exceed by far the benchmark of a great free ADC portfolio. Alpha is the angle of attack in my mind. It's the speed of innovation, the cutting edge, the power of our innovation. It is to deliver drugs that truly change standard of care. This is how we describe the major R and D pipeline. We do recognize we do not have, Andy, a fully scaled operation delivery machine. Daiichi is still new in the field of large scale massive drug development in oncology. The ability to secure our success through typical transactional fee for service relationship with CROs is modest. It's not specific to Daiichi Zanqiu. It is true for the entire industry. To resolve for our opportunity, we met with the CEO and the leadership teams of all major CROs and are in the process of finalizing what we call the ADC Development Coalition with a selected CRO. This is a new integrated delivery model meeting both companies' needs and it goes beyond the traditional penalty discount and earning back incentives, which are typical in the fee for service transactional relationship. So key characteristics of this correlation are listed here. I will not read them, but needless to say that we are extremely excited that these new ways of working will uniquely serve our one of a kind portfolio. Finally, the news flow and future events. Here are the critical news flow we anticipate for the next coming six to nine months, first for EC201 and ten sixty two as well as on the next slide for fourteen oh two, pexidatinib and G47 delta. I will stop here and I think we will take questions from that point on. Thank you very much for your attention. Thank you, Antoine. Hello. Yamaguch from Citigroup. I have three questions, which are different questions I didn't answer in the Tokyo version. I give you a new question. The first one regarding the general strategy about the second and third ADC. And also, you got the fourth and fifth. So the first one, already done with AstraZeneca. The second one, the third one, do you have kind of a time frame and idea are you going to have a codevelopment partner in the future? And how about fourth and fifth? So that's the first question. So we are equipped, willing, able and committed to develop these ADCs independently so far. Well, I may have some comments. To maximize value of 08/21, we started the collaboration with AstraZeneca. Also, we'd like to maximize the value of the second and third and the following ADCs. As you know, the clinical trials of second and third ADC is ongoing, which was explained by Antoine. We can give the top line result early fiscal year early next fiscal year around ASCO. So I think that is a very good timing to start discussions about our development strategy. And one of the option is, of course, partnering. So then that is a good timing for us. How about the fourth and fifth, which is outside of three and alpha? It's four and fifth, especially on the fourth one, that's 7,300. Is that also kind of given up to the Sarcannon? Or is that something you're going to do by yourself? So the cooperation with Sarcannon is just an academic research organization. Sarcannon and Skip Baritz. Skip Baritz is a good friend. Sarcannon has tested as in the world, the largest experience of first time in human with ADCs. They have tested more than 30 new ADCs. They have by far the largest experience. So they are the best partner for us to actually figure out quickly the safety and activity profile of our drugs. This is why we're partnering with them. Okay. The second question is, you talked about ILD and thank you very much for the update, especially on the DS-eight twenty one. In a general term that you understand the eight twenty one IOT situation much, much better than any other drug because you have seen down the campaign. About regarding the one hundred sixty two and also AT2 sorry, U31, compared between the two, which one do you are you more not concerned, but you have to be careful about the IoT situation between the two, HER3 and Trop2? So I think it is pretty I mean, I presented you with data which had not been presented before with respect to the ILD update, just like it is clear that DXD platform shares an ILD risk. And then so we have to pay attention on how we observe, mitigate and reduce the risk across all three. I don't think we can say anything more than that. We have to be careful about this. This is typical drug development, which is the last thing you want to do is to ignore the risk. We actually are much, much better proactively recognizing the risk, finding the risk factors if there are any and we're working on this. So far, we've identified only two risk factors, maybe a third one. So two risk factors are the dose and the exposure. And the second is the Japanese descent. There's a third one, which is not completely significant but it's likely, which is a prior treatment, the amount of prior treatment received, any prior treatment received by patients, which is making biological sense because these patients mean, ILD is not specific to DXD. ILD is actually a very common drug induced toxicity for a lot of drug, cancer drug and non cancer drug. I I think there are three forty different drugs with ILD as recognized ILD. And the lung is probably an organ where you accumulate insult and at some point you just tip over. So having prior exposure to multiple line of treatment as a risk factor is probably plausible, but there's nothing more that we can say at this point in time. We're paying attention a lot to all ADCs and ILD. We have a dedicated, essentially, ILD gsar internally, somebody who only looks at ILD and makes sure that the campaign and the assessment and risk factors and everything is done to the best of what we can. The last one is nothing to do with the company. But yesterday, the infolksome of benzodiazepine of other companies, the ADC has been approved three months ahead of the PDUFA date by the U. S. FDA. And I don't know anything about your company, but is there a possibility that your DS-eight twenty one is also approved prior to the PDUFA date? So yes, so I'll be very careful here, obviously. To your question, literally to your question, is there a possibility? Yes, there's absolutely a possibility that DS-eight twenty one is approved by the FDA prior to the PDUFA date. Let me remind you is that we are probably one hundred and thirty days still from today to the PDUFA date, there's one hundred and thirty days. The PDUFA date is April 29. So it literally is so we are that's all we can say. We I mean, the review is actively progressing, and we're not commenting any further. But we obviously will let you know as soon as we can. No, it's not. It's Karl Brown from Acxiom. Specifically on ILD, could you talk about what are the protocols that you've given to health care providers to help them identify cases of ILD earlier? And when you say that post the implementation of these protocols that the rate rose from eight percent to thirteen percent, what are we comparing? Are we just comparing within the 8201 study, the BREST-one study that we saying that we were tracking at an eight percent rate and then the new protocols went into place and that caused it to rise to thirteen percent? Or are we comparing to other rates? Okay. I like you guys. You have sharp questions. So to your first question, what is the protocol? The protocol to especially for breast cancer and especially with the kind of activity that the drug has, the biggest challenge we have with both docs and patients are the fear of being forced to interrupt the treatment because of ILD. So the protocol is to recognize and characterize ILD, to make them aware of the fact that ILD presents itself low grade as a very, very nonspecific and nonbothering. These are very minor symptoms. It can be a low grade fever on and off. It can be a little shortness of breath. It can be a little cough. And it's very easy to attribute any and all of these symptoms to something else. You had prior metastases. You had chest lung chest irradiation. Your kid has a cold and you also have a little runny nose, to just attribute any and all of these symptoms to something else because the drug is so active and just not deliberately, but naturally, instinctively turn an eye away from nonspecific symptoms. So that's one of the things which is to have top of the mind, any time they see a patient, they must screen out the potential of ILD, make sure that there's really no sign and symptom which suggests ILD. The first thing you do then if you have a suspicion, do high resolution CAT scan of the chest to see if there's any gray opacities. You also if you have any sign or symptom, then you also do blood gaze. After your blood gaze, you do gas exchange. So you investigate any sign. So that's the very first thing. The second thing we obviously do is that if there is anything, you stop the drug, you screen again if it is low grade or if it is high grade if it is grade two and above, you actively treat, which is high dose steroids. That's your first question. The second question, the eight percent to fourteen percent, what are we comparing to? We are comparing to the initial data cut and the more recent updated data cuts. And the initial data cut in the submission was back in March, if I remember well, or April. It was March 2019. And part of the normal process with the U. S. FDA is that we always update in so called ninety day safety update post submission. And that's the difference. The difference is between the initial observation and then with more follow-up. Remember that the last patient was enrolled in this Phase II study in September, so we now have eighteen months. We started the Safe Use campaign in January, February, so meaning five months after finishing enrollment. And the Safe Use campaign, what we've observed is that from March, which was the first data cut to the latest data cut, this is where we observed nothing new, but the increase in the frequency of low grade, which is exactly what this is exactly what we want. We absolutely want that. We want to have more and we want to over diagnose and then screen and then see if it is ILD, yes or no. And avoid patients and yes. So I hope I've answered your question. If I may, I may just add one thing. You're interested in the protocols of how we deal with ILD. I suggest you look at the New England Journal of Medicine. There's a supplement there that exactly explains our approach to ILD identification, treatment, etcetera. Ron Su from Artisan Partners. I just have a question on +1 062. Is there a reason you didn't give an explicit plan to study explicit plan to study the drug in triple negative breast cancer given the higher expression levels of Troq2 in that tumor type? And if you did, would you do you think you would have to run a head to head study against ME-one hundred thirty two? So we have planned to expand beyond lung cancer, obviously. We have not listed which tumor types we will test ten sixty two next. I've shown you that graph where we looked at all indications across fourteen oh two and ten sixty two. You can see the gray dots and the blue dots or whatever dots for different indications across the different the two assets. Triple negative is obviously part of that, but we have not disclosed how we would which tumor types we're going next beyond lung cancer, monotherapy and IO combination. With respect to your question of a head to head, you need to run a head to head comparison once the drug is fully approved. We obviously wait to see what the fate and future of IMU-one hundred thirty two is compared to our own data. So that's as far as I can comment. We certainly believe that the two drugs have different characteristics and certainly different profiles and potential. Sorry, the last one. Forgot to ask. Regarding HAS three, you talked about the HAS three is stable depending on the situation. But regarding TROP two, did you find something in the similar situation where it depends on the cancer or depends on the situation TROP2 is stable or not stable? So TROP2, the amount of expression on a protein basis between ERF3, ERF2 and Trop two is actually two logs. So ERF3 is expressed at 1%, Trop two at 10% and I'm sorry, ERF2 at 10% and Trop-two at 100%. So really, I mean, you have 10 times more Trop-two compared to ERF2 and only 10% of ERF3 compared to ERF2. So the amount of protein expression is highly, highly different between these different receptors. That's number one. Number two is that Trop-two seems to be highly stable as far as we know. So we've not observed. But this is a new science. I mean, nobody has ever really we never had the tools to pharmaceutically understand what happens with these ADC receptor expression. So we're discovering a new science. This is why we are transparent with you and say, URF3 definitely works. I mean, the drug works. We have multiple, multiple examples of tumor regressing after failing everything and so on. So we know the drug works. We just have to figure out how to select the patient and or modify or stabilize the HER3 expression so that we can carry the effect. There are other ways of doing it that you can combine. For instance, you have dimerization between HER2 and HER3, we also can have combination between ADC. I mean, there's lot of things we can do. We just have to do the work. It's just Trop-two the result I've presented are patients who are not selected for Trop-two expression. They're not selected. And so far, we actually we have not published, but so far we didn't see a great correlation between medium and high expression of Trop-two and the intensity of the activity, which means that probably there's enough Trop-two in these cancer cells no matter what to absorb all of what is needed, release the payload and have the bystander effect. So there's much, much less concern for Trop-two. But on this one, you're checking TROP two even though it's not selected, but you're also checking TROP two status. Correct. It's never really disclosed as far as the relationship between the positivity and the efficacy so far. We have not disclosed that so far. I'm just telling you the primary data not suggesting there's a massive correlation. Will disclose at ASCO. We will report at ASCO. Okay. Because I got a lot of question on this milligram thing that nobody can read, but people trying to read much as they can. I can you say the ORR rate on this one is around forty, fifty or it's hard to say. It's hard to say, yes. Are absolutely Yes, would All right. Thank you. We it's not typical to disclose new data on R and D Day. I don't want to disclose any more than what we have. Here what you see are obviously far more I mean, have many, many more patients treated. And this is a data cut we have as of mid November. And obviously this is six weeks old because you are on this graph only if you have at least one scan. So it just shows you a few things. Number one is that there are many, many more patients. We're expanding at six and eight. And then you also maintain the same dose effect as what we have observed so far. And suffice it to say that our CEO and Board agreed to invest $1,000,000,000 in CapEx in manufacturing of ADCs. We are relatively confident in what we're observing so far with Truck two. But I'm not going to tell you where the dots are. Okay. Any other questions? Little bit too early to close that event, but if you don't have any question, I'd like to close this event