R&D Day 2017

Dec 13, 2017

Slides

Thank you, George, and good afternoon. It's an extreme pleasure for me to be here and to share with you the progress of our enterprise in fighting cancer and bringing valuable new drugs changing the standard of care. Of course, today, Daiichi Sankyo will be a clear leader tomorrow. Eighteen months ago, we introduced Cancer Enterprise, which is a virtual matrix organization within Daichi Sankyo with a clear focus, clear accountability and new ways of working. We quickly assessed and prioritized the portfolio. We are now here today delivering on goals with a twentytwenty five vision and tangible data to demonstrate our progress in the short term prospects. On this slide is the road map for the next hour or so. We will first review the Cancer Enterprise 2025 vision, the source of our competitive advantage and our bold ambition, which is to deliver seven distant enemies or new molecular entities in eight years. We will review how we are delivering now the portfolio. First and foremost, DS8201, our flagship ADC, as well as the following ADCs using the exact same ADC technology. We will give you a hint about our next generation ADC, still in the lab and improving further. We will cover quisotinib and our plan and progress in establishing an AML franchise. Please note that I will share new clinical data and new plans never disclosed before. Next slide, please. The very reason I joined Daishi Sankyo eighteen months ago is science. Daishi Sankyo is very unique. It has a world class outstanding medicinal chemistry, antibody engineering and discovery biology. Our researchers have an exceptional scientific attitude. They solve almost any problem when the right questions are asked. This is the very source of our advantage, the ability to discover drug and technology where others fail or find less advanced options. On this next slide, we see how I believe we have a clear competitive advantage. First, a world class research. Second, an exceptional focus. We relentlessly align biology to unmet needs. We only research and develop drugs that address biogenicity, which is differentially. Third, Cancer Enterprise is now a nimble, agile global delivery machine. Fourth, we set for ourselves challenging goals. We aim for high goals. In my past life, going for high goals is in itself a source of advantage. Our goal is credible, as I will show, and at the same time very competitive compared to great established oncology companies. Finally, the job is done only once drugs are approved, there is adequate market access and successful launch. This will be achieved through seamless integration across the enterprise. Next slide please. So Cancer Enterprise 2025 vision is seven in eight. By 2025 Cancer Enterprise will be a leading world class science organization built on three pillars and delivering seven valuable distinct NMEs or new molecular entities. We will lead in smart treatment with best in class and first in class ADCs. We will maximize the existing smart chemo portfolio. We will develop an incredible next generation of smart chemo. We will disrupt smart treatment technology by developing developing really fascinating new approaches, which are in the labs now. We will establish a competitive hematology franchise. We aim to lead the FLT3 segment. We will expand beyond FLT3 and expand beyond AML. And finally, we will lead in breakthrough science by delivering best in class or first in class NMEs with really disruptive new mechanism of action and we will embed new technology to magnify the value of our science. Cancer Enterprise will deliver through these three pillars seven enemies in eight years and will be a cross functional value creation team changing standard of cares with each of these enemies. Let's review each pillars. By 2025, Cancer Enterprise will be leader in smart treatment with best in class and first in class asset. Cancer Enterprise will have delivered three best in class smart chemo enemies changing standard of cares. We will also have seven new smart treatment in clinical stage, including at least one disruptive smart treatment. We are currently maximizing the existing smart chemotherapy with a clear focus initially on the ES8201 and U31402. I will spend quite some time on these two asset layers and give you new data there. We are growing fast to selected group of patients and expand to broader population in earlier line. We are positioning Smart Chemo as a modality of choice for combination, and we are addressing China opportunity and challenges. Number two, we are developing next generation smart chemo and pivoting development to be target centric, agnostic of organ and of cancer organ. Number three, we are applying the DS technology to create disruptive smart treatment to sustain our leadership beyond twenty twenty five. Now let's look at the next pillar. By 2025, Cancer Enterprise will have delivered three NMEs in AML changing standard of care and will have four to five new hematology clinical stage assets, of which at least two will be in hematology malignancies other than AML. We expect to lead INFIT3 mutant segment with cusitinib as monotherapy or in combination. We have a potential submission in 2018 for relapsedrefractory AML and a best in class potential in first line setting. We aim at establishing crizetinib as a backbone for combination and lead in understanding the mechanism of resistance in FLT3 disease. Number two, we're extending beyond FLT3 mutated AML and follow the science of our current asset beyond AML, including ADC based on our next generation technology. Finally, the third pillar of our CE twenty twenty five vision. By 2025, Cancer Enterprise will have delivered one NME with a disruptive MOA or mechanism of action or best in class profile, changing standard of care. And we will have seven new clinical stage assets in this area and a dynamic translational biomarker program across the board. Here, we plan to leverage DS-twelve oh five, which is an XL inhibitor and DS-ten fifty five with an undisclosed target to position Cancer Enterprise as a leader in delivering disruptive best in class or first in class. We also want to lead the science by identifying and selecting new target MOAs through our internal discovery and active partnership. On this slide, you can see major assets in the clinical stage pipeline organized through these pillars. It is an extremely impressive pipeline, especially when looking at the individual strengths and value of these assets. It is well positioned to deliver seven enemies in eight years. You can see here a third ADC now reaching clinical stage, our Trop-two ADC ten sixty two. I will spend some time on this one as well. So what is the vision for Daiichi Saint Laurent Cancer Enterprise in 2025? It will be a science company. It will have succeeded by leveraging clear sources of competitive advantage and it will have delivered seven NME changing standard of care and a healthy refreshed clinical stage pipeline. Now let's move on to how Cancer Enterprise is delivering now. Next slide, please. Let's spend some time on this slide. On the left, you see an updated version of the ADC franchise portfolio. DS1062, the Trop-two has now reached clinical stage, as I said before. There's a couple of additional updates on the bottom left, disclosing two more ADCs, DS-six thousand one hundred fifty seven for GIST and DS-six thousand for renal and ovarian cancer. We are on purpose not revealing the exact targets. On the right, you see a cartoon and the list of seven key characteristics of our DXD ADC technology, the technology which is employed across all our ADC assets on the left. Each of these characteristics was specifically researched and designed by our research teams and this is why in my belief, this ADC DXD technology is performing as it seems to do. First, the payload. It is a novel cytotoxic mechanism of action, one not seen by the cancer cells before and thus unlikely to have preexisting resistance. It is 10 times more potent than SN38, the active moiety of urinotecan. It is by design with high cell membrane cross penetration for a clear bystander effect killing neighboring tumor cells. Then our researcher further improved the payload and made it to have a short systemic half life to avoid blood exposure. Second, the linker. The linker is a peptide with high stability sparing noncancerous tissues from toxicity, protein as tables in the blood. It is selectively cleaved by lysosomal enzyme that are upregulated in tumor cells. The linker attaches a high number of payloads per antibody. This is DAR or drug antibody ratio, which is double the number of payload attachment reported for TDM-one. It is a very unique and advanced best in class technology, which is applied across multiple ADCs. Now DS8201. It has received breakthrough therapy designation or BTD by U. S. Food and Drug Administration for patients with HER2 advanced breast cancer who have received trastuzumab, birtuzumab and progressed after TDM-one. This is the first agent ever with breakthrough therapy designation for HER2 disease. The SA801 is in pivotal development with DESTINY Breast one and DESTINY Gastric one studies, which are both under ways. We have made critical partnership in IO immuno oncology, where recent results reported at Santonio reveals the needs for HER2 disease and partnership with Puma Biotechnology and their unique irreversible HER2 TKI inhibitors, which offer unique benefits for ADCHER2 combo. This last collaboration we just announced this morning. We have a healthy data release and we expect more new data at the January 2018 ASCO GI meeting. On the front of what is new for DS8201, we are tracking to plan and that is news. We had yesterday an FDA comprehensive BTD meeting, which was extremely helpful. And most importantly, we are considering further acceleration. We are contemplating a first BLA in fiscal year twenty nineteen and we are expanding beyond HER2 breast and HER2 gastric. Let's review now critical data for DS-eight thousand two hundred one. On this slide, you see the waterfall plot as of October 2017 for any HER2 expressing tumor for 165 subjects treated at either five point four or six point four milligram per kilo. We have not shown the totality of this data before. Any vertical bar represents an individual study subject. Any bar going below the horizontal line represents a tumor size reduction compared to baseline. Tumor size shrinkage is observed in most subjects. The overall response rate is fifty three percent in this Phase I study. Next slide, please. On this pilot plot, you see durability of response and tumor control for the same one hundred and sixty five subjects with tumor expressing HER2, high HER2 as well as lower HER2, breast HER2, gastric HER2 and other tumor type. We again have not shown this data before. Each individual line represents a single subject. It is virtually impossible to graphically separate high or low HER2 through different outcomes with respect to sustainability and duration of tumor control. Tumor size control is durable in the majority of subjects. Let's look at breast cancer, high HER2 as well as low HER2 in a total of 105 subjects. These data were presented last week actually earlier this week at San Antonio. So top graph represents high HER2, the bottom graph represents lower HER2 breast cancer subject. Again, it is difficult to visually predict different outcome with respect to durability of tumor control and response depending on higher HER2 and lower HER2. This is exactly what DS8201 was and the DXD ADC technology was designed to provide. Next slide please. This slide is a busy slide. It gives you the numerical values regarding confirm and I insist confirm response rate and disease control rate for breast cancer on top as was presented at San Antonio and gastric cancer at the bottom based on ASCO earlier this year in June. All subjects in the breast cancer cohort on top have received and failed trastuzumab and TDM-one and the vast majority have also failed pertuzumab. As shown in the yellow row, the response rate in subject to have failed all three, pertuzumab, trastuzumab and TDM-one is sixty two percent with a disease control rate at ninety four percent. The PFS median estimate is now at ten point three months, with an observed range from one point two and sixteen point eight months and continuing. For HER2 gastric cancer at the bottom as was shown at ASCO, the response rate observed after failing CPT eleven is forty four percent with ninety four percent disease control rates. On the next slide, we see a summary of safety and tolerability as observed to date. We continue to observe the same safety profile as reported before, with the majority of treatment emergent adverse events being hematologic, anemia, platelet and neutrophil count decrease as well as GI gastrointestinal disorders, mostly nausea, decreased appetite and some degree of vomiting, diarrhea and constipation. The majority are mild to moderate grade one or two with fewer grade three and four. As shown on the bottom of the slide, we have observed two cases of potential grade five pneumonitis or death in the context of pneumonitis. These cases are assessed by an independent interstitial lung disease or ILD adjudication committee as is typical in drug development in oncology. On this next slide, I'm providing a summary of a design of a Phase II study we have just posted on clinicaltrial.gov in subject with advanced colorectal cancer expressing HER2. This study will start enrolling immediately and will enroll subject in three cohort based on decreasing degree of HER2 expression as measured by IHC and or by FISH. We will typically look at response rate as well as a series of typical secondary endpoint. On this slide is a cartoon representation of the comprehensive translational research plan for DS8201. Through multiple methods and evaluation, we are planning to gain insight from many studies. Regarding the mechanism of action, MOA, we'll test why DS8201 appears active in wide range of HER2 expressing tumors. Regarding mechanism of resistance or MOR, we'll try to elucidate how tumor become resistant to DS-eight thousand two hundred one. Finally, regarding the rationale for combinations, we'll search for complementary mechanism beyond IO combination. The collaboration we have just announced with Puma and the Meroenelstrom Cancer Center and neratinib, which is an irreversible HER2 TKI inhibitor falls in this category. We also do the right translational research to define how best to enter and develop in earlier line of treatment, first line metastatic breast cancer and early breast cancer, neoadjuvant treatment or adjuvant treatment. We want to follow the science here and there's a real potential for DS-eight thousand two hundred and one to disrupt the current first line metastatic breast cancer setting as well as the early breast cancer treatment paradigm. On the next slide, see let me show you an example of this research in the low HER2 IHC I plus FISH negative patient. On the left, you have the low HER2 expression. On the top, you see that very few cancer cell express the HER2 protein and there's no gene amplification by FISH on the bottom, which is seen or very, very little. On the right, you see the PDX, a patient derived xenograft, so the actual tumors in animals for these subjects, which shows that TDM-one and trastuzumab are inactive as one would predict in lower HER2, whereas DS-eight thousand two hundred and one is active. This is also what DS-eight thousand two hundred and one was researched and designed to do. With all of this, what is the clinical development plan for 08/2001? It's a broad and a bold program. Highlighted in the red boxes are newly disclosed studies. The timelines shown here are estimated timelines. For breast cancer, we have a clear path to proof of concept and fast to market plan based on clear unmet need and lack of standard of care. We plan three separate breast cancer Phase three studies, one post TDM-one failure versus physician choice, one versus TDM-one head to head as well as a Phase three study in low expressing HER2 breast cancer. For gastric cancer, we are conducting the pivotal randomized Phase two study in advanced gastric HER2 and plan the confirmatory Phase three study versus standard of care. Reconducting study in lung and colorectal cancer as well as immuno oncology combination study in breast, gastric, lung and bladder cancers. On this slide, you see summarized the DS-eighty two program and how it delivers and meets its goal. Two thirty subjects have been treated to date program wide. So pivotal studies are actively recruiting. U. S. And Japan are fully operational and the rest of the world will be early in calendar year 2018. We are planning seven additional studies, including head to head versus TDM-one and two more IO combos. Drug supplies are on track and we conduct the necessary consultation with global regulatory agencies and HTA, health technology assessment agencies. Next slide please. We believe 08/2021 is a best in class asset in technology and the leader in the next generation of HER2 ADCs. We have advantages in both timelines and payload, construct and technology. We expect to deliver in this competitive advantage. Actually, like competition, it keeps us, me, on our toes. The SAT-two zero one is delivering in HER2 expressing tumors, high or low. We lead and are contemplating 2019 submission. We have a clear potential, best in class. We are looking convincingly at a pan HER2 approach, meaning HER2 expressing high or low across many tumors. We also deliver on our strategy to be the partner of choice in IO and in TKIs in particular. Now let's move to U3-fourteen oh two, the second DXD ADC in the clinic and a first in class opportunity. U3-fourteen oh two uses the exact same technology with a drug antibody ratio of eight and patutamab, an HER3 monoclonal antibody with a well established safety data set. In one hundred and eighty eight subjects with advanced breast cancer who were screened for the Phase I study, twenty percent at IHC II plus III plus and an additional twenty nine percent at IHC I plus HER3 expression. U101 study is a first in human study initially in Japan and now global. I'm now describing data never shown before. We've just reached the fifth dose level at eight milligram per kilo every three week. The MTD, the maximum tolerated dose have not been reached so far. Multiple confirmed partial responses have been observed and durable stable disease tumor control have also been observed. We will show the details at ASCO twenty eighteen. What about HER3 disease? This is not a well established disease entity and targeting HER3 biology has not been successful. Here with U31402, we target HER3 expression and use expression binding and enterization as our tool to target the tumor. So this is not about the IRF3 biology, it's about the IRF3 target binding and internalization. This is a very different approach. On this next slide, you see a high and early internalization rate of HER3 patisiran compared to HER2 trastuzumab, HER2 pertuzumab or EGFR cetuximab. Each graph show the internalization rate at one hour, four hours and twenty four hour, very different graphics. On this next slide, you see the rate of protein expression by IHC across three fifty breast cancer samples with a further distribution by subtype of breast cancer, HER2 negative, HR positive, triple negative as well as HER2 positive. On this slide, you see that the URF3 protein is up regulated by fulvestrant or FasoDex, which is a typical SERD or selective estrogen receptor degrader. This is an important observation as immunotherapy for ER expressing breast cancer is here to stay and an important therapeutic tool. U3-fourteen oh two has also an important fast to market opportunity in non small cell lung cancer. So target indication is in EGFR mutant either after Osimertinib or in T790M negative after TKI, so TKI refractory. The prevalence of expression of HER3 in these patients is approximately seventy five percent, but by our in house use of a Ventana assay. We are pursuing here a rapid dose escalation, which is informed by the breast cancer data I've just described. And the first subject dose is three point two milligram per kg. The study is conducted in The U. S. On this slide, you see the IC data by Vantana on the left and the TGS I'm sorry, the CGA, the Cancer Genome Atlas project mRNA expression for URF3 across a large variety of tumor. Much is left to do to understand and pursue HER3 indication with U1402. And we will do so as soon as the drug declares itself and once we secure and focus on the fast to market lung cancer option. Next slide, please. DS1062 is our third DXD ADC in the clinic. It is designed to be best in class. It uses the same DXD technology. We choose a selective DAR drug antibody ratio of four to protect the safety margin, and we have done so through a sophisticated optimization of the conjugated method. On this slide, you can see on the left hand side that DS1062 is highly effective and able to deliver the payload through great stability of the payload in the plasma. On the right hand side, animal PK shows how stable the ADC is and the ability to dose as planned every three weeks. On this slide, you see the design of the first in human study. It is designed to rapidly substantiate best in class status. If we fail to achieve best in class, we will not pursue an ADC which is not differentiated. So first in human study is in non small cell lung cancer third line or greater with a typical dose escalation and parallel expansion once you reach the expected therapeutic range. We will use efficacy and safety to define gono go criteria and following non small cell lung cancer proof of concept, we will expand across other Trop-two expressing tumor types. Now one slide on our next generation ADC, the one after DXD, a generation which is still in the lab and aiming at being better than our current DXD ADC technology. I will not describe this technology. We shall do so in the future. All I can and will show is here. When tested versus our DXD technology after a single injection, at two months plus, the effect on tumor volume and control is fascinating, especially if one knows that this is achieved with a much smaller milligram dose. On the right hand side, you see that the animal experiments showed no impact on the animal body weight, suggesting a comparable durability. In summary, we are swiftly progressing the ADCs. We have a proven ability to moderate and adapt the technology to the circumstances of a monoclonal and a smart chemo. And I just gave you a compelling hint about our next generation ADC technology. Now let's move to the AML franchise and our pipeline. We are currently progressing assets in three of the six emerging classes of target in AMLs. On the right hand, you see how these assets are distributed. We perform swift and quick development combination as studying and addressing the emergence of resistance. Having a multiple asset portfolio allows us to think about outcome based pricing and access, which is an advantage in it by itself. Next slide please. For quasitinib, the AML franchise flagship asset, the QUANTUM R Phase III study in relapsed refractory AML has completed enrollment. So QUANTUM first study in first line AML is on track and this despite the availability of midostaurin. We have established a major multimillion dollar partnership with MD Anderson Cancer Center. We are about to start our first novel novel combination, quisetinib and DS-three thousand and thirty two, our MDM2 inhibitor. And as you may have seen or heard, we have a healthy flow of data publications at all major conferences. Overall, we are tracking to plan with five different axes. First, we are planning for global simultaneous submission. The timing is obviously event driven. Number two, we are accelerating the first line AML study. Number three, we deploy the AML franchise asset through single agent and combination. We are enhancing through internal research and collaboration the franchise and we're enriching with targeted business development and licensing. Next slide please. We all know that AML has a complex biology. Our two pivotal trials, QUANTUM R and QUANTUM FIRST, aim at changing standard of care by exploring the role of a specific and potent FLT3 inhibitor. So a cartoon shows that AML is initially a monoclonal malignant disease, which evolves and relapses through the emergence of resistant and more aggressive clones. The emerging treatment algorithm on the bottom for patients with FLT3 mutated AML induces remission through chemo with or without a FLT3 inhibitor followed by consolidation chemo plus or minus transplant plus or minus maintenance FLT3 inhibitor. In the event of relapse, patients are offered salvage chemotherapy with or without transplant. Quizotinib as a potent and specific FIT free inhibitor is tested on all three phase of this paradigm through both Quantum First and Quantum R studies. These studies will establish a role of a potent and specific FLT3 inhibitor at these various stages of disease. On the next slide, you see that cusotinib is indeed a selective and potent FLT3 inhibitor. On the top, the kinomes show high specificity on the right compared to midostaurin on the left. The IC50 for quasetinib is 18 nanomolar and shows the drug is approximately 100 times more potent on FLT3. This shows itself under treatment at the bottom at day fifteen and twenty eight with a continued suppression of the expression of phosphoFeed free, so PFLT3 for Western blot. On the next slide and with all the limitations attached to indirect cross trial comparison, we see a difference in the response rate, complete response or CRPR and duration of response in relapsedrefractory AML, where the FLT3 driven clones dominate the disease. For all of these reasons, because the trials are well designed, we believe that quisetinib will be establishing itself as a backbone in FLT3 segments. QUANTUM R will deliver first and best in class potential. It is a Phase III registrational study large with three sixty three subjects in relapsedrefractory FLT3 ITD AML. It is a single agent study with primary endpoint of overall survival. The Japan Phase two study is underway. We're preparing for global submission. Enrollment was completed in August. The top line is expected in 2018 and we prepare for global simultaneous submission in U. S, Europe, Japan in the 2018. Quantum First will deliver a best in class potential is a key value driver. It is a Phase III registrational study with five thirty six subjects in newly diagnosed FLT3 ITD AML. It is a combination study with chemotherapy with a primary endpoint of event free survival. First subject was randomized in September 2016. This is a global trial in 28 countries to date. The study is ahead of initial projection with more than 25% enrollment complete and we are focusing on global deployment. Now we turn our attention to the second asset in the AML franchise, DS-three thousand two hundred and one or dual EZH1N2 inhibitor. It is a potent and selective dual inhibitor of the histone methyltransferase, EZH1 and EZH2 at histone H3 and a promising new epigenetic approach. So dual inhibition of EZH1 and EZH2 is hypothesized to allow for more potent blockade of hypermethylation and overcome compensatory mechanism between EZH1 and EZH2. It is a first in class. On the next slide, I'm showing preliminary results in relapsed or refractory non Hodgkin lymphoma just presented at ASH a couple of days ago. We see on this waterfall plot an overall response rate of fifty nine percent with one CR and nine PRs in seventeen A variable patients. The overall response rate is one hundred percent in four out of four peripheral T cell lymphoma. Interestingly, the drug seems very active in T cell lineage disease, an observation which has not been achieved with EZH2 inhibitor. And further evaluation seems warranted in adult T cell lineage leukemia and lymphoma. On the next slide, I'm showing data we published last year regarding the activity single agent of DS3032 and MDM2 inhibitor in relapsedrefractory AML and MDS. This showed bone marrow blast reduction in approximately sixty percent of evaluable subjects. These observations led us accelerate the possibility of combination between these two assets. On this slide, on the left is preclinical evidence suggesting synergy of a novel novel combination of cusatinib and DS-three thousand and thirty two. The idea is to combine molecular targeted agents with broad acting mechanism to address the AML heterogeneity and complexity, including multiple mechanism of resistance and to extend the benefit, death and duration response transplant rate survival beyond single agent FLT3 inhibition. In summary, for the AML franchise, Quantum R is delivering data and submission top line results 2018. Quantum first is accelerating global recruitment to exceed target enrollment in fiscal year twenty eighteen. We're expanding collaboration, business development and licensing to advance the portfolio. We follow the science and expand beyond AML. And we are focusing on combination within our own portfolio, but also with external assets. Now other updates before concluding and moving into Q and A. First, an update on our collaboration with Kite for Japan. For KTE C19, the recently approved asset in The U. S, the Japan study is similar to ZUMA-one study, the basis for approval in The U. S. The Japan study is aligned with PMDA and we expect enrollment in fiscal year twenty eighteen. We are working on the technology transfer from Kite. Also to note, the agreement we concluded in January 2017 includes optional licensing rights for KAID's CAR T product candidate that will progress into clinical development in the three years following signing of the agreement. Next slide. For pexilatinib, the ENLIVEN Phase III study in TGCT or PVNS met its efficacy endpoint. Our intent is to proceed with formal pre submission with U. S. FDA on a narrow indication. We observed low single digits percent serious liver toxicity with two cases program wide resulting in or associated with either death or liver transplant in the context of bile duct loss syndrome. Also of note, the pembrolizumab combination is terminated for lack of accompanying evidence of synergistic activity. Next slide. This is a summary of our major research and or development collaboration we have concluded in 2017, including the most recent one announced today with Puma Biotechnology and the Memorial Sloan Kettering Cancer Center. These collaborations cover the full spectrum of research and development activities as you would expect from a company like our company where our primary strength is science. The next slide is my one before last slide. As you hopefully have seen by now, the Aichi Sankyo Cancer Enterprise is a cutting edge science machine. It has a valuable portfolio. It is a delivery focused, capable and agile organization with credible progress and clear momentum. Cancer Enterprise is a fourth year to stay, transforming Daiichi Sankyo into a recognized leader. These last slides give you a road map for the Cancer Enterprise fiscal year twenty eighteen major R and D milestones. It is healthy and we have plenty to talk about in the months to come. I thank you for your attention. I apologize again for my accent, my passion, which makes me speak way too fast. Speed is a good thing. Speed is good for delivering great science on how I know to do that. Speed is not so good when presenting. Thank you. And now Glenn, please. Thank you, Antoine. That was a very nice update on the progress of our oncology portfolio. My name is Glenn Gormley, and I'm the Global Head of Research and Development at Daiichi Sankyo. I would like to now summarize the full R and D 2025 vision and show you how it links to the corporate vision. Earlier this afternoon, Nakayama san described the transformation of our company to achieve our 2025 vision of becoming a global pharma innovator with a competitive advantage in oncology. To accomplish this vision, R and D must transform itself from our previous focus on cardiovascular and primary care products to now delivering sustainable growth based on our oncology pipeline. And we need to do this in a way that continues to support our late stage pipeline and marketed products in the areas outside oncology. The R and D transformation began in 2015 and has continued through 2017 in order to provide a strong foundation to ensure success of our vision. During this time, we have clearly defined two core therapeutic areas that will drive our strategy. The most important, of course, is oncology. The second core area is called specialty medicine, which is similar to the new Horizon area, consisting of projects in the areas of pain management, CNS disease, heart and kidney disease and rare diseases. The reason for the name change is to emphasize that we are no longer focusing on primary care products in these areas. The specialty area medicine also includes support for the life cycle management of our late stage and marketed products. We have also made other changes in the past few years, including the transformation of our research organization into a bioventure like model, where discovery units have been created consisting of research scientists with expertise in many different fields, such as biology, pharmacology and medicinal chemistry, who all work together under the same leadership rather than being separated into functional units under different leadership. Last year, we established the Biologics unit by consolidating expertise from within the R and D and Pharmaceutical Technology units to ensure the seamless cross functional development of our Biologics pipeline. This was an important step to accelerate the antibody drug conjugate products you just heard about. We also simplified the decision making process for our project teams to provide them with greater empowerment to accelerate programs. With this strong foundation, R and D has now defined four key elements of the 2025 vision. The first element is to clearly prioritize the oncology portfolio while maintaining a limited investment in specialty medicine. As you heard from Nakayama san, we are prepared to increase the budget for the oncology pipeline, if needed, to maximize the value of these projects. This will require R and D to decrease our investment in other areas. The second element is to shift resources to align with our priorities. We are also prepared to invest in critical capabilities needed to deliver the pipeline. The fourth element of our vision is to continue to establish new and diverse scientific platforms and modalities, which will allow us to maintain the scientific leadership necessary to ensure sustainable growth. The success of the R and D transformation depends on delivering the oncology portfolio by becoming a leading world class organization focused on the three pillars just outlined by Antoine. Lead in the field of antibody drug conjugates, establish a competitive hematology franchise and continue to lead in the development of new breakthrough science. From these three pillars, we believe seven new drugs can be developed, approved and launched in the next eight years. Within specialty medicine, our goal is to protect near term revenue and transition to specialty areas where the medical need is the greatest. We will maximize near term revenue by completing the development of our late stage assets and supporting the life cycle management of our marketed products. We believe that two new drugs can be delivered by 2020 with this strategy. We will continue to grow new franchises with a limited investment in the areas of pain management, CNS disease, heart and kidney disease and rare diseases. By 2025, an additional three new drugs that will change the standard of care can be delivered. The second key element of the R and D twenty twenty five vision is to shift resources from specialty medicine to oncology, which includes both funding of projects and people. This process has already started both in research and in development based on the targets defined by our vision. In 2017, thirty nine percent of our research effort was focused on oncology. By 2020, 60% of our effort will be dedicated to oncology. To accomplish this shift, resources in specialty medicine will be reduced from 61% to 40%. We've established even more aggressive targets for development. In twenty seventeen, forty seven percent of our resources were focused on oncology. By 2020, 70% will be dedicated to oncology, with a reduction of specialty medicine resource to 30%. With this shift, we can secure the resources necessary for acceleration of the oncology pipeline, while maintaining diversity within our portfolio to ensure sustainable growth beyond our 2025 targets. The third key element of our 2025 vision is to invest in critical capabilities necessary to deliver the exciting pipeline you just heard about. The two most important areas are IT infrastructure and translational research capabilities. We plan to enhance our R and D IT infrastructure to support multiple and sometimes simultaneous global regulatory submissions. These systems will also help us reduce the cost of conducting clinical trials and to accelerate time lines. Success in the field of oncology today requires a deep understanding of the complex molecular biology of tumor growth and the development of resistance. Antoine cited just two examples of this in his presentation: the importance of understanding HERG3 expression and upregulation by hormone therapy and the clonal evolution of AML leading to FLT3 dependence. We need the tools to understand this rapidly evolving biology. By investing in the expansion of our translational capabilities, we will achieve closer alignment of our discovery and clinical activities. We can conduct just the right experiments to quickly establish proof of concept. And we can more easily identify new targets and new indications for our drugs. The fourth key element of the R and D vision is to continue to develop new and innovative technology platforms and modalities, which can fundamentally change the standard of care in medicine. We think of progress in technology as having three waves. The first wave was the technology to develop naked humanized monoclonal antibodies. As we move to the second wave, we see the use of more complex biology, such as antibody drug conjugates with chemotoxic warheads and the creation of bispecific antibodies and protein scaffolds. In the third wave of technology, we see the harnessing of even more complex biologic systems such as nucleic acid based therapies, cell therapies and the use of oncolytic viruses. At Daiichi Sankyo, we have been actively pursuing both second and third wave technologies to develop highly innovative therapies such as our antibody drug conjugate portfolio. And our collaboration with ZymWorks, which takes advantage of their unique platform technologies to develop novel bispecific antibodies. We also have several exciting third wave programs, including DS-five 141, our antisense oligonucleotide designed to increase the expression of a functional dystrophin protein in patients with Duchenne's muscular dystrophy. We anticipate top line results before the end of this fiscal year. Another example is our collaboration with Kite Pharma, now part of Gilead Sciences, to develop their novel CAR T therapy here in Japan. Finally, Antoine has already highlighted our interest to develop a new generation of antibody drug conjugates with potency never seen before. Let me summarize a few important messages from our presentations today. Nakayama san has communicated our 2020 vision and willingness to invest selectively in oncology to achieve it. Antoine has provided an important update on the rapid progress of our oncology portfolio. I believe we have a real opportunity to not only meet but even exceed our 2025 vision. But to do this, R and D needs to rapidly evolve. We need to shift our resources to maximize the value of our ADC and AML portfolios. We need to continue with a limited investment in specialty medicine in areas with the highest potential in order to diversify our portfolio. We need to invest in a few critical capabilities to enable continuous innovation. And finally, we need to develop new technologies as a source of new therapies in the future and sustainable growth beyond our 2025 vision. Thank you. Can you okay. So thank you. The next generation ADC is new technology. We are not describing how we achieve better results without impacting body weight. But it is disruptive. It is more than just a traditional thinking. We have multiple technological innovation which result into these constructs and these constructs exist and are tested in the labs. We're just not yet describing this, but they are disruptive. So UNIDENTIFIED the probability, Harvay, we will do what it takes to deliver a submission as soon as is humanly possible. We had the meeting with the FDA indeed, actually one of many meetings, but the first full comprehensive breakthrough designation meeting at the FDA actually overnight, literally overnight for us. We carefully said that our base plan is to submit the BLA in 2020, fiscal twenty twenty. The only thing we say is contemplating. Contemplating meaning we're looking at and we're seeing if we see an options to do 2019. We are not committing to submit the BLA in 2019. But if we can, we will. It is an option. I will not give you a probability of these options to be realized. It is an option which was not there before, but it is not something we are willing to commit now. Sorry to talk about the very detailed stuff, but it's so important for a kind of a this side of the market. So you confirm 2020 is okay, but this time you are kind of thinking about possibility of 2019. Does the situation change after BTD meeting or not? So you are correct. We're thinking of and the situation did not change in either way. So we prepared the slides before the meeting, and we kept the slides as they were after the meeting. So in a sense that if you decided to commit for 2019, the description will change from that description, right? If and when we decide to commit, we will communicate because it is material to the company. Glen? So as you know, we have breakthrough therapy designation with the FDA. And one of the things that goes along with that is FDA commits to work with companies to find ways to accelerate where possible. It is not entirely up to us. It is a relationship that has to be worked through and Antoine and his team are working with health authorities to determine if it's possible to accelerate. When he has confidence, we give you that confidence. But it wouldn't be misleading to give you that confidence today, but we are trying hard. Yes. Number one, yes, we did observe actually pneumonia, which are potentially interstitial lung disease. Until it is adjudicated, it's not. So we're reporting this in the full disclosure. But as is typical and as I've done before for Tagrisso and other drug, ILD is very typical. It's a serious issue. It's a very typical and especially in targeted therapy. So we expect these cases to be educated. We have communicated these cases to the agencies, to the IRB, to the investigators. We're continuing ahead. I'm personally not concerned by this. We have a lot of marketed drugs have ILD, including Grade five meaning death associated with ILD on their label. And it's just a risk if it exists, which has to be very well characterized. And we are identifying the risk factor for this, how we can mitigate, how we can assess for it. I did not answer your question specifically about the dose and the study, but we will disclose this data when it comes. So I have many questions for this 08/21. So firstly, you talked about your contemporizing to file in 2019, and you just talked about the option to file in 2019. So would you be happy to talk about what type of option you have? Submitting a BLA requires that you submit a certain number of evidence. One evidence is about the response rate. Response. The third is how predictable it is and the best way to predict is to reproduce that. The fourth is you have to demonstrate enough safety. And the fifth, you have to justify your dose. And the final piece is you need to have enough evidence with your commercial material. As you know, we can go very fast. I've done it before and be assured that the faster we can go, I find a way to do it. In this particular case, the most difficult part is actually CMC, is the manufacturing the product. This is an extremely complex product to produce. It takes approximately more than a year to produce a product. You have to produce a monoclonal. You have to produce the payload. You have to produce a linker. You have to link the two. You have to put everything together on the monoclonal and then you have to formulate the product and do a dry sort of life realized. It's approximately taking twelve months, very different from Tagrisso where it's a small pill and a small molecule. The biggest challenge we have is to scale up, I. E, to increase the number of vial that we can produce and to do this in the commercial scale and commercial setting. So the options for filing the BLA depends on our ability to deliver on all six evidence and that's what we are actively discussing with the agency. But we as Glenn said, the FDA and the other authorities, but mostly the FDA because that's the most important one, is very, very open and collaborative, helping us. They're really helping us on all of these different challenges. So we see option if we can land all of these evidence. But there's not one more than the others which are driving the timing. Thank you. And my second question is the spider chart you just showed. So it seems the we saw the durability of response like the IO compound or Opdivo. So what's your rationale or scientific understanding for the durability? That's a very, very good question. I mean we describe ADCs as smart chemotherapy and you would expect that the tumor behaves like in typical chemotherapy, meaning that after seven or eight months, especially in very advanced tumor, the tumor escapes. So far it seems not to be the case on what we're observing. So that's part of the reason why we're doing some very substantial translational research work on understanding what is the mechanism of escape to this 08/2001, why the tumor finally escapes, manages to regrow because we don't see that too often and we don't fully understand and understanding this will be important because it may help us select better the patients, it may help us combine with something else or it may help us design the next treatment. So it is true that it is the durability, I mean the most impressive pieces of data that we presented today are number one in breast cancer HER2 failing trastuzumab, pertuzumab and TDM-one, a sixty two percent response rate. That's an extremely important finding. The number two, probably most important finding is that the drug seems to be active across high and lower to different tumors and it is durable. This is unprecedented. We've never seen this. So just like IO was new, this is new. We have to investigate. This is also the reason why we're working with immuno checkpoint inhibitors in combination because there is a potential to even further extend and we're also working with TKIs and especially the YTKIs, the one which increases the internalization of HER2. But we have to do the science and then we will follow the science. Thank you. And my last question is the Page 31, so the time line for the clinical development. So you are going to initiate the two Phase onetwo study for the IO combo next year. So would you specify which IO antibody are you going to combine? I'm asking because you show two boxes here. So I wonder why you show separately here. So short answer is no. We will not we are not specifying which antibody we're using in these two, But we will in due time. These are fascinating questions and extremely important questions. And you're absolutely right. I mean we are not targeting accepting yet, and there's a very specific reason. I briefly mentioned that the first line metastatic breast cancer combined has a well established combination and the first line in early breast cancer adjuvant, new adjuvant also accepting So accepting prasinezumab taxol in first line metastatic breast cancer and then the new adjuvant adjuvant setting is relatively well established. We had two options. One is to try to get into this, just add or replace 1A agents, say replace Herceptin with our drug. That's one option. There's potentially a better option which is to actually substantially change the paradigm of treatment of HER2 disease instead of adding or replacing to actually create a new therapeutic strategy. We have enough time. It's better to take the necessary time, six months, nine months and biology, research biology to really have the best possible treatment option for first line metastatic breast and also neoadjuvant adjuvant as opposed to going too fast and then missing on the real disruptive option. So I'd rather do the right science and define the right treatment for first line metastatic as well as new adjuvant adjuvant than trying to replace Herceptin. So that's the reason why it is not yet there. It's not that we are not thinking about it, it's just we want to do the best thing. And part of the collaboration we have with Jose Basalga's lab as well as at Memorisum Kettering as well as Puma is actually there's a lot of science where neratinib is a drug which is approved. But it's a great drug for us because it increases seemingly the internalization of HER2 receptor. It also has an effect on CNS disease. So one may think very differently on how to approach earlier line of therapy. So that's a long answer to your first question. To your second question, you're absolutely right. Ertu low is not a defined disease and there's a reason for this because there was no agent working. So it has been tried. Roche had just reported the failed trial where patisiran added to did not deliver any benefit in lower to breast cancer. So we will have to define A, the biology to make sure that the tumors are tested for lower to and B, insert ourselves into the treatment strategy because as you know, HER2 low is expressed actually very frequently. HER2 high is expressed only in 20, but HER2 low in breast cancer is expressed much more frequently. It is I think forty eight percent to fifty percent of breast cancer expressed are too low. And there are many other treatment options. So we have to sub segment and develop the drug in these different segments. It can be done, it will be done. We just have to find the right way. Once you have a drug which targets something, you can shift the practice. We've seen that with ALK. We've seen that with EGFR. We've seen that with T790M. We can change your practice if you have a great drug. It just requires to be smart and to know how to do this. I know how to do this. Antoine's answer to your question highlights why it is so important for us to increase our investment in translational sciences. As I said, we're making a major commitment to understand that biology and have the capabilities both in house and with our partners to be able to answer exactly those questions. So yes, there are different. So the disruptive SMART treatment. By SMART, we mean the concept of ADC, so delivering exactly on the cell, which needs to have the therapeutic impact. That's what we call smart treatment. Disruptive strat treatment, I will not describe, but it is extremely disruptive. It's a completely different thinking. It's the same concept of delivering but instead of delivering chemo or in the manner that we do, we will do things differently. We will it is extremely exciting. It's in the lab. It is constructed, so we have the construct. We're testing in animals. Have I'm personally very excited. We are just not ready to disclose that. This is very, very competitive. Because once we will describe that, we need to have enough lead time before we disclose what we do to secure our lead position. But the disruptive on Page 17 is different. Disruptive in Page 17, it is the ability of our chemists to actually deliver a highly potent, highly selective drug. Twelve oh five is a good example about that, Axle inhibitor. Nobody has ever been able to produce a pure Axle inhibitor without touching MER, which actually makes you blind if you have any impact. And MER and AXL are extremely close, and nobody has been able to target one without targeting the other. This is disruptive because you have a really new biology that you can finally test. The reason why we want to have many attempts is because I know that it's when you go after new biology, you have higher risk. So you need many attempts, and we only plan on to have one which is successful. We currently have twelve oh five, which is clinical stage. It should enter the clinic very soon. And we have another, which is we are not disclosing the target. But and we are researching others. So I'm using disruptive in both instances because there are new ways of thinking, new ways of approaching things but in different context. So the purpose of this slide is to show you that we believe it's important to shift the scientists, both clinical and basic scientists we have in the company today to focus on oncology. So the height of the bar is the same because the ratio of our commitment to oncology is now increasing. In research, it's increasing more towards sixty-forty in development, even more aggressively to seventy-thirty. The second question that you are asking is, is that total research effort enough? Do we need more researchers than we have? That will depend on the shift that we can make. It will depend on the speed in which Antoine's programs progress. And I think you heard Nakayama san say in the opening that he's prepared to give us the resource we need to ensure that these programs move as quickly as possible. But this slide shows that we're focusing our priority on oncology and decreasing it on specialty medicine, which we believe is the right strategy for the portfolio we have. It will not cover necessarily all HER2 low, you are correct. And the reason because the HER2 low expression, the breast cancer almost half of breast cancer express HER2. And the standard of care across these different subset population is different. And thus, you have to prove your benefit versus the standard of care. So it will not necessarily be the whole thing. You're right, but we have not yet finalized which it is. So when do you start to the second or third trial for HATURO in 2019 or after the Phase three result of this study? I think I'm very keen on going fast. We just have evidence now that the drug seems to be active and durable in ERTULO, which is a major finding. And we if you look at the results we've shown that it seems to be we have very, very little result in HR negative, so hormone receptor negative, but we have a little bit of result and it seems that it is the same across the board. So obviously, the HR positive is where we would want to go first, but we just need a little bit more data to actually define exactly what we will do. So when exactly we will have enough data to actually commit to additional Phase III, we will commit to this additional Phase III if we do this additional Phase III. But at this point in time, I think it's already bold to say that we will do an HR HER2LO Phase III trial. So but if we can and we will, we will. But I just think committing to multiple Phase III trial in HER2LO, it's a long answer to say that if the science is there, we will do what it takes. At this point in time, we know that we have to do at least one Phase III in Ertugrul because we have very compelling results, at least in the HR positive. Okay. Thank you. So far, we have observed a low percent of low grade reversible ILDs, which as you would typically, even chemotherapy gives ILD. Mean, ILD is very common. So far, we have no indication that we have to change the dose. And actually, as you've seen the dose, we continue to carry two doses, five point four, six point four milligram. The pivotal Phase II studies in breast cancer continue to test multiple doses because part of what we have to provide is a strong justification of a dose. We have not yet defined which dose it is for that we will seek approval for. And but so far, we've not seen any indication that ILD or the risk of ILD will lead us to reduce the dose. Sure. Thank you. I just want to correct a couple of things. The HER2 low, the ability of a drug to work in HER2 low, it's not only in my opinion. We have not proven that yet. It's not only because of the DAR. It's also probably because the payload is extremely potent, highly diffusible and a very short blood exposure, short half life. It was designed to be highly diffusible, highly potent and very short half life. It was specifically designed for each of the three. And I think the ability to work in HER2 low is because the payload can be released in the cancer and then travel around, but once which is the blood, it has low systemic exposure. So the DER is only one of the component of HER2 low, but it's multiple technology aspect which makes it work in HER2 low. And the DAR of 8,201 is actually 8,000, it's not 7,000 to 8,000. It is really mostly eight It's a very narrow distribution. And that's our because our researchers and our chemists are able to actually manage the conjugation extremely well. So the production is very narrow. The U3-fourteen oh two DAR is eight, so it's exactly the same. So fourteen oh two, we choose to go for DAR four. And actually not only DAR four, but what we call I'm blanking. The ten sixty two, the selective DAR4 on ten sixty two. And the selective DAR4, so you move from the left where you have a distribution to a much more selective DAR. And the reason for this is because when we tested, found the optimal therapeutic window and the safety margin with this particular target, TROP-two. We found that we have a better efficacy to safety ratio with DRR4 compared to DRR8. We will publish more results here. We are not publishing we have many more data than this. We're just not publishing these data. So it's there is evidence as to why we choose the DER4, but it is and the key point here is we have the ability to modulate. So we have a very strong technology but for a given target, if we need to modulate, we can modulate. You say you can Just to confirm, you said you can moderate the AR level itself and selectivity? Correct. UNIDENTIFIED can. And this is very unique. I mean remember at the beginning of my presentation, I said that we have exceptional medicinal chemistry. We also have protein engineering. The ability to produce this and to do this is it really requires a very sophisticated scientist to actually modulate that not only in a test lab but on commercial scale. It's very sophisticated protein engineering. You are correct. I mean the competitive landscape will change. It really matters when you are slow. When you're going very fast, actually, you define the competitive landscape. If you are first in class or best in class, you define the competitive landscape. So I think our intent, my intent is not to develop drug slowly or not to develop drug which are differential, so which are differentiated. So in either case, we it takes time. We know from the today's science, it will take time before it actually changes the landscape. So we believe that we have to lead or we have to be best. Or if we can, we can lead and be best. But if we are not best or lead, then we will just drop. So here, we believe that we have an advantage and we maintain that advantage. I cannot I mean, I can't comment to a certain extent on the competition. From what we've seen published so far, we believe we continue to lead the race. And I personally believe we continue to have the best in class drug. So we not only lead, but also have a best in class technology in HER2. And then let me complement Antoine's comment. The reason we're making the investment in the IT infrastructure is to allow us to proceed with simultaneous global submissions if we need or rapidly following submissions so that our timing for delivering all of this portfolio is not limited by technology or ability to create the dossiers. It will be decided by the science and by the strategy of delivering each of those products in a competitive way. Also, I'd like to emphasize that we are clearly stating today that we are not going to pure oncology. We continue to to invest in our specialty medicine area, but at a lower rate. We have several programs we're moving forward in Japan. The miragabalin program that was successful in Japan will move forward. Our hypertension drug, esaxerenone, moving forward in Japan. And then we have a pipeline beyond that, that is both global and Japan focused. We will just invest less resource in that, but do a tough prioritization to maintain diversification. We think it is quite important that our portfolio over the next decade or so is not only oncology, but today, the most exciting opportunities are in oncology, and that's where the investment will be focused. So you're correct. I mean the Trop-two as a target is a validated target for ADC in clinical because of that IMU-one 132 breakthrough designation triple negative. It clearly is a valid target. So IMU-one hundred thirty two has relatively limited experience in non small cell and less impressive data. It is mid teen percent response rate. So it clearly is a place where this product seems to be less impressive. Our product is targeting Trop-two. It's a different monoclonal obviously and it's a different ADC technology. It is we have a lot of reason to believe that our product is best in class because of the DXD technology and also because how we're applying it. The reason we chose non small cell is exactly for the reason you mentioned is that I want to prove that we are truly best in class with a validated target. If we cannot deliver better than what IMU-one hundred thirty two delivers in lung cancer, then we I don't believe we necessarily have a best in class. So instead of going broad or doing triple negative where the product is already in Phase three, I'd rather prove that we have a best in class product and then we can really change the Trop to Field. That's the reason why we chose non small cell. The percent of expression of Trop-two, we've not I don't have that number at my hand. It is highly expressed in non small cell lung cancer. It's not 100% but close to 100%, so we don't need to select the patient on Trop-two. But it may be that the Trop-two expression as we measure it by may not necessarily be the right thing. In ADC, what matters is not the amount of protein present at the surface. What really matters is that the receptor goes in the surface isn't randomized. So if you have high protein expression and internalization, but you have little staying on the surface, we are researching this. The internalization of the expression internalization rate is actually what we're researching because that's really what matters. So we will see what we have. But that's the reason why we've ten sixty two, I want to prove we have best in class. I believe we can be, but until the data are there, we're just not we're not there. That's the reason why we're doing this in this manner. Sure. Thank you. Mean it's a good question, and it happens that I know Tagrisso very well, very, very well. And so a few things. Number one, Eressa was approved in Japan, I think, in 02/2004. In 2015 or 2016, there were still ten percent of Japanese patients with EGFR mutation not treated with ERSA or Tarsiva and receiving chemotherapy in first line. So you still have so even if you have a drug approved, not all patients are treated with that drug. That's number one. Number two, Tagrisso is not approved yet in first line in Asia. It is it may be used, I don't know about it, I suspect it is, but it's not yet approved. So you still have a good number of patients treated with the approved indication in Asia. And in Asia, it means including China because Tagrisso was approved very fast in China. And you still have patients who have approximately ten to twelve months progression to survival on Tagrisso in second line or third line. So there's still a lot of patients treated with Tagrisso in second or third line. And even after Tagrisso is approved in first line, it may not necessarily be always used in first line because there is generic Tarsiva and generic Eressa. So I'm not worried about having patients failing Tagrisso, having to wait for everybody one years, point one million progression for survival in first line. So I think there will be plenty of patients in second and third line because the drug will be used in this setting. It is the actual biology we are targeting is a very new biology actually which has not been fully researched. And the reason it was not fully researched because there was no drug targeting. So why research something that you cannot influence? Now that we can influence that we are actively researching it. So we will see and we will follow the signs. So we are prepared but I agree with you, it's an innovative way of developing drugs. The next two questions are for, I guess, Doctor. Antoine. I guess, I'm very mystified by the HER2LOW data as you I'm guessing you are and I guess everyone is. So the as you said, it's been designed as a bystander effect. So the implication is that there is as you know cancer is very heterogeneous. There's not it's not just a homogenous structure. So that we've been missing something in these HER2 positive cancers. There is a more dangerous moiety that you're killing off with this poison, perhaps a cancer stem cell. I don't know. Do you have any implication is there any hints that you could give on what you were considering as the reason behind the duration and the fact that it works for Doher too? These are fascinating questions and there are two answers to this. One is the cancer stem cells and second is the reason behind the duration. So reason behind the duration, I believe, is actually as you kill cancer cells, you actually create inflammation, you probably make the tumor hot. And there is some degree of control, especially on the cancer stem cells, which is exerted not only directly by ADC, but actually by the immune system. And this is the reason why we want to combine this with immunotherapy checkpoint inhibitors. We know the concept is correct. I mean, Genentech did it. Merck did it in lung cancer and combining with chemo and also ADCs, nivolumab was combined with ADCs in non Hodgkin lymphoma and also produced. So there's a whole series of evidence which says that when you kill cancer cells with chemo, you actually make them more the tumor more susceptible to IO. That is the reason why we are and it may be that part of the effect we're observing is actually also controlling through an immune reaction that we trigger. Your second question about the cancer stem cells. I mean, one of the the benefit of AD201 in the DXD technology is that it only it's a topoisomerase one payload. So it only kills cancer cells which are replicating. So it requires a cell division. So cancer stem cells are obviously not dividing unless they commit to be progenitor. So we are not targeting the cancer stem cells. So the next generation our next generation of ADC will address that. And that's why we're researching the mechanism of resistance of 8,201 to understand how frequently this is. So if we can define which patient will require a different mechanism of killing with the same ADC the same concept of ADC, but the next generation ADC and a different wave of killing cells, which are not cell cycle dependent. So the last question, I guess, is the when you look at the entire oncology landscape and when you look at the engineered antibodies, the one camp, obviously, would be Daiichi Sankyo and others believe ADC. The other camp is using bispecific antibodies specifically with CD3. And I guess at least one company suggests that that may be sort of a poor man's CAR T could be a substitute or possibly a simplified version of it. And obviously you've been it seems to me like you are putting all your eggs in one basket. I know you have a collaboration with ZymWorks, but how do you think about the bispecific and also the potential of CAR T encroaching on the solid tumor space? That's my final question. So number one, I think there's room for a lot of innovation. When I was at AstraZeneca, we embarked into trying to improve EGFR M, TKIs. Pfizer has tried, Boehringer and I have tried multiple companies have tried to improve TKIs. Nobody really succeeded. The dacumetinib and afatinib were kind of okay drug, but really not disruptive. And trying to go for best in class is sometimes felt like, can you really improve? With Tagrisso, we proved you can really improve even when you think that there's no improvement. It's a way to say that I believe there's room for improvement in ADC as there is an improvement through CAR T and bispecific. I don't think it is eitheror. I think both can improve because we are far from having cured every single cancer. So that's so I'm not worried if advances are made in engineered antibodies, great, because we still we will not cure all cancers with ADC. I still believe we can improve and deliver great value for patients for ADCs. That's the first question the first answer to your question. The second is that you're right, I mean, have had collaboration with Zimura. We also have the CAR T therapy. I do believe the CAR T and the bispecific will encroach in solid tumors. I firmly believe this. If not the current generation, the next generation, which we are working on. That's the reason why we have cell therapy part of our research portfolio. We're using advanced technology to actually improve on the CAR TIG technology as well as on the cell therapy. So I do believe ultimately we will and that's part of our longer term strategy. It's not going to be a product for 2020. It's going to be later than that. That's where we are working. This is why we are working on design works and also doing some research collaboration because we're not saying we are an ADC company. We are a company where we will treat cancer with next the immediate future, but also the long term future. And so we're not putting all our eggs in one basket. We have one basket that is overflowing right now where we are seeing fantastic results, and we are pursuing that as hard as we can in the antibody drug conjugate. But we have the bispecific antibody work going on. We have the early CAR T collaboration with KITE and IDEAS to expand it. So We're going to take advantage of each wave of the science as it comes. But right now, the focus has to be on the ADCs because of the great data that you saw today. At least that's what we think.