R&D Day 2020

Dec 15, 2020

Slides

Hello, I'm Sonoma Nabe, CEO of Daishankyo. Thank you very much for joining Daishankyo's R and D Day twenty twenty during your busy end of the year season. This is the second time for me to host our R and D Day as CEO. I make multiple important presentations in the course of the year, but I always enjoy to present here. I will present our progress over the last year and then Antoine, our Global Head of Oncology R and D, will take you through where we are relative to oncology R and D as well as future plans. I am satisfied with the development of our three ADCs since R and D Day twenty nineteen. First, Enhertu. We have successfully launched EiHAT2 in The U. S. And in Japan with breast cancer indication. The product has been submitted for approval in Europe and we think the review is on track. The second indication, gastric cancer, has launched in Japan and in The U. S, FDA accepted our supplemental BLA even though the data are all from Asian population. Lung and colorectal studies as well as early line therapy for breast cancer are all progressing well. Our partnership with AstraZeneca has entered its second year and the relationship between the two companies is excellent. I am absolutely confident that AstraZeneca is our best partner. Next is our second ADC, DS1062. A competitor was launched, but we continue to be confident that our DXD ADC is the best in class. I'm also confident that we selected the best partner for DS-ten sixty two as well. Anton will present some of our recent discussion with AstraZeneca. With regard to the third ADC U3-four thousand two, the lung data presented at ESMO gained our confidence for the product and we will start our Phase II study which could be registrational depending on the results. Breast data presented at the San Antonio Breast Cancer Symposium, which will be discussed later, are important as they help us understand the biology of HER3. In addition, a Phase II study of colorectal has started. This steady progress of the three ADCs gain our confidence for achieving Dai Sankyo's 2025 vision. There have been good progress for the ALPHA Project two. Clinical trials for the full on DXD ADCs, DS7300 and DS6157 are on track. We are starting to see some early efficacy and safety clinical information, which will be provided by Antwan later. Our top line results for DS-five thousand one hundred forty one, the Exon forty five skipping drug using our proprietary nucleic acid technology should be obtained at the end of this month. Depending on the results, we believe that ENA can be our next platform technology after DXD ADC. DS1055 was included in our second quarter financial results presentation in October. We are hoping that ES1055 will become a novel immuno oncology drug in the future. This is not on the slide that on December 3, our CAR T therapy Axisel passed the subcommittee of Japan's Ministry of Health, Labor and Welfare. We are now preparing for the launch of our first cell therapy product. In maximizing shareholder value, shareholder return is always a high priority. During the current fiscal year, we have increased dividends and are currently carrying out share buyback. In addition, we have decided on cancellation of treasury shares in next April. Another high priority is optimal investment for future growth. With the current pipeline, we will be aggressive around R and D and capital investment. We will aggressively strive to maximize future profitability as well as shareholder value and sustainable growth. Presenting enhanced capital investment verbally is not easy, so I will show three photos instead for you to confirm the good progress. Commercial manufacturing for the follow on ADCs also need to be considered now and we are increasing manufacturing capacity through capital investment and utilizing CMOs. While our current priority is to invest in the pipeline for future growth, there is another important area when the world is suffering from pandemic. We want to contribute through COVID-nineteen countermeasures, vaccines and therapeutic agents. Today I will briefly introduce DS-five thousand six hundred seventy, our messenger RNA COVID-nineteen vaccine. With DaiSankyo's original Cationic Lipid, our objective is efficient encapsulation of messenger RNA into nanoparticles and efficient delivery to cells. We think the lipid is applicable to pandemic and other vaccines. Encouraging data is being obtained from non clinical pharmacology studies and clinical studies currently planned to start in March 2021. We are currently putting together a new five year business plan that starts from fiscal year twenty twenty one. Core part of the plan will be our strategy to enhance the pipeline and the product portfolio, firstly the three ADCs for sustainable growth. We are planning to present the plan in March or April of next year, so please look forward to that presentation. This is all from me for today and we'll pass the baton to Antoine. Antoine, you are up. Thank you, Malabesen. Good evening from Bastion Ridge, New Jersey, our North American headquarters. My name is Antoine Iver and I'm the Global Head of Oncology R and D for Daiichi Sankyo. I'm really energized today to be in front of you on behalf of Daiichi Sankyo for the fifth R and D Day I have the honor to provide at Daiichi Sankyo. Four years after launching Cancer Enterprise as an internal platform for leadership in oncology, we're proud to now stand up on the global scene on our own feet as a global oncology leader now recognized for the quality of our own science and for delivering the science the patients deserve. Next slide. Today we'll review briefly our scientific and competitive environment before spending most of the time in reviewing data and plans for our clinical stage DXD ADCs before moving on towards our transformation towards a biologics and multi modality company. Next slide. First, our environment. Next slide. How did we collectively get here to our current world in oncology? So 2000 was a decade where excellent drugs like Glyvec, Eressa and Avastin unleashed the power of targeting and suppressing cancer pathways. The 2010s saw the wonders of immune checkpoints inhibition and the power of redirected T cell therapy. Despite its excessive exuberance considering the amount of money invested, so 2010 remains a glorious decade for IO. As we predicted few years back from this podium, so 2020s are now recognized as a new era where high-tech pharmacology propels a century old idea where today's magnificent technology of ADC would change the treatment paradigm away from typical chemotherapy where you poison both a person and a tumor, wait for the recovery of the person, heat again until you can't do anymore. On the contrary, ADCs as a true chemotherapy free approach offers continuous hits on the tumor 20 fourseven enabling durability of direct lethal hit on the tumor itself. Next slide. So what is important regarding the ADCs from Daiji Sankyo? Uniqueness of our DXD ADC technology platform is a duration of effect. This is not a surprise as the technology was specifically designed for that purpose. It is an integrated multi modality, high-tech molecular construct with a unique mode of action, a high potency payload, 10 times more potent than SN38, and hyper stable linker, an exquisite delivery to the tumor and a unique bystander anti tumor effect by design associated with a world class protein engineering and manufacturing processes. At Daiichi Sankyo, we are now discovering major new avenues of science in acquiring mastery in a new critical pathophysiology regarding the receptor dynamic and its pharmacomodulation. Overall, duration of response is a direct and the most critical benefit of a Daiichi Sankyo proprietary VXD ADC design and this is what can establish true chemotherapy free regimens as new paradigm and mainstay of cancer treatment. Next slide. Nevertheless, the competition in ADC is now real, but we are already tackling what is next. We respect our competitors, in particular Trodelvy, which is a great drug with a bright future. We also see the likes of Merck, Pfizer, etcetera. But the ADC concept alone is old news. Daiichi Sankyo is already blazing new trials aiming at chemotherapy free regimen and further exploiting the unique biology of ADCs. Next slide. We're making major headways in the pharmacological manipulation of the ADC receptor biology in selecting the right patients and tumors, in predicting outcomes and designing and enriching for the right patients. Next slide. The immediate value of our top three ADC is very clear: breast and lung cancer and this is our utmost focus. Like Samurai's have an exquisite focus on humbling delivering on their obligation. For breast and DS8201, in HER2 metastatic and early breast cancer, we have a suite of Phase three trial with the most respected global academic trial partners. In HER2LOW, the DESTINY Breast four study is fully enrolled and is tracking to read out in fiscal year twenty twenty one. For lung, with DS1062 we are implementing a swift development post IO chemo with a definitive Phase three just announced as well as IO combination aiming at first line lung cancer, more on that later. For lung also, U3-fourteen oh two, our U3 ADC pursues a fast to market development in EGFR M non small cell lung cancer as well as a combination with Osimertinib based on fascinating science of pharmacomobilization. As we shape the possibilities of our ADCs, we are resolutely focused on our duty, our obligation: deliver the science patients deserve. Next slide. Let's move to our clinical stage DXD ADCs. Next slide. And first, the SATA-eight thousand two hundred and one also known as trastuzumab deruxtecan or TDXD in short. Next slide. In brief, but representing major advances in value for patients, we will cover five different aspects. For gastric cancer, the Japan approval in September and the US FDA acceptance of a priority review submission with a PDUFA date of 02/28/2021. For breast cancer, we will spend time on the big story and a big story is not even the positive opinion received this past Friday from the EU CHMP, which makes ENERTU the first new molecular entity in more than two decades to be approved or recommended for approval in breast cancer on the basis of Phase two single arm not controlled data. This is one of the fastest reviews by CHMP, faster than Tagrisso in particular, which speaks to the unique profile of this drug and the strength of the Daiichi Sankyo and AstraZeneca collaboration. No, the big story is the publication at San Antonio Breast Cancer Symposium in the past few days of the unprecedented duration of response for an HER2 monotherapy in six or seven lines of treatment, the duration which mimics the duration of response reported in first line HER2 metastatic breast cancer with a triplet of THP or Taxotere, Herceptin and Perjeta. We will also cover lung cancer, the IO combo, important new unpublished data on file for ILD. Next slide. First, gastric cancer. Here is a brief reminder of the design of DESTINY gastric one which randomized subject to either TDXD six point four mgkg or the choice of Irinotecan or Paclitaxel. Next slide, here are the efficacy results delivering the first evidence for ENER2 of a clinically relevant and statistically significant survival benefit with a four month improvement in median, the hazard ratio of zero point five nine and a compelling difference in response rates with many cases of all target lesion achieving one hundred percent reduction. Next slide, here is the summary of the safety finding including ILD with an overall incidence of ILD at nine point six percent and no grade five death event. Next slide. Looking ahead in HER2 advanced gastric cancer, we are announcing DESTINY Gastric four, a large randomized Phase three study in second line testing DS8201 monotherapy versus active control. The study start is imminent as are the details to be published on clinicaltrials.gov. Next slide. Now on to breast. As said before, the European Union CHMP has just adopted a positive opinion recommending approval for ENERTU on a basis of an initial submission made as recently as this last May 2020 making this an extremely fast review. The indication as shown on this slide as well as the approved SMPC does perfect justice to the data presented as well as the patient's need. We're looking forward to soon receiving the European Commission approval. Now, next slide, on to the duration of response. This is a schematic of the study DESTINY BREST one, the basis for first approval in all three regions, U. S, Japan and now EU. It is a somewhat complex design. Highlighted in green is the main cohort of 184 subjects for evaluating efficacy at the dose of five point four mgkg. Next slide. Here is a critical slide not only for Enhertu and patients worldwide with Enhertu breast cancer, but also for the Daiichi Sankyo DXD technology as these findings show the very special and unique nature of our technology delivering unique durability of response, durability of effect. Let me explain. On the left hand side is the monotherapy duration of tumor response. You see that duration of response is at twenty point eight months and the slope of a curve which indicates the stable residual risk over time so far. On the bottom right you see a table which gives updated response result. At twenty point five months of median follow-up, the confirmed overall response rate by independent central review is now at sixty one point four percent, a slight increase compared to The U. S. And Japan labels with also an increase in the number of complete responses. And in green is a key reference point. This is a golden THP regimen, the true global center of care in first line HER2 metastatic breast cancer. This is from the CLEOPATRA study with the triplet of THP, but the duration of response observed there was twenty point two months. At twenty point eight months in six or seven lines and by monotherapy, our results are unprecedented in breast cancer and a testimony to the unique nature of NR2. Next slide. Here is an important slide as well, Now for ILD by independent adjudication committee. With updated follow-up, the ILD risk clearly appears to flatten after approximately twelve months of exposure. Next slide. So why does durability of response matter? It justifies an accelerated ambitious HER2 positive metastatic and early breast cancer plan. Let me discuss two critical design features of this plan. First, what to do with respect to first line treatment? The clear unmet need in first line treatment is to increase overall progression free survival and further prolong the duration of response to treatment. Consequently for NR2, we have an aggressive and bold plan aiming at first line metastatic breast cancer. More detail soon. The prevention of brand metastasis is not the critical need at that stage. Brand mates failure after current first line THP treatment is infrequent. It is terrible but affects only thirteen point seven percent of patients. Second, the potential of NR2 to be superior to TDM-one leads to two questions. First, after TDM-one in second line, Bren MET failure is uncommon. Only two percent in patients who did not have Brand METs at treatment start and only if I may say so twenty two percent if Brand METs were present at start of treatment. The clear medical need in second line treatment is to improve the frequency of overall response and more importantly durability of overall response and of tumor control overall. Obviously the direct treatment of BrenMed is warranted when BrenMed represents the cause of failure. Our DESTINY Breast03 study in second line metastatic breast cancer head to head versus CDM-one will answer the question. It is scheduled to read out in second quarter fiscal twenty twenty one with an exact timing yet to be determined. I will describe more on this later. Second, in early breast cancer, we are proud to have launched with the NSABP and other highly reputable academic groups, a large post neoadjuvant trial in high risk early HER2 positive breast cancer. Next slide. Here are the two pillars for our approach to establish the role of DS8201 in first line metastatic breast cancer. First, DESTINY BREST-nine which is a randomized active control phase three study of DS8201 monotherapy versus DS8201 in combination versus standard of care of THP. We have completed our deep and detailed interaction with the FDA and other agencies and are ready to roll. Second, DESTINY Breast seven as well as the Begonia study at AstraZeneca are combination studies which will inform at least another Phase three in the first line setting versus THB. Next slide, here are some more details about DESTINY BREST-five, our post neoadjuvant study versus TDM-one. This is run with the US NSABP as well as the German GBG group and the IGO B group, SALTY and many others including in Asia. This study is conducted in subjects with residual invasive disease in breast or X-ray lymph nodes following neoadjuvant therapy for high risk HER2 early breast cancer. A total of sixteen hundred patients approximately and IDFS as a primary endpoint. Next slide. What about HER2 low? In other words, HER2 negative breast cancer either HR plus or triple negative breast cancer. In late line post chemotherapy, our entry point is DESTINY breast four. The rationale for that study is in J101 study where we observed a confirmed overall response rate of thirty seven percent, a median duration of response of ten point four months in the HER2 low metastatic breast cancer cohort. Destiny BREST-four has fully enrolled approximately five forty subjects and tests the AS8201 versus the physician choice of eribulin, gemcitabine, paclitaxel or nab pac with PFS by blinded independent central review as the primary endpoint. An event driven analysis is projected in the 2021. In first line chemotherapy, we are running DESTINY Breast six, eight fifty subjects, DS8201 versus physician choice of capcitabine, paclitaxel or nab pac with PFS by Baker as primary endpoint. Finally, in earlier metastatic breast cancer line, bold innovative plant will be announced. Of note, in HR positive and early breast cancer, the adjuvant segment is not our area of focus and between Jose Biserga, my counterpart and my long time friend at AZ and myself, we know very well drug development and breast cancer. We will make no more comments. Next slide, moving on to lung cancer, a quick review of critical data presented at ASCO last June in HER2 mutant non small cell lung cancer. An impressive response rate, duration of response, PFM that formed the basis for U. S. FDA breakthrough designation. We expect the final analysis of the HER2 mutation expanded cohort to place in the 2021 with analysis criteria meeting the FDA's expectation. Next slide. So what do we do to design and maximize the benefit of durability? In HER2 mutant on the left hand side beyond the DESTINY Lung-one expansion which I've just described, we are conducting DESTINY Lung-two comparing two doses of AT201 after detailed FDA consultations. And we'll start destinin lung XX, a possible first line Phase three study in the planning stage for now and aiming at 2021. In HER2 expressing, the current generation of IHC monoclonal antibody cross reacts in lung cancer with non HER2 protein, some non HER2 epitopes, some of which have now been identified. The next generation IHC is under development for lung cancer. Meanwhile, we wait for the fully enrolled DESTINY Lung-one IHC expressing cohort to mature. Next slide, now colorectal. A quick review of critical data presented at ASCO in June in HER2 expressing meaning IHC three plus colorectal cancer. A forty five point three percent overall response rate with a median duration of response not reached at the time of this analysis. We are conducting a non registrational study DESTINY CRC-two testing five point four and six point four milligram per kilogram and also sorting out the role of RAS mutation if any. Next slide. We have covered a lot of ground so far and the next three slides are graphical integrated schematic representation of the clinical development plan here for breast cancer. Note that some of these are purely directional. Next slide. And here for gastric and lung cancer and next slide for CRC as well as other cases I've not described in much detail. Next slide. Here you see the DS8201 critical short term Phase III study data forecast. First, DESTINY Breast two in HER2 positive metastatic breast cancer third line versus standard of care. The event driven final analysis is projected for the 2021. We still at this time a pretty wide 95% confidence interval on the date projection of approximately five months. Second, the critical DESTINY Breast03 in HER2 positive second line metastatic breast cancer, the head to head comparison versus TDM-one with an event driven planned interim analysis projected for second quarter fiscal twenty twenty one and the same uncertainty of approximately five months on the actual data cut off date. And finally, the DESTINY Breast four in HER2 low metastatic breast cancer versus standard of care with an event driven final analysis projected for second quarter fiscal twenty twenty one and a smaller uncertainty of approximately four months. Next slide, now moving on to the nivolumab combination just presented at San Antonio breast cancer few days ago. Here is the study design. Next slide. And here the efficacy highlight, not that we could expect to predict the success and efficacy of the IO combo. There are just no good surrogate markers for the benefit of adding IO to a standard of care in a non IO sensitive tumor. Next slide. And here are the spider plots. The key question of this study was to establish that both drugs can be safely and durably administered at therapeutic doses. Next slide. Here is the safety. On the left, the ILD in percent, first the total of any grade and then from left to right by increasing grades. We clearly do not see any comparing risk increase. We are obviously planning to move with IO combination with ES8201 and also borrow these data for the other DXD programs to perform accelerated safety assessment. This represents a nice transition to another important subject presenting now data not published before. Next slide. Here you see the preliminary cumulative ILD data from all phase three monotherapy study now ongoing. It uses the same format percent, first total and then increasing grade from left to right. Since these studies are controlled, we assume that all ILD cases regardless of randomization arm and adjudicated by the adjudication committee are in fact related to the DS8201 treatment. We then estimated the number of subjects treated with DS8201 in this study at approximately nine seventy nine. The graph shows a very reassuring picture. Our ILD Safe Use campaign seems to be effective. It combines clear selection out of patients with risk factor, awareness and rapid investigation of any possible case as well as good treatment of any case. Next slide, here you see the post market cumulative pharmacovigions reported data left in The U. S, right in Japan. More than one thousand patient years exposure in The U. S, two fatal cases and an added 160 patient years in Japan and no death reported. Next slide. So where do we stand? We focus on a massive opportunity for DSCT-two zero one to address many unmet medical needs and increase our competitive edge by acceleration, large scale and global program, bold plan aiming at first time HER2 metastatic breast cancer as early HER2 breast cancer and a critical role for HER2 low breast cancer. We also pursue a broad tumor expansion and we will build on the I O DXD combo. Next slide, moving on to DS1062, our Trop-two DXD ADC, Detopotamab Teruxtecan or dedo DXD in short. Next slide, here are key characteristics for DS1062. It is engineered to be best in class Trop-two ADC. It carries all the characteristic of our DXD ADC technology so critical to deliver its most important feature, durability response and overall tumor control. All seven technology features listed on the right hand side equally contribute to the profile. Next slide, here is the first in human study design in subjects with advanced or metastatic non small cell lung cancer relapsed from or refractory to standard of care and for the very vast majority IO and platinum based chemotherapy. The dose escalation has completed as adds the enrollment of a dose expansion for a total of 180 subjects across three doses in dose expansion. So triple negative breast cancer cohort recently added is also nearly complete. Next slide. A quick glimpse at data. Here spider plots across the three doses with still immature data at the September 2020 cutoff and the pattern clearly matching that observed with the DXD platform, I. E. Excellent durability. Next slide. On the ILD side, here are the graphs, top left for the total incidence regardless of the doses and tumor type and the next three for the doses of four bottom left and six and eight mgkg on the right. What do we do with this? We are running. Tropion Lung one is a pivotal Phase three study in post IO and chemotherapy non small cell lung cancer. Patients with non small cell lung cancer without actionable mutation and one to two prior lines of platinum based and immune checkpoint inhibitor treatment are eligible regardless of Trop-two expression by current test. All subjects will provide a fresh biopsy to support our prospective plan to retrospectively test. A total of five ninety subjects will be randomized one to one to DS62 at a dose we have selected of six mgkg or docetaxel seventy five mgm2 with a primary endpoint of PFS by Baker and overall survival. We are really excited by the level of evidence we have observed to support this critical study. We also have a massive in house as well as an externally partnered research effort on the biology of TRK2 as a receptor for ADC therapy and we are very confident to bring substantial discovery to this field. These very new understandings will inform this study as well as our development plan and the DXD franchise at large. This is where Daiichi Sankyo also leads and blazes a new trail made possible by the advent of this highly innovative high-tech pharmacology. Next slide, what else are we doing with our partner AstraZeneca? We are bold, we are looking at non small cell lung cancer first line, non small cell lung cancer activating mutation, breast cancer and beyond. In non small cell lung cancer, first line is a clear and immediate objective. To that effect, enabling immuno oncology Phase I combination plan is underway. Tropion Lung two with pembrolizumab in collaboration with Merck and Tropion Lung four with AstraZeneca borvalumab. Finally, for lung, Tropion Lung five is for DS1062 monotherapy in non small cell lung cancer with activating mutation. For breast cancer and beyond, the triple negative breast cancer phase one cohort has nearly completed enrollment as I said before and is maturing. For breast cancer at large, we are planning a very substantial plan and other tumor cohorts are also planned. We appreciate you may be looking for more details. We are short here on purpose but DaiSiSanQ and AstraZeneca have a clear game plan. We have a bold, large clinical development plan which we will characterize in due time. Our strategy is to win with utmost focus in lung and breast cancer. This is a very reason why we choose to collaborate with AstraZeneca. Next slide. Moving on to U3-fourteen oh two, opitutamab diruxtecan or in short, U3DXD. Next slide. Here are the highlights of our non small cell lung cancer EGFR M Phase I study presented at ESMO this year. Subjects are resistant to or refractory to EGFR TKIs as well as platinum based chemotherapy. If they had a T790M mutation, they also must have failed the simertinib before being considered for this study. Both the waterfall plot and the spider plot appear familiar for our DXD technology. Next slide. Here is a highlight of safety, very consistent with previously seen profile. Combined together, these results form the basis of our recent extensive consultations with FDA and the design of our pivotal study. Next slide, here is a design Afuna Lung-one, a pivotal Phase II study in advanced EGFR mutated non small cell lung cancer to start in January 2021. EGFR M lung cancer is a tumor type where we have now observed stable FRE expression and U3-fourteen oh two offers a unique simple opportunity post eKIN chemo. This is also important as we have now observed compelling opportunity for pharmacomodulation of the receptor and receptor ADC interaction in combination with osimertinib. Next slide, here is a new study also to start in January 2029, testing in Phase one the combination of fourteen oh two with osimertinib. While this is a combination trial with an AstraZeneca drug done in partnership, please remember we do not have a co development collaboration with AstraZeneca for 1402. Next slide, now moving to breast cancer. Here's a snapshot of updated data breast phase one cohort just presented at San Antonio Breast Cancer Symposium across ERF free high, ERF free low and two doses of four point eight and six point four mgkg. These look fine on the surface. The spider plots seem to raise question on durability with some heterogeneity on how tumor growth control is observed over time. Next slide. Here is a safety summary, again very consistent with prior reports and the lower frequency and severity of ILD. So real questions are suggested on the next few slides. Next slide. First, even before treatment with U3-fourteen oh two in breast cancer we observed on the left panel a reduction of IHC level of HER3 expression. More importantly on the right panel we see a very substantial and frequent decrease of HER3 membrane positivity level between pre treatment level and at cycle two day three or cycle three day three, meaning approximately day twenty four or forty five post first dose. We are actually beginning to decipher quite well the ERF3 receptor biology implicated here and will present more data at the forthcoming scientific conferences. There is seemingly a strong element of tumor type and specificity which is not surprising. Next slide. Here we see that UFRI expression in breast cancer by membrane IHC positivity on the top two graphs or by mRNA expression, the bottom two graphs, this expression does not correlate with best tumor response as assessed by blinding independent control review. Much work to do if we want to find the right selection test in breast cancer. This is now a key part with TropTube of our massive precision medicine and translational science effort at many globally leading places such as the Memorial Sloan Kettering Cancer Center, the Dana Farber Cancer Institute, Gustav Roussi Cancer Campus, Sarah Cannot as well as the National Cancer Center in Japan and of course our great internal labs. Finally, ILD4U3-fourteen oh two clearly not an issue at this development stage. Next slide. Moving on to our next to come DXD ADC. Next slide. This table summarizes key features and status for our next in line ADC. The S7300 is our B7 H3 and is now in its fifteen months since starting the first in human study. We have completed enrollment in dose level seven at twelve mgkg and assessment up to dose level six with so far not a single DLT observed. Even in an unselected patient population, we have observed multiple separate persist confirmed responses. DS-six thousand one fifty seven is progressing nicely. DX6000 is a new not yet disclosed until now ADC targeting KADRIN-six with a drug antibody ratio of eight of the DXD technology. It aims at ovarian and renal cell carcinoma. We're planning to hopefully initiate the first in human study in the next quarter. Finally, DX3939 is our TMUC1 ADC, still a good year plus away from going in the clinic. Next slide. Here are some of our key non ADC so called alpha asset and best status. We recently announced initiation of the first in human study of DS-ten fifty five, our anti GARP positive or anti activity T cell reg asset. DS-three thousand two hundred and one is our dual EZH12 inhibitor. It is in pivotal phase in Japan under second decade designation for ATL and in global pivotal phase in Phase II in relapse and refractory PTCL. We are actively exploring the clinical relevance of a dual inhibition in over hematological malignancy. Axi cel or KITE C19 which will license Forgepan from KITE pre Gilead KITE acquisition is expecting approval in Japan this very month. Pexidatinib is progressing nicely in Japan and Southeast Asia and for quisatinib, despite our setbacks in U. S. And Europe for the relapsedrefractory indication, we continue to believe that the placebo controlled ContramFirst Phase III study in first line AML is a critical and important study and will be the first of its kind to report final analysis in 2021. Next slide. Overall, I hope we've been able to give you a tangible measure and feel of the continued transformation of Daiichi Sankyo towards being a biologics and multimodality global company. Next slide. As briefly alluded to by Madhavinsan earlier, we are serious and delivering extremely well on our ADC clinical and commercial supply strategy. We are delivering on the needs and on our promises. We are meeting commercial and development obligation with a massive scale up and acceleration. We are also powering through some residual pinch point so that the S1062 supply will not slow down the Daiichi Sankyo AstraZeneca acceleration. Next slide. As previously explained, we truly believe in our uniqueness in being serial innovator. We investigate deeply the biology and pharmacology of ADC at the receptor and cellular biology level as previously said. Our next ADC construct continues to track for fiscal twenty twenty two. Next slide. Here is our top line news flow for the next six months and also key catalysts. This completes the primary presentation and we will now take question. Yamaguchi from Citigroup. And I'd like to ask a question one by one in Japanese. My first question is about ES8201. And Antoine san mentioned that you have a more aggressive plan for early metastatic breast cancer you're considering. So is are you referring to something different from the current idea in this respect? If you have any particular idea, please share. Anna Bisson speaking. For this question, Antoine, please answer this question. Hello. Good evening. This is Antoine Yves. So thank you. We have more plans than what is presented. We are presenting one study now And this study will be followed by other study, at least one or two study informed by the Begonia study in particular. So we are planning to have more than one study to define a new standard of care for first line metastatic breast cancer HER2 positive. I hope I'm answering the question. We will disclose later the detail. I have another question. And thank you for the earlier question and answer. And I have another question. Regarding DS-twenty eight thousand two hundred one in lung cancer, it has been granted a breakthrough designation, and you are now accumulating final data of the patient. And once you collect the data in The United States, it sounded that it's possible to file immediately after the collection of the data in The United States. Is my understanding being correct? That's my second question. Mano Deshan speaking. Antoine, please answer this question. Yes. Thank you for the question and clarification. Yes, the plan is to submit as soon as we have accumulated the necessary data from BESTINI Lung-one expansion primarily. This will be a submission in The U. S. The European plan are still under discussion. So The U. S. Will be primarily based on the DESTINY LUND one and will be later supported by the DESTINY LUND two. Thank you very much. This is my last question regarding DSO 73,000. This could be the fourth ADC UNIDENTIFIED Whenever I would like to respond, this is often asked question also about the third ADC, fourteen oh two. But regarding this DS-seventy three thousand eight hundred, for the time being, we'd like to do the development in house for this compound. And for the fourth product, we still do not have the data yet. So we do not have any specific or concrete plan for the alliance for the time being. Thank you very much. Muraoka from Morgan Stanley is speaking. And I would just like to ask a question one by one. First of all, I'd like to ask you about DSN-sixty 2 in triple negative breast cancer. And I heard that enrollment is almost complete. And can we expect the ORR data at ASCO meeting next year? And also, if the ORR is going to exceed thirty three percent in triple negative breast cancer, meaning it's going to exceed Trodelvy. Can I understand that you can file immediately based on this level of data if you have such data? Manabe san speaking. I'd like to ask Antoine to respond to this question. Thank you. So the enrollment is almost complete. We will not publish at ASCO, but at San Antonio most likely. ASCO will be too early because the data cut off is in a month and a half from now. So there's not enough time. We are not speculating about the results and not speculating about just potential submission in triple negative breast cancer. Our fast to market is currently our efforts on lung cancers. Thank you. My next question is about U3-fourteen oh two in lung cancer. You have a Lung one study with U3-fourteen oh two, and this study is going to start from now on. And regarding the result, are they going to become available in 2022 or rather 2023? Or is it possible to see ORR data in 2022 as well? What I want to say is that regarding October, lung cancer results will become available mainly in 2022. And almost at the same timing, can we also expect the results from the U3-fourteen 2002 lung cancer study, one study as well? Managuchan speaking. Antoine, please answer this question. Thank you. So the end of the Lung Study one for Erfrey will depend if we complete enrollment at two ten subjects in each of arm number one and arm number two. That will depend on external data on whether or not we carry both dosing regimen forward or drop one. So the end of enrollment and results are most likely to be in 2022 at the same time as lung for October. Remember that October is in non EGFR mutant and fourteen oh two is in EGFR mutant, both in late line. Thank you very much. This is my last question. It's not about oncology, but your vaccine product, DS-five thousand six hundred and seventy for COVID-nineteen. And we are going to initiate a Phase I study in March. And Shionogi, part of the top running group, to that, just three months behind. So you have to consider your supply at this moment. And Kyunoji is saying that they can provide doses, thirty million doses in the middle of next year. So what about the level of Daiji samplers capacity? Manabe would like to respond to this question. Manabe, I would like to respond. In March year, we are aiming to start the clinical activities, and we are ready and preparing for the PPM or investigational product. But with regards to commercial production and also the implementation of the studies, we still do not know what it's going to be like Phase one, two and three studies. And we are increasing our capacity, but I'd like to refrain from giving you an accurate answer to your question at the moment. One additional question. Are you having an idea or considering possibility of the scale of dozens of millions of doses for your vaccine? That's the additional question. And Manada san's response, we are hoping that we can achieve that level, but number wise, it could be difficult. That's all from me. Thank you very much. Shiguchi from Daiwa Securities. I also would like to ask a few questions. First, I'd like to ask you about the data on the combination of NHERT and Opdivo. And the efficacy in the combination may not be so different compared to the monotherapy, but it's important to see consider the potential of the combination of ENHEAD and other DXP and IO therapies. And you have to consider what kind of data you can obtain. And what's your view on the synergy effect of these combinations? That's my question. Manal Deshun speaking. Antoine, please answer this question. Thank you. The Phase I data in the IO combination had one purpose, which was to prove that both drugs could be given at therapeutic doses. And we were very pleased in patients with five prior lines of treatment to be able to give the normal doses and at the time on of data analysis fifty six percent of patients were on treatment and at that time the median duration of treatment exceeded six months. So we have regimen which can be given a full dose and give good results and continues on treatment. There is no measure of the potential for synergy, especially when IO is as in breast cancer not an active therapy. The only proof of synergy will be by doing the randomized Phase three combination study versus standard of care to prove the added benefit of IO and this is our plan. Thank you very much. Thank you very much. My second question is about the safety of DS-ten sixty two. This time today, there was a presentation of the data on ILD only. But what about the adverse event toxicity for the GI and membrane toxicities? And in the six milligram per kilo, what kind of data do you have? Compared to the data presented at ASCO, what is your latest data on the toxicity other than IOD for six milligram per kilo dose? And how this is going to change the sales potential, if any? For the AEs and toxicities other than ILD, Manabe san would like to ask Antoine to respond. Thank you. So we have not updated the data for the other toxicity. We will present the data in months from now at World Lung Cancer Conference in January. The only data I presented are a snapshot of the duration of response by not duration, the spider plot and a snapshot of ILD. We have not observed any concern new in the non ILD general safety profile. So we have not observed anything of relevance for the conduct of the clinical development of ten sixty two. But we will update in details at World Lung Cancer. Manabe speaking. Because of those situations, there is no change to the sales potential for the time being. Thank you very much. This is my last question. This is about the DSO6000 and you're targeting Kadoshiren six. And I'd like to know the characteristics and the features of this target or the drug. A few years ago, there was a Phase one study for an ADC by another company, but I don't think their development is making progress since. I would like to ask you why you are targeting KADOHEREON six? And why do you think this ADC target can be promising? And why do you think the other company was not so successful in their development? And why do you think you can be successful by using DXP? And Manabe san would like Antoine to respond to this question. Thank you. So we are confident in the target. And we have the necessary preclinical. We have a drug antibody ratio of eight for this particular target, which indicates that in our preclinical and toxicology studies, we believe that eight is a correct drug activity ratio just like AT201 or we also have belief in this target which is highly expressed in renal cell carcinoma as well as in lung cancer and differentially expressed compared to normal. I cannot speculate why the prior company failed. There are many reasons why an ADC failed and many of these reasons are not linked to the target. Most of the time it is a construct itself which is insufficient which doesn't have the full necessary technology to succeed. So I cannot speculate but we are very confident and we will give more details as we actually progress the asset in the clinic in the next three or four months. Thank you very much. Sakai from Credit Suisse speaking. I have three questions. First of all, I'd like to ask you a question about ILD risk management for DS-eight thousand two hundred one. And there are cases you talked about the IRB cases for talk to ADC as well in the presentation. But most of the time, these cases can be controlled and managed with steroids in principle, I think. And Antoine san also says that it's possible to manage the risks based on the experiences you have accumulated. And can I understand that most of the cases can be controlled substantially with steroid treatment? That's my first question. Madhavi speaking. I would like to ask Antoine to respond to this question. Thank you. Very important question and a lot of efforts to educate, to monitor, to assess and to treat any potential risk of ILD in clinical development but also in the market. And we also exclude patients with prior history of lung disease which may make them at risk. So yes, IRD can be managed. It cannot be eliminated. I think the slide number 43 in the presentations where we present all Phase three monotherapy studies as of less than a month ago is very reassuring. These are preliminary data. The denominator is an assumption and we assume all cases were from the treatment. But this is very reassuring as we have very, very few cases overall, much fewer than what we had observed initially and very few grade three, four and five cases out of nearly one thousand patients. These studies are ongoing, but most of these studies will report in the next year. So most of the treatments are very advanced and we've seen for AT-two zero one that the risk after twelve months plateaus. So really this picture is reassuring to us. Could you also talk about the effectiveness or the efficacy of steroid treatment for ILD as well? Yes. One of the last observation we made was that investigators and doctor recognize ILD much, much better now, but they tend to under treat, meaning treat without high enough doses of steroids or for too short period of time. So the last efforts we have had in the marketplace and in clinical development was to educate doctors about the importance of steroids. And this is probably what is the reason why we're observing the number we're observing in the market, in the post market data as well as in the Phase three monotherapy study. There is a very important and they need to be administered correctly. They do have an effect. That's what we seem to be seeing. Thank you very much. I have another question, this time about TOP2 ADC DS-ten 62. And I understand that this is an all comer study, and you are there is no particular impact of the TROP-two expression on the patient's response rate. And this is how you are assuming in this study, it seems. So I'd like to confirm whether my understanding is correct that you're assuming that there's going to be no impact of the Echokto expression on the response rate. And also, I might have missed, but this time you talked about the Pfizer plot. And I thought that eight milligram per kilo dose, a high dose, can be difficult to be used. You were saying before that you were exploring or trying to find the dose among four, six and eight milligram per kilo. But looking at the results, can I understand that you have a certain direction for the dose selection for the future? So these are my two questions on TOP2 ADC. Manabe san speaking. Antoine, please answer this question. Thank you. So we have I'll answer the second question. We have decided on the dose and in launching the Tropium LUN-one Phase three study, which is pivotal after IO and chemotherapy non small cell lung cancer, we are testing DS1052 at six milligram per kilogram versus docetaxel. So we have chosen the dose of six in collaboration with AstraZeneca. On your question about TROP-two expression, with the current test, we are not observing the predictive value of TROP-two expression on response rate. We are very confident that we will find the correct measure to predict patients will most benefit from this particular therapy. We are not describing this method or method now, but we are very confident we will have a method to discriminate. And in Tropium-one all subjects will provide a biopsy so that we can prospectively plan to retrospectively test for the marker selection. Thank you very much. This is my last question. And I'd like to ask this to Manabe san. What's the on the litigation pending on ADC with C Gen? To this question, Manabe would like to respond. Manabe would like to respond to that question. And C Gen is saying that based on their patent they have acquired recently, they are saying that we are infringing their patent. And Daiichi sanjo believes that C Gen's newly acquired patent itself is invalid. So we don't think we are infringing their patent. So we'd like to clarify our assertion in rule of law or court through the ruling by the Justice. And we filed a lawsuit against them in November with the Federal District Court in the State of Delaware. And that's the current update. And if there is any progress in this case, I'd like to report this to you. Thank you very much. UNIDENTIFIED REPRESENTATIVE:] Redoubt from Goldman Sachs securities and first about 08/2001, and I have an additional question about ILD with DS-eight 201. There was a chart on Page 44 in the presentation, and you talked about the incidence of ILD in Japan and The United States. But it seems that there is a big difference in the incidence of ILD between Japan and The United States. So are there any factors behind this big difference in the ILD incidence? And also to identify patients at high risk of ILD, before you were saying that you're also looking at their past history of treatment with multiple drugs, particular drugs. But how are you identifying high risk patients right now? So that's my first question. Manabe san would like Antoine to respond. So number one, you are correct. The number of events reported in Japan relative to the number of events reported in The U. S. Appears to be different. These are number of events reported through the pharmacovigilance system. It is likely to reflect two things. One is that ILD awareness in Japan is much higher and that's more likely to be reported. And more importantly, there's also a higher incidence of lower grade. So grade one, grade one and grade two in Japan, not only for eight thousand two hundred and one, but generally speaking for drug inducing ILD. So where is the key numbers here are less the any grade and more the deaths of fatal cases. And what was reassuring in these pictures that we only had two and zero in The U. S. And in Japan. With respect to the high risk, what we've identified are risk of and risk factor are history of pulmonary disease, you know, such as BPCO, obviously, pneumophagia, ILD risk factors, abnormal lung function at entry. The prior treatment has not been and is not an exclusion factor. So the prior anti cancer treatment is not an exclusion factor. Although we seem to observe that the longer the patient has had cancer treatment and the more likely that the patient has ILD. It's probably the cumulative total dose of cancer treatment which makes it a risk factor but we are still investigating that aspect. Thank you very much. My second question is about DS-ten fifty five. And I'd like to know your development strategy. Theoretically speaking, there can be an add on effect by the IO therapies and there are more doublet IO therapies and PD-one, PDL-one antibody to be combined in the doublet therapy that's increasing these days. So is there any possibility of combining DSK-fifty five on top of the other two IO antibodies to make triplet therapy? And what is going to be your development strategy? That's my second question. And Manav Patan would like Antoine to respond. So thank you. We are excited to enter IO with an asset of DaiQSNQ discovery. ES1055 target is not a new target, but it had been before tested by others and they failed. We believe our construct is more likely to succeed. The first in human study will have to establish not only the safety, but also some biological evidence that we reduce the regulatory activity regulatory T cell. So reduce the number of the activity Tregs in the tumor. Then our development is to indeed combine with immunotherapy agent one hundred two. But this will come once we have established safe dose and a dose which is biologically active on the depression of activity Tregs. Thank you very much. And my last question is about DS-five thousand six hundred seventy. And you are using your own unique eposomes, and it's different from what Pfizer and Moderna are using. So you may have to take more time in your development and look at this more carefully perhaps. So for the antigen protein, are you using S protein? And are you also using the proline metastasis to stabilize the structure like Pfizer or Moderna? So this is my last question. And Manabe san would like to ask Takashaki san to respond. Tsukashaki would like to respond. First of all, our unique karyonic lipid, we think it has very high efficiency in the delivery of messenger RNA. And also the lipid composition ratio and also the ratio of messenger RNA, we have already established these ratios. And we are now discussing the way of mass production right now. Therefore, we have high expectations about its efficacy and the effectiveness. But with regards to the antigen, please allow us to refrain from disclosing. Thank you very much. That's all from me. From BoSA Securities. And we are behind. So I would like to briefly ask two questions with regards to DSN-sixty two. And what you are planning to develop this in first line lung cancer settings? And what kind of milestones you need to achieve to enable your development of first line lung cancer indication? And this is my first question. And secondly, about the difference compared to TODALBI from Gilead, They also developed they developed the compound in lung cancer developing this in lung cancer, and they also have data of about twenty percent response rate. And I understand that DS-ten sixty two has a different structure compared to Trodelvy. But based on the current available data, how much expectation do you have about DS-ten sixty two vis a vis Trodelvy? And one other thing I would like to ask Antoine to respond. Thank you. So I will answer the second question first. Our belief is that the DFD technology is unique in allowing for durability of treatment. We've proven that multiple times not only with 8201 but with our other clinical stage asset But the most important effect of this technology is how stable it is in the blood, how high potency with bystander it is in the tumor and how little systemic toxicity there is. And versus Trodelvy for instance where the drug is relatively unstable must be administered day one and day eight and creates a safety profile which is closer to that of chemotherapy with GI toxicity, neutropenia, febrile neutropenia, death by neutropenic infection. We have with ten sixty two a construct which we believe is best in class and primarily with duration of response. I will let the translator and come back to the first question. With respect to the second to the first question, the milestone to go first line is simply to have a safe combination with an IO region. We have an active collaboration with Merck and we have started the Tropion Lung two on an accelerated schedule because we've proven with nivo and ES8201 that the combination of DXD and immune checkpoint is safe in particular in liver and in lung toxicity. So, we feel comfortable to have an accelerated testing of the DS-ten sixty two and pembrolizumab combination in the Tropium Lung two. And as soon as we have enough safety evidence, we will move in first line. We are actively discussing with Merck the detail of that extended collaboration for this particular study and indication. Thank you very much. Mizuno from Tokyo Marine Asset Management speaking. And I'd like to briefly ask two questions. First, about DS-eight thousand two hundred and one and its pan tumor study. And I think this study can be passed to approval regardless of the organs with HER2 positivity. So what kind of results would be necessary to use it as a path to approval? And that's my first question. And my second question is about the muscular dystrophy. And you are having the data on the first drug for this indication, DMD. And you're also developing follow on compounds as well. And do you need the success of the first drug to proceed with the follow on comparative development, I'd like to confirm. Mandabe san want Antoine to answer the first question and want Takasaki san to respond to the second question. On the pan tumor HER2 is an important study which will give us initial evidence of activity across different tumor type with less frequency of HER2 expression or HER2 mutation. To have an indication regardless of the tumor requires that we select the patient on the biology which is unique and similar across all of these different tumor types. So far HER2 expression by IHC has not met this criteria. We've discovered that the typical IHC for HER2 in some cases identifies antigen which are not HER2 antigen. And we are creating the next generation of tests. So we may or may not be able in the near future to have a test which is valid across all tumors. We are actively looking with different major collaborators to define which test. Meanwhile, we are conducting the pan tumor assessment and keeping the tumor blocks for future testing. Mr. Kasaki, you'd like to respond to the second question about 5,141. Because of its action, it seems to have on cardiomyocytes, so we are having high expectations on this project. And by the end of this month, we will have top line results. And with regards to the so called follow on projects, they are using the same ENA technology, but the size of skipping is different for these follow on projects. And we are also beginning to observe non clinical profiles as well. So regardless of the outcome or the status of the development of 05/1941, we'd like to continue promoting R and D for the follow on projects as well. Thank you very much for answering my two questions. Very clear. Thank you very much. From JPMorgan speaking. I only have one question about eight thousand two hundred and one. And I'd like to ask you about the level of your expectations about the adjuvant with ODS-eight thousand two hundred one and if you're able to comment. And you are demonstrating high efficacy and durability of effect and also the manageable ILD profile. And I'm sure that you are having higher expectations for the first line settings. And can we apply these features also to the adjuvant as well? And compared to the terminal cancer patients, these patients in those settings still have some physical stamina. So do you think that you can have high expectations? Or if any, still have to look carefully at the adjuvant, any particular element, if any? Another sounds like Antoine's response. So I'm glad you asked this question. This is the STNE breast five, which is described on Slide 30, is really an exciting study for Daiichi Sankyo. This is a study which is starting just one year or less than one year after the first approval. All the major world group in breast cancer have collaborated with us for the past twelve months to design and launch this study. And we are really excited because this is a head to head study versus TDM-one where we absolutely believe DS-eight thousand two hundred one to be substantially superior to TDM-one. TDM-one has proven a role in the adjuvant setting or post neoadjuvant to be technically correct. And what this particular study where we will compare with TDM-one is on the sixty percent or seventy percent of patients, we do not do very well in the post neurogen setting with TDM-one. And we are really very confident that AT-two zero one will substantially improve the benefit for patients in this particular setting. So it's an extremely exciting study and we have very high expectation on this study. Thank you very much. So it concludes the Daiichi Sankyo R and D Day. Thank you for your participation