Hello, I am Sunao Manabe, the CEO of Daiichi Sankyo. Thank you very much for joining Daiichi Sankyo's R&D Day 2020 during your busy end of the year season. This is the second time for me to host our R&D Day as CEO. I make multiple important presentations in the course of the year.
I always enjoy to present here. I will present our progress over the last year. Antoine, our Global Head of Oncology R&D, will take you through where we are relative to oncology R&D, as well as future plans.
I am satisfied with the development of our three ADCs since R&D Day 2019. First, ENHERTU. We have successfully launched ENHERTU in the U.S. and in Japan with the breast cancer indication. The product has been submitted for approval in Europe. 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. A 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, DS-1062. A competitor was launched. We continue to be confident that our DS-1062 ADC is the best in class. I'm also confident that we selected the best partner for DS-1062 as well. Antoine will present some of our recent discussion with AstraZeneca.
With regard to the third ADC, U3-1402, 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. These steady progress of the three ADCs gain our confidence for achieving Daiichi Sankyo's 2025 vision. There have been good progress for the Alpha project, too. Clinical trials for the following DS-ADC, DS-7300 and DS-6157, are on track. We are starting to see some early efficacy and safety clinical information, which will be provided by Antoine later.
Top line results for DS-5141, the exon 45-skipping drug using our proprietary nucleic acid technology, ENA, should be obtained at the end of this month. Depending on the results, we believe that ENA can be our next platform technology after DS-ADC. DS-1055 was included in our second quarter financial result presentation in October.
We are hoping that DS-1055 will become a novel immune oncology drug in the future. This is not on the slide, on December 3rd, our CAR T therapy, Axi-cel, passed the subcommittee of Japan's Ministry of Health, Labour 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&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 following 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-19 countermeasures, vaccines, and therapeutic agents. Today, I will briefly introduce DS-5670, our messenger RNA COVID-19 vaccine.
With Daiichi Sankyo'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 plan to start in March 2021.
We are currently putting together a new five-year business plan that starts from fiscal year 2021. Core part of the plan will be our strategy to enhance the pipeline and the product portfolio.
Firstly, the 3 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 will pass the baton to Antoine. Antoine, you are up.
Thank you, Manabe-san. Good evening from Basking Ridge, New Jersey, our North American headquarters. My name is Antoine Yver, and I'm the Global Head of Oncology R&D for Daiichi Sankyo. I'm really energized today to be in front of you on behalf of Daiichi Sankyo. For the fifth R&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 multimodality company.
Next slide. First, our environment. Next slide. How did we collectively get here to our current world in oncology? 2000 was a decade where excellent drugs like Gleevec, Iressa, 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, the 2010 remains a glorious decade for IO. As we predicted a few years back from this podium, the 2020s are now recognized as a new era, where high-tech pharmacology propels the century-old idea, where today's magnificent technology of ADC will change the treatment paradigm away from typical chemotherapy, where you poison both the person and the tumor, wait for the recovery of the person, hit again until you can't do any more.
On the contrary, ADCs, as a true chemotherapy-free approach, offers continuous hits on the tumor 24/7, enabling durability of direct lethal hit on the tumor itself. What is important regarding the ADCs from Daiichi Sankyo? The uniqueness of our DXd ADC technology platform is the duration of effect.
This is not a surprise, as the technology was specifically designed for that purpose. It is an integrated multimodality, high-tech molecular construct with a unique mode of action, a high-potency payload, 10 times more potent than SN-38, a hyperstable linker, an exquisite delivery to the tumor, and a unique bystander antitumor 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 DXd ADC design. 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, et cetera. The ADC concept alone is old news. Daiichi Sankyo is already blazing new trails 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 samurais, I have an exquisite focus on humbly delivering on their obligation. For breast and DS-8201, in HER2 metastatic and early breast cancer, we have a suite of phase III trial with the most respected global academic trial partners.
In HER2 low, the DESTINY-Breast04 study is fully enrolled and is tracking to read out in fiscal year 2021. For lung, with DS-1062, we are implementing a swift development post IO chemo with a definitive phase III just announced, as well as IO combination aiming at first-line lung cancer.
More on that later. For lung, also, U3-1402, our HER3 ADC, pursues a fast to market development in EGFRm non-small cell lung cancer, as well as a combination with osimertinib based on fascinating science of pharmacomodulation.
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. First, DS-8201, also known as trastuzumab deruxtecan, or T-DXd in short.
Next slide. In brief, representing major advances in value for patients, we will cover five different aspects. For gastric cancer, the Japan approval in September, the U.S. FDA acceptance of a priority review submission with a PDUFA date of February 28, 2021.
For breast cancer, we will spend time on the big story, and the big story is not even the positive opinion received this past Friday from the EU CHMP, which makes ENHERTU the first new molecular entity in more than 2 decades to be approved or recommended for approval in breast cancer on the basis of phase II 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 ENHERTU 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, an important new unpublished data on file for ILD. Next slide. First, gastric cancer.
Here is a brief reminder of the design of DESTINY-Gastric01, which randomized subject to either T-DXd 6.4 milligram per kilogram or the choice of irinotecan or paclitaxel. Next slide. Here are the efficacy results delivering the first evidence for ENHERTU of a clinically relevant and statistically significant survival benefit with a four-month improvement in median, a hazard ratio of 0.59, and a compelling difference in response rates, with many cases of all target lesion achieving 100% reduction. Next slide.
Here is the summary of a safety finding, including ILD, with an overall incidence of ILD at 9.6% and no grade 5 death event. Next slide. Looking ahead, in HER2 advanced gastric cancer, we are announcing DESTINY-Gastric04, a large randomized phase III study in second line testing DS-8201 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 the positive opinion recommending approval for ENHERTU on the 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 are looking forward to soon receiving the European Commission approval. Next slide. On to the duration of response. This is a schematic of the study DESTINY-Breast01, the basis for first approval in all three region, U.S., Japan, and now EU. It is a somewhat complex design. Highlighted in green is the main cohort of 184 subject for evaluating efficacy at the dose of 5.4 milligram per kilogram.
Next slide. Here is a critical slide, not only for ENHERTU and patients worldwide with HER2 breast cancer. 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 20.8 months, and the slope of a curve, which indicates a stable residual risk over time so far. On the bottom right, you see a table, which gives updated response result. At 20.5 months of median follow-up, the confirmed overall response rates by independent central review is now at 61.4%, a slight increase compared to the U.S. and Japan labels, with also an increase in the number of complete responses.
In green is a key reference point. This is a golden THP regimen, the true global standard of care in first-line HER2-positive metastatic breast cancer. This is from the CLEOPATRA study, with a triplet of THP, with the duration of response observed there was 20.2 months.
At 20.8 months in 6 or 7 lines and by monotherapy, our results are unprecedented in breast cancer, and a testimony to the unique nature of ENHERTU. Next slide. Here is an important slide as well. For ILD by independent adjudication committee. With updated follow-up, the ILD risk clearly appears to flatten after approximately 12 months of exposure.
Next slide. 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 ENHERTU, we have an aggressive and bold plan aiming at first-line metastatic breast cancer. More detail soon.
The prevention of brain metastasis is not the critical need at that stage. Brain mets failure as the current first-line THP treatment is infrequent. It is terrible, but affects only 13.7% of patients. Second, the potential of ENHERTU to be superior to T-DM1 leads to two questions. First, after T-DM1 in second line, brain mets failure is uncommon.
Only 2% in patients who did not have brain mets at treatment start, and only, if I may say so, 20%, 22%, if brain 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 brain met is warranted when brain mets represents the cause of failure. Our DESTINY-Breast03 study in second-line metastatic breast cancer head-to-head versus T-DM1 will answer the question.
It is scheduled to read out in second quarter fiscal 2021, 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 DS-8201 in first-line metastatic breast cancer. First, DESTINY-Breast09, which is a randomized, active control, phase III study of DS-8201 monotherapy versus DS-8201 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-Breast07, as well as the BEGONIA study at AstraZeneca, are combination studies which will inform at least another phase III in the first-line setting versus THP. Next slide.
Here are some more details about DESTINY-Breast05, our post-neoadjuvant study versus T-DM1. This is run with the U.S. NSABP, as well as the German GBG group and the AGO-B group , SOLTI, and many others, including in Asia. This study is conducted in subjects with residual invasive disease in breast or axillary lymph nodes following neoadjuvant therapy for high-risk HER2 early breast cancer.
A total of 1,600 patients approximately. iDFS as a primary endpoint. Next slide. What about HER2 low? In other words, HER2-negative breast cancer, either HR-positive or triple-neg breast cancer. In late-line post-chemotherapy, our entry point is DESTINY-Breast04.
The rationale for that study is in J101 study, where we observed a confirmed overall response rate of 37%, a median duration response of 10.4 months in the HER2- low metastatic breast cancer cohort.
DESTINY-Breast04 has fully enrolled approximately 540 subjects and tests DS-8201 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 second quarter of fiscal 2021. In first line chemotherapy, we're running DESTINY-Breast06, 850 subject, DS-8201 versus physician choice of gemcitabine, paclitaxel, or nab-pac with PFS by BICR as primary endpoint.
Finally, in earlier metastatic breast cancer line, bold, innovative plans will be announced. Of note, in HR positive and early breast cancer, the adjuvant segment is not our area of focus.
Between José Baselga, my counterpart, and my longtime friend at AstraZeneca 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 ER/EGFR mutant non-small cell lung cancer.
An impressive response rate, duration of response, PFS that formed the basis for U.S. FDA breakthrough designation. We expect the final analysis of the ER/EGFR mutation expanded cohort to take place in the first half of 2021, with analysis criteria meeting the FDA's expectation.
Next slide. What do we do to design and maximize the benefit of durability? In ER/EGFR mutant on the left-hand side, beyond the DESTINY-Lung01 expansion, which I've just described, we are conducting DESTINY-Lung02, comparing two doses of DS-8201 after detailed FDA consultations.
We'll start DESTINY-LungXX, the possible first-line phase III study in the planning stage for now and aiming at first half of FY 2021. In ER/EGFR expressing, the current generation of IHC monoclonal antibody cross-reacts in lung cancer with non-ER/EGFR protein, some non-ER/EGFR 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-Lung01 IHC-expressing cohort to mature. Next slide. Colorectal. A quick review of critical data presented at ASCO in June in ER/EGFR expressing, meaning IHC 3 plus colorectal cancer.
A 45.3% 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-CRC02, testing 5-4 and 6-4 mg per kg and also sorting out the role of RAS mutation, if any. Next slide.
We have covered a lot of ground so far. 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. Here for gastric and lung cancer. Next slide. For CRC, as well as other cases I've not described in much detail.
Next slide. Here you see the DS-8201 critical short-term phase III study data forecast. First, DESTINY-Breast02 in ER/EGFR-positive metastatic breast cancer, third line versus standard of care.
The event-driven final analysis is projected for the second quarter of fiscal 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 ER/EGFR-positive second line metastatic breast cancer, the head-to-head comparison versus T-DM1 with an event-driven planned interim analysis projected for second quarter fiscal 2021 and the same uncertainty of approximately five months on the actual data cut-off date.
Finally, the DESTINY-Breast04 in ER/EGFR-low metastatic breast cancer versus standard of care with an event-driven final analysis projected for second quarter fiscal 2021 and a smaller uncertainty of approximately four months. Next slide. Moving on to the nivolumab combination just presented at San Antonio Breast Cancer a few days ago. Here is the study design.
Next slide. Here, the efficacy highlights. 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.
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 %. First the total of any grade, and then from left to right by increasing grade. We clearly do not see any comparing risk increase.
We are obviously planning to move with IO combination with DS-8201, and also borrow this data for the other DXd program 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 III monotherapy study now ongoing. It uses the same format, %, first total, and then increasing grade from left to right.
Since these study are controlled, we assume that all ILD cases, regardless of randomization arm and adjudicated by the adjudication committee, are in fact related to the DS-8201 treatment. We've estimated the number of subjects treated with DS-8201 in this study at approximately 979.
The graph shows a very reassuring feature. 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 pharmacovigilance reported data. Left, in the U.S., right, in Japan. More than 1,000 patient years exposure in the U.S., two fatal cases, an added 160 patient years in Japan, no death reported. Next slide. Where do we stand?
We focus on a massive opportunity for DS-8201 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. We will build on the IO DXd combo. Next slide. Moving on to DS-1062, our TROP2 DXd ADC, datopotamab deruxtecan, or Dato-DXd in short. Next slide. Here are key characteristics for DS-1062. It is engineered to be best-in-class TROP2 ADC.
It carries all the characteristics of our DXd ADC technology so critical to deliver its most important feature, durability of 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 human study design in subject 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.
Dose escalation is completed as has the enrollment of a dose expansion for a total of 180 subject across three doses in dose expansion. 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 incidents, regardless of the doses and tumor type. The next three for the doses of four, bottom left, and six and eight milligram per kilogram on the right. What do we do with this? We are running. Next slide. TROPION-Lung01 is a pivotal phase III 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 line of platinum-based and immune checkpoint inhibitor treatment are eligible, regardless of TROP2 expression by current test. All subject will provide a fresh biopsy to support our prospective plan to retrospectively test.
A total of 590 subject will be randomized 1 to 1 to DS-1062 at the dose we have selected of six milligram per kilogram or docetaxel 75 milligram per meter square with a primary endpoint of PFS by BICR 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 externally partnered research effort on the biology of TROP2 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're 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-Lung02 with pembrolizumab in collaboration with Merck. Tropion-Lung04 with AstraZeneca durvalumab. Finally, for lung, Tropion-Lung05 is for DS-1062 monotherapy in non-small cell lung cancer with activating mutation. For breast cancer and beyond, the triple negative breast cancer phase I 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. Daiichi Sankyo 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 U3-1402, patritumab deruxtecan, or in short, HER3-DXd. Next slide.
Here are the highlights of our non-small cell lung cancer EGFRm phase I study, as presented at ESMO this year. The 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 osimertinib 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 they design our pivotal study. Next slide. Here is a design of HERTHENA-Lung01, a pivotal phase II study in advanced EGFR mutated non-small cell lung cancer to start in January 2021.
EGFRm lung cancer is a tumor type where we have now observed stable HER3 expression, U3-1402 offers a unique, simple opportunity post-TKI and 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 I the combination of 1402 with osimertinib. 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. Moving to breast cancer. Here's a snapshot of updated data, breast phase I cohort just presented at San Antonio Breast Cancer Symposium across HER3 high, HER3 low, and two doses of 4.8 and 6.4 milligram per kilogram. These look fine on the surface. Next slide.
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. Very consistent with prior reports and a lower frequency and severity of ILD. Real questions are suggested on the next few slide.
Next slide. First, even before treatment with U3-1402, 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 pretreatment level and at cycle 2, day 3 or cycle 3, day 3, meaning approximately day 24 or 45 post first dose. We are actually beginning to decipher quite well the HER3 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 HER3 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 Blinded Independent Central Review. Much work to do if we want to find the right selection test in breast cancer.
This is now a key part with TROP2 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, Gustave Roussy Cancer Campus, Sarah Cannon, as well as the National Cancer Center in Japan, and of course, our great internal labs. Next slide. Finally, ILD for U3-1402, 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. DS-7300 is our B7-H3 and is now in its 15 months since starting the first-in-human study.
We have completed enrollment in dose level 7 at 12 milligram per kilogram, and assessment up to dose level 6 with, so far, not a single DLT observed. Even in an unselected patient population, we have observed multiple separate persistent confirmed responses. DS-6157 is progressing nicely. DS-6000 is a new, not yet disclosed until now, ADC targeting cadherin 6 with a drug antibody ratio of 8 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, DS-3939 is our TMEM101 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 their status. We recently announced initiation of a first-in-human study of DS-1055, our anti-GARP-positive or anti-activated T cell REG asset. DS-8201 is our dual EZH1/2 inhibitor. It is in pivotal phase in Japan under the SAKIGAKE 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 other hematological malignancy. Axi-cel, or KTE-C19, which we licensed for Japan from Kite pre-Gilead Kite acquisition, is expecting approval in Japan this very month. pexidartinib is progressing nicely in Japan and Southeast Asia.
For quizartinib, despite our setbacks in U.S. and Europe for the relapse refractory indication, we continue to believe that the placebo-controlled, controlled first 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 second half of fiscal 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 Manabe-san earlier, we are serious in 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're also powering through some residual pinch point so that DS-1062 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 continue to track for fiscal 2022. Next slide. Here is our top-line news flow for the next six months and also key catalyst. This completes the primary presentation, and we will now take question.
Thank you for waiting. Now let's begin the Q&A session.
Yamaguchi from Citigroup. I'd like to ask a question one by one in Japanese. My first question is about DS-3201. Antoine mentioned that you have a more aggressive plan for early metastatic breast cancer you're considering. Are you referring to something different from the current idea in this respect? If you have any particular idea, please share.
Manabe speaking. For this question, Antoine, please answer this question.
Hello, good evening. This is Antoine Yver. Thank you. We have more plans than what is presented. We are presenting one study now. This study will be followed by other study, at least one or two study informed by the BEGONIA study in particular. 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 details.
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I have another question. Thank you for the earlier question and answer. I have another question regarding DS-8201 in lung cancer. It has been granted a breakthrough designation, and you are now accumulating final data of the patient. Once you collect the data in the U.S., it sounded that it's possible to file immediately after the collection of the data in the U.S. Is my understanding correct? That's my second question.
Manabe-san 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 DESTINY-Lung01 expansion, primarily. This will be a submission in the U.S. The European plan are still under discussion. The U.S. will be primarily based on the DESTINY-Lung01, and will be later supported by the DESTINY-Lung02.
[Non-English content]. DESTINY-Lung01 [Non-English content]. DESTINY-Lung01 [Non-English content]. DESTINY-Lung02 [Non-English content].
[Non-English content].DS-7300 [Non-English content].4 [Non-English content].ADC [Non-English content].
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Thank you very much. This is my last question regarding DS-7300. This could be the fourth ADC become available. I'd like to ask whether this could also be a target or the subject of the alliance.
Regarding this matter, Manabe would like to respond.
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This is an often asked question also about the third ADC, 1402. Regarding this DS-7300, for the time being, we'd like to do the development in-house for this compound. 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.
[Non-English content]. Morgan Stanley MUFG [Non-English content].
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Hello. Muraoka from Morgan Stanley is speaking. I would also like to ask a question one by one. First of all, I would like to ask you about DS-1062 in triple negative breast cancer. I heard that enrollment is almost complete.
Can we expect the ORR data at ASCO meeting next year? If the ORR is going to exceed 33% 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-sun speaking. I would like to ask Antoine to respond to this question.
Thank you. 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 is not enough time. We are not speculating about the results and not speculating about the potential submission in triple negative breast cancer. Our fast-to-market currently our efforts are in lung cancers.
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[Non-English content] U3[Non-English content] HERTHENA-Lung01[Non-English content] 2022[Non-English content] 2023[Non-English content] ORR [Non-English content] 2022 [Non-English content] DS-1062[Non-English content] 2022 [Non-English content] U3[Non-English content] Lung01[Non-English content].
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Thank you. My next question is about U3-1402 in lung cancer. You have Lung01 study with U3-1402. This study is going to start from now on. Regarding the results, are they going to become available in 2022 or rather 2023? Is it possible to see ORR data in 2022 as well?
What I want to say is that regarding 1062 lung cancer results will become available mainly in 2022. Almost at the same timing, can we also expect the results from the U3-1402 lung cancer study, Lung01 study as well? Manabe-san speaking. Antoine, please answer this question.
Thank you. The end of the DESTINY-Lung01 for HER3 will depend if we complete enrollment at 210 subjects in each of arm 1 and arm 2. That will depend on external data on whether or not we carry both dosing regimen forward or drop one. The end of enrollment and results are most likely to be in 2022 at the same time as lung for 1062. Remember that 1062 is in non-EGFR mutants and U3-1402 is in EGFR mutants, both in late line.
[Non-English content] HERTHENA-Lung01 [Non-English content] HER3 [Non-English content] Arm1 [Non-English content]Arm2[Non-English content] 210 [Non-English content] DS-1062 [Non-English content] EGFR [Non-English content]
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Thank you very much. This is my last question. It's not about oncology, but your vaccine product DS-5670 for COVID-19. You are going to initiate a phase I study in March and the Shionogi, part of the top running group. Compared to that, just three months behind. You have to consider your supply at this moment. Shionogi is saying that they can provide 30 million doses in the middle of next year. What about the level of Daiichi Sankyo's capacity?
Manabe would like to respond to this question.
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Manabe would like to.
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Manabe would like to respond. In March next year, we are aiming to start the clinical activities and we are ready and preparing for the CCM 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 I, II, and III studies. We are increasing our capacity. I'd like to refrain from giving you an accurate answer to your question at the moment.
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One additional question. Are you having an idea or considering a possibility of the scale of dozens of millions of doses for your vaccine? That's the additional question and Manabe-san's response. We are hoping that we can achieve that level, but number wise it could be difficult.
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That's all from me. Thank you very much.
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Hashiguchi 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 ENHERTU and OPDIVO, and the efficacy in the combination may not be so different compared to the monotherapy, but it's important to consider the potential of the combination of ENHERTU and other DXd and IO therapies.
You have to consider what kind of data you can obtain. What's your view on the synergy effect of these combinations? That's my question.
Manabe-sun speaking. Antoine, please answer this question.
Thank you. The phase I data, the IO combination had one purpose, which was to prove that both drug could be given at therapeutic doses. We were very pleased in patients with five prior lines of treatment to be able to give the normal doses, and at the time of data analysis, 56% of patients were on treatment.
At that time, the median duration of treatment exceeded six months. We have a 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 III combination study versus standard of care to prove the added benefit of IO, and this is our plan.
Thank you very much. My second question is about the safety of DS-1062. This time today, there was a presentation of the data on ILD only. What about the adverse events and toxicity for the GI and the membrane toxicities? 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 ILD for six milligram per kilo dose? How this is going to change the sales potentials, if any, for the AEs and toxicities other than ILD? Manabe-san would like to ask Antoine to respond.
Thank you. We have not updated the data for the adverse toxicity. We will present the data in months from now at World Conference on Lung Cancer in January. The only data I presented are a snapshot of the duration of response by spider plots and a snapshot of ILD. We have not observed any concern new in the non-ILD general safety profile. We have not observed anything of relevance for the conduct of the clinical development of DS-1062. We will update in details at World Conference on Lung Cancer.
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Because of those situations, there is no change to the safety potential for the time being.
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Thank you very much. This is my last question. This is about DS-6000 and you are targeting Cadherin 6. I'd like to know the characteristics and the features of this target or the drugs. A few years ago, there was a phase I 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 Cadherin 6, and why do you think this ADC target can be promising? Why do you think the other company was not so successful in their development? Why do you think you can be successful by using DXd? Manabe-san, I would like Antoine to respond to this question.
Thank you. We are confident in the target. 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 the correct drug antibody ratio, just like CT-8201.
We also have belief in this target, which is highly expressed in immunocell 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 fail, 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.
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.
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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. We also exclude patients with prior history of lung disease, which may make them at risk. Yes, the ILD can be managed.
It cannot be eliminated. I think the slide number 43 in the presentations where we present all phase III 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. This is very reassuring as we have very, very few cases overall, much fewer than what we had observed initially, and very few grade III, IV and V cases out of nearly 1,000 patients.
These studies are ongoing, most of these studies will report in the next year. Most of the treatment are very advanced and we have seen for 8201 that the risk after 12 months plateaus. Really this picture is reassuring to us.
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Yes. One of the last observation we made was that investigators and doctor recognize ILD much, much better now. They tend to undertreat, meaning treat without high enough doses of steroids or for too short period of time.
The last efforts we have had in the marketplace and in clinical development was to educate doctors about the importance of steroids. This is probably the reason why we are observing the number we are observing in the post-market data as well as in the Phase III monotherapy study. Steroids are very important, and they need to be administered correctly. If they do, they have an effect. That's what we seem to be seeing.
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Thank you very much. I have another question. This time about TROP2-ADC-DS-1062. I understand that this is an all-comer study, and there is no particular impact of the TROP2 expression on the patient's response rate. This is how you are assuming in this study, it seems. I'd like to confirm whether my understanding is correct, that you are assuming that there's going to be no impact of the TROP2 expression on the response rate.
Also, I might have missed, but this time you talked about the spider plot, and I thought that 8 mg/kg 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 4, 6, and 8 mg/kg. Looking at the results, can I understand that you have a certain direction for the dose selection for the future? These are my two questions on TROP2-ADC. Manabe-san speaking. Antoine, please answer this question.
Thank you. I'll answer the second question. We have decided on the dose, and in launching the TROPION-Lung01 phase III study, which is pivotal after IO and chemotherapy in non-small cell lung cancer, we are testing DS-1062 at 6 mg/kg versus docetaxel. We have chosen the dose of 6 in collaboration with AstraZeneca.
On your question about TROP2 expression, with the current test, we are not observing a predictive value of TROP2 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 methods now, but we are very confident we will have a method to discriminate. In TROPION-Lung01, all subjects will provide a biopsy so that we can prospectively plan to retrospectively test for the marker selection.
[Non-English content] TROPION-Lung01 [Non-English content] NSCLC[Non-English content] IO chemotherapy[Non-English content] 6mg/kg[Non-English content] 6mg/kg[Non-English content] TROP2[Non-English content] TROP2[Non-English content] predictive valueという[Non-English content] TROPION-Lung01 [Non-English content]
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Thank you very much. This is my last question. I would like to ask this to Manabe. What's the update on the litigation pending on ADC with Seagen? To this question, Manabe would like to respond.
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Manabe would like to respond to that question. Seagen is saying that based on their patent they have acquired recently, they are saying that we are infringing their patent. Daiichi Sankyo believes that Seagen's newly acquired patent itself is invalid. We don't think we are infringing their patent.
We'd like to clarify our session in the rule of law or court through the ruling by the judges. We filed a lawsuit against them in November with the Federal District Court in the State of Delaware. That's the current update. If there is any progress in this case, I'd like to report this to you.
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Thank you very much.
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Ueda from Goldman Sachs Securities. First, about 8201, I have an additional question about ILD with DS-8201. There was a chart on page 44 in the presentation, you talked about the incidence of ILD in Japan and the United States, it seems that there is a big difference in the incidence of ILD between Japan and the United States.
Are there any factors behind this big difference in the ILD incidence? 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. How are you identifying high-risk patients right now? That's my first question. Manabe-san, would like Antoine to respond.
Number 1, 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 events reported through the pharmacovigilance system. It is likely to reflect two things. One is that ILD awareness in Japan is much higher and thus more likely to be reported.
More importantly, there's also a higher incidence of lower grades, so grade 1 or grade 1 and grade 2, in Japan, not only for CT-201, but generally speaking, for drug-inducing ILD. Where the key numbers here are less the any grade and more the deaths, the fatal cases.
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 as risk factors are history of pulmonary disease, such as COPD.
Obviously, pneumopathy, ILDs are risk factors, abnormal lung function at entry. The prior treatment has not been and is not an exclusion factor. 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.
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Thank you very much. My second question is about DS-1055, 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 therapy, PD-1, PD-L1 antibody[Non-English content] therapy [Non-English content] DS-1055[Non-English content] IO antibodies [Non-English content] triplet therapy [Non-English content] Manabe-san, Antoine
Thank you. We are excited to enter IO with an asset of this Daiichi Sankyo discovery.
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Thank you very much. My last question is about DS-5670. You are using your own unique liposomes. It's different from what Pfizer and Moderna are using. You may have to take more time in your development and look at this more carefully, perhaps.
For the antigen protein, are you using S protein and are you also using the proline mutation to stabilize the structure like Pfizer or Moderna? This is my last question. Manabe-san would like to ask Takasaki-san to respond.
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Takasaki would like to respond. First of all our unique cationic lipid, we think it has very high efficiency in the delivery of messenger RNA.
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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.
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We have high expectations about its efficacy and effectiveness. With regards to the antigen, please allow us to refrain from disclosing.
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Thank you very much. That is all from me.
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Arai from BofA Securities. We are behind. I would like to briefly ask two questions with regards to DS-1062, and you are planning to develop this in first-line lung cancer settings. What kind of milestones you need to achieve to enable your development of first-line lung cancer indication? This is my first question. Secondly, about the difference compared to the TRODELVY from Gilead.
They developed the compound in lung cancer, developing this in lung cancer, and they also have data of about 20% response rate. I understand that DS-1062 has a different structure compared to TRODELVY. Based on the current available data, how much expectation do you have about DS-1062 vis-à-vis TRODELVY? Manabe-san would like to ask Antoine to respond.
Thank you. I will answer the second question first. Our belief is that the DXd technology is unique in allowing for durability of treatment. We've proven that multiple times, not only with AT201, but with our other clinical-stage assets, that 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.
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, deaths by neutropenic infection. We have with 1062, 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.
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With respect to the first question, the milestone to go first line is simply to have a safe combination with an IO agent. We have an active collaboration with Merck, and we have started the TROPION-Lung02 on an accelerated schedule because we've proven with nivo and DS-8201 that the combination of DXd and immune checkpoint is safe, in particular in liver and in lung toxicity.
We feel comfortable to have an accelerated testing of the DS-1062 and pembrolizumab combination in the TROPION-Lung02. 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.
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Mizuno from Tokio Marine Asset Management speaking. I'd like to briefly ask two questions. First, about DS-8201 and its pan-tumor study. I think this study can be a path to approval regardless of the organs with HER2 positivity. What kind of results would be necessary to use it as a path to approval? That's my first question.
My second question is about the muscular dystrophy. You are having the data on the first drug for this indication, DMD. You're also developing follow-on compounds as well. Do you need the success of the first drug to proceed with the follow-on compound development? I'd like to confirm. Manabe-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 types 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.
Far, HER2 expression by IHC has not met this criteria. We've discovered that the typical IHC for HER2 in some cases identifies antigens which are not HER2 antigens, and we are creating the next generation of tests.
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.
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Takasaki would like to respond to the second question about 5141. Because of its action, it seems to have on cardiomyocytes. We are having high expectations on this project. By the end of this month, we will have top line results.
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With regards to the so-called follow-on projects, they are using the same ENA technology, but the science of skipping is different for these follow-on projects. We are also beginning to observe non-clinical profiles as well. Regardless of the outcome or the status of the development of 5141, we'd like to continue promoting R&D for the follow-on projects as well.
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Thank you very much for answering my two questions. Very clear. Thank you very much.
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Wakao from JP Morgan. I only have 1 question about DS-8201. I'd like to ask you about the level of your expectations about the adjuvant with DS-8201, if you're able to comment. You are demonstrating high efficacy and durability of effect and also the manageable ILD profile. I'm sure that you are having higher expectations for the first-line settings.
Can we apply these features also to the adjuvant as well? Compared to the terminal cancer patients, these patients in those settings still have some physical stamina. Do you think that you can have high expectations, or if any, you still have to look carefully at the adjuvant? Any particular element, if any? I'd like Antoine to respond.
I'm glad you asked this question. This is DESTINY-Breast05, which is described on slide 30. It is really an exciting study for Daiichi Sankyo. This is a study which is starting less than one year after the first approval. All the major world group in breast cancer have collaborated with us for the past 12 months to design and launch this study.
We are really excited because this is a head-to-head study versus T-DM1, where we absolutely believe DS-8201 to be substantially superior to T-DM1. T-DM1 has proven a role in the adjuvant setting or postneo adjuvant to be technically correct. What this particular study, where we will compare with T-DM1, is on the 60%-70% of patients who do not do very well in the postneo adjuvant setting with T-DM1.
We are really very confident that DS-8201 will substantially improve the benefit for patients in this particular setting. It's an extremely exciting study, and we have very high expectation on this study.
Thank you very much.
It concludes the Daiichi Sankyo's R&D Day. Thank you for your participation.