Good morning, ladies and gentlemen. Welcome to Daiichi Sankyo R&D Day. Thank you for your participation today. My name is Junichi Onuma. I am the emcee today. Let me introduce our presenters. Our President and CEO, Sunao Manabe. Our Global R&D Head, Junichi Koga. Our Global Oncology R&D Head, Antoine Yver. Our presentation will take about one hour. After the presentation, we will answer your question until 12:30 P.M. In Q&A session, our Global Head of Oncology Development, Gilles Gallant, will also answer the question. Okay. Now, I hand it over to Manabe.
Good morning, ladies and gentlemen. My name is Sunao Manabe, and I'm the President and CEO of Daiichi Sankyo. I would like to thank you for your participation in Daiichi Sankyo's R&D Day. I will explain the strength of Daiichi Sankyo's R&D and share some top-line strategic direction. Following my presentation, Junichi Koga, our Global R&D Head, will explain our R&D strategies, and Antoine Yver, our Global Oncology R&D Head, will provide an update on the status of R&D in the oncology area and our plans moving forward. First, I would like to talk about the emphasis I place on research and development at Daiichi Sankyo. I believe that the strength of our R&D comes from leveraging the combined science and technology capabilities from across our organization. There are three sources. The first source is our in-house drug creation capabilities cultivated over many years.
Since our foundation more than 100 years ago, Daiichi Sankyo has developed innovative pharmaceuticals as a drug discovery-oriented company. Our capability to create new drugs has always been based on our in-house science and technology. The second source is our culture of sharing knowhow and outcomes and refinement. I have a long career in our research center and was directly involved in the creation of in-house discovery products. I know that there is a well-established culture at our R&D operations which encourages individual researchers share their knowhow and acquired outcomes. Based on this knowledge sharing, our researchers make improvement and refinement, which enhance our scientific and technological capabilities as an organization. The third source is the assessment capability for science. I am in constant contact with my colleagues at our R&D site.
The ability to evaluate new science has become even stronger based on continuous knowhow sharing and greater effort to refine acquired outcome. I place a lot of trust in them. By effectively leveraging our science and technology, Daiichi Sankyo is able to pursue innovation and continuously deliver new drugs, which makes a significant contribution to patients. DXd ADC assets, such as DS-8201, are the direct result of our focus on science and technology and our drive for innovation. DXd ADC is a new, highly promising asset that we created based on science and technology that Sankyo and Daiichi cultivated prior to our integration. By leveraging highly promising assets, my mission as CEO is to deliver DXd ADC assets to as many patients and as quickly as possible.
To fulfill my mission, I aim to enhance our global development and commercial capabilities. Specifically, I will prioritize enhancing our capabilities in the U.S., which is the most important market for the growth of our oncology business. We will focus R&D investment in three Antibody-Drug Conjugate: DS-8201, DS-1062, and U3-1402. We will newly invest more than JPY 100 billion to prepare for greater anticipated demand for investigation of drugs and commercial products. By delivering ADC assets to as many patients and as quickly as possible, we aim to become the number one ADC company globally. This will ensure we realize our 2025 Vision of becoming a global pharma innovator with a competitive advantage in oncology. I believe that my mid to long-term mission is to steer the company to create assets beyond DXd ADC to ensure sustainable growth.
To create beyond DXd ADC assets, we will expand our drug creation technology platform by utilizing our competitive new modalities and technologies. We will identify competitive assets through our enhanced evaluation capability and by focusing management resources. Over the long term, we aim to deliver drugs for diseases that can make use of our new modalities, not limited to specific therapeutic area such as oncology. Delivering new drugs with significant contribution for patients by pursuing innovation is the key driver for growth. Under my leadership, Daiichi Sankyo will pursue innovation based on advanced science and technology in three ways. Firstly, by acquiring the world's cutting-edge science and technology necessary for global expansion through open innovation. Secondly, by acquiring the most innovative talent from around the world. Thirdly, by seizing the opportunities generated by digital revolution in areas such as AI and big data.
Currently, we are focusing on our five year business plan ending in fiscal year 2020. We are aiming to get closer to our 2025 Vision of becoming a global pharma innovator with competitive advantage in oncology. We plan to develop and announce the next five year business plan in 2021. In parallel, we will renew our mid to long-term vision for beyond 2025 to create a roadmap for sustainable growth. Thank you very much. Now I would like to hand over to Junichi Koga.
Okay. Thank you, Manabe-san. I'm sorry I broke my voice, this is just a practice of this session. Thank you very much coming here. I try to deliver you our new strategy. Manabe-san touch upon middle term, long-term vision toward 2025, beforehand such a good result based on ADC, three ADC result, we are working on a new strategy. Let me summarize how we are going forward. Next slide, please. Here, beforehand what happened for our present product, our present development outcome as approval? This is what we show at the 2017 as Cancer Enterprise 2025 Vision and Specialty Medicine 2025 Vision, where we have ADC franchise, Acute Myeloid Leukemia franchise, and a breakthrough science franchise for Commercial Excellence, and also maintain the revenue and for future growth we have a true pillar for Strategic Marketing.
What happened is [quizartinib] approval in Japan in Cancer Enterprise AML franchise, [Enhertu] approval in U.S. In Specialty Medicine, [olmesartan] approval in Japan, esaxerenone approval in Japan. That's a tremendous result for totally new drug approval. We have many other amendment or many other small approval, these four are really a good achievement this year. May I have next slide? Having said that, we have been getting an excellent result in ADC, which was Manabe-san touched upon, later on Antoine will touch upon. The potential of three ADC, DS-8201, DS-1062, U3-1402, are increasing a lot. We are pretty much sure that a successful result on this development, how we can care of this product, potential this product, or accelerate this product. That's the kind of the discussion we have in R&D, global R&D setup. Three important pipelines are already pillar for us.
Next slide, please. New R&D strategy. Catchy phrase is three and alpha. Of course, three ADCs. We have many more ADCs based on our own technology or next generation, after next generation technology. We have those, but now we are seeing three ADC are so successful, DS-8201, DS-1062, U3-1402, together with precision medicine science, which is based on biomarker analysis and so on. Those are kind of the asset we should focus on. Others. Others may not be a right expression. Beyond 2025, we should have a valued project in-house. Although those are early asset, so why not potential those? How we do that? That is the kind of the difficulty. Three and alpha is easy to say, but the other specialty medicine pipeline together. Together mean nothing, something the rest list. No. The timely and flexible resource allocation could be realized.
Seamless collaboration among organization that will be realized. Also less resource should be allocated for alpha, but we will work it out. That is the kind of the strategy we are taking. Next slide, please. I'm sorry, this is a very busy slide. Not only three oncology asset or other oncology Specialty Medicine asset. Many of the asset are there. Other than three asset, three oncology asset, rather early stage, then maybe we need reprioritize. Well, maybe some of a delay or out license, we will do it. Still we have a good room, good resource to work it out. Next slide, please. Having said so that all asset other than three ADC is prioritized, right? Whether or not there is a first-in-class drug can be or whether or not that's the best-in-class drug, either way, we can change standard of care.
That is a measurement to analyze and prioritize our asset. Those are prioritization is going on. Maybe we can show later next year. The next slide, please. Let me discuss about our science, our scientists, because recently, last couple of years, I was frequently asked, "Why Daiichi Sankyo change such much?" Why you can find your own asset by your own science? Basically, I have two answer last 10 years or even before. One is excellent junior scientist. That's a Japan custom that every year, new graduate we are hiring, Master, PhD, or even the postdoc we are hiring. Those we throw into the laboratories, then transfer the laboratory and laboratory, then try to educate, learn our culture, and learn other science. Also we try to implant the mentality of resilience.
That is the kind of thing we can be innovative product to realize, because early research is not always straightforward. Many against window there. The mindset to resilience is a critical thing for us. That is one of the reason we can find our own asset, own innovative asset. Next is more strategical things. Can I have a next slide? Yes. We have working ADC, for example, even 1990s, but a small group are working. Last 10 years, we established new modality research laboratory. Our own laboratories who focus on new modality other than small molecule. Together with technology research, we can make it. Also together with discovery research, what type of modality can be applicable. That is the thing we can work on. That the reason why antibody, peptide or protein mimic, DNA oligo, those technology are born. Can I have a next slide?
This is a similar slide Manabe-san already expressed. These modalities are already in our hand by our own technology. We can throw those technology, any of the asset discovery group find out the mode of action. That is a strength. Like even messenger RNA or lipid nanoparticle or antibody mimic bispecific, or even cell therapy or gene therapy. That's technology in our hand. That is our strength. These are two reason we can find our own innovation in-house. Also, we are in a good position to evaluate external asset on that. Next slide, please. Maybe I touch upon two slide about our lipid nanoparticle. Of course, this is too early to say, but we have a more advanced product, but I cannot show here. That is why let me talk about the very early asset. Lipid nanoparticle.
Know everybody, listen, we have our own chemistry. This original cationic lipid that will help us improve the profile of lipid nanoparticle. There are many other modality that by our own technology like ENA bridged nucleotide technology by our own so on. Even lipid nanoparticle, we have our own technology to work. Next slide, please. This is others. MEDSI RNA technology. This is also our own technology to stabilize nucleic acid, then utilize. Maybe we can throw this in our own lipid nanoparticle, then we can deliver too by using our antibody technology or protein chemistry. That's a kind of combination of our own internal asset to work with, then to create our own new innovation. This is just a small example. We can work out many of the asset, although it are more than handful, but people are working on.
Next slide, please. Yes, we are Japan-based company started. As Manabe-san mentioned about, we are now focusing how to build up the capability in U.S. Beforehand, of course, we are working world-class science technology inside the company. We, of course, we have been serving patient globally. Now even more. How we nourish those cultures? Trust, blend the best of East and West, then great unity, embrace our difference, then appreciate disruptive mindset, then transparency and collaboration. All together this. We try to nourish our world-class science and technology and serve patient globally. I think we can do it. Now let's introduce Antoine Yver. He has plenty of slide to talk with. Please have a good time. Thank you.
Thank you, Junichi. Good morning. My name is Antoine Yver, for those of you who do not know. I'm happy because we will share a good amount of time and data together, and this will be evidence of our progresses towards becoming a globally recognized force in oncology. Expect a lot of slides and a lot of data. Actually, some of these data are new, and have not been presented before except couple of days ago in Tokyo. A quick reflection on the journey so far after years of highly innovative research preparing for today's successes. As you remember, we launched Cancer Enterprise approximately three years ago, and that included a capital investment of JPY 300 billion to support the ADC manufacturing on the recognition even then that the manufacturing was probably the most critical factor in pushing forward the delivery of our ADCs.
We established ambitious 2025 target. We reassigned the majority of the R&D budget to Cancer Enterprise, we propelled ourself at the forefront the ADC strategy, a strategy which has been validated by the AstraZeneca collaboration. We are now onto what we call the three ADCs and Alpha strategy, which is based on finally seeing the ADC technology bound to dominate for a while in oncology. We all know that Tyrosine Kinase Inhibitors were the dominant feature of the 2000s, Immuno-Oncology is a dominant feature of the current finishing decade. It is probably the beginning of the ADC decade. Not that the ADC is a new concept. It's actually quite the opposite. It was first brilliantly described in 1913, meaning really more than 100 years ago, by Paul Ehrlich, a Nobel Prize winner.
Later on, the first ADC construct, combining methotrexate with a murine anti-leukemia serum, was administered to a patient in 1958 by Georges Mathé, a brilliant French oncologist, who I had the honor to have as a mentor when I started myself medical school in 1975. Since then, there has been few successes as shown here. Why now? The 1913 concept was brilliant. It is impressive to see on this cartoon to which extent Paul Ehrlich described all the components of an ADC. Breakthrough came with the creation of a DXd technology, and the most important is a safe and effective delivery in a tumor of a bystander effect. This slide we have seen multiple times.
It doesn't hurt to remind ourself that first and foremost, DXd is a highly technologically advanced smart chemotherapy platform, where each of the seven components described here are equally critical to the unique activity and safety profile observed with our drug candidates. We've recently added a further twist, the so-called D4, DAR4 or D4 ANDR, Drug-to-Antibody Ratio 4 , making the final drug product optimized for the best Drug-to-Antibody Ratio . This DAR4 has been used for DS-1062 and 7300, two of our five clinical candidates. It appears now that DXd is a very mature and portable technology, and our challenge is to have the right target coverage. We're currently aiming at approximately 10 targets, expanding to a hematological disease, and obviously maintaining the right development focus. Meanwhile, we are progressing our next generation of ADCs, and we are aiming at the clinical stage around 2022 or 2023.
I know this is a question that everybody asks, which is what is coming next? Before going next, let's go into DS-8201. Next slides will be directly from this presentation made last week at San Antonio Breast Cancer Symposium during the opening presidential symposium, which was part of the official SABCS press program and published simultaneously in The New England Journal of Medicine. Data were extremely well received. I'm sure we are very familiar with this data. I will explain them, but emphasize one key aspect, Interstitial Lung Disease, which may have been misinterpreted by some. This pivotal study is the last part of the data that we submitted to FDA and PMDA to support the first approval of DS-8201. Study enrolled women with Human Epidermal Growth Factor Receptor 2 centrally confirmed metastatic breast cancer resistant to or refractory to prior T-DM1. Stable brain metastases were permitted at entry.
This presentation focuses on all subjects treated at the recommended dose of 5.4 mg/kg, i.e., a total of 184 subjects. Data cutoff for this data is August 1st, 2019. Subjects were enrolled globally, approximately a third in each of the three regions, North America, Asia, and the European region. 91.8% of women had visceral disease at entry and 13% had brain metastases. As we anticipated, this subject had exhausted all available treatment options and had received a median six prior lines of therapy for their metastatic breast cancer. 100% had received trastuzumab and T-DM1, and 2/3 had received pertuzumab as well. Here is the primary endpoint, the RECIST-confirmed response rate by independent central review. On an intent to treat analysis, the confirmed overall response rate is 60.9%, and an impressive 6% of subjects achieved a complete response, a complete disappearance of all tumor.
97.3% of subject achieved disease control rate, only 1.6% of subject had progression of disease as the best response. Duration of response measured from the time the response is first observed was 14.8 months. The time to observing first response was six weeks, meaning the first scheduled CT scan. Here is the corresponding waterfall plot of the best change in tumor size. I'm sure you've seen this, with brain metastases at entry. That's the third row. The effects observed across all subgroups are extremely consistent. Finally, the progression to survival and overall survival Kaplan-Meier estimates are shown here. Since the overall response rate is greater than 60%, the PFS is logically the combination of the six weeks to observe the first response and the additional 14.8 months of duration of response. The PFS of 16.4 months. Of interest are two things.
Number one, the median follow-up for this patient is still less than the estimated medians, showing that the estimates may vary with additional follow-up. Second, the Progression-Free Survival in the 24 subject with brain metastases was 18.1 months, which appears no different from the other subject, and this is a critical finding. On this line, I showed by adverse event term the frequency and severity of adverse events, Grade 1 or Grade 2 in light blue, dark blue for Grade 3 and above. Serious AEs were observed in 22.8% of subjects, which is remarkable given the long duration of treatment administered. 15.2% of subject discontinued treatment for adverse event, a little more than half of this case, or 8.7% due to ILD. As we will show, the safe use campaign has led to slightly increase the frequency of reported ILD.
Overall, it did not bring the drug discontinuation rate to anything above typical for a cancer drug. In particular, for subjects with Grade 1 ILD fully recovering after temporary drug stop, DS-8201 treatment could restore it. Left Ventricular Ejection Fraction or LVEF was an important safety concern given the history of such toxicity with prior HER2 targeting therapies. Despite intensive monitoring for detecting any such LVEF toxicity, especially at the FDA's request, no drug-related signal was observed with respect to cardiac toxicity. The ILD. Here we need to spend some time. 25 subjects reported adverse event adjudicated as drug-related ILD by the ILD adjudication committee. Majority were Grade 1 and Grade 2, one was Grade 3, and four cases were fatal cases. All these fatal cases have been previously reported, in particular during the ASCO June 2019 investor call. They occurred before the ILD Safe Use Campaign was initiated.
We will come back to this later today. How do these data compare? Obviously, on the left-hand side is the CLEOPATRA regimen. It's a combination of dual HER2 suppression with trastuzumab and pertuzumab, combined with docetaxel. This regimen is a firmly established gold standard for first-line treatment of metastatic HER2 breast cancer, and it provides a solid 18.5 months progression-free survival. On the right-hand side is DS-8201 after a median of six prior lines of treatment in the metastatic setting. PFS at 16.4 months is extremely impressive. Drug clearly warrants both bold and safe development attempts in the earlier line metastatic setting in early breast cancer as well as in other tumor types. What have we seen so far? ADCs started in 1913, and it took until now to really break through. 2020s will be the ADC decade.
DS-8201 is first and foremost a massively advanced technological breakthrough. It was designed to achieve breakthrough. It delivers unique practice-changing evidence. Breast cancer doctors do not think ILD. This is why we do not shy away from discussing the importance of monitoring and actively screening and treating any suspicion of ILD. Everybody talks about acceleration and expansion, and that will be a critical point going forward. I want to take a moment to recognize just what we, Daiichi Sankyo, have accomplished. The first subject dose in the first human trial for DS-8201 was September 2015. The Biologics License Application submission took place in August 2019, in under four years. This is a remarkable speed in development, in plan, and delivered by Daiichi Sankyo on its own.
This was coupled with a massive manufacturing scaleup thanks to delivering on the dot the benefit of a JPY 300 billion CapEx triggered in July 2016 on the basis of my views and a handful of patient data. Now the cherry on the cake. KEYTRUDA, a well-established drug, is currently the second fastest U.S. biologic ever. From first time in human to market in the U.S. took 4.5 years for KEYTRUDA. DS-8201 can possibly break this record. In order to maximize the product value of DS-8201 and allow us to support independently the rest of our portfolio, as you know, we signed a global development and commercialization agreement with AstraZeneca in March 2019. AstraZeneca has, of course, an extensive experience in the global resources for oncology. We have a Sorry. We may receive up to $6.9 billion from AstraZeneca.
We believe that the establishment of our oncology business will be accelerated through jointly designing and implementing various strategy with AstraZeneca. We believe that this collaboration will maximize the value of not only DS-8201, it will also allow and help Daiichi Sankyo as we are independently developing our other ADCs as well as our other oncology project in the future. I will not read this slide, but it does provide concrete evidence of the immediate benefits of the AstraZeneca collaboration. From a seamless collaboration as we were finishing the regulatory submissions and met all prior deadlines to an ambitious plan going forward. Can I have my tea, please? Thank you. Sorry. In a nutshell, the benefit of a collaboration is to be able to be both bold in our development option as well as safe and secure. More traditional step-wise progression in development.
In particularly, we have updated the joint clinical development plan and added 26 new studies, which I will present only directionally. Very concretely, it is clear that the Daiichi Sankyo AstraZeneca collaboration fully finances the DXd ADCs development. For DS-8201, this is at a speed and scale Daiichi Sankyo alone could not have supported, while we are also preserving Daiichi Sankyo's ability to progress the rest of our portfolio. Next fiscal year 2020, we're planning to spend externally for DS-8201 approximately 175% of the current spend for the current fiscal year on the Daiichi Sankyo part. 175% of what we're currently spending. For DS-1062 and U3-1402, we're also planning to increase our spend by approximately 175% on these two assets. On that basis, what is our obligation for DS-8201? It is clearly to transform the treatment for patients who have HER2 disease as they will be newly defined.
For HER2 metastatic breast cancer, it is to establish AT201 as a new standard of care in HER2 positive breast cancer and optimize the role of DS-8201 in early breast cancer setting. For the HER2 low metastatic breast cancer, it is to redefine the breast cancer treatment paradigm. Finally, it is to expand leadership across other tumors. This slide is here to briefly explain what we mean by changing the breast cancer clinical paradigm. For 20 or 20+ year, breast cancer has been categorized at diagnosis with a status sticking throughout the entire disease and treatment history, just like you're stuck in a swimming lane. DS-8201 by offering a possible treatment intervention on a basis of a new marker, has a potential to break these lanes and shift how the disease is fought off and cared for.
Concretely, we are planning to start 16 new studies in the next 18 months, distributed as shown on this slide between the plan for new standard of care in HER2 breast cancer, the redefinition of breast cancer treatment paradigm, and the expansion beyond breast cancer. Here is a more traditional view of a directional clinical development plan now comprising 43 studies. As backup, you will find two charts, one for breast cancer and one for non-breast cancer clinical development plan, which gives you placement of these studies relative to future standard of care in a group of seven countries, the G7 group of seven countries. A quick note to finish on the alliance. We are here to transform treatment for patients with HER2 disease. Our obligation to patient is beyond what one company can achieve alone. We are very proud, I'm very proud personally of this collaboration.
Moving on to the next ADCs. Here is DS-1062, our TROP2 ADC, probably our second most interesting asset. I think you will agree. We are very proud of this DAR4 technology, as it allowed us to more precisely create a better therapeutic window. The next few slides I will present rapidly as these are slides which were presented after the World Conference on Lung Cancer in September. Here's a phase I, first in human study design in non-small cell, not selected for TROP2 expression, after failing immunotherapy for greater than 85% of subjects. Maximum tolerated dose was reached at 8 mg/kg , both the 6 mg/kg and 8 mg/kg are now under expansion cohorts. This is a waterfall plot across all diseases, which we have all seen before.
A famous dose effect spider plot with a cutoff date of July 2019. Here is a slide summarizing safety as was observed last summer and presented at World Conference on Lung Cancer. I'll update the ILD in a moment. Now is the interesting part. Here are preliminary efficacy data up to November 16, 2019, data which have not been presented before except 48 or 36 hours ago in Tokyo. With a total of approximately 60 subjects, we continue to see good and compelling tumor response with a dose effect, and now with durability of response. What does it mean for Daiichi Sankyo? DS-1062 continues to appear to be and have the characteristic of a drug to be. It maintains clear activity, dose effect, durability, and tolerability with obviously ILD to watch.
DXd portability is further established, adding the technology of DAR4 and reached DAR4. That technology is validated. Driven by the emergent non-small cell lung cancer data, we believe the differentiation versus IMMU-132 appears highly credible. We clearly see a fast to market path in the U.S. emerging in non-small cell lung cancer. The non-small cell development plan is fairly simple. As a phase I expansion accrues and matures, a pivotal monotherapy phase II study in non-small cell without actionable mutation and after IO will be set up as soon as feasible, approximately second half of calendar 2020. This will lead to a randomized phase III versus docetaxel plus/minus ramucirumab, aiming at a post-approval commitment. Obviously, we still have to consult the FDA on this plan. In parallel, should the early result in Epidermal Growth Factor Receptor mutant confirm themselves, a parallel track in EGFR mutant might be pursued.
Finally, we'll start as soon as we can phase I IO combination with key players, meaning pembro, nivo, and durvalumab as enabling study for an eventual first-line randomized study versus IO or IO-chemo. On to U3-1402, our HER3 DXd ADC with a drug-antibody ratio of 8. Again, quickly review that the slide of phase I study in EGFR mutant lung cancer failing TKIs. These data were presented also at the World Conference on Lung Cancer. Here is the waterfall plot and the interesting tumor control and response profile observed regardless of the underlying mechanism of resistance to the prior TKI-based line of treatment. What does it mean for Daiichi Sankyo? U3-1402 appears active in non-small-cell lung cancer. Targeting HER3 with U3-1402 may be a practical approach to treat EGFR mutant non-small-cell lung cancer. Only 14 out of 82 subjects responding.
The disease control rate stayed high at 89%. What have we learned? As I will show in the next slide, HER3 expression in breast cancer is more variable and heterogeneous than we anticipate. Immunohistochemistry detection, even if specific, might not be sensitive enough to best detect the breast cancer population most likely to benefit. We know the drug works. We just have to find how. Kinetics of the HER3 receptor in breast cancer is clearly different from that of HER2 in breast cancer and HER3 in lung cancer. I'll show you some data. Let me show you some data supporting these observations. First, based on fresh biopsies right before treatment in 43 subjects, the best overall response rate shows that all responses observed, which are in green color, are in the IHC high group on the left.
However, IHC does not enrich matching responses, which are still only six out of 31 subjects in the IHC high. Second, on the left panel, we know now that HER3 expression frequently varies in breast cancer over time. This is shown here comparing HER3 expression level on archival biopsy testing, meaning the initial biopsy, and on the fresh pre-treatment biopsy. This is an important finding that as unlike HER2, which is highly stable in breast cancer, or HER3, which is also highly stable in EGFR mutant post TKI, HER3 in breast cancer cannot be predicted based on archival sample.
More importantly, on the right panel, you see that under treatment with U3-1402 in breast cancer, the level of HER3 expression seems to consistently drop between immediately pre-treatment and day 42 on treatment. Finally, these dynamic receptor expression changes are consistent with the observation we make regarding the payload Cmax.
For U3-1402, as shown on the top left panel, the payload Cmax at Cycle 1 appears double of that at Cycle 3, at both 4.8 mg/kg and 6.4 mg/kg . This is higher exposure and different compared to DS-8201 on the right-hand panel. This is consistent with thrombocytopenia shown in the bottom panels, which is more pronounced during Cycle 1 for U3-1402 and virtually inexistent for DS-8201. We're beginning to see that in breast cancer, HER3 receptor is not a typical receptor. It's highly variable over time, under treatment, and it affects the kinetic of a payload release. In lung cancer, experiment made at Dana-Farber Cancer Institute by Pasi Jänne show that unlike in breast cancer, there is a sustained internalization rate of U3-1402 in EGFR lung cancer.
This is true for monotherapy in the black line, and it further increases and is sustained in combination with osimertinib in the red line. We are obviously actively discussing with AstraZeneca on how to further test this in human and test these hypothesis. What does it mean for Daiichi Sankyo U3-1402? In lung cancer, EGFR mutant presents a clear monotherapy opportunity. HER3 is consistently expressed and internalized post TKI, HER3 is probably a likely passenger expression of EGFR TKI resistance. The combination with osimertinib is also being pursued. In breast cancer, the biology of receptor dimerization, internalization, trafficking is substantially modified by yet unknown factors. Intensive translational research is now ongoing at the Memorial Sloan Kettering, at MD Anderson, with the SOLTI group in Europe and others, as well as Gustave Roussy.
This likely will create an 18-24 months delay to be able to select the subject with highly sensitive tumors. We know they exist. We just can't select them now on the basis of even a fresh biopsy IHC. Colorectal and prostate cancer phase IIs are planned and progressing. We have initiated, as you know, a clinical trial with our fourth DXd-ADC conjugate, DS-7300, in collaboration with the Sarah Cannon Research Institute. The first-in-human phase I/II study evaluating DS-7300, a B7H3 ADC, is in patients with advanced or unresectable or metastatic solid tumors. B7H3 is a protein which is overexpressed in various types of cancers. Again, here we have chosen a DAR4 construct. B7H3 is a member of a B7 immune checkpoint family, including PD-L1. The role of B7H3 is actually currently unknown. The precise function is not elucidated.
We know it is expressed at high level in multiple solid tumors with low expression in normal tissues. This particular DXd-ADC was designed with the selective Drug-to-Antibody Ratio 4 to mitigate any potential for toxicity. Here is a phase I design, fairly typical now. A number of tumor types are considered, head and neck, esophageal, non-small cell lung cancer, bladder, et cetera, with a mandatory fresh biopsy at study entry, no selection based on B7H3 expression. We're planning to expand in three pre-specified tumor type, squamous cell carcinoma of head and neck, squamous esophageal, and squamous non-small cell lung cancer. This first-in-human phase I dose escalation is ongoing with active site both in the U.S. and Japan. Here is the fifth ADC soon, very soon to enter the clinic as well. This one is a plain DAR8 .
GPR20 is highly specific for Gastrointestinal Stromal Tumor. This will be tested with George Demetri at Dana-Farber Cancer Institute. Here's again the study design. It's a typical design for our ADC first time in human studies. Extension will be clearly in GIST. Now an update on the DXd ADC platform ILD experience. As you will recall, early in the current calendar year 2019, we initiated for DS-8201 a phase I investigator safe use campaign for the ILD detection and management. Goal was to drive ILD awareness, detection, and management. With AstraZeneca, we created a comprehensive education for medical science liaisons. We developed tools for the Medical Science Liaisons to use in proactive direct communication with treated physician. We developed internal understanding and external communication plans. We directly targeted healthcare providers, prioritizing investigators with patients under treatment.
We ensured continuous education and top-of-mind status through numerous outlet, in-person, online, et cetera. We gave Healthcare Professional tools to reduce ILD severity and improve management. Finally, we developed resources for patients themselves. We provided education of patients around the risk of ILD and the need to self-monitor for symptoms. The purpose was to drive awareness and give patient tools to support detection and management. We are extremely pleased with the effect of this campaign. With respect to DS-8201, the critical finding is at the bottom of this slide. After the initial phase I safe use campaign was initiated, majority of the new cases were low grade, Grade 1 and Grade 2, and only one subject was diagnosed with a Grade 3 ILD. No new Grade 4 and Grade 5 were reported program-wide at a dose of 5.4 mg/kg . Let me repeat, just again.
No new Grade 4 or Grade 5 was reported program-wide at a treatment dose of 5.4 mg/kg . The next slide. I'm sorry. You messed up. Just go back on the script, please. Yeah. Good. Thank you. For U3-1402, I'm just confused. Yeah, we good. I'm sorry. It's Yeah. Other things on this slide. The adjudicated drug-related any Grade ILD for DS-8201 increased from 8.2% to 13.5%. The new adjudicated related ILD events included two Grade 1, seven Grade 2, and one Grade 3. Discontinuation associated with TAE increased from 8.2% to 15.2%, mainly driven by the new event of low-grade ILD. For U3-1402, of 205 subjects treated, nine had adjudicated drug-related ILDs with one case of Grade 5 fatal outcome.
For DS-1062 of 88 subject treated, 4% or 4.5% had adjudicated drug-related ILD with one case of Grade 5. Daiichi Sankyo and AstraZeneca has convened an advisory board consisting of oncologists and radiologists in order to discuss the ILD management algorithm and their current inclusion and exclusion criteria. As a result, the management algorithm of ILD has been updated in consultation with the FDA, and a new phase of a safe use campaign has started across the ADC franchise. The algorithm is even more prescriptive with respect to how to manage the patient, and we are assisting treating physician in how they manage the ILD risk for patients. The inclusion and exclusion criteria have been refined to exclude patient that could be at higher risk of developing ILD. Finally, the three and Alpha Strategy
Our clear focus now is on the ADC, as you may have sensed. We nevertheless do not want to leave beyond our obligation to continue discover great medicine and integrate great technology to produce a steady flow of first or best-in-class drug, as Koga-san just explained before me. Daiichi Sankyo is probably one of the best discovery machine, and it is our pride and our duty to deliver the value stemming from our labs. To that effect, we keep critical attention on the potential of the alpha asset to contribute to a robust science and technology-driven portfolio. We want to maximize the development of the three ADCs with breadth and depth expansion and fully leverage the value of our collaboration with AstraZeneca.
Regarding DS-1062 and U3-1402, we aim at a swift and independent development of these next ADCs. To maximize value of development, we look rigorously at every various opportunities for indication development, and we applied strict prioritization. Illustrated here is evidence that out of 38 indication that could be pursued for DS-1062 and U3-1402 combined, the top 17 indication of these 38 give approximately 90% of the value and require approximately 60% of clinical supply, and not only here, but approximately 55% of the R&D costs. On the graph, you see that on the y-axis is a measure of value, which is approximately the first 10-year value minus the development cost. In the x-axis, you have a number of supplies needed. We use similar analysis for R&D spend, complexity, and we reach very consistent conclusions.
Interestingly, the first two indication at the bottom of the graph, the non-small cell lung cancer EGFR wild type post Immuno-Oncology second line for DS-1062 and the first line for DS-1062, both of these indication represent approximately 50% of the total value. Our prioritization is extremely clear. What is the three and Alpha Strategy ? Koga-san briefly explained that. In my world, this is to deliver the full value of a three ADC and to ensure longer-term performance that will exceed by far the benchmark of a great three ADC portfolio. Alpha is the angle of attack, in my mind. It's the speed of innovation, the cutting edge, the power of our innovation. It is to deliver drug that truly change standard of care. This is how we describe the major R&D pipeline. We do recognize we do not have handy a fully scaled operation delivery machine.
Daiichi Sankyo is still new in the field of large scale, massive drug development in oncology. The ability to secure our success through typical transactional fee for service relationship with Contract Research Organizations is modest. It's not specific to Daiichi Sankyo, it is true for the entire industry. To resolve for our opportunity, we met with the CEO and the leadership teams of all major CROs and are in the process of finalizing what we call the ADC Development Coalition with a selected CRO. This is a new integrated delivery model meeting both companies' needs, and it goes beyond the traditional penalty discount and earning back incentives, which are typical in the fee for service transactional relationship.
Key characteristic of this coalition are listed here. I will not read them, but needless to say that we are extremely excited that these new ways of working will uniquely serve our one-of-a-kind portfolio.
Finally, the news flow and future events. Here are the critical news flow we anticipate for the next coming six to nine months, first for DS-8201 and DS-1062, as well as on the next slide for U3-1402, pexidartinib, and G47Δ. I will stop here, and I think we will take questions from that point on. Thank you very much for your attention.
Thank you, Antoine.
Hello. Hi, Hidemaru Yamaguchi from Citigroup. I have three questions, which are different question I didn't answer in the Tokyo version. I give you a new question. The first one regarding the general strategy about the second and the third ADC, and also you got the fourth and fifth. The first one already done with AstraZeneca, but second one, the third one, do you have kind of a timeframe and idea? Are you going to have a co-development partner in the future, and how about fourth and fifth? That's the first question.
We are equipped, willing, able, and committed to develop these ADCs independently so far.
Well, I may have some comments. To maximize the value of DS-8201, we started the collaboration with AstraZeneca. We'd like to maximize the value of second, third, and the following ADCs. As you know, the critical trials of second and third ADCs ongoing, which was explained by Antoine. We can give the top line result early next fiscal year around ASCO. I think that is a very good timing to start discussions about our development strategy. One of the options is, of course, partnering. That is a good timing for us.
How about the fourth and fifth, which is outside of van city and alpha? It's a four and fifth, especially on the fourth one, that's DS-7300. Is that also kind of giving up to the Sarah Cannon, or is that something you're going to do by yourself?
I'm sorry.
Go ahead.
The collaboration with Sarah Cannon is just an academic research organization. Sarah Cannon and David Spigel. David Spigel is a good friend. Sarah Cannon has tested as in the world, the largest experience of first time in human with ADCs. They have tested more than 30 new ADCs. They have by far the largest experience. They are the best partner for us to actually figure out quickly the safety and activity profile of our drugs. This is why we're partnering with them.
Okay. The second question is that you talk about ILD and thank you very much for the update, especially on the DS-8201. In a general term that you understand DS-8201 ILD situation much better than any other drug because you have done the campaign. Regarding the DS-1062 and also, sorry, U3-1402.
Yes.
Compared between the two, which one are you more, not concerned, but you have to be careful about the ILD situation between the two agent, either HER3 and the TROP2 ?
I've presented you with data which had not been presented before with respect to the ILD update, just like it is clear that the DXd platform shares an ILD risk. We have to pay attention on how we observe, mitigate, and reduce the risk across all three. I don't think we can say anything more than that. We have to be careful about this. This is typical drug development. The last thing you want to do is to ignore the risk. We actually are much better proactively recognizing the risk, finding the risk factors if there are any, and we're working on this. So far, we've identified only two risk factors, maybe a third one. Two risk factors are the dose and the exposure, and the second is the Japanese descent.
There's a third one, which is not completely significant, but it's likely, which is a prior treatment, the amount of prior treatment received, any prior treatment received by patient, which is making biological sense because these patients. ILD is not specific to DXd. ILD is actually a very common drug-induced toxicity for a lot of cancer drug and non-cancer drug. I think there are 340 different drugs with ILD, recognized ILD. The lung is probably an organ where you accumulate insults, and at some point, you just tip over. Having prior exposure to multiple line of treatment as a risk factor is plausible, but there's nothing more that we can say at this point in time. We are paying attention a lot to all ADCs and ILD.
We have a dedicated, essentially, ILD Czar internally, somebody who only looks at ILD and make sure that the campaign and the assessment and risk factors and everything is done to the best of what we can.
The last one is that has nothing to do with your company, yesterday, the enforcement visiting of other companies, the ADC has been approved three months ahead of the PDUFA date by the U.S. FDA. I don't know anything about your company, is there a possibility that your DS-8201 is also approved prior to the PDUFA date?
I'll be very careful here, obviously. Literally to your question, is there a possibility? Yes, there is absolutely a possibility that DSA221 is approved by the FDA prior to the PDUFA date. Let me remind you is that we are probably 130 days still from today to the PDUFA date, there's 130 days. The PDUFA date is April 29th. That's all we can say. The review is actively progressing. We're not committing any further. We obviously will let you know as soon as we can. No, it's not.
Thank you.
Thank you.
Other question? [audio distortion]
Hi, Carl Brown from Axiom Investor. Specifically on ILD, could you talk about what are the protocols that you've given to healthcare providers to help them identify cases of ILD earlier? When you say that post the implementation of these protocols that the rate rose from 8%- 13%, what are we comparing? Are we just comparing within the 8201 study, the DESTINY-Breast01 study that we were saying that we were tracking at an 8% rate, and then the new protocols went into place and that caused it to rise to 13%? Are we comparing two other rates?
Okay. I like you guys. You have sharp questions. To your first question, what is the protocol? The protocol to, especially for breast cancer and especially with the kind of activity that the drug has, the biggest challenge we have with both docs and patients are the fear of being forced to interrupt the treatment because of ILD. The protocol is to recognize and characterize ILD, to make them aware of the fact that ILD presents itself low grade as a very, very non-specific and non-bothering. These are very minor symptoms. It can be a low-grade fever on and off, it can be a little shortness of breath, it can be a little cough. It's very easy to attribute any and all of these symptoms to something else. You had prior metastases, you had lung chest irradiation.
Your kid has a cold, and you also have a little runny nose. To just attribute any and all of these symptoms to something else because the drug is so active and just not deliberately, but naturally, instinctively turn an eye away from non-specific symptoms. That's one of the thing which is to have top of the mind, any time they see a patient, they must screen out the potential of ILD, make sure that there is really no sign and symptom which suggests ILD. The first thing you do then, if you have a suspicion, you do high-resolution CAT scan of a chest to see if there's any ground-glass opacities. If you have any sign or symptom, then you also do blood gas, arterial blood gas, you do gas exchange, you investigate any sign. That's the very first thing.
The second thing we obviously do is that if there is anything, you stop the drug, you screen again if it is low grade, or if it is high grade, if it is Grade 2 and above, you actively treat, which is high-dose steroids. That's your first question. Your second question, the 8%-14%, what are we comparing to? We are comparing to the initial data cut and the more recent updated data cuts. The initial data cut in the submission was back in March, if I remember well, or April. It was March of 2019, and part of a normal process with the U.S. FDA is that we always update in so-called 90-day safety update post-submission, and that's the difference. The difference is between the initial observation and then with more follow-up.
Remember that the last patients was enrolled in this phase II study in September of last year, so we now have 18 months. We started the safe use campaign in January, February of this year, so meaning five months after finishing enrollment. In the safe use campaign, what we've observed is that from March, which was the first data cut, to the latest data cut, this is where we observe nothing new.
Yeah.
The increase in the frequency of low grade, which is exactly what we want. We absolutely want that. We want to have more, and we want to over-diagnose and then screen and then see if it is ILD, yes or no. Avoid patients. And yeah. I hope I've answered your question.
If I may, I may just add one thing. You are interested in the protocols of how we deal with ILD. I suggest you look at The New England Journal of Medicine. There is a supplement there that exactly explain our approach to ILD identification, treatment, et cetera.
Yeah.
Hi. Ron Su from Artisan Partners. I just have a question on DS-1062. Is there a reason you didn't give a explicit plan to study the drug in triple?
I'm sorry, explicit what?
Oh, is there a reason you didn't give us explicit plan to study the drug in triple-negative breast cancer, given the higher expression levels of TROP2 in that tumor type? If you did, do you think you would have to run a head-to-head study against IMMU-132?
We have planned to expand beyond lung cancer, obviously. We have not listed which tumor types we will test DS-1062 next. I've shown you that graph where we looked at all indication across U3-1402 and DS-1062. You can see the gray dots and the blue dots or whatever dots there are for different indication across the two assets. Triple negative is obviously part of that, we have not disclosed which tumor types we're going next beyond lung cancer, monotherapy and IO combination. With respect to your question of a head-to-head, you need to run a head-to-head comparison once the drug is fully approved. We obviously wait to see what the fate and future of IMMU-132 is compared to our own data. That's as far as I can comment. We certainly believe that the two drugs have different characteristics and certainly different profiles and potential.
Sorry, the last one I forgot to ask. Regarding the HER3, you talked about the HER3 is unstable depending on the situation, but regarding TROP2, did you find something in the similar situation where it depends on the cancer or depends on the situation, TROP2 is stable or not stable?
TROP2, the amount of expression on a protein basis between HER3, HER2, and TROP2 is actually two logs. HER3 is expressed at 1%, HER2 at 10% and TROP2 at 100%. Really, in your 10 x more TROP2 compared to HER2 and only 10% of HER3 compared to HER2. The amount of protein expression is highly different between these different receptor. That's number one. Number two is that TROP2 seems to be highly stable as far as we know. We've not observed, but this is a new science. We never had the tools to pharmacogenetically understand what happens with these ADC receptor expression. We're discovering a new science. This is why we are transparent with you and say HER3 definitely works. I mean, the drug works. We have multiple examples of tumor regressing after failing everything and so on.
We know the drug works. We just have to figure out how to select the patient and/or modify or stabilize the HER3 expression so that we can carry the effect. There are other ways of doing it that you can combine. For instance, you have dimerization between HER2 and HER3, we also can have combination between ADC. There's a lot of things we can do. We just have to do the work. TROP2, the result I've presented are patients who are not selected for TROP2 expression. They're not selected. So far, we have not published, but so far, we didn't see a great correlation between medium and high expression of TROP2 and the intensity of the activity, which means that probably there's enough TROP2 in these cancer cells, no matter what, to absorb all of what is needed to release the payload and have the bystander effect.
There's much less concern for TROP2.
On this one that you're checking TROP2, even though it's not selected, but you're also checking TROP2 status.
Correct.
It's never really disclosed as far as the relationship between the positivity and the efficacy so far.
We have not disclosed that so far. I'm just telling you [crosstalk] t he primary data are not [crosstalk] s uggesting there's a massive [crosstalk] correlation. We will disclose at American Society of Clinical Oncology. We will report at ASCO.
Okay, because I got a lot of question on this 8 m things that nobody can read, but people trying to read as much as they can.
Yeah. Of course.
Can you say the OR rate on this one is that around 40/50, or it's hard to say?
It's hard to say. Yes, you're absolutely right.
It's hard to say. Okay. All right. Thank you.
It's not typical to disclose new data on the day. I don't want to disclose any more than what we have. Here, what you see are obviously We have many more patients treated, and this is a data cut we have as of mid-November, and obviously, this is six weeks old because you are on this graph only if you have at least one scan. It just shows you a few things. Number one is that there are many more patients. We're expanding at six and eight. You also maintain the same dose effect as what we have observed so far. Suffice it to say that our CEO and board agreed to invest JPY 100 billion in CapEx in manufacturing of ADCs. We are relatively confident in what we're observing so far with TROP2. I'm not going to tell you where the dots are.
Okay. Any other questions? A little bit too early to close that event, but if you don't have any question, I would like to close this event.