Genmab A/S (GMAB) Earnings Call Transcript & Summary

Thank you for joining us today for the Genmab Capital Markets Day. Please welcome Jan van de Winkel.

Good morning, and good afternoon from Genmab's state-of-the-art facilities in Princeton and Utrecht. I'm Jan van de Winkel, President and CEO of Genmab. Our 2020 Capital Markets Day event may look a bit different than in the past years. Since for the safety of all participants and attendees, we are fully virtual this year. But as always, we have many exciting presentations for you from a variety of Genmab speakers. And we are looking forward to a lively Q&A session at the end. So slides from today's presentation will be available for the download on our website immediately following today's event. As a reminder, this presentation may contain forward-looking statements, and as such, may contain certain risks and uncertainties. Next slide. I'm really pleased that today, you will have the opportunity to hear from a variety of Genmab team members, all of whom share a passion for our core purpose of improving the life of patients. And so it now gives me great pleasure to introduce today's speakers. Today, you will hear from our experienced executive management team, including myself, our Chief Development Officer, Judith Klimovsky; our Chief Financial Officer; and Anthony Pagano; and our Chief Operating Officer, Anthony Mancini. We also have exciting slide presentation for you from Tahi Ahmadi, our Senior Vice President and Head of Oncology; Kate Sasser, our Corporate Vice President and Head of Translational Research, David Satijn, Vice President of New Antibody Products and Rob De Jong, our Director of Antibody Research and Technology. So let's now turn to our agenda for today's events. In 2018, the focus of our Capital Markets Day was transformation and our plans for the future. And now just 2 years later, I'm extremely pleased to tell you that the future we are planning for is clear. And now, we are well on our way not only to within ambitious 2025 vision of launching our own products, but also to evolving into a fully integrated biotech innovation power house, supported by our strong financial foundation, maturing and expanding differentiated pipeline, our next-generation proprietary antibody technologies, strategic partnerships and growing capabilities. If you want to hear Genmab's story, well, then join for a great treat. As we may have been in business for 21 years, our exciting journey has truly only just began. As you can see here after a brief introduction, we'll move to Princeton and Anthony Pagano will provide you with an overview for strong financial foundation. And next Judith Klimovsky will share an overview of our innovative differentiated pipeline and our growing world-class capabilities. We'll then come back to Utrecht for presentation for Rob De Jong and David Satijn on our innovative next-generation antibody technologies, including a closer look at our truly differentiated DuoBody technology. And then we will seamlessly move back to Princeton to hear from Tahi Ahmadi, who will share the exciting first clinical data from DuoBody-PD-L1x4-1BB that was also unveiled this week at SITC. And then Kate Sasser will give you more information on translational research and approach to data sciences. Anthony Mancini will then set a stage for a discussion of late-stage assets, epcoritamab and tisotumab vedotin, including how we are preparing to meet the unmet medical need of patients and move them into the commercial space. So let's get started with today's event. I'll review just why we are so effective in progressing and progressing well on the road to reaching our ambitious 2025 vision. For over 20 years, we have not wavered in our commitment to Genmab's core purpose of improving the lives of patients by creating and developing innovative and antibody products. In 2010, we linked these core products to an extremely effective strategy. By focusing on our core competencies of being able to identify the best disease targets, develop differentiated next-generation antibody technologies and creating unique best-in-class or first-in-class antibodies, And this day, we have been able to turn Genmab's innovative science into medicines. This has effectively allowed us to build a profitable and successful biotech. I'm extremely pleased with our track record of success, but we are only just getting started. We are getting very close now to successful achievement of our 2025 vision to have our own product on the market that has transformed cancer treatment. Next slide. We have been so successful and are so close to achieving our vision because Genmab is a world-class antibody innovation powerhouse. This is the phrase you may have heard from me many times over the years, and today, we will share with you how our innovations are already transforming cancer treatment and why we are so confident that we are building a company that can go even further. Because we are not only an innovation powerhouse, but also an integrated 1 with growing capabilities and strategic partnerships that are allowing us to evolve into a fully integrated biotech. So now let's take a closer look at what exactly we mean when we say innovation powerhouse. Earlier this year, the journal Nature published a very impressive paper. It is quite a key transformative way to drug development all the time. Starting with Aspirin, which you all know, it took more than 30 years before its mechanism of action was identified. People knew that it works, but not how it works. And of course, it's the how that today allows us to create more effective and targeted medicines for patients. The first monoclonal antibody was out of the market in the mid 1980s. And now there are over 90 FDA-approved antibody therapeutics available to patients. Biologic drugs are playing an ever important role in medicine, especially as they are evolving. Starting with Mylotarg, the prototype molecule medicine, targeted medicine against acute myeloid leukaemia and now the next wave of innovation focuses on multi-specific drugs as you see here on the slide. This includes bispecific antibodies that are responsible for over 60% of the growth of the antibody market over the coming years. Well, and we have actually over 75% of Genmab's pipeline based on our DuoBody technology, including therapeutic candidates and our proprietary clinical pipeline like epcoritamab and DuoBody-PD-L1x4-1BB and assets in our partners' pipelines, including Mim8 by Novo Nordisk, which has just launched into Phase II in the past few weeks and amivantamab by Janssen. This is already in a very large randomized Phase III and Janssen is preparing for filing this year with the FDA. The rest of all pipeline is either created via HexaBody, HexElect, or next-generation ADC technology. So we are excellently positioned for transforming the treatment of cancer, with a unique multispecific antibody drugs. Next slide. While our world-class insight into antibody biology and disease targets positions us well to create novel and differentiated therapeutic candidates, we know that working collaboratively with strong partners will take us even further. Some of our strategic partnership provides us with access to high-quality unique disease targets and cutting-edge technologies or else, like our collaborations with AbbVie, Seagen and BionTech will help us bring our next-generation antibodies to patients and needs much faster than we could do on our own. And of course, partnerships have also provided us with the financial foundation for our current success. DARZALEX is now a backbone therapy for multiple myeloma, with the potential to expand even further with this year's approval of the convenient subcutaneous formulation and the recent submissions in the U.S. and Europe for a new indication, Al amyloidosis. In 2020, we also had the highly anticipated approval in the U.S. of Kesimpta, a subcutaneous ofatumumab formulation for treatment of relapsing MS by Novartis as well as the very rapid approval and extremely successful launch of TEPEZZA for treatment of thyroid eye disease by Horizon Therapeutics. To share with you more about Genmab's very strong financial foundation, I would now like to welcome Anthony Pagano, our CFO, Anthony, the floor is yours.

Great. Thanks, Jan. We've never been in a better position to achieve our vision of transforming the lives of cancer patients and at the same time, create value for shareholders. My objective today is to explain why I say that with such confidence, and I want to start by reminding you of the very strong foundation we've built. You can see the key elements here. First, at the very core is great technology. We've built a rich pipeline in several novel technology platforms. In fact, we're excited by the prospect of potentially launching 2 of our own product candidates in the coming years. Second, we're leveraging partnerships with industry leaders and innovators to enable us to do more and faster. Third, we've got a very focused and disciplined approach to investment and capital allocation. We're seeking to drive better outcomes for patients as well as ultimately create shareholder value. Finally, another cornerstone of our foundation is the strength of our financials, sound balance sheet, and growing recurring revenues affords us a great platform to invest for the future. So let's look at those revenues in a bit more detail. Our successful investment strategy is enabled by these growing recurring revenue streams. Assuming we meet consensus expectations for 2020, and we think that's a reasonable assumption that will have increased our revenues fivefold since 2016. What's even more encouraging is that we've grown the recurring revenue component, shown in the green bars here by nearly 9x over the same period. There are 3 drivers of these recurring revenues. First, DARZALEX. And here, we're looking forward to further growth as DARZALEX continues to transform the treatment of multiple myeloma. Then we've also Kesimpta and TEPEZZA, which were launched earlier this year, both our potential blockbusters according to Novartis and Horizon Therapeutics. And of course, that all adds up to significant cash flows which we can use to invest further in the business to deliver our vision. And as you can see on the next slide, we're well on our way. Our 2025 vision has acted as a guiding light for us. It's focused us on our core purpose to meaningfully impact the lives of cancer patients. And today, we've reached an inflection point where we find ourselves with 2 potential product launches in the next couple of years and with more to come. And that's a great place to be. But it also means we've now reached a point where there's a strong rationale to invest. We've got all the ingredients to become a fully integrated biotech powerhouse. Let me expand on that. We want to get our pipeline and especially our 2 near-term product launches to as many patients as possible, and we want to do it as quickly as possible. As you can see, we plan to retain at least 50% ownership of our pipeline products. We also intend to directly influence and control the development and commercialization of our new products. Clearly, we're bringing the team and capabilities to enable us to succeed in this as well as driving better patient outcomes, this will capture more value for our shareholders. Ultimately, this is about focused execution. So how are we going to do that? You can see here the 3 key areas where we are investing. First, in research. We're investing to ensure that we can build on our strong track record. As you know, we've invested in state of the art facilities in the Netherlands and here in Princeton, and we continue to invest in new technologies and formats. Second, for development. We're really focused on scaling up so that we can expand from early to late-stage development. And third, we're also investing significantly in commercialization. We've put a strong leadership team in place, and we're now expanding the team to enable us to bring our new products to market. Underpinning all this is investment in key enabling functions to both support growth and manage risk. Finally, we see significant potential to drive insights through data sciences all across our value chain. So we're investing to do just that. So that's the theory. What does this look like in practice? What you can see on the next slide is our priorities for where we are going to invest. On the left, you can see our priorities for today. Priority number 1 is filing and launching tisotumab vedotin; two is accelerating the development and launch of epco. three is expanding DuoBody-PD-L1x4-1BB. And priority number 4 is standing up our commercial capabilities, both here in the U.S. and also in Japan. This is essential to realizing our full potential. So these are our immediate priorities. You'll hear a lot more about these from the team later in the session today. But we're not just focused on today. In line with our vision, we're also very focused on long-term value creation. So here, we're investing to progress our early-stage pipeline and to generate the next wave of IND candidates. We're also investing to ensure that we maximize the value of our current technologies and that we stay right at the forefront of antibody science. And finally, we continue to look for good ideas and innovation outside the 4 walls of Genmab, including adjacent technologies. So while on the subject of external opportunities, let me turn now to partnerships. We've achieved a huge amount with partnerships over the years. And it will remain an important part of our business as we look to the future. But not surprisingly, we're evolving the nature of the partnerships we sign up to. And you can see the evolution on this slide. Clearly, our historical partnerships based on out licensing, have been great for generating the very significant cash flows that underpin the business today. But as you know, we're now focused on partnerships, which give us more control and the ability to get to more patients and faster. And going forward, partnerships will continue to play a vital role as we build out our business. They allow us to bolster our internal strengths while leveraging external ideas, and capabilities. So hopefully, by now, you've got a good feel for the strength of our foundation, the clarity of our strategy, our priorities for investment, and our continuing appetite to create value through partnerships. What does it all add up to? This next slide shows what consensus expectations are for our recurring revenues over the next 5 years. As you can see, the future looks very promising. Just looking at our 3 existing products, our recurring revenue is expected to grow more than 2.5x. On the left, you can see the component parts of our future recurring revenue streams. As I covered at the start, that's DARZALEX, Kesimpta and TEPEZZA. And each of these products are well positioned provides significant cash flow and growth in the years to come. As potential upside to our existing royalty streams Janssen is making significant progress with their DuoBody programs. Most advanced is Amivantamab, which has received breakthrough therapy designation and is expected to be filed with the FDA later this year. Finally, and most importantly, our 2 potential near-term launches of tisotumab vedotin and epcoritamab. Together with Seagen, we look forward to submitting a BLA for T cell with the goal to make this potential treatment option available as quickly as possible. In addition, we continue to invest in multiple clinical trials to potentially expand this opportunity. For epco, we are working with AbbVie on a broad and comprehensive development plan to realize its full potential. This includes trials in several B-cell malignancies, trials across multiple lines of therapy, and we also plan to explore epco as both a monotherapy and as a combination therapy. Now we shouldn't forget that the AbbVie partnership includes approximately $3 billion in potential milestones, which could further bolster revenue growth in the coming years. As you can see, there is significant potential for strong growth in recurring revenues through 2025, with our own Genmab products expected to contribute significantly to this growth. Now for my final slide, let me pull this all together for you. We've got a very strong foundation. Great technologies and an exciting pipeline, a highly capable team that we continue to strengthen, really meaningful partnerships with innovators and industry leaders. And strong financials, both from a balance sheet and cash flow perspective, giving us the capacity to invest. We've got a clear strategy focused around driving better patient outcomes and creating long-term shareholder value. We've got 2 near-term product launches. And these give us a strong rationale to make focused investments to get the most from the opportunities ahead. Thanks. And now I'd like to turn it over to Judith.

Thank you, Anthony, for the introduction, and good morning, good afternoon to everyone joining us today. As Jan noted, we have an ambitious vision. By 2025, we will have our own product on the market that will transform cancer treatment. Today, we would like to share with you the recent progress we have made that indicates we are well on track to reach this vision. Through Genmab's more than 20-year journey, we have taken steps towards our goal of improving the lives of patients. Now more than ever, we are delivering on this promise, and we will not rest until we have fully delivered. In the next 3 slides, I will provide you with a high-level overview of what we have accomplished and why this is just the beginning. This slide illustrates how Genmab's pipeline has evolved over time. Let's review the last 4 years and how we have grown the breadth, depth and maturity of our proprietary pipeline. On the left, we have a chart showing the total number of product candidates in the clinic year-by-year since 2016. Beginning with 9 in 2016 and expanding to 23 by 2020. The chart on the right represents the growth and phase advancement of our proprietary pipeline. In 2016, Genmab had only 2 product candidates in the clinic, 1 in Phase I and 1 in Phase I/II, tisotumab vedotin. Today, we have 8 product candidates in the clinic. One of them completed a Phase II study, and we are planning our first BLA in partnership with Seagen. This progress is the result of our continuous investment in R&D and commitment to innovation. Listed here are all the compounds created by Genmab science and technologies. Those at the top are the 8 compounds owned by Genmab, defined as no less than 50% ownership. Notably, most of our product candidates are first-in-class, illustrating the innovative nature of our pipeline. This is the result of our differentiated proprietary technologies, novel approaches to target discovery and collaboration with partnership. Our innovative science and technologies have also contributed to 15 products being developed by our partners, appearing in the slide at the bottom. Among them, the approved medicine, DARZALEX, Kesimpta and TEPEZZA. We will continue to invest in research and development because science is the engine that will allow us to maintain this pace of innovation in the years to come, turning what was yesterday's dream into tomorrow's reality. We are confident that we will be able to continue to build and advance our pipeline on a strong foundation of cutting-edge tiles. This confidence is based on our track record of success and the multifunctional integration of R&D, which makes Genmab special. We have a deep understanding of antibody biology and target, multiple next-generation technologies and diversification in our pipeline. From this diversified and rich pipeline, we identified lightly winners and maximized their potential. Another critical component of what we do are our many strategic collaborations and partnerships, which are a very efficient way to enhance our ability to do even more, more research, more projects and scale up those projects. And finally, we believe that data science and real-time integration of translational research are key to accelerate development and ensuring the right therapies get to the right patients. Taking all together, these are the pillars that support Genmab's past and future success. Our solid science driven by data and our collaborative approach through all aspects of research and development. Now let's take a closer look at 2 key factors in our future success in these live partnerships. This slide gives an overview of many of our current partnerships and collaborations. These are not collaboration with just any partner, but with particularly complementary partners in terms of technologies, capabilities and knowledge. As you can see, we have a variety of collaborations across the whole ecosystem of pharma, biotech and academia, which will help us to continue to create innovative next-generation antibodies and to potentially make them available for patients faster. The other key factor is people. We have added capabilities, such as medical affairs and data science. We are strengthening R&D teams with key talent and growing our internal competencies to become an end-to-end biotech. Now if you attended our prior Capital Markets Day, you had the opportunity to experience firsthand our state-of-the-art facilities in The Netherlands. Now we will give you another glimpse with a video tour of our cutting-edge labs in Princeton. Kate Sasser, our Head of Translational Research will be your tour guide. Enjoy. [Presentation]

I hope you enjoyed the virtual tour. It will be great to see you in person at our next Capital Markets Day. I would like to introduce now Rob De Jong, who will expand on our proprietary technology. Rob, the floor is yours.

Thank you, Judith. At Genmab, we are truly fascinated by antibody molecules. Can't help it. He does love him. The power of our natural immune system inspires us to create therapeutic antibodies that have a real impact on the lives of patients with cancer and their families. To do so, we want to deeply understand basic and logical principles, down to the smallest molecular details illustrated here. Curiosity and scientific knowledge, fuel our passion to translate science into innovative technologies and into products that has the potential to transform the treatment of cancer patients that need them. So let's have a look at Genmab's antibody technologies now, starting with our bispecific antibody platform, DuoBody. Bispecific antibodies were conceived decades ago, but faced challenges limiting their application as therapeutics. Upscaling was hampered by low yields and portability. There was risk of neurogenicity due to heavy engineering of the antibody backbones. And complex material production made it challenging to determine what concentration of binding specificities create a very best bispecific product. You may have wondered why DuoBody products have such a high hit rate and low attrition and clinical development. So I will summarize key DuoBody advantages. In brief, illustrated by more than 10 DuoBody programs currently in the clinic. With the invention of DuoBody, we solved all of these issues. DuoBody molecules are made from 2 parental IgG antibodies, each with a single point mutation, that exchange half molecules in controlled reducing conditions. Reoxidation yields stable DuoBody molecules with over 90% efficiency. [indiscernible] engineering preserves regular IgG1 structure, stability and functional properties, such as low half-life for PK, and it minimizes immunogenicity risk. DuoBody can make use of any known IgG antibody sequence because original heavy lighting pairing is preserved and a common [indiscernible] lighting is not required. But its complete time lines are minimized by a fully automated process that can convert panels of parental antibodies into DuoBody libraries in the final therapeutic format, which enables us to quickly spot the winners. Another key advantage is seamless upscaling. Our GMP manufacturing is compatible with IgG standard unit operations. The DuoBody exchange process has been scaled up at multiple CMOs and collaboration partners. We also have identified the CD3 arm used in T-cell redirection, and the inert backbone used in, for example, agonistic applications. And actually, being able to reduce parental antibodies from different clinical programs, increases the speed and decreases the cost of development substantially. Moving on. Our HexaBody technology is a platform for the discovery and development of multi-shaded IgG antibodies. HexaBody molecules assemble into organized teams of 6 around hexamers that can force start a clustering and induce [indiscernible]. HexaBody sickening induction differs from regular antibodies because HexaBody does not depend on cross-linking binding cells. HexaBody preserves IgG1 like PK and stability and our investigational HexaBody products have provided us with clinical and manufacturing experience. If we want the best of both worlds, we turn to DuoHexaBody, a combination of DuoBody and HexaBody that creates multi-shaded bispecific antibodies. DuoHexaBody provides the benefits of fuel targeting with the benefits of target clustering preserves IgG1 like PK and stability. Within our DuoHexaBody-CD37 program, we get our clinical and manufacturing experience with the platform. So in summary, our suite of proprietary antibody technologies enables to create more cure [indiscernible] product candidates. And we need this diversity in technologies because products have very different molecular requirements depending on their application or the biology of the target or target combination. At Genmab, we feel uniquely positioned to make the most of our combinations. We use DuoBody, we DuoHexaBody and we preclinically investigate applications of our novel HexElect technology that increases the therapeutic index of antibody drugs by maximizing selectivity and potency at the same time. Our technology platforms also make us a partner of choice, as shown by our numerous partnerships, partnerships that help us build our pipeline of truly differentiated first-in-class or best-in-class products. And now David will talk about how the DuoBody technology is used in new product applications. David?

Well, thank you. In this part of the presentation, we will highlight the use of our DuoBody bispecific antibody platform for the generation of new products. New products were either activated immune system or kill tumor cells in a direct manner. So how do we approach this? An interesting observation is that health cell science communication can be limited by bispecific antibodies. The cartoon in this slide represents different immune cells and tumor cells. Further, a subset of immune activating and immune inhibiting cell surface proteins are depicted in grinned as the interface between the different cell types. Protein-protein interactions on the surface of different cell types can induce and transmit a communication signal resulting in, for example, activation or dampening of an immune response. Bispecific antibodies bind to 2 different epitopes, either on the same cell or on different cells. Cell-cell trans interaction is a unique feature of bispecific antibody molecules. Cell-cell trans communication can be mimicked by bispecific antibodies and applied for different product applications. We use our unique DuoBOdy antibody technology for the generation of bispecific antibodies. The DuoBody platform enables for the generation of large libraries of bispecific antibodies. Depending on the number of targets, the size of the antibody panels, hundreds of thousands of DuoBody variants can be screened and tested. With standard bispecific discovery processes, the antibodies with the best characteristics as monoclonal antibody is often picked for the generation of the bispecific lead. The DuoBody platform enables for the generation of large libraries of bispecific antibodies, screening in an unbiased and empirical approach. This enables the selection of the bispecific, lead candidate based on functional criteria. This slide explains the identification of new immune-oncology products with our DuoBody platform. The cartoon on the left represents different immune and tumor cells, which express immune co-stimulatory and-co inhibitory proteins from the B-7, CD28 and TNF receptor superfamilies. These proteins play an important role in the activation of the immune system. Agonistic and blocking antibodies can mimic the activation or inhibition of these co-stimulatory and co-inhibitory proteins. We performed functional, unbiased, high throughput DuoBody screens testing multiple different targets from these families. Several thousands of new body variants have been generated. These high throughput, functional new body screens identified DuoBody-PD-L1x4-1BB, which is also known as GEN1046 and the DuoBody-CD40x4-1BB, also known as GEN1042 as product candidates. This slide explains our CD3 DuoBody application for the T cell mediated kill of tumor cells. When both T cells and tumor cells are bound in CD3 DuoBody molecule, acetylene kinase is formed leading to killing of the target cell, which is independent of the co-stimulation of T cells. The functional screening of multiple B-cell targets and the use of different high and low affinity CD3 arms allows for the identification of the optimal target pair for the T cell-mediated kill in B sub malignancies. We created and screened several hundred DuoBody molecules made up of several dozen B cell targets and use both affinity -- the high and low CD3 affinity variance for screening. A high affinity CD3 arm and 1 of our CD20 clones was selected for this product concept, which is now known as Epcoritamab. Here you see a summary of the different DuoBody transactivating product applications that we are developing preclinically and are progressing in the clinic. The upper part represents the cells of the innate immune system, macrophages and natural killer cells can also be targeted using DuoBody for tumor-specific and enhanced induction of ADCC or ADCP mediated tumor cell killer. Identification and generation of product concepts starting in macrophages or NK cells is in programs using tumor-specific and checkpoint targets performing functional DuoBody screens. At the moment, DuoBody-based product applications for enhanced immune modulation and T cell muted tumor cell kill are most advanced. One of these products is DuoBody-PD-L1x4-1BB, also known as GEN1046. So now I'd like to hand over to our Head of Oncology, Tahi Ahmadi, who will tell you more about this exciting program.

Thank you, David. GEN1046 is a first-in-class next-generation checkpoint immunotherapy jointly developed by Genmab, in partnership with BionTech for the treatment of advanced solid tumors. GEN1046 is designed to block PD-L1 on tumor and/or immune cells within the tumor microenvironment or draining lymph nodes and simultaneously activate 4-1BB on antigen experienced T cells as well as NK cells. The [indiscernible] portion of 1046 is silent and consequently, the tap arm binding PDL-1 blocks the PD-1 -- PD-L1 axis, while 4-1BB is conditionally activated only when the PD-L1 arm respond. This focuses 4-1BB activation on the tumor immune synapses and is intended to avoid or reduce some of the systemic toxicities that have been observed with 4-1BB agonism in the past. A detailed mechanism of action video has been uploaded onto the registration website, and I would encourage you to check it out. GEN1046 also highlights the power of our DuoBody platform as both Rob and David alluded to, the ability to screen several thousands of antibody combinations in order to identify the right set of clones with the appropriate biophysical properties to harness the therapeutic potential of the proposed mechanism of action. In this specific case, the conditional activation of 4-1BB. The first in-human trial for GEN1046 started in May of last year. The program exemplifies our vision for drug development at Genmab. We concluded a dose escalation from 25-milligram all the way up to 1,200 milligram flat dose. And as we proceeded with the dose escalation, we continuously integrated the emerging clinical, pharmacokinetic as well as translational data, together with existing preclinical models and the scientific knowledge of 4-1BB biology. This allows us to understand the pharmacologically complex target engagement and identify the optimal dose of GEN1046. We've initiated dosing on the expansion cohorts within less than a year from the first patient dose. And Kate Sasser will discuss some of the model data and inform the selection of the vacant Phase II dose in a few moments. The expansion cohorts is on the right side of this slide are meant to explore opportunities for GEN1046 in disease settings of either checkpoint naive tumor types, those in which checkpoint in additional reports limited single-agent activity, and that can serve as a clear benchmark or in cancers that are refractory or relapsed after checkpoint inhibition. These data sets will help us to further elucidate the differentiated biology and clinical opportunities for 1046 and its unique mechanism of action. And as you can see from the data, we will also explore opportunities to combine GEN1046 with other modalities in a rational scientific manner, which will inform our next steps in the clinical development plan. In the next few slides, I will summarize some of the key data that have been presented by Dr. Melero as part of the virtual SITC conference this week. We enrolled a total of 61 patients across the range of doses explored. The study population, as presented here on this slide, was heavily pretreated with a median of 3 prior lines of therapies. Majority of cancers involved are considered to be less likely to respond to immunotherapy. 38% of the patients have received prior checkpoint inhibition with either a PD-L1 or PD-1 antibody alone or in combination and frequently in more than one line. In terms of the safety profile, we observed 6-dose emitting toxicities across the entire dose range. But importantly, did not reach the MTD, and it doesn't really seem to be a clear dose toxicity relationship. We do see transaminase elevations, again, across the entire dose spectrum and about 26% of the patients. So the 10% of these patients experiencing grade 3, but this has been manageable so far. The LFT elevations resolve, and we have been able to reexpose patients even with grade 3 LFT elevations to GEN1046 without meaningful transaminase elevations at subsequent exposures. As I mentioned earlier, the patient population within the dose escalation represents a broad mix of cancers, which are either not necessarily considered to be sensitive to immunotherapy or have failed checkpoint inhibition. Nonetheless, 2/3 of the patients achieved stabilization of the disease. In many cases, over a prolonged period of time and partial responses were observed in 4 patients, 2 of which with non-small cell lung cancer, both of these patients have failed prior checkpoint inhibition. We started enrolling patients across all expansion cohorts and presented at SITC a early snapshots from cohort 1. These are patients with non-small cell lung cancer that have failed both doublet chemotherapy and checkpoint inhibition, either alone or in combination. The study includes a comprehensive translational research component, which Kate will expand in a few moments, that will allow us to further define the characteristics of the responders. On the left, you see a waterfall plot for the 12 patients with post-baseline assessment. 3 PRs, 2 of which are confirmed and ongoing. The third unconfirmed response is also still ongoing on treatment. 3 additional patients achieved stable disease and all are continuing treatments. 6 patients discontinued due to progressive disease. On the right side, you see the sprial plot. This is preliminary data, and we intend to present a larger data set of the entire cohort of 40 patients at an upcoming medical conference. We are very encouraged by the initial efficacy signal and early evidence of durability we are observing in these patients with non-small cell lung cancer, who, for the most part, meet criteria for primary resistance to checkpoint inhibition. And I hand over to Kate to talk a little bit about the translational aspects of this program.

Thank you, Tahi. As you heard earlier, we have built a translational research organization, which is closely integrated with both our discovery and clinical development functions and our efforts for GEN1046 have really been focused on real-time integration of PK, biomarker and clinical data to further understand the safety, efficacy and biological activity of GEN1046, especially since the bispecific agent is unique in that it targets both the PD-1, PD-L1 axis and the 4-1BB co-stimulation pathway. Our PK data here on the left demonstrate that GEN1046 has a peak concentration shortly after the end of infusion and a mean half-life between 2 and 10 days. After repeat dosing, you can also see some accumulation in the periphery at doses above 80 mg. Not shown here, but further evaluated by the PK and biomarker team was the ability of the bispecific to form trimers in the tumor. And based on qualitative modeling, peak trimers formation in the tumors occurs at 100 mg. On the right-hand side, you can see a profile of the pharmacodynamic biomarkers in our patients, where we monitored for known biological mechanisms of action for both PD-L 1 and 4-1BB activities, including cytokine production, in this case, showing interferon gamma and IP-10 as well as changes in peripheral T cells, showing activation by KI-67 of both cytotoxic CD8 T cells and also memory T cells. We determined that all the biological and functional activities for GEN1046 were induced at lower dose ranges between 25 and 200 but we're diminished at the higher doses of GEN1046 above 400 mg. This totality of PK, modeling and biomarker data, combined with the safety and efficacy, which Tahi just presented, led us to select 100 mg every 3 weeks as the dose for moving forward in the current expansion cohort. In addition to dose escalation and selection, the team has been focused on further understanding of the right patient populations that will gain the most benefit from GEN1046. We're incorporating robust biomarker profiling as part of our study. Including PD-L1 expression shown here underneath the waterfall plot, PD-L1, as most of you know, is a known biomarker predictive of response for other checkpoint inhibitors. As you can see underneath the PD-L1 expression, we have several patients who were primarily refractory to checkpoint inhibition, even with PD-L1 expression. And yet they have gained clinical benefit from GEN1046, indicating to us that this mechanism of action is much broader than PD-1, PD-L1 inhibition. So we are incorporating additional biomarker profiling to fully understand, which patients can benefit the most from the dual PD-L1 4-1BB targeting. And this program, in a way, highlights our Genmab philosophy you heard earlier for how we intend to utilize translational research to help speed the development of our antibody therapeutics. As oncology is becoming more and more complex, we see this as a differentiating component of Genmab. And we're building our R&D team to be fully integrated and data-driven with this in mind. We're also expanding our partnership model to incorporate collaborations in areas that can add synergy to this R&D approach. Tempus is 1 of these new partners that you've heard about earlier in the year. We are partnering with Tempus on multiple fronts. They are a sequencing provider for our clinical trials but much more than that, we're using this molecular data to understand our patients in the context of their much larger real-world data set. We are also working with Tempus on using large data sets to find and validate novel targets of interest, which can be married to our antibody technology, which you heard about earlier, to ultimately develop new antibody products in a faster and more data-driven manner. To tell you more, here's a short video featuring Ryan Fukushima, the COO of Tempus, talking about our unique partnership. [Presentation]

So hopefully, you enjoyed that inspiring video of how we collaborate with companies like Tempus. And now I would like to hand it over to our Chief operating, Anthony Mancini.

Thanks so much, Kate, for an exciting look at all the advances being made in Genmab's foundational technologies for GEN1046 and beyond. We're also making meaningful advances towards becoming a fully integrated biotech leader. As you know, the entire team at Genmab is driven to achieve our 2025 vision to build a pipeline of knock-your-socks-off antibodies, and for Genmab-labeled medicine to transform cancer treatment. To achieve this vision, it will take each of the 3 key elements that are on slide: first, our foundation, the discovery of innovative antibodies, which we heard a little bit about earlier; second, the continued strengthening of our development capabilities; and third, now we're in the process of building the important next piece of the equation, commercialization. And we're making great progress scaling up the commercialization efforts at Genmab. It's all about focus and a thoughtful, deliberate approach. First, the focus is on our priority products and priority partnerships. And our late-stage development products and partners are shown here: epcoritamab, our bispecific CD3/CD20 antibody partnered with AbbVie; and tisotumab vedotin, our tissue factor-targeted antibody drug conjugate, which we plan to commercialize with Seagen. Next, a deliberate focus in the near term on priority markets. For us, that's the U.S. and Japan. And we've made great progress, already appointing talented key leaders as part of the global commercialization team and to lead in each key market. And we continue to attract top-tier talent from top oncology companies to join our team. And along with our partners, we're making great progress in building the strategy and the plans to achieve impactful launches. We'll now spend a little bit of time digging more into epcoritamab and tisotumab vedotin. So for both of our late-stage development assets, in collaboration with my R&D colleagues, we'll describe the target patients and the unmet medical need as well as the size of the market opportunity. We'll then take a look at in greater detail, the clinical data and provide a bit of a market perspective on the potential of each asset. So epcoritamab, as many of you know, is being studied in diffuse large B-cell lymphoma or DLBCL and follicular lymphoma. These are the 2 most common types of non-Hodgkin's lymphomas. And epcoritamab has the potential to also be useful across a broad range of B-cell malignancies. Now let's have a look at the DLBCL patient. Unfortunately, DLBCL patients have a poor prognosis with about 36% of U.S. patients dying within 5 years of diagnosis. In refractory patients, it's even more concerning with about 80% mortality within 2 years. The patient pictured here is [ Gemma ]. She's not a typical DLBCL patient as she's actually a lot younger, but she is a patient that's near and dear as she shared her personal story with the entire Genmab team and how it impacted her quality of life. DLBCL accounts for about 1/3 of lymphomas in the U.S. and is the most common form of non-Hodgkin's lymphoma. It's a disease that's typically diagnosed in an older population and upon progression, can have a really major impact on patient quality of life. There really is a high unmet medical need, particularly in recurrent and refractory DLBCL due to the fact that there's a low duration of response and relatively poor, long-term outcomes with current salvage therapies. So really, we think there is significant opportunity for novel treatments in this space. This chart shows the number of patients with DLBCL treated in the United States, the 5 largest European markets and Japan. Disease prevalence of DLBCL is likely to increase by about 2% per year, primarily due to the aging population. Epcoritamab is being studied in the third line plus DLBCL space shown here, which accounts for just about -- just a little over 9,000 patients. And also, as you can see here, should epcoritamab demonstrate a benefit in earlier lines of therapy, you can see that the potential is significant. With that, I'll ask Tahi Ahmadi to take us through the exciting data we've seen to date with epcoritamab.

Thank you, Anthony. We, at Genmab, together with our colleagues at AbbVie, fundamentally believe that the mechanism of T-cell redirection against CD20 has the potential to truly disrupt and transform the treatment paradigm for patients with B cell malignancies across all lines of therapies. Epcoritamab continues to show data that supports its potential for best-in-class. The data shown here was recently publicly released as part of an ASH abstract. There will be an oral presentation at ASH in a few months. All 7 patients with relapse/refractory diffuse large B-cell lymphoma achieved a response at the recommended Phase II dose of 48 milligram or higher. Among them, are 4 patients post CAR therapy. 3 of those were refractory to the prior CAR therapy. It's worth noting that at the time of this abstract, most of these patients had only 1 post baseline scan at week 6. Similarly, all patients with follicular lymphoma treated across a wide range of doses, achieved a response. I'd like to note that 2 of the 3 patients dosed after the institution of PET imaging and all -- PET imaging was not initially part of the protocol at the time it was initiated as a first-in-human trial, achieved CR based on PET and CT. This data will be updated in a presentation by Martin Hutchings, with a larger number of patients at the recommended Phase II dose of 48 milligram as well as a longer follow-up and durability of response. We continue to see a tolerable safety profile, most AE reported, such as pyrexia, tachycardia or hypertension, being related to cytokine release. It's important to note that cytokine release syndrome is actually a composite term of multiple AEs, which we are deliberately collecting separately in our trials in order to accurately understand the safety profile of epcoritamab at this point in time. CRS was generally restricted to the first cycle. It is observed in a little bit more than 50% of the patients and is all grade 1 or 2. Injection site reactions are all grade 1 and generally a self-limited first injection phenomenon. And so in summary, as the data continues to mature, we like what we see, both in terms of efficacy as well as tolerability. To give you a bit of a flavor of what a response looks like. Here, a short little vignette. This is a case of an elderly lady with diffuse large B-cell, refractory disease, 3 prior lines of therapies within a short period of time of less than 2 years but made a progression on her last line. Best response she achieved on all 3 lines was stabilization of disease. This is a patient of the 12 milligram cohort first presented at last year's ASH. PET and CT imaging on the right allow you to appreciate the significant disease burden at the time of enrollment. She achieved a PR at the first assessment, and with continued treatment, achieved a CR, and she continues to be at remission at this point now a year later. We started the first-in-human trial in June of 2018 at a priming dose of 4 microgram. And we determined the recommended Phase II dose based on a sophisticated PK/PD model, which incorporated PK modeling work, translational data, and clinical efficacy. It's another example of the vision that both me and Kate have already talked about when we talked about GEN1046, that we have at Genmab of a truly integrated approach to drug development. And the details of this particular modeling approach will be presented at ASH this year. And pretty much 2 years after the first patient was dosed at an enabled dose in this study, we initiated 2 expansion cohorts that are now actively enrolling patients with relapsed/refractory diffuse large B-cell lymphoma and follicular lymphoma and are intended to generate data that could support accelerated approval. A third expansion arm for patients with relapsed/refractory mantle cell lymphoma will also open for recruitment very soon. To complement our single-agent data sets, we initiated 3013-02. This is a basket safety study of epcoritamab in combination with several established backbones across multiple lines in both diffuse large B-cell and follicular lymphoma: R-CHOP in newly diagnosed, high-risk diffuse large B-cell; [ are strict ] the combination of lenalidomide and rituximab in relapsed/refractory follicular lymphoma; bendamustine and rituximab in frontline follicular lymphoma; in combination with induction therapy for those patients who are transplant eligible; as well as with GemOx for those who are ineligible for auto transplant. The study is now open and actively enrolling patients. To extend our development across the spectrum of B cell malignancies, we also initiated 3013-03. This is a 1B -- Phase Ib study of epcoritamab as a single agent in relapsed/refractory CLL. It is a Genmab-sponsored study that has the support of key European CLL study groups that is meant to define a safe dose and schedule for epcoritamab in CLL as well as to generate early evidence of clinical efficacy in these patients that have failed or are intolerant to BTK inhibition. Again, the study is also now actively enrolling patients. To conclude the presentation of our current ongoing clinical activities, we publicly announced last week the initiation the first Phase III epcoritamab as a single-agent, randomized against the investigator choice of either R-GemOx or bendamustine plus rituximab in patients with relapse or refractory diffuse B-cell lymphoma with at least one prior line of therapy and who are either ineligible or failed auto transplant with a primary end point of overall survival. So as I alluded to in the beginning, we, in partnership with AbbVie, have a broad and ambitious vision for the development of epcoritamab. And we have been accelerating the clinical program over the last couple of weeks and months including a PK safety study in Japanese patients that is very well underway. These trials form the building blocks as we, together with AbbVie, plan to initiate several additional studies in the upcoming months. And I hand it back to Anthony.

Thanks, again, Tahi. So what are customers thinking about this class? And I can tell you that there's already high enthusiasm and awareness for this new mechanism of action. CD3/CD20 antibodies are being seen as the next major opportunity in non-Hodgkin's lymphoma. And the rationale for this is that opinion leaders and oncologists and hematologists who've had a chance to get their hands on this have a very favorable perception of the efficacy and safety profiles in the class. And as Tahi showed, with strong single-agent overall response rates and complete responses as well as a manageable safety profile, we believe this class has the potential for a lot. It also has the potential for subcutaneous administration, which can offer both patients and health care providers, a convenience advantage and may help favorably impact the rate and severity of cytokine release syndrome and ultimately result in fewer hospitalization and complications. So the initial therapeutic profile emerging for epcoritamab as a single agent is clearly very encouraging, with very high overall response rates and a manageable safety profile. The convenient route of administration, through an easy-to-administer 1 cc small volume injection and a low rate of high-grade CRS can also be an important differentiator for the product. So in summary, epcoritamab has a potential to be best-in-class and to positively impact DLBCL patients by delivering durable responses and improved survival, along with a manageable safety profile. It's clear that epcoritamab also has the potential to be very competitive beyond DLBCL in other B-cell malignancies with high unmet medical needs, such as the ones shown here, such as follicular lymphoma, chronic lymphocytic leukemia and mantle cell lymphoma, with potential utility in each in combination as well as in earlier lines of therapy. So in conclusion, epcoritamab has shown very promising efficacy and safety as a single agent in late-line DLBCL. And based on its overall profile, we believe it also has significant potential to be beneficial across patients with B-cell malignancies. Let's transition to tisotumab vedotin. As you know, we've been developing tisotumab vedotin, or TV, in a collaboration with Seagen. And as we announced on our Q3 call last week, we're really pleased to have finalized the joint commercial agreement, whereby Genmab will co-promote TV in the U.S. and lead all commercialization efforts, including booking sales in Japan. Seagen will lead operational execution of future clinical trials as well as commercial operational activity in the U.S., the EU and China. And all of the major markets, and that for this agreement is the U.S., Japan Europe and China, will be a 50-50 cost and profit split with Genmab. In markets outside these major markets, Seagen will commercialize and Genmab will receive royalties in the mid-teens to mid-20s based on net sales performance. Of course, we'll continue to work together on all strategic decision-making related to the development and commercialization of TV. The first indication that we're pursuing for TV is in metastatic or recurrent cervical cancer where tissue factor is highly expressed. TV also has the potential to be useful in other solid tumors where tissue factor is highly expressed. So let's take a deeper look. What about the patients with advanced cervical cancer? Although metastatic or recurrent cervical cancer impacts a relatively small group of women, it's characterized by really very poor outcomes. The woman shown here is [ Linda ]. She's a cervical cancer patient who also shared her journey with our team, and it's really clear that better treatments are needed for patients like her. This cancer is diagnosed at a relatively young age and tends to impact more women in a lower socioeconomic status. In addition to dealing with a cancer diagnosis, many of these patients feel the stigma due to the link to HPV infections. Lastly, the prognosis for patients diagnosed in the later stages is very poor with a mortality rate of 83% in 5 years. So the need for better treatments is high as recently approved options also have a relatively low overall response rate at less than 15% and relatively poor overall survivals in the 6- to 9-month range. This next chart shows, again, the number of women treated with metastatic cervical cancer in the U.S., the 5 largest European markets and Japan. The market size in second-line plus metastatic cervical cancer is around 6,000 patients with just over 3,700 patients in the U.S. and Japan. It's a relatively modest initial patient population, but we believe it represents a meaningful opportunity as the unmet medical need is significant. Now Judith Klimovsky will present the most recent TV clinical data. Judith?

Thank you, Anthony. The following slides were presented at the late-breaking oral session at the 2020 virtual ESMO congress. InnovaTV 204 is a Phase II, single-arm double study of tisotumab vedotin in patients with recurrent or metastatic cervical cancer. Patients that progressed on doublet chemotherapy with bevacizumab, if eligible, received tisotumab vedotin once every 3 weeks. The primary end point was confirmed objective response rate, ORR, assessed by independent review committee. Clinically meaningful and durable responses were observed. Confirmed ORR was 24%, with 7% complete responses. At the median follow-up of 10 months, the median duration of response was 8.3 months. Responses were generally consistent across most evaluated subgroups. A picture is worth a thousand words. Shown here, a clinical vignette of a 42-year-old patient with a very aggressive disease as we see in the nodes. As the images reflect, she got a CR that lasted 8.5 months. Secondary efficacy results shown in this slide. Median PFS was 4.2 months and median overall survival, 12.1 months. The most common treatment-related adverse events included alopecia, epistaxis, nausea, conjunctivitis, fatigue and dry eye. Most were grade 1 or 2. We are pleased that this data was very well received by the medical community and for the potential of TV to become an option for patients with recurrent or metastatic cervical cancer. In partnership with Seagen, we are actively working preparing for our first BLA. Now I will turn the presentation back to Anthony.

Thanks so much, Judith. We really believe TV can play a leading role in the second-line plus metastatic cervical cancer segment. As Judith outlined, the efficacy, durability and safety profile across all comers in second-line plus patients can provide a new and valuable alternative to currently approved therapies. If you consider the fact that data with checkpoint inhibitors shows only about a 14% overall response rate in a subpopulation of PD-L1-positive metastatic cervical cancer patients, it's clear that the TV data is compelling as it shows a meaningful benefit regardless of PD-L1 status. Clearly, an all-comer approach is simpler for clinicians, primarily in the community who are treating this disease as screening patients for a biomarker isn't needed. And this profile is based on a single agent TV activity. We think that's the beginning, and we're hopeful that the combination of TV with checkpoint inhibitors in this setting can lead to even better overall response rates. And we've seen with our partner, Seagen, showing other vedotin ADCs have demonstrated improved responses in combination with PD-1s in other malignancies, and this is something we're exploring with our partners. So based on the product profile and upon a successful regulatory review, we have an opportunity to position TV as a first-in-class ADC, with a strong efficacy and manageable safety in a metastatic cervical cancer population across all comers regardless of PD-L1 status. Now almost 3/4 of oncologists that we surveyed stated that they would prescribe TV within 3 months of it being available based on the impressive overall response rates and duration of response. And about half of those would recommend TV to their peers and believe it meets a significant unmet need in their practice. So clearly meaningful potential for patients with metastatic and recurrent cervical cancer, and that's our main focus in the near term. So to conclude and to tie back into the near-term priorities that we covered earlier in the presentation, we're making excellent progress standing up our 2 priority markets: the U.S. and Japan. We're continuing to work closely with our partners to bring these 2 exciting late-stage development assets to patients. And in so doing, Genmab is well on its way to achieving our 2025 vision. Thank you. And with that, let me pass it back to Jan van de Winkel.

Thank you, Anthony. So let's conclude with a look at where we have been and where we are going. So here's a glimpse of our 21-year history and some of the milestones that have propelled us to where we are today. And as you can see to the far right, 2020 has been yet another record year for Genmab and our now more than 20 Genmab-created antibody therapeutics in active, full-blown clinical development. All the events that you see here and many others have led to the inflection point at which we find ourselves today. While our 2018 Capital Markets Day was aspirational, our 2020 Capital Markets Day shows that we have already begun to deliver on our promise and how we will continue to do so over the next 20 years and beyond. Because we are only at the beginning, we are well positioned for continued success, built upon a solid financial foundation as described by Anthony Pagano, and our expanding capabilities shared with you by Judith and Kate. As Rob and David discussed, our unique, differentiated, proprietary antibody technologies will continue to allow us to be at the forefront of the next transformative wave of innovation and medicine. So supported by our strategic partnerships, as mentioned by Judith (sic) [ Tahi ], we are already delivering on our promise as our pipeline matures, as we move our later-stage therapeutic candidates forward and hope that this will soon progress, as Anthony Mancini, has discussed to the ability to address unmet medical needs with our own first products on the market. Taken together, we are clearly on the path to very soon becoming a fully integrated biotech innovation powerhouse that continues to meet our core purpose of fundamentally transforming the life of cancer patients. So thank you all for your attention over the last 2 hours or so. We are now pleased to answer your questions. [Operator Instructions] So who wants to start?

We have Michael Schmidt from Guggenheim.

Thanks for this overview. It's super interesting how progress the company has made. I just had a couple on GEN1046 and some of the SITC data. So maybe first, can you just help us understand how you ended up selecting the 100 milligram dose as recommended Phase II dose? And I'm trying to better understand the dose response here. It looks like your pharmacodynamic analysis kind of points to maybe an inverse correlation there with dose? And help us understand what your thoughts are behind that. And then I had a couple of follow-ups as well.

Thanks, Michael, for the question. And you're definitely right. Many of these bispecifics can have bell-shaped curves. I would like to propose that Tahi Ahmadi handles this question. Tahi?

It's a very good question. I think as you think about how we selected the dose, there are 2 dynamics that you have to consider: one is the pharmacokinetic behavior of bispecifics in general, dealing with 2 targets and 2 different target-mediated clearances and how that impacts the dose; and the second one is the biology of agonists. It's well-known that there is some element of a bell-shaped curve, those efficacy response that doesn't really necessarily go linear. And so we picked those, not necessarily by safety at all. Actually, it was primarily driven by the PK translation components, a strong modeling approach around what we call trimerization, the idea of PD-L1 having to be bound on a PD-L1-positive cell, 4-1BB having to be bound on a 4-1BB-positive cell by an antibody, so that's a trimer. And we tried to model the optimal trimerization concentration. And Kate talked a little about this. So I don't know if you want to allude a little bit more on some of the data that went into the model.

Yes. So the data that we showed you was primarily focused on the peripheral PK, where we start to see some accumulation in the periphery above 80%. But the team, as Tahi mentioned, also did really nice quantitative modeling looking at intratumoral PK and the expectations there. And there, we see that, again, 100 mg was the dose where we expected optimal trimer formation. And interestingly, this was also the dose where we would still expect between 60% and 75% full occupancy for PD-L1, shown by other checkpoint inhibitors. So we felt that this range based on also the PD biomarker data that you asked in your question. And there, we showed some today, but we've looked, of course, at many other biomarkers associated with T-cell activation, expansion and functionality. And combining all of that data together really suggested that the 100 mg Q3 weeks would be the optimal dose.

Okay. And how confident are you that there is no liver signal? When we look at the ALT and AST elevation frequencies, they look somewhat similar to what had been seen with urelumab early on. I'm just curious what your thoughts are on that front.

So maybe, Kate, do you want to take it. Or let's Tahi -- also Tahi for that.

I think, as I presented this, and I think also as Dr. Melero presented this at SITC, we do see transaminases. We find them so far to be manageable. They are also probably more manageable because we have actually clinical activity, which was not necessarily the case in the past. And so the biology that drives the transaminases may also be a little bit different in our situation. But nonetheless, we see, as I said, 1/3 of the patients have grade 3 out of -- have TRAE elevation, 10% have grade 3. It has not precluded us from continuing exposing patients. And I think it's important to know, as I touched on it in the presentation, that we actually were able to reexpose patients after they have experienced grade 3 toxicities. And they appear in these cases that we have, we are still dealing with a relatively small data set, able to tolerate the exposure to GEN1046 with less transamination elevations afterwards.

Thanks, Tahi. And what I can say here, Michael, is that we are still actively recruiting in this trial. We have now up to 9 expansion cohorts, so this is continuously progressing, and there seems to be a very good level of enthusiasm, both with the doctors and the patients to progress this trial. So let's see how data looks next year. As Tahi has already alluded to, look at more data next year in 2021, but you probably have to keep it with us. Are there other questions?

The next question we have is from James Gordon from JPMorgan.

Hopefully, can you hear me okay?

Perfect, James.

James Gordon, JPMorgan. A couple of questions, please. One is a follow on PD-L1. The data clearly shows promise in PD-L1 high expression on small cell cancer patients who failed IO. But you did mention a couple of other subgroups. But can you talk about -- which other subgroups are you most bullish about? And what data do you have that justifies that? So that would be the first question about 4-1BB. The second question, which mechanisms are you most excited about combining the agent with? Also a question on epco. So on Wednesday night, we saw Xencor and MorphoSys announce a collaboration. So combining a [ Judie ] with CD3/CD20. Is that an exciting approach? Is that something that maybe you need to do as well to keep up with them? Or are there other combos that could be more interesting for CD3/CD20? And then a third and final question. Just in terms of news sense, there are loads of news flow in 2020 on the pipeline, but 2021 looks like it'd be a little bit quiet maybe. Is that fair? Is there lots of other stuff to sustain the pipeline momentum in 2021? What do we need to look forward to for next year, please?

Thanks, James. So some good questions, I can tell you. So I think Tahi can handle the PD-L1, 4-1BB question, what are we most excited about. Maybe speculate a bit or give James color, Tahi, on what we could combine in a bit there. What are we thinking about? And then maybe also then progress with epco after that, the CD19 combination with the MorphoSys antibody. CD19 and CD20, of course, are company-expressed. And James, you know this concept quite well. So maybe, Tahi, you can add a bit on that as well. And then we'll park the 2021 question. I think, James, this going to be an absolutely fantastic here, a very data-rich year. And we'll give you some further color so you will warm up completely on that after Tahi answers the first 3 questions. Maybe Tahi, over to you.

Very good. So 1046 first. So as Jan said and I touched on this in my presentation as well, we are actually actively enrolling in all cohorts. And so there, we're also generating data there, and we will be sharing the data with you in the near future. The reason why the lung cancer call was part of the SITC abstract is essentially a function of when the abstract was due and the patients that were enrolled at that time point. If you look at the dose escalation, just to give you a little of a hint, there's also an ovarian cancer patient who has a very long duration of response, actually still in response. And there's also a triple-negative breast patients that responded. So there are some -- there's a number signals that make us quite excited about what we see, but it's still low numbers. So we'll be able to share this data very, very soon, I think. I mean because we are very aggressively enrolling on this expansion cohort at 1046. CD3/CD20, epcoritamab, so we are starting to generate safety data with a number of backbones. In the beginning, we are clearly focused on the generation data with backbones that help us drive very expeditiously our strategy towards an approval. That does not preclude, and we will continue to generate data in combination with other experimental drugs. And I think it's fair to say that the CD19 antibody from MorphoSys is now part of it. Incyte has a very interesting component in that space as well. So we will look at these combinations as well as others as well.

Okay. Thank you very much, Tahi. Then a bit on 2021, and I will definitely ask Judith Klimovsky to step in there in a sec. But what you can expect, James, is a lot of data on PD-L1, 4-1BB, and potentially near the end of the year. Also in other programs like DuoHexaBody-CD37, which is well progressing. The second BioNTech program, the CD40x4-1BB program is also progressing very rapidly. Of course, other cancers with tisotumab vedotin, we expect data from Seattle in 2021 for 5 other solid tumors. And we are very excited about that product, as you could hear today from Anthony and also from Judith. And then, of course, you will see a fantastic expansion of epcoritamab in multiple Phase IIIs and other -- in several different settings. And hopefully, we got a feeling in the new year for a very exciting program, James, HexaBody-CD38, the next-generation CD38, which we are going to move into the clinic in the coming months. We have filed IND and CTAs already this year -- or second IND this year. And so hopefully, by the end of next year, we get a better feeling for the safety. Of course at ASH this year, James, you will see some further preclinical data, not only in multiple myeloma, but also in diffuse large B-cell lymphoma and acute myeloid leukemia. And we're very excited about that data. But of course, we don't know, James, whether this will be safe in human patients. So I think I will stop here and see whether Judith sees some further light for you, James, to warm up for 2021. Judith?

Yes. Thank you, Jan. I think that Jan provided a very detailed answer. I would say like in general, we are looking if -- continue to mature the pipeline, progress the agents and understand better next steps. So as you -- as Tahi alluded, the parallel expansion cohorts in 1046 will guide us on next step, which will be super exciting and continue to mature epco. Of course, the BLA filing is in our radar screen as the potential first approval for Genmab in partnership with Seagen and the new IND. So overall, we've continued to grow the breadth, depth and maturity of the clinical pipeline, plus continued the innovation and research, technologies and targets that has led us to where we are today.

Thanks, Judith. And what I forgot to mention, of course, is HexaBody-DR5/DR5. I think, also more data there next year, James. So I hope that makes you a bit happier.

Next question we have from Trung Huynh from Crédit Suisse.

I have 3, if I can. So the first one on 4-1BB, just a clarification. I may have missed it, I don't know. But in the summary waterfall plots of the 4-1BB data, the best relative change from baseline from that was a partial response from another cancer. Could you tell us what that tumor type was? Second question on epco. In the presentation, you noted there's a preference for subcu dosing. But when I've spoken to KOLs, one of the things that we've had then raise is that IV is actually quite convenient because DLBCL patients have ports already for the administration of R-CHOP and also weekly labs. And also prescribers, they may favor IV because of the better economics of an IV over a subcutaneous dose. So do you think there's going to be any hesitation from prescribers wanting to administer a subcu dose? And have you got an IV dose of epco also in development? And then finally, I'm sorry to kind of keep asking this question, but you're very clear on the investment that you need in the short term to grow into the long term. You're moving tisotumab into the U.S. and into Japan. You're expanding aggressively with 4-1BB with BioNTech. I think we understand this, but perhaps can you just give us some help on how we should think about the cost lines as you become a commercial biopharma and get to that 2025 ambition?

Thanks, Trung, for the questions, very good questions. I think I will hand over the first 2 to Tahi, the 4-1BB, the waterfall plot, the patient there. That's a quick one. Then epco as well for subcu dosing. What I want to remind you of, Trung, is that the doctors we speak with are super enthusiastic about the potential for a subcu version of the antibody because of the fact that we and they believe that in the future, we are moving towards an era where we will not use chemotherapy anymore. So chemo, so patients will not have direct intravenous lines. And you probably will treat them with other combinations of antibodies, hopefully subcu, or antibodies with small molecule inhibitors. And we're going to test that also in the clinic fairly soon, as Tahi has described. But I will let Tahi give some further color there. And then the last question about how are you going to see Genmab move to the next phase as a fully integrated, commercial biotech. Cost-wise, I will ask Anthony Pagano to give you a bit more color, Trung. Today is not the time to give you guidance for 2021. And beyond that, we'll try to give you an even clearer picture to what Anthony already showed in his part of the presentation after we ask Tahi to comment on the first 2. Tahi, can you take the 4-1BB and the epco subcu questions for Trung?

Sure. If I understood the question correctly, the question was related to the waterfall plot for the dose escalation. So there's 4 patients who responded: 2 patients with non-small cell lung cancer, both of them were primarily refractory to checkpoint inhibition; 1 patient with triple-negative breast; and 1 patient with ovarian cancer. And what you already I think can appreciate that the responses that we see here and then also in the cohort 1 that we presented are in patients that are not necessarily usually expected to respond to current available immunotherapies. So it's a differentiated pattern of responses completely. Hope that was the question that you asked, that I answered that question. As related to epcoritamab subcu, I think it's important to also remember why we started with subcu [ formulation ] with epcoritamab. It started with the observation that in the xeno-safety monkey studies, the administration of subcutaneous epcoritamab was going to avoid -- it was avoiding the peak Cmax on the PK and the peak on cytokines. And we believe that this allows us to be a little bit more tolerable. We have a 50% rate of cytokine release, but it's all grade 1, grade 2 so far. And it's only in the cycle, in the first cycle. And it's a little bit different than what some of the other programs have been described. You also asked, I think, a question of how confident we are at the recommended Phase II dose. So 48 milligram is the recommended Phase II dose. I mentioned that in the ASH abstract, 7 out of 7 patients responded, pretty good response rate. And you will see more on that data at ASH. And we obviously initiated a Phase III that's going to enroll any moment with that dose. So we are very, very confident that 48 milligrams is the appropriate dose for epcoritamab.

Thanks, Tahi. And Trung, you will get a lot more firework on epco at ASH in the oral presentation, we can promise you today. Let's move to Anthony Pagano and then ask Anthony for a bit further color for Trung on how we should think about our stepping up our investments into the future, as you already explained, Anthony. But maybe you can give Trung a bit more clarity and concrete information, if you're open for that. Otherwise, you will park that till February next year.

No, happy to do so. Thanks, Jan, and thanks, Trung. But maybe just want to provide a bit of context and a framework for how we sort of think about this, right? Starts with our proven track record. Our strong foundation and our exciting growth opportunities. Let's first start with this proven track record. And let's start there on the R&D or business side. We've had just an absolutely tremendous hit rate and productivity rate. We look at our novel tech platforms we've developed. We look at 3 marketed products. We look at our exciting pipeline. That is absolutely phenomenal. On the financial side in terms of our proven track record, we stay true to our strategy. We've stayed focused and disciplined, and we've run a profitable business and build a strong balance sheet. So I'll leave it for you to judge, but for me, this is truly exceptional. Now if we look at our strong foundation and our exciting growth opportunities, you've heard a lot about these today from my colleagues. So in summary, we have all the ingredients to become a fully integrated biotech powerhouse. We have these 2 near-term potential product launches and very clear set of priorities. So given that, it's up to us to figure out what the right investment levels are, and it's exactly what we're going to do. We'll continue to be focused and disciplined in our approach, but as I've talked about previously, being focused and disciplined has 2 sides to that coin. On the one hand, it's about taking a stepwise approach, derisking investments when you can and making tough decisions along the way. The other side of the coin in terms of being focused and disciplined is really around when you have these exciting growth opportunities to really make sure that they get the focus and capital that they deserve. And that's exactly what we're going to do. So hopefully, this gives you some context, Trung, on how we think about investing here at Genmab, continue to be focused and disciplined. And finally, in terms of our guidance, we'll come back to that at our earnings release in February.

Thanks, Anthony. So Trung, to sum up, it's focus on the potential winners and kill the other programs if they're not differentiated or truly differentiated. And that, in combination, will give us a very sharp profile towards the future. Hope that is okay with you for the moment, Trung.

We have Sachin Jain from Bank of America Merrill Lynch.

It's Sachin Jain from Bank of America. Just a few questions, if I may. Firstly, on epco into ASH and an update on the DLBCL data you've referenced. There's some focus on how the 29% CR rate improves with further follow-up. So just to frame expectations on that data, what do you think a benchmark is that you've seen from competitive assets that we should view as a benchmark, acknowledging the different patient baseline characteristics across studies. Second on epco combos. And so you briefly touched on an answer to an earlier question. About the time of the AbbVie deal, there was some discussion of combinations with some of AbbVie's proprietary pipelines, IMBRUVICA, Venclexta, and then combos with CD37. So I just wondered whether there's any update on that. On 4-1BB, in your news flow answer, Jan, you referenced a imminent conference. I wanted to just to avoid all speculation. If you could reference which conference you're targeting? And then last question is on a couple of assets, which haven't really been a focus today. So DR5/DR5, you mentioned some updates next year. Where are you with that? And AXL-ADC, no mention on the slides and not mentioned in the news flow due next year. So any update there?

Thanks, Sachin, for the questions and for attending. The first 2 questions on epco, I will pass over to Tahi. And then the 4-1BB -- PD-L1, 4-1BB, we haven't yet decided this conferences to send our data to. We are very rapidly moving up the number of patients and 9 expansion cohorts there, Sachin. So we cannot give you an update today, and we'll do that in future events. We definitely have the ASH review meeting on December 8. That may be a sign that we can give you further color on that. And I will actually pass the fourth question over to Judith Klimovsky to give you a bit more color on where we are with the HexaBody-DR5/DR5 program. And that enapotamab vedotin, where we also expect data this year, Sachin. So let's first move to Tahi to answer the epco questions, the benchmark basically, Tahi, for the diffuse large B-cell lymphoma data. What should we let Sachin and other analysts focus at or think about or dream about and then hopefully be better at ASH -- at upcoming ASH. So I'll leave it now to you, Tahi.

Sure. Thank you for the question. Not an easy question to answer, actually. The response rate, as you look at them across the field of CD3/CD20, there is a little bit of a fluctuation. If you just focus on the [indiscernible] for different assets based on response rate and CR rate, some of it may be a reflection of biological properties. Some are more potent than others. There is another component that needs to be considered and that is the duration of exposure and the time of responses. So if you look at our CRA data in the ASH abstract, I mentioned this -- most of this were at week 6, first response assessment. And we know that responses can deepen over time. So if you think about benchmarks I would say it's probably fair to say across the spectrum that the higher ceiling of ORR is somewhere in the public domain 70-ish percentage for the 2 [indiscernible] is a little bit higher. And the CR rate is like high 20-ish, 30-ish. And I cannot give you the data. It will be presented at ASH. But I do think that I mentioned this, we continue to believe that [indiscernible] is the best-in-class and it will show itself.

Thanks, Tahi. And maybe a bit on combination therapies that like ibrutinib and venetoclax and other potential small molecules we are thinking about, and they'll likely move into action in clinical trials, Tahi?

Question on the combination with ibrutinib and venetoclax. Obviously talking to our colleagues at Abbvie, and I'm working right now actively on the strategy, for where best to position these combinations, and you will see some activity on this in the near future.

Thanks, Tahi. And then maybe over to Judith. Maybe you can give a bit of color, Judith, on where we are with the DR5/DR5 program. And what can be expected on the enapotamab vedotin program going forward. Judith?

Yes. Thank you, Jan, and thank you for the question. So DR5/DR5, our first HexaBody in the clinic, as we all know, in December last year, we share that after a short clinical hold, we resumed enrollment. This is what we have done along the year. And we are in the process of collecting data, activity and safety to determine the therapeutic index for this compound. So stay tuned, more to come as we collect data and understand the benefit risk based on the new data that we are getting. For enapotamab vedotin, as we know, I mean, we presented data on one of the expansion cohorts, the lung cancer, last year in September. We already shared that the study required fresh biopsy because [ AXL ] is an inducible target. And it was a little bit delay behind projections in terms of enrollment. But we think that we have the right critical mass of data that assess safety, efficacy and biomarkers. And based on this totality of the data, we will decide next steps. So stay tuned, more to come as our teams are actively working on collecting all these data, cleaning and putting all together for us to understand better where we stand.

Thanks, Judith. Thanks, Sachin, for the questions. Let's move to the next question.

We have Michael Novod from Nordea.

Yes. It's Michael Novod frim Nordea. And also, first of all, congrats with running a very professional and smooth virtual CMD. So just to start with that. First on HexaBody-CD38 and how -- maybe you can just remind us how fast can you run this? Do you see good data and can it also be run in a subcu version because we can see that the uptake on subcun DARZALEX is obviously starting. So just to get a feeling of whether this can be done also quickly with the HexaBody-CD38. Secondly, maybe that's for -- both for CFO and also for [ FM and C ]. The size of the organization, I think Trung was trying to get an answer on the cost base going forward. Maybe you can talk a bit about the size of the organization going forward? What is needed in order to run an efficient commercial operation in the U.S. together with AbbVie, of course, for EPCO, but also in Japan, leading the commercial efforts there, just so we can get sort of a feeling of how this is building? And then lastly, to the sort of the revenue slide, I still don't really understand sort of that slide, maybe it's just me, but consensus is around $3 billion in revenues in 2025. You show the $1.9 billion, and then you show some upside you think that consensus at $3 billion in revenues in 2025 is conservative? Is that what that slide is about to tell us?

Thanks, Michael, for the questions. Thanks for attending. And thanks for the -- congratulations. I can tell you, it's a military operation, [indiscernible]. So I'm happy that we didn't lose the connection and that things went fine up to now. But thanks for mentioning that. It's greatly appreciated from all of the team working on the Capital Markets Day. Then HexaBody-CD38, I'm going to propose to move it over to Tahi to say a little bit about the clinical trials, the 2 trials that we are planning there, how fast we can potentially run them and also the aspect of whether we could conceptually think about a subcutaneous formulation for the HexaBody-CD38. But while Tahi is thinking about that, let me introduce Anthony Mancini for the Q&A for the first time, I think on this Capital Markets Day. Anthony, a little bit of color please on the potential size of the U.S. and Japanese organization, not jeopardizing, of course, the competitive positioning versus competitors who are listening into this Capital Markets Day at the same moment. So why don't you give maybe some color to Michael Novod on the potential size of the U.S. and Japanese operations for TV, EPCO and give him a bit to work on for his modeling so that it improves in the coming time.

Thanks, Jan. I'll try my best. And thanks, Michael, for the question. I think as we said earlier, we're really focused on making sure that we're focused and deliberate. And we're really focused on the 2 products in the 2 priority markets. And some of the drivers of what we'll look at that will shape resourcing decisions in those 2 markets are the size of the target audience and the size of the opportunity. And what I can say is that we're working very closely with our partners to make sure that we're investing to win so that we can make the biggest impact, but we're also doing it appropriately to the size of the opportunity. So I think we can provide, Michael, more details as and when we achieve a launch. And to Jan's point, not jeopardize any of our competitive positions both for TV and EPO.

Thanks, Anthony. Maybe move over to Tahi now for HexaBody-CD38, maybe a little bit of color on how fast we can run the dose escalation in auto myeloma tie and the potential of a scenario for a subcu version.

How fast can we on the HexaBody-CD38. I would say we gave you 2 programs today where we talked a little bit about speed of execution, right? So epcoritamab from label through the initiation or the announcement of a Phase III 3 years [indiscernible] from first in human to defining the recommended Phase II and open expansion cohorts in 9 or 10 months. I think we can move fast. We are -- with the INDs filed, we are looking forward to initiating the trial and see the first placement in dose escalation. As it relates to subcu, that's certainly something that we are thinking about as the program continues to evolve.

Thanks, Tahi. And maybe the last question, Michael, to Anthony Pagano will give you a bit more color on the revenue. Anthony?

Yes. Thanks, Jan. Yes. And Michael, maybe just put a bit more perspective on to the projections that we provide today. And you're correct, these are looking at consensus moving forward. And really, what we're trying to show is that based purely on the 3 existing marketed products, right, DARZALEX, Kesimpta and TEPEZZA that we're looking at our potential revenue growth of more than 2.5x. And these are examples of products with very strong product profiles, excellent partners, very committed partners and ongoing investment to sort of further solidify their position and potentially grow the market opportunity. So we think looking at that, just based upon the 3 existing products, we have very significant and meaningful growth for the years to come. But it doesn't stop there. If we look at the royalty streams, most advanced is amuvatinib, but this could potentially be, as I mentioned, be filed later this year with the FDA, and it could add to that recurring revenue stream. That's not what's most exciting for us. What really is most excited about is adding on top of that, our own products. And we talked a lot today about the near-term opportunities: tisotumab vedotin and epcoritamab. So Michael, no specific numbers for you today. We spoke a lot about our strong foundation, our exciting pipeline, the near-term growth opportunities, so the future for Genmab is very bright. And today, I just want to give you a bit of glimpse, even based upon the existing products, we're looking at significant growth moving forward.

Thanks, Anthony. Thanks, Michael, for the questions. Move on to the next one.

We have Carsten Lønborg from SEB.