Oncopeptides AB (publ) (STO:ONCO)

CMD 2020

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Nov 30, 2020

Okay. Thank you. And welcome to our Capital Markets Day at Oncopeptides. I'm Marty Duvall, the CEO of Oncopeptides and proud to open and close the presentation here today. I'd like to thank everybody for their participation and continued interest in helping us to build the company and deliver new products to patients. So the next slide and I'm not seeing the slides, but I think we have a disclaimer slide up. So just as a reminder, we are seeking a new drug application in the FDA that is pending review. I'm going to be making some forward looking statements, and you should look to some of our detailed filings for any assumptions and risks that we have in building the business. So we will be talking about future results. So the next slide should be the title slide and let's move to Slide 4. So a lot is going to come at you over the next couple of hours. So I wanted to provide an opportunity upfront to share with you what the 5 key takeaway messages are. So first of all, we are now a global company. Oncopeptides is a global company. We have our R and D roots in Sweden and we're very proud of that heritage and those roots. We are operating with our lead program in a very large market with high unmet need that being multiple myeloma. 3rd message here is about milfluthin. This product does have the potential to become a backbone treatment in the treatment of relapsed refractory multiple myeloma. I'll talk at the end about our U. S. Organization to build and our preparation as it relates to the U. S. Launch and we are ready for our U. S. Launch. And finally, we're more than just melflufen in myeloma. We have a peptide drug conjugate platform that is broadening our portfolio and positioning us as a strong player in hematologic malignancies. So we'll move to the next Slide 5, which is the agenda. So following my introduction, I'll be joined by Doctor. Richter. He will provide a perspective on the unmet needs in hematology. We will then have a panel discussion hosted by Doctor. Klosbacher, our Chief Medical Officer and he will be joined by Doctor. Mateus and Doctor. Richardson to provide their experiences clinically with melflupin. We'll then transition to detail on our clinical development program. Jacob Lindbergh will walk us through that and I'll come back at the end to talk about what we're doing in preparing the U. S. Market for our launch of melfluthen. So the next slide, just touching here on the wonderful history of Oncopeptides and really appreciate everything that's going in the 1st 19.5 years prior to my joining and I feel so fortunate to be able to pick up the ball, tracing back to 2,000 when melfluthen was patented and oncopeptides was founded. Really a key event in the company was the delivery of vials of melflufin in 2009 to the Dana Farber Institute in Boston. So we really feel like that partnering in collaboration with leading cancer institutes around the company is an important part of who we are. In 2013, based on we initiated our 1st in human trial. So that's the Oncopeptides 2012 myeloma 1 trial, so the O12M1, which was published this summer in The Lancet, so first patient in 2013. So then over the past 5 years, the focus has been on the melflefin development program and trials you'll hear about today, mostly the Horizon trial, which is most mature, but also the OCEAN trial and the ANCHOR trial, which has an oral presentation at the ASH program in the upcoming week. And there in 2020 on the time line, you see our key milestone, which is our FDA user fee date of February 28 for the action on melflutin for accelerated approval in relapsed refractory multiple myeloma. So again, with the roots in Stockholm, Sweden, my office is in Boston, Massachusetts. We also have a strong presence in San Francisco that really enables us to recruit talent from a key biotech talent base on the West Coast here in the United States. So next slide, the company has undergone some rapid growth and what we accomplished will be done through the outstanding people, the strong and diverse team that are really unified and focused to drive value. Our core values will always lead with science. We will be an extremely data driven company. I think you'll see from the employees that talk today a passion, a collaboration, courage, come through trials like Ocean and building trust. So really fantastic team and we are 1 Oncopeptides. Next slide, please. Since joining the company in July of this year, my focus has been on the transformation of the company from a discovery IND generating company through this portfolio development and life cycle management and now moving into this launch in geographic expansion. So lots happening in each of these three phases, but suffice it to say that we have rapidly transformed into a fully integrated biopharmaceutical company and we're excited about delivering our first product to patients. So next slide please is Slide 9. So the platform, as you know, is the peptide drug conjugate technology platform. The addition of a cytotoxic agent to a peptide carrier. So a highly lipophilic molecule that has more selective uptake in a myeloma cell, where we have high expression of immunopeptidases that essentially hydrolyzes these agents and deliver a concentrated toxic payload into cancer cells, sparing the healthy cells. So that's really the backbone of our technology and certainly what we see both preclinically and clinically with melflufin. So on the next slide. So in thinking about our discovery and IND generation, we've done a lot over the past year or so in significantly expanding this group. First point came with our acquisition of a Solna based laboratory in June of 2020. This really provides us a number of capabilities in house, which allows us to do things a lot more quickly and obviously in a lot more prioritized manner. We're no longer at the whim of deep project portfolios of CROs and the like, but rather we're able to do it ourselves. So we built a team of passionate and very externally focused scientists. They enjoy immensely interacting with key opinion leaders, drug discoverers and developers around the globe. That's what fuels their energy and passion each and every day. We have state of the art medicinal chemistry and modern biophysical and in vitro cell culture. I'm also pleased to reinforce the fact that we are no longer just a one drug company that in 2021, we anticipate having our second drug in the clinic that has been known to you in the investment community as OPD5. So this comes to us off of the peptide drug conjugate platform. We do have IND approval and this is an analog amalfluffin, but it's particularly formulated to enable us to deliver a much higher dose of the toxic payload directly into those cells. So a Phase 1 trial is currently in planning and we look forward to 1st patient in, in early 2021. So the next slide please. So portfolio development and life cycle management, is really represented quite the bulk of our investments. Obviously, over the past 10 or 15 years, particularly on the lead program of melflupin in multiple myeloma and now beyond. So it's really about melflupin. And this is one of the things that really attracted my attention and interest in becoming part of Oncopeptides was this very deep and sophisticated development program on a product that we think can be foundational in the treatment multiple myeloma. So we've done a lot of work preclinically and continue to do it clinically and you'll see some new information, new cuts of the horizon data at ASH that show a very strong differentiation versus other products that were previously in the alkylating class, we like in and position melflutphen as a new drug class, this peptide drug conjugate class. Very broad preclinical activity, Jacob Lindbergh will touch on this a little bit as we think about the expansion of our clinical development program on melflutin. But with that focus on multiple myeloma, obviously, triple class refractory patients, heavily pretreated patients were the focus in the M12-one trial M1 trial and also the Horizon trial. But we're moving with OCEAN, ANCHOR, Lighthouse and the earlier lines of therapy and of course combination therapy, which is we'll see as we look at the landscape is becoming increasingly more important. And in the year ahead, we look forward to expanding this clinical trial portfolio, looking to treat patients who outside of multiple myeloma who can benefit from the drug based on the preclinical evidence. So you can see the chart in the right that Jacob Lindbergh will go over in a little more detail, a hint at where we might be heading as we think further about the development of this lead product. So next slide, please. So the final arm of the stool, so to speak, in that transformation is the geographic expansion, our launch and commercialization of melflutphen. As you can see on this slide in the bottom left, it's a very large market. In 2019, it was estimated to have global revenue in the $19,000,000,000 range with strong growth projected over the next 5 years reaching $23,000,000,000 in 2024. So you see a heavy dominance in the U. S. And the Rest of World as you might expect, there's a pretty large emphasis on Europe and Japan that make up that Rest of World segment. So it's an area of significant unmet need. As we'll see, survival is increasing. We still don't have a cure in multiple myeloma. And certainly, these new mechanisms of action are needed above and beyond the triple class of agents that are predominantly used today. And we're pleased to offer be offering in the future a new class with melflufin to help overcome the resistance that patients are realizing through their long course of treatment in multiple myeloma. On the next slide, just thinking about the geographies and the areas of focus, getting back to the large unmet need here in this category. So as it relates to the U. S. In the first column, we are in the launch phase. We've made, as you know, a formal decision to go at it alone. We've built a very talented team. I'll go over that in greater depth at the end of the session here. Based in Boston, we have the regional office in San Francisco and some outstanding employees as part of our team on the West Coast. We are launch ready and look excitedly to that PDUFA date established by the FDA of February 28, 2021. On the European side, we're making a lot of progress. I would suggest that the title here is we are in the regulatory phase, engaging with the regulators in Europe. We're excited about bringing melflufin to patients across Europe. Our early thinking is that we would also go at it alone. Our strategy is to build our own footprint. Obviously, with our global headquarters based in Stockholm, we're able to leverage a lot of talent, a lot of experience that can be brought to bear in helping to meet the needs of patients, investigators and health care providers in Europe. So our original strategy was to utilize the OCEAN trial for approval in Europe. But based on some activity in the marketplace, some competitive activity, particularly as we look at Glaxo SmithKline and belantamab on a trial based similar in scope, size and scope to the RYISON trial, we're able to move forward with conditional approval. So we've shifted our thinking towards bringing the product earlier to patients in Europe by utilizing the HORIZON trial as our backbone. I'm pleased to announce that we do have a rapporteur and co rapporteur that have been assigned and we are currently in the process of recruiting leadership into this European team. So we're excited about the regulatory phase for melflufen in Europe. And then finally, as it relates to Japan, we would suggest that we are in kind of this early regulatory phase. As we know, there are additional requirements from the regulatory authority in Japan relating to the treatment particularly of Asian patients. So we are exploring that. A GAAP analysis is underway with some consultants that are providing us some insights, interface with PMDA. In all likelihood, this is not a geography that we would go at it alone. It would likely be a partnering strategy. And in 2021, we'll continue this assessment of the gaps to be able to bring this product to market, engaging with key opinion leaders, being active in the local congresses in Japan and more work to come. And I would say that overriding or underwriting all of this, we are working with a distribution partner that will be able to bring Melfluffin to other geographies upon its approval in the United States through a special license sales opportunity. So that kind of concludes the first section here and the transformation of Oncopeptides. Again, I'm very, very proud to be a part of the company and to lead this transformation and really excited about the milestones that lie ahead that you'll hear a little bit more about as we proceed through the program. So with that, I'm going to turn it over to Doctor. Richter and he is going to provide us some further insights on multiple myeloma and the large area of unmet need that exists in the treatment of patients with multiple myeloma. So thank you, Doctor. Richter, for being part of the program. Thank you so much for having me and thank you to everyone tuning in. Hopefully, everyone is wide awake and not still reeling from too much turkey from last week. So next slide, please. Multiple myeloma continues to represent one of the most complex arenas in terms of not only active drugs in the current setting, but drugs in clinical trial. And whereas in the U. S, the NCCN guidelines provide discrete algorithms of how to treat patients, the kind of standard of care in myeloma gets more obscure and more obscure every day. Next slide, please. So are we on the is the 2nd most common malignancy slide? Apologies. Yes, Joshua. It's the right one. Okay. So Slide number 3. Thank you. So myeloma still represents the 2nd most common hematologic malignancy. Although, of course, we recognize that, although non Hodgkin's lymphoma is considered the most common this encompasses a wide array of diseases including follicular, diffuse large B cell, marginal zone, mantle cell. Ultimately, myeloma as a discrete entity is the most common hematologic malignancy representing just under 1.8% of all new cancer cases in the U. S. With just over 2% of the cancer deaths each year in this country. If you look at the most recent SEER data, it evaluates 5 year survivals from 2010 to 2016, giving a 5 year survival rate of about 54%. However, again, this represents people diagnosed in 2010, The exact survival rates of someone diagnosed in 2020 or soon to be 2021 is yet to be known. However, as these rates have continued to rise, we're hoping that it is getting closer and closer to 60%. There are approximately 150,000 patients in the U. S, a250,000 worldwide, with the prevalence for people in the older years of life with a median age around 69. The prevalence does rise year after year, giving a predilection for a risk factor of age for the development of multiple myeloma. Other risk factors include male gender and African or African American heritage. Next slide, please. So if we look across the variety of hematologic malignancies, we recognize that we have come a far way in myeloma. If we look only a generation ago and we talk about the entire journey of a myeloma patient from diagnosis to death, the entire journey lasts on the order of 2 years. Now with upfront therapies, giving progression free survival rates that are in the 4 to 5 year plus range, we are really achieving new grades for the disease, but compared to some of our partners with diseases such like chronic lymphocytic leukemia and non Hodgkin's lymphoma as a general concept, we are still generally underperforming. And despite these great advances in the clinic, great advances in clinical research, we are still well behind the curve and have a large unmet need in treating the majority of our myeloma patients. Next slide, please. So ultimately, we discuss how myeloma is treated. And although there is no clear standard of care, there are clear do's and don'ts, clear optimal strategies or at least clear optimal drugs and drug classes that we know had a major impact on the way we treat the disease. And ultimately, we talk about this concept of clonal selection. A lot of this work published by Doctor. Morgan and Doctor. Keats that at the time of diagnosis, most people develop around 4 to 6 sub clones of the disease. And as we go from relapse 1 to relapse 2 to relapse 3, this evolves clones exert different levels of dominance of recessiveness. And ultimately, the clone that does lead to a patient's demise is either minimally or not even represented in the original diagnosis. We recognize that the key to improving survivals is deep responses at each level and there's been data to support that a deeper remission upfront or in the relapse setting does correlate to better outcomes. We achieved this through multimodality therapy and the 4 main classes of drugs that we've been utilizing are alkylating agents, proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies, recognizing that it's not simply these individual agents, although all these agents start out as single agent in their approval towards the end of the line, ultimately as drugs, development strategies evolve, we recognize that different combinations, dosing strategies and utilization earlier on in the disease process leads to improved outcomes, not just for the drug itself, but to patients globally. We now refer to the disease in terms of refractoriness to different classes. So a term that was coined originally by Doctor. Kumar of the Mayo Clinic, the concept of dual refractory, refractory to both an IMID and a PI, and at the time that meant refractory to lenalidomide and bortezomib. You recognize that despite the advent of 2nd generation PIs and IMIDs, once you refractory to 1 drug within each class, that denoted a worse outcome. Now we note, with the advent of monoclonal antibodies, triple class refractory disease, those who are refractory to a PI and IMID and monoclonal antibody. And for the purposes of this, it's typically an anti CD38 antibody. In the U. S, it's primarily daratumumab. We recognize that once patients are exposed to 5 of the major drugs, including lenalidomide, pomalidomide, carfilzomib, bortezomib and daratumumab, ultimately, even if you're not refractory to all of those drugs, because of the cross reactivity of mechanisms of resistance, you will become more refractory and unfortunately have a poor outcome. Next slide, please. So ultimately, how we choose our therapies from myeloma still is a class system. So we have the image, the proteasome inhibitors. We do utilize classical chemotherapeutics such as anthracyclines, usually in regimens such as VDPACE, alkylators, some of them we use in cyclic fashion like bendamustine or cyclophosphamide or melphalin, which is classically been administered either in low doses as oral Alkeran in regimens such as melflan and prednisone or melflan prednisone and thalidomide or VMP, or high doses of that have been used in autologous stem cell transplantation. Steroids still represent a major class of action within the myeloma landscape and do represent an important synergistic component. We have other newer classes of agents like the histone deacetylase inhibitor, panobinostat, a number of monoclonal antibodies, including daratumumab, iletuzumab, isatuximab, and although not a naked antibody, but an antibody drug conjugate, more recently we now have belantamab, mafedotin, and of course the signs, the selective inhibitors of nuclear export, selinexor or Xpovio. Ultimately, we have been approaching the disease in combinations of 1 drug from each class, and we've demonstrated to this point that 1 drug is better than 0, 2 is better than 1, 3 is better than 2, and in some cases, 4 is better than 3. And ultimately, this is how we are building up our regimens to induce deeper and deeper emissions by using multiple mechanisms of action to kill as many of the sub clones as possible. Next slide, please. But again, one of the things we recognize is as we travel through the myeloma journey from 1st relapse to 2nd, 3rd and 4th, regardless of which pathway we choose in terms of our sequencing strategy, we ultimately end up with more of poor and poor outcomes, both in terms of progression free survival, duration of remission, depth of remission and unfortunately overall survival. And again, classically defined by Shaji Kumar, this concept of dual refractory that once you've seen at least 1 image, 1 proteasome inhibitor, despite the other IMIDs and PIs, despite the other therapies, you overall have a worse outcome. Next slide, please. So ultimately, this really needs to lends itself to how do we strategize. At least in the U. S, we are extremely lucky to have not only so many drugs, but a relative freedom of where to use them, what order, what combinations, obviously within certain constraints. But essentially, the way that we attack many of our patients' disease in the relapse setting is to evaluate specifically what drugs they're refractory to. So this is a slide that is a little dizzying at first, but at least brings up the concept of once you get beyond your first line, we then want to think are you bortezomib refractory, in which case we tend to use a lenalidomide, pomalidomide or carfilzomib based approach. If you're len refractory, we use a pomalidomide, bortezomib, carfilzomib or daratumumab based approach. Once you do refractory, we start thinking a little more outside the box. There are more recently regimens such as the Candor regimen, daratumumab and kryprolis has a great role there or some of the pomalidomide based regimens. But then we start getting further and further down the road. And even after only a few lines of therapy, we start having more and more difficulty controlling the disease and ultimately have to start looking towards new avenues of approach. Next slide, please. And really what this shows is that in the U. S, there's an extreme fragmentation of the entire marketplace across the relapsed and refractory world. We can see trends here from 2017 to more recent. And although this only represents a snapshot of some of the options that we have, we do notice a few trends that are occurring throughout this. One of them is of recent patients with more refractory disease, obviously now having the advent of drugs like EXPOVIO or selinexor. However, the other thing that we see, which is a really good sign, is the adoption of utilization of triplets over singlets or doublets. In the U. S, approximately 80% of myeloma is treated in the community as opposed to academic centers. So although in academic centers like the ones from the speakers you'll be hearing from today, where we use 3 drugs and 4 drugs routinely in both induction and the relapsed refractory setting, the community still has a large percentage of their treatment at all lines of therapy given a single singlets and doublets. We are slowly chipping away at this, recognizing that 3 drug regimens generally improve outcomes. Next slide, please. So when we look from front line to second line to third line to 4th line, if you were looking at an outside vantage point of myeloma, you would say, well, what is the unmet need? There's been a dozen drugs approved in the last decade. There are newer drugs on the horizon. Patients are living longer. Why is this concept of still an unmet need? And one of the things that we note is that despite all of these drugs, despite all of our options, as people go from frontline to second line to 3rd and 4th, we lose a significant number of people along the way, both to treatment related toxicities, disease related toxicities, age related comorbidities and other medical problems. And ultimately, we still have a large unmet need of getting all of those patients through all the options that we do have available. Next slide, please. In a more granular fashion, we can look here at the number of patients who entered from the diagnostic phase, the frontline, 2nd line, 3rd and beyond. One of the most important things about this is to look that between the time of diagnosis and frontline therapy, you already have about a 5% drop off. There are a number of people who present so advanced or so sick that they never make it to frontline therapy. And although the overwhelming majority of people will receive frontline and second line therapy, You start to look at the 3rd, 4th and 5th line and ultimately those numbers drop precipitously. And we recognize that in the United States, few people get beyond 3rd or 4th line. So although in my clinic today, I'll be seeing someone who's had 19 lines of therapy, That person is the exception and by far not the rule. So ultimately, we need better strategies to prevent non hematologic toxicities and death from infections and cardiac issues. We need better strategies to control disease at a deeper level, especially when they've received the standard regimens of IMIDs, PIs and monoclonal antibodies. Next slide, please. Moreover, the increased utilization of triplets and quadruplets in earlier lines has led to an evolution of what a relapsedrefractory patient actually looks like in the outpatient clinic. Whereas we now use this term triple class refractory, and you could think about this only a few years ago as being a relatively uncommon phenomenon, in that most patients got sequential doublet or singlet therapy, only made it to 3 or 4 lines, they would not end up triple class refractory. And if they did, it was a small percentage. Now with regimens in the U. S. Under clinical trials such as the GRIFFIN trial, which is a combination of daratumumab, lenalidomide, bortezomib and dexamethasone, if you were to progress on that early induction phase, which would be uncommon, you would already be triple class refractory in the second line alone. So we're starting to see not just a higher rate of triple class refractory myeloma, but we're seeing it in earlier and earlier lines, and this really has to change the way we approach the relapse setting. For example, the last 10 years have seen a litany of trials using LENDEX as a backbone. We look at the Aspire, Tourmaline, Pollux, there's one other that's going to come to me in a minute, But essentially, LENDEX as a backbone of triplet based therapy in early relapse. However, nowadays in the U. S, the majority of patients, whether transplant eligible or ineligible, already entered the 2nd line LEN refractory, we need to adjust how we approach things. Next slide, please. Ultimately, in academic centers, we often run into the realm of running out of novel agents throwing classical chemotherapy at these more end stage patients with regimens such as higher doses of bendamustine or infusional chemotherapy such as DCEP, VDCEP or VDPACE, 96 hour infusional chemotherapy rates regimens. And ultimately, despite transient responses to these approaches, these patients still continue to have quite poor outcomes despite the fact that it is quite toxic to give some of these regimens and VD set and VD pace although theoretically cyclable are not regimens we typically want to give patients in a cyclical fashion as it often requires hospitalization. Next slide, please. So very briefly, as was already mentioned, the Horizon trial is a registration trial for accelerated approval of melflufen. It's a Phase 2 single arm open label study. And essentially, these are patients who are relapsed from refractory to PAM or an anti CD38 monoclonal antibody or both. They were administered, melfluffin 40 milligrams and weekly dexamethasone on a 28 day cycle. And they were treated until progression or intolerable toxicity with primary endpoints of overall survival and secondary endpoints as seen here below, including not just survival outcomes, but healthcare related quality of life outcomes, which is becoming an increasingly, increasingly important factor to understand how to manage a heavily relapsed patient as many of them will start to have significant treatment related toxicities, which will alter therapeutic approaches. Next slide, please. And we can see here in the swimmer's plot, a really great, viewpoint of a pentorefractory based drug with an overall response rate of 29%, duration of response around 5.5 months. And for those people who see the overall response rate of 29% and feel that it is an anemic number, you need to think about the more all the recent approvals in myeloma, daratumumab in the late stage setting, single agent, 29 percent, carfilzomib in the late stage setting, 23.2% from the 3A1 study, daratumumab from the SERIUS study. If you look at pomalidomide from the 3 study, it's about 28%. If you look at selinexor from the STORM study, 26%. So melfluthen is right on target with the late stage development of single agent pentorefractory or advanced stage patients. And again, ultimately, as the drug gets combined and used earlier on, these rates go up and up. Next slide, please. So one of the things that I like to think about, and this is my last slide, I swear, is how would I envision melflufen in my clinic for the patients that I like to see. And there's a couple of key points for me. One is it's an effective alkylator based option for patients in the more advanced setting. One of the things in the U. S. That is changing is the rates of autologous stem cell transplant. As our induction rates get better and the data from novel therapies get better in the earlier lines, people are often delaying autologous stem cell transplant. Add on the data from studies such as the IFM 2013 and the a Forte study showing the advantages of a IMID PI dex over PI alkylator dex combo in the upfront setting. And ultimately this leads to patients entering early and even late relapses, alkylator naive. Having an option for an effective alkylator in later line settings is actually quite key for many of our patients. Also, the toxicity for the drug is essentially heme related, there's limited non heme toxicity. And as we look to the more recent approvals with drugs such as belantamab, mafedotin and selinexor, although excellent drugs, viable drugs and heavily utilized in our clinic, they do have significant non heme toxicity, which makes their utilization somewhat more complex in a more advanced patient who may have already had a decline in performance status and other problems from prior therapies. And at its core, when we talk about all these great drugs like monoclonals and bifunctionals and carts, but still the best drug is Melfelmann at its core. There are very few drugs that have ever been given in a myeloma patient, yet a cancer patient that can be infused over half an hour and a patient remains in remission for years, if not longer, with some of the high dose Melphalan studies. But in my mind, melphalan has struggled from 2 problems. 1 is sometimes it's too much. We have a number of patients who are ineligible for high dose melphalan in transplant due to comorbidities, age, performance status, etcetera. And even though it's a great therapy, it's too much for them and sometimes not enough. We've noticed after years of advances that oral Alkuran is not the optimal way to deal with some of our patients. At least based on the first trial, we've seen that LENDEX is better than regimens such as MPT. And in many ways, I kind of envision moflupulin as the Goldilocks alkylator. It's mid range. It's not too much. It's not too little. It's the porridge is just right. It's cyclable, tolerable and effective. And with that, I'd like to thank you all and open up to a few questions. Thank you, Doctor. Richter, and this is Klas Burkhard. I would like to draw everybody's attention that it is possible to post questions on the message board for Doctor. Richter, but also in the forthcoming parts of this presentation. But if I may kick off the question section, Doctor. Richter, based on what we've now seen and the importance actually of getting control of the disease, especially in these later stages. Where do you see melflusen fit in the near and midterm future if we take an eye to that future? What would be your thoughts there? So I can give you the thoughts, my general thoughts and then I had a crazy idea based on a patient I'm going to see this afternoon. My general thoughts are patients who in the U. S. Receive something like VRD upfront, then go on a LendMeIn strategy, get Darapom Dex, then get Kyprolis and are now multi drug resistant, but still alkylator naive, I think this represents an excellent modality and something that we can really use to control disease in a cyclable way, especially for the alkylator naive. Unclear yet how it would work in the alkylator exposed patient population. So if we've had patients who've received 1 or more infusions of high dose melphalan, it's still not clear how optimal the strategy will be, more data is clearly needed. As an absolutely off the wall strategy, I'm seeing a patient this afternoon and I was just going through my patients this morning, this is someone who's had everything, absolutely everything and developed plasma cell leukemia and malignant effusions. And eventually, with pancytopenia and declining performance status, we admitted him to the hospital for an infusion of BCNU and Melphalan 100 milligrams per meter squared apiece. He's coming out now and he's had complete resumption of his counts, no longer has effusions. The catheters were taken out, no longer has plasma cell leukemia and his M spike, which had gotten up to over 7 is now down to 2. His free line chains which were 1400 are now 10. So he's in remission. I did great by giving him a melphalan based therapy. One thing I cannot do is give him BCNU and melphalan every month or every few months to control his disease. It's simply too much. There is no maintenance strategy available for him. However, knowing that he has proven a sensitivity of his myeloma to classical chemotherapy and specifically Melflin strategies, if I had moflufen in my clinic today, I'd actually put them on moflufen maintenance. That's good to hear. And there should be options in the near future and also with our expanded access program in the U. S. There. I'm just looking at the message board if there is any other question coming in at this stage. So then maybe I have one other question and we can maybe finalize this section there. And that is about the adverse event profile of moflufen and especially the heme tox? How would you consider that and how to manage? So I think one of the things that's very user friendly about this is, new drugs are coming out all the time for both myeloma specialist and general hematologist oncologists. And it is quite difficult, especially for the myeloma specialist, to incorporate a new drug into his or her regimen if you have to start thinking outside your training. So filantamab mafedotin, excellent drug, although I have to sit down and learn how what OU, OD and learn how to manage grade 2, 3 keratopathy, it's difficult to get that into my armamentarium as a drug I want to use all the time. But physicians who treat blood cancers are exceedingly used to using drugs with heme toxicity. We all know how to give white cell growth factors, red cell growth factors, how the whole drug dose adjusts. So the fact that the non heme toxicity is quite limited actually makes this a more advantageous drug to use, especially in a setting where heavily refractory patients may have significant neuropathy or other things like cardiomyopathy, it gives you concern for using drugs that have either a neuropathic signal, cardiotoxic signal, GI signal. So ultimately, the AE profile makes it a little more user friendly, both for docs to take it in as part of their armamentarium and to give it on a clinical basis without fear of missing something like a corneal event or some obscure toxicity. Very good. Thank you. And I see that questions have come in actually. So Doctor. Richter, I don't know if you have some minutes left, but then I'd like to go through some questions. So one question from Susanne Van Fortheisen from Kempen. It's actually about the OCEAN study, which acts as our confirmatory trial, which is a head to head study against pomalidomide. And to what extent do you see the OCEAN study results better guide treatment in practice dependent on the results, of course? And then to that extent, how do you look to the lenalidomide refractory inclusion criteria? So I think what that really does is if we're looking at a lenalidomide refractory based patient population, this gives us the first inkling of what melflufen would look like in an earlier setting and not just in a late stage patient. Again, we have to look to all new approvals beyond the standard therapies that are available. But then when we look to earlier utilization and more novel combinations, this simply improves overall outcomes. Take daratumumab, for example, we recognize that in advanced patients from the SERIES trial, there's a 29% response rate. When we move it into areas like polyps, first relapse, it gave us a 93% response rate and upfront it gives us 100% response rate. So what this really clues us into is that in the U. S, if you are transplant eligible, your pathway is typically VRD transplant LEND maintenance. For those who are transplant ineligible, they receive usually something like VRD Lite or Rev Dex and ultimately just end up on a rev maintenance strategy anyway. So regardless of how you start off, most patients enter the 2nd line LEN refractory where a pomalidomide based regimen, whether or not it's DPD, Eso PD are all extremely applicable options, noting that when we have data versus POM, this will give us our first inkling about not just the advanced advanced patient, but earlier on tolerability as single agent, which is something we don't have for daratumumab. We don't know dara single agent activity in the early relapse, but we will have a little more inkling of that with melflufin. And then ultimately in combinations with other drugs, this will be even better. Very good. And I think if I look at some of the other questions that do come in, like do you see a place from Aflufin earlier in the treatment algorithm or only in the triple class refractory setting actually based on what you say there may very well be an opportunity there also based on the OCEAN data? Absolutely. I think if I wanted to imagine a patient, let's imagine a patient who gets induction, gets an auto transplant and gets an extremely durable remission such that they don't relapse from their Melphalan high dose Melphalan for 5, 10 years. Now they are over the age where you feel comfortable giving them an autologous transplant. However, you recognize their myeloma's exquisite sensitivity to melphalan. As a second line therapy, that may be the optimal patient, either a single agent or in combination with drugs such as daratumumab to capitalize on the known sensitivity to the MOA. Very good. Thank you very much. So this is, I think, the last question for this section or maybe 1 or 2. So we've seen quite some patients with extramedullary disease in the Horizon study. So I had about 55 patients and a total of 157 patients. So what's your view on the data that has been shown with moflufen in the extramedullary disease setting? Again, I think it's been quite impressive and unfortunately something we have to deal with more and more. As we're able to sub select out a more resistant and virulent clone of myeloma, we're seeing a rise in extramedullary disease in all of its forms. Now classically, we think about this as bone based and extra osseous plasmacytoma, but extra medullary disease includes things like plasma cell leukemia, includes things like CNS disease, and this is becoming harder and harder to control. The other thing that we're also seeing is the evolution of nonsecretory clones earlier on in the disease, making people ineligible for the majority of our clinical trials. So having an effective option for extramedullary disease in patients who may otherwise not be eligible because we've seen these as many of these as nonsecretory provides a really great venue to control those patients. Thank you very much. And then as a last question, I think that has come up and from Boris Peaker. In terms of adoption of new treatment regimens, do you think that selinexor is a reasonable alternative here to lampliv? And what's your clinical view on that? So, I think the question is one of the most important questions asked and also the one that's the most impossible to answer. Myeloma is such a heterogeneous disease. I can envision a patient where selinexor is absolutely the right answer and that is case where moflufen is absolutely the right answer. I doubt we will have head to head data on the 2. I think that both drugs provide a specific niche. I think that one of the ways that I would guide myself has been patients' prior responses and tolerability to alkylator based therapy. If someone has had 2 auto transplants, 3 cyclophosphamide based regimens and bendamustine, I would be slightly less inclined to use melflufin as opposed to selinexor. However, if they had one transplant 10 years ago, had 10 other therapies and no real alkylator experience beyond that, that would give me much more towards melflufen. But again, the devil is always in the details. Absolutely. And I'd like to thank you so much for your presentation and time to answer these questions. To the people that are listening in, we will have some room for more questions after we have gone through the panel discussion, which is, I guess, upcoming next. So stay tuned for that. And with that, I'd like to turn to the panel discussion. And I think we can move to the slide there. Very good. And for the panel discussion, we are really fortunate to have 2 key opinion leaders as how we would call them, but 2 physicians with a lot of experience with multiple myeloma, but also with the use of noflufen. And therefore, I'd like to welcome Doctor. Marie Vima Tejos from Spain, who is joining us this afternoon. Thank you very much for joining us. And I'm also very pleased to actually have Doctor. Richardson from the Dana Farber Cancer Institute in Boston on the line. And Doctor. Richardson, thank you for making time on this early time of the day for you, and it's great to have you both here being present with us today. Thank you very much. I think you're right, Doctor. Richardson. Sorry, let me unmute. Is that can you hear me now, Klaus? Absolutely. Yes. Beautiful. Good morning, guys, and good morning, Ravi, and thank you so much, Josh, for that super presentation. I apologize for being slightly windswept and behind here because I had to put in a ton of orders just before joining. So literally live to the meeting as it were, but good morning, everyone. Lovely to see everyone on the call. Thank you. Very good. So I think based on the questions that have come in from the audience as well, I think it's good to have a kind of like a small panel discussion on some of the topics around the use of NELFLUFA. And I think one of the things that we have seen in Doctor. Lifter's presentation is the scattered landscape after the first or second line of treatment of multiple myeloma these days. So if I may start with Doctor. Mateus here. So where do you see mafluthan fit in also in the near future and also taking into account potential future combination studies that are ongoing such as our ANCHOR trial? Yes. So this is an excellent question. And I think that Doctor. Richard has well, has elegantly presented what is the current landscape of treatment for patients with multiple myeloma. So you should do that right now. I would say that after the first and the second line of therapy, most of our patients are going to be exposed to proteasome inhibitors in its anti CD30H monoclonal antibodies. And many of these patients will have the opportunity to be exposed not only to vortezomib, lenalidomide, daratumumab, but even also the 2nd generation, I would say, pomalidomide, and carfilzomib. So I would say that basically we are going to face with 3 tracker class of refractory myeloma patients just at 3rd line of therapy, maybe in the future, even after the first line of therapy. But I would say that at 3rd line of therapy, it is possible to face with 3 drug class refractory myeloma patients. And I think that in this situation, Melfluffin plus dexamethasone has a role. While if we look into the ORION study, it's true that patients were more heavily pretreated because the moment at which this trial was conducted was different than the current situation and patients needed to receive at least 4 or 5 lines of therapy in order to be free drug class refractory. But this is not going to be the situation in the near future. And this is the reason why I see melflupen plus dexamethasone in the near future maybe in third line and beyond. But if we look into the future, I would say no near future, I think that definitely the ASEAN study will put melfrufen plus dexamethasone maybe earlier on. And if we move to the potential new combinations, I think that at the end of this week at ASH meeting, we will have the opportunity to see excellent results combining melprofen with either bortezomib or especially with daratumumab. Clearly, the efficacy is comparable with other combinations we are utilizing right now in 3rd line and beyond. So definitely, today, 3rd line triple drug class refractory patients, or I would say patients exposed to PI emits an anti CD38 monoclonal antibodies and maybe refractory to the last line of therapy in the near future earlier on and in combination with either proteasome inhibitors or monoclonal antibodies anti CD30H. Thank you very much, Doctor. Matheus. Anything to add there, Doctor. Richardson? Claus, yes. I mean, I think Marie Vie captures it beautifully. I think the important point is that increasingly as we use 4 drug platforms in first line of therapy, so for example, you'll hear at ASH really outstanding data using PI IMID steroid and antibody combination. Increasingly, the second line becomes essentially functionally the equivalent of what we now consider 3rd line. And I think importantly, what's so encouraging about the data with Melflufen to date is that it is well tolerated in the absence of the hematologic issues. If you put those to one side and those are manageable, the absence of alopecia, the absence of mucositis, the fact that quality of life is preserved makes it an ideal targeted peptide drug conjugate with cytotoxic properties that in my view are so encouraging because they target stemness in myeloma in my opinion. I think that's particularly important in the wake of biological therapies used upfront that this may become a challenge. So I see for example an older patient who may have had a daratumumab based approach in first line, a meloprofen based platform combined with a proteasome inhibitor would be an ideal next line of therapy for that patient as we think to the future because essentially you use your cytotoxic platform at that point synergizing with your PI, but most importantly in a non toxic fashion that's also highly convenient, very real world. This is a once in a 4 week infusion. It takes around a half an hour. It's an outpatient procedure. It doesn't involve complexity And again, for us as hematologists, the management platform or the management challenges are kind of bread and butter. They're neutropenia, thrombocytopenia and so forth. There's nothing unusual, peculiar or complex in the way we deliver the drug. And I think that's important, particularly in the COVID era that we have very practical user friendly approaches that can make patient management that much easier. Very well. Thank you, Darren. And that was actually probing into one of my other questions and that goes to current times with COVID and we don't although know when things will return to normality. So to what extent you've already mentioned the applicability of melflusen there, but to what extent do you think that will drive utilization of newer drugs in the coming year or 2 years? Marivi, do you want to? Yes, sure. I think that while the unmet medical needs in the management of patients with multiple myeloma is there and definitely we need the novel agents that Paul alluded to the COVID-nineteen pandemic and we have to try to protect it to our patients of becoming infected when they are coming to the hospital. So Melfluffin is an excellent drug because it is given just in a single infusion every 4 weeks. This means that the patients would need to come to the hospital just once per month what is relevant in order to maintain the disease under control and avoiding frequent visits to the hospital. So I think that melflufenplastexamidazone will cover 2 important requests sites in order to optimally manage patients with myeloma under this pandemic. I would echo that. And I think the important point is that in the horizon study for one example and indeed for that matter with our initial experience with O12M, we did not see atypical infections. We did not see in fact particularly with Horizon, which is a vulnerable population of triple class refractory antibody exposed patients, we didn't see a high rate of pneumonia. Now this is very relevant because in the antibody space, one of the challenges that we run into is an up to 30% incidence of significant chest infections. And that's very relevant in practical terms because if you've got a platform that can provide you or can spare you or Okay. Thank you very much. And in the meantime, I'm also looking at the message board and I will actually cut mix some questions that I have prepared to ask some of the questions that are coming in from the audience. And this is about actually, Doctor. Richter talked about the use of noflutphenin also in patients that actually have had prior exposure to inoculator. Doctor. Matthias, do you have any concerns there with moflufen or what's your experience there? And I know we have some data upcoming at ASH talking about efficacy of noflufen in these patients. But do you have any experience there? Or would you like to share us your thought? Yes. And I think that this is an excellent and practical question and Joshua Richard previously alluded to this. Well, because it is possible to have myeloma patients at relapsed alkylator naive because, while we know that there may be more and more newly diagnosed myeloma patients don't want to perceive autologous extensive transplantation because of the lack of benefit in overall survival. At the end, in the French study that will be presented also at ASMEDIEN or even in the elderly population in which we can select combinations, alkylators free. In this situation, we know that melflufen plus dexamethasone is going to work extremely well And there is a sub analysis conducted in all patients included in the OP12M study and ORION study under the group of patients, alkylator naive, responded extremely well. But for me, it's important to remark that most patients had been previously exposed to the alkylator 1 or 2 and even some patients were refractory to the alkylator and the efficacy was maintained. What is important because even although we can utilize high dose Melphalan or just Melphalan or maybe cyclophosphamide as part of the prior lines of therapy, At the moment of the relapse, the patient can receive again this data because and in this sub analysis, it is confirmed how the ficus is quite sustained and I think major issues retreated my patients with an alkylator, a different alkylator like Merfluffin. And in fact, in my clinic, while I have included quite many patients in the ORION study, in this situation, most patients had been previously exposed to alkylators and most of them had those melphalan followed by autologous extensive transplantation. Thank you very much. And Doctor. Richardson, to add on that, would there be any hesitation with you on patients that have received alkylators in the past with noflutphen? It's a great question. And I think obviously practice patterns differ. And I think certainly in Europe, there is a very appropriate use of alkylation and to a greater extent arguably than we do in the United States simply because we have access to so many new drugs. And so consequently, in my practice, for example, I relatively spare my patients initial treatment with alkylators as much as I possibly can. So I'll share with you a patient example from the OCEAN study. This gentleman had 2 prior lines of therapy, had only had hydrocyclophosphamide to mobilize stem cells and he was assigned to Melflufen Dex in that study and had a complete response to therapy. He was arguably alkylator exposed, but relatively naive. And I think that's how I see the drug actually positioning itself ultimately. I think it's clear that it works after prior alkylation has failed a patient. But I think as we go forward relatively alkylator spared patients may be ideal candidates to receive Melflufin, not least of which because I think it's relevant to potential long term toxicities. I do think we have to be careful about those patients who've had a lot of Melflufen exposure then being exposed to melflufen, but those patients have to be approached with care. But having said that, we clearly see that the drug works particularly in the horizon setting after extensive prior alkylation. But in the future, Klaus, I kind of pick up on a point that Marie Vie made, which is that I could foresee it being used as a cytotoxic or a targeted cytotoxic. So I don't really think of it as a classic alkylator as a targeted cytotoxic of choice in the future, because of its extraordinarily favorable therapeutic index in my opinion. And on the other hand, also the fact that it is distinct from prior from alkylators in the classical sense, quite so actually, both for resistance characteristics and importantly for toxicities as well. Right. Thank you. Thanks for that answer, Doctor. Richardson. And then this was alluded to previously, and that is the use of belflutin in patients with extra medullary disease. So, Doctor. Mateus, with the use of multi combination treatments in upfront with even droplets. Ultimately, patients may develop extramandulary disease and that proportion may be higher actually than that we actually now see. So what's your impression there? And are there any viable alternatives to melatonin for this growing patient population? Yes. So this is also an excellent question because extramedullary disease is basically characterized by myeloma cells that can grow independently of the bone marrow microenvironment. And it is usually always associated with a worse prognosis. And in many clinical trials, the patients with extramedullary disease are not well represented. So it is impossible to recognize what is the real efficacy of many of the new drugs in this specific population. And I think that the good news is that in the ORION study, quite a high proportion of patients included in this study presented with extra medullary disease. And important to see that not only bone related plasmacytomas but also pure extra medullary disease. And I would say that approximately 55 patients in the ORION study presented with these characteristics, extramedullary disease. And what is important to see is how the efficacy was sustained in comparison with the overall population, indicating that melflufen works in patients with extra medullary disease. And I can say that I've seen in my clinic at least 3 or 4 patients with relevant extra medullary disease and to see how just after the first cycle of melfluefen plus dexamethasone, the extra medullary disease, the plasma cytoma clearly disappeared, almost disappeared. So I think that this is a special feature and a specific feature for maflufen plus dexamethasone that as I previously said, it is not usually observed with other novel agents. Yes. I think that's an excellent summary, Claus. I think the other point I'd like to make is that in the Horizon study, Maribyr is absolutely right. We had 55 patients with extramodullary disease and in our analysis which we're presenting at ASH, but it has been discussed before, so I can share some of the information. The overall response rate was 24% in this specific subgroup, which we have to recognize as being an important signal because these are patients who were almost all CD38 antibody exposed. And this is the strongest single agent signal we've seen in this signal in this setting of extramedullary relapse and triple class resistant disease. And I think it represents an important milestone actually in the development of melflutin because my I would foresee that melflutin could become a mainstay of targeting tumor delivery disease in the future. Marie B touched on this very nicely in that there are specific properties to Melfufen that make it attractive. Glypophilicity, the fact that it's a highly targeted entrapment mechanism that occurs within the tumor cell and most importantly preclinically, it is a potent anti angiogenic. Now that in terms of solid tumor behavior is extremely important and that's not what we see with classic alkylators such as cyclophosphamide or very importantly melflan. We do not see that same effect. So this sets melflufin apart in my opinion and provides a platform particularly with combinations such as a proteasome inhibitor where actually the platform may be the treatment of choice after CD38 monoclonal antibody failure in terms of extra medullary relapse because just as lenalidomide failure was our biggest challenge some years ago, now when CD38 targeting fails a patient, that is our new challenge in the relapsed refractory space. And I think actually melflufin is very well positioned, Klaus, to take advantage of that unmet medical need. And I think the data from Horizon are very encouraging in that regard. Thank you, Doctor. Richardson. I think and the time goes fast. We have only little time left, but there are a lot of questions still coming in. So I'll segue there now into the OCEAN study as well. So if we look at a positive outcome for the OCEAN study, which would be either a non inferiority result or a superiority would help. To what extent would that could that position Novlefin as a future backbone with other combinations, Doctor. Matheus? Yes. So I think that the OCEAN study will be, what I would say, a confirmatory study supporting the role of melflufen plus dexamethasone while the efficacy and safety data we've seen in the horizon because it's true that the horizon has been conducted in heavily recruited myeloma patients. But when you asked us where we will see melfluffin in the near future, we said, well, in third line after prior exposition to progression inhibitors, it meets anti CD38 monoclonal antibodies. And I would say that this is the place in which the OCEAN study is going to convert the melfluefen plus dexamethasone versus pomalidomide and dexamethasone after 2, 4 prior lines of therapy with one specific feature. All patients are going to be LEM refractory. And we know that right now this is a challenging population that again it is not very frequent in almost all phase 3 clinical studies. Even if we evaluate new combinations based on new potassium inhibitors plus anti CD30H monoclonal antibodies, IMEI plus anti CD30H monoclonal antibodies. When we look at how many patients were relaying refractory, no more than 30 percent. In the OCEAN study, all patients will be relaying refractory. And we will see if it is better to continue with the immunomodulation through pomalidomide and dexamethasone or maybe to change and to go to the melflutane plus dexamethasone. For me, OCEAN study is a critical study that I repeat, I will support what we envision about the specific place for melfrufen plus dexamethasone. Yes. And Claus, I would again, that's beautifully put by Marie Vie. I think the for example, lenalidomide failure, obviously, I firmly believe cytotoxic approaches that are targeted will add benefit there, particularly as we then move into combinations. I think one very important other point to add though is that targeting BCMA has become obviously a go to after we've failed in the context of CD38 targeting. So if a monoclonal antibody approach using a CD38 targeting platform fails, BCMA is a logical next choice. One thing that's very striking to me is that BCMA is a relatively unstable platform in some respects in terms of duration of response and the ability to maintain minimal disease. And so this points to another challenge that we face. And this is this whole construct of myeloma stemness. In other words, the core of the disease. And I think what's really important to share with our listeners is we have emerging data that melflufen is particularly active in high risk disease and diseases characterized as enriched for adverse cytogenetics such as 17p deletion. And our biggest clue actually so far has been actually in the Horizon dataset in the extramodullary disease group where they've been enriched for high risk cytogenetics and we've seen activity. So I can foresee the platform coming in combination. And I completely agree with Marie Vie, the OCEAN study provides an absolutely critical proof of principle where we will then move into using melflufen as a pillar or a backbone of combinations in a variety of different settings. Okay. Thank you. Thank you very much, Doctor. Richardson. I see that our next speaker is already lined up. So for now, first, I would like to thank you, both Doctor. Mateus, Doctor. Richardson for your participation here. That's really appreciated. So thank you very much for that. You're free to stay on the should time allow. But for now, I'd like to actually hand over to our Chief Scientific Officer, Jacob Lindbergh. Jacob, the floor is yours. Thank you so much, guys. Thank you very much. Thank you. Thank you very much. And thank you, Klas. And I just would like to start to thank Doctor. Richardson, Doctor. Matthias and Doctor. Richter. I hope everyone understands that, that group constitutes basically a full panel of myeloma experts that could host any type of panel discussion at the major scientific symposium, and we are very fortunate that they wanted to be here today to talk about the drug and their experience. So I will go through our peptide drug conjugate platform and the clinical development program we have for molesleufen. Some of these slides are slides that we have presented multiple times before, so I will be fairly quick through them. Other sections are more new, and we'll spend more time there. Please note that the full presentation will be available on our website afterwards. And of course, we will have a Q and A session after Marc de Waal has presented the commercialization piece as well. So if you would like me to go more in-depth on slide that I go through a little bit fast, please ask questions in the chat and we'll return to it. Before we go through the development program, I would like to spend a little bit time on the drug that we have talked about today. I wish we have designed it this way from the beginning that we knew that we added some novelty really to this platform, but that's not true. We kind of stumbled upon this molecule or Doctor. Gullbo did. From the beginning, we thought that we could enrich for an alkylator and fundamentally, it would function as an alkylator. As we have mapped the molecule over the years, we have realized that the aminopeptidase binding motif actually is a key aspect of the drug, and it fundamentally changes how it works in some aspects. So while it clearly is an alkylating agent, and we can talk about it as such, it also introduces a completely new element, which is the peptide that binds aminopeptidases. Binding is interesting because in pharma, we use the word target. And target is interesting because target is an activity verb, right? You target something. And that implies that something is sentient. Molecules are not sentient. Molecules just bind to each other. So one molecule has an affinity for another molecule. One part is not active in that relationship and one is passive. They are just binding each other. This construct binds aminopeptidases. And that means also for all practical purposes, we target aminopeptidases. This targeting of aminopeptidases increases the potency of the construct, but it also changes the molecular footprint of the molecule. So we see a lot of effects that you don't see with a normal alkylator. Doctor. Richardson brought up the angiogenesis signal. He also brought up the high risk cytogenetics part. We don't kill cells in the same way as other alkylating agents, and this is a key aspect. So and this makes it kind of hard to describe sometimes because it contains something new and something old. We're both an alkylator and the new class at the same time, which is slightly schizophrenic. So why is targeting of aminopeptidases important? Well, we have known for 30 years that aminopeptidases are oncogenic. That is that they are overexpressed in cancer cells, but they are very hard to target because they are intracellular in nature. As something is intracellular, it means it's not at the cell surface, so it's hard for an antibody or normal molecules to actually access it and bind to it in a good way. Due to the lipophilicity of melslefins, it traverses cell membranes very rapidly and passively and then binds to intracellular aminopeptidases. And once again, I wish we knew that we designed it this way from the beginning, but we didn't. But the molecule obviously targets aminopeptidases, and this is a very important part of the mode of action. And we have just summarized some features. I've already said that aminopeptidases are overexpressed in cancer, but more importantly, the expression goes up as the degree of malignancy goes up or the amount of motational burden goes up, I. E, the more aggressive, the more advanced the disease is, the more this targeting mechanism is relevant. This doesn't mean that the activity of millefins goes up because these cells are increasingly hard to kill, but it means that the relative advantage of nilsifen over other drugs increases as the disease express high risk features or is more aggressive in nature. And that is, of course, where the unmet medical need is at its peak. In this sense, it acts very similarly to an antibody drug conjugate. An antibody drug conjugate binds to target at the cell surface, gets incorporated into the cell and releases the toxin inside then preferentially the cancer cell because they express more of the target. With melflufen, it traverses the cell membrane passively, binds to immunopeptidases that are overexpressed in cancer cell and releases the toxin inside the cancer cell, hence expanding the therapeutic index of a known cytotoxic class. With melflufen, this is an alkylating agent. Most antibody drug conjugates use tubulin inhibitors. All cytotoxic classes with therapeutic indices in themselves, but these targeting mechanisms expand those indices, which is very important because it means that you can dose higher and achieve higher efficacy. We have spent a lot of time on something today, and that is what is the treatment landscape in multiple myeloma. I will try to look at that through the lens of the regulatory bodies and labels. And this picture depicts how the myeloma landscape looked a few years ago. And to some extent, it still looks like this today. Doctor. Richter brought this up, but looking at the epidemiological data and patients is a little bit like looking at the stars. The light is old. So the events you visualize and see are events that occurred years ago. And this is exactly the case when you look at the current patient population that is late stage. It is a representation of patients that got diagnosed years ago and doesn't look like the patients that get diagnosed today, it will look differently, and we'll come back to that. So a few years ago, you had a fairly large population of newly diagnosed that stayed for a long time on therapy. The majority of them would relapse in their disease and become a relapsed multiple myeloma patients. Patients. That is depicted as RMM. And you see that the box is fairly large. Then the patient would progress while on therapy and become a relapsedrefractory multiple myeloma patient. At some point along this journey, once their tumor map got approved, this patient would receive anti CD38 based therapy and become triple class refractory. So triple class refractory was a niche indication at the very end of life of a myeloma patient. And to some extent, these patients are still around. But this is not how it is starting to look. And the numbers that Doctor. Richter showed in terms of growing population for triple class refractory shows this. This is much more how it looks today. We are front loading the algorithm aggressively by using triplets, quad therapies in the newly diagnosed setting. That gives an advantage, and you see that the newly diagnosed box has grown in size. They stay longer on therapy, so it gives an advantage. But since we also use therapies either continuously or as maintenance at the back end of that, normally Revlimid, very few of these patients actually ever become a relapsed patient. They become relapsed refractory straight off the bat. And that means that the relapsed box you see is smaller than on the previous slide. And since we use both IMIDs, PEIs and anti CD38 so early in the treatment algorithm, it means that the relapsed refractory multiple myeloma box and the triple class refractory box starts to merge. They become the same. Patients, of course, not all RRMM patients are triple class refractory, but the trend is clearly that the majority of RRMM patients will be triple class refractory. And this means that this indication and this label that we're seeking, we don't know if we're going to get it yet, is not a niche indication anymore. It's more or less the same as saying that the drug is approved for use in RRMM. And I think this is a very important point. We have, of course, developed a vast clinical development program for small biotech, clearly vast program in relapsedrefractory multiple myeloma. All trials are in RRMM, except our signal seeking trial in light chain amyloidosis patients. I will not spend time on that topic today. Looking at these trials, we first did 2 signal seeking trials, O12M1 and Horizon, which explored malslufineplastexamethasone single arm, open labels trials in highly refractory patients. And as we have heard today, we have a very encouraging activity signaled in both these data sets that, of course, have paved the way for our submission for accelerated approval with the FDA and now the regulatory phase with EMA. In Ocean, we go head to head with pomalidomide. Now why did we choose palm all these years ago? Because it is the backbone in RRMM. It still is. It's still the most used drug in RRMM, and it's squarely placed there. So since that is perceived as the most efficacious and most used drug, to actually understand how mlslufen's activity compares to pomalidomide is a key aspect to understand the potential potency or the potential for mlslufen to help RRMM patients. In ANCHOR, we combine our drug with protozome inhibitors and anti CD38 therapy. In BRIDGE, we look at the subpopulation of patients with renal impairment. In Lighthouse, which is a trial we are soon to be to initiate, we had planned to initiate it earlier this year, but COVID put some problems to that. We combine with daratumumab in a randomized fashion. It's also registrational trial, and we hope to use that show that the anti CD38 combination therapy makes sense with melsuthan. We then have the light chain amyloidosis trial, and we also have supporting programs looking at administration as well as early or expanded access programs in the U. S. And we hope to initiate similar studies in Europe on the expanded access side as time matures. We have actually planned 2 new trials in RRMM in 2021. Please note planned. It doesn't mean it will happen, but we are fairly certain, otherwise we wouldn't write it here. That is we're going to do a study in patients with extramedullary disease. We have already had a lot of information regarding this that actually Milsufin is the only drug so far in the clinical trial setting that has shown promising activity in late stage patients with EMD, especially when they have triple class refractory feature sets. We also have the analog to Nilsifen, OPD5, which we're going to initiate to look at the high dose setting. It's a formulation specialized for the high dose setting to allow for the use of the peptide drug conjugate platform in the stem cell transplant setting. Please note that the IND for OPD5 was just recently approved in the U. S. And the planned study start, just like the MD study, is during 2021. Implicitly, this was discussed a lot actually today with the clinicians, and we have shown this slide before, but I think it's worth mentioning. What do you need to show to be able to help patients with multiple myeloma? And you need to show that as a single agent plus minus steroid, you have activity levels north of 20%. Doctor. Richter went through all the previous trials here, and I know a lot of people look at combination. But as a single agent plus steroid, it's very important to create the baseline, what level of activity do you see with the drug to understand its potential utility. And you need to be north of 20%. And we have been at 31% and 29%. So really excellent activity numbers. You need approval as a single agent plusminus steroid in multi refractory patients. That's exactly what we seek with the Horizon accelerated approval and of course also with the Ocean registrational trial and confirmatory trial. You need to show synergy with other drugs. Doctor. Richter showed this as well. Each patient is an individual and you need to look at the previous treatment history and the exact characteristics of the patient to know how to treat him or her. So you need to show that you can be combined with the other drug classes and you need to show that you have a synergy on the efficacy side. That is why we conducted ANCHOR. That is why we do Lighthouse. You cannot have any major quality of lifetolerability issues. And I think it was made very clear today, but this is a very important point. Drugs with quality of life issues simply have not succeeded historically in multiple myeloma. We have an excellent quality of life profile. We have hematologic suppression, but it's a lab value. And it's absolutely an important side effect, but it is clinically manageable, which is the key topic. The tolerability side of things, that is safety or adverse events or safety signals outside of the hematologic arena are rare with Milslufen. You cannot have any major comorbid limitations. These patients have kidney function problems. They have often cardiovascular issues, both effects of the disease itself. And then they have peripheral neuropathy from the use of protosome inhibitors. And we have no limitation with regard to these three comorbidities. Also very important to be able to be utilized broadly in multiple myeloma. And you need an easy administration schedule. We have a once monthly 30 minute infusion. It is basically as easy as it gets. So when we look at the trials and how they map out to the labels, these are U. S. Numbers for patients. And please note the orange area to the left of this slide. It depicts roughly 30,000 patients because there's an overlap between the two populations of either patients with very high risk feature sets, such as extramedullary disease or triple class refractory disease. This is where Horizon as where we hope that Horizon will result in an accelerated approval label in the U. S. To begin with. Then you have another 45 patients of relapsedrefractory multiple myeloma patients that either treated with 1 drug, 2 drugs or more. Now as you can see, the orange area is expanding just in line with the discussion that was previously in the panel as well as what I described earlier. The triple cross refractory field is becoming the relapsed refractory field. And ultimately, the orange field will be the dominant area of all these circles. And of course, with Ocean, Anchor and Lighthouse, we are also expanding into how to combine the drug, how we compare with the biggest drug in multiple myeloma, etcetera. So the program is really developed to fully capture and try to characterize how melsuffin acts and can bring clinical help to patients with relapsedrefractory multiple myeloma. Well, this is a busy slide. We have shown this a lot. This is a comparative slide and one needs to be careful because these are 3 distinct different trials and a lot of numbers. Joshua talked about this. I just want to say that our data holds up really, really well in this field in terms of tumor burden reduction and for how long the tumor burden reduction lasts, but we do not have the same non hematologic tox profile. If you look at the hematologic toxicities that normally shows in either dose reductions or bleedings, you can see comparisons where actually the amount of dose reductions with melsleufen here actually is the lowest among the 3, in line with blendrep, but still lower and significantly lower both for blendrep and Melslef and overexposure. And when it comes to the bleeding rate, it is practically the same. It's plusminusone patient here. So this is the same from a statistical point of view, mainly then a cause from the disease. So we believe that there is a clear place for us to help patients very much in line with what our clinicians told us here before on the panel as well as Doctor. Richter's presentation. We have 2 pivotal trials registrational or trials with registrational intent, either ongoing or planned for mlslufen plus dexamethasone or in combination. Ocean is the most important one because it will read out fairly soon during the first half of next year. That is a head to head comparison with the most used drug in RRM, pomalidomide. And given that pomalidomide is perceived as the drug with the best combination of efficacy and safety in RRMM, this comparison is key to understand what role molybden plus dexamethasone and in essence molybden also in combination can play. And I cannot stress this enough, but both non inferiority and superiority outcome from Ocean is a positive. It means we have met the primary endpoint of that study. In Lighthouse, we combine ourselves with anti CD38 based therapy. In the specific here, it will be subcutaneous daratumumab. And this target then patients that either receive daratumumab in the upfront setting, but is not refractory to daratumumab yet or has become refractory and is being retreated with daratumumab. Please note that, that would be off label use. I need to be very careful. My U. S. Colleagues will probably say something now. But fundamentally, we see patients getting retreated with direct anti CD38 based therapy up to 3, 4 times because of the efficacy of the drug, but you then want a novel combination partner. And that is what Milslufen can represent. When we look at Ocean, as you know, it became a 4 95 patient trial. We expanded it with up to 10% due to COVID. It was a precaution. In the end, we wouldn't have required to do that, but it was still good. It means that we get a bigger safety margin to reach all the numbers we need to reach. And it's fully enrolled, and we're currently waiting for the right number of events to perform the statistical analysis. And we believe that we will have the final result during H1 first half of next year. So why do we then believe in this trial? Well, the key thing is that all the data with pomalidomide comes from a time when Revlimid or lenalidomide wasn't as extensively used in the upfront setting, that is in newly diagnosed patients. We have increased the amount of lenalidomide we use dramatically over the years. And current patients are basically using Revlimid, significant number of them at a full dose of 25 milligrams, all the way to progression for 2, 3 years in the first line of therapy. And this creates a very IMID resistant disease. And of course, we believe that pomalidomide would then benefit from waiting that you would benefit from waiting to use pomalidomide. And then the question is, what backbone in RMM should you use in between? And obviously, our belief as a company and as a development group is that mlslufen can play that role. We can see from data that pomalidomide basically loses its activity when the revrefractory event or lenalidomide refractory event has occurred fairly recently. And that's exactly how lenalidomide is used in the clinic. And in the OCEAN trial, all patients need to have recently failed on lenalidomide based therapy upon randomization. So we meet the primary endpoint with both the supriaortic and non inferior aortic result in with the OCEAN study. There is a question mark here though, and that is with the FDA and non inferiority endpoint. Why is that? Because it's not part of the special protocol assessment. So obviously, we will still go with the data to the FDA, but that means that we don't fully know exactly how they will look at the data and if they will like it. And we believe that ultimately, they will look at the totality of the data and say then what they think. But we will, of course, go to the FDA with this data set regardless if it's a superiority or non inferiority outcome. Lighthouse is now we have now set the protocol. So it's a 240 patient trial and it requires patient to be either double refractory or have undergone at least 3 lines of therapy where they have been double exposed, that is the IMGs and PIs. And have millelufen daratumumab plus steroid in one arm and daratumumab in the other and the primary endpoint is PFS. It is randomized 1 to 1 and we hope to initiate this trial within short. Now we have talked about myeloma today and that is, of course, the main topic. But this peptide dry corrugate platform has great activity against a broad spectrum of cancers. And this is an old slide that we have used a lot. It's based on primary tumor samples from patients with both liquid tumors and solid tumors. And you can see that in AML, NHL and breast cancer, the activity level is really, really good from a preclinical signal point of view. This is the main reason why we plan in 2021 explore to both do a signal seeking trials in patient with AML as well as patients with non Hodgkin's lymphoma, specifically DLBCL patients with high risk features. We have both for both of these indications, we have strong preclinical rationale and there is a strong interest to see what Milsufen can do for these patients that both represents very significant unmet medical need in subgroups. So we're looking forward to initiate these. And of course, I would hope we could start these trials in the earlier part of next year, but it will most likely be in the later part of next year. We have already mentioned that we have more molecules. The PDC platform doesn't end with Milslufen. OPD5 is the analog that we're going to go into stem cell transplant with, but we also have new CDs going. We called this OPS2 before, but we have really worked through the options and we're optimizing and we think we can find a truly differentiated 2nd generation TDC, most likely with an alkylating payload again that we can bring into the clinic. We'll come back when we have more information, but there is so much more to this platform, and it feels sometimes that we have only scratched the surface. Happy to take questions after Marti's presentation. But otherwise, Marti, I think you should present how we plan to commercialize this successfully in the U. S. To begin with. Thank you, Jacob. And thank you to Claus as well. And most appreciative for Doctor. Richter, Doctor. Richardson and Doctor. Mateus as well for sharing their time. As Jacob mentioned, to have such an esteemed panel is remarkable and really pleased that they would dedicate their time to help us here at oncopeptides with melflufen. So if I could have the next slide, let's talk about what we're going to do to successfully make this drug available for patients in the U. S. On Slide 38, we're looking at the melflefin positioning and I would consider this to be aspirational positioning. We're talking about our product here used alone and in combination. And by combination, not talking about DEXIR, but the daratumumab, otezumab, the things we're doing in the ANCHOR study and in the future with respect to Lighthouse. And that we're a 1st in class peptide drug conjugate that targets these aminopeptidases and rapidly releases these alkylating payloads into tumor cells preferentially. So really taking advantage of the biochemistry here. So 1st in class peptide drug conjugate and here we're really leveraging the success that we're seeing commercially in the marketplace with companies like Seattle Genetics or Cgen with their ADC conjugates, very similar type play here with our drug. Targeting these immunopeptidases and as Jacob mentioned, there is increased expression of these immunopeptidases associated with advanced disease and tumor mutational burden. So really playing up a key role for our drug and a key role for our platform kind of moving forward. So we will be the 1st and only PDC that targets these immunopeptidases, which are highly expressed in myeloma cells. So really exciting positioning and launch for us as a company. On the next slide, I'm reinforcing kind of a key point that has been made and across a number of different presentations. So here, we see that improved outcomes in patients being treated with newer therapies, additional lines of therapy is resulting in an improvement in overall survival, not a cure, but we're seeing annual growth that is very significant in first line, second line, third line and fourth line treatment of myeloma patients. So again, driving home the point that this is a very large market and one of continued unmet need. Switching over to Slide 40. This is a slightly different cut than what Doctor. Richter showed. He was focused more on the relapse refractory market. This looks at all products utilized in multiple myeloma today. So we see a clear cut lenalidomide and birtesimibe at the top, looking at moving annual treatment of patients in the United States treated with these drugs. So clear cut frontline therapy. The 2 fastest growing agents are daratumumab and pomalidomide that are used somewhat in Adara, somewhat in upfront, but also a lot in the 2nd line setting and really points out, of course, when we look at that pomalidomide growing line and the LEN refractoriness that Jacob talked about, the significant opportunity that we have with the pending results of the OCEAN trial in growing our regimen as a key backbone in the treatment of a resistant refractory multiple myeloma. The rest of the spaghetti plot, as we call it, at the bottom of the slide, just kind of represents that noise, some of the newer products that are launched, products that are being used in about 10,000 or so patients on an annual basis. So this represents that triple class refractory type population that of course we're seeing growing on a regular basis due to the more aggressive treatment of patients with multiple myeloma. So switching to Slide 41, really interesting slide here. And again, I think Jacob really characterized this well in a more simple form. But here, let's just look at an annual comparison of 2016 2018 and talk about the percentage of patients treated by line of therapy that are already triple class refractory. And you note that from a second line perspective, 3% in 2016 has quadrupled to nearly 12% or 11% as represented here in 2018. In the 3rd line setting 2016, 4% of the patients were triple class refractory. We see that growing 7 fold in 2018 and then a doubling of patients who are triple class refractory in 2018 compared to 2016. So this is that front loading of the algorithm that has been talked about and the fact that the pool of population that are eligible for melflupin treatment assuming a triple class refractory label is indeed continues to grow. On the next slide, here we outline our commercial strategy. We want to become a leading choice in this category of triple class refractory multiple myeloma. But likewise, we want to expand that market, essentially accelerate the utilization of new classes of drugs. So in the bar chart at the bottom, we look at a snapshot of today where the majority of products fall into that triple class category and the recycling of old classes. And there's just a percentage, a small percentage of the market that is dedicated to those new mechanisms of action. But where we're going in the future is increased utilization of these new mechanisms of action. And our first strategy is to become a leading choice for patients that are opted to give these new classes of product. But the second strategy is to expand the market. And again, no more recycling of these classes. The OCEAN trial will help us to establish that looking at these LEN refractory patients and the comparison of pomalidomide to melflutin. So we've become a leading choice and we expand the market. That's our commercialization strategy in the United States and beyond for belfulfin. So next slide, Slide 43. We are paving the way for a successful launch through people and through an excellent team of people. You can read through some of the background and description here, but three points: people with significant experience in our industry, people with significant oncology experience and people with significant launch experience. So we're bringing to bear quite a talented team and I'm proud of the team that we've built and look forward to helping to reach as many patients as possible who are appropriate for melflefin therapy in the United States upon launch of this drug. We're led by Mohammad Lada, General Manager of our U. S. Business unit and also on the medical affairs side, Doctor. Paul O'Connor. What a great thing it is for an organization to have someone with a balance of academia and biopharmaceutical experience that Doctor. O'Connor brings to the table each and every day. But folks like Chris Black, Sarah Donovan, Matt Smith bring a significant amount of commercialization experience as well. And I've been so proud of some of the things that they've put together and I look to share those with you in the next couple of slides. And also on the analytics business planning side, some of the things on the commercial operations side, both Jacob Lai and Nick Holtzman are doing an outstanding job in helping to prepare us for the launch of noflupin in the United States. On the next slide, focus here is really on our approach. And our approach is one that's customer focused. Obviously, each arm of our commercial and medical affairs organization can bring differentiated resources to bear to help healthcare professionals, help patients or help our customers improve the patient experience. So it's really an outside in type approach, a team approach with the oncology account manager in the middle supported by medical science liaisons, oncology nurse educators, key customer marketers that are unique to their regions, headquarter based functions and the important national account executives that reside underneath Matt Smith's team that are calling on some of the larger networks across the country. So we've done our homework in profiling the customer base, dividing the country and are poised for the launch of melflupin in the United States. Next page, please. So we're putting patients first. And by putting patients first, we are focused on making sure that all barriers to getting the therapy are eliminated and providing continuous support for our patients along their entire journey. So we will have a branded patient support program that will look to help patients along their entire journey. The first point that we'll be looking for is making sure that they have access to the product. We want no patient left behind. So we are engaging with payers now to make sure we understand what the needs might be from a prior authorization perspective and that we're poised with a team of people to accelerate that process to make sure that patients can get their melflutin as quickly as possible. In a case where there is and this is very typical in a launch phase, you've got a new product, a new label, there might be a denial, We're going to support the appeals process, again, to make sure patients can get the drug as quickly as possible. For patients that are uninsured, we will have free drug program. For patients that need to get their therapy quicker, while managed care benefits are being assured, we'll have a quick start program. Affordability, it's critical that patients are able to afford the product. And our focus from a commercial perspective is to reduce the patient expense. We're doing that through copay cards that will be available to patients as well as connections to additional resources that can provide them the funding to make sure that the therapy is affordable. And then we'll support them along the journey to make sure that they're remaining on therapy and can benefit in all ways that they can. So we'll have patient outreach, continuous support through a 3rd party mechanism, of course, to remain HIPAA compliant. We'll have educational materials to help that support that patient along the journey so that they remain on therapy. Next slide, please. Kind of a busy slide, but the important thing here that I want to communicate to everyone is that we're focused on making sure access is there. So we're already engaging with payers that represent more than 95% of covered medical lives in the United States and making much progress to ensure that patients have access to melflufin upon its launch. Next slide please. Of course, we also need to be prepared and have the drug available through the network in the United States. And the product will arrive via a company called SYNEXI from Brussels, Belgium, will come into our 3PL Cardinal Health and then we've chosen and selected a pretty traditional specialty distributor model that according to our calculations will reach 99.9% of our customers in the relapsedrefractory multiple myeloma market. So we are ready for the next stages of an approval to import the drug and having supply available at the time of launch. Next slide please. Commensurate with discussions upcoming discussions with the agency on the label, given that we're a priority review accelerated review product to subpart H review mechanism. So all of our promotional materials need to be prepared in advance for review by the FDA. So we're well along that path. I provide here a slightly redacted version of some of those core sales materials and some of the messages that we intend to deliver that will be targeted based on whether we're discussing with a healthcare professional, an academic physician, a physician in the community setting, an oncology nurse, a hematology nurse, a pharmacist. So we have a wide range of materials that will address the unique needs of the wide range of patients that we'll be calling on as we launch nelflutin in the United States. Next slide please. I'm pretty excited about what the team has put together, a state of the art customer information management system and given the wealth of resources that are available that aren't in an integrated way, we are working to track and leverage integrated healthcare patient level data and provide in the hands of our customer facing team insights and updates in kind of a real time weekly way. So we're utilizing artificial intelligence and predictive modeling to kind of map and look at patients who are progressing through therapy based on the longitudinal products that they're receiving, who might be becoming eligible and what clinic, obviously not by name, but we will know by account kind of things that are going on and alert would be sent to our oncology account managers and our MSL team. In this way, we're showing up with knowledge, information and making sure that we're able to help meet the needs and increase the possibility and probability that a patient who could benefit from melfluthin will get on therapy. So I would consider this to be a state of the art system and we're really pleased to have it in place. Next slide please. Our medical affairs organization has been in place for quite a while. A lot of great strides have been made across the area of medical information and communication, scientific exchange, data generation. As you might expect, we're launching and have addressed some areas of unmet need as it relates to investigator initiated trials. So we are currently receiving new ideas and ready to continue to meet the changing needs of our customers as we move from this pre launch phase to the launch phase. This team will be providing, of course, that ongoing feedback into our development organization as we think about the clinical development program that Jacob described, new ideas, new trials, new information, again getting back to the core values of the organization being very science driven and data driven. Next slide please. We are working and tracking our generation and building of awareness in the U. S. And pleased to show that the awareness of Melflupin continues to grow across our target audience. And certainly with the presence that we've discussed at ASH and I believe we're planning a webcast to kind of outline some of those outstanding posters and the oral presentation on Anchor, we would expect that given that volume and comparative to our core set of competitors, we're proud of the science, the number of clinical studies, the analysis has been done on the horizon data to really help provide more insights on patients who can uniquely benefit from elflupin and give hints to where our development program can go from here. So a lot of work will go into have gone into the ASH program and we would expect that this would translate into increased awareness timed well to our launch. And on the right hand side, you see the growth or the physician's projection of their likelihood to use melfluthin. This was a snapshot in time back in the summer and we would expect that with the additional data that's being communicated that their readiness to prescribe melfluthen is appropriately increasing. Doctor. Richardson talked uniquely about extramedullary disease, so that's called out here on the right hand side. So next slide, please. So this is a snapshot of the effective drugs in our space that are without major side effects or comorbidity that have significant potential. And what you see in the bar chart is a snapshot of sales on a worldwide basis looking at year on year growth and where things stood through Q3 of 2020. So you see daratumumab approaching $4,000,000,000 with 30 7 percent growth. You see pomalidomide or pomelast 22% growth, nearly a $3,000,000,000 drug. So when you think about the OCEAN trial, you think about those possibilities on those 2 successful outcomes and a direct comparison with melflufen, having data showing non inferiority or superiority to a $3,000,000,000 drug that's growing at more than 20%, certainly puts us in a good place, to help treat more and more patients with our drug. Across the bottom, you kind of get a feel for 1st year sales and where some of the products have when they during their 1st year of sales. So not providing any guidance at this point in time on what our expectations are for 2021, but just wanted to put some numbers out there as we move further and think about our guidance on the sales trajectory for melflefin in the United States in 2021. And I'll close with the final slide, which takes a look at our value drivers and news flow. We've touched on all of these. So green is in the past. So we do are expecting Horizon to be published in the Journal of Clinical Oncology. That is imminent. Obviously, the anchor presentation and other presentations of data upcoming at ASH in 2021 in the Q1, 1st patient in a lighthouse looking at OPD5 and the 2nd product in our peptide drug conjugate platform, starting to accrue patients, the potential approval of the launch, EU submission, thinking about if that's on a conditional approval basis in the latter half latter part of the first half of twenty twenty one. As Jacob mentioned, Ocean and top line results on Ocean, we would anticipate being available in the latter part of the first half of twenty twenty one and a number of other milestones. So we're very excited and I will close with the summary slide before moving over to the Q and A. Coming back again to the takeaway messages that we want to deliver and hopefully we hit the mark on this. First of all, that we're now a global company, strong R and D roots, heritage and a heritage that we respect and are proud of with the roots in Sweden where this very interesting technology was discovered and developed. That multiple myeloma, very large market of unmet need and melfluthin based on the clinical trials that have been completed as well as those on the near term horizon and those being planned can be a backbone treatment in this growing space. That organizationally, we are fully prepared for a launch in the United States and also that we are more than just melflutin. We have a peptide drug conjugate platform and we are poised to broaden our portfolio So with that, I will pause there. So with that, I will pause there as questions come in and I will be able to monitor those as they come in. So please take the opportunity to send in. So I will facilitate these and hand them over and this can go either to Jacob or to Klaus with respect to the EMD trial and what we're thinking. Would that be a single arm trial, comparator trial? How are we thinking about extramedullary disease and our company sponsored trial at this point? Right. Marty, do you want me to take it? That would be great. Thank you. Yes, of course. Yes. And we are looking forward to this trial in extramedullary disease. And at this stage, we could either end up with being a single arm or 2 arm study. And that also depends on the interactions and the final interactions we will have with the regulatory authorities later this year and around year end. So that is still a possibility to have either a single arm or a 2 arm study where we will even look at a combination in EMD patients, which is something that people are really excited of thinking of the potential there to also combine noflufen with other drugs such as PI. So that is that's both still very much in play. Okay. Thank you. Thank you, Klas. So we have another question, kind of looking for what our expectations might be in the Lighthouse study. And it's differentiated by a second or third line therapy and how we see the long term safety of melfluthen in that second or third line of therapy. So I'll send that over to either Klas or Jacob or both to touch on the answer there. If I can take the safety piece first there, what is referred to if we move into an earlier line of treatment. I think when we talk about safety, so far, we haven't seen any concerning signals of long term toxicity of patients. Of course, our trials haven't run that many years. It's not that we have tens of years of follow-up. But so far, what we see is actually very reassuring when it comes to long term sequelae, such as myelodysplastic syndromes or AML. So that's where we feel really confident that if Lighthouse may move the needle there and we move into an earlier line of treatment that it doesn't necessarily bring additional long term side effects. So we feel very confident there. Great. Thank you, Claus. Any further addition, Jacob? So yes. So hi, thank you, Martin. I think on the efficacy side, we have a very promising signal in ANCHOR, and that's, of course, the reason for why we do Lighthouse. And I think Doctor. Richter, he phrased it very well or framed it. We use immunomodulators and proteasome inhibitors in daratumumab daratumumab so aggressively upfront that if you're going to do retreatment with daratumumab, whether the patient is only is non daratumumab refractory or refractory to daratumumab, you need a novel combination agent. And if you look at real combination data where patients are truly refractory, for example, to an IMID when you use palm, you approach roughly 7 to 8 months median PFS. And there is another trial now APOLLO that will be presented at ASH, but there 20% of patients are not even refractory. Several of the patients are not even relapsed refractory. They are relapsed. And then, of course, the median goes up. But in this context, our data so far has been very promising. And of course, we need to conduct Lighthouse to see exactly where we end up. But we believe we have a good chance to have really solid data sets in patients that are truly refractory to image and PIs. And then daratumumab, if you're going to reuse it, needs a novel combination agent, and we believe that Nulslofen can be that Okay, super. Thank you, Jacob. We have a question coming in on the marketing materials and specifically around subpopulations of Horizon and there was a notice that maybe in one of the bullet points we called out EMD but not high risk cytogenetics. So I would just make the general point there that this is all work in progress and is just a draft. Certainly, when we get that final label in, all of this will be adjusted and there is no hidden intent here to signal in any one particular direction around high risk populations and what may or may not be acceptable from an FDA perspective. Okay. Just looking down the list. We do have a question or 2 around and I just think this is interesting to highlight in light of comments we've made on some of our preclinical observations about immunopeptidase expression and higher degree of expression as the disease progresses. So the latest thinking as it relates to nelflutin development and newly diagnosed disease, is that something that's still on the radar screen? So I could answer that. It's Jakob. And Klas, please add if you would like to add. In our mind, the relapsed refractory market is so vast that we have just begun to touch how nelslefins can be utilized for these patients. Of course, if our data would be extraordinarily good, we could potentially think about newly diagnosed, but this is not something we're putting any thought into right now. You need to establish, improve yourself in the population where you're in. And right now, we see this as a relapsedrefractory multiple myeloma drug. And please note, the market potential there is not the limiting factor. It will be the clinical data that determines the success of this drug. As Marc alluded to, pomalidomide is approximately $3,000,000,000 today only in RRMM. Yes. And just to briefly add there, Jacob, I think if we talk about newly diagnosed, we automatically also think about transplant setting, especially these days. And this is specifically why we filed this new IND OPD5, which is just more convenient for an ablative setting, which may be the case in newly diagnosed multiple myeloma. And that's, I think, a nice addition to the treatment armamentarium that we can bring to multiple myeloma. Okay, super. So one that just came in, you're guiding for approval in Q1 2021, what are the odds for approval ahead of the PDUFA date? Is the sales force already higher than just waiting for the approval and costing money in the meantime? Have you guided for when approval could come in Europe? So good questions. And we've been poised as we were kind of guiding towards launch readiness in 2020. So we were hard charging towards that. There's obviously a lot that needs to be done. We utilize the acceptance of the file for accelerated priority review as a trigger for our scale up. I'm pleased to report that the team is in place, trained as we've suggested, profiling customers, building their action plans. So there's a lot of valuable investment of time that is ongoing from a field team perspective and that cross functional model that I put out there. So understanding the tools that we'll have at the time of launch, all of that training. So time well invested in terms of these folks being on board and better to be prepared than to not be prepared. Can it come in sooner? Sure. I mean, it's I can't put the odds on it, but certainly when approval happens, we will adjust accordingly. We're sitting here last day of November, few more months of opportunity for this to be done ahead of time and we'll keep you posted accordingly. As for guidance in Europe, we have not put a specific guidance out and we will consider that over the next month or so. So thank you for those questions. I know we're a little over time. I'm just looking to see if there's anything. Klas, are you able to see the questions or? I'm looking at them now. There is a question on cash position, burn rate. I'm not sure if Anders can pick up the mic and maybe respond to that? So yes, so the cash position as of the end of the Q3 was roughly SEK 1,250,000,000. And the cash burn for the Q4, we guided that to be roughly €400,000,000 So towards the end of the year, we should have around €850,000,000 in cash. And we have previously guided that, that is sufficient to bring us through the Q2 without any revenues, and that guidance still remains. Okay. There is a little segment on here. When do you expect the company to be profitable? Do you want to comment on that, Anders? Yes. I would love to be able to say that exactly, but we're not guiding upon that right now. It, of course, depends on when we launch, how successful we'll be in the launch and what the uptake will be. So it's too early to tell. We need a label. We need a date. We need to see what happens in the 1st few months before we will be able to say something about that. Super. Thank you. I kind of expected that. Anyway, I can see we're about 7 minutes over the top of the hour and I think we'll call it conclusion to a very successful Capital Markets Day. Really appreciate, as mentioned at the outset, your engagement, your continued interest, your continued help in the role that everyone on the line is playing in terms of providing us access to capital to really help leverage against this platform, this clinical development program with the ultimate goal of helping as many patients as we can around the world. Certainly, thank the organizers of the day and the participation of those on the leadership team, Iir Klaus and Jacob in particular, for their help in making for a very meaningful session and interaction with the key opinion leaders. So thank you very much. We look forward to our next opportunity to interact and certainly look forward to talking to everyone on the other side of ASH as well. Take care and have a good rest of the evening. Bye now.

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