Okay, thank you. 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. The next slide, and I'm not seeing the slides, but I think we have a disclaimer slide up. 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. We will be talking about future results. The next slide should be the title slide, and let's move to Slide 4.
A lot is going to come at you over the next couple of hours. I wanted to provide an opportunity up front to share with you what the five key takeaway messages are. First of all, we are now a global company. Oncopeptides is a global company. We have our R&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. Third message here is about melflufen. 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, the build, and our preparation as it relates to the U.S. launch, and we are ready for our U.S. launch. 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. We will move to the next Slide 5 , which is the agenda. Following my introduction, I'll be joined by Dr. Richter, h e will provide a perspective on the unmet needs in hematology. We will then have a panel discussion hosted by Dr. Klaas Bakker, our Chief Medical Officer, and he will be joined by Dr. Mateos and Dr. Richardson to provide their experiences clinically with melflufen. We'll then transition to detail on our clinical development program. Jakob Lindberg 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 melflufen.
The next slide, just touching here on the wonderful history of Oncopeptides and really appreciate everything that's gone in the first 19 .5 years prior to my joining, and I feel so fortunate to be able to pick up the ball. Tracing back to 2000 when melflufen was patented and Oncopeptides was founded. Really a key event in the company was the delivery of vials of melflufen in 2009 to the Dana-Farber Institute in Boston. We really feel like that partnering and collaboration with leading cancer institutes around the company is an important part of who we are. In 2013, we initiated our first in human trial. That's the Oncopeptides 2012 Myeloma One trial; t he O-12-M1, which was published this summer in "The Lancet." First patient- in in 2013.
Over the past five years, the focus has been on the melflufen 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. There in 2020 on the timeline, you see our key milestone, which is our FDA user fee date of February 28th for the action on melflufen for accelerated approval in relapsed refractory multiple myeloma. 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.
Next slide. The company has undergone some rapid growth and what we accomplish 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 comes through trials like OCEAN, and building trust. Really fantastic team, w e are one 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 lifecycle management, and now moving into this launch and geographic expansion.
Lots happening in each of these three phases. 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. Next slide, please, is Slide 9. 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 aminopeptidases that essentially hydrolyzes these agents and deliver a concentrated toxic payload into cancer cells, sparing the healthy cells. That's really the backbone of our technology, and certainly what we see both pre-clinically and clinically with melflufen.
On the next slide. 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. We've 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. This comes to us off of the peptide-drug conjugate platform. We do have IND approval, and this is an analog of melflufen, but it's particularly formulated to enable us to deliver a much higher dose of the toxic payload directly into those cells. A phase I trial is currently in planning, and we look forward to first patient in early 2021. The next slide, please. Portfolio development and lifecycle management, this has really represented quite the bulk of our investments. Obviously, over the past 10 or 15 years, particularly on the lead program of melflufen and multiple myeloma, and now beyond.
It's really about melflufen, 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 of multiple myeloma. We've done a lot of work pre-clinically 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 liken and position melflufen as a new drug class, this peptide-drug conjugate class. Very broad pre-clinical activity. Jakob Lindberg will touch on this a little bit as we think about the expansion of our clinical development program on melflufen.
With that focus on multiple myeloma, obviously triple-class refractory patients, heavily pre-treated patients were the focus in the O-12-M1 trial, M1 trial, and also the HORIZON trial. We're moving with OCEAN, ANCHOR, LIGHTHOUSE into earlier lines of therapy, and of course, combination therapy, which as we'll see as we look at the landscape, is becoming increasingly more important. 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 pre-clinical evidence. You can see the chart in the right that Jakob Lindberg 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. Next slide, please.
The final arm of the stool, so to speak, in that transformation is the geographic expansion, our launch and commercialization of melflufen. As you can see on this slide in the bottom left, it's a very large market. In 2019, was estimated to have global revenue in the $19 billion range, with strong growth projected over the next five years, reaching $23 billion in 2024. 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. It's an area of significant unmet need. As we'll see, survival is increasing, w e 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.
We're pleased to be offering in the future a new class with melflufen 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. 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 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 the 28th of 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 regulators in Europe. We're excited about bringing melflufen to patients across Europe, o ur early thinking is that we would also go at it alone, o ur 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 healthcare providers in Europe. Our original strategy was to utilize the OCEAN trial for approval in Europe.
Based on some activity in the marketplace, some competitive activity, particularly as we look at GlaxoSmithKline in belantamab on a trial based, similar in size and scope to the HORIZON trial, we're able to move forward with conditional approval. 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. We are currently in the process of recruiting leadership into this European team. We're excited about the regulatory phase for melflufen in Europe. 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. We are exploring that.
A gap 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, i t would likely be a partnering strategy. 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. I would say that overriding or underwriting all of this, we are working with a distribution partner, that will be able to bring melflufen to other geographies upon its approval in the United States through a special licensed sales opportunity. That kind of concludes the first section here and the transformation of Oncopeptides.
Again, I'm 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. With that, I'm going to turn it over to Dr. 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. Thank you, Dr. Richter, for being part of the program.
Thank you so much for having me, thank you to everyone tuning in. Hopefully, everyone is wide awake and not still reeling from too much turkey from last week. 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. 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. Are we on the MM is the second most common malignancy slide? Apologies.
Some. You go after. Joshua, say yes. Yes, Joshua, it's the right one.
Okay.
Slide 3 .
Thank you. Myeloma still represents the second 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 five-year survivals from 2010 to 2016, giving a five-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., 250,000 worldwide, with a 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. 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 two years. Now, with upfront therapies, giving over progression-free survival rates that are in the four to five-year plus range, we are really achieving new greats for the disease.
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. 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. Ultimately, we discuss how myeloma is treated, a lthough there is no clear standard of care, there are clear dos and don'ts, clear optimal strategies, or at least clear optimal drugs and drug classes that we know have had a major impact on the way we treat the disease. Ultimately, we talk about this concept of clonal selection.
A lot of this work published by Dr. Morgan and Dr. Keats, that at the time of diagnosis, most people develop around four to six sub-clones of the disease. 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 achieve this through multimodality therapy. The four 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. A term that was coined originally by Dr. Kumar of the Mayo Clinic, the concept of dual refractory to both an IMiD and a PI, and at the time, that meant refractory to lenalidomide and bortezomib. He recognized that despite the advent of second-generation PIs and IMiDs, once you were refractory to one 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, an IMiD, and a 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 five 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 poorer outcome. Next slide, please. Ultimately, how we choose our therapies for myeloma still is a class system. We have the IMiDs, the proteasome inhibitors. We do utilize classical chemotherapeutics such as anthracyclines, usually in regimens such as VD-PACE.
Alkylators, some of them we use in cyclic fashion, like bendamustine or cyclophosphamide, or melphalan, which has classically been administered either in low doses as oral ALKERAN in regimens such as melphalan and prednisone, or melphalan, prednisone, and thalidomide, or VMP, or high doses of melphalan 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 now have other newer classes of agents like the histone deacetylase inhibitor, panobinostat, a number of monoclonal antibodies, including daratumumab, elotuzumab, isatuximab, and although not a naked antibody, but an antibody drug conjugate, more recently, we now have belantamab mafodotin, and of course, the SINEs, the selective inhibitors of nuclear export, selinexor or XPOVIO.
Ultimately, we have been approaching the disease in combinations of one drug from each class, and we've demonstrated to this point that one drug is better than zero, two is better than one, three is better than two, and in some cases, four is better than three. Ultimately, this is how we are building up our regimens to induce deeper and deeper remissions by using multiple mechanisms of action to kill as many of the subclones as possible. Next slide, please. Again, one of the things we recognize is as we travel through the myeloma journey from first relapse to second, third, and fourth, regardless of which pathway we choose in terms of our sequencing strategy, we ultimately end up with more of poor and poorer outcomes, both in terms of progression-free survival, duration of remission, depth of remission, and unfortunately, overall survival.
Again, classically defined by Shaji Kumar, this concept of dual refractory, that once you've seen at least one IMiD, one proteasome inhibitor, despite the other IMiD and PIs, despite the other therapies, you overall have a worse outcome. Next slide, please. Ultimately, this really 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. 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. 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're dual refractory, we start thinking a little more outside the box. There, more recently, regimens such as the CANDOR regimen, daratumumab, and carfilzomib has a great role there, or some of the pomalidomide-based regimens. 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. Really what this shows is that in the U.S., there's an extreme fragmentation of the entire marketplace across the relapse 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 XPOVIO or selinexor. 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.
Although in academic centers like the ones from the speakers you'll be hearing from today, where we use three drugs and four drugs routinely in both induction and the relapse refractory setting, the community still has a large percentage of their treatment at all lines of therapy given as singlets and doublets. We are slowly chipping away at this, recognizing that three drug regimens generally improve outcomes. Next slide, please. When we look from front line to second line to third line to fourth line, if you were looking at an outside vantage point of multiple myeloma, you would say, well, what is the unmet need? There's been 12 drugs approved in the last decade, t here are newer drugs on the horizon, p atients are living longer. Why is this concept of still an unmet need?
One of the things that we note is that despite all of these drugs, despite all of our options, as people go from front line to second line to third and fourth, 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. 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 to frontline, second line, third, 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. Although the overwhelming majority of people will receive frontline and second-line therapy, you start to look at the third, fourth, and fifth line, and ultimately, those numbers drop precipitously. We recognize that in the United States, few people get beyond third or fourth line. 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. 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. The increased utilization of triplets and quadruplets in earlier lines has led to an evolution of what a relapse refractory patient actually looks like in the outpatient clinic. 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 three or four lines, they would not end up triple-class refractory, and if they did, it was a small percentage. 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.
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. 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 enter the second 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 and throwing classical chemotherapy at these more end-stage patients with regimens such as higher doses of bendamustine or infusional chemotherapy such as DCEP, VD-CEP, or VD-PACE, 96-hour infusional chemotherapy regimens. 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. VD-CEP 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. Very briefly, as was already mentioned, the HORIZON trial is a registration trial for accelerated approval of melflufen.
It's a phase II single-arm open label study. Essentially, these are patients who are relapsed and refractory to POM or an anti-CD38 monoclonal antibody, or both. They were administered melflufen 40 mg and weekly dexamethasone on a 28-day cycle. 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 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. We can see here in the swimmers plot a really great viewpoint of a penta-refractory peptide-drug with an overall response rate of 29%, duration of response around 5.5 months.
For those people who see the overall response rate of 29% and feel that it is an anemic number, you need to think about all the recent approvals in myeloma. Daratumumab in the late stage setting, single agent, 29%, carfilzomib in the late stage setting, 23.2% from the 003-A1 study, daratumumab from the SIRIUS study. If you look at pomalidomide from the 003 study, it's about 28%, i f you look at selinexor from the STORM study, 26%. Melflufen is right on target with the late stage development of single agent penta-refractory or advanced stage patients. Again, ultimately, as the drug gets combined and used earlier on, these rates go up and up. Next slide, please.
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. 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 FORTE study showing the advantages of an IMiD/PI/dex over PI alkylator dex combo in the upfront setting. 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. The toxicity for the drug is essentially heme related. There's limited non-heme toxicity. As we look to the more recent approvals with drugs such as belantamab mafodotin 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. At its core, when we talk about all these great drugs like monoclonals and bifunctionals and CAR-Ts, but still the best drug is melphalan 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. In my mind, melphalan has struggled from two problems; o ne is sometimes it's too much. We have a number of patients who are ineligible for high-dose melphalan and transplant due to comorbidities, age, performance status, et cetera. 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 ALKERAN 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. In many ways, I envision a melphalan as the Goldilocks alkylator. It's mid-range.
It's not too much, it's not too little. The porridge is just right. It's cyclable, tolerable, and effective. With that, I'd like to thank you all and open up to a few questions.
Thank you, Dr. Richter. This is Klaas Bakker. I would like to draw everybody's attention that it is possible to post questions on the message board for Dr. Richter, but also in the forthcoming parts of this presentation. If I may kick off the questions section, Dr. Richter. Based on what we've now seen and the importance actually of getting control of the disease, especially in its later stages, where do you see melflufen fit in the near and midterm term future if we take an eye to that future? What would be your thoughts there?
I can give you 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 if patients who in the U.S. receive something like VRd up front, then go on a lenalidomide strategy, get dara-pom-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. If we've had patients who've received one or more infusions of high-dose melphalan, it's still not clear how optimal the strategy will be, m ore 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 mg/m(2) a piece. He's coming out now, and he's had complete resumption of his counts, no longer has effusions, t he catheters were taken out. No longer has plasma cell leukemia, and his M- spike, which had gotten up to over seven, is now down to two, h is free light chains, which were 1,400, are now 10. 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, i t'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 melphalan strategies, if I had melflufen in my clinic today, I'd actually put him on melflufen maintenance.
That's good to hear. There should be options in the near future, 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. Maybe I have one other question, then we can maybe finalize this section there, and that is about the adverse event profile of melflufen and especially the heme tox. How would you consider that and how to manage?
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 specialists 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. Belantamab mafodotin, excellent drug, although I have to sit down and learn 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. 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 to hold drug, dose adjust.
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. 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, t hank you. I see that some questions have come in, actually. Dr. Richter, I don't know if you have some minutes left, but then I'd like.
Sure.
To go through some questions. One question from Suzanne van Voorthuizen from Kempen is actually about the OCEAN study, which acts as our confirmatory trial, which is a head-to-head study against pomalidomide. To what extent do you see the OCEAN study results better guide treatment in practice dependent on the results, of course. To that extent, how do you look to the lenalidomide refractory inclusion criteria?
I think what that really does is if we're looking at a lenalidomide refractory base 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. When we look to earlier utilization and more novel combinations, this simply improves overall outcomes. Take daratumumab, for example, w e recognize that in advanced patients from the SIRIUS trial, there's a 29% response rate. When we move it into areas like POLLUX first relapse, it gave us a 93% response rate, and upfront, it gives us 100% response rate. What this really clues us into is that in the U.S., if you are transplant eligible, your pathway is typically VRd transplant len maintenance.
For those who are transplant ineligible, they receive usually something like VRd lite or RevDex, and ultimately just end up on a Rev maintenance strategy anyway. Regardless of how you start off, most patients enter the second-line len refractory, where a pomalidomide-based regimen, whether or not it's DPd, Isa-Pd, are all extremely applicable options, noting that when we have dara versus pom, this will give us our first inkling about not just the 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 melflufen, and then ultimately in combinations with other drugs, this will be even better.
Very good. I think if I look at some of the other questions that do come in, like do you see a place for melflufen 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 high-dose melphalan for five, 10 years. They are over the age where you feel comfortable giving them an autologous transplant. 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, t hank you very much. This is, I think, the last question for this section, or maybe one or two. We've seen quite some patients with extramedullary disease in the HORIZON study. I had about 55 patients in a total of 157 patients, w hat's your view on the data that has been shown with melflufen in the extramedullary disease setting?
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. Classically, we think about this as bone-based and extraosseous plasmacytoma. Extramedullary 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 non-secretory clones earlier on in the disease, making people ineligible for the majority of our clinical trials. Having an effective option for extramedullary disease in patients who may otherwise not be eligible because we've seen many of these as non-secretory, provides a really great venue to control those patients.
Thank you very much. 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 melflufen? What's your clinical view on that?
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 a case where melflufen is absolutely the right answer. I doubt we will have head-to-head data on the two, 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 two auto transplants, three cyclophosphamide-based regimens, and bendamustine, I would be slightly less inclined to use melflufen as opposed to selinexor. However, if they had one transplant 10 years ago, had 10 other therapies, and no real alkylator experience beyond that would gear me much more towards melflufen.
Again, the devil is always in the details.
Absolutely. 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. Stay tuned for that. With that, I'd like to turn to the panel discussion, and I think we can move to the slide there. Very good, f or the panel discussion, we are really fortunate to have two key opinion leaders, as how we would call them, but two physicians with a lot of experience with multiple myeloma, but also with the use of melflufen. Therefore, I'd like to welcome Dr. Mariví Mateos from Spain, who is joining us this afternoon. Thank you very much for joining us.
I'm also very pleased to actually have Dr. Richardson from the Dana-Farber Cancer Institute in Boston on the line. Dr. 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 are muted.
Dr. Richardson.
Sorry, let me unmute. Can you hear me now, Klaas?
Absolutely.
Yes.
Oh, beautiful. Good morning, guys, good morning, Mariví, thank you so much, Joshua, 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. Good morning, everyone. Lovely to see everyone on the call. Thank you.
Very good. I think, and based on the questions that have come in from the audience as well, I think it's good to have a kind of small panel discussion on some of the topics around the use of melflufen. I think one of the things that we have seen in Dr. Richter's presentation is the scattered landscape after the first or second line of treatment of multiple myeloma these days. If I may start with Dr. Mateos here. Where do you see melflufen fit also in the near future, and also taking into account potential future combination studies that are ongoing, such as our ANCHOR trial?
Yeah. This is an excellent question, and I think that Dr. Richter has elegantly presented what is the current landscape of treatment for patients with multiple myeloma. It's true 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, IMiDs, and anti-CD38 monoclonal antibodies. Many of these patients will have the opportunity to be exposed not only to bortezomib and lenalidomide, daratumumab, but even also the second generation, I would say, pomalidomide and carfilzomib. I would say that basically, we are going to face with three drug class refractory myeloma patients just at third line of therapy, maybe in the future, even after the first line of therapy.
I would say that at third line of therapy, it is possible to face with three drug class refractory myeloma patients. I think that in this situation, melflufen plus dexamethasone has a role. While if we look into the HORIZON study, it is 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 four or five lines of therapy in order to be three drug class refractory. This is not going to be the situation in the near future, and this is the reason why I see melflufen plus dexamethasone in the near future, maybe in third line and beyond. If we look into the future, I would say no near future. I think that definitely the OCEAN study will put melflufen plus dexamethasone maybe earlier on.
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 melflufen with either bortezomib or especially with daratumumab. Clearly, the efficacy is comparable with other combinations we are utilizing right now in third line and beyond. Definitely today, third line, triple drug class refractory patients, or I would say patients exposed to PI, IMiD, and 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-CD38.
Thank you very much, Dr. Mateos. Anything to add there, Dr. Richardson?
Klaas, yes. I think Mariví captures it beautifully. I think the important point is that increasingly as we use four-drug platforms in first line of therapy, so for example, you'll hear at ASH really outstanding data using PI, IMiD, steroid, and antibody combinations. Increasingly, the second line becomes essentially functionally the equivalent of what we now consider third line. 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. I see, for example, an older patient who may have had a daratumumab-based approach in first line. A melflufen-based platform combined with a proteasome inhibitor would be an ideal next line of therapy for that patient as we think to the future. 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 four-week infusion. It takes around a half an hour. It's an outpatient procedure. It doesn't involve complexity. 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. 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 there. That was actually probing into one of my other questions, and that goes to current times with COVID, and we all don't know when things will return to normality. To what extent, and you've already mentioned the applicability of melflufen there, but to what extent do you think that will drive utilization of newer drugs in the coming year or two years?
Mariví, do you want to?
Yes, sure. I think that the unmet medical needs in the management of patients with multiple myeloma is there. Definitely we need the novel agents that all alluded to the COVID-19 pandemic. We have to try to protect our patients of becoming infected when they are coming to the hospital. Melflufen is an excellent drug because it is given just in a single infusion every four 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. I think that melflufen plus dexamethasone will cover two important requisites in order to optimally manage patients with myeloma under this pandemic.
I would echo that, I think the important point is that in the HORIZON study, for one example, and indeed for that matter with our initial experience with O-12-M1, 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. 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. That's very relevant in practical terms, because if you've got a platform that can provide you or can spare you or can minimize that issue, that's a potentially tremendous advantage.
Okay. Thank you very much. In the meantime, I'm also looking at the message board, I will actually mix some questions that I had prepared to some of the questions that are coming in from the audience. This is about, actually, Dr. Richter talked about the use of melflufen and also in patients that actually have had prior exposure to an alkylator. Dr. Mateos, do you have any concerns there with melflufen or what's your experience there? I know we have some data upcoming at ASH talking about efficacy of melflufen in these patients, do you have any experience there or would you like to share with us your thought?
Yes, I think that this is an excellent and practical question. Joshua Richter previously alluded to this. Well, because it is possible to have myeloma patients at relapse alkylator-naive. Well, we know that maybe more and more newly diagnosed myeloma patients don't want to receive autologous stem cell transplantation because of the lack of benefit in overall survival at the end in the French study that will be presented also at ASH meeting, 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. There is a sub-analysis conducted in all patients included in the O-12-M1 study and HORIZON study, and the group of patients alkylator-naive responded extremely well.
For me, it's important to remark that most patients had been previously exposed to the alkylator one or two, 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 alkylator because it is different. In this sub-analysis, it is confirmed how efficacy is quite sustainable. I think major issue, retreating my patients with an alkylator, a different alkylator like melflufen. In fact, in my clinic, while I have included quite many patients in the HORIZON study, in this situation, most patients had been previously exposed to alkylators, and most of them high-dose melphalan followed by autologous stem cell transplantation.
Thank you very much. Dr. Richardson, to add on that, would there be any hesitation with you on patients that have received alkylators in the past with melflufen?
It's a great question, and I think obviously practice patterns differ. 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. Consequently, in my practice, for example, I relatively spare my patients' initial treatment with alkylators as much as I possibly can. I'll share with you a patient example from the OCEAN study. This gentleman had two prior lines of therapy, had only had high-dose cyclophosphamide 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. 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. I think as we go forward, relatively alkylator-spared patients may be ideal candidates to receive melflufen, 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 melphalan exposure, then being exposed to melflufen. Those patients have to be approached with care. Having said that, we clearly see that the drug works, particularly in the HORIZON setting, after extensive prior alkylation.
In the future, Klaas, I pick up on a point that Mariví made, which is that I could foresee it being used as a cytotoxic or a targeted cytotoxic, because 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. On the other hand, also the fact that it is distinct 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, Dr. Richardson. This was alluded to previously, and that is the use of melflufen in patients with extramedullary disease. Dr. Mateos, with the use of multi-combination treatments in upfront, but even quadruplets, ultimately, patients may develop extramedullary disease, and the proportion may be higher, actually, than that we actually now see. What's your impression there, and are there any viable alternatives to melflufen for this growing patient population?
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. In many clinical trials, patients with extramedullary disease are not well represented. It is impossible to recognize what is the real efficacy of many of the new drugs in this specific population. I think that the good news is that in the HORIZON study, quite a high proportion of patients included in this study presented with extramedullary disease. Important to see that not only bone-related plasmacytomas, but also pure extramedullary disease. I would say that approximately 55 patients in the HORIZON study presented with these characteristics, extramedullary disease.
What is important to see is how the efficacy was sustained in comparison with the overall population, indicating that melflufen works in patients with extramedullary disease. I can say that I've seen in my clinic at least three or four patients with relevant extramedullary disease, and to see how just after the first cycle of melflufen plus dexamethasone, the extramedullary disease, the plasmacytoma, clearly disappeared, almost disappeared. I think that this is a special feature and a specific feature for melflufen plus dexamethasone, that as I previously said, it is not usually observed with other novel agents.
Yes, I think that's an excellent summary, Klaas. I think the other point I'd like to make is that in the HORIZON study, Mariví is absolutely right. We had 55 patients with extramedullary disease. 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. This is the strongest single agent signal we have seen in this setting of extramedullary relapse and triple class resistant disease. I think it represents an important milestone, actually, in the development of melflufen, because I would foresee that melflufen could become a mainstay of targeting extramedullary disease in the future.
Mariví touched on this very nicely in that there are specific properties to melflufen that make it attractive. Its lipophilicity, 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, melphalan. We do not see that same effect. This sets melflufen 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 extramedullary 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 relapse refractory space.
I think actually melflufen is very well-positioned, Klaas, to take advantage of that unmet medical need, and I think the data from the HORIZON are very encouraging in that regard.
Thank you, Dr. Richardson. I think the time goes fast. We have only a little time left, but there are a lot of questions still coming in. I'll segue there now into the OCEAN study as well. If we look at a positive outcome for the OCEAN study, which would be either a non-inferiority result or a superiority result, to what extent could that position melflufen as a future backbone with other combinations, Dr. Mateos?
I think that the OCEAN study will be, well, 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. When you asked us where we will see melflufen in the near future, we said, well, in third line after prior exposure to proteasome inhibitors, IMiDs, anti-CD38 monoclonal antibodies. I would say that this is the place in which the OCEAN study is going to compare the melflufen plus dexamethasone versus pomalidomide and dexamethasone after two-four prior lines of therapy with one specific feature. All patients are going to be len-refractory.
We know that right now this is a challenging population that again, it is not very frequent in almost all phase III clinical studies, even if we evaluate new combinations based on new proteasome inhibitors plus anti-CD38 monoclonal antibodies, IMiDs plus anti-CD38 monoclonal antibodies. When we look how many patients were len-refractory, no more than 30%. In the OCEAN study, all patients will be len-refractory. 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 melflufen plus dexamethasone. For me, OCEAN study is a critical study that I repeat, I will support what we envision about the specific place for melflufen plus dexamethasone.
Yes. Klaas, I would again, that's beautifully put by Mariví. I think the important message as well is that you need to look at different mechanisms of action in different settings. 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. 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 and of response and the ability to maintain minimal disease.
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. 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, in disease that's characterized, that's enriched for adverse cytogenetics such as 17p deletion. Our biggest clue actually so far has been actually in the HORIZON data set in the extramedullary disease group where they've been enriched for high-risk cytogenetics, and we've seen activity. I can foresee the platform coming in combination, and I completely agree with Mariví, 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 very much, Dr. Richardson. I see that our next speaker is already lined up. For now, first I would like to thank you both, Dr. Mateos, Dr. Richardson, for your participation here. That's really appreciated. Thank you very much for that.
Pleasure.
You're of course free to stay on should time allow. For now, I'd like to actually hand over to our Chief Scientific Officer, Jakob Lindberg. Jakob, the floor is yours.
Thank you so much, guys.
Thank you very much.
Thank you.
Thank you very much.
Thank you.
Thank you, Klaas. I just would like to start to thank Dr. Richardson, Dr. Mateos, and Dr. 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. I will go through our peptide-drug conjugate platform and the clinical development program we have for melflufen. Some of these slides are slides that we have presented multiple times before. I will be fairly quick through them. Other sections are more new. We'll spend more time there. Please note that the full presentation will be available on our website afterwards.
Of course, we will have a Q&A session after Marty Duvall has presented the commercialization piece as well. If you would like me to go more in depth on a 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 had 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 Dr 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. 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 active, it's a verb, right? You target something, and that implies that something is sentient. Molecules are not sentient. Molecules just bind to each other. 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, that means also, for all practical purposes, we target aminopeptidases. This targeting of aminopeptidases increases the potency of the construct, it also changes the molecular footprint of the molecule. We see a lot of effects that you don't see with a normal alkylator. Dr. 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, this is a key aspect. This makes it kind of hard to describe sometimes because it contains something new and something old. We're both an alkylator and a new class at the same time, which is slightly schizophrenic. 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.
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 melflufen, it traverses cell membranes very rapidly and passively and then binds the intracellular aminopeptidases. Once again, I wish we knew that we designed it this way from the beginning, but we didn't. The molecule obviously targets aminopeptidases, and this is a very important part of the mode of action. 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 mutational 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 melflufen goes up because these cells are increasingly hard to kill. It means that the relative advantage of melflufen over other drugs increases as the disease express high risk features or is more aggressive in nature. 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 aminopeptidases 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. Old 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. This picture depicts how the myeloma landscape looked a few years ago. To some extent, it still looks like this today.
Dr. Richter brought this up, looking at the epidemiological data in patients is a little bit like looking at the stars. The light is old. The events you visualize and see are events that occurred years ago. 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 does not look like the patients that get diagnosed today. It will look differently, and we will come back to that. A few years ago, you had a fairly large population of newly diagnosed patients that stayed for a long time on therapy. The majority of them would relapse in their disease and become a relapsed multiple myeloma patients. That is depicted as RMM, and you see that the box is fairly large.
The patient would progress while on therapy and become a relapsed refractory multiple myeloma patient. At some point along this journey, once daratumumab got approved, this patient would receive anti-CD38-based therapy and become triple-class refractory. Triple-class refractory was a niche indication at the very end of life of a myeloma patient. To some extent, these patients are still around. This is not how it is starting to look, and the numbers that Dr. 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.
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, that means that the relapsed box you see is smaller than on the previous slide. Since we use both IMiDs, PIs 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, the trend is clearly that the majority of RRMM patients will be triple-class refractory. 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. I think this is a very important point. We have, of course, developed a vast clinical development program for a small biotech, clearly vast program in relapsed refractory 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 two signal-seeking trials, O-12-M1 and HORIZON, which explored melflufen plus dexamethasone, single-arm, open-labels trials in highly refractory patients. As we have heard today, we have a very encouraging activity signal 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.
Why did we choose pomalidomide all these years ago? It is the backbone in RRMM. It still is. It's still the most used drug in RRMM, and it's squarely placed there. Since that is perceived as the most efficacious and most used drug to actually understand how melflufen's activity compares to pomalidomide is a key aspect to understand the potential potency or the potential for melflufen to help RRMM patients. In ANCHOR, we combine our drug with proteasome 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 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 a registrational trial, and we hope to use that to show that the anti-CD38 combination therapy makes sense with melflufen. We 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 two 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 melflufen 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 melflufen, 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. The planned study start, just like the EMD study, is during 2021. Implicitly, this was discussed a lot actually today with the clinicians. We have shown this slide before. I think it's worth mentioning.
What do you need to show to be able to help patients with multiple myeloma? You need to show that as a single agent plus/minus steroid, you have activity levels north of 20%. Dr. 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? You need to be north of 20. We have been at 31% and 29%. Really excellent activity numbers. You need approval as a single agent plus/minus 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.
Dr. Richter showed this as well. Each patient is an individual. You need to look at the previous treatment history and the exact characteristics of the patient to know how to treat him or her. You need to show that you can be combined with the other drug classes. 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 life/tolerability issues. I think it was made very clear today. 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. It's a lab value. It's absolutely an important side effect. 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 melflufen. You cannot have any major comorbidity limitations. These patients have kidney function problems. They have often cardiovascular issues, both effects of the disease itself. They have peripheral neuropathy from the use of proteasome inhibitors. We have no limitation with regard to these three comorbidities. Also very important to be able to be utilized broadly in multiple myeloma. You need an easy administration schedule. We have a once monthly 30-minute infusion. It is basically as easy as it gets. When we look at the trials and how they map out to the labels, these are U.S. numbers for patients. 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 we hope that HORIZON will result in an accelerated approval label in the U.S. to begin with. You have another 45,000 patients of relapsed refractory multiple myeloma patients that are either treated with one drug, two drugs, or more. 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-class refractory field is becoming the relapsed refractory field, and ultimately the orange field will be the dominant area of all these circles.
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, et cetera. The program is really developed to fully capture and try to characterize how melflufen acts and can bring clinical help to patients with relapsed refractory multiple myeloma. 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 three distinct different trials and a lot of numbers. Joshua talked about this. I just want to say that our data holds up really well in this field in terms of tumor burden reduction and for how long the tumor burden reduction lasts. 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 the comparisons where actually the amount of dose reductions with melflufen here actually is the lowest among the three in line with Blenrep but still lower and significantly lower both for Blenrep and melflufen over ixazomib. When it comes to the bleeding rate, it is practically the same. It's plus minus one patient here, so this is the same from a statistical point of view, mainly then a course from the disease. 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 this panel, as well as Dr. Richter's presentation. We have two pivotal trials, registrational or trials with registrational intent, either ongoing or planned for melflufen 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 RRMM, pomalidomide. 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 melflufen plus dexamethasone, and in essence, melflufen also in combination can play. I cannot stress this enough, but both a 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. Fundamentally, we see patients getting retreated with anti-CD38-based therapy up to three, four times because of the efficacy of the drug. You then want a novel combination partner, and that is what melflufen can represent. When we look at OCEAN, as you know, it became a 495-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. It was still good. It means that we get a bigger safety margin to reach all the numbers we need to reach. It's fully enrolled. We're currently waiting for the right number of events to perform the statistical analysis.
We believe that we will have the final result during H1, first half of next year. 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 A significant number of them at the full dose of 25mg all the way to progression for two, three years in the first line of therapy. This creates a very IMiD-resistant disease. Of course, we believe that pomalidomide would then benefit from waiting, that you would benefit from waiting to use pomalidomide. Then the question is, what backbone in RRMM should you use in between?
Obviously, our belief as a company and as a development group is that melflufen can play that role. We can see from data that pomalidomide basically loses its activity when the Rev refractory event or lenalidomide refractory event has occurred fairly recently, and that's exactly how lenalidomide is used in the clinic. In the OCEAN trial, all patients need to have recently failed on lenalidomide-based therapy upon randomization. We meet the primary endpoint with both the superiority and non-inferiority result 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. 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.
We believe that ultimately they will look at the totality of the data and say then what they think. We will, of course, go to the FDA with this data set regardless if it's a superiority or non-inferiority outcome. We have now set the protocol for LIGHTHOUSE. It's a 240-patient trial, and it requires patients to be either double refractory or have undergone at least three lines of therapy where they have been double exposed, that is to IMiDs and PIs. We have melflufen daratumumab plus steroid in one arm and daratumumab in the other, and the primary endpoint is PFS. It is randomized one-to-one, and we hope to initiate this trial within short. We have talked about myeloma today, and that is of course the main topic. This peptide-drug conjugate platform has great activity against a broad spectrum of cancers.
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. You can see that in AML, NHL, and breast cancer, the activity level is really good from a preclinical signal point of view. This is the main reason why we plan in 2021 to 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. For both of these indications, we have strong preclinical rationale, and there is a strong interest to see what melflufen can do for these patients that both represent very significant unmet medical need in subgroups.
we're looking forward to initiate this 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 melflufen. 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 second-generation PDC, 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. it feels sometimes that we have only scratched the surface.
Happy to take questions after Marty's presentation. Otherwise, Marty, I think you should present how we plan to commercialize this successfully in the U.S. to begin with.
Thank you, Jakob, and thank you to Klaas as well, and most appreciative for Dr. Richter, Dr. Richardson, and Dr. Mateos as well for sharing their time. As Jakob 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. 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 melflufen 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 dex here, but the daratumumab or bortezomib, the things we're doing in the ANCHOR study and in the future with respect to LIGHTHOUSE.
That we're a first-in-class peptide-drug conjugate that targets these aminopeptidases and rapidly releases these alkylating payloads into tumor cells preferentially. Really taking advantage of the biochemistry here. First-in-class peptide-drug conjugate. Here we're really leveraging the success that we're seeing commercially in the marketplace with companies like Seattle Genetics or Seagen with their ADC conjugates. Very similar type play here with our drug. Targeting these aminopeptidases, and as Jakob mentioned, there's increased expression of these aminopeptidases associated with advanced disease and tumor mutational burden. Really playing up a key role for our drug and a key role for our platform moving forward. We will be the first and only PDC that targets these aminopeptidases which are highly expressed in myeloma cells. Really exciting positioning and launch for us as a company.
On the next slide, I'm reinforcing a key point that has been made and across a number of different presentations. 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. 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 Dr. Richter showed. He was focused more on the relapse refractory market. This looks at all products utilized in multiple myeloma today. We see a clear cut, lenalidomide and bortezomib at the top, looking at moving annual treatment of patients in the United States treated with these drugs.
Clear-cut frontline therapy. The two fastest-growing agents are daratumumab and pomalidomide that are used somewhat with DARA, somewhat in upfront, but also a lot in the second-line setting, really points out, of course, when we look at that pomalidomide-growing line and the len- refractoriness that Jakob 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 resistant refractory multiple myeloma. The rest of the spaghetti plot, as we call it, at the bottom of the slide, just 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.
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. Switching to Slide 41. Really interesting slide here. Again, I think Jakob really characterized this well in a more simple form. Here, let's just look at an annual comparison of 2016 and 2018 and talk about the percentage of patients treated by line of therapy that are already triple class refractory. 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 third-line setting, 2016, 4% of the patients were triple class refractory. We see that growing sevenfold in 2018, and then a doubling of patients who are triple class refractory in 2018 compared to 2016.
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 melflufen treatment, assuming a triple-class refractory label, 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. Likewise, we want to expand that market, essentially accelerate the utilization of new classes of drugs. 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. There's just a small percentage of the market that is dedicated to those new mechanisms of action. Where we're going in the future is increased utilization of these new mechanisms of action.
Our first strategy is to become a leading choice for patients that are opted to give these new classes of product. The second strategy is to expand the market. 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 melflufen. We become a leading choice and we expand the market. That's our commercialization strategy in the U.S. and beyond for melflufen. Next 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.
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 melflufen therapy in the U.S. upon launch of this drug. We're led by Mohamed Ladha, general manager of our U.S. business unit, and also on the medical affairs side, Dr. Paula O'Connor. What a great thing it is for an organization to have someone with the balance of academia and biopharmaceutical experience that Dr. O'Connor brings to the table each and every day. 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.
Also on the analytics business planning side, some of the things on the commercial operations side, both Jakob Lindberg and Nick Holtzman are doing an outstanding job in helping to prepare us for the launch of melflufen in the U.S. On the next slide, focus here is really on our approach. 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. 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.
We've done our homework in profiling the customer base, dividing the country, and are poised for the launch of melflufen in the United States. Next page, please. 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. 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.
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 melflufen as quickly as possible. In a case where there's, 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 a 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.
Our focus from a commercial perspective is to reduce the patient expense. We're doing that through co-pay 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. 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. We'll have patient outreach, continuous support through a third-party mechanism. Of course, to remain HIPAA compliant, we'll have educational materials to help 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.
We're already engaging with payers that represent more than 95% of covered medical lives in the U.S. and making much progress to ensure that patients have access to melflufen upon its launch. Next slide, please. Of course, we also need to be prepared and have the drug available through the network in the U.S., and the product will arrive via a company called Cenexi 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 relapsed refractory multiple myeloma market. 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 upcoming discussions with the agency on the label, given that we're a priority review, accelerated review product to Subpart H review mechanism, all of our promotional materials need to be prepared in advance for review by the FDA. 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. 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 melflufen 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. 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. We're utilizing artificial intelligence and predictive modeling to map and look at patients who are progressing through therapy based on the longitudinal product 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. An 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 melflufen will get on therapy. 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. We are currently receiving new ideas and are 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 Jakob 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 US, and pleased to show that the awareness of melflufen continues to grow across our target audience. Certainly with the presence that we've discussed at ASH, and I believe we're planning a webcast to 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 that's been done on the HORIZON data to really help provide more insights on patients who can uniquely benefit from melflufen and give hints as to where our development program can go from here. A lot of work has gone into the ASH program. We would expect that this would translate into increased awareness timed well to our launch. On the right-hand side, you see the growth or the physicians' projection of their likelihood to use melflufen. This was a snapshot in time back in the summer. We would expect that with the additional data that's being communicated, that their readiness to prescribe melflufen is appropriately increasing.
Dr. Richardson talked uniquely about extramedullary disease, that's called out here on the right-hand side. Next slide, please. This is a snapshot of effective drugs in our space that are without major side effects or comorbidity that have significant potential. 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. You see daratumumab approaching $4 billion with 37% growth. You see pomalidomide or Pomalyst, 22% growth, nearly a $3 billion drug. When you think about the OCEAN trial, you think about those possibilities on those two successful outcomes and a direct comparison with melflufen.
Having data showing non-inferiority or superiority to a $3 billion 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 get a feel for first-year sales and where some of the products have come in during their first year of sales. 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 melflufen in the United States in 2021. 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. Green is in the past.
We are expecting HORIZON to be published in the "Journal of Clinical Oncology." That is imminent. The ANCHOR presentation and other presentations of data upcoming at ASH in 2021 in the first quarter. First patient in a LIGHTHOUSE looking at OPD5 and the second product in our peptide-drug conjugate platform starting to accrue patients. The potential approval, the launch. EU submission, thinking about if that's on a conditional approval basis in the latter part of the first half of 2021. As Jakob mentioned, OCEAN and top-line results on OCEAN we would anticipate being available in the latter part of the first half of 2021, and a number of other milestones. We're very excited, and I will close with the summary slide before moving over to the Q&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&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 melflufen, 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 melflufen.
We have a peptide-drug conjugate platform, and we are poised to broaden our portfolio, obviously with OPD5, but we look to become an even stronger player in the treatment of hematologic diseases. With that, I will pause there as questions come in, and I will be able to monitor those as they come in. Please take the opportunity to send in. I will facilitate these and hand them over. This can go either to Jakob or to Klaas 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, we are looking forward to this trial in extramedullary disease. At this stage, we could either end up with being a single-arm or a two-arm study. That also depends on the interactions and the final interactions we will have with the regulatory authorities later this year and around year-end. That is still a possibility to have either a single-arm or a two-arm study where we'll 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 melflufen with other drugs, such as a PI. That's both still very much in play.
Okay. Thank you. Thank you, Klaas. 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 melflufen in that second or third-line therapy. I'll send that over to either Klaas or Jakob or both to touch on the answer there.
Yeah. Maybe 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. So far what we see is actually very reassuring when it comes to long-term sequelae, such as myelodysplastic syndromes or AML. 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 that doesn't necessarily bring additional long-term side effects. We feel very confident there.
Great. Thank you, Klaas. Any further addition, Jakob?
Yeah. Hi. Thank you, Marty. 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. I think Dr. Richter, he phrased it very well or framed it. We use immunomodulators and proteasome inhibitors and daratumumab so aggressively upfront that if you're going to do retreatment with daratumumab, whether the patient is non-daratumumab refractory or refractory to daratumumab, you need a novel combination agent. If you look at real combination data where patients are truly refractory, for example, to an IMiD when you use POM, you approach roughly 7-8 months median PFS. There is another trial now, APOLLO, that will be presented at ASH, but there 20% of patients are not IMiD refractory. Several of the patients are not even relapsed refractory. They are relapsed.
Of course, the median goes up. 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. We believe we have a good chance to have really solid data sets in patients that are truly refractory to IMiDs and PIs, and then daratumumab, if you're going to reuse it, needs a novel combination agent, and we believe that melflufen can be that one.
Okay, super. Thank you, Jakob. 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. I would just make the general point there that this is all work in progress, and this 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 two around, and I just think this is interesting to highlight in light of comments we've made on some of our preclinical observations about aminopeptidase expression, and higher degree of expression as the disease progresses. The latest thinking as it relates to melflufen development and newly diagnosed disease, is that something that's still on the radar screen?
I could answer that. It's Jakob. Klaas, 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 melflufen 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 and prove yourself in the population where you're in. Right now we see this as a relapsed refractory multiple myeloma drug. 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 Marty alluded to, pomalidomide is approximately $3 billion today only in RRMM.
Just to briefly add there, Jakob, I think if we talk about newly diagnosed, we automatically also think about transplant setting, especially these days. 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. That's, I think, a nice addition to the treatment armamentarium that we can bring to multiple myeloma.
Okay, super. 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 hiring, just waiting for the approval and costing money in the meantime? Have you guided for when approval could come in Europe? Good questions. We've been poised, and as we were kind of guiding towards launch readiness in 2020. 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. Pleased to report that the team is in place, trained as we've suggested, profiling customers, building their action plan.
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. Understanding the tools that we will have at the time of launch, all of that training. 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 can't put the odds on it, but certainly when approval happens, we will adjust accordingly. We're sitting here last day of November. A 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. Thank you for those questions.
I know we're a little over time. I'm just looking to see if there's anything. Klaas, are you able to see the questions?
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.
Yes. The cash position as of the end of the third quarter was roughly SEK 1.25 billion, and the cash burn for the fourth quarter, we guided that to be roughly SEK 400 million. Towards the end of the year, we should have around SEK 850 million in cash. We have previously guided that that is sufficient to bring us through the second quarter 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. It's too early to tell. We need a label. We need a date. We need to see what happens in the first 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 seven minutes over the top of the hour, and I think we'll call conclusion to a very successful Capital Markets Day. Really appreciate, as mentioned at the outset, your engagement, your continued interest, your continued help, and 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 here, Klaas and Jakob in particular, for their help in making for a very meaningful session and interaction with the key opinion leaders. 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.