Oncopeptides AB (publ) (ONCO) Earnings Call Transcript & Summary

Yes. And I think that this is an excellent and practical question, and Joshua Richter previously alluded to this. Well, because it is possible to have a myeloma patients that relapse alkylator-naive. Because, well, we know that maybe more and more newly diagnosed myeloma patients don't want to receive autologous essential transplantation because of the lack of benefit in overall survival. At the end, in the French study that will be presented also at as ASH meeting or even in the elderly population, which we can select combinations alkylators free. In this situation, we know that melflufen plus dexamethasone is going to work extremely well. And there is a subanalysis conducted in all patients included in the OP-12M study and HORIZON study. And the group of patients, alkylator-naive, responded extremely well. But for me, it's important to remark that most patients had been previously exposed to the alkylator 1 or 2, and even some patients were refractory to the alkylator. And the efficacy was maintained, what is important because even, although we can utilize high-dose melphalan or just melphalan or maybe cyclophosphamide as part of the prior lines of therapy, at the moment of the relapse, the patient can receive again this [indiscernible] because it's still present. And in this analysis, it is confirmed that the high efficacy is quite sustained and I guess major issue repeated my patients with an alkylator , a different alkylator like melflufen. And in fact, in my clinic, well, I have included quite many patients in the HORIZON study situation, most patients have been previously exposed to alkylators and most of them high-dose melphalan followed by autologous expense transplantation.

Thank you very much. And Dr. Richardson, to add on to that, would there be any hesitation with you on patients that received alkylators in the past with melflufen?

It's a great question. And I think, obviously, practice patterns differ. And I think certainly in Europe, there is a very appropriate use of alkylation, and to a greater extent, arguably than we do in the United States simply because we have access to so many new drugs. And so consequently in my practice, for example, I relatively spare my patient's initial treatment with alkylators as much as I possibly can. So I'll share with you a patient example from the OCEAN study. This gentleman had 2 pro lines therapy, had only had high-dose cyclophosphide to mobilize stem cells, and he was assigned to melflufen/dex in that study and had a complete response to therapy. He was arguably alkylator-exposed but relatively naive, and I think that's how I see the drug actually positioning itself ultimately. I think it's clear that it works after prior alkylation has failed a patient. But I think as we go forward, relatively, alkylator-spare 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 because those patients have to be approached with care. But having said that, we clearly see that the drug worked, particularly in the HORIZON setting after extensive prior alkylation. But in the future, Klaas, I kind of pick up on a point that Marivi made, which is that I could foresee it being used as an -- sorry, as a cytotoxic or a targeted cytotoxic, so I don't really think of it as a classic alkylator as a targeted cytotoxic of choice in the future because of its extraordinarily favorable therapeutic index, in my opinion. And on the other hand, also the fact that it is distinct from alkylators in the classical sense, quite so actually, both for resistance characteristics and importantly for toxicities as well.

Right. Thanks for that answer, Dr. Richardson. And then this was alluded to previously, and that is the use of melflufen in patients with extramedullary disease. So Dr. Mateos, with the use of multi-combination treatments in upfront, but even quadruplet, ultimately, patients may develop extramedullary disease, and the proportion may be higher even than we actually now see. So what's your impression there? And are there any viable alternatives to melflufen for this growing patient population?

Yes. So this is also an excellent question because extramedullary disease is basically characterized by myeloma cells that can grow independently of the bone marrow microenvironment, and it is usually always associated with a worse prognosis. And in many clinical trials, patients with extramedullary disease are not well represented. So it is impossible to recognize what is the real efficacy of many of the new drugs in this specific population. And I think that the good news is that in the HORIZON study, quite a high proportion of patients included in this study presented with extramedullary disease. And important to see that not only bond-related plasmacytomas but also pure extramedullary disease. And I would say that approximately 55 patients in the HORIZON study presented with these characteristics, extramedullary disease. And what is important to see is how the efficacy was sustained in comparison with the overall population, indicating that melflufen works in patients with extramedullary disease. And I can say that I've seen in my clinic at least 3 or 4 patients with relevant extramedullary disease and to see how just after the first cycle of melflufen plus dexamethasone, the extramedullary disease plasmacytoma clearly disappeared, almost disappeared. So I think that this is a special feature an -- 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 that I'd make is that in the HORIZON study, Maria is absolutely right. We had 55 patients with extramedullary disease and in our analysis, which we're presenting at ASH, but it has been discussed before, so I can share some of the information, the overall response rate was 24% in this specific subgroup, which we have to recognize as being an important signal because these are patients who almost all CD38 antibody exposed. And this is the strongest single-agent signal we've seen in this setting of extramedullary relapse in triple-class resistant disease. And I think it represents an important milestone actually in the development of melflufen because my -- I would foresee that melflufen could become a mainstay of targeting extramedullary disease in the future. Marie-Vi 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. So 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 relapsed/refractory space. And 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 -- and the time goes fast. We have only little time left, but there are a lot of questions still coming in. So I'll segue there now into the OCEAN study as well. So if we look at a positive outcome for the OCEAN study we would be either on a non-inferiority result or a superiority result, to what extent would that -- could that position melflufen as a future backbone with other combinations, Dr. Mateos?

Yes. So I think that the OCEAN study will be well, I would say, a confirmatory study supporting the rolloff 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 pre-treated myeloma patients. But when you asked us where we will see melflufen in the near future, we said, well, in third-line after prior exposition to proteasome inhibitors in its anti-CD38 to monoclonal antibodies. And I would say that this is the placing which the OCEAN study is going to compare to melflufen plus dexamethasone versus pomalidomide and dexamethasone after 2, 4 prior lines, so therapy with 1 specific feature. All patients are going to be len-refractory, and 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 at how many patients were len-refractory, no more than 30%. In the OCEAN study, all patients will be then refractory. And we will see if it is better to continue with the immunomodulation through pomalidomide and dexamethasone or maybe to change and to go to the melflufen plus dexamethasone. For me, OCEAN study is a critical study that I repeat, I wouldn't support what we envisioned about the specific place for melflufen plus dexamethasone.

Yes. And Klaas, I would again ask -- beautifully put by Marie-Vi, I think the important message as well is that you need to look at different mechanisms of action in different settings. So 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 1 very important other point to add though is that targeting BCMA has become obviously a go-to after we've failed in the context of CD38 targeting. So if a monoclonal antibody approach using a CD38 targeting platform fails, BCMA is a logical next choice. One thing that's very striking to me is that BCMA is a relatively unstable platform in some respects, in terms of duration of response and the ability to maintain minimal disease. And so this points to another challenge that we face, and this is this whole construct of myeloma stemless. In other words, the core of the disease. And I think what's really important to share with our listeners is we have emerging data that melflufen is particularly active in high-risk disease and disease that's characterized as enriched for adverse cytogenetics, such as 17p deletion. And our biggest clue actually so far has been actually in the HORIZON data set in the extramedullary disease where they've been enriched for high-risk cytogenetics and we've seen activity. So I can foresee the platform coming in combination, and I completely agree with Mary-Vi, 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. So for now, first, I would like to thank you both, Dr. Mateos, Dr. Richardson for your participation here. That's really appreciated. So thank you very much for that.

Pleasure.

Please feel free to stay on, should time allow. But 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. And thank you, Klaas. And 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 a major scientific symposium. And we are very fortunate that they wanted to be here today to talk about the drug and their experience. So I will go through our peptide drug conjugate platform and the clinical development program we have for melflufen. Some of these slides are slides that we have presented multiple times before, so I will be fairly quick through them. Other sections are more new and we'll spend more time there. Please note that the full presentation will be available on our website afterwards. And of course, we will have a Q&A session after Marty Duvall has presented the commercialization piece as well. So 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. Gulbo did. From the beginning, we thought that we could enrich an alkylator and fundamentally it would function as an alkylator. As we have mapped the molecule over the years, we have realized that the aminopeptidase binding motif actually is a key aspect of the drug, and it fundamentally changes how it works in some aspects. So while it clearly is an alkylating agent and we can talk about it as such, it also introduces a completely new element, which is the peptide that binds aminopeptidases. Binding is interesting because in pharma, we use the word target. And target is interesting because target is an 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, so 1 molecule has an affinity for another molecule, 1 part is not active in that relationship and 1 is passive. They are just binding each other. This construct binds aminopeptidases and that means also, for all practical purposes, we target aminopeptidases. This targeting of aminopeptidases increases the potency of the construct, but it also changes the molecular footprint of the molecule. So we see a lot of effects that you don't see with a normal alkylator. 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. And this is a key aspect. So -- and this makes it kind of hard to describe sometimes, because it contains something new and something old. We're both an alkylator and a new class at the same time, which is slightly schizophrenic. So why is targeting of aminopeptidases important? Well, we have known for 30 years that aminopeptidases are oncogenic. That is, that they are overexpressed in cancer cells. But they are very hard to target because they are intracellular in nature. As something is intracellular, it means it's not at the cell surface so it's hard for an antibody or normal molecules to actually access it and bind to it in a good way. Due to the lipophilicity of melflufen, it traverses cell membranes very rapidly and passively and then binds to intracellular aminopeptidases. And once again, I wish we knew that we designed it this way from the beginning, but we didn't. But the molecule obviously targets aminopeptidases, and this is a very important part of the mode of action. And we have just summarized some features. I've already said that aminopeptidases are overexpressed in cancer, but more importantly, the expression goes up as the degree of malignancy goes up or the amount of mutation 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, but it means that the relative advantage of melflufen over other drugs increases as a disease express high-risk features or is more aggressive in nature. And that is, of course, where the unmet medical need is at its peak. In this sense, it acts very similarly to an antibody drug conjugate. An antibody drug conjugate binds to target at the cell surface, gets incorporated into the cell and releases the toxin inside then, preferentially, the cancer cell, because they express more of the target. With melflufen, it traverses the cell membrane passively, binds to aminopeptidases that are overexpressed in cancer cells 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. And this picture depicts how the myeloma landscape looked a few years ago. And to some extent, it still looks like this today. Dr. Richter brought this up, but looking at the epidemiological data and patients, it's a little bit like looking at the stars. The light is old, so the events you visualize and see are events that occurred years ago. And this is exactly the case when you look at the current patient population at this late stage. It is a representation of patients that got diagnosed years ago and doesn't look like the patients that get diagnosed today, it will look differently and we will come back to that. So 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 relapsed multiple myeloma patients. That is depicted as RMM and you see that the box is fairly large. Then the patient would progress while on therapy and become a 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. So triple-class refractory was a niche indication at the very end of life of a myeloma patient. And to some extent, these patients are still around. But this is not how it is starting to look, and the numbers that 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. But since we also use therapies either continuously or as maintenance at the back end of that, normally REVLIMID, very few of these patients actually ever become a relapsed patient. They become relapsed/refractory straight off the bat, and that means that the relapsed box you see is smaller than on the previous slide. And since we use both IMiDs, PIs, anti-CD38 so early in the treatment algorithm, it means that the relapsed/refractory multiple myeloma box and the triple-class refractory box starts to merge. They become the same. Patients, of course, not all RRMM patients are triple-class refractory, but the trend is clearly that the majority of RRMM patients will be triple-class refractory. And this means that this indication and this label that we're seeking, we don't know if we're going to get it yet, is not a niche indication anymore. It's more or less the same as saying that the drug is approved for use in RRMM. And I think this is a very important point. We have, of course, developed the 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 2 signal-seeking trials, O-12-M1 and HORIZON, which explored melflufen plus dexomethasone, single-arm, open-label trials in highly refractory patients. And 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. Now why did we choose pom all these years ago? Because it is the backbone in RRMM. It still is. It's still the most used drug in RRMM and it's squarely placed there. So since that is perceived as the most efficacious and most used drug to actually understand how 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 in 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 combined 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 then have the light chain amyloidosis trial, and we also have supporting programs looking at administration as well as early or expanded access programs in the U.S., and we hope to initiate similar studies in Europe on the expanded access side as time matures. We have actually planned 2 new trials in RRMM in 2021. Please note, planned. It doesn't mean it will happen but we are fairly certain. Otherwise, we wouldn't write it here. That is, we're going to do a study in patients with extramedullary disease. We have already had a lot of information regarding this, that actually 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 the formulation specialized for the high-dose setting to allow for the use of the peptide drug conjugate platform in the stem cell transplant setting. Please note that the IND for OPD5 was just recently approved in the U.S., and the planned study start, just like the IND study is during 2021. Implicitly, this was discussed a lot actually today with the clinicians, and we have shown this slide before but I think it's worth mentioning. What do you need to show to be able to help patients with multiple myeloma? And you need to show that there's 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 as its potential utility? And you need to be north of 20%, and we have been at 31% and 29%, so really excellent activity numbers. You need approval as a single agent 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, and you need to look at the previous treatment history and the exact characteristics of the patient to know how to treat him or her. So you need to show that you can be combined with the other drug classes, and you need to show that you have a synergy on the efficacy side. That is why we conducted ANCHOR. That is why we do LIGHTHOUSE. You cannot have any major quality of life/tolerability issues. And I think it was made very clear today, but this is a very important point. Drugs with quality of life issues simply have not succeeded historically in multiple myeloma. We have an excellent quality of life profile. We have hematologic suppression but it's a lab value. And it's absolutely an important side effect, but it is clinically manageable, which is the key topic. The tolerability side of things, that is safety or adverse events or safety signals outside of the hematologic arena are rare with 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. And then they have peripheral neuropathy from the use of proteasome inhibitors. And we have no limitation with regard to these 3 comorbidities, also very important to be able to be utilized broadly in multiple myeloma. And you need an easy administration schedule. We have a once-monthly 30-minute infusion. It is basically as easy as it gets. So when we look at the trials and how they map out to the labels, these are U.S. numbers for patients, and please note the orange area to the left of this slide. It depicts roughly 30,000 patients, because there's an overlap between the 2 populations of either patients with very high-risk feature sets such as extramedullary disease or triple-class refractory disease. This is where HORIZON as, where we hope that HORIZON will result in an accelerated approval label in the U.S. to begin with. Then you have another 45 patients of relapsed/refractory multiple myeloma patients that either treated with 1 drug, 2 drugs or more. Now as you can see, the orange area is expanding just in line with the discussion that was previously in the panel as well as what I described earlier. The triple-class refractory field is becoming the relapsed/refractory field. And ultimately, the orange field will be the dominant area of all these circles. And of course, with OCEAN, ANCHOR and LIGHTHOUSE, we are also expanding into how to combine the drug, how we compare with the biggest drug in multiple myeloma, et cetera. So the program has really developed to fully capture and try to characterize how melflufen acts and can bring clinical help to patients with relapsed/refractory multiple myeloma. Well, this is a busy slide. We have shown this a lot. This is a comparative slide and one needs to be careful because these are 3 distinct, different trials and a lot of numbers. Joshua talked about this. I just want to say that our data holds up really, really well in this field in terms of tumor burden reduction and for how long the tumor burden reduction lasts, but we do not have the same non-hematologic tox profile. If you look at the hematologic toxicities that normally shows in either dose reductions or bleedings, you can see the comparisons where actually the amount of dose reductions with melflufen here actually is the lowest among the 3, in line with BLENREP but still lower, and significantly lower both for BLENREP and melflufen over XPOVIO. And when it comes to the bleeding rate, it is practically the same. It's plus/minus 1 patient here, so this is the same from a statistical point of view, mainly then a cause from the disease. So we believe that there is a clear place for us to help patients very much in line with what our clinicians told us here before on the panel as well as Dr. Richter's presentation. We have 2 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 built readout fairly soon during the first half of next year. That is a head-to-head comparison with the most used drug in RRMM, pomalidomide. And given that pomalidomide is perceived as the drug with the best combination of efficacy and safety in RRMM, this comparison is key to understand what role melflufen plus dexamethasone and, in essence, melflufen also in combination can play. And 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 received daratumumab in the upfront setting but is not refractory to daratumumab yet or has become refractory and is being re-treated with daratumumab. Please note that, that would be off-label use. I need to be very careful. My U.S. colleagues will probably say something now. But fundamentally, we see patients getting re-treated with that anti-CD38-based therapy up to 3, 4x because of the efficacy of the drug, but 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, but it was still good. It means that we get the bigger safety margin to reach all the numbers we need to reach. And it's fully enrolled and we're currently waiting for the right number of events to perform the statistical analysis. And we believe that we will have the final result during H1, first half of next year. So why do we then believe in this trial? Well, the key thing is that all the data with pomalidomide comes from a time when REVLIMID or lenalidomide wasn't as extensively used in the upfront setting, that is in newly diagnosed patients. We have increased the amount of lenalidomide we use dramatically over the years. And current patients are basically using REVLIMID, a significant number of them at the full dose of 25 milligrams all the way to progression for 2, 3 years in the first line of therapy. And this creates a very IMiD-resistant disease. And of course, we believe that pomalidomide would then benefit from waiting -- that you would benefit from waiting to use pomalidomide. And then the question is, what backbone in RRMM should you use in between? And 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. And in the OCEAN trial, all patients need to have recently failed on lenalidomide-based therapy, upon randomization. So we meet the primary endpoint, with both a superiority and non-inferiority result in -- with the OCEAN study. There is a question mark here, though, and that is with the FDA and non-inferiority endpoint. Why is that? Because it's not part of the special protocol assessment. So obviously, we will still go with the data to the FDA, but that means that we don't fully know exactly how they will look at the data and if they will like it. And we believe that ultimately, they will look at the totality of the data and say then what they think. But we will, of course, go to the FDA with this data set regardless if it's a superiority or noninferiority outcome. LIGHTHOUSE is now -- we have now set the protocol. So it's a 240-patient trial, and it requires patient to be either double refractory or have undergone at least 3 lines of therapy where they have been double exposed, that is, the IMiDs and PIs. And we have melflufen daratumumab plus steroid in 1 arm and daratumumab in the other, and the primary endpoint is PFS. It's randomized 1:1 and we hope to initiate this trial within short. Now we have talked about myeloma today, and that is, of course, the main topic. But this peptide drug conjugate platform has great activity against a broad spectrum of cancers. And this is an old slide that we have used a lot. It's based on primary tumor samples from patients with both liquid tumors and solid tumors. And you can see that in AML, NAHL and breast cancer, the activity level is really, really good from a preclinical signal point of view. This is the main reason why we plan, in 2021, to explore to both do the signal-seeking trials in patients with AML as well as patients with non-Hodgkin's lymphoma, specifically DLBCL patients with high-risk features. We have both -- for both of these indications, we have strong preclinical rationale, and there is a strong interest to see what melflufen can do for these patients that both represent very significant unmet medical need in subgroups. So we're looking forward to initiate these. And of course, I would hope we could start these trials in the earlier part of next year, but it will most likely be in the later part of next year. We have already mentioned that we have more molecules. The PDC platform doesn't end with 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 and it feels sometimes that we have only scratched the surface. Happy to take questions after Marty's presentation, but 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. So if I could have the next slide, let's talk about what we're going to do to successfully make this drug available for patients in the U.S. So 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, bortezomib, the things we're doing in the ANCHOR study and in the future with respect to LIGHTHOUSE. And that we're a first-in-class peptide drug conjugate that targets these aminopeptidases and rapidly releases these alkylating payloads into tumor cells preferentially, so really taking advantage of the biochemistry here. So first-in-class peptide drug conjugate. And here, we're really leveraging the success that we're seeing commercially in the marketplace, with companies like Seattle Genetics or SeaGen, with their ADC conjugates, very similar type play here with our drug. Targeting these aminopeptidases and as Jakob mentioned, there is increased expression of these aminopeptidases associated with advanced disease and tumor mutational burden. So really playing up a key role for our drug and a key role for our platform kind of moving forward. So we will be the first and only PDC that targets these aminopeptidases which are highly expressed in myeloma cells. So really exciting positioning and launch for us as a company. On the next slide, I'm reinforcing kind of a key point that has been made and across a number of different presentations. So here, we see that improved outcomes in patients being treated with newer therapies, additional lines of therapy is resulting in an improvement in overall survival, not a cure, but we're seeing annual growth that is very significant in first-line, second-line, third-line and fourth-line treatment of myeloma patients. So again, driving home the point that this is a very large market and one of continued unmet need. Switching over to Slide 40. This is a slightly different cut than what Dr. Richter showed. He was focused more on the relapsed/refractory market. This looks at all products utilized in multiple myeloma today. So 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, so clear-cut frontline therapy. The 2 fastest-growing agents are daratumumab and pomalidomide that are used somewhat in -- dara, somewhat in upfront but also a lot in the second-line setting and 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 a resistant refractory multiple myeloma. The rest of the spaghetti plot, as we call it, at the bottom of the slide, just kind of represents that noise, some of the newer products that are launched, products that are being used in about 10,000 or so patients on an annual basis. So this represents that triple-class refractory type population that, of course, we're seeing growing on a regular basis due to the more aggressive treatment of patients with multiple myeloma. So switching to Slide 41. Really interesting slide here. And again, I think Jakob really characterized this well in a more simple form. But 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. And you note that from a second-line perspective, 3% in 2016 has quadrupled to nearly 12% or 11% as represented here in 2018. In the 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. So this is that front-loading of the algorithm that has been talked about and the fact that the pool of population that are eligible for melflufen treatment, assuming a triple-class refractory label is indeed, continues to grow. On the next slide, here, we outline our commercial strategy. We want to become a leading choice in this category of triple-class refractory multiple myeloma. But likewise, we want to expand that market, essentially accelerate the utilization of new classes of drugs. So in the bar chart at the bottom, we look at a snapshot of today, where the majority of products fall into that triple-class category and the recycling of old classes. And there's just a percentage, a small percentage of the market that is dedicated to those new mechanisms of action. But where we're going in the future is increased utilization of these new mechanisms of action. And our first strategy is to become a leading choice for patients that are opted to get these new classes of product. But the second strategy is to expand the market. And again, no more recycling of these classes. The OCEAN trial will help us to establish that, looking at the BLEN refractory patients and the comparison of pomalidomide to melflufen. So we've become a leading choice and we expand the market. That's our commercialization strategy in the United States and beyond for melflufen. So next slide, Slide 43. We are paving the way for a successful launch through people and through an excellent team of people. You can read through some of the background and description here. But 3 points: People with significant experience in our industry, people with significant oncology experience and people with significant launch experience. So we're bringing to bear quite a talented team, and I'm proud of the team that we've built and look forward to helping to reach as many patients as possible who are appropriate for melflufen therapy in the United States 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. But folks like Chris Black, Sarah Donovan, Matt Smith bring a significant amount of commercialization experience as well, and I've been so proud of some of the things that they've put together, and I look to share those with you in the next couple of slides. And also on the analytics business planning side, some of the things on the commercial operations side, both Jacob Lai and Nick Holsman are doing an outstanding job in helping to prepare us for the launch of melflufen in the United States. On the next slide, focus here is really on our approach, and our approach is one that's customer-focused. Obviously, each arm of our commercial and medical affairs organization can bring differentiated resources to bear to help health care professionals, help patients or help our customers improve the patient experience. So it's really an outside-in type approach, a team approach with the oncology account manager in the middle supported by medical science liaisons, oncology nurse educators, key customer marketers that are unique to their regions, headquarter-based functions and the important national account executives that reside underneath Matt Smith's team that are calling on some of the larger networks across the country. So we've done our homework in profiling the customer base, dividing the country and are poised for the launch of melflufen in the United States. Next page, please. So we're putting patients first. And by putting patients first, we are focused on making sure that all barriers to getting the therapy are eliminated and providing continuous support for our patients along their entire journey. So we will have a branded patient support program that will look to help patients along their entire journey. The first point that we'll be looking for is making sure that they have access to the product. We want no patient left behind. So we are engaging with payers now to make sure we understand what the needs might be from a prior authorization perspective and that we're poised with a team of people to accelerate that process to make sure that patients can get their 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. And 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. And then we'll support them along the journey to make sure that they're remaining on therapy and can benefit in all ways that they can. So we'll have patient outreach, continuous support through a 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. So we're already engaging with payers that represent more of -- more than 95% of covered medical lives in the United States 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 United States. 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. So we are ready for the next stages of -- and approvals to import the drug and having supply available at the time of launch. Next slide, please. Commensurate with discussions -- upcoming discussions with the agency on the label, given that we're a priority review, accelerated review product to Subpart H review mechanism, so all of our promotional materials need to be prepared in advance for review by the FDA. So we're well along that path. I provide here a slightly redacted version of some of those core sales materials and some of the messages that we intend to deliver, that will be targeted based on whether we're discussing with a health care professional, an academic physician, a physician in the community setting, an oncology nurse, a hematology nurse, a pharmacist. So we have a wide range of materials that will address the unique needs of the wide range of patients that we'll be calling on as we launch 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. And given the wealth of resources that are available that aren't in an integrated way, we are working to track and leverage integrated health care patient-level data and provide, in the hands of our customer-facing team, insights and updates in kind of a real-time weekly way. So we're using -- utilizing artificial intelligence and predictive modeling to kind of map and look at patients who are progressing through therapy, based on the longitudinal products that they're receiving, who might be becoming eligible and what clinic. Obviously, not by name, but we will know by account kind of things that are going on. 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. So I would consider this to be a state-of-the-art system, and we're really pleased to have it in place. Next slide, please. Our medical affairs organization has been in place for quite a while. A lot of great strides have been made across the area of medical information and communication, scientific exchange, data generation. As you might expect, we're launching and have addressed some areas of unmet need as it relates to investigator-initiated trials. So we are currently receiving new ideas and ready to continue to meet the changing needs of our customers as we move from this prelaunch 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 idea, new trials, new information, again, getting back to the core values of the organization being very science-driven and data-driven. Next slide, please. We are working and tracking our generation and building of awareness in the U.S. and pleased to show that the awareness of melflufen continues to grow across our target audience. And certainly, with the presence that we've discussed at ASH, and I believe we're planning a webcast to kind of outline some of those outstanding posters and the oral presentation on ANCHOR, we would expect that given that volume and comparative to our core set of competitors, we're proud of the science, the number of clinical studies, the analysis that's been done on the HORIZON data to really help provide more insights on patients who can uniquely benefit from melflufen and to give hints as to where our development program can go from here. So a lot of work will go into -- have gone into the ASH program, and we would expect that this would translate into increased awareness timed well to our launch. And on the right-hand side, you see the growth or the physician's projection of their likelihood to use melflufen. This was a snapshot in time back in the summer. And we would expect that with the additional data that's being communicated, that their readiness to prescribe melflufen is appropriately increasing. Dr. Richardson talked uniquely about extramedullary disease so that's called out here on the right-hand side. So next slide, please. So this is a snapshot of effective drugs in our space that are without major side effects or co-morbidity, that have significant potential. And what you see in the bar chart is a snapshot of sales on a worldwide basis, looking at year-on-year growth and where things stood through Q3 of 2020. So you see daratumumab approaching $4 billion with 37% growth. You see pomalidomide or Pomalyst, 22% growth, nearly a $3 billion drug. So when you think about the OCEAN trial, you think about those possibilities on those 2 successful outcomes and a direct comparison with melflufen, having data showing noninferiority 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 kind of get a feel for our first year sales and where some of the products have come in during their first year of sales. So not providing any guidance at this point in time on what our expectations are for 2021, but just wanted to put some numbers out there as we move further and think about our guidance on the sales trajectory for melflufen in the United States in 2021. And I'll close with the final slide, which takes a look at our value drivers and news flow. We've touched on all of these, green is in the past. So we do are expecting HORIZON to be published in the Journal of Clinical Oncology that is imminent. Obviously, the ANCHOR presentation and other presentations of data upcoming at ASH in 2021 in the first quarter, first patient in LIGHTHOUSE, looking at OPD5, and the second product in our peptide drug conjugate platform, starting to accrue patients. The potential approval of a launch. EU submission, thinking about if that's on a conditional approval basis in the latter half -- 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. So 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. So with that, I will pause there as questions come in and I will be able to monitor those as they come in. So please take the opportunity to send in.

So I will facilitate these and hand them over. And this can go either to Jakob or to Klaas with respect to the EMD trial and what we're thinking. Would that be a single-arm trial compared to a trial? How are we thinking about extramedullary disease and our company-sponsored trial at this point?

Right. Marty, it's -- do you want me to take it?

That would be great. Thank you.

Yes, of course, yes. And we are looking forward to this trial in extramedullary disease. And at this stage, we could either end up with being a single-arm or 2-arm study. And that also depends on the interactions and the final interactions we will have with the regulatory authorities later this year and around year-end. So that is still a possibility, to have either a single or more a 2-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 PIs. So that's both still very much in play.

Okay. Thank you, Klaas. So we have another question, kind of looking for what our expectations might be in the LIGHTHOUSE study. And it's differentiated by a second- or third-line therapy and how we see the long-term safety of melflufen in that second- or third-line therapy. So I'll send that over to either Klaas or Jakob or both to touch on the answer there.

If I can take the safety piece first there with what is referred to if we move into an earlier line of treatment. I think when we talk about safety, so far, we haven't seen any concerning signals of long-term toxicity of patients. Of course, our trials haven't run that many years. It's not that we have tens of years of follow-up, but so far, what we see is actually very reassuring when it comes to long-term sequela such as myelodysplastic syndromes or AML. So that's where we feel really confident that if LIGHTHOUSE may move the needle there and we move into an earlier line of treatment, that it doesn't necessarily bring additional long-term side effects. So we feel very confident there.

Great. Thank you, Klaas. Any further addition, Jakob?

So yes. So 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. And I think Dr. Richter, he phrased it very well or framed it. We use immunomodulators and proteasome inhibitors in daratumumab so aggressively upfront that if you're going to do re-treatment with daratumumab, whether the patient is only is non-daratumumab refractory or refractory to daratumumab, you need a novel combination agent. And if you look at real combination data where patients are truly refractory, for example, to an IMiD, when you use POM, you approach roughly 7 to 8 months median PFS. And there is another trial now, Apollo, that will be presented at ASH. But there, 20% of patients are not IMiD refractory. Several of the patients are not even relapsed/refractory, they are relapsed. And then, of course, the median goes up. But in this context, our data so far has been very promising. And of course, we need to conduct LIGHTHOUSE to see exactly where we end up. But we believe we have a good chance to have really solid data sets in patients that are truly refractory to image and PIs. And then daratumumab, if you're going to reuse it, needs a novel combination agent. And we believe that 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 -- I noticed that maybe in 1 of the bullet points, we called out EMD but not high-risk cytogenetics. So I would just make the general point there that this is all work in progress and 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 1 particular direction around high-risk populations or what may or may not be acceptable from an FDA perspective. Okay. Just looking down the list. We do have a question or 2 around -- and I just think this is interesting to highlight in light of the comments we've made on some of our preclinical observations about aminopeptidase expression and a higher degree of expression as the disease progresses. So the latest thinking as it relates to melflufen development and newly diagnosed disease, is that something that's still on the radar screen?

So I could answer that, it's Jakob. And 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. And right now, we see this as a relapsed/refractory multiple myeloma drug. And please note, the market potential there is not the limiting factor. It will be the clinical data that determines the success of this drug. As Marty alluded to, pomalidomide is approximately $3 billion today only in RRMM.

Yes. And just to briefly add there, Jakob, I think if we talk about newly diagnosed, we automatically also think about the transplant setting, especially these days. And this is as well as specifically why we filed this new IND, OPD5, which is just more convenient for an ablative setting, which may be the case in newly diagnosed multiple myeloma. And then, that's I think a nice addition to the treatment armamentarium that we can bring to multiple myeloma.

Okay, super. So 1 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 and just waiting for the approval and costing money in the meantime? Have you guided for when approval could come in Europe? So good questions. And we've been poised and as we were kind of guiding towards launch readiness in 2020, so we were hard charging towards that. There's obviously a lot that needs to be done. We utilize the acceptance of the file for accelerated priority review as a trigger for our scale-up, and pleased to report that the team is in place, trained, as we've suggested, profiling customers, building their action plans. So there's a lot of valuable investment of time that is ongoing from a field team perspective and that cross-functional model that I put out there. So understanding the tools that we'll have at the time of launch, all of that training. So time well invested in terms of these folks being on board and better to be prepared than to not be prepared. Can it come in sooner? It -- sure. I mean, it's -- I can't put the odds on it, but certainly when approval happens, we will adjust accordingly. We're sitting here last day of November. Few more months of opportunity for this to be done ahead of time and we'll keep you posted accordingly. As for guidance in Europe, we have not put a specific guidance out, and we will consider that over the next month or so. So thank you for those questions. I know we're a little over time. I'm just looking to see if there's anything. Klaas, are you able to see the questions or...

I'm looking at them now.

There is a question on cash position, burn rate. I'm not sure if Anders can pick up the mic and maybe respond to that.

So yes. So the cash position as of the end of the 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, so towards the end of the year, we should have around SEK 850 million in cash. And 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, what the uptake will be. So it's too early to tell. We need a label. We need a date. We need to see what happens in the first few months before we will be able to say something about that.

Super. Thank you. I kind of expected that. Well anyway, I could see we're about 7 minutes over the top of the hour, and I think we'll call it a conclusion to a very successful Capital Markets Day. Really appreciate, as mentioned at the outset, your engagement, your continued interest, your continued help in the role that everyone on the line is playing in terms of providing us access to capital, to really help leverage against this platform, this clinical development program with the ultimate goal of helping as many patients as we can around the world. Certainly thank the organizers of the day and the participation of those on the leadership team here, Klaas and Jakob in particular, for their help in making for a very meaningful session and interaction with the key opinion leaders. So thank you very much. We look forward to our next opportunity to interact and certainly look to -- 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.