Circio Holding ASA (CRNA) Earnings Call Transcript & Summary

Thank you very much, Øystein, and good morning and good afternoon to all of you listening. So as Øystein already alluded to in his introduction, this is a very exciting time for Targovax. We're really turning that corner from an early development company into a late-stage development company, which is what this Slide 41 is showing. And as you're going to hear in the moment, the focus now for us, the primary focus is going to be PD-1 refractory melanoma. I think Alex's presentation of the data have set this whole topic up quite nicely before us in this meeting. And not to forget as well that there are lots of expansion opportunities and something I will touch on a little bit later in my talk. So if we go to the next slide, 42. So checkpoint inhibitors in the clinic. Well, again, Alex have set the scene nicely. I was personally very pleased to have been able to help the development of the first checkpoint inhibitor, YERVOY, as Chief Medical Officer of Bristol-Myers Squibb in Europe quite some time ago. And of course, since then, there's been a tremendous development on not just products but also indications for which checkpoint inhibitors are suitable. And I think when you look at that, it's really quite fascinating how in less than 10 years, we now have checkpoint inhibitors as standard of care in a number of solid tumor indications. However, we need to be aware that the response rates do vary a fair bit actually. So melanoma, as Alex pointed out, is a bit of a testbed for an immuno-oncology intervention in that, we see a tumor type that's fairly easy to treat and to measure. We have about 40%, 45% response rate when you use a checkpoint inhibitor monotheraputic. If you combine it with another checkpoint inhibitor, we end up somewhere 55%, 60%; lung cancer, about 30%; and head and neck, about 20%. So there's a fair bit there to be able to improve in the future. So in other words, checkpoint-inhibitor refractory cancer is a significant medical need. Now what does the physician do in this case? And again, Alex's presentation touched on that. We do differ now between primary refractory disease and secondary refractory disease. So primary refractory disease is one where the patient's tumor is not responding while being treated with a checkpoint inhibitor. So in other words, progressing, while a secondary refractory disease is one where the patient's tumors did respond during the checkpoint inhibitor treatment, and then some time later on started to progress again. Now what can a clinician do? Fairly limited, as Alex said. I mean, the most common way for a primary refractory tumor is to just change the checkpoint inhibitor. It could be a CTLA-4 instead of a PD-1 antagonist or it could be another type of PD and CTLA-4 combination. In secondary refractory disease sometimes the clinician will repeat the same checkpoint inhibitor that was used earlier on as that patient had already responded some time ago. So I think we can sort of clearly establish that most patients, unfortunately, don't respond to checkpoint inhibitors even after adding or changing a checkpoint inhibitor. So what's happening out there? Well, there is a growing trend, not just among jobbing clinicians but also researchers, to add an immune-activating agent to change the tumor microenvironment in order for checkpoint inhibitors to work better. And this is where ONCOS-102 fits in very nicely. So next slide. Slide 43 I think it is, yes. Now where is this going in terms of patient numbers? Well, if we look at Stage 3 and Stage 4 melanoma, and in the major Western countries, we have about 100,000 new patients every year. And of those, about half of those are not resectable. Of course, surgery is the first thing that you wish to consider. But about, unfortunately, half of those can't be operated on. So that reduces the figure to 50,000. And then as we just discussed a few times, we have this issue of checkpoint inhibitor resistance. So that will again lower the figure by 50%. We end up with 25,000 patients per year. And then if you then look at how many of those patients could be treated with an intratumoral type of therapy, we think maybe somewhere between 10,000 and 20,000 patients per year. Now that's just melanoma. Of course, there are lots of other indications where checkpoint inhibitors are used and where we have, as I said earlier on in the previous slide, the challenge of checkpoint inhibitor is not working properly. So if you just look at 2 indications that are fairly common, just look at lung cancer, the figure is going to be well over 100,000 addressable patients in that indication. If we look at head and neck, maybe somewhere between 50,000 and 70,000 patients per year. So melanoma is just the beginning, and the same thing for us in Targovax, melanoma is just the first indication that we will pursue in our development program. Next slide. Well, this is the really exciting bit for me as Chief Medical Officer, having spent some 7 years in the company, taken the ONCOS-102 from Phase I to now Phase II, which is that we're now moving into registration path of this compound. And the target here is really to go after an accelerated approval in anti-PD-1 refractory melanoma. Now why are we doing that? Well, the rationale, hopefully, to everyone is pretty clear. The data, as Alex outlined, are pretty competitive actually, whichever way you look at it. And whichever competitor you look at, 35% ORR looks good. There is no standard of care, which leads me on to the third point on the rationale, which is that, that does make it somewhat easier when you speak to FDA and EMA and other regulatory authorities to discuss how many patients will need and what kind of data we need to succeed in our accelerated approval. So where are we in terms of next step? Well, Alex actually alluded to it, we spoke to him and Jedd Wolchok only last week, we're speaking to a number of other experts around the world. But we're now looking at a single-arm trial somewhere between 180 and 200 patients. We're, of course, focusing on refractory disease. So the definition of refractory disease is going to be very important to agree between us, the researchers and the FDA and EMA. Our primary endpoint, overall response rate, we will focus on systemic effect. It's important to map out very clearly how ONCOS-102 is able, not just to make injectable lesions respond but also noninjectable lesions responding, clearly in distant metastases. Durability is key, again, Alex referred to that. The trial we just completed lasted 6 months. It was a proof-of-concept study, but as we're now moving into registrational path, we really need to follow these patients much longer, at least 1 year and maybe even 2 years. The dosing, well, Alex also explained how Part 2, where we continued to administer ONCOS-102 throughout the trial, did turn out to be associated with a significantly better immune activation level. Plus, clinically, we heard him talking about he is keen to be able to offer ONCOS-102 to patients who are responding and not just stopping at some arbitrary point but be able to extend that administration for a protracted period of time. In terms of planning then, well, we are talking right now to our melanoma experts around the world, U.S., Europe and Australia. We will, of course, consult with the FDA. That's important to nail down the patient numbers, the endpoints and the layout of the study. And we'll, of course, also explore opportunities of partnering with other companies. That's something we're always looking for. Now where are we in terms of time lines? Well, we think if everything goes according to plan, we hope to enter the first patient at the beginning of next year. So a very exciting time for Targovax and one which will be the main focus of the company actually as we go forward over the next few years. Next slide. Colorectal cancer. Well, I have spoken to you before about our important collaboration with AstraZeneca and Cancer Research Institute and Ludwig Cancer Research. This is a study where instead of injecting ONCOS-102 into the tumor, we are delivering the ONCOS-102 intraperitoneally, through an indwelling catheter. And we are doing so in order to target micro metastases in the peritoneal cavity. And we are treating here colorectal cancer that has metastasized in such a way, these are patients who no longer respond to chemotherapy. And in fact, this is an indication where checkpoint inhibitors virtually have no effect, maybe in some cases, 5% to 10%. So the rationale here is to combine, again, with a checkpoint inhibitor, in this case, it's AstraZeneca's PD-1 antagonist durvalumab. And the layout of the trial, you can see in this slide, where after a safety lead-in, we have a Simon's two-stage. Well, the Simon two-stage design means that in the first part of the trial, what we call Part 1, we'll look to see to get certain level of response. And if we do so, we expand the trial into the full, outsized trial. And that's where we are at the moment. So in the first part, we had as a hurdle, 1 out of 13 patients to develop stable disease at week 27. We actually had 3 out of 13, so it was actually above that hurdle. And that means we're now in Part 2. Time-wise, we hope to have completed recruitment a little bit later on this spring, which would take us into the first set of data early next year, which should be very interesting as we then have the opportunity to sit down with AstraZeneca and discuss what we're going to do next. Next slide. Few words about mesothelioma. As many of you will remember, we have been running a small randomized study in first- or second-line malignant pleural mesothelioma, a very hard-to-treat highly malignant cancer, for which there's only been 1 standard care for close to 20 years. And thus pemetrexed/cisplatin, the combination of those chemotherapeutic agents, until recently, I should say and coming back to that point. Anyhow, this is a small randomized trial. After a safety lead-in, we then ended up with 20 patients who received chemotherapy standard of care pemetrexed/cisplatin intravenously. And then ONCOS-102 on top of that, compared to 11 patients who received just a chemotherapy combination of pemetrexed/cisplatin. We have released data on this before, but I just felt that we should remind everyone of what we've seen so far in first-line disease. I should say that this trial has not finished in the sense that we're still following survival. But at the 18-month interim analysis, which we released to the market in November, we did see in the first-line setting how the experimental group of patients already had a median overall survival of at least 18 months. And that should be compared with, as you can see here, represented by gray dots, what's been seen with pemetrexed/cisplatin before, hovering around 1 year median overall survival. So that's a good figure, but not the final figure because we are still following patients for survival, and we should come back to you later on this year with an update on that point. I've also put in here a reference point, which is the recently FDA-approved combination of ipilimumab and nivolumab. In first-line disease, they landed on 18 months median overall survival. So time will tell where we'll end up, but it certainly looks very promising so far. Next slide. We now have Fast Track designation. And as I said, an evolving pretty promising survival rate in first-line disease. And that puts us in good position to take this further. The product is well tolerated. We've seen that in combination with chemotherapy. We've seen it, as Alex mentioned, in combination with checkpoint inhibitors. We clearly have already a clinical signal in first-line disease. Interim survival data do look promising without a checkpoint inhibitor. And as I said, we now have a Fast Track designation. And I think that Fast Track designation is an important validation by the FDA of our virus, ONCOS-102. And it's, of course, also in the context of mesothelioma important to mention and remind everyone that we have an orphan drug designation for ONCOS-102 in this indication. Where we go next? Well, we will, of course, follow survival. And we shall be back to you when we have some more survival data. That will determine what we're going to do in terms of deciding development. And finally, it goes without saying that we will continue to monitor and discuss how we could best collaborate with our partner, Merck, in this indication. Next slide. That's Slide 51. So I've talked a little bit about melanoma plans, a little bit about mesothelioma, but what else is there? And do we have any other plans? Well, of course, the important collaborative trial with AstraZeneca and Cancer Research Institute is another area that we will pursue, clearly it will depend on where we end up. But as I mentioned earlier on, we have already met the predetermined efficacy in the Simon 1 to 2 stage design. Those are big medical lead, as I mentioned, where checkpoint inhibitors hardly work in this indication. We are expecting data to come out at the beginning of next year and then of course, that's when we'll sit down and discuss what we're going to do next. Other opportunities, well, something that we talked about before, which is that the melanoma trial that -- the 20-patient melanoma trial that we've just reported on wasn't just a trial of checkpoint refractory melanoma, but it's also a proof-of-concept study of ONCOS-102 in other potential checkpoint refractory indications. We've now seen how it appears to work very nicely in this particular melanoma setting. But that also gives us a hint of what it might be able to do in other indications. And I've just mentioned 2 here. Head and neck cancer is one attractive indication and since it's easier to inject head and neck lesions, checkpoint inhibitors don't work particularly well. And breast cancer, another indication, in particular, triple-negative breast cancer is something that we would like to look at. Next slide. Right. Finally, what does this look like in its totality for Targovax? Well, a pretty exciting program, I think, in terms of clinical and preclinical activities. Melanoma has start at the top, as I mentioned. We're now rapidly setting up a registrational program where we hope the first patient will go in beginning of next year. Colorectal cancer. We are collaborating, and we're waiting for the sponsor of the study to release data early '22, so we can sit down with AstraZeneca and see where we're going to take that. Mesothelioma. Well, we're still waiting for survival data. And of course, those will determine how we're going to take that forward and an important discussion with Merck in that context. Preclinically, ONCOS-200 series. So we're here referring to newly cloned follow-up compounds that my colleague, Victor, is going to talk about in a minute or 2. Important collaborations in that area, but also important collaborations that we are establishing to pursue the mutant RAS vaccine in various indications. So I shall stop there and hand back to our conferencier. Thank you.

Thank you, Magnus. Now we are running a little bit behind schedule. We had a small pause planned, and we'll limit that to 3 minutes to fill up the coffee mugs, and don't forget also to post your questions. See you in 3 minutes. [Break]

Good. So we are then back again. And next on the agenda is our Chief Scientific Officer, Victor Levitsky. He's having a double session. First, presenting immune activation data and then giving an update on the pipeline project. So please go ahead, Victor.

Good morning. Good evening, everyone. So can we go to the first slide, which would be Slide 54 in our presentation. Here, I would like to recap very quickly with you what reasons are behind collecting of immunological data during our clinical trials. And clearly, for an agent like ONCOS-102, it is quite important to be sure that the agent was delivered into the tumor and executed its effect. We can also understand and confirm the anticipated mechanisms of action, but also understand maybe a little bit better other mechanisms, which were not really appreciated before, a priori, without specific experimental knowledge. The strength, the amplitude of response and its persistence, as had been already touched upon by the discussion that we had during the presentation given by Alex, would allow us to plan better and understand better mechanistically the dosing and scheduling in our subsequent clinical trials. And finally and probably most importantly, we can establish associations between specific changes in the immunological profile of the tumor or peripheral immunological changes within improved clinical outcomes in our patients. Now going to the next slide. It is useful to discuss immune markers -- immune marker analysis that we do in our clinical studies in the context of tumor immunity cycle, which has been introduced some years ago by Chen and Mellman and is quite familiar to people in the field. Operationally, this cycle is necessary, represents a chain of events happening within the immune system while it interacts with the tumor. And it represents a chain of events that can be operationally divided into 3 major stages. The first stage constitutes a release of tumor antigens. They're processing neoantigen presenting cells and then presentation to T cells, which become primed and activated; then they migrate from the site of activation, which is usually represented by regional lymph nodes to the tumor, where they survive, expand, acquire additional effector functions at Stage 3 of this cycle; and then eventually, at Stage 4, they execute the most important function, which is killing of tumor cells and elimination of the tumor. Unfortunately, for many patients who progress with the cancer, this cycle experiences a number of problems amounted by the tumor through a number of mechanisms. So going now again through different stages, we can mention low tumor immunogenicity and ineffective T-cell priming because of the lack of danger signals associated with tumor growth, which makes it very different from, for instance, bacterial pathogens or viruses. Then T cells, in many cases, might be not able to reach the tumor. And if they reach the tumor, they become exhausted or inactivated by many other mechanisms operating in the tumor microenvironment. And finally, they do not acquire proper killing activity and become unable to eliminate cancer cells. So what I will do with you now is to tell you some -- show you some snapshots of our immunological data demonstrating how ONCOS-102 deals with these type of problems. And on the next slide, 57, you can see that one example of that. Here in mesothelioma tumors, which were injected with ONCOS-102, TLR9 expression has been upregulated. And TLR9 is one of the receptors which recognizes danger signals. In this case, the danger signal is represented by replicating the adenoviral DNA. And also, as this slide shows, this upregulation has been primarily detected in individuals who benefited clinically from injections of ONCOS-102, when we compare the expression of this receptor at the baseline tumor and over several weeks post-treatment. The same trend has been observed in another indication, melanoma, in this case, where in Part 1 and Part 2 of the disease, we saw differences in TLR9 expression. And by now, you should be well familiar with what Part 1 and Part 2 represent. So in Part 2, patients received many more injections of ONCOS-102. And it is interesting that practically every patient who showed response in this Part 2 of the study or abscopal effect in non-injected lesions showed upregulation of TLR9. And the only 1 patient where we cannot demonstrate this with response is the one for whom we unfortunately lacked the data point at the last biopsy. So it seems that the capacity of ONCOS-102 to generate danger signal and resulting in TLR9 upregulation correlates with its capacity to induce clinical benefits. When we progress to the next stage of the tumor immunity cycle, represented by migration of T cells in the tumor, I can show you now an example of a patient with ovarian cancer, where intraperitoneally administered ONCOS-102 completely converted a very immunologically silent, what we call cold tumor, into a tumor which has been heavily infiltrated by CD8 positive T cells. the type of cells, which we believe are most important for tumor elimination. And I have to say that this effect shows the most impressive change that I have seen in response to any kind of treatment in my 25-years-or-so career both at academia and industry in this particular space. Not only we have seen these changes in ovarian cancer patients, but also in mesothelioma patients receiving ONCOS-102, we have seen that tumor cells migrate. Now we are looking at Slide 60. We have seen that cytotoxic T cells migrate into the tumor and accumulate into the tumors treated with ONCOS-102. And this correlates with, again, clinical benefit. So accumulation of CD8 positive T cells and particularly CD8 positive T cells with high cytotoxic potential, which were defined as expression of granzyme B in these tumors by immunohistochemistry, is associated with good clinical response. While we do not see this in control patients who were alive or diseased on -- at a particular point of the trial on the study, only on chemotherapy or did not derive clinical benefit from ONCOS-102 treatment. Interestingly, not only numbers of cytotoxic T cells were increased within the tumors, but other important mechanisms of immune suppression have been modulated by the virus by our product and now moving us to the third cycle -- to the third stage of the cycle. So we have also seen changes in one -- in the ratio between so-called M1 and M2 macrophages. And the increase of this ratio is very well documented to be associated with better functionality of T cells, which are present within the tumor bed. And this capacity of the -- of ONCOS-102 to modulate tumor microenvironment is represented also at the level of viral gene expression -- sorry, at the level of cellular gene expression. And Alex already introduced this slide to you, again, comparing Part 1 and Part 2 study in melanoma, we can see that ONCOS-102 has relatively minor effect on gene expression in Part 2 patients who received a limited number of injections, but the modulation of gene expression is significantly enhanced as we progress with additional injections of the virus. And importantly, many genes such as cytokines and chemokines are increasingly upregulated, and that could be -- these genes could be responsible for infiltration of T cells in the tumor, but also lymphokines and co-stimulatory molecules, strongly upregulated in this case, would also promote the functionality and survival of T cells within the tumor bed. And upregulation of cytotoxicity genes brings us to the last, fourth component of the cycle that we can see also on the next slide, 62, where now we look again into different tumor, mesothelioma in this case, where we have seen, again, higher infiltration of the tumor with the cytotoxic T cells expressing high levels of granzyme B, which is a critical component of the cytolytic machinery. This you see on the left part of the slide. And on the right part of the slide, you can see data of cellular gene expression, where again, not only granzyme B is upregulated, but other cytotoxicity-related genes are enhanced. And the cytotoxicity genes represent the most modulated group of genes which have been studied in this particular case. The same observations hold for melanoma on the next slide, 63, where we now look at individual genes and again, comparing study Part 1 and Part 2. At the bottom panel, you can see clearly that in noninjected lesions, the expression of these genes has not been modulated. But on the upper panel showing you injected lesions, in study Part 1 and Part 2, it is clear that, again, additional injections of the virus, which patients receive in study Part 2, results in progressive upregulation of cytotoxicity genes from the first on-treatment biopsy taken at 3 weeks to the second on-treatment biopsy taken later at day 64. And I understand that these slides were pretty heavy in data, but we thought that it was important to present these results to you to really stress very interesting findings during our clinical trials and substantiate the conclusions that we make on the following Slide 64, that ONCOS-102 represents a very interesting reagent, which both activates simulating components of the immune system and counteracts multiple immunosuppressive mechanisms operating in the tumor microenvironment. And this allows the tumor immunology cycle to be completed effectively and rotate with high speed, so to say. This multifaceted effects, multifactorial effects of ONCOS-102 are associated very importantly with clinical benefits that we see in patients treated with the product in different cancer types. And this, of course, sets then the virus, as we have already stated many times in our presentation today, as a perfect partner for combination with checkpoint inhibitors, then providing good scientific rationale for our late-stage clinical development in melanoma and hopefully in other indications. So this then naturally brings us to the next part of my presentation, which starts with Slide 64 -- 66, where I will discuss with you shortly our ongoing attempts in regard to development of our preclinical portfolio. And these attempts are focused primarily on 2 aspects: further development of ONCOS platform and improved technologies to enhance our approaches for vaccination against mutated RAS. And we are doing this both through internal efforts and external collaborations and some of these external collaborations I will discuss with you in more detail as we proceed in my slides. So on Slide 67, you can see that our current pipeline and research and development strategy can be divided into 3 major pillars. The first pillar is represented by our attempts to study ONCOS-102 in combination with different immunomodulatory agents and checkpoint inhibitors primarily. And that was the subject of our presentation before today. Then in the second pillar, we are developing new generation ONCOS constructs, with the aim to add additional functionalities to the natural backbone of the adenovirus and GM-CSF, which is present in our lead candidate right now, ONCOS-102. And we are trying to develop additional armamentarium, additional ammunition to the virus. And I will try to explain to you what we are trying to achieve with that. And finally, we are trying to improve our -- the potency of our mutant RAS vaccination platform. Now if we go into more details on that on Slide 68, we have decided to prioritize, out of our internal pipeline, a construct that we refer to as ONCOS-211. And this construct then calls for 2 additional payloads. One is adenosine deaminase, ADA, which takes care of high levels of adenosine, which are intrinsically characteristic for many tumors in different indications due to abnormal metabolism in tumor cells. Adenosine accumulates at high concentrations in the tumor and exerts suppressive effects on different subsets of tumor cells, including T cells, which are supposed to take care of elimination of cancer targets. So a decrease of concentrations of adenosine would be very beneficial in the tumor. And the second transgene, which is inserted in the same virus and calls for ICOS-ligand. And ICOS-ligand is naturally expressed by several types of antigen-presenting cells. And what it does, it provides a co-stimulatory signal to T cells, which recognize specifically sort of the T cell receptors or engaged by other means, novel reagents such as T cell engagers. They receive signal which can be further enhanced by molecules like ICOS-ligand. And this results in better survival expansion and enhanced cytotoxic potential of the cells within the tumor. Just to give you one short example of a proof of concept for this model, which comes out of our recent clinical study, and this is the study in melanoma that we have discussed today quite extensively already. Here, you can see on the left side of the slide, immunohistochemistry data shown as this heat map plot. And as you can see looking at the color, then blue color illustrating very low signal. At the baseline, when the tumor was first biopsied before initiation of the treatment, it was very cold. There were no cytotoxic T cells, there were no conventional CD8s present in that tumor. However, quite surprisingly and unexpectedly for us, we've seen that this -- the same tumor expresses very high levels of ICOS-ligand. And this allowed that effective response that Alex actually described to you quite well in his presentation. And if you look at the level of the signal in other patients included in the study, you can also notice that patients who respond partially to the treatment or demonstrate stable disease, they also had higher levels of ICOS expression in the tumors compared to the patients who did not respond and whose disease progressed. So we are hoping now that with ONCOS-211, we will be able to recreate the situation observed in complete response patients to all other individuals who will be treated with this new virus. The next slide, I would like to spend maybe a minute or 2 describing to you our novel new collaboration, which has been recently announced with Papyrus Therapeutics. It's a U.K.-based company. We've spent a lot of time through the academic research performed by the co-founders on OPCML. It's a very interesting protein, which is inactivated in a large proportion of all different cancers. And inactivation of this protein correlates very well with a bad prognosis in many cancer indications, so with a more aggressive behavior of the tumor. In contrast to many known tyrosine kinase inhibitors, which either based on antibodies or small molecules and the ones which act on a particular tyrosine kinase. Nevertheless, this specific selectivity does not prevent these kinases to be effective in many cancer types. And we have many examples of clinical validation from this class of reagents in the clinic. But OPCML acts differently, affecting several receptor tyrosine kinases expressed at the surface of cancer cells at the same time. So there have been at least 8 different tyrosine kinases abnormally activated in different cancer types identified as interacting partners of OPCML. And in addition of -- or in addition to this direct inhibition of tumor growth, because of inhibition of this abnormal signaling, OPCML also suppresses a epithelial-to-mesenchymal transition, a process which is important in 2 aspects. One is promote the metastatic events. And another is to further decrease the immunogenicity of the tumor and the capacity of tumor cells to service targets for recognition by T cells. So inhibiting this EMT transition, we will be able to block the tumor growth and make it more susceptible to our immune interventions that we are planning to achieve with other components of our portfolio, thereby achieving a very strong synergistic effect here. On Slide 71, I would like to round up pretty much by discussing another collaboration that we are now running with a company called Valo Therapeutics, where the principle here is to form complexes between ONCOS variants and short-mutated peptides from RAS oncogene, which we have been previously using as a component -- as components of our TG vaccines. And Valo Therapeutics has generated quite convincing data, that formation of such complexes between peptides and variants significantly enhances the immunogenic potential. I think this is especially appealing these days in light of experience that the world has had now with the anti-COVID vaccines based on adenoviruses. And this got -- these vaccines based on adenovirus platform seem to be -- turned to be the most efficacious ones, again supporting the capacity of adenoviral vector to be a good immunostimulator. And we are hoping to capitalize on this capacity of adenoviruses to enhance the stimulatory properties of our vaccination approaches. And now really the last slide from me, where I want to bring you back to the tumor immunology cycle and highlight again the parts of the cycle where the components of our new preclinical portfolio are going to be affecting the performance of the cycle. So priming of antigens will be promoted by our new approaches to KRAS vaccination. And hopefully, this approach is effective, then it can be extended to mutations in other shared tumor antigens or unique mutations for generation of individualized vaccines. Then in the third component, through our internal activities on ONCOS-211 that I have described to you and another collaboration with a U.S. company, Leidos, where we are trying to add the capacity of inhibition of the PD-1 and CTLA-4 signaling pathways to our products. At this stage of the cycle, we are hoping to promote expansion of T cells in the tumor, which will spill out from the injected site and then promote that those abscopal effects that we observed in our melanoma study in several patients. And in the Papyrus collaboration, we will be effecting the final stage of tumor elimination also inhibiting directly its capacity to proliferate. And this concludes my presentation for today. Thank you very much.

Thank you, Victor. And then just to remind the audience that this is also our fourth quarter update. So going on the next page, the fourth quarter highlights and the subsequent events. This is really a busy slide, and that also represents how this period has been for us. And that's really how we like it. So there has been a lot of important events. We have talked about most of them. Clearly, the melanoma data with 35% ORR and also noninjected lesions that have responded. That's very encouraging and the main highlight for us. Also, an important milestone was the colorectal trial, where we managed to meet the threshold set on clinical benefits and opened up the Part 2 for recruitment. That's also an important trial for us now progressing well. Also on mesothelioma, it was an eventful quarter. We released the 18-month survival sweep with encouraging data, and we did also present our data at SITC Conference. Regarding the mesothelioma data, I will also come with updated overall survival in the near future for -- from the 21 months time points. So over to the corporate part. We did a small raise back in October, and that was important to increase the runway a bit on the back of the data. So now we have a runway into 2022. Also, we were granted a patent for the ONCOS-102 and the anti-PD-1 checkpoint inhibitor combination. And that's certainly very important, as you heard, all our plants are focused towards that now in the short and medium term. And securing this patent is of great importance. Also, the process in the U.S. is going quite well on that front. We also established our Scientific Advisory Board. Certainly important for us to keep close with the world-leading experts. So that's providing valuable input for us when we assess our data and decide on our future plans. Also after the quarter, there has been events, we would mention the Papyrus Therapeutics collaboration Victor just explained, but it again highlights the potential of ONCOS-102 as a payload vector and also generating the immune response in patients. So very excited about that collaboration. The IOVaxis collaboration, we provide -- we gave them a 3-month extension on the option. I will talk a bit more about that on the next slide. But continuing now with the SOTIO collaboration. This trial was stopped. It was by far our least important clinical trial. It was investigating whether ONCOS-102 could enhance their dendritic cell vaccine. And due to few patients and challenging inclusion criteria, it's been challenging to recruit patients, and it was stopped. So that's not a big event for us, but still, we stopped the trial. And importantly, also, this week, we got the Fast Track designation in mesothelioma for ONCOS-102, and that is a very important milestone for us and highlighting the potential of ONCOS-102. But on the next slide then, just a bit more information on the IOVaxis agreement and collaboration. As you may remember, they have taken an option for an exclusive license in Greater China and Singapore. IOVaxis is responsible for the trials coming up and all the regulatory filings. And the license option will expire closely after an approval from the Chinese authorities to run a trial. So IOVaxis are now in a process of getting an IND approval. It has taken somewhat longer time than anticipated. The Chinese authorities have somewhat different requirements for approving the IND. So it's still in process. And based on that, we also will extend the option further 6 months, so through September '21. Moving over to the numbers. We continued with a good cost control in the fourth quarter as we have had the last quarters. And as we are now ramping down our self-sponsored trials in mesothelioma and melanoma, the external R&D expenses are on the lower end, in line with the third quarter. Payroll, more or less in line with the previous quarters, except from third quarter, which always is a seasonal variability due to holiday months. And also on the other operating expenses, we are now quite lean and very selective on costs we're taking on. And then of course, also the reduced travel has contributed to the reduction. So with that, on the next slide, we are currently funded into 2022. We had NOK 122 million cash at the end of the year. And then the cash flow was positive due to the raise, but the burn from the activities was around NOK 25 million over the quarter. And currently, the market cap is close to $100 million. We continue to see a strong trading in our shares and with the 170% of the shares traded over the last 12 months, corresponding to around NOK 3.5 million in daily trades. So with that, I conclude the fourth quarter update, and then we will open up for questions.

Very good. We have many questions in the feed. Since we have the CFO going, maybe we start with some of the corporate questions. One question is on the financing going forward. You're planning some relatively big trials here that presumably will cost significant funds. How do you plan to finance this?

Yes. It will cost money to run such a trial, the melanoma trial that we are planning. And it should be an interesting investment opportunity based on the strong data we have. And I think also the design of the trial, a single-arm trial, allows us to have interim readouts. So we're not dependent on fully financing the trial before we start. I think that's important. And then, of course, also, we are exploring partnering opportunities. If there are ways to get the cofinancing from a partner, that's something we'll look into. But it's also important for us not to give away the rights to ONCOS-102 without a proper deal as well.

Very good. On TG, can you make some comments on the next steps for the TG program? You have previously guided on collaborations in the future. And number two, you mentioned an extension on the IOVaxis license option. What are the expected time lines?

So I can answer the question about investigator-sponsored trials, also update the market when they actually come to fruition. As of now, there's nothing that we have signed anything on, so we can't really go out with it, but there are things in the pipeline that we hope will materialize. And the second question was about the time line for IOVaxis. Well, as Torbjørn just said, we just expanded or extended the option for IOVaxis. And as Torbjørn just said, it has to do with the Chinese regulatory authorities that are working according to their own time lines, and we just have to adhere to them. And by the way, we are not the one working with the Chinese authorities on this, that's actually IOVaxis' doing. So we don't have the direct contact and direct information either.

Then we have some questions for Victor related to immune data and the next-generation constructs. Do we have Victor ready to go?

Yes.

Super. So Victor, maybe I start with some questions on the next-generation ONCOS, ONCOS-211. The transgenes that are in 211, ADA and ICOS-ligand, what -- how unique are these transgenes? And what indications do you anticipate this virus could be relevant in?

Yes, we have cloned the natural sequences for these proteins. So they are not artificially designed, but we're -- at least at the moment, we are not aware of any other oncolytic virus company, which is actively pursuing this type of payloads. There are similar activities, somewhat similar activities related, for example, to expression of 4-1BB, which is another co-stimulatory molecule, which could be viewed as a similar one to ICOS-ligand. But there is a pretty strong basic research demonstrating that the functionalities of these co-stimulatory ligand and the effects on T cells are not completely overlapping and not completely redundant. So -- and also I think that some recent lack of success, I would put it like this, in the field of small molecules affecting adenosine pathway could maybe favor the use of the natural enzyme, which would do that. And we are confident that the combination of these 2 activities might be a quite unique aspect of this product -- future product. Regarding indications, I think that is the best aspect of immuno-oncology that mechanistically, the effects that we achieve are usually not limited by a particular combination -- by a particular indication, sorry. And that's what I was trying to highlight in my presentation today, that we see this immunostimulatory effects of the virus across various tumor types. And if we succeed in enhancing these effects further by ONCOS-211, then these effects are likely to be applicable in different indications, regardless of which particular tumor type we are talking about.

And then we have a follow-up question on this, which I think is maybe harder to answer. How much control do you have over the dosing and the therapeutic window when you try to deliver these type of transgenes and the effect that you expect them to provide in the tumor?

Yes. This is, of course, a tough question, as you pointed out, Erik, because the performance of oncolytic viruses is affected by many different factors related to the expression of receptors in the tumor, the background immune response against the virus. And that is rather difficult to control at the level of one given individual. And I think that one way to compensate for this potential variabilities is in fact to go ahead with more extended scheduling schemes for all viruses. So to give them, if not more frequently, which just could be also an option, but give them also for a longer period of time. And therefore, kind of saturating the system even for patients where less intensive scheduling would not be optimal. And I think in the light of comments that we have heard from Alex today that this product is very well tolerated, I think this approach is -- makes a lot of sense. But we are not in danger of inducing some unexpected damaging side effects if we increase the amount -- or if not the amount, then the frequency of administration for our viruses.

Thank you. So then over to the immune data. You show a very broad set of different immune markers that are reacting favorably to the ONCOS-102 treatment. But one piece that was missing is CD4 T cells and the immunological memory. Can you comment on whether you have seen any difference in the CD4 population intratumorally?

Yes, we looked at CD4 cells by different ways. And I have to say that generally speaking, CD4 cells are -- the biology is different. They expand to a much lower extent than CD8s. That's just a natural kind of default characteristic of this subset of cells. It is a very well-known phenomenon for CD8 versus CD4 cells, recognizing other immunogenic moieties such as viruses or bacteria. So it is kind of in-built in the biology of CD8s that they expand more. And therefore, it is more difficult to see significant -- statistically significant and biologically obvious changes in the CD4 compartment. So the answer -- the honest answer is that we do not really know what is happening with CD4s, but of course, that would be an interesting aspect for future studies where we can maybe use additional technologies such as Class 2 polymer staining if we would like to assess particular specificities within the tumor, which would be probably more informative than just looking at the frequencies of CD4s for the reasons that I've just outlined.

And finally, before we wrap up, Victor, it was mentioned both by Alex and you that adenovirus has been used successfully in several COVID vaccines. How do you see this success in the COVID vaccines impacting the development and performance of ONCOS? And as a follow-up on that, could there be an issue with vaccinated patients having then some pre-existing immunity to an adenovirus, which could hamper the benefit of such patients to be treated with ONCOS-102 at some point in the future?

Yes, I think I understand the concern. If we were discussing systemic delivery of an oncolytic virus, then I think that could be a reason for being concerned due to potential neutralizing -- neutralization activity of adenovirus-specific antibodies. But I see this as a rather positive development for us in the context of intratumoral delivery. Because I think that an immune response -- effective, strong immune response, T cell immune response against adenovirus will help us to induce this modulatory effects in the tumor that I've been describing today. And if nothing else, then cytotoxic T cells against the virus could act directly by killing tumor cells, which will be infected at the site of injection. And the activity and the capacity of our specific T cells to proliferate and secrete high level of lymphokines, they eventually can be very beneficial for us to drive the second wave of immune response against tumor-specific antigens, which are not viral antigens. Capitalizing on this pretty well-established concept of epitope spreading, epitope diversification during immunity. So I think that to simplify -- to -- just to simplify my questions, I think that more T cell immunity against adenovirus is good for us and more antibody responses against adenovirus is not a concern for us.

So yes, we're now on Slide 78, moving to Slide 79, and we are wrapping up. And we're a little bit over time. So I'll go through my closing remarks quite quickly. On Page 79, you get an overview of the activity. And as Torbjørn already alluded to, there has been a very high activity level in the company in 2020. Also, already in 2021, we have read out mesothelioma data, we have selected ONCOS-211 for further development, and we have signed a preclinical collaboration deal with Papyrus. So 2021 is getting on to a good start. But of course, as should be clear by now, the big activity standing in front of us for 2021 is starting the trial -- the next trial in melanoma that will eventually take us to a -- hopefully to a registration. Going on to the next slide and take a look at the pipeline. We expect to have the first patient in this pivotal trial in the beginning of next year. On the colorectal cancer trial, there may be updates during the year, but we're guiding conservatively on the first half of 2022 for the next data set coming out. But the first data point that we will be able to share with you, and hopefully not before very long, is the updated survival data from the mesothelioma trial. So that's going to be a 21-month survival update that we will share in the not-too-distant future. So that's the end of today's session. Hopefully, you have been a bit wiser when it comes to our good clinical data and immune activation, also seen some of the expansion opportunities going forward. And last but not least, you have been able to understand fully that we are taking the step from an early-stage development company to a late-stage development company. And hopefully, the next time when we have a Capital Markets Day, there will be more people in the room. Thank you, and goodbye.