Circio Holding ASA (CRNA) Earnings Call Transcript & Summary

Thank you for attending the European Biotech Investor Day hosted by Solebury Trout, Goodwin, Deutsche Bank and Nasdaq. My name is Nick Colangelo. I'm an analyst here at Solebury Trout. Before I introduce the next speaker, I would like to remind you to please feel free to submit your questions throughout the presentation via the web platform. If the company does not have time to answer them during the presentation, they will follow-up individually. And with that said, it is my pleasure to introduce the next speaker, Dr. Magnus Jäderberg, Chief Medical Officer of Targovax. Magnus, please go ahead.

Thank you very much, Nick, and welcome to my talk. So Targovax is a Norwegian biotech company focusing on immuno-oncology products. And I have the pleasure today to talk to you about what we're up to. And my talk will fall into introductory part, mesothelioma and melanoma, which are our sponsored indications. A collaboration around peritoneal malignancies, but also some information about our pipeline and the all-important news flow. So I think everyone's followed the tremendous development in checkpoint inhibitors. I personally have the privilege of working with the Bristol-Myers Squibb to support the development and launch of ipilimumab, the first checkpoint inhibitor. And of course, we're all aware of what's happened since then with a plethora of checkpoint inhibitors and indeed, other immuno-oncology compounds. I think, though, that what's clear from more and more information for various indications is that only some 10% to 40%, 45% possibly, will respond to checkpoint inhibitors. And so the idea of combining checkpoint inhibitors with some kind of immune-priming agent or an immune activator has become a big interest, not just for big pharma, but small companies. And of course, that's led to a number of interesting deals. And this slide shows a number of those deals I referred to, where big companies have seen the benefit of combining with products outside their own pipeline to improve their own oncology or immuno-oncology efficacy for their own products. And there are some pretty significant deals here. As you can see, the U.S. dollars between $100 million up to $250 million and $400 million. And I guess the market deal with Viralytics for USD 400 million acquisition is a good example of that. Now moving on to our lead compound, which is in adenovirus for the GM-CSF transgene called ONCOS-102. That's our lead clinical asset. And we have targeted hard-to-treat solid tumors. We have been around for about 10 years. The company was formed in 2010 and done a lot of studies and gathered a lot of data on over 200 patients in total. And we have decided to go for a number of different indications, which not just helps us to learn about how this virus is able to perform at different indications, but also provides a rich news flow, and I'm going to come back to that later. We've already shown some strong clinical and immune data in -- as a single agent with our Phase I study published in 2016, but we've also, over the last couple of years, shown combination data with checkpoint inhibitors and chemotherapy. And the most recent one, of course, was in mesothelioma data we released on Monday of this week. And we do have an endorsement of our platforms through some pretty significant pharma and biotech collaborations. That's something I will also mention. So how does this oncolytic virus work? Well, we inject ONCOS-102 straight into solid tumors. And what then happens is that the virus will replicate selectively. We have ensured that through genetic modification of the backbone adenovirus 5. We have breakage of cancer cells or lysis, as we call it, with a release of cancer antigens. Both cancer antigens are then picked up by antigen-presenting cells or dendritic cells transported into the lymph nodes, where we will have a subsequent production of T cells that are specifically targeting that antigen profile. And then in the next step, these counter antigen-specific T cells, CD8+ T cells, in particular, then seek the target throughout the system, latch on to the cancer cell and kill the cancer cell. The development strategy we have is one of combinations and in particular, checkpoint inhibitor combinations. So mesothelioma is our lead indication at the moment. I'm going to come back to that later. It's, of course, an orphan disease. But what's important to remember is that nothing's really happened treatment-wise for the last 15 years since pemetrexed was approved by the FDA in 2004 and Europe the same year. And on the checkpoint inhibitors, and in fact, the immuno-oncology active agents have not really made any great inroad into this indication. That's why we find it an important one to pursue, and we do have orphan status, both with the FDA and EMA. The second targeted indication that we are sponsoring is one where we look at checkpoint refractory melanoma. So as I mentioned earlier on, having helped BMS to develop ipilimumab, this is an area that myself and Jedd Wolchok at Memorial Sloan Kettering found interesting, and we now have a trial running in this area. And I think despite the 40%, 45% response rate with a checkpoint inhibitor, and if you combine 2 checkpoint inhibitors, you may came up -- come up to some 55%, maybe even closer to 60%. About half of patients don't respond to checkpoint inhibitors. So it's an important area to address. We're also interested in expanding our checkpoint inhibitor indications by pursuing a big collaborative study, which I will also come back to in a moment, in peritoneal malignancies. And what we're doing here is that we are not injecting the virus directly into cumulations, but we're actually infusing it through an indwelling catheter intraperitoneally. So we are, by doing that, also exploring additional ways of administering the virus. We're also very excited having now cloned 3 new double transgene viruses that we're able to talk more about when we have secured our patents. But the intention here is, of course, to look for new targets and different modes of actions and different combinations. So the clinical development program is one where based on a large compassionate use program and a Phase I study completed about 4 years ago, we're now running a study in mesothelioma, as I said, the Phase I/Phase II study on 31 patients in combination with standard of care in mesothelioma is pemetrexed/cisplatin. We have some exciting data, which I'm going to present to you in a moment. And what we've found that's particularly important when you're dealing in immuno-oncology that we found a very robust and broad immune activation. We are running a study in checkpoint refractory melanoma in the U.S. and Norway with Memorial Sloan Kettering as the principal investigator center. We completed the first part with good response rate of 33%, and we've now fully recruited the second part and what we expect in the final date at the end of the year. And as I mentioned earlier on, the third big study is a collaborative study in up to about 75 patients who have peritoneal malignancies and specifically ovarian cancer and colorectal cancer with disseminated disease. Again, Memorial Sloan Kettering is the principal investigator center, and there are 7 other centers in the U.S. recruiting into this trial. So let's look a little bit more at mesothelioma. So it's a difficult disease to not just diagnose, but also treat. And suddenly, by the time that most patients are being diagnosed, it's too late for surgical resection. Maybe only about 10% of patients are surgically eligible. So the main part of these patients will be offered double chemotherapy, pemetrexed/cisplatin. And as I alluded to earlier on, nothing has really happened in the last 15-plus years in providing anything new in terms of chemotherapy. Radiotherapy is sometimes used for palliative reasons, and immunotherapy has been remarkably unsuccessful. There was one checkpoint inhibitor, I mean, the large Phase III program, trametinib, but that failed to show superiority over chemotherapy a few years ago. There are a couple of smaller checkpoint inhibitor trials with pembrolizumab and nivolumab that showed some activity in second-line disease, and they made it into the U.S. NCCN guidelines. But for first-line disease and in Europe, there are no immuno-oncology products that can be offered to these patients. So a major medical need. The trial that we're running at the moment is one where we included both first and second line patients. And as I said, we combine with pemetrexed/cisplatin. Six cycles is a standard of care in U.S. and Europe. And we are giving these patients 6 intratumoral injections during the trial after a short safety lead-in phase, where we could see that there were no additional safety signals over and above those of chemotherapy. We open up the trial into a full randomized trial. And at the end of that, we ended up with 6 plus 14, so 20 patients in the experimental group receiving chemotherapy in ONCOS-102 and then 11 patients in the control group receiving just chemotherapy. And I should say that the primary objective of this trial was safety and immune activation. So it's clear to anyone who see this slide at the moment that there was no intention of showing clinical superiority with such small patient numbers. So here are the data from the 12-month analysis that we've just released this very Monday, actually. So what you can see at the top of the slide is a profiling of the 2 groups. And whether you look at the number relations, tumor burden or staging of the patients, you will notice that patients in experimental arm had a more advanced disease than those in the control arm, and that's an important consideration as we look at the figures. Starting off with first-line patients. DCR, as you know, is a combination of complete response, partial response and stability. It was pretty similar between the 2 groups. The medium progression for the survival for the experimental group was 8.9 months. And for the control group was 6 -- 7.6 months, sorry. 12-month survival rate was something we calculated because we're still too early to calculate median overall survival. And when you look at then how many patients were alive at one year, you found that 64% were alive from experimental group and 50% were alive in the control group. In the second-line patient sector, you can see that patient numbers are pretty small now. We have a picture where the control group is actually performing better than experimental group. There's no real clinical or scientific answer to that, except to say that this is based on a chance finding from very small numbers of patients where, for example, with 5 patients in the control group, each patient, of course, would represent a 20% shift on disease control rate as an example. Now how are these data stacking up against what's in the literature? And I guess the most important study is the one long way down in the left-hand corner called Vogelzang. So Vogelzang was the principal investigator of the large study that formed the basis for approval of pemetrexed in 2004, the FDA and European approvals. You can see here what we've done. We plotted response rate on one axis, then median progression-free survival on the other. So median progression-free survival for chemotherapy has been hovering around half a year, 6 months, in this case, just under 6 months for the Vogelzang, a study that was reviewed by the FDA and subsequently published. And then you can see at the very other end of the slide, the Targovax experimental group in first line. So overall, we're pretty happy with what we're seeing. As I said earlier on, this trial is certainly not meant to show any clinical superiority over the control group. But it's more a trial to look at safety and immune activation. And on top of that, any signals on the clinical side, and we believe there are some positive signals, as I've just shown. Now when you deal with immuno-oncology compound, of course, equally important is the immune activation profile. And here is something that I'm personally very excited about. I'm going to show you a couple of slides in a moment. But what we've seen here at this 12-month analysis is that a very clear and profound innate immune activation, whichever way we look, we look at clinical picture of fever, which pretty well every patient developed; cytokines, microphage; gene expression data. And in the same way, we have excellent adaptive immune activation. And maybe most importantly, we can see a remodeling of the tumor microenvironment. And of course, remodeling is what we all try to achieve with our priming agents so that the micro tumor environment is susceptible to, for example, checkpoint inhibitors or other immune therapies or indeed, chemotherapy. Now let's look at some of those details. And here is a slide of gene expression from key immune cells. We have compared here, ONCOS-102 treated patients. So those who had device plus chemotherapy with those who just had the chemotherapy that we call the control patients. And you can see here, there's a clear difference in ONCOS-102-induced immune activation compared to chemotherapy only. Whichever key immune expression you're focused on, there's a difference. So a confirmation of what I said earlier on, which is good innate immune activation and good adaptive immune activation. Cytotoxic CD8+ T cells is something we will talk about. So we're here talking about granzyme B producing CD8+ T cells. So these are the kind of T cells that are able to kill cancer cells. And what we've done here, we've split patients up into those who were alive at 12 months and those who had died within the first 12-month period. And you can see here that there's a very significant difference in the relative level of the cytotoxic CD8+ T cells compared to all CD8+ T cells for those patients who received ONCOS-102 and were alive at 1 year. Big difference compared to those who were deceased or in the control group. So another example of an immune-activating agent is able to activate the adaptive immune system, but also remodeling the tumor market environments. Macrophages are an interesting group of immune cells, and there are macrophages that we call M1 and M2. And you could also call them the good macrophages and the bad macrophages. So an interesting immune cell that can either help the immune system to fight cancer or hinder the immune system to fight cancer. So the good ones from the M1s and the bad one from the M2. And we are very interested in the ratio of good and bad here, M1 and M2. And you can see here, if you look at the ratio, and again, splitting patients into those who were alive at 1 year and those who had died during the first year, you can see a big difference between those who received ONCOS-102 and were alive. And in fact, even those who were deceased. While the control group either didn't change or in fact, they had a reverse. They had an increase of the bad macrophages, M2 macrophages relatively to the M1. So an important example of how ONCOS-102 is able to remodel the micro tumor environment. Now as a summary, this is a started plot to just highlight the features of ONCOS-102 treated patients who were alive, represented by the blue lines. And you can see here how we are hitting the ratio of cytotoxic T cells, the M1 to microphages and the PD-L1 expression, which I haven't had time to show you today, but which are also the -- plus the CD8 -- cytotoxicity CD8+ T cells. So overall, good tolerance. A favorable median progression-free survival of 8.9 months, stacking up well and a signal, I would say. But maybe more importantly, we have confirmed the mode of action in mesothelioma. We have good immune data, and we have remodeling of the micro tumor environments. Our next step is now to focus on first-line indication. And we are in discussion and agreed with Merck. As you might have seen, there is a press release around this week to collaborate on a large Phase-II study. This is a 100-patient study, where we're going to combine ONCOS-102 with KEYTRUDA and chemotherapy, and in the control arm, we're going to have KEYTRUDA and chemotherapy. And by the way, that is a combination that's already been tested in Canada by a big oncology network in a Phase-III trial. So that trial will start sometime first half of next year, which will be an important study to look what happens when you add KEYTRUDA to the combination of ONCOS-102 in chemotherapy, which we've already tested in the ongoing trial. Melanoma. So the patients that we're looking at in this ongoing trial are, as I said earlier on, patients who have not responded to checkpoint inhibitors and are progressing. And they are being given ONCOS-102, followed by KEYTRUDA as a rechallenge. In the first group, they have 3 injections and in the second part of the trial, they receive 12 injections. Data are very promising. These are data released last summer of 33% response rate in the first group. So 3 out of 9 patients responded and good immune activation data on top of that. This is the representation of those 9 patients. Here's one of the patients. I think it's a particularly interesting patient. This patient, if you look at the prior therapies in the bottom right-hand corner, has actually received not just ipilimumab and KEYTRUDA, but also BRAF inhibitors. And if I can focus your attention on week 3. So this is before KEYTRUDA has been reintroduced to these patients. They've only received 3 ONCOS-102 injections. And by that point, the melanoma had actually cleared. Good immune activation, whichever you look at it, in terms of innate immune response, adaptive immune response. We also looked with ELISpot analysis that tumor-specific activation. So we know systemically, we have cancer antigen-specific T cells circulating, which are relevant to this disease. Peritoneum malignancies, as I mentioned, we have a big collaboration with AstraZeneca, that's providing durvalumab. Cancer Research Institute, the Ludwig Cancer Research. We are here looking at ovarian and colorectal cancers that have spread into peritoneal with disseminated disease. We are here in the Simon's two-stage design, and we haven't reached Simon's two-stage yet. We did present at ASCO recently some dose escalation data, which had good safety and early signs of signal of efficacy. So this is -- these are indications where less than 10% of patients respond to checkpoint inhibitors. And we had -- in the high dose of ONCOS-102 plus durvalumab, we had 2 out of 5 patients with colorectal cancer with disease control and 1 out of 3, we had ovarian cancer with disease control. So early data, too early to say too much about, but certainly a signal in the right direction. Pipeline and news flow. We have, as I said earlier on, the pipeline, our newly cloned oncolytic viruses with double transgenes that we are now in, in vivo stage, and we'll, later on this year, select for clinical development. And at the bottom of the slide, you can see here that we expect to release melanoma data from that melanoma trial at the end of this year. We will have survival data on mesothelioma studies. We will have, in the first part of next year, peritoneal update. Also in the first part of next year, we will start the Phase II trial that we're running with Merck. Later on in '22, of course, there will be more peritoneal data coming out of that collaboration. So ONCOS-102 then is a clinically proven oncolytic virus, which is in terms of development, up at the top 3, 4 oncolytic viruses now in development. We have seen some good clinical data with the all-important strong immune activation. We have good backing, both from big pharma and biotech collaborations. We have released some of those thesis recently. And we've got a very good team, I'm pleased to say, to work with. And we have now several ongoing combination trials that will ensure that there are news coming out, the all-important news. We have a pipeline that we're also excited about. I'll stop there and happy to take any questions. Thank you.