PCI Biotech Holding ASA

Welcome to PCI Biotech third quarter 2021 presentation. My name is Per Walday and I'm the CEO of PCI Biotech. I have with me today three other members of the management team. Ronny Skuggedal, who is the CFO, but in addition also the CMO, Amir Snapir, and the CSO, Anders Högseth. Before we continue, please notice this important disclaimer. The presentation today will be given here for the first time in a long time with a live audience, which is very nice, but also as a webcast. And we also have a phone line for callers who want to ask questions after the presentation. So it's possible to ask questions through a call system, as you can see on the current slide. We will start by doing the presentation and then we will take questions from the audience here in the room and thereafter we will do the call questions and it's also possible to ask questions through the webcast system and we'll take them last in the presentation. We've modified the presentation slightly today since we have more members participating as well. So we are not going into detail on the technology itself. There's a lot of good information around that on the website and our homepage. But we will go through the highlights and then we will have an operational review that is divided into a clinical part done by Amir Snappi, the CMO, and a preclinical part done by the Anders Högstedt, the chief scientific officer. And then Roni Skogedal will talk about the key financials, while I will do the outlook at the end. So then, let's start with the highlights for the third quarter. The pandemic still has an effect, unfortunately. And we can see that also in the hospitals and the numbers of people with COVID-19 in the society right now. And we see this clearly also in our study. Enrollment of patients into release study is still challenging. and it is fluctuating from month to month. It has a continued negative impact on the study, and also with August, due to the holiday season being normally a low recruitment month, we didn't have more than five patients, unfortunately, in the third quarter. We have enrolled three patients into release study in October and we continue to work hard with regular site calls and a lot of different activities going on to focus on recruitment into this study. We are emphasizing now regular trial management including overall performance and site replacement and we have replaced five sites during the 2021 to replace sites who are not contributing to the study with more promising other sites. We are also pursuing strategies to address recruitment and retention. We have so far in the study recruited a total of 30 patients per end October. And the timeline that we reported in the second quarter remains. It's still second half 2023. Now, as I said, we are proactively pursuing strategies to address recruitment and retention, which we talked about before. And we are in these also having interactions with both the FDA and the EMA about an alternative study design enriching the patient population, the control arm, with external patients. That is something we are working on. And Amir will come back to that later in the presentation, what we are doing with regard to retention and recruitment. Then for Firmavac, it is progressing towards the initiation of a phase two study, a clinical proof of concept study. We have product definition now. We have a study design clarified. We had comprehensive consultation with international experts. And Amir will also talk a bit more about what this study really entails and what we're doing in that area. And for the FIMANAC, we've talked about that we are now focusing our efforts to the areas which where the sort of PCI technology is most suited. And we have on the basic of strategic research and the collaboration and the result from the collaborations now focused on specific applications that Anders will talk more about later in the presentation. And also, importantly, we have strengthened in the third quarter of the organization with three new key employees, really skilled individuals, competent individuals, who, one, is an operational leader for release, who have done pivotal studies before and have done orphan disease studies before, and two key employees also within clinical science and within business development and alliance management. which is important specifically for FIMAvac and for FIMANac. So those were the highlights. Briefly about a glance of what we are. We are located here at the Oslo Cancer Cluster, very close to the Norwegian Radiome Hospital where the PCI technology originated. We have three different programs which are based on this platform technology. We call them FIMAchem, FIMAvac and FIMANac and FIMAchem. With Amphinex as the lead product, Femaporphine is the active ingredient, is in a pivotal trial, global pivotal trial in bile duct cancer, enhancing the effect with our technology of Gemcitabine in this patient population. We are also in the clinical setting with Femavac using the same platform technology as a vaccination technology where we can enhance therapeutic cancer vaccines with the technology which has attributes which really strengthens the T-cell response and that is important, specifically important for therapeutic cancer vaccines. And then for FIMANAC, Nucleic Acid Delivery Technology, we are in a preclinical stage with several collaborations in interesting areas where we are now focusing our efforts. And PCI, it is photochemical internalization. It is an intracellular delivery platform that is used to get molecules who have difficulties getting into cells to reach the target, to get them into cells. And then we will start with the operational review in the clinical side, and I will start talking a little bit about the release study before Amir talks more in details about recruitment and retention. So what we are developing here is Amphinex. This is a formulation of the active ingredient Femaporphin and it's developed as first-line treatment for the orphan indication bile duct cancer, a rare disease with a very high unmet medical need. We have some very positive early clinical results encouraging tumor response and also encouraging survival data from the phase one study. We took these to the regulatory authorities and discussed what is needed to take this to the market and we have agreed a pathway with a single pivotal study with potential accelerated approval based on an interim analysis during the study. And that study has been initiated, so we are now running a global pivotal registration intent study with recruitment ongoing at almost 50 hospitals across three different continents. So why bilock cancer and what is the fit between our technology and the need that we see in bilock cancer? Well, first of all, we have some very positive results from the phase one with regard to both tumor response and survival, as you can see on this slide. This is an illumination technology where we illuminate tumors to enhance the effect of gemcitabine. And this is easy to use in this perspective because illumination can be done through standard endoscopic methods that are being used in these patients anyway for stenting and so on. And the gemcitabine is today the first-line treatment together with cisplatin. So we can enhance what is today recommended as a first-line treatment. And we boost effect locally. And for this specific disease, what really is harmful to the patients is the effect locally. So you need better local regional control of the tumor. And in that sense, there is no direct competition with us and our technology in relation to enhancing the effect of the standard first line locally where it's most needed. We have protection on this through orphan drug designations, both in Europe, in the US, and in South Korea, which offers market exclusivity. And we also have a patent that has been granted in Europe, but is still pending in US and other key markets, which lasts until 37 approximately, around using our technology for treatment of bile duct cancer with gemcitabine. And of course, for an orphan disease like this, there is a premium price potential. And with regard to competition, what we've seen mostly of here is precision genes, small molecules, targeted treatments that are mainly either second line or towards targets present mainly in intrahepatic bile duct cancer. And there have been two approvals in that area recently. But those are really targeting only intrahepatic. Now, the exceptions from this are acelerin, which we talked about before, and also some immune checkpoint inhibitors, which is being developed, durvalumab and pembrolizumab, which are also being developed in a phase 3 study for this specific indication. The results that have been seen so far has been a little bit sort of both ways. Some failures, a recent failure in August, some bad results last year with one of these drugs. Excuse me. But now recently, the Ruvalumab in the phase three study reported a positive interim analysis. Now, this is a study which comprise not just our patient population, but also gallbladder population. We have the perihilal and the distal, but this also is gallbladder and it's intrahepatic. We know nothing about the results yet, so we don't know what the results are in total. We know that it's positive, but we don't know what about the results in different subgroups. And this has been differing quite a lot in earlier studies when you look at targeted treatments of different kinds. So we have to wait for these results before we can say how this will affect, whether it will affect the real study and to what extent and how. The study that we agreed with the regulatory authorities was to do a one-to-one randomized study between control and experimental. Control is standard of care today, which is gemcitabine plus cisplatin in up to eight cycles, and then adding onto in the experimental arm up to two treatments with FemaChem to enhance the effect of gemcitabine. And this is now then ongoing across 47 different clinical sites across three different continents. And you can see at the lower end here how this treatment is done. At the start of the cyclic treatment of cisplatin and also potentially if the investigator and the patient wants it, also a second treatment later in the cyclic treatment of cisplatin and gemocytobin. The status of that study is today that we have 47 sites currently open for patient enrollment, 32 sites in Europe, nine in Asia and six in the US. We have implemented a lot of different initiatives to try to recoup the COVID-19 cause delays to the study. And the most important of those being the increased number of sites, expanding the study to new areas and more sites, and also the protocol amendment to expand eligible patient population. And we clearly saw that these initiatives provided increased screening and increased enrollment into the study. But the level has been fluctuating during 2021. We didn't think that the pandemic would affect the study to the extent that it has for such a long time, but it continues to have an effect on our study. And the reason behind this, I think Amir will come more back to later in the presentation. Now we had, as I said, five patients enrolled during the third quarter, and we had three patients enrolled in October, and the total enrollment then is 30 patients into the study. We have a continued strong focus on recruitment, on enrollment of patients. We are emphasizing really regular trial management, but doing it in a boosted and powerful way. We have a lot of performance evaluation, motivation, and booster visits, and we replace sites where we don't think they are motivated enough or don't contribute sufficiently to the study. And as I said, more than 10% of the sites have actually been replaced so far in 2021. So looking forward, what are the endpoints, the milestones and the timelines? We have then an interim analysis where we look for objective response rate, so the response to the tumor of the treatment, and of course a secondary endpoint of overall survival, which is always important and the authorities will always look at. And then the final analysis, the primary endpoint there, is progression, free survival, and the secondary endpoint, overall survival. We had our first patients enrolled in May 19 in Asia in October 2020, in the US in April 21, and we are now enrolling patients then in three continents. We have established an independent data monitoring committee which will regularly look at this trial, and the first time is when we have eight patients that have undergone two FEMA chem treatments and have passed through a safety window, so you can look at whether it's safe to do two treatments. And that safety review is expected before the end of this year. The objective response rate is the endpoint, as I said, which will be looked at after 120 patients have been enrolled. That's the interim analysis, which is expected second half 23. And then the timing and the format for the study conclusion can be impacted, of course, on the outcome of the interim analysis. But it is expected approximately second half 24. So these are the broad terms, the study. And I will now hand over to our CMO, Chief Medical Officer, Amir Snapir. He is joining us from Finland, where he lives. So we have some new technical things that we are trying to, we hope will work well. So Amir, can you hear us? Yes, I can hear you very well. Can you hear me? Yes, we can. And we can see you as well now. Thank you.

Very good.

Next slide, please, Per.

So we wanted to expand some more about the challenges or two of the main challenges that we are facing in release and tell somewhat about the background, what the challenges are, and what are our strategies to mitigate these specific challenges. And the two main challenges that we consider are the retention and, of course, the recruitment. And retention is really an important challenge of all clinical trials. And maybe it takes somewhat a backseat and not under focus many times. But for studies like the RELEASE study, it's really an important challenge. And there are two reasons for this. So the main reason is that the RELEASE trial is what we call event-driven. analysis. It requires a specific number of events, in our case, events of progression, to be able to analyze the study. And if patients discontinue the study before they provide data, this will not allow powerful evaluation of the treatment. And for this purpose, we can We need to do everything possible to take care that patients adhere to the study. Now, it is just normal that in all, especially cancer trials, but in all trials, patients discontinue the trial before some patients discontinue the trial before they contribute data. But the magnitude of this is taken, or at least is assumed when the study is designed, the number of patients are determined. There are assumptions about the proportion of patients that are expected to leave the study before they contribute data. If this proportion is above this expected level, then there is risk for the analysis of the study. And this is why we follow so closely on this. And we can see some signal that we'll talk about. The other aspect that is really important around the retention is this. Even if patients leave the study, when they leave equally from both arms, it's substantially less a problem than if they leave from one of the arm more than the other arm. And this is what is called imbalance discontinuation. And the reason this is important because it can lead to bias of the results. And also, once this imbalance is above a certain level, this potentially can trigger additional statistical analysis by regulatory authorities. And this additional statistical analysis is making it harder to demonstrate the effectiveness of the treatment. So this is the background for why retention, why we focus on retention and why this is important. Now, specific challenges for release are the open label. Release from ethical reason cannot, in release for ethical reason, we cannot unblind, we cannot blind the treatment. So in our case, all patients that are randomized into the trial, they know what treatment they're going to get. And of course, it's natural that patients that are randomized to the control arm and receive the standard of care are less enthusiastic about taking part in the study and are more prone to leave the study. And this is true for all open-label studies, and this is now... maybe a bigger challenge in the settings of a pandemic where patients that have cancer are vulnerable and they might think Well, I just get the standard of care that I get it far away. Why would I do this, all the travel and the risk, while I can get it next to home? So this is another reason specifically for our time that patient might decide to discontinue the study. Now, what we see in release currently is lower retention rate in the control arm. Numerically, in absolute number terms, this is a very small number, but we consider that there is potentially a pattern that we need to focus on and to take care of this before this becomes a challenge already from the higher absolute number of patients. So what we can do to mitigate this, our strategies are in a way in two directions. One is what is normal practice in clinical trials to reduce patient discontinuation from the study. And this is to work closely with sites. The biggest reason or the most important reason patient adhere to studies because they are aware they get better treatment while they are in clinical trials. And the commitment that the patient have to the trial is based on the relationship with the site. So we work hard with clinical sites to improve or to take whatever is possible to strengthen this commitment. And of course, we support the patient in all aspects of the trial to reduce the burden to minimum, and that includes travel, accommodation if relevant, and any other aspect that can make the trial easier for this patient. The other big direction that we take with strategies to look for bigger or more stronger solutions to the risk of low retention. And this is to evaluate the possibility to convert the randomized control arm to a hybrid control arm by adding external patient data. This is a very good mitigation for this risk, but it's not easy to do. The reason it's not easy to do that it is a golden standard to use randomized control trials for pivotal development. So when we get to trial like release that have a registration intent, are done as randomized control trial in most cases. And regulators are taking care that this standard is maintained as much as possible. But we have a good case, and we are in discussions with regulators about this. We also evaluate options to decentralize the site, the study, which means allowing treatment near clinics, so saving on the travel cost or reducing the burden to the patient, from the perspective of the treatment and also aiming to replace some site visit with home visit again to reduce the burden of the study. The other important challenge we are facing of course is recruitment and this has been followed for a long time in these meetings. The background to this is that CCR, cholangiocarcinoma, is a rare disease. And it's not only that it's rare, the release trial targets subpopulation of perihilar and distal cholangiocarcinoma, so even harder to find these patients. Now, this is known, and we planned the study accordingly. And we took this into account when we selected the number of sites in all our assumptions. So this is known and was planned to be mitigated with the number of sites. However, this study, the release study, shortly after the release study started, started COVID that definitely was not planned for. And this affected both the patient and the clinicians and it's Difficult to quantify, but we definitely hear clear feedback from investigators around the strong effect of COVID from the beginning. And this changed over time. Initially, it was this unknown and how to deal with it. But now that it's known and there are more patients vaccinated, there are still substantial effect on sites. with hospital shifting resources and increased workload on healthcare staff, which affect all clinical trials, but more trials like release where patient require in-hospital procedure. It is challenging in our settings where a rare disease and the pandemic to maintain momentum. Momentum in recruitment is really important so that investigators don't forget about the trial, don't forget about the protocol. They develop confidence in finding the patient and doing the procedures. And in our case, where there was stalling of recruitment for a long period and now slow recruitment, this is difficult to develop. So maintaining the momentum is one of the challenges. The interdisciplinary coordination that is required in release, because we have both infusion of chemotherapy that is many times done by medical oncologists, and endoscopy that is part of the procedure of illumination, makes it much harder during pandemic, where everyone, the resources are stretched, and everyone is stretched to the maximum with other tasks. And then the last point that is part of our design, we anticipated it, but it is still, we hear this feedback often, is about the 50%, because Rayleigh's randomizing one-to-one ratio, patients have 50% chance to end up in the control arm, and they perceive the control treatment as inferior. And with this, um patient and investigate or may choose to pursue other investigational treatments for example or reduce the burden and get the standard of care next to home rather than getting into a trial so this is another challenge that we are facing and changing from one to one we are not going to get into the statistics of this but Randomizing, like many other studies do in these settings, they randomize two to one or three to one. For every two patients that go into the investigational treatment, one patient would go into the control arm. But this requires a larger population to achieve the same power of the study, power to analyze the results. And in the setting of rare disease, this is very difficult to achieve. Now, our strategies are, we have started these long ago, of course, once we recognized the challenges and the pandemic started. We optimize, we are optimizing, we optimize the eligibility criteria and study processes based on the feedback that we get from investigator and from experts in the field. We frequently interact with sites trying to or aiming to maintain this momentum, keeping the investigator involved in the trial, knowing about what we are doing, reminding them about the procedure, providing them training as much as needed. So we are in constant interaction with clinical trials. We provide the support to sites and patient to help make this easier for everyone involved. And this requires much effort all the time, and it's taken care by the team at PCI Biotech and the CRO, the clinical CRO that we have. We are also working with patient organization and online initiatives to increase study awareness. This is important, but it has not... brought the effect that we were looking for. It is dependent on the way that patients are identified for clinical studies, and in this rare disease of cholangiocarcinoma with the network and treatment in hospital, this potentially has less effect on recruitment. Importantly, it's difficult to quantify, but we do believe that conversion into a hybrid control arm is going to have an effect on recruitment through elimination of the challenge to be randomized to the control arm. In this case, if this is implemented, all patients will be randomized to active treatment and therefore will have greater incentive to get into the trial.

Next pair. This was for me about retention and recruitment. Yeah. Yeah.

Can you hear me?

Yes, now we can. So now we will move over to the Femavac study, where we have some really compelling preclinical results and particularly strong T-cell and CD8 T-cell immune responses in the preclinical setting, which has also been successfully translated into humans when we look at peptide and protein based vaccines. And we have a really versatile vaccination platform because it can also potentially be used in several other modalities including nucleic acid based technologies. We have done the phase one study with some really good results and what Amir and I will be talking about is the next step and what we are planning to do with the FEMAVAC technology. So back to you then Amir.

Thank you Per. We have worked in the last since the completion of the phase one study with healthy subject we have worked assessed evaluated the best way forward with the FEMA back program and we now have a plan that is based on the strategy that is common in oncology clinical development to start small and build upon the results. The selection of indication and the population for us is important because the goal of this study that we are going to have, although small, is definitely to see hint of anti-tumor activity. The goal is not scientific from the perspective to show immune response or some biomarkers, but actually to demonstrate that with the product that we develop, one can see shrinkage of tumor. And the study is designed, although small, primarily to be able to assess anti-tumor activity. We are going to start with one specific cancer type that we perceive to have the highest likelihood of response to our treatment and has also high unmet medical need. Our approach is to combine different therapies to achieve maximal immunotherapy effect. And for this, we have worked for some time now. with large or with a large form of international experts that we have been in fairly intensive contact for the last year or so over the year.

Next, please.

So just in short, what the study is about, the study treatment that or the product that we use and additional treatment in the study is a combination. And we look for combining relevant immunomodulation therapies that will fit one with the other to generate maximal immunotherapy as a whole treatment. Fumaporphine and a mix of relevant peptide antigens and a synergistic adjuvant will be included in the product. This is the PCI product, and this study treatment is going to be administered intradermal, primarily, and intratumoral, where possible. The study population is a patient with recurrent or metastatic solid tumors who progressed on first-line immune checkpoint inhibition therapy. And that means that we are developing this treatment as second-line treatment for the indication. And these patients are, this is a later stage of disease that is common and usually the place where new treatments start the development. The overall aim is to convert cold tumors into hot tumors and achieving long-term response to checkpoint inhibitors. That is a well-known goal for immunotherapy. Immunotherapy has limited number of patients that respond to the treatment But patients that do respond, many times respond for a very long time. And the goal for us is to expand this population that responds to immune checkpoint inhibitor therapy. This is the goal of this study and the combination and the design of the treatment. What we plan to do from study design is a two-stage study, starting with a small cohort And based on the result, expand to a larger cohort to verify or confirm the results that we see in the smaller cohort. We plan to start the study in Europe and expand upon the results to the US. And currently, what we are doing, we are developing the study protocol. We work on the drug product. and operational activities. And we also established a network of clinicians, the investigators that are going to work with us during the study. We engage them already at the early stage of the design, involve them in the development of the protocol, and overall increase the engagement of the core team of investigators into this program.

Thank you, Per.

Thank you so much, Amir.

This was then the clinical review. And we will now move over to an operational review of the preclinical part. And for this, Anders Högseth, who is the chief scientific officer and is here in the room, will come up and do this presentation. So please, Anders.

Yes, hello, everybody. The focus of this preclinical review will mainly be on using PCR for nucleic acid delivery. As you will know, nucleic acid is a rapidly growing therapeutic area with a very high potential and also now with several products coming up. Everybody knows the success of this technology in COVID-19 vaccination, of course. But there are also other products, for example, recently approved products of Densma for treatment of spinal muscular atrophy. And there are also several other products coming up. And these are, in a way, on both ends of the scale. While COVID-19 vaccination is mass vaccination with a quite low price per vaccine, the other treatments are very highly priced treatments in small patient populations. Despite these successes, the potential of nucleic acid therapies are by no means realized as yet. There are many other diseases that could in principle be treated with nucleic acid therapies, but still delivery of nucleic acids to the target tissues is the main barrier for realization of this potential. As you know, lipid nanoparticles work well for vaccination purposes. There are also technologies for delivery of nucleic acids to the liver. But for other tissues, good delivery technologies are mostly lacking. And also, the optimal delivery solution will probably vary between different tissues. That is, you use one technology for delivering to muscle, one to tumors, and one to the heart, for example. So there is a large area here still to be explored. And as I will show you now in the next slide, PCI is a technology that can both enhance and direct nucleic acid delivery to target sites, of course, to sites that can be illuminated. And these such sites can be both on the surface or on the inside of the body. For example, to the skin and to tumors, as I will show you now. Yeah, I can do this myself then. This then shows using PCI for mRNA delivery to skin. What we use in these experiments is an mRNA coding for an enzyme called luciferase. which is the enzyme that fireflies employs to generate light. So if the delivery of this mRNA is successful, you will have an area in the animal just making light. And we do this in mice. We inject this mRNA into the skin, and then we can image the mice afterwards to see if they produce light at the injection sites or not. And as you can see here are two parts of two mice anyway, where we have injected the mRNA into two sites. One is the control sites, the blue or the black squares in this case, and the other are PCI-treated, the red squares. And as you can see, we get the significantly enhanced delivery and expression of these mRNA in the PCI-treated sites. And if you do a more quantitative analysis of this, as you can see to the right panel, as compared to the naked mRNA we used in this case, that is mRNA without any lipid nanoparticle or other formulations, we got about a 30 times enhancement of the mRNA delivery employing PCI as compared to naked mRNA alone. So this is a very good result. It shows that we can improve delivery of naked mRNA, which is also pursued in several areas and by several companies. In the next slide, I'll show you another comparison, and this is to comparing PCI with naked mRNA, in this case to lipid nanoparticles. This was a collaboration with AstraZeneca, who provided us with the mRNA and with the lipid nanoparticles. And this is then for intratumoral delivery. We did the same type of experiments as I showed you in the previous slide, injected mRNA into the tumor and assayed for light production in the tumor. And firstly, if you look at the light produced inside the red and yellow circles in this slide, you can see that much more light is produced in the tumors injected with naked mRNA and PCI treated than what was achieved by using the lipid nanoparticles. So, PCI with naked mRNA in this tumor model is significantly more effective than lipid nanoparticles. The other thing you can see is that in the PCI treated tumors, the expression of the mRNA was strictly confined to the tumor inside the area we illuminated. While with the lipid nanoparticles, you can see that you have expression also several other places in the animal This shows that the lipid nanoparticles leaks out into the tumor and probably goes into the bloodstream and ends up among other things in the liver. As you can see also in the bar diagram to the right here, we have also taken out the liver and tumors after treatment and assayed for the activity of this luciferase enzyme. And if you compare the blue and the red bars here, which is LNP delivery to tumor, either to tumor, which is the blue, and LNP expressed in the liver. You can see that the expression in the liver was at least as high as in the tumor. While with PCI, you can see two things. Firstly, that the expression in the tumor is significantly higher than in the tumor with the LNPs, as also shown on the picture to the left. But the other thing you can see is that there were no expression at all in the liver. You can barely see the small bars to the right of the brown bars here, showing that the expression in the liver was actually non-existent with PCI. And this is very important because especially, for example, for tumor treatment, what you want to deliver to the tumor is mRNA molecules expressing potent molecules with a potent biological activity. Often, for example, enhancing immune responses and stimulating the immune system. And you really don't want this to happen in the liver where it can generate very serious side effects. So this shows that PCI both can enhance delivery of mRNA and also make it possible to get a strictly targeted delivery. This just sums up the experiments we have done with mRNA delivery so far. In addition to the delivery to skin and tumors, as I've shown you, we have also showed that PCI can enhance mRNA delivery to muscle. As you can see here, also the best effects we have got so far is in tumors. We have two different tumor models here showing between 40 and 50 times enhancement of the delivery of naked mRNA, and also compared to LNPs, lipid nanoparticles. So we want to explore this further, both in collaboration with other companies, but also internally in the company, focusing more on our own research in these areas to try to exploit the most promising areas of PCI for nucleic acid delivery. Of course, there is a limitation that it is a local delivery. We can only use it for diseases where a local delivery can give a proper therapeutic effect. This is a limitation, but it's also an advantage in a way that we are able to keep the effect locally, as compared, for example, to LNPs, where you can see that you've got also off-target effects. There are also many applications where a local effect is desired. This can be delivery, for example, to skin, tumors, muscles, eyes, joints, lymph nodes, and as you can see, there's a large area here that can be explored. And we have then chosen to focus our internal research on two different areas. One is intratumoral immunotherapy, which falls under the hat here of because it's kind of a vaccination technology. As I've shown you already, we have very good results for mRNA delivery to tumors in animals. And also for tumor treatment, even as they call it complicated technology like PCI can be employed many different places in the body. I mean, if you want to treat a tumor, you can clearly envision also to illuminate tumors inside the body, for example, although it's practically a little bit more complicated. The very attractive thing about this type of technology is that you treat one tumor, but what you aim for is to have an effect also on other tumors in the body. In a way, you use one tumor to generate the vaccine that will also work on other similar tumors in the body. So this, in a way, represents kind of a vaccination where you deliver some things into a tumor, making the body recognize the tumor as foreign and generate an immune response to this tumor. And this might be kind of, you might deliver mRNA encoding antigens as you use for a normal vaccination, but also what you do here is to, for example, use mRNAs encoding immune stimulating factors of various kinds. So this is an area that is actively pursued in clinical studies by several other companies and academic groups, and we have a very good and interesting ongoing collaboration here with a Belgian company called Etherna, which is a well-known company in this area, developing intratumoral and other mRNA-based tumor therapies. The other area we will focus on is the so-called easily illuminated conditions. These are, say, less complicated treatments in a way. What we envision here is to treat, for example, lesions on the skin. It could be in the eye and other places where it's easy to illuminate the body from the outside. And here we have also a very interesting collaboration with a Korean company called Olix, which are focusing on scar revision and also on eye treatment and several other interesting areas. And as I've already shown you, we have very good results for delivering mRNA to the skin. So we have a solid preclinical basis for focusing also on this area. So what we aim to do then within these areas is for the intratumoral immunotherapy. We will actively, proactively develop the technology further to optimize it and also seek further partnerships based on the current data. And as we've already seen, we have interest from Eterna and there are also several other companies that are very relevant for this type of therapy. Here there are also possibilities in a bit longer term for generating our totally own products because we have a good patent on using PCI for mRNA delivery that could be explored for own patents. Regarding the easily illuminable conditions, we will also actively develop this technology further. For example, regarding generating light sources and that kind of thing for practical use of this technology on body surfaces and easily illuminable areas. And of course, we also develop this technology with collaborators as we already do in the OLX collaboration. Okay, thank you.

Thank you.

Yes, thank you Anders. Hello, my name is Ronny Skugedal and I'm the CFO. So just a brief touch upon the financial figures. Here, other income, meaning public grants for the quarter, 1.1 million compared to 1.9 last year. And that is mainly due to this FIMAVAC BIA program ending June this year. So from now on, we currently have the Skattefund public grant with a level of 4.8 million annually. And this grant was received late September this year compared to early October last year. That's why it's impacting the cash flow here on the bottom. And also the operating results, minus 22 million in line with last year. And we have for the last year or so had a cost base of around 20 to 25 million minus each quarter. And this cost base can easily be estimated to give us a financial runway into Q4 next year. And yes, so the cash position, 135 million, and no other major changes. Yes, Deb.

Thank you, and thank you, Anders, also for this presentation about the FEMA NAC and the possibilities in nucleic acid therapeutics. So what I am to do then is just to summarize. This has been quite a long presentation, and I apologize for that, but I hope it has shed some light on the interesting areas where we are working. So for FemaChem, it's really to progress the development in biolog cancer towards marketing authorization application. We have the release study which has an interim analysis for potential accelerated approval and this is studies ongoing across three continents and we have implemented an improved trial design with relation to eligibility of patients and so on, and several initiatives to optimize execution during the pandemic, as you've heard details from by Amir today. And we are also proactively pursuing strategies to address recruitment and retention challenges going forward, also in relation to study design changes that require regulatory acceptance. So we are in interactions with both the FDA and the EMA around this. We have established an IDMC which will have their first safety review and that is of two treatments to see whether two treatments is safe and that is expected before end of the year. And we also have then the interim analysis for a potential accelerated approval which is expected second half 23. And now you've also seen that with Fimavac, we are moving ahead towards a clinical proof of concept study, building on the phase one results that have been published this year within frontiers of immunology, showing that we have very good immune responses also in man with this technology. And it is a versatile technology that can be used for many different things and it's also available for partnering and licensing. And our collaboration with Etherna is actually under the FIMAVEC umbrella because this is where we can use this for immunotherapy in intratumoral treatment. And then for FIMANAC, as I hope you heard from Anders here, there is really a good potential to direct and really constrain the effect of these drugs to specific areas by using the PCI technology. We have presented encouraging mRNA data this year. We have established a new extensive research collaboration in RNAi, interference technologies for RNA, with OLIX in South Korea. And we are now, as explained by Anders, actively centering our internal research efforts towards the most attractive applications. Instead of just letting collaborators work with the technology, we are now focusing in to where we think and where we have seen from our collaborations we have the best opportunities. Okay, so with that, thank you for your attention. We will now go over to the questions and we will start with questions from the audience. We will then go to questions from callers and we will in the end, if there is time, look into questions from the webcast as well. We will probably go a little bit further than just one hour because we have we have only a few minutes left so but please sort of be concise and Both in the questions and in the answers, okay So first question from the audience No questions from the audience

Could you maybe say something about the recruitment in the USA? Is it the same issues like before or is there any progress?

The recruitment in the US is challenging. It is more challenging than in other areas. This is not an area where we expect a lot of recruitment because we don't have many sites there. And the prevalence and incidence of the disease is not as high. But we are still having challenges in relation to these investigators being able to find the patients in the current situation that they have in the US.

One more question was, there was mentioning in the FEMA camp that you could possibly look at other studies on the control arm for looking at patient groups and how they were affected instead of using the control arm. Could that be also retrieved from the studies where the results are now coming in from the other studies going on now?

No, this is studies where the data is owned by the companies who are doing the studies and I doubt very much that they will allow us to have those data. So we will need to go and look for clinical trials that have been done by academic institutions and there's a lot of data available there and there is also networks with databases that are available. Thank you.

First, I would like to thank you for a very good and very interesting presentation. The chairman of the board, Hans Peter Bern, has said that there will be a change in communication. I think we have clearly seen that today, and I very much like the new format for this presentation. Thanks a lot for that. Just following up on that, will there be more changes in the communication strategy compared to what we have seen today here? Is there anything else you would like to add to what's going to happen in the future?

So in relation to the communication strategy, I mean, this quarterly presentation, we will not bring in Amir and Anders for every quarterly presentation. But I think it's good from time to time to have this. We have more deeper insight to specific themes. We will also look into other ways to communicate with you to make sure that you get a good and deeper understanding of what we're doing. We will focus more on the communication strategy around this than we've done previously based on the feedback that we have from the shareholders on this.

It was said in the presentation that you have been in contact with FDA and AMA about chasing the release study. I guess you said in what you sent out this morning that the answer from the authorities so far has not been positive. Do you have any backup? Are there any other things you could do with regard to solving the retention problem that were presented to FDA and AMA so far?

What we are discussing with the regulatory authorities is primarily the potential use of external control patients. Because that would clearly solve the retention issue and may also help on the recruitment issue. This is the thing we are discussing with them. So decentralization is something we're looking into and evaluating and is based on what Amir talked about today. But there are no, I think Amir very well reviewed the opportunities and the possibilities that we have in this area.

Anders Högseth went through some of the results from the FIMA-NAC work that had been done in the past. This seems to be very good. He also talked about, I guess, what you are doing internally together with two companies. But I was wondering if Anders Högseth could say something about, I guess, the feedback he gets when he's out presenting these things from other companies. How are the industry receiving, I guess, the result that you have achieved so far? So is Andrew's microphone active?

Yeah, OK.

Yes. I mean, of course, there are a lot of complex work. No, no, his microphone is OK. of course there are a lot of companies working in this area and what we see is that there is a great interest from from several companies i mean it depends also of course where you are working for for companies working with prophylactic vaccines like covet 19 there are probably nothing we can do to help it because it works well and and it's not the area we want to focus on but intratumoral immunotherapy for example there is a significant interest from other companies like eternal but also other ones and also for this kind of more superficial treatment of scars and also in the eye, there are many companies that are interested in developing our technology or testing our technology. So there's great interest, but of course, it always takes time to establish new collaborations. There are a lot of things that has to come together to make such collaborations successful and to get them started at all. But we are working very actively on this. We contacted many companies, also from the business development side, of course.

We have strengthened also the business development with one new person because there is a lot of activity going on in that area. And I think it can be summarized to yes, we have some really interesting results and there is interest out there.

Good, yeah. I'm also glad to see that the FEMAVAC arm seems to move forward. Could you say something about the cost? I guess it's going to be a two-stage approach to this. Could you say something about the cost? I assume the cost for the first phase is probably not going to be that big. It's something you're going to do yourself, so you have to cover the entire cost yourself. Could you say something about cost, potentially timing of when you are starting up this? Is it going to be this year, first half next year?

So I think what was on that slide was timelines to be announced and I think that is where we will keep it because things need to be sorted out before we go out with timelines on this. But we are actively working on this and we are progressing those activities we can do without large financial commitments. When we have sorted everything, we will come back to more information about this. But this is to show you that we are actively working internally and with external experts. And we have what we think is a very good plan for how to move this forward.

Good, yeah. You have earlier said there will be published a paper together with AstraZeneca about the work that you did together here. When do you think that the paper will be published and are you getting the expected contribution from AstraZeneca? Are they spending the necessary time on putting this paper together?

I think first of all, We don't want a guide on when things are being published because sometimes this takes much longer than you think. But this work is ongoing and we absolutely get the good work together. This is Anders who is doing this. I don't know if you want to add something, Anders, but we are working closely with them to do this and we get absolutely the support and the work from their side that is required.

Okay, good, yeah. You don't have enough money to continue the release study to the dream analyze. How much additional money do you think you need to get there?

Since we have the CFO in the room, I will pass on this question to Ronny Skogedal.

Yes, and as usual, we need to come back to that question when we know more about how the release study evolves.

You talked a little bit about AstraZeneca cancer study. We haven't got any data so far, so I guess it's difficult to say anything about what kind of competition you'll get from that company. Are you worried about how it's going to potentially affect the approval process?

Not necessarily the approval process. I mean, it all depends on the data that comes out of this, and specifically the data in the patient population that we have. So, I mean, pipeline developments within... Oncology and within pharma in general happens all the time and the bile cancer has really been sort of lacking good progress in the last 10 to 12 years. Nothing has been approved more or less. Now recently we've had the intrahepatic that has been approved, two different compounds, one for FGFR and one for IDH. And now, despite what has been sort of not very good results early in checkpoint inhibitors, there is one that has apparently had good results in the overall setting with more or less a basket study with four different indications. How the authorities will treat this will probably depend on how big difference there is between the different subpopulations. change in the potential hurdle we see to get the approval. So it's impossible to say anything about this really until we see results of the study. But it can affect, if it's very good in our in our patient population, then the hurdle that we need to match or pass is getting increased, so to speak. But it doesn't mean that it's impossible to do the study. If we have as good result or better result in the specific patient population, that should be a basis for approval if the safety and everything else is fine.

You have been looking for a partner for the release study in Asia for a long time now. We have talked about that several times before. In the Q2 presentation you said that you are working actively to find a partner and you want to find out this as soon as possible if you could find a partner for the release study in Asia. Could you say something? interest at all, I guess, for being a partner for release in Asia? I was hoping that. I know you have to be careful with what you are saying here, but you know.

Yes, there is interest. I will stop and say that there is interest, and I say no more on that. But there is interest.

Thank you, and thanks again for a very good and interesting presentation.

Thank you. And then... I guess if there is any more further questions from the audience? Do we have time for a couple of questions from the call?

Yes, sure. Thank you. Ladies and gentlemen, if you would like to ask a question, please signal by pressing star 1 on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. We'll now take our first question from Adam Carson from ABG. Please go ahead, sir. Your line is open.

Hi, thank you very much for taking my questions. Just a few, if I could. Firstly, if you're able to comment on the geographical split of the HSO patients recruited so far in H221 and yeah, I'll stop there.

So we are giving, we have now changed our communication because we have seen challenges in the pandemic that has continued much longer than we expected. We want to now to provide the full transparency into those challenges and therefore we changed the communication strategy with regard to that and are now talking about how many patients we are getting and a total recruitment. But we will not go into details on geographical splits. That's where the limit is today. We can tell you that we have challenges in the US. Looking at how many sites we have in Asia versus Europe, Asia is the best contributor. That's what I can tell you.

In terms of the IDMC safety review occurring now in Q4, that would imply around 20-25% of patients recruited to the trial having received two Fumacam treatments. Is that your rough conclusion as well? And how does that compare to your expectations or hopes or so?

I'm not sure how your calculation came to 25%, but it is more or less so that all patients that could have had two treatments have chosen to get two treatments. So it's because some patients go out or cannot have the second treatment for different reasons, but most patients that could get the second treatment actually have got the second treatment.

Okay, yeah, no, I mean, I'm looking at if we know that the first eight patients who received two Femachem treatments triggers the IDMC safety review and based on how many patients recruited today and how many might be recruited in Q4, That's how I get to 2025, thereabouts, as a rough approximation.

Much more actually. It's much more than that, but that's fine. We can come back to that at some other stage. I don't have the details on this.

Okay, but it is higher than that, receiving two FIMA chem treatments. Alrighty, okay. And a question on Patients who withdraw soon or immediately after randomization to the control arm, how are those patients managed sort of in terms of the inevitable statistical analysis? And as part of that, if such patients are included or are not included, can you say anything in terms of how many of the 30 patients recruited so far or of that kind that were kind of immediately withdrawn and not very useful in terms of the data analysis?

So we are not going into details on this, but I think, Amir, maybe you can talk a little bit on how we handle this from a statistical point of view and what we're trying to do to get data out of these patients.

Yeah, sure.

So patients, when they decide to not continue with the study, they have several options in front of them. And the first is to withdraw consent, or continuing in the study and withdraw consent for follow up of overall survival. These are the two options. We do everything we can to allow patients to stay in the study with minimal burden. And For this, we offer the patient to, even if they don't want to receive the standard treatment within the study, we offer them to stay in the study and to follow them with imaging that will let us know about their status of progression. Now, patients that withdraw consent will be censored from the analysis. They will be included but censored. Patients that remain despite deciding not to receive the standard treatment within the control arm, but decided to stay within the study. and to be followed up with imaging, will be just followed and be used as any, their data will be used as any other patient in the study. There are some sensitivity analyzes that have been implemented in the statistical analysis plan to handle this almost hybrid situation. But this is what we do with this patient. Patient that we drew consent, we have two sensor analysis and patient that allow continuation of follow-up. The data will be used as any other patient, but with knowledge of their standard of care treatment.

Okay. And in terms of the patients that do withdraw, is the sense that... of what proportion roughly or so would be still agreeing to being followed up for progression or so. Is it a very small portion that are allowing that or is there any meaningful

So the numbers are very small right now. And as you understand, proportion of small numbers are basically meaningless at this stage. So we are not going to provide proportions or numbers. The absolute numbers are small. We are following on the pattern and we are doing what we can to maintain the discontinuation at a level that would allow us to analyze the results. But we are not going to provide the proportions or numbers at this stage?

It's too early to put it that way. The numbers are so small that it's not meaningful.

Alrighty, thank you.

Thank you. Any further questions from the call?

It appears there is no further questions at this time. I'd like to turn the conference back to you for additional closing remarks. Thank you.

There is an additional question in the audience, it seems. So I don't think we have time for questions from the webcast unless there is specific things that Roni think is very important that we cover and that has not been covered at all. But we have another question and last question from the audience.

A final question from me. Many companies have Capital Market Day. You had one back in 2016 that I think was very successful. Are you planning on having another one? I guess today we get a lot of disinformation compared to what we get. But are you planning to have one in the near future?

You're looking over to the chairman, but he doesn't have a microphone, and maybe I should answer the question.

You can try to answer the question if you want to. I guess the reason I ask that, I understand, when you read tech investors and things like that, there is a lot of, I guess, mistrust maybe to management and things like that. And I think maybe a potential capital market day where you talk

more in detail you have invited guests and things so people could ask questions in Norwegian maybe that will increase the trust and you know better the communication and things like that so maybe something you should consider to have yeah so and we are considering it that's what I can say so this is part of when I said that we're looking into what we can do with communication we're also looking into how we could sort of provide the more deeper insight to what we do through other forums and in other ways So that's part of it.

Thank you.

Okay, very good. Thank you all and thank you to the audience for coming here today. And thank you for your attention.