Imunon, Inc. (IMNN) Earnings Call Transcript & Summary

Good day, and welcome to the Imunon 2023 Virtual R&D day. [Operator Instructions] Please note that today's event is being recorded. I would now like to turn the conference over to your host. Please go ahead.

Good afternoon. I'm Corinne Le Goff, I'm President and CEO of -- Imunon is a clinical stage biotech company that is focused on harvesting the power of the immune system, as you can see on my slide. I'm here today from Imunon with Dr. Khursheed Anwer, who is our Chief Scientific Officer. Please take a few seconds to look at our safe harbor statement. So I'm very pleased to welcome you to our first R&D Day. I will start this meeting with a short introduction of our company, our technology, our strategy and our pipeline. But then we are going to talk about exciting science. Imunon is developing a proprietary nonviral DNA technology platform in immuno-oncology and in infectious diseases. And we are going to focus our conversation today on the future of prophylactic vaccines and on the remaining unmet needs in immuno-oncology. So I'm thrilled to welcome as our speakers today to imminent physicians and scientists and leaders in their fields. Dr. Sallie Permar is the Nancy C. Paduano Professor and Chair of Pediatrics at Weill Cornell Medicine and its Pediatrician-in-Chief at New York-Presbyterian Weill Cornell Medical Center and New Presbyterian Komansky Children's Hospital. Dr. Permar has done a lot of work and with our team in the prevention and treatment of neonatal viral infections. And Dr. Patrick Ott is also with us today, and we'll talk about the remaining [unmet needs] in immuno-oncology. He is the Clinical Director of the Melanoma Disease Center and the Director of Clinical Sciences of the Center for Immuno-Oncology at the Dana-Farber Cancer Institute. He's also an attending physician in the Department of Medicine at Brigham and Women's Hospital and is an Associate Professor at Harvard Medical School. And Dr. Ott and his team have worked and published on the development of cancer vaccines since really the beginning of this vaccinal approach 10 years ago. So we believe at Imunon that our technology is transformative and certainly will be the key driver of the future of global medicines. Now you should look at our nonviral DNA technology as a toolkit, right? And that has the potential to be developed across many [indiscernible] areas and many modalities. Now we have chosen to develop our technology across four modalities. We have modality called TheraPlas, which is for the expression of cytokines with one clinical program right now in Phase II. PlaCCine is our modality in -- for the next generation of prophetic vaccines. And then we are now developing two new modalities, one called FixPlas, which is for the development of off-the-shelf cancer vaccines. So tumor-associated antigen vaccines. And the next step will be the development of IndiPlas, so going towards the development of personalized cancer vaccines with neoepitope cancer vaccines. Our strategy is built to become a fully integrated biotech company. We are a very focused organization. So our focus in immuno-oncology with the cytokine's coding and cancer vaccines is an opportunity for us to develop assets we have the capabilities to do so. Our focus on infectious disease is -- it is about coding for pathogen antigens and developed vaccines not dissimilar to what mRNA has done with COVID-19. This modality is for us an opportunity for partnerships and out-licensing opportunities. Now an essential element of our strategy is the vertical integration of our -- of the core elements of our business, like production of our plasmid or production of our facilitating agents. And we've just, in fact, unveiled our CGMP manufacturing in Hanesville Alabama, so we all know we have the capability for in-house early development for our vaccine programs. We also focus on establishing value-accretive collaborations. And this is really the bedrock of our business model. And you might have seen, if you have followed us that over the last year or so, we've placed a number of partnerships to expand our R&D capabilities. And finally, I want to mention here that we are always on the lookout for potential asset acquisitions in areas that are adjacent to what we know and what we do to our dominant expertise. And that's the way for us, of course, to balance the risk profile of our portfolio. Now I will show you a slide -- that my last slide, as part of this introduction. To show you that we have a strong balance sheet that supports the strategy into 2025 until the end of 2024. So we believe that our technology has advantages. I'm going to start with -- our focus on prophylactic vaccines as we want to develop and be positioned in -- for the next generation of vaccines. And we believe that our technology can address a number of shortcomings of the current technologies that are commercially available. When is there ability of protection? It is absolutely essential to ensure that you don't have to get a booster shot every 6 months. And here, maybe the DNA has an opportunity. What we see with DNA is durable antigen expression that potentially can induce robust immunological response. And we have preclinical data to show that. Another important criteria for the next-generation vaccine is speed, and we've definitely learned this with the pandemic. Like similar term mRNA, DNA is a platform, and we have the ability to go from the sequence of the antigen to the clinic, to an approved product potentially in record time. So that's extremely important. And finally, I want to mention the flexibility of the manufacturing here. And DNA, again, is very interesting because it is stable and has a long shelf life at workable temperature. So obviously, it simplifies all the handling and distribution of vaccines. And the flexibility of manufacturing means also greater capital efficiency for us. Now when it comes to cancer vaccines. You can apply that the day that I talked about two cancer vaccines. The durability of expression of the antigen expression, potentially calls for potent T-cell response, and the fact that our technology is -- doesn't require a virus. It's a nonviral DNA technology, means that you have the potential for repeat administration, which is obviously important in the treatment of cancer patients. Now DNA again, is a code. So with FixPlas we could [indiscernible] [three of] antigens and with IndiPlas we got for individualized antigens or individualized and personalized neoepitopes. Here is the state of our pipeline today. As I mentioned earlier, we have a clinical program in ovarian cancer. It's for the expression of an IL-12. It's an intraperitoneal. This is a Phase II program that will read out next year in Q3. We also just started a new Phase I/II program with the same asset, IMNN-001 and this time in combination with bevacizumab in the same population of patients. And this is a partnership with the Break Through Cancer Foundation. Now for PlaCCine modality, we are getting ready to file an IND early next year for COVID-19 seasonal vaccine. And we just announced a partnership with the NIH and NIA, National Institute of Allergy and Infectious Diseases for the development of Lassa virus vaccine. And for FixPlas modality, we are developing a Trp2 [indiscernible] tumor associated antigen in Melanoma. It's IMNN-201, so of course, we are at a preclose stage right now. And based on proof of concepts here that we are going to establish before the end of the year, we'll go forward and work on developing our next modality that will be IndiPlas. Now as I said, we have enough cash on the balance sheet to support our strategy and to lead to key milestones over the next 12 months. What you can expect is for IMNN-001, so the IL-12 in ovarian cancer, you can expect interim data in the next few weeks. And the final top line results in Q3 next year. And we will also certainly be in a position to produce interim results for the combination trial with bevacizumab. For the vaccine programs, as I mentioned, we'll file our IND early next year and start a Phase I/II program. And then this year, for IMNN-102, the Lassa virus, we are starting in [indiscernible] phase with working together with the NIH. And for IMNN-201, so the trp2 IMNN-201 assets, we should be able to generate proof-of-concept data this year. So stay tuned for more information on very important phase and value-creating activities. With this short introduction, I have promised it would be short, but I really want to make sure that we have the time to talk about the science. I'm very pleased to turn the call to Dr. Sallie Permar. Sallie?

Thank you, Dr. Le Goff for having me. And yes, we definitely need to prepare for what are certainly going to be new pandemics and this platform is an exciting one. So I'll start with the first slide. Can move on? And I just have some disclosures that I do consult for a number of companies, mainly focused on the development of a cytomegalovirus vaccine. So next slide. So we all lived through the SARS-CoV-2 pandemic and really started a new era for vaccine development in that relying on nucleic acid-based vaccines, where the cells produce the antigens for us, had a major advantage over either viral-based or recombinant subunit vaccines. Next slide. And however, that is very much in contrast to a disease that I have spent a lot of my career working on which has been in need of a vaccine for -- since as long as we know that, that congenital CMV has been going on, which is millions of years at this point. It's a very common congenital infection with one out of every 200 live babies born with this infection. There are 40,000 cases in the U.S. annually, but it is throughout the entire globe, and it costs $4 billion of U.S. healthcare dollars. It is the leading infectious cause of neurologic deficits, including 1/4 of all infant hearing loss. And for all these reasons, it's been a tough tier priority vaccine from the National Academy almost for over 20 years. And on the next slide, you can see all of the different vaccine platforms that have been applied to this virus. But so far, only partial effectiveness has been achieved by either a subunit vaccine or impaired virus sector. And so this is an example of an endemic pathogen that we have needed a vaccine for many years, but now we have new exciting opportunities with DNA and RNA technologies to be applied to it that can be rapidly iterated and iteratively modified in order to really achieve efficacy that's needed. So the next slide. We know that the rate of pandemics is increasing, that there's no doubt about that. Because of globalization and global travel, et cetera. I was just seeing today, there's a Nipah outbreak in India being reported. So these are going to be upon us and the NIH and WHO have both made a list of their -- the viral pathogens in particular, that are going to be likely to create pandemics. And therefore, we should be developing vaccines not after they hit but ahead of when they do. And on the next slide, though, really, that's alongside the need to develop a number of vaccines for pathogens that we already live with, that were -- have been pandemics for hundreds and thousands of years, and we need novel technologies to address these as well. So on the next slide, you'll see that we also have a change of demographics going on in our population where those individuals who are more vulnerable to infections, is increasing in not only U.S. population but other developed nations, where the number of elderly patients has increased dramatically over the last 50 years. And then also the number of patients that are on immunomodulatory therapies is also increasing. And this, again, is a vulnerable population for any new infection but higher ones as well. And then another vulnerable patient on the next slide, population is pregnant women and children. This is an area where I focus, pregnant women and lactating women are often left out of vaccines in the early phase development of vaccines, and this really limits the innovation when so many of the newer viruses or even viruses we have lived with can be more severe or cause issues in the fetus. And then developing vaccines for children is very specific as well as we saw in SARS-CoV-2 pandemic needed specific dose ranging. And -- but it was a health disparity that children didn't have access to the SARS-CoV-2 vaccine for any months and year even after the rest of us did. So on the next slide, what I think of as the ideal immunity for what novel vaccine platform should be seeking is to be able to vaccinate in early life when pediatricians are very good at getting their patients into their care and vaccinated, especially with multi-dose vaccines. And then that illicit immunity that is going to be protected for the whole lifelong. The best example of this is the hepatitis B vaccine which is given on the birth visit in the hospital with the first dose. There are two subsequent doses that come within the first 1.5 years of life. And this is a neonatal transmitted infection as well as one that can be acquired later in life. And so there is even a combination of a passive antibody approach that is a type of vaccine and then active vaccination as well. So this is a lifelong protection that's provided by an early-stage vaccine. So -- but on the next slide, I kind of laid out two advancing areas that I see in the field of vaccinology because of these nucleic acid-based platforms that are really transformative. And I think Imunon has an opportunity to put their platform into the mix of what an mRNA LNP vaccine was able to do. So two areas that I see developing in vaccinology is the increased use of reverse vaccinology. Reverse vaccinology is when you isolate a specific type of antibody or immune response to a pathogen from a previously infected patient, and you prescreen that patient to see that they developed the right type of response that would be potentially protected. And then you design antigens that can bind to those antibodies, that then becomes the immunogen of the future. Those types of strategies were used for the RCF and for SARS-CoV-2 antigen vaccines. The other area that's increasing, and we saw this with SARS-CoV-2 as well, is passive immunization. So passive immunization is providing individuals with a preformed antibody. And this we're seeing with the new infant RSV vaccine -- become into the clinic. And here, we have a much greater ability to design monoclonal antibodies that are both potent as well as long-lasting, and even better than having to IV infuse them, which was the bottleneck for using monoclonal antibody technology in the SARS-CoV-2 pandemic if they can be vectored by RNA or DNA technology, then you don't have to rely on IV infusion capabilities. Next slide. The way that now we see vaccine science developing is that often an antigen is identified from prior virus that known to have high pandemic potential as well as there are a lot of individuals who spend time trying to find those few injected patients when it wasn't quite a pandemic virus yet, but one that was shown to have local spread and could be concerning for a future pandemic to then isolate those antibodies and do the antigen design that then goes into structural biology development, which is much user to do in the setting of having a nucleic acid-based vaccine platform that can be rapidly mutated and changed based on the structure design. And then development of assays and animal models where the new antigens can go into, to see if you're eliciting that type of best response that it does bind to those important antigens and then also whether it's protective in challenged trials prior to going into human studies. So next slide is the one next level of this reverse engineering that I've also seen that's being applied and having some success in terms of challenging vaccines, challenging vaccines, such as those of HIV, malaria, TB, those where natural immunity is not protective. I think one thing vaccinologist think about is that Sars-CoV-2 was actually fairly easy to elicit neutralizing antibody response against -- that's not the case for some of these other pandemic pathogens that have been without a vaccine for many years. Is that the reverse vaccinology strategy, which is not only do you look for the protective antibodies in patients, but you also look at how those antibodies were developed over time, what mutations went into developing a B-cell that then became a potent antibody, and designing vaccines that engage with the early precursors of those B-cells in order to drive that type of lineage. This is an approach that's being taken in HIV and now being applied in other pathogens. This also requires iterative vaccine approaches of which the nucleic acid-based vaccines are going to be most suited for. Next slide. This is an example of identifying a -- here's a lineage of a monoclonal antibody that's potently neutralizing inside cytomegalovirus. We identified key mutations that needed to happen in the early Phase B-cell mutation there at the beginning of that phylogenetic tree. And then structurally developed where that antibody down to the antigen that here, we are neutralizing the glycoprotein B fusion of them outside of cytomegalovirus, and identified that the vaccine antigen here would have to engage the early-stage B-cell receptor that had a specific mutation. And so this then is the type of iterative design that, again, can be most well produced by nucleic acid-based vaccine technology. Next slide. The other exciting science that I see developing is this protective transfer or providing designer antibodies for delivery to especially specific sites of virus acquisition. In the maternal fetal interface that I'm often thinking about, we're thinking about antibodies that go beyond just ITG, which is -- has been the typical therapeutic up to now. When we think about all of the places that antibodies traffic to between the maternal fetal interface, an IgM-based antibody would stay in circulation. It does not cross the placenta. It has very little transfer in [indiscernible] surfaces. So that would be one in which you might want to protect against the mother, against virus acquisition, such as for Zika infection. Whereas an IgG may be designed because you want to get the antibody over -- across the placenta to the fetus to be there when the baby is born. That's an example of a -- the RSV F vaccine is utilizing that IgG transfer pathway. And then another antibody that has come into play is dimeric IGA, which is designed to cross on [indiscernible] surfaces. And this, we can think about during breast feeding. This is a way that antibodies can be transferred directly to the infant gut to then protect against the diarrheal diseases that are frequently killers in the first few years of life. Antibodies have the advantage of being very safe and are utilized in pregnancy already. On the next slide, you can see another infection that I have thought about that a lot and work to develop vaccines for, which is Zika. This is one that we are not prepared for what is going to be a new outbreak of Zika when the immunity from the last outbreak wanes. It's one in which we need to prevent the new acquisition of the virus in the [indiscernible] in order to prevent the congenital transmission. There is no licensed vaccine. And certainly, no vaccine has been tried in pregnant subjects. So on the next slide, looks at some exciting novel antibody that we isolated from a pregnant patient that had prolonged virus replication in their blood that did not pass the virus onto the baby. And we wondered maybe these types of patients could give us clues about what is the protective in [ neuro ] response against Zika. This was a potent IgM antibody that was isolated, that was more potent than any of the IgG antibodies from this woman. You can see the electron micrograph with the 5 or 6 arms that an IgM has. And then we later found through structural biology that all five of those arms of the antibody could bind to [Liverion] at the same time and therefore, why it was so potent and has the advantage of not having any cross-reactivity to dengue viruses, which can lead to antibody enhancement. On the next slide shows how an antibody like this may be able to be utilized. It could be provided pre-exposure when maybe a pregnant person is traveling abroad or to an area of transmission or potentially in the post-exposure prophylaxis to reduce viremia soon after infection. And this would be much easier to use, not as an infusion of an antibody, but as a vectored vaccine. Next slide shows another example of a dimeric IgA approach. The trafficking pattern of dimeric IgA is that it binds to a poly-Ig receptor, which is on the basolateral surface of mucosal epithelial cells passes through that cell layer and comes out on the other side as a secretory IgA that then is protected from degradation [omnicoastal] surfaces. On the next slide is some data where our team developed a dimeric IgA designer antibody that utilized a -- potently neutralizing rotavirus antibody the design, the dimeric IgA, they're shown in the electron micrographs. And on the next slide, we were able to show some protection of that dimeric IGA provided to post-part Mice who had just given birth gave them this antibody here in protein form which then tracked into the breast milk and was able to protect against diarrheal disease in the cubs and had a reduced intestinal virus load. And this, again, is an example how potentially after delivery, a mom could be immunized with a DNA that could express long-term an antibody that is specific to be trafficking into breast milk that they could provide this protective antibody directly to the infant gut. So the last slide here, just summing up again where I see some novel approaches in vaccinology that I think a DNA-based vaccine would have a lot of advantages for. Again, the reverse vaccinology of identifying what our potent response is and then recreating those through utilizing structure-based design that our antigens can bind to those protective antibodies and that they can be elicited through a vaccine technology is going to be best done with rapidly developed and iteratively tested vaccines. And the protective transfer, I think, is another great opportunity for a platform like this that can be durable, can deliver a full protein that could reach into the systemic circulation that then allows for that protection to be delivered either stay in the circulation or to mucosal surfaces or even across the placenta. So thank you very much, and I'm happy to take questions.

Thank you very much, Dr. Permar. Fascinating presentation. Maybe we'll take the question at the end of our presentation. But I'm [indiscernible] Khursheed to share where we are with IMNN-101 and our development plan.

Good afternoon. My name is Khursheed Anwer, and I'm Chief Science Officer at Imunon. But a great presentation by Dr. Permar, clearly, she underscores the need for new types of approaches for vaccine, especially there are pathogens where there's no vaccine despite conventional vaccines have been used for other pathogens. There's also an increase in rising pandemics as she alluded to. And clearly, speed is very important. And as she mentioned, new types of approaches are needed such as nucleic acid vaccines, so to continue with that theme, I would like to share our approach to developing novel vaccines. Especially here, I'll talk about IMNN-101 that's lead product of our PlaCCine platform, Dr. Le Goff mentioned about PlaCCine platform in her presentation. So IMNN-101 is a next-generation COVID-19 vaccine that addresses the limitations of current vaccines. The key distinguishing attributes of 101 and this class of platform or technology is that the antigen expression is durable compared to the mRNA or protein vaccines. The vaccines are stable at working temperature and there's a plug-and-play design for rapid response as Dr. Permar point out that has been lacking. So these distinguishing attributes are intrinsic to the type of molecule you use for vaccination, which is DNA. Now DNA has these properties that really brings new opportunities or novel approaches in vaccines, but the delivery of DNA has been challenging. Either viruses has been used, where safety is a concern, some adverse events have been seen. And then on the other hand, we have devices, which is a compliance issue if you have mass vaccination with the device. So our approach is an antigen DNA that's put into a plasmid and then delivered with a synthetic delivery system. So no device, no viruses, delivery system that is safe and highly efficient. The IMNN-101 has the antigen DNA for Omicron XBB.1.5. Spike antigen, that's in the current vaccine that was just recently approved by FDA this week, and it's delivered with a synthetic delivery system, as I've mentioned earlier to you. So really, we feel that using a simple system, really IMNN-101 could be potentially the first vaccine capitalizing on DNA advantages. We have lots of preclinical data to demonstrate the proof of concept. This slide shows the evidence of robust immunogenicity in a mouse model in a prime and boost format. On the left side, the graph shows ITG responses light bars are prime and then darker bars are boost. And you can see that at two -- multi different doses, immune responses that's boosted. And then on the right panel is the neutralizing antibody. So these antibodies are neutralizing as well and same relationship you see with respect to prime and boost. The bottom graph shows the robust T-cell responses with IMNN-101. As I mentioned earlier that we do have more persistent responses with the DNA-based vaccine, this slide shows T-cell response durable for greater than 12 months in mice, and you can see the responses are higher than a commercial mRNA vaccine that was tested side by side. Then also, we saw IgG utilizing antibody and T-cell responses, but the vaccines. These vaccines are also protective in a challenged model. So an IMNN-101 prototype, which was against an earlier version of SARS-CoV-2 that's D614G and Delta where vaccinated mice cleared the virus or 90% same case of D614G, the left set of bars or complete clearance of the virus delta variant, challenge of the vaccinated mice. And we've monovalent vaccines such as [ PCV15 ] and PCV16 are [indiscernible] one [ PCV17 ] expresses two variants in a single plasma. We then took our technology or some of the lead vaccines into nonhuman primates, of course, demonstrated the IgG responses. And now this slide especially shows the protection or the clearance. Monkeys were vaccinated with our monovalent vaccines again, the earlier variants at SARS-CoV-2 and also with a commercial mRNA vaccine side by side, and you can see that interestingly, within a couple of days, it's a complete clearance of the virus from lung, that is a Bronchoalveolar lavage and also from nasal passages that is the bottom set of these slides. The key point is not only that the PLACCINE vaccine clears the virus effectively, but also the activities very comparable to a commercial vaccine. So think about if a vaccine approach that does not require a device and virus that has durable immune responses, stable at workable temperatures and also has a comparable efficacy to a commercial mRNA vaccine, clearly, this approach has a potential. This is stability data at 4-degree more than 12 months, where you have a pairs of bars, which means a freshly made formulation and the one that's been stored for several months, starting from 1 month up to 12 months. And every time a payer is a freshly made and the one that was stored. So you can see the very right most payer is 4-degree centigrade kept a 12 month and very comparable to a freshly made. This is looking at the IgG responses in mice. So this is especially very important to -- in developing countries where mRNA vaccine has certainly requires minus 80-degree of freezers, and so it will be very handy to be able to maintain at workable temperatures, that room temperature is stable for 1 month. So clearly, this is more feasible in terms of mass dissemination of vaccine in different economic areas of the world. So based on a comprehensive set of preclinical data, we decided to move 101 into an IND path. So IMNN-101 expressing XBB.1.5 and deliver with the synthetic delivery system. IND-enabling studies are ongoing. We plan to complete safety talks and biodistribution studies in mice by the end of this quarter. Clinical lot is due for production first quarter next year. I would like to mention that we have our own capability to produce plasmid, GMP plasmid for clinical grade, the delivery system clinical grade that gives us more flexibility in terms of time to be able to produce a lot. And of course, cost is also in our -- is a factor. So this is a huge benefit to be able to rapidly produce ourselves in a timely manner that we can control. The IND filing is planned for end of first quarter 2024. First patient will be in April 2024 and Phase II study in rapidly within a couple of months in 2024. This is a synopsis of the clinical trial Phase I/II in healthy subjects. three doses of IMNN-101 plus placebo control. We inject a single dose on day 1 and for 7 days, look for reactogenicity. By day 28, we'll have safety and immunity data to make a decision at the dose going forward into Phase II with up to 100 subjects starting in June. The Phase I subjects continue for 1 year for us to collect data on immunegenicity and safety, especially the immunogenicity over a long period of time, stability beyond 6 months that has been a benchmark with kind of vaccines. So lastly, the plug-and-play, as we said, speed is very important. Dr. Permar also mentioned that in case of pandemics or endemic. And here, at the very left side, the top row is the clinical backbone that we have developed with plasmid. And you can excise the antigen of a current vaccine and replaced with an emerging variant very quickly and being able to manufacture and formulate. Currently, we can do that in a 90 day, which is similar to what's the commercial mRNA vaccine can deliver. So rapidly mutating virus can be addressed with this plug-and-play approach. Now not only just the variant of one pathogen, but this is also adaptable to any pathogen. And we have shown proof of concept with other viruses, pathogens, such as flu, Lassa, Marburg and monkeypox, clearly, through some collaborations. The Lassa project is with NIT and NIH and flu and Marburg with Wistar Institute. So we're pretty excited about taking this DNA-based approach that does not have virus or device in the clinic, and hopefully, we're hopeful to make a difference in the current vaccine landscape. Where a DNA-based approach with a lot of inherent advantages over other approaches such as protein and mRNA could become a valuable tool to fight against pathogens. Now with this, I do appreciate your patience and listening. I would like to now introduce Dr. Patrick Ott, who is Associate Professor of Medicine at Harvard Medical School, also Clinical Director, Melanoma Center; at Dana-Farber Cancer Institute. So with this, I will hand over to Dr. Ott. His talk's title is Personalized Immunotherapy.

Thank you, Dr. Anwer for the introduction. It's my pleasure to present today at this virtual R&D day. My title of my talk is going to be Personalized Immunotherapy and I'll kind of talk mainly about [ neupogen ] personalized cancer vaccine, a little bit about adoptive cell therapy. And then some thoughts on the idea of personalized immunotherapy and what that means. [Here are] disclosures. So what is personalized immunotherapy, really? In one sense, one could think of this as biomarker-driven tailoring of immunotherapies and patients. And the example in high-risk model, a patient and your adjuvant setting here would be to really tailor the extent of immunotherapy, for example, combination, immunotherapy versus monotherapy based on [ rigid ] biomarkers on [complexicity] or response. Also using the pathology, example from the surgery potentially to tailor adjuvant therapy after the surgery. Maybe even the duration of adjuvant therapy or the surveillance. And then, of course, even the extent of the surgery could also be tailored based on what the pathology sees in terms of pathologic response on the microscope. So another way to think of this is this could be called personalize, but in some sense, it's also a stratified therapy. Another example for that would be targeted therapy, they're be -- by using in no [indiscernible] other cancers, for example, chemo [indiscernible] therapies, EGFR, [indiscernible] targeted agents or a new drug in melanoma that as a bio-specific antibody that's really only effective in patients that have an [ HLA-A2 ] background. Another way to think about personal therapy would be -- that it's actually truly custom made therapy based on each one [indiscernible] patients or rather than selecting patients given treatment and would be actually making a unique treatment for each patient, and that's where personalized vaccines and in some sense, also adoptive T-cell therapy comes up. The target of the therapies are really neoantigens, which are tracked of antigens because they are really uniquely expressed in the tumor, and I have the ability, obviously, to identify them. But as I sort of this personalized approach where you have to custom at each vaccine. The reason why do we have to do this? Well, because the overwhelming majority of mutations are really unique to an individual tumor. So while there are driver mutations, those are only present in subset of patients. And then there's also HLA restriction targeting there also would really only be effective in relatively small subsets of patients. And then some customization sounds great. But of course, we have to acknowledge that this is a relatively challenging approach because it takes time, it costs money. Because every individual patient needs polycom sequencing, we need to do RNA sequencing for each tumor. Also, we have the wholesome sequencing on normal tissue in order to reliably call mutations. And then once we have [indiscernible] with like the right mutations, we then actually use prediction algorithms in silico that help us to identify the most immunogenic neoantigens. That's, as I mentioned, a complicated process that took over -- takes weeks sometimes even months, although timelines are shrinking as we are scaling these processes up. How can neoantigens be targeted therapeutically? In principle, there are two general strategies. One is vaccines. The other one is adopted cell therapy. [Neoantigens] prime, activate and clonally expand endogenous neoantigens [indiscernible] responses and work primarily in the lymph nods during priming of an immune response. Adoptively transferring tools that are enriched for [ neon ] specific T-cells or even endogenous T-cells that are transduced with [ neonic-specific ] T-cell receptors that was -- can vastly increased numbers of cells that are effective and therefore, really are primarily exerting their function at the effector phase of the immune response. Initial studies using such approached, certainly, adoptive T-cell therapy with tumor [and preparing] lymphocytes, using [indiscernible], but also increasing using transgenic TCRs have been reported and have, in the case of the TIL therapy and have shown quite remarkable efficacy with response rates by 30% to 40% in heavily pretreated patients with melanoma, leading to a wide expectation of [indiscernible] as potentially an FDA-approved truck in a fairly new future. When you think about [indiscernible] TCR sort of in general, there are two different approaches. One, would be to enrich tumor infiltrating lymphocytes, so essentially, as the collective -- the collection specimen using the lymphocytes that are already present in the tumor and so arguably, tumor specific, many of them will be the item specific. Enrich them, potentially even in -- an isolate the TCRs, clonic TCRs and then use the [ host ] TCR, in a sense a highly purified population, this could be up to a hundred or so different antigens. That will be one approach where one essentially has as a source, the TILs and then enriches and uses the TCRs from those lymphocytes. The other approach will be to actually first identified a neoantigen and then pull the T-cell receptor out from the peripheral blood and then clone them into T-cells and then expand and reinfuse it in a patient. That has also already been done by a company called [ PAT ], but it is like a really labor-intensive approach. And so essentially, just to summarize these approaches, one is basically just using the TILs, [indiscernible] to [indiscernible] [tumor preparing lymphocytes] versus pulling TCRs out from TILs and then using selected TCRs that are to probably a large extent, neoantigen specific versus really identifying neoantigen TCRs peripheral T-cells flowing them and then transduce them into T-cell populations. And so by order -- by this order is there's more -- the most scope evidence is the TILs and then there is some clinical reports, mean the case reports about them from the Rosenberg groups that have shown remarkable efficacy using those neoantigen selected populations and then sort of a feasibility approach of that [indiscernible] technology. So with regards to vaccines, as I mentioned, those were primarily in the lymph nodes. So they have the -- really the ability to generate new antigen-specific T-cell responses against tumor cells. They can also amplify existing tumor -- specific T-cell responses and increase the breadth and diversity of the tumor specific T-cell [indiscernible]. As we have all witnessed with the development of COVID 2 -- SARS-CoV-2 vaccines, there are many choices of exceeding delivery platforms, including, of course, RNA, but also DNA, protein, peptides, as well as microbial and cellular vectors such as adenovirus and dendritic cells. The vaccine platform and many other variables can have substantial impact on the vaccine manufacturing time, which in and by itself influences the [ compatible ] setting that these vaccines then can be used. There are also many choices as to how to dose vaccines, including dosing intervals as well as prime boost approaches, in addition to different routes of administrations. And then vaccines can and, arguably, you should be combined with [indiscernible] cell stimulation or costimulatory agonist to improve priming, as well as agents directed at the reversal of immunosuppression in the tumor microenvironment. To test the concept of vaccinating against neoantigen cancer, about 10 years ago now we started a first in-man clinical trial in patients high-risk melanoma utilizing long, personal and peptide. And so these peptides and coding neoantigens were formulated as 4 distinct pools and mixed with the TLR3 agonist Poly-ICLC and the vaccines were then administered subcutaneously into 4 different anatomical sites and given it a prime boost schedule, which is shown here. In this study, we saw robust de novo ex vivo reactivity against peptide pools. And -- It's a really small study, in all 6 -- but in all of the 6 vaccinated patients, we saw these ex vivo responses really suggesting the induction of response against multiple epitopes. And this was pretty -- quite attractive and rewarding because, in the past, these types of ex vivo responses with these types of consistency -- we saw the responses against multiple immunizing targets as well as nearly consistently in all of the patients that was quite novel at the time. We saw a predominance of CD4 response as shown on the right side. Deconvoluting those immune responses further, we also established that they were really specific against the mutant epitopes versus wild-type. We saw responses of these -- so these vaccine-directed T-cell responses were also reactive against the tumor -- autologous tumor, in a subset of patients. We saw broadening of the vaccine responses after 2 out of the 6 patients actually had subsequently received PD-1 inhibition, and potentially and arguably most excitingly, those 2 patients who have received PD-1 inhibition after the vaccines then actually went on and had complete responses that are ongoing to this day, like more than 6 to 7 years later. In a follow-up study, we evaluated the functional states of circulating vaccine induced [ neoantigens ] across the course of vaccination using single cell transcriptomics of T cells that we identified by tetramer staining. And so we generated Class II tetramers. And initially, as shown here on the right side, demonstrated that tetramer specific CD4 T cells could be detected ex vivo in PBMCs at serial time points. And so they were persistent over the course of treatment. And this was -- in 3 out of the 4 patients, we then were able to assess transcriptomes at single cell resolution, and we observed 4 different clusters that were each composed of cells from 3 patients. And then looking at the gene composition of the cluster, we found that they represent a distinct T cell state [indiscernible] specific gene signatures. Neoantigen specific T cells isolated right after priming and at early time points after boosting it, mostly cytotoxicity and an activation [ induced cell then ] phenotype, while neoantigen specific T cells towards the end of the vaccination course mostly had a memory-like phenotype. We then assessed single-cell clonotypes, TCR clonotypes, and saw diversification of TCR over time, as shown here on the left side by additional colors from left to right, illustrating novel TCR clones as the vaccine induced immune responses evolved over time. In the same follow-up analysis, we were also able to test for persistence of vaccine immune -- of vaccine-induced immune responses up to 4.5 years after vaccination. By the way, all of these, of the now 8 patients, we had vaccinated an additional 2 patients. So in the analysis, we were able to look at immune responses from 8 patients. They were all alive, but there were recurrences in 3 out of the 8, which were surgically resected. Also rewardingly, we were able to detect both CD4 and CD8 T cell response against large proportions of immunizing the neoantigens. So essentially, as you can see in the filled blue bars here on the left side CD4 responses, on the right side CD8 responses, is essentially the proportion of vaccine responses that were still persistent years after vaccination. And an example is shown here on the right side. So the week 16s -- pretty immediately after the vaccination and then 47 months, so 4 years after vaccination. You can hopefully appreciate that those -- so those are ex vivo responses and they're all really quite robust. In a separate study to test personalized neoantigen vaccines in metastatic cancers and in combination with the checkpoint inhibition, we conducted a Phase Ib study, which was sponsored, but it's not a Dana-Farber effort, as well as like the vaccine that was like developed at Dana-Farber. The company was founded by folks from Dana-Farber, but the study was conducted by Neon Therapeutics, and I was the national PI there. Neon Therapeutic has since been bought by BioNTech is now called BioNTech US. But the way the study was designed, as I mentioned -- actually, I did not mention, but the title say it's not -- was advanced melanoma, non-small cell lung cancer and urothelial cancer. These patients received PD-1 inhibition while the vaccines were made for the first 12 weeks. They were then vaccinated over a course of 12 weeks, and then continue with nivolumab when -- as long as this didn't have toxicity and were responding. And we made a pretty good effort on the study to really learn by really collecting very consistently [ immune ] samples, including leukapheresis samples prior to the nivolumab, prior to the vaccine and post vaccine, and also serial tumor biopsies, which really allowed us to assess the immune activity of these -- of the vaccines. Very similar to the initial Dana-Farber study, we saw ex vivo responses, the proportion of immunized and peptide induced vaccine specific response at those about 50% to 60%, again, with the predominance of CD4 responses. In terms of clinical activity here, here shown melanoma, the largest patient population around 30 -- around 40 patients who were vaccinated, is melanoma, non-small cell cancer -- lung cancer in the middle, bladder cancer on the right. And you can see that -- there was a number -- a good number of responses in melanoma. The response rate was 60%, non-small cell lung cancer 40%, bladder cancer about 30%. Not enough to really tell us that these vaccines were effective. There was a couple of signs I'd argue in the clinic that were suggestive of responses, particularly the deepening of response that we saw after vaccination, and they're certainly in line, sort of the response rate were better than what one would expect from historical controls. We saw 2 specific immunological and pathological features that also indicated potential antitumor efficacy. One was epitope spreading where we tested for the presence of immune responses against neoantigens that were present in the tumor from the whole exome and RNA sequencing, but they were actually not contained in the vaccines, giving us an opportunity to test for these targets and see whether the vaccine-induced responses have actually expanded to non-vaccinating targets. And in fact, we saw this in a large proportion of the patients and actually this phenomenon tracked with prolong progression-free survival, as you can see here on the right side. And then as I mentioned, in terms of path response, we had 14 patients where we had serial tumor biopsies across the 3 time points, so prior to PD1 inhibition, prior to vaccine, post vaccine. And 5 of these patients had a complete path response right after the PD-1 inhibition, but prior to the vaccine, versus 9 of 14 patients actually did not have a path response after PD-1 inhibition but then developed a path response after the vaccine, which is, I think, quite remarkable, although with one caveat is that these -- [ I'm going to ] not call them path, responses that were from core biopsy and not from surgical samples. But nevertheless, this phenomenon also tracked with prolonged progression-fee survival. So those are, what I just went over now in terms of the vaccine, was like the initial Dana-Farber experience in melanoma and then a larger trial with Neon Therapeutics. And then I also alluded to sort of signals of activity that we saw in these trials. There were other signals from 2 additional trials that I don't have a time here to go over. One was from the initial BioNTech study, also in melanoma, where they saw a decreased rate of recurrences after personalized RNA vaccine. And then there's another study from Gritstone where they saw a decrease of ctDNA in patients that were vaccinated -- that correlated with improved survival. I just wanted to go over 2 really exciting studies that were both published or reported this year -- we all -- all very excited about. One is an effort from Sloan Kettering by Balachandran who used the BioNTech RNA vaccine that is an RNA lipoplex vaccine targeting up to 20 neoantigens of nodes that has intrinsic adjuvant activities given as properties as a TLR7 agonist. I'm not going to go through all the specifics of the trial, but it's was basically -- it was done in pancreatic cancer. Resected. The patients received 1 dose of atezolizumab and then the vaccines, 9 different vaccines every week, and then adjuvant chemotherapy. And what was exciting about this study was that they had 2 immune assessments types -- one was [indiscernible] so they looked at vaccine-specific [indiscernible] response, and then they also looked at TCR clones going up after vaccination. And patients who did have both [ eligible ] responses and TCR expansion were considered immune responders. And as you can show -- as you can see here on the left side, there were -- in the 16 patients that were treated, 8 had immune responses and 8 didn't. And the 8 patients who did not -- the 8 patients who did have immune responses did not recur, versus like 6 out of the 8 who did not have immune responses had a recurrence. So quite intriguing, not a randomized study, suggesting that there is a direct therapeutic benefit, but nevertheless, quite suggest that -- not directly showing, I should say, there was a therapeutic benefit, but quite indicative. And then, of course, there's the Moderna study done in Stage 3, high-risk melanoma patients where there was randomized 2-to-1 where about 100 patients received RNA vaccine targeting up to 34 neoantigens plus pembrolizumab versus pembrolizumab alone. And really excitingly, shows a quite remarkable recurrence-free survival difference of about 15%, which is actually pretty similar to the benefit of PD-1 inhibition versus placebo in this population. And so this is really absolutely -- I find it exciting for the field because it could really suggest that these vaccines are effective, not only in melanoma, but potentially in other cancers as well. So where are we now in terms of what are the challenges and opportunities. I just want to point out again, time and cost is an issue, but there's many things that we can still work on, including the magnitude and quality of the immune responses. We can certainly improve the formulation and the immune adjuvant in order to enhance T cell priming. We need to look at approaches where can manage the tumor -- immunosuppressive tumor microenvironment better. And then there's a lot of discovery and signs that can still be done to really hopefully improve neoantigen discovery so we can actually immunize with most immunogenic neoantigens, so select them better, but we can also increase the space of neoantigens by taking advantage of different types of mutations. So not only SNVs and indels but also other RNA-level different mutations, but also like alternative translation products. I can't go into all the details, but is essentially called the dark matter because we so far have not been able to really take advantage of it because whole exome sequencing simply doesn't discover those types of mutations. But with that, I'd like to stop and just acknowledge the team at Dana-Farber and the other Boston Institution. And just to point out that these efforts really require a village and have been funded by many different institutions. Thank you for having me today.

Thank you very much, Dr. Ott. It was a very interesting presentation, giving us an overview of where we are with the development of cancer vaccine and how this approach fits with other approaches in immuno-oncology. Khursheed, if you would like to take us through our development programs and what we have currently in our pipeline.

Great. Sure. Thank you, Corinne. Let's see. Okay. All right. Thank you, Dr. Le Goff. Excellent presentation by Dr. Ott. Clearly with the approval of checkpoint inhibitors, the interest in immunotherapy has surged. Cancer vaccines have seen a lot of failures in the past, but the advent of nucleic acid-based approaches, there's a research in cancer vaccine, and especially with the use of new antigen approach, clearly there has been a difference. But as we saw in Dr. Ott's presentation, a combinatorial approach is probably valuable, combining vaccines with the immunotherapy approaches. Well, getting back to program, you had seen -- I talked about our DNA-based platform for vaccines against infectious diseases. We have now expanded that platform into cancer vaccines. We already had immuno-oncology program in place at a clinical stage. So I'll talk about our immuno-oncology and cancer vaccine platforms in this set of slides. So there are 3 platforms in immuno-oncology at IMUNON. TheraPlas is the most advanced one where expressing a potent immuno-cytokines locally at the site of tumor using a plasmid DNA that expresses IL-12, a powerful anticancer immunocytokines, with a synthetic delivery system that does not require a device or virus. So that's -- the lead product is IMUNON 001, that is in Phase II randomized clinical trial in ovarian cancer at this stage. Then we have these cancer vaccine platforms, FixPlas and IndiPlas. FixPlas is targeting tumor-associated antigen in this respect. And the IndiPlas is neoantigens. Of course, tumor-associated antigens are over-expressed in tumor tissue but also have some expression in normal cells as well, while neoantigens are more personalized and specifically expressed in an individual or a small group of individuals. So I'll talk about a little bit of TheraPlas since that has -- is our elite product in advanced stage, immuno-oncology, and then I'll talk about our FixPlas program. So IMUNON 001, as I said earlier, persistent local delivery of IL-12 with formulated plasmid. This is targeting epithelial ovarian cancer, disease of unmet need, late-stage diagnosis, high recurrence rate, and hence, poor survival, and novel approaches are certainly warranted beyond chemotherapy, radiation. IMUNON 001 is a gene therapy product for safe and effective delivery of IL-12, which a powerful immunocytokines, a safe alternative to recombinant IL-12 therapy that is short-lived and insert serious systemic toxicity. We have done a few clinical trials with 001 in different patient population, platinum resistant, and more recently into newly diagnosed new adjuvant population. We've seen some encouraging results in clinical efficacy, some biological activity, and certainly good safety data from these trials. A Phase II trial OVATION 2 is underway. We will be sharing some interim data this quarter and next year, our final analysis from that study, where chemotherapy alone versus chemotherapy plus IMUNON 001 is being examined. So let's move to cancer vaccine, the FixPlas. FixPlas is the targeting tumor-associated antigens that will express in cancer, both monovalent and bivalent, means either targeting 1 antigen and more than 1 antigen. Our approach, like in COVID-19 for infectious diseases, DNA-based vaccines. Clearly, we saw some rationale for why DNA as a good candidate for infectious agent vaccine. Similar thing applies here, for cancer vaccines. First of all, DNA gives durable antigen expression. So you can get a durable immune responses against cancer antigens plus memory T cells could be long-lasting with that exposure of the antigen. DNA is known to elicit very strong cellular responses. And that's really key to cancer therapy. So durability advantage of mRNA and strong cellular response, that's the advantage with protein-based vaccine. So clearly, DNA-based vaccines are well suited for cancer therapy if effectively and safely delivered. And certainly, we do not use a virus or devices for that purpose, but synthetic delivery systems. So this is a more recent program where we have initiated proof-of-concept studies, with the bivalent vaccine in the mouse melanoma model. Of course, melanoma is attractive target for immunotherapy, but still a lot of melanoma patients who do not benefit from current approaches. So new approaches in immunotherapy or vaccines for melanoma is strictly warranted. In an experimental way for proof-of-concept, we're targeting NY-ESO-1 and TRP-2 in a mouse melanoma model, and using 2 approaches of proof-of-concept to see if DNA-based synthetic delivery system approach works using a prophylactic approach where we vaccinated animals, and then challenged with tumor or treated the already existing or established tumor with the vaccine. It's a little bit busy slide, but I'll walk you through. This is -- looking at a prophylactic approach with FixPlas. And on the very left side column, top panel is a tumor growth rate with a monovalent vaccine that targets TRP-2 antigen. And you see that green ones are the vaccinated animals, red one are control, and you can see it delayed in growth, that translates into survival and benefit. This is a very aggressive model, and the benefits in survival, you're seeing a pretty consistent with what you normally see with a good approach in an animal model. So that's with a single antigen TRP-2. And the middle column with the graphs is a combination vaccine, TRP-2 and NY-ESO combination. And here you can see that further extension or delaying of the tumor growth, again, the green bars as opposed to the control which are red, and that also correspondingly translates into better survival in a combination approach. That gets to prove that a single antigen approach that has been used for many years in the past may not be sufficient. You have to target tumor with combination antigen approaches. The third column shows that the -- there are T cell responses also with these vaccines, which is very critical because you want to generate CD4/CD8 cells to be able to engulf and specifically kill tumors. But this -- like I said, this is an early program in cancer vaccine. This demonstrates that DNA-based approach with synthetic delivery system, does have an efficacy responses in a very challenging, aggressive mouse melanoma model. Then if we move down to therapeutic approach with the same vaccine, bivalent TRP-2, NY-ESO. Here the tumors were established and then they were treated intramuscular with a vaccine approach. And here also we see benefit in tumor growth rate and survival. So again, these studies, there are at least enough evidence that there's a direction to move forward with this program. Clearly, we have to optimize the antigen, there are ways to optimize antigens, stabilize the structure secretion, expression to surface, increase expression with MHC Class 1 molecules to get T cell responses, adjuvancy, some of those optimization studies have to go on. But clearly, we are looking at this program into further product development selection of the disease target melanoma is an interesting and attractive target. As I mentioned, that is a great target for immunotherapy, highly immunogenic tumor, yet there's still a need for therapies that are effective in melanoma. So we do like to create a program around melanoma selection of an optimization of the antigen targets. You saw TRP-2 and NY-ESO, but that's not the end of the story. That's the proof-of-concept of our formulation. But we'll be plugging in a best candidate as a target for antigens. And then again demonstrate robust anticancer activity. And around this time next year, before that start IND-enabling studies and we target a clinical trial with the FixPlas 1Q 2025. In parallel, we're also developing an animal model for new antigen approach, a mouse model where we can take epitopes, multiple epitopes, and that's the advantage of plasmid DNA, you can pack into single product multiple epitopes and being able to deliver that and go after cancer with that approach. So I think it's pretty exciting. As I said, going into clinic with infectious disease vaccine, early spring next year and going into Phase II instantly or very quickly, it's very exciting for us. Now with DNA -- cancer vaccine also, it's very promising to use DNA where it has a lot of promise and has not been fully capitalized. And we feel that IMUNON is in a position to use these nonviral, nondevice based system to make an impact in immuno-oncology cancer vaccines. Thank you very much for your patience. With this, I would like to now transfer to Dr. Le Goff.

Thank you very much, Dr. Anwer. It was very interesting, and thank you for your enthusiasm, as I think you [indiscernible] as I am on the potential of DNA in areas of immuno-oncology and infectious diseases. Now we have time for questions. So I'd like to open up the Q&A portion of our discussion today. You see that, unfortunately, Dr. Ott cannot be with us for the Q&A. So we'll do our best to answer questions that are addressed to him. And if we can't, we'll make sure that we obtain the answers directly from him. I'm going to get that to you. I would like also to introduce Kim Golodetz from LHA, who will actually let us know if we already have some questions in the queue for us.

Okay. Thank you, everybody. And yes, we do have some questions in the queue. [Operator Instructions]. We have 2 questions from Emily Bodnar at H.C. Wainright. The -- And I'll do one at of time. The first is, can you discuss your T cell results more specifically, particularly CD8 T cells? And now that we know more about mRNA vaccination, which doesn't induce high amounts of CD8 T cells, how important is it to see a high CD8 T cell response?

Thank you very much, Emily. And I think this is a question for you, Khursheed.

Yes. Thank you, Emily, for your question. Yes, the CD8 cell response is important for -- but see, once the virus has entered the cell, and I'm speaking for infectious disease point of view, then antibodies are not as effective. Also antibody-directed cell killing is a mechanism. Clearly, you need a T cell response for that to completely eliminate the virus. We have looked at different factor CD8 cells, memory T cells. Of course, for the sake of time, we're not able to share some of that facts data with you. But besides ELISpot data that I've shared with you and from gamma response, we do see subsets of CD8 cells post vaccination in infectious disease model. We're also looking at CD8 it cells where it's even more important cancer vaccine subtypes in our analysis of cancer vaccine. So yes, it is important, especially to completely eliminate the virus from the system. And memory T cells, of course, they play a pivotal role in keeping you protected for a long time from reinfection.

Okay. The second question from Emily is, we've seen data from BioNTech's mRNA that counter vaccines and also Gritstone's cancer vaccines, which have had lackluster data. Why do you think that a DNA approach could be superior to these approaches?

Yes. So once again, a good question. As I mentioned earlier, that clearly, both from Dr. Permar's talk and Dr. Othat's talk, that the new approaches with nucleic acid-based approaches are the way to go. Clearly, mRNA is ahead of the game, especially with COVID-19, the approval of the mRNA vaccine really gave it an edge. But DNA has more durable expression. And that could potentially translate into longer immunity and more memory T cells. So we think DNA from that point of view, in terms of immunology, has an advantage over mRNA. And of course, it has to be proven in human data. Clearly, that would be the next step in the DNA field, to get that recognition. But at least knowing from the durability of expression, which is the antigen exposure, it's important we have done experiments where we see expression of protein from RNA peaks about a day or 2 and then comes back to within 3 to 4 days. Maybe in infectious disease, that early exposure is important, but certainly maintaining it, especially in cancer vaccine, you need to have durability. So it's good that you have some positive data from mRNA, and we believe that DNA has some edge in some areas in immunological that would perhaps even capitalize -- further capitalize on the gains that the mRNA has made, and of course, the storage of vaccine and plug and play rapid production is also an advantage.

Okay. We also have a 3-part question on IndiPlas and FixPlas. How would you describe the differences between IndiPlas and FixPlas? How do you go about personalizing a cancer vaccine? How can a personalized cancer vaccine be made in a cost-effective way, especially given the constraints on reimbursement that we are seeing?

Kim, they are great questions, thank you. Maybe I'll start and then I'll hand it to Khursheed. I gave like maybe a crude definition of those modalities, FixPlas, saying that's more of an off-the-shelf approach, and IndiPlas is a more personalized approach. I'm sure Khursheed will have more to say about it. And then we go to the next part on the costs.

Yes. Clearly, good question. So FixPlas is targeting tumor-associated antigens that are overexpressed in tumor, and they are overexpressed in many different tumor types as well. So in that sense, if you develop a vaccine under FixPlas, that could be effective, as Corinne said, off the shelf, could be given to a larger patient population. But we also know that there are differences from individual to individual in tumor genetic makeup. So the FixPlas is really going individual, specifically an individual where a tumor may have very different types of mutation that's not overall in general population. Maybe a small subset of patients or that individual patient. So FixPlas is targeting the new antigens that are in a specific patient or a subgroup of patients. So those are the 2 differences between Fix -- I mean, that's the difference between FixPlas and IndiPlas. How do you go about personalized medicine? Of course, since it is about a person, individual specific, you have to collect the tumor tissue and do the genomic sequences of the tumor genome and the normal tissue and identified mutations. And then from that mutations, you're using algorithm, identify the epitopes of high affinity that would be reactive to the T cells and then made vaccines from a combination of epitopes into a 1 vaccine. That's where the DNA plasmic has advantage, where you can put dozens of epitopes, neoantigen in a specific vector. So once you put those epitopes in the vector, high affinity, then you formulate if it is the [ R ] system, and then give that to that individual. So that vaccine will be very specific to those mutated antigens that are in that individual. And one of the reasons why cancer vaccines have not been very successful over the years, because the tumor is different. Different entities are expressed in different individuals.

And maybe briefly because I want to make sure that we have also questions for Dr. Permar. But briefly, on the cost, our focus is on developing innovative approaches. But the definition of innovation is that it's only innovation if it ends up in the hands of patients. And if the costs are too high or whether it's in oncology or in other therapeutic areas, if they don't correlate with the burden of disease, that is problematic for society in general. So our focus -- our strategic focus is really to make sure that as we go forward and develop therapeutics, we are cost conscious, and we understand how our therapeutics will be used, whether it would be used in combination or not. I would say here that DNA might have an advantage over other technologies that are more complex and longer to develop. DNA basically uses your body's machinery to produce your therapeutic, right? And in that sense, and because I talked already about the flexibility of the manufacturing of nucleic acid, in that sense, I think we can develop a cost-effective, very efficient therapeutics.

Okay. So we have some infectious disease questions. Could you discuss the differences between a potential DNA-based vaccine that's used in an adult versus one that's used in a pregnant woman or a newborn, if any?

Thank you. I can address that. Yes, I think one of the biggest questions, first, is safety in each of the populations does need to be studied in particular. There, at this point, have been slow introduction of a testing in those populations, which I think we need to have innovative approaches to improve on, something like do we really need HD escalation in children versus can different ages be tested at the same time? Also to think about preclinical systems that can better predict any safety events. But actually, the vaccines at this point have not had more events -- safety events with the recent mRNA vaccines in those populations, children or pregnant women. The one major difference, I think, when it comes to what vaccines we're actually putting in arms is dosing for children, and that's something that clearly had to be worked out with the mRNA-based vaccines. I think there's some ways that we could be more prepared with preclinical models that would grease the wheels for the human phases that would maybe reduce the amount of time that would be needed to do all the dosing studies. But that's one where -- does not impact the pregnant -- pregnancy setting as much as the children's setting because it's the immune system that's developing in the child, less so the per kilogram size. And so that's what really has to be dose-adjusted.

Okay. Thank you. And we also have some combination infectious disease questions here. So related to COVID, given the rapid mutations of COVID, is your plug-and-play strategy fast enough. You also mentioned Lassa and Marburg viruses. Are these quickly mutating viruses? Does the market size warrant commercial development.

Right. So I'll start there and maybe, Dr. Permar, you have a perspective on this as well. Well, COVID for sure mutates a lot and very fast. And what we have learned through the pandemic is that you needed to have a technology that could adapt quickly to the different mutations. So what Dr. Anwer described as a plug-and-play strategy for our DNA technology, which -- is essential because it allows us to basically change the DNA cassette, right? If there is a mutation, to get the sequence, change the DNA cassette, the backbone is already characterized and put this into the clinic. And through our discussions with the regulators [indiscernible] and others, it is clear that there is this mandate of being able to develop a commercial vaccine in 100 days. And we can do that. And we tested it, we will be able to deliver on this.

Yes. And I can just add that speed is of the essence and especially for these RNA viruses of which Lassa and Marburg as well, where we know that mutations can evolve rapidly. However, it's -- they're not -- you don't always need an additional design variant that keeps up with the evolution. For some viruses, the response to any one of the variants may be enough to provide protection, at least against severe disease. And so I think that's the hope with the virus -- some of the pandemic viruses, that if we could have prototype vaccines that are designed based on the sequences that are already available, and if it's in a rapidly modifiable platform, then the current sequence that's spreading around the world could be put into an already developed vaccine and really needs very little additional testing and immunogenicity studies because it's already been through the gamut of those studies prior to that.

Yes. With respect to the market, if I may add, currently, Lassa is more into the West and West Africa and Latin America, but there's prediction in new market analysis that it could -- the market would increase and there's potential to have -- in western countries through migration. So yes, we have to just watch and -- in terms of its spread. Currently, it's confined in a couple of areas.

I can also add that is a virus that is more severe in pregnant women and can cause deleterious [indiscernible] outcomes. So it's going to be -- if it becomes a virus that's more easily spread, it's going to be like a Zika pandemic. And we know how much attention there was because the effects were not just on the person who's initially infected. And so that is something that we have to be ready for.

We have another question that now goes back to the cancer vaccines. There seems to be a lot of work in melanoma with respect to vaccines. What other therapeutic areas do you think IndiPlas and FixPlas could be directed towards?

Yes. Maybe I'll start there. I've worked, over the years, I worked a lot in melanoma. In fact, Dr. Ott mentioned the targeted therapy, targeting BRAF and those approaches, which actually launched. So now what we have seen as well is that there is still, despite those improvements in the therapeutics, still like -- there's still a great unmet need in melanoma. When you use targeted therapies, patients tend to become resistant a year into treatment. And then the PD-1 PD-L1 inhibitors have been approved as well in melanoma, but they don't work in all the patients. So there is -- I think the vaccinal approach seems to be very promising and this -- and I believe DNA has -- is going to play there as well. Now to the question, yes, should we -- could we look at other tumor types? Absolutely I mean I think it makes sense to envision other possibilities for cancer vaccine, which I strongly believe will be immense in the treatment of cancer in -- now maybe the reason for picking melanoma as the first indication, and as we study this and develop those vaccinal approaches, is the fact that melanoma is a very immunogenic tumor type and it's a good tumor to start working with. I don't know if, Khursheed, if you have anything to add to this.

Yes. I mean our approach is more generic, right? So it's not a specific to any particular antigen or disease. So initially, we are to demonstrate proof-of-concept in melanoma, but we could expand into other diseases. For example, it could be hot versus cold tumor. If it's a hot tumor, that's very good candidate for a T cell therapies or checkpoint inhibitors. Cold tumor may need an immune environment where you may need to prop the immune system through vaccination. Even hot tumors also, some of the cell therapies don't work because highly immunosuppressive environment. So there's an application to other disease areas as well. It's just that you can plug in any antigen to the plasmid if there's the right environment in terms of the immunogenicity condition, that should be a good target for IndiPlas or FixPlas.

Great. We just have a couple more questions that have been submitted. With respect to synergistic M&A, what kinds of technologies do you view as being synergistic?

Yes. So I mentioned this earlier in my presentation saying that we're always on the lookout for potential acquisition. And what we're looking for are technologies that could be -- that could complement our approaches in immuno-oncology or infectious diseases. So of course, interested in nucleic acid, of course, interested in adaptive cell therapies. So it's where we can complement our efforts, be synergistic with what we do, and also derisk our pipeline.

Okay. And we have a question on intellectual property. What kind of intellectual property do you have around IndiPlas and FixPlas, and have any patents issued?

Yes. So of course, we take -- intellectual property is at the core of our business model. So we, of course, protect the work that we do, but I'll let Khursheed answer this question.

Yes, of course. As Corinne said, we have to protect innovation. So we have filed multiple family of patents covering these technologies, both for composition of the matter, use of the composition, disease targets, and several applications have been filed over the last few years.

Okay. We had one last question that's come in, what's your manufacturing strategy for your facility in Huntsville?

All right. So we just unveiled in June our CGMP manufacturing in Huntsville and we now have the capacity for producing our own plasmid and facilitating agents for our vaccine programs, at least in the early phases, right? So that's [indiscernible] for us. It's a way for us to control costs and to control quality. So for now, that's where we are. But we'll see moving forward as we go towards the later phase -- later phases of development if we need to partner with someone or not. So that's not out of the question, of course.

Okay. There appear to be no more questions that have come in.

Very good. Thank you very much, Kim. And listen, I'd like to thank everyone who were on the call today. Thank you for attending our first R&D Day. I want to thank Dr. Sallie Permar very much for her presentation and insights into the future development of vaccinology and what we should expect in the coming years as we think of the next generation of vaccines. Dr. Anwer, thank you very much for telling us all about our clinical programs. And I will thank Dr. Ott for being with us for the first part of this presentation. I just want to conclude by saying that we are very optimistic and enthusiastic about this technology. I think this can be transformative across many disease areas. And we'll keep you updated on our progress. Thank you very much.

The conference has now concluded. Thank you for attending today's presentation, and you may now disconnect.