Inovio Pharmaceuticals, Inc. (INO) Earnings Call Transcript & Summary

Good morning. My name is Ben Matone, and I'm Senior Director of Investor Relations at Inovio. We're excited to have you join us for the first ever Inovio webinar entitled DNA Medicines from COVID-19 to Cancer. Before we begin, I'd like to remind everyone that we will be making certain forward-looking statements regarding future events that relate to our business plans to develop Inovio's integrated platform of DNA Medicines. These include clinical and regulatory developments and timing of clinical data readouts and strategic matters. All of these statements are based on the beliefs and expectations of management as of today. These statements involve certain assumptions, risk and uncertainties and could cause actual results to differ materially. We assume no obligation to revise or update forward-looking statements, whether as a result of new information, future events or otherwise. Thank you again for being with us today. And with that, I would like to turn the presentation over to Dr. Joseph Kim, President and CEO of Inovio.

Good morning, and thanks, everyone, for joining today. My name is Joseph Kim. I'm the President and CEO of Inovio. And I am delighted to be hosting our first DNA Medicines' Virtual Meeting from COVID-19 to Cancer. Our goal is to provide you with an overview of our unique DNA Medicines' platform and our most recent data achievements, including our preclinical and clinical work on our COVID-19 DNA vaccine INO-4800 and also the data we just recently presented at ASCO on our DNA immunotherapy, INO-5401, for the devastating brain cancer, glioblastoma or GBM. Today, we will be hearing from our Inovio team, including Dr. Kate Broderick, our Senior VP of R&D and Team Leader for our COVID-19 DNA Vaccine Development Program; and Dr. Jeffrey Skolnik, who is our VP of Clinical Development for Oncology in Inovio. Doctors Broderick, Skolnik, and I will also have the distinct privilege and pleasure of speaking to renowned experts, including Dr. David Weiner, who is often referred to as the father of DNA Medicines; Dr. Stanley Plotkin, who is considered among the world's leading vaccine experts and the scientist who developed many of the vaccines that have protected humanity from such viruses such as rubella and rabies; and Dr. David Reardon, who is a leading neuro oncologist focused on brain cancer research at the Dana-Farber Cancer Center. My team and I are coming to you live today now and for our Q&A at the end. Our conversations with Dr. David Weiner, Plotkin and Reardon were recorded previously. Later this year, Inovio will host a similar webinar focused on our lead asset, VGX-3100, currently in Phase III trials to treat cervical precancer related to the human papilloma virus or HPV. We'll have Phase III data to share with you at that time. So let's get started, and please be sure to type in your questions as we go along, and we will do our best to answer everyone at the end of our presentation. Inovio is powering a new decade of DNA medicines. We have done this by developing a powerful platform that involves precisely designed plasmids, delivered with smart proprietary devices. We have gathered a strong safety data in over 2,000 patients along with immune responses in these volunteers and patients in clinical trials, including our lead product that is already in a Phase III randomized, double-blinded pivotal trials for VGX-3100. We have already presented great data from our Phase II trials involving our glioblastoma treatment, INO-5401. We've also demonstrated previously a strong meeting of primary and secondary efficacy endpoints from our Phase IIb trial for VGX-3100. Of course, our fast response vaccine platform has demonstrated off-the-shelf speed and efficiency as well as immune responses from our technology platform. Inovio has been executing on this vision to build and lead a DNA medicines company. Our vision has been executing our precisely designed plasmids that target specific antigens, whether they're from viral sources or from cancer. We use our smart proprietary device, CELLECTRA, to safely deliver directly into the cell of a person our DNA plasmids that can generate very strong and robust immune responses. And of course, we have validated this work with extensive partnerships and collaborations and peer review publications. We have been executing in the near-term by advancing our products against HPV, cancer and infectious diseases. And of course, we are here to meet the urgent medical needs of the patients worldwide. In the long-term, we feel that we have the extensive and strong financial position in terms of cash, also the human resources position and our network of partners and collaborators globally to create and deliver safe and effective DNA vaccines. How is our proprietary technology platform built and how are we executing this? Well, as I mentioned before, Inovio has been executing the precisely designed, optimized plasmids by targeting the gene sequences for a specific antigen from COVID-19 to GBM target antigens. We plug that in to our backbone plasmid, and we deliver efficiently using our proprietary smart CELLECTRA devices shown here, both our immunotherapy device in CELLECTRA 5PSP on the left and our new commercial vaccine device called CELLECTRA 3PSP. When delivered, these plasmids then can generate powerful and safe immune responses, and we have demonstrated this in over 2,000 patients and volunteer thus far. Now Inovio's technology has demonstrated significant advantages over time. We have demonstrated clinical efficacy in our randomized double-blinded Phase IIb efficacy trials. We've also demonstrated an ongoing safety across over 2,000 patients and volunteers in over 6,000 separate administrations with very favorable safety profile. Compared to other platforms out there, we think this is one of the strong advantages of Inovio's product platform. Because also that there is no anti-plasmid immune responses that can thwart our efforts to generate additional boosting effects, we can certainly dose multiple times using the same vaccines and immunotherapies. In fact, our cancer trials, including GBM and prostate, these patients have been receiving our immunotherapy up 2 dozen times or even more across their treatment with a favorable safety and tolerable profile. And lastly, one of our greatest advantages is the stability of DNA vaccines products, where we have demonstrated a strong and stable -- stability of the product long-term, up to 5 years in refrigeration, normal 2- to 8-degree Celsius without requiring the deep freeze stability that many of the other platforms require, up to minus 80 deep freeze conditions. We've also incredibly demonstrated over a year is -- of storage at room temperature of our vaccine candidates, which is amazing. And we're able to scale up using the standard bio-manufacturing processes, the manufacturing of the plasmids and the devices, of course, we are increasing the manufacturing scale of our devices and arrays through automation and additional contract manufacturing lines. Next, I'd like to go through a summary of our very extensive DNA medicines pipeline. In this slide, we show our overall immunotherapy clinical pipeline, headlined by VGX-3100, which is a treatment for precancerous conditions caused by HPV infections. The lead indication is for treating cervical precancer called dysplasia or HSIL. And we're looking forward to providing top line efficacy data from our first Phase III trial, REVEAL 1, in the fourth quarter of this year. We have already presented some very exciting interim Phase II data for our vulvar and anal dysplasia studies this year. We would also report a complete set of those Phase II data later this year. Next is our recurrent respiratory papillomatosis, or RRP treatment, INO-3107. RRP is a rare orphan disease, and we are very excited to open this trial in Phase I/II setting to demonstrate the safety and efficacy of this treatment in preventing or extending the needs for surgery of this tumor that grows out of control from HPV 6 or 11 infection. So we're very excited to start this trial midyear this year. MEDI0457 is a product that we licensed out to AstraZeneca, and they're conducting multiple Phase II trials of 457 plus their PD-L1 checkpoint inhibitor in multiple HPV-caused cancer indications. And as I mentioned earlier, we will also be talking about INO-5401 with this risks and data that we have presented at this year's ASCO with Jeffrey Skolnik and David Reardon. But our GBM therapy INO-5401 has demonstrated better than standard of care in PFS6 and also overall survival at 12 months. Stay tuned for this information. And we have also Phase II studies, efficacy setting trials going in our collaborations with PICI and Cancer Research Institute in prostate cancer of combining our INO-5151 plus multiple immune modulators in castration-resistant prostate cancer patients. Moving over to our DNA vaccines pipeline targeting infectious diseases, really is headlined by our work against COVID-19, which is INO-4800, you would hear a lot about our advancements and progress in this vaccine in very short periods of time. Inovio has built a global coalition of collaborators, partners, manufacturers and funders to advance INO-4800. And we're looking forward to reporting on Phase 1 data later this month, but also starting potentially our Phase II/III efficacy trial in July-August timeframe, and we're very excited about the progress of this program. We also have other vaccine work that's advancing to the next stages, including our vaccine for MERS, which we plan to enter into Phase II trials later this year with the full funding from CEPI as well as our Lassa fever vaccine INO-4500, which we plan to enter into Phase Ib study in West Africa with our eye towards starting the Phase II trials in the region later -- following the Phase Ib study. Lastly, I'd like to introduce how, even in this day and age, especially during the pandemic situation where the speed and the sharing of the information is so critical, Inovio is very proud to say that we have been publishing our research and development results in peer-reviewed journals, including over 150 preclinical and clinical trial data in peer-reviewed journals and papers such as the Lancet, New England Journal of Medicine, JIB and Nature. Most recently, we have published the immune responses data from our preclinical model for our COVID-19 vaccine INO-4800. And Inovio believes in sharing and letting the information to be shared with the public through our peer-review system through these world-class journals and publications. All right. Now it's my pleasure to introduce Dr. David Weiner, considered to be the father of DNA vaccines, one of the key pioneer in the field of DNA medicine. David, it's great to be with you here.

Joseph, it's wonderful to be here with you.

So I have some questions about DNA Vaccines and DNA medicine. So how did this start?

Well, that's a really interesting question. When we started this several decades ago, really, there were 2 technologies for making vaccines, live approaches or dead approaches or nonlive. And live approaches really were our favorites because by growing inside our bodies the immune system learns to fight off the infection. And also because the virus actually replicates and produces proteins inside our bodies. We can not only make antibodies to the soluble proteins that are produced, but also our killer T cell compartment, the Navy SEALs immune system are engendered, which can then expand and contribute to viral clearance and better protection and control. And so that was the hallmark of live infection. However, live infection can take very long to make and be safe and have -- has lots of other developmental issues. Nonlives really have a whole safety advantage because they're nonlive, but they lack many of the immune functions of the live approach. And so we were thinking if we could deliver a nonlive, nonreplicating, completely controlled piece of DNA and code the instructions, the cell would -- the cells of the body would make the proteins, they would again stimulate an immune response, antibodies by being shed from the cells. And because it's also made within the cells, it would have the hallmark of induction of killer T cells. And because they're nonlive and can't spread, they would actually have the safety, therefore, of the nonlive. And so you'd wind up with the best of all worlds and also DNA is really simple to manufacture.

So what do you think is the most unique character of DNA vaccines?

Well, that's another really important focus that we have been on and along this journey collaborating with Inovio, the sequences themselves are not derived from any organism. They are designed by computer. And there are algorithms that Inovio has now developed that enhance this design and make it very rapid and very reproducible. It's also the vectors themselves are reduced to practice. The manufacturing system is very consistent. And the delivery has been simplified and the formulations have been improved. And so this is a local delivery for a local expression only in the skin or in the local arm. No production, other parts of the body that can produce proteins that can be seen by the immune system and stimulate a strong immune response as if they're an infection and also generate very consistent levels of CTLs in this very reproducible, consistent delivery platform.

So David, you and I have been working on DNA vaccines for over 25 years. So a lot of people ask me, what makes mRNA different from DNA and vice versa? And how would you compare and contrast 2 different technologies?

Well mRNA and DNA are both genetic material, but they have very different purposes. DNA is kind of the library of information, it's very stable. It can be extracted from extinct animal systems from thousands and thousands of years ago. And that is just a credit to how stable it is. And one piece of DNA can make many, many messenger RNAs when it gets into a cell.

So I believe the main difference between DNA and mRNA vaccines in people are DNA's ability to generate, as you mentioned, CD8-positive killer T cell responses and mRNAs have not. Can you explain why that might be so? And what people have been seeing in the clinic?

Well, right now, we have very little DNA -- sorry, information about RNA in the clinic. There's only been a few studies reported. And of course, we're learning more and more. But what has been reported is they can with multiple injections drive T cell responses, but it seems like they're biased towards CD4. The DNA seems -- which we have a lot more data for, a lot more published data, there's -- especially in the clinic, is driving both antibodies and CTLs.

So what concerns you most, if you look at the DNA vaccines and also looking similarly at mRNA vaccines? Well, from a scientist and from a vaccine developer's perspective, what would be your greatest concern? And what could be the greatest positive from those 2 vaccines?

So I think we're in a unique time that nucleic acid approaches such as DNA and RNA are being considered and moved to the forefront, and we're on display through the CEPI funding for COVID. They were the first 2 vaccines that were moved forward in the United States, for example, through CEPI funding, and they were both part of the first 3 groups that were funded by CEPI so that's quite an interesting thing. And that speaks to the advantages and concept these have for moving into the clinic rapidly, delivering something people believe in a simple, rapid fashion and also possibly providing benefit. DNA, we have had several indications in the clinic of the first appearances of efficacy. The treatment of HPV-induced cervical neoplasia, a double-blind, placebo-controlled trial that was published in Lancet a few years ago showed efficacy, early effects in GBM have now been reported out of Harvard that this was having some effect, although we haven't hit a true efficacy endpoint yet. And immune responses in infectious diseases that -- for emerging infectious disease that look very, very similar to what we might need and might be associated with protection, but we haven't -- we have more work to do. RNA is still earlier. We've seen some reports. We've seen a flu report from Moderna, particularly, and then we've seen some other public reports, but those papers are not out yet. There have been some reports from other groups as well. However, the -- so we have a lot more that we would like to see there, and it would be great to have more demonstration. So I guess what I would say is on the RNA side, I would -- it would be really important to see more demonstrations of something that we can read and get our handle on and understand. On the DNA side, since it's further along, I think we are very confident about the safety and the reproducibility of that and that there hasn't been significant adverse events. But now expanding those and moving over the goal line is really the most important thing in the DNA space.

So speaking of nucleic acid vaccines, there are other vaccine platforms, like the viral vectors and protein and adjuvant vaccines, can you give a little bit of pluses and minus of your thoughts on those platforms as well?

Well, viral vector vaccines are our historic favorites. They are the kind that we made measles, mumps, rubella that most of us have taken around the planet. The newer ones are really recombinant viral vectors we're mostly hearing about. And those are really, for the most part, unlicensed technologies as well. But most of those, there have been a lot of development, and there have been slow and that is because the live vaccines have advantages in safety of these recombinant vectors over the historical vectors and that they can't just replicate on their own for the most part the ones we developed -- most people developing now. But their boosting and serology issues have to be really delicately worked on and tiptoed around. So they have advantages in that they can be made in large amounts, but their ability to be boosted and readministered and things like that require a lot more work. The nonlives, we've really seen the heyday of recombinant protein, I would say, plus some of the newer adjuvants, and these are very exciting. And those tend to give antibodies and really very little or very, very poor CD8 T cells and actually weaker CD4 in most cases. And so there -- they've been particularly advanced in certain infections where it's a single type of antibody response that's most associated with protection. However, there's a lot of safety work and all that, that is built around them as they're developed. Because of the combination of the 2 platforms, the adjuvant that stimulates immune response and the building of the protein and having it stay in its right shape, if that's important. And so there's work in those. But those are very exciting and important approaches. And of course, it's sort of a hybrid of those that's conjugate vaccines, which is the fusing of sugar molecules to proteins, which is also very important.

So David, back to what we are talking about in this webinar from DNA medicines, from COVID-19 to GBM. What really gets you excited about all of the potential that Inovio and the collaborators are going to demonstrate with respect to the DNA medicines in the clinical setting, both for the vaccines for COVID-19 as well as an immunotherapy for GBM?

So I can say that it's a very exciting time for the DNA field. We've spent -- as you know, we've traveled this road together. It's been a very focused and accomplished, but step-by-step journey to build the platform and get it to the point where we start to see the amount of consistency we see now in the clinic and the number of people vaccinated goes up to the thousands without significant adverse events and the reproducible introduction of antibodies and T cells in multiple, multiple trials. As well as the impacts now in cancer, the first impacts we're seeing likely mostly due to the cellular immune response that is being generated, the T cells that are -- CD8 T cells are being generated that not only are induced in the periphery, but go, find the tumor, turn a cold tumor hot, so-called when it's filled with CD8 T cells and then can eliminate or control the tumor. I mean these are very dramatic things that are now being reported in different papers that have been through peer review. And so -- and you had very prestigious groups like David Reardon's at Harvard report on the GBM data, which is a very difficult tumor that requires generating T cells that can cross the blood-brain barrier and still have effect of function, still kill. That's a very unusual thing. And so I think we're in sort of a new phase of DNA, a phase of expanding what we've already accomplished. We now see we can get responses very consistently. We kind of have established a very broad number of different diverse types of people have received these vaccines with both disease conditions such as very serious, like cancer as well as healthy individuals. So that we now really understand a lot more about what our platform can do and how consistent it can be and seeing responses across them. And so I think we're kind of in a new age. We're in an age where DNA can start inducing and living up to its potential, that potential we've been thinking about for a few decades now and really cross that barrier and provide us a really new and exciting tool for both vaccine-immune responses and in the immune therapy arenas.

Yes, absolutely, David. So lastly, what do you think is the future for DNA vaccines?

So that is one of -- that's a very important question. What is the future? So DNA is an enabling technology for delivery in vivo and local production of biologics that are customized by each person that receives them. And there are chemicals that we're full of that we're used to getting exposed to that is very natural and really is the instructions for making something. And so some of the other exciting things besides this are, of course, the introduction of biomolecules as reported with the dMAbs and the new cancer-targeting, self-assembling, bispecific targeting reagents that the patient would make themselves, which could really open up to many more patient populations access to these type of drugs. And then self-assembling molecules that do many other things one could use as well as drug therapies themselves. So I think the vaccines and the immune therapies have -- are an enormous thing, but they really are the scratching the surface of where we can go, and I'm going to be just so excited to see where this field goes and where we can go over the next 15 to 20 years. It should be a very, very interesting and exciting ride.

Yes, David, I agree with you. I think we can change the face of medicine using this platform and really maximizing all of the gene products that we can deliver using this platform from vaccines to immunotherapies, to mAbs, to BiTEs and bispecifics, therapeutic proteins, and I believe there is some amazing future lying ahead for this technology and this platform. So I'd like to thank you for your time and really being the true pioneer in this field, sticking with this from the beginning and really seeing -- starting to see the fruits of your labor and our collective labor going forward. So thank you very much, David.

Well, thank you, Joseph. It's been an honor to be part of this group.

Great. Thanks. Now it's my great pleasure to introduce you to Dr. Kate Broderick, Inovio's Senior VP of R&D and Team Lead for our COVID-19 DNA Vaccine Program. To say that Kate and her team have been working very hard is an understatement. We're all grateful to her for her leadership and dedication as well as her expertise and meticulous approach to driving forward our INO-4800 DNA vaccine development program. Over to you, Kate.

Thank you so much, Joseph. So just starting with, I think, a very nice summary, and I do think that this particular slide really helps to highlight a very tangible level, some of the really key characteristics of the DNA medicine vaccine platform. In particular, I would draw your attention to the central tenant, really, the foundation of the whole platform, which is the perfect marriage, I like to think, between our optimized DNA constructs with our smart delivery technology. So what you're looking at here is the CELLECTRA 3PSP device, that's our intradermal handheld device, that I'll speak about a little bit as I move through my slides, but I just think it really -- that particular device really showcases Inovio's pioneering efforts in the field of DNA delivery. So the marriage of those 2 entities together is really what I believe is the formulation for success of the platform. And by success, obviously, a key driver of that is the robust immune responses that we've been able to generate extensively in both preclinical, and of course, most importantly, clinical trials and data sets. And really, one of those key differentiators is the fact that not only are we able to reproducibly and robustly generate B cells. And by that, I mean B-cell responses. And by that, I mean, of course, binding antibodies but also neutralizing antibodies, but also so importantly, those critical T cell responses, those CD8 killer T cell responses that we believe are going to be absolutely critical to the protection of some of these awful disease targets that we have assessed over the years, and of course, are currently looking at with COVID-19. And of course, I'm going to come back to that a little bit as we talk through the data specifically for INO-4800. Two of the other areas, you'll see on the right-hand side of the slide are kind of inherent characteristic specific to DNA themselves. Obviously, the fact that there's no anti-vector response. So that really allows us to effectively boost. Whereas some other vaccine platforms, of course, it's unfortunately a one-and-done due to the vector used, that's not the case for DNA. And in fact, as you'll hear with Dr. Skolnik, we can continue to boost subjects multiple, multiple times in a supportive therapy. Another area of interest, of course, is the fact that DNA itself is, of course, nonreplicating and nonintegrating. So there's no concerns about that from the perspective of safety or on a regulatory basis. And that's very well established and accepted by the authorities. Continuing on the right-hand side of the slide, this interesting concept that -- because of the nature of plasma DNA, there's no issue with combining or, as I like to think of, cocktailing up vaccines for different targets into a single vial, thus allowing the patient to receive potentially multiple immunizations with a single treatment shot. Just as an example of that, we're working here in the R&D group together and coming up with a multi-hemorrhagic fever vaccine approach. So combining vaccines for Lassa, for Ebola, for Marburg together into a single vial. So that from the patient's perspective they get 1 shot, but protection against 3 diseases. And the same, as you can imagine, can be said for mosquito-borne illnesses as well. So let's move down the circle now to the lower point, the SynCon rapid design. Before the last few months, I would have given you the example of our Zika vaccine development program as an idea of how rapidly our technology can be used to go from bench to bedside. And in that case, we did that in 7 months, and that was unprecedented, certainly for us, and something we were very proud of. As you can imagine, under our current circumstances, we've now really changed that whole dynamic. And instead of 7 months, we went in 83 days from bench to bedside for our COVID-19 vaccine. But I'll elaborate a little bit more on that as we move through the slides. And last, but certainly not by any means least, is a very, very important characteristic that I think is absolutely inherent to Inovio's DNA technology. And that is the remarkable stability program -- profile that we have generated with our products. We specifically have come up with a formulation that allows us to completely remove the need for frozen cold chain. So I'll just repeat that again, absolutely no need for frozen cold chain for our products. They can be stored for over 4 years at 2 to 8, so just standard refrigeration temperature. But more remarkably than that, they can be kept at room temperature for approximately a year. They can be kept at 37 for approximately 2 months. So that's really, when you're thinking about deploying a vaccine, about shipping a vaccine, about storing a vaccine, those kind of characteristics are really quite remarkable. So instead of shipping sites minus-80 freezers that might be required for other vaccine platforms, really just a standard fridge is all that's required for Inovio's DNA products. And then last is, of course, the rapid and scalability of the manufacturing itself. For those who aren't familiar with the way that we manufacture our DNA products, it's fermentation process based in E. Coli. For those not familiar with that, think kind of brewing beer, but instead of using yeast we're using E. Coli here. It's a very scalable process. In fact, here in San Diego, we make small batches in our benchtop fermenters. But of course, there are large-scale manufacturers, you're talking about things -- fermenters, much, much larger, approaching the size of a room. So moving on to the next slide. So looking here. So what is it inherently about Inovio's platform, which makes it so well-fitting for emerging infectious diseases? Well, I really believe that there are multiple areas about Inovio's technology that are just a perfect fit for responding to outbreaks like, of course, we're all experiencing right now. So I'm just going to go through each of them and maybe elaborate and just give a little bit detail on each different area. Firstly, speed. And certainly, I think we're all aware of the need for speed at the moment. When we think about traditional vaccine development time lines, gosh, potentially ranging from 3 to 20 years, that's not something that we have time for here. And that's really where DNA medicines can be very, very clearly differentiated. The design of the vaccine candidate itself, specifically in the case of our COVID-19 program, the whole vaccine design was completed in 3 hours. And that's really with the support of our proprietary DNA optimization algorithm that's been generated over years and years of expertise that's allowed us to upload essentially a sequence into our algorithm, and at the end of that process come out with a fully designed vaccine. Again, under the speed characteristic, the rapidity of manufacture, and I really mentioned that in the previous slide. And also, of course, the ability to harness established regulatory platforms. Okay. So that moves -- lets me move on to my second bullet point, and that is, of course, the safety profile. So we've treated over 2,000 subjects in the clinic with our DNA and our delivery technology and over 6,000 doses of DNA totally delivered. And so far, really, we have a completely benign safety profile in the clinic. And I do think that will be a differentiating characteristic as we compare ourselves to potentially other vaccine platforms, especially in the current ongoing effort for COVID-19. Coming back to those all-important immune responses that I discussed in the opening summary slide. And just to reiterate, again, one of the very powerful abilities of the DNA technology platform is its ability to produce both robust B and T cell responses. And I really think it's so vital that we have this breadth of response as we think about protection from a variety of different diseases, but specifically thinking about coronaviruses and COVID-19. Of course, we're also able to generate those all-important neutralizing antibodies, too. So of course, very important that a vaccine has immunogenicity, but truly, the all important, of course, is that it has efficacy. So we, as a team here at Inovio, we're so incredibly proud to be pioneering the path for DNA vaccines when we were the first team to show efficacy of a DNA vaccine delivered with our enhanced delivery technology to show efficacy in the clinic for our lead HPV program. Of course, that program has now proceeded into Phase III trials, and we'll be very excited to see that data as it amasses. Of course, we've also produced and published multiple demonstrations of protection from challenge in animal models with MERS, Lassa, influenza, Ebola and Zika as examples. But the last point here is one that I would like to specifically highlight and that's also our ability to generate immune responses in an elderly population. And we demonstrated that in an influenza trial where we specifically vaccinated people in an elderly population with, I believe, the oldest subject being 89 years old. And in that, notoriously difficult to vaccinate group of people, we were able to demonstrate, of course, are those humoral responses, but also incredibly importantly, the ability to drive those T cell responses in an elderly population. And I do think that will be a vital characteristic for our vaccines as we move forward through the clinic. And again, just to reiterate, that stability profile that we see in our DNA products is absolutely key. So as an example for COVID-19 or really any vaccine that might need to be dispersed around the globe, the ability not to have to have this deep frozen cold chain as part of their logistics, it will be absolutely vital. The ability for doctors' offices just to store it in a standard fridge will be absolutely key to the uptake of this vaccine technology. So this beautiful time line here really just kind of gives you a visual of where we were back in December of 2019 and where we are today and where we hope to be in the near future. I'll always cast my mind back to the 31st of December when I was scrolling through my phone one morning at breakfast and came upon an article about this unknown pneumonia outbreak in China. And I thought to myself, gosh, that's interesting. I wonder what's going to come of that. And certainly, I could never have predicted that we would be in the situation that we're in today. So that was really a very profound moment for me. And I think one that will stick with me for my whole career. But really truly, it wasn't until kind of mid-January when we got access to the virus sequence itself. That was really the catalyst for us being able to put the wheels of our technology into action. And as I mentioned, within 3 hours, we had a fully designed vaccine against COVID-19, which we, of course, now call INO-4800. From that point onwards, we went on to, of course, manufacture lots of the vaccine itself, both in a GMP format for potential human trials, but also in a research grade format to allow us to really amass a database of preclinical data to support the use of INO-4800 in the clinic. We were also incredibly honored to receive ongoing funding support from our partner, CEPI, very early on to support taking our vaccine into Phase I clinical trials, also from, of course, the Bill & Melinda Gates Foundation who have been very long-term partners of us, and also the Department of -- the U.S. Department of Defense. So 3 great partners for us as we move that program forward. And really that coalesced in the announcement on April 6 that we had initiated our Phase I human clinical trial in the U.S. of our COVID-19 vaccine INO-4800. And remarkably, with great thanks to the volunteers and also the clinical sites that participated, we were able to fully enroll that trial in a remarkable 17 days. In mid-May, we also published our early preclinical data in the world-renowned journal Nature Communications. And as we project into the future, just a few short weeks away in June, we will be announcing our clinical trial results, and we hope to be able to very rapidly move through the processes to allow us to start our efficacy trial shortly thereafter. And of course, as you can imagine, as we push to scale up the efforts for manufacture of this vaccine, all those discussions, those extensions of partnerships and development of new partnerships are, of course, ongoing. So what's our internal strategy for our COVID-19 program? Well, I've kind of listed them off here, and I've tried to check off where I think we've achieved them. And you can also see ones that are still ongoing or will be positioned in the future. So firstly, we would like to achieve licensure for INO-4800 using a dual strategy of emergency use authorization, and of course, a traditional approval pathway, too. So first check box, of course, is that we were able to move rapidly into our Phase I study, and that is, of course, as the Phase I always is, is to demonstrate safety, tolerability and immunogenicity. And of course, we achieved that in a remarkable 83 days from bench to bedside. Prior to doing that and in parallel to those efforts, of course, we've generated a very strong preclinical database, supporting the safety, the immunogenicity, and of course, the neutralization capacity of this vaccine. And we've also partnered with several labs around the world who are considered absolute experts in their area to support the generation of preclinical efficacy model. Although, of course, this is a future projection, we're aiming to be a leader to proof of -- human proof-of-concept efficacy data. So that's getting, if the Phase I data is supportive, which we have every confidence it will be, to move into that all important clinical efficacy trial later in the summer. We have a strong track record of leveraging external funding to support this effort. And again, we're very grateful to CEPI, to the Bill & Melinda Gates Foundation and to the U.S. Department of Defense for their ongoing support to this program. We are, of course, expanding our manufacturing capabilities so that by next year we will be delivering hundreds of millions of doses of our vaccine, which, of course, will be key when we think ahead to potential global vaccination campaigns. And we'll be expanding partnerships for further manufacturing scale up, but also, as we already have done to ensure clinical trials across a multitude of demographic areas on the globe. And that's highlighted, of course, with our collaboration with Advaccine in China and IVI in Korea. So what really put us in a pole position for our work on SARS-CoV was the fact that we already through an existing partnership with CEPI have the lead MERS coronavirus vaccine. That vaccine is currently being tested in the clinic at Phase II. And this year, we'll move into Middle East and African trial for a Phase II trial for MERS -- against the MERS vaccine -- disease as well. Of course, as I'm sure everyone is aware, MERS is another coronavirus related to the SARS-CoV2 virus. So in -- from the perspective of the design and the immunogenicity of the vaccine, I really feel strongly that, that put us in a very strong position where we had a foundational understanding of what a successful vaccine looked like and what successful immune responses looked like for a coronavirus vaccine. And here, I'll just very quickly summarize the output of many years of work in that area. Our MERS vaccine was also based on the spike protein. So we had much confidence in that design strategy. And really, we've shown that that vaccine design has a track record of success in a preclinical format. And in fact, we demonstrated 100% protection from clinical disease in a very tough primate model after 2 immunizations. But remarkably, we also demonstrated 75 protection after a single immunization. And I'd also like to iterate, and I'd love to tell the story, but I think it's out of time constraints at the moment, that we also looked at immune responses in primates, of course; mice, of course; but also in camels, which are one of the zoological syncs for this disease. So really, it was that strong, strong preclinical data set that supported the movement of this vaccine into the clinic. And of course, again, we have a track record of success there. In our Phase I U.S.-based trial and our Phase II Korean-based trial, we generated 76% seroconversion after a single immunization with our MERS vaccine candidate and 80% seroconversion after 2. And those all important T cell responses were generated and noted at all-time points. So moving on now to this next slide, and I'm the first to admit that's rather a busy slide, but I do think that it does a very nice visual representation of really what the team at Inovio has been doing for the last few months. And I hope that it conveys to you how busy the team has been, how dedicated the team has been. And really, the large levels of success that we've achieved in such a short period of time. Really, this time line shows the efforts from the research team on the preclinical side of things. You can see all the different models that we have tested our vaccine in, and we really -- gives us a huge amount of confidence as we've moved into the clinic for both a safety perspective, but also an immunogenicity perspective. And you can see there, of course, we're also in the process of working towards preclinical efficacy data as well with our partners at CSIRO and also our partners at Public Health England. They have also been assisting us with those live virus neut assays. As of course, I've mentioned previously, all of this culminated in our ability to move into our Phase I trial, which we initiated on the 6th of April. So what about the actual design of our INO-4800 vaccine itself? So as I mentioned previously, it really shared a lot of similarities to the design for INO-4700, which is our MERS vaccine construct in the sense that we used the full-length spike protein. So as I mentioned, we used our gene optimization algorithm. So we received the viral sequence from the Chinese authorities. We uploaded that into the algorithm. In 3 short hours, we had a fully designed vaccine sequence. We synthesized that into a copy of DNA, cloned that into our expression vector. And then on the right-hand side, did the necessary in vitro studies here in the laboratory to show that it was indeed producing the protein that it should. And you can see here both expression on a western blot and also expression in vitro and cells culture. So that box was checked. We knew it was expressing the spike proteins. So immediately, we moved the testing into animals. Started with small mammals, but immediately started also working on large animals, as I'll discuss in the next slide. So firstly, the first set of data here that we show is in mice. And what was quite remarkable was that after a single dose of vaccine, we very rapidly were able to detect T cell responses. So you can see here at day 7 with both doses of the vaccine, we were able to detect really quite robust interferon-gamma ELISpot responses. And the same can be said also on the right-hand side, the humoral binding titers that you can see on the right-hand side. We move on to guinea pigs, and you may well ask why guinea pigs? Well, it turns out that guinea pigs are actually an incredibly good, solid physiological model for human skin. And since we were positioning this vaccine to be delivered to the skin and not the muscle as differentiates us from many of our other colleagues in the vaccine development field. We wanted, of course, to assess this vaccine in the guinea pig. And not in any way to our surprise because we had expected this to be the case, we were able to demonstrate very robust humoral antibody titers as well as T cell antibody titers. But we also expanded our plethora of assays using this model and used a surrogate for neutralization, and that's really the ACE2/spike blocking that you can see on the second figure here under the guinea pig. And you can see very clearly that INO-4800 is able to block that binding. We also wanted to look at the presence of antibodies really in the organ where the disease most takes hold, and of course, that's the lung, and very clearly, after a while, we were able to detect IDg, the biodistribution within the guinea pig lungs. And last but not least, using an in-house pseudoneutralization assay, we were able to show very clear neutralizing antibodies. Then moving on to perhaps the more clinically relevant nonhuman primate model, and this was in rhesus macaques. Again, we were able to replicate the data that we saw in the small animals and very clearly showed very nice cellular responses, both at a 1 and a 2 mg dose and also very nice binding titers for both the 2 doses as well. So interestingly, certainly, in the monkeys, there doesn't appear to be a huge difference in the dosing regimes. So, of course, the all-important neutralization antibodies, we were able to partner with some global laboratory to our experts in this field. For mice, we used the Chinese National Laboratory at the Peking University, and were able to detect very nice live neutralizing antibody titers. And with our partners at Public Health England in Porton Down, you can see here the results of the guinea pig neutralizing titers using a live virus. And really, when you look at the levels for INO-4800, which are all over a 1 to 320 titer because we believe that protection against the disease is coming in somewhere around the 1 to 100, 1 to 150 range. So we're way, way, way in excess of that. Of course, efficacy is the true test of a vaccine. And so, as I mentioned earlier, we are currently running several studies addressing the question of preclinical efficacy. And we've partnered with CSIRO in Australia to test our vaccine in a ferret model. And that data should be available in the relatively near future. And also with Public Health England at Porton Down to test efficacy in the primate model as well. And that data should be available in the late June, early July time frame. Both these models will also help us to assess the question around vaccine-enhanced disease. We do not feel that there is any likelihood that our platform will be impacted by that on the basis that we didn't see that for our MERS data. But I think it's an important safety box to check, and we'll be able to do that with these challenge studies. So what about the progress in the clinic? So we very rapidly moved from preclinical testing straight into Phase I testing. And we did this in partnership with Dr. Pablo Tebas at the University of Pennsylvania and also the AMR site in Kansas City, both of whom we're extremely grateful to for their support and their determination through this rapidly evolving process. We started a small Phase I study, 40 healthy volunteers, to really gain a preliminary assessment, of course, on safety, tolerability and immunogenicity. The sites were extremely motivated as were the volunteers themselves. And again, just so grateful for their time and their effort in being involved in this study. And really that -- again, to highlight that unprecedented speed that we went 83 days from plasma design to testing, to treating our first subject in the clinic and full completement of enrollment within 17 short days. So really very, very exciting time. And we hope, of course, to be announcing the data, at least the interim, early read data from this trial in the June time frame. So really just a final slide to really give a huge shout out to the team at Inovio here. I can't convey my honor to work with these people every day to convey to you, the listeners, the determination, all of these people who have truly worked night and day to get us where we are today. And it's an honor, I think, for the whole team at Inovio to be able to be working towards a solution for this terrible outbreak that we're all experiencing at the moment. And of course, it would be only correct to thank again our fantastic partners and supporters who have been really with us this whole journey over these few short months, but incredibly busy months. And again, I would like to verbally thank CEPI, the Bill & Melinda Gates Foundation for their financial support, the Department of Defense for their financial support, for DTRA for their financial support and also our partners, our collaborative partners, IVI, Advaccine, CSIRO, Public Health England, the Chinese National Laboratory, the Wistar Institute and the University of Penn, all who have made this process possible. So I thank you so much for your time. And hope that this has given you some insight into our activities over these last months. And also, I hope that it gives you some hope, some hope towards the potential possibility of a DNA-based vaccine against COVID-19 that is both safe and effective in the clinic. And that just leaves me now to introduce a conversation that I had recently with Professor, Stanley Plotkin to talk about the COVID-19 outbreak. It's an absolute pleasure to be here today and to be able to introduce Professor Stanley Plotkin, who shouldn't really need introduction to anyone because he's so very clearly a luminary in the field of vaccine development. So Professor Plotkin it's such a pleasure to have you here with us today.

Thank you.

So as we touch on vaccines and as, of course, you are literally the world expert on it, I'd have to ask you, Professor Plotkin, what characteristics are we going to need to see in a successful vaccine for COVID-19?

Well, I think the most important characteristic of a vaccine against SARS2 will be to protect the respiratory tract. Or to put it another way, to prevent the virus from spreading from the upper respiratory tract to other parts of the body. Now it may be that a vaccine -- successful vaccine will not prevent infection. Because we know from other vaccines that frequently the case is that the effect on mucosal replication is not terrific. Now with live-attenuated vaccines, we often do control mucosal replication. But with nonliving vaccines, it's often the case that mucosal replication can occur, but systemic invasion does not. So what we have with this coronavirus is a virus that is able to infect the upper respiratory tract and which -- because the receptors of the virus exist in the lower respiratory tract as well as the upper respiratory tract, it can spread downwards. And what blocks it or what blocks other agents as well in the lower respiratory tract is the presence of antibody. And so that is the first goal, should be the first goal of a successful SARS2 virus to produce antibodies that convey the lower respiratory tract. Whether it prevents upper respiratory infection remains to be seen. One, of course, would like that to be the case, but I don't think we can be sure that, that will be the case even with a vaccine that protects the respiratory tract. Now the other aspect of this coronavirus, which is unfortunate is that it produces immune responses that can be exaggerated. So the so-called cytokine storm. And in particular, the cytokine IL-6 and that cytokine storm, even when the virus replication has begun to disappear, can kill the patient. Now we don't yet really understand the phenomenon. We don't understand how this virus does that. But I suspect that cellular immune responses will be important in preventing that. Now this has to be cellular responses that are just right in a sense. That both CD4 and CD8 responses that can control the infection and prevent this late phenomenon of exaggerated immune responses and production of cytokines. But that is a phenomenon, which I'm not sure anyone anticipated, and we're just beginning to learn how to deal with, by, for example, with antibodies, monoclonal antibodies against IL-6. But my point here is that we have 2 separate phenomena that we want to control, the virus replication and also the host response, the exaggerated host response. Now just one last point is, at least to me, I don't yet understand why the exaggerated response is occurring largely in the elderly. In a way that seems counterintuitive since the elderly -- the immune system is not as good as it is in the young. Yet, this exaggerated response is occurring in them. And I think we need to learn a lot more about the physiology of that response. And what it is about the elderly that permits that response to occur.

So professor Plotkin, you may be aware that we, at Inovio, published our first manuscript containing data of our own SARS-CoV vaccine, this is called INO-4800 in Nature Communications. I don't know if you've had a chance to look at that publication yet.

I've seen the early data with the Inovio vaccine. They're very promising. And, of course, what we need now is to show that indeed the immune responses are protective. Clearly, we want a vaccine to induce antibodies against the SARS2 virus. But there are other responses also, which may be critical to control. And, therefore, we have to analyze deeply the immune responses that are produced by different vaccines because they almost certainly are different. The contrast, I guess, could be between the DNA vaccine and the inactivated virus vaccine that is being produced. I would be very surprised if the responses were identical. I feel pretty certain that they're not. And what we need to know is what is or what are the important responses, physiological responses? Anyway, my point here is that the -- not only the height of immune response is important, but the breadth of immune responses. And immune responses are multiple. They're not only what we show in a neutralization test by incubating a virus with serum.

Yes. And certainly, something from our perspective, Professor Plotkin that we were so proud of and we're able to publish in that Nature Communications manuscript was our ability to generate robust antibody responses, including neutralizing antibodies, but also those T cell profiles, too. I think that tends to be kind of a key characteristic of DNA vaccines. Certainly, one question that I'm asked frequently. And I can understand why is that kind of compare and contrast DNA vaccines to RNA vaccines. So I would really love to hear your opinion on that.

Well, so my simple response or simplistic response to that question is that there's no doubt that the DNA vaccines induce strong cellular responses. And they may well be critical depending on the agent that you're talking about. The -- we don't have head-to-head comparisons. We -- as you know, we have heard -- we don't have a lot of data, but we have heard that the first mRNA vaccine produces an antibody response, a neutralizing antibody response. The trouble, of course, is that we can't really compare until serum specimens are available from both types and can be run in the same laboratory. But I guess my question about the mRNA at this point would be not only the height of the antibody response, but also what kind of cellular responses are produced by mRNA vaccines? And I think we will have this information in the next couple of months, I would expect.

Yes. Indeed, it's an unusual situation that we find ourselves in today. I don't know, certainly not in my career, and I don't know about yours sir, but the opportunity to really have head-to-head comparisons in all vaccines in kind of real time, I don't know that we've ever had that opportunity before. So it's going to be an interesting few months to be able to analyze all that data together. Could you talk about specific characteristics that you think might be advantageous to our Inovio INO-4800 vaccine and how it might be particularly appropriate for the COVID-19 outbreak?

Well, so I think I would go back to what I was alluding to before. The positive thing that I see is that DNA vaccines can produce a broad range of immune responses. And we don't know for sure what the immune responses to SARS2, which immune responses are critical. But I think we can infer that certainly antibody is going to be critical. And as I said before, I think that cellular responses will also be important in view of the pathology that we're seeing with the disease. And there, of course, I would mention the Th1/Th2 dichotomy that for most vaccines one really prefers the Th1 response. And I think that's definitely the case here for SARS2. So from my point of view, the more approaches available, the better because this is the first time -- yes, I think it's really the first time in history that we will be, in principle, trying to immunize 7 billion people as soon as possible. And the only way that, that could be possible is if we have multiple different vaccine producers producing at high-quantity levels. So the world needs a plan based on what we hope is multiple successful vaccines, a plan to produce them and to distribute them. And that's not going to be easy.

And you ended that very important answer talking about the need for governments to form a consensus really in regards to the global access of this vaccine and its distribution. You and everybody listening to this discussion will have heard the time line of having a vaccine ready for fairly widespread distribution in the 12- to 18-month time line. Do you sir, as an expert in the area, think that is achievable?

Well, long life has taught me never to make predictions. But all that one can say is if everything goes well, yes. But that is a big assumption that everything goes well. I think it's feasible to produce a certain amount -- a certain amount of vaccine. But again, if we're talking about 7 billion or potentially 14 billion doses, I cannot imagine that they would be available in 12 to 18 months unless there is a plan made now how to do that. Who's going to do it? How is it going to be done? Where is it going to be done? So will there be a successful vaccine in 12 to 18 months? I think so. I think it's likely. Will there be enough vaccine to immunize everyone? Big question, big -- I remain dubious about that.

So my final question for you, Professor Plotkin, and this might require a fairly lengthy answer. But, so once we get through this outbreak, and I personally believe that we will, and it's just a matter of time. And obviously, the development of a successful vaccine will be critical to that. But when we do get through this, how do you think the experience of the COVID-19 outbreak is going to shape vaccine development in the future?

Well, that's, of course, a very interesting question. Well -- so perhaps a few obvious answers. One is that we will have, fortunately, more strategies, successful strategies to develop vaccines. That is the most positive result of this epidemic. We'll have more tools to make vaccines. Another result, I hope, that the realization that there are numerous viruses out there, replicating in animals that could transmit to humans, that could adapt to humans. And I'm not the only one saying this, this has been said by other people before. And one can identify some -- many likely suspects and study them so that you are prepared. It would have -- I guess, the most obvious thing to say is that had we gone on to produce a vaccine against SARS1, we would be in a better position to know what vaccines against SARS2 will do. Unfortunately, we didn't do that. But I think the lesson is to be ready for adaptation to humans of viruses in the environment. And it's not just SARS. Zika is another example. Zika was isolated first in Africa, not in humans, by the way, it was in primates and then began to adapt to humans and began to spread. And we didn't do anything about it until it spread to Latin America and the effect on the fetus in utero was demonstrated. Now we should have -- actually, if that had really been studied, it happened in French Polynesia first. So we should have been ready for that, but we weren't. And so I think those are the things we really need to do to appreciate that nature is dangerous. And that we have to -- even with our civilization we have to be ready for natural disasters.