Good afternoon, welcome to the Vaccitech KOL webinar. At this time, all attendees are in a listen-only mode. A question- and- answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the Vaccitech website following the conclusion of the event. I'd now like to turn the call over to Geoffrey Lynn , Senior Vice President at Vaccitech. Please go ahead, Geoffrey.
Great, thank you. We're very glad to have you joining us and pleased to be hosting this webinar focused on status of tolerogenic immunotherapies for celiac disease with a focus on Vaccitech's candidate VTP-1000. Next slide, please. Really, I think what's gonna make this discussion really special today is we have two amazing KOLs joining us. Professor Jewell is the MPower Professor and the Minta Martin Professor of Engineering at the University of Maryland in the Fischell Department of Bioengineering and the Medical School, many other distinctions. Professor Jewell's expertise is in biomaterials approaches for engineering immune responses with a focus on immunotherapies for inducing tolerance for treating autoimmunity and other inflammatory diseases. We also have Dr. Anderson joining us.
He is a translational immunologist and practicing gastroenterologist as well as founder and director of Novoviah Pharmaceuticals in Brisbane, Australia, focusing on Novoleukin and whole blood cytokine release diagnostic platform and innovative biopharmaceuticals for immune and gastrointestinal diseases. He's also current President of the International Society for the Study of Celiac Disease. Among other accomplishments, his work has characterized the gluten peptides that drive adaptive immunity in celiac disease, and he designed and led the preclinical and clinical development of the first antigen-specific immunotherapy developed for celiac disease. In terms of an agenda today, Professor Jewell will begin with a discussion of therapies for inducing tolerance, with a focus on his work studying biomaterials for promoting tolerance for treating autoimmunity. Dr. Anderson will then discuss the need for immunotherapies for celiac disease, including his own work in this field. Next slide, please. Next slide, please.
As a representative of Vaccitech, I'll then discuss our SNAPvax platform technology, which was first described in Nature Biotechnology in 2020, please see the reference below, for use as a cancer vaccine. Then discuss how we're utilizing this platform for inducing tolerance for treating autoimmune diseases, then introduce Vaccitech's candidate for celiac disease, VTP-1000. Bill Enright, our CEO, will then conclude with a company overview on how pursuit of tolerogenic immunotherapies really fits within the broader mission of the company. This will then be followed by a Q&A session at the end. I'll now hand it over to Professor Jewell to kick off the discussion. Thank you.
Dr. Jewell, you're on mute.
Hi, everyone. I'm Chris Jewell. Excited to be here and to share some of my perspective on sort of the cutting edge with material science and opportunities in nanotechnology to drive antigen-specific tolerance. I'll just briefly show my disclosures here. Then really just say that, you know, my lab, as Geoff said, focuses at the interface of material science and immunology, trying to understand the interactions between biomaterials and the immune system, design new materials that give us unprecedented control to try and direct immune processes. Then we're focused on therapeutic vaccines, in particular, driving antigen-specific tolerance. I just wanna shout out to my lab. It's an amazing group of people that help us do some really exciting work. I'll show a few different snippets of things we're doing today as well as funding sources.
As many folks in this call know, autoimmunity, transplantation, if you incorporate other inflammatory diseases, this impacts a lot of people in the United States and across the world. And despite the diversity of different diseases, there are some commonalities in terms of unmet needs. For the most part, diseases like MS and Celiac, Crohn's, you know, there aren't cures. It's really focusing on stabilizing and slowing disease, addressing symptoms. These also require lifelong treatment, so there's often a compliance issue. Certainly patient's quality of life suffers. Really, even the newest therapies are not for the most part, not antigen-specific, and so that can have a number of different impacts in terms of both efficacy and also side effects.
Some of these, you know, historically have ranged from broad immunosuppressants to kind of the newest technologies, which are monoclonal antibodies. These obviously are molecularly specific, but they don't necessarily differentiate between healthy cells and dysfunctional cells, expressing the specific target. As I mentioned, you know, there are some really exciting advances. I just wanted to highlight a couple of things, both to bring up, you know, the advances this has brought to patients, but also think about where we might go next. In MS, for example, Ocrevus, a couple of years ago, this was the first drug approved for treating a kind of a primary progressive MS, and, you know, the first opportunity for that. This is a monoclonal targeting CD20.
Another interesting drug, more recently, also targets CD20 with a monoclonal, but it can be self-administered. With MS and, you know, the coordination impact, this is obviously a really exciting development. Most people probably saw the exciting news last week for type 1 diabetes. First, type 1 diabetes therapy that actually delays onset, and pretty significantly so. This is also a monoclonal. This is delivered through 14 consecutive daily infusions and has some pretty significant impacts on delaying disease. You know, a lot of really exciting opportunities and advances for patients. What about things that aren't approved yet? You know, where are some of the development opportunities?
One, I think CAR T-cells, and other types of cells, now, obviously, in cancer, this has been transformative. Generally, there's a few different strategies developing for this. One, you know, it's kind of the same concept as a monoclonal, where you use CAR technology to target or deplete a specific cell type. Some folks may have seen this clinical trial for lupus just in September. This was reported using anti-CD19 or T cells to target B cells expressing CD19. The other area, what we're all here focused on today is actually, you know, antigen-specific tolerance.
There's some work in the CAR field to try and engineer TCRs to target with, you know, to recognize self-antigens that might be useful to then redirect responses of populations expressing those receptors. As well as, you know, a lot of the unique advantages of nanotechnology really are around control. When you can control the integration of signals, that also creates significant potential for driving antigen-specific tolerance. I just wanted to kind of reflect a little bit on traditional vaccines for a second, because I think this really informs the, you know, the coming decade of how immune tolerance might really be transformative. You know, when you think about smallpox or polio and, you know, a few drops of oral vaccine here, you get protection for, you know, years or a lifetime. Pretty amazing.
Lots of other success stories, you know, in the traditional vaccine field. You know, what might we want to see in next-generation therapies for autoimmune diseases? Well, certainly potency. We don't have curative therapies for the most part. We'd like to see selectivity to both improve our ability to give appropriate doses while also limiting side effects. Then, yeah, durability, just like in a traditional vaccine. Could you generate resident regulatory populations or other mechanisms that control the already existing self-reactive cells? You know, I just wanted to bring those points up and then recap just briefly antigen-specific tolerance. I know a lot of folks here are already experts, but, you know, if you have a disease like MS, you already have dysfunctional cells that might recognize, be self-reactive against myelin, in this case.
When they come into tissues such as lymph nodes, they see cues that drive their differentiation towards inflammatory subsets. Of course, autoantibodies are also involved. These T cells go out, and they attack the cognate antigen. Kind of the idea of antigen-specific tolerance is you could use, whatever technology, whether it's nanotechnology or other approaches, to control the signals presented in lymph nodes to direct functions such as, for example, could you direct other types of phenotypes and make regulatory T cells that are antigen-specific? Could you co-opt mechanisms to drive the deletion of self-reactive cells?
The key premise is that, you know, you're going to control the signaling in a way that, for example, you now have myelin-specific Treg that can go out and selectively control self-reactive populations or maybe even help drive conversion of inflammatory cells to regulatory cells in a way that is going to let you correct defects or address underlying issues without, you know, creating side effects. Nanotechnology, as I mentioned, one thing it does is provide control. That, I think, is what is going to be really exciting when we start thinking about how we actually implement some of these strategies clinically. I just tried to think about what are the major strategies? There's a lot of great work done in this area, so I put some of the classics down here.
Just if I can kind of grossly mention two approaches that I think have, that have kind of developed. One, you take a self-antigen and some kind of regulatory cue. This could be a mTOR regulator, it could be some kind of cytokine or some kind of innate immune antagonist. The idea is you deliver a cue with a regulatory signal that redirects response to the antigen. Nanoparticles, scaffolds, microparticles, there's a lot of different approaches, but basically, you can incorporate and display cues at certain densities with molecular specificity. You can target or provide stability or co-delivery of cues to drive certain outcomes. That's one approach where you've got the self-antigen and the regulatory cue. There's another approach where it's more focused just on the self-antigen.
You know, this was really interesting when some of these papers first came out, because if you think about a particle displaying an antigen, it's actually a lot like the factors that usually drive tolerance. You don't have an inflammatory cue. You might be able to display it at a low level and persistently. It's particulate, so that can help drive uptake by scavenger receptors and other things that are looking for, you know, apoptotic stealth cells. This is actually another really interesting strategy to drive tolerance. In all of these cases, as I mentioned, the biomaterials, I think, provide control that, you know, might give some hints as to why some of these strategies could work clinically when a lot of the efforts that have been tried for instance of tolerance in human trials haven't panned out.
First of all, if you can control the density that ligands are presented at, the exact combinations, you know, the first thing is you have the opportunity to induce sufficient tolerance or deletion or other mechanisms. If you can achieve selectivity through things like targeting or, you know, focusing resources on specific epitopes, that also gives you the opportunity to use higher doses that could help drive number one on this slide. Of course, also that might help you minimize or limit side effects through targeting. Also, by leveraging some of these capabilities, could you induce maintenance or survival? Depending on the audience, we might be brave enough to call this regulatory memory, but you could also just think about durability or creating lasting populations of Treg or other types of cells.
Lastly, you know, some of the emerging immunological goals for clinical studies. You know, could you actually get conversion of inflammatory cells back to Treg through processes like transdifferentiation? All of these really, I think, are levels of control. I just wanted to summarize, like, okay, what are sort of the major categories of biomaterials? There's a lot of work here, so I just did it by length scale. Many strategies that we'll be talking about are nanoparticles. You'll see different definitions of this, but I just use a little bit broader definition, less than 100 nm, or practically something small enough that could efficiently drain through lymphatics, you know, 30 nm, 40 nm, 50 nm.
You might conjugate self-antigens or other cues to these particles, and they can reach lymph nodes or spleen, using things like conjugates or albumin shuttling. Microparticles, these are going to be too large to reach, travel through lymphatics, but antigen-presenting cells could encounter them, carry those cues back to nodes or other sites. You might have a depot at the injection site, that as cues get released, those cues could drain directly through lymphatics. There's another class that's also very interesting, scaffolds. These are macro- scale, could be what we call a hydrogel that can be injected and solidifies at body temperature or, an implantable scaffold.
I think some of the areas of work in this realm are, you know, loading cues that recruit APCs or other immune cells to the scaffold, programming them, and then they could maybe go back to the lymph node or some other site to have a function that's been endowed. Again, all of this is about control, and that's really what we want when we're talking about regulating an immune process that's either excess or defective without compromising all the healthy pieces we need for normal responses. In terms of the specific materials, I'm not going to go through this. This is a review I recently put out, but in the review it does go through a lot of different types of materials and routes, which also have a big effect on tolerance.
I just put this reference up there in case folks want to take a look at it. Now, I just wanted to close with a couple of quick snippets of, you know, examples that we've done in my own lab that demonstrate some of the opportunities to use the controlled biomaterials convey. This first one is a concept of self-assembly. We're actually using self-assembly to build nanoparticles completely from immune signals. We get a very high density of these, in this case, a self-antigen, the myelin that's attacked during autoimmunity. We're using an antagonist of an inflammatory pathway that blunts a key pathway that helps drive autoimmune disease or inflammation. That creates an opportunity for Treg to form. This is just a mouse model of autoimmunity, with higher scores of more severe disease.
When we use these structures, we eliminate the disease entirely. What's neat, though, is if you look at the signaling, you see a lot of blue here, a lot of red here, and these are all genes that are inflammatory genes that increase when we remove the regulatory cue that I mentioned and replace it with a scrambled version. All of these kinds of turn off inflammation. We've got the ligand present. If we use a scrambled version, that turns back on. We've shown that this impacts how Treg develops. Also, we've done this in vivo. This is all in mice, but we've now been working with samples from human MS patients, and kind of the same idea. We can take samples, these are patients with different disease histories, and genders, and other characteristics.
If we re-stimulate their cells with these structures containing myelin and a regulatory cue or myelin and a scrambled version of that, we can actually turn down the myelin- specific responses across these different patients. I'll end with another example that's kind of on the opposite end, where we're actually just trying to physically or mechanically locate our cargo into a lymph node. We make particles that are too large to drain out of lymph nodes. We can introduce them, and that's what you see these green dots are, and then they slowly degrade in that site and create local niches in the lymph node that are tolerogenic. You can program the cells that go into that site, it's almost like a factory.
They then leave and give you a systemic antigen-specific response. Again, this is that same mouse model of autoimmune disease. This is an animal at the peak of disease. Right after this, we treated the animals with a single treatment of these diffusion -limited depots. Then this is the same animal. You can see that we got a dramatic reversal of disease. With that one treatment, this is a permanent, durable tolerance. We've also shown that it's pretty neat, it's antigen- specific. If we replace these, therapeutic peptide myelin with an irrelevant peptide, that efficacy goes away. Likewise, if we look at the actual sites of disease, in these cases we treated the inguinal lymph nodes kind of down in the groin.
We looked then at the brain and the spinal cord, and you see that in an animal with disease, there's a lot of infiltrating T cells. It's bad, pathogenic. Animals we treat with, instead of a sham, we treat with the therapeutic version, we have a marked reduction in infiltration of these T cells. You know, it's really the idea that with a biomaterial you could treat at a site to direct an immune kind of outcome, but then get systemic and very selective effects in other places, such as the pancreas or such as the, you know, CNS or whatever antigen might be relevant, if it's gluten or something else. The last point is the modularity of many biomaterials lets you change out antigens or other cues.
We've used the same approach that will hopefully be published very soon. To get 500% improvement in non-matched islet transplants or tolerizing against pancreatic islet antigens to get 500% improvement in animal survival. In this very quick overview, I hope I've given you a little bit of a crash course in some of the emerging themes in nanotechnology and some of the levers that I've listed here, where I think the control the materials provide might help make some real differences in antigen- specific tolerance in the clinic. With that, I'd be just turn it over to Robert, who's going to do a deeper dive into celiac.
Thank you, Chris. Let's have these slides. I'm a gastroenterologist. I trained in Australia, and then I worked in Oxford as a postdoc celiac disease. I did a peptide. My work began with discovering peptides, driving the T cell response through to designing and then the preclinical and clinical development of the first antigen-specific therapy using gluten peptides. I'll talk a bit about that. Next slide, please. I'll focus on the clinical need, a few basics about celiac disease, and why alter. Look at the unmet need, the work that I've been involved in over about the last four or five years, particularly in terms of biomarkers, which is now a very rich and productive area which really makes celiac disease stand out. The immunodominant gluten why we think they are the correct peptides and the therapeutics in development.
A quick note, though. Celiac disease has become the indication of choice for many companies developing tolerogenic therapies, and it's because of the ability to reintroduce the antigen gluten and then understand within a matter of hours of whether the clinical and the immunological response has been modified. Compared to MS or rheumatoid arthritis, we have much better understanding of the immunodominant peptides, and we have a clinical approach to antigen challenge, which is essentially impossible in the conventional autoimmune diseases. This has led to platforms being tested in celiac disease and then, with the expectation that the success in celiac disease will provide confidence that they are likely to be therapeutic in these other indications. Next slide. I have a variety of disclosures.
I'm currently director and co-founder, as you heard, of Novoviah Pharmaceuticals, developing T cell diagnostics and monitoring tools for celiac disease. I consult for many of the drug developers in celiac disease. Until three years ago, I was based in Cambridge, Massachusetts, at ImmusanT before it was wound up. Next slide. Celiac disease, like many of the traditional autoimmune conditions, is strongly linked to HLA, MHC class II antigens. In celiac disease, as with thyroid disease, type 1 diabetes, Sjögren's and Addison's disease, it's HLA-DQ2.5, which is the really striking genetic association. We think about half the genetic risk in celiac disease is conveyed by HLA-DQ2.5.
90% of patients are HLA-DQ2.5, and that has turned out to be really important because that shapes the T cell response in terms of which gluten peptides are being recognized. In celiac disease, the big breakthrough, I guess a little over 20 years, well, nearly 25 years ago now, was realizing that it's not gluten that drives celiac disease. It's a modified deamidated version of celiac disease. The enzyme transglutaminase 2, which is in the gut, it's released. It's normally intracellular, but it's released from cells if they're injured. Modifies gluten, selectively changing glutamine residues to glutamate. It's about 40% of the amino acids in gluten are glutamine. The transglutaminase modifies only some of those glutamine residues, but they allow certain peptides to bind much more efficiently to the HLA-DQ2 molecule.
We think it's clearly an acquired immune response. It usually begins by about the age of three, and it's associated with the development of antibodies against deamidated gluten peptides, DGP IgG. The hallmark for screening is serology based on autoantibodies directed against transglutaminase 2. It's not what you might expect of a traditional autoimmune disease. It's like we think what's actually happening is the gluten peptides are cross-linked onto the transglutaminase molecule. The complex is driving an immune response, at least a humoral immune response against both the transglutaminase 2 and deamidated gluten peptides. However, it's the CD4 T cells which are driving the pathology. We don't think CD8 T cells are relevant because this is an extrinsic antigen rather than an intracellular antigen.
We're very focused on the CD4 T cells, and it now appears that the CD4 T cell is directly implicated in the acute symptoms and a systemic cytokine release response after eating gluten. We think that ultimately the gut pathology is driven by CD4 T cell. Next slide. The only treatment that we have to offer patients is a gluten-free diet. Effectively, it's not gluten-free, it's a gluten-reduced diet. We think most people are actually being exposed to gluten, every day, well, most days, and as I'll show you in a moment, many of the pathologies in the gut are improved but not resolved by gluten-free diet. A lot of people have celiac disease.
About a third of them are likely to be diagnosed in the United States and in Europe, which results in somewhere between 1 million Americans and 1 million-2 million Europeans diagnosed with celiac disease. Typically, the age of diagnosis is about 40. Remember that these patients are probably developing celiac disease about the age of three. Most of are females. There are many others on a gluten-free diet who don't have a clear diagnosis, and many of them do not have celiac disease. Currently, we require biopsy of the duodenum for diagnosis, combined with serology. Now it's beginning to be accepted that very high levels of serology are acceptable for diagnosis in children. Next slide. A lot of shortcomings with current treatment. I guess I would highlight the last bullet point there. The treatment may be worse than the disease.
Patients are really upset when they find out they have to have a lifelong gluten-free diet and appreciate quite how challenging being on a gluten-free diet is. When they do go on a gluten-free diet, sometimes their symptoms are actually worse. When they have acute gluten exposures, they can develop quite significant GI symptoms like food poisoning, vomiting, nausea. I'll show you in a moment. When we've looked more carefully at the gut biopsies, about 60% of patients who appear well controlled still have villous atrophy, which is the hallmark feature of the duodenal injury in patients with celiac disease. The other thing which we've discovered and I've been involved in the last couple of years is there's a systemic cytokine release phenomenon after eating gluten in patients on a gluten-free diet.
Treatment at the moment is really directed fundamentally at gluten-free diet. It's difficult. The FDA is encouraging us to develop treatments to go on top of the gluten-free diet initially, but this could well lead to treatments that could replace gluten-free diet. Next slide. The effects of gluten in people with celiac disease who are on a gluten-free diet are time- dependent. The most rapid onset symptoms are nausea and vomiting, which occur typically between one to two hours after gluten exposure. This is accompanied by cytokine release, and interleukin-2 is the biomarker which has emerged as an indicator of gluten exposure. It goes up quickly. It correlates with nausea and vomiting. It's accompanied, though, by relatively smaller increases in a variety of other cytokines and chemokines. We can monitor all of them quite easily by taking blood samples over the six hours after a gluten exposure.
More slower, potentially very useful is that you get expansion of the gluten reactive T cell population, which can be measured in blood over the days after a gluten exposure. It turns out that a week after eating gluten, we see about a tenfold rise in the number of gluten- reactive T cells circulating in blood. Much slower are the traditional markers, the serology markers, and the injury in the gut. These typically take more than two weeks. About six weeks is required, sometimes more, to achieve consistency in the injury in the gut and the elevation antibodies. This is the full collection of biomarkers. Some, yeah, is focused on symptoms and on histology as endpoints. Next, next slide, please. The acute reaction to gluten is just characterized here. It peaks at about three hours in terms of symptoms.
Nausea is the most prominent symptom. This is in a group of 295 patients who all had the same gluten challenge, 10 g of vital gluten. Next slide. This is quite doable in a, in an early phase study to characterize what's going on. The nice thing here as shown, is the interleukin-2 levels and serum following, the same gluten challenge. You're seeing the patients with the most severe reactions, which almost always include vomiting, as the ones with by far the highest levels of interleukin-2. Although we find about 80% of patients diagnosed with celiac disease have a demonstrable interleukin-2 release phenomenon based on the serum IL-2. Even patients who deny symptoms have elevations in interleukin-2. Next slide. IL-2 is emerging as a really valuable marker.
There are, though, a variety of other cytokines as shown here. Very clear difference between the celiac, treated celiac population consuming gluten, versus unaffected patients. It's pretty clear that there's a coordinated cytokine release beginning with IL-2 which implicates the T cell as the driver of this phenomenon, even though it's occurring rapidly. Next slide, please. The basis for our understanding of the T cells and the peptides in gluten that drive celiac disease comes from two sources. The first is the traditional approach to T cell profiling, which is utilizing biopsies, isolating T cells that are cultured in vitro over a period of days and weeks with gluten. This was the basis for the initial work in this field of T-cell epitope mapping.
The method I developed, when I was in Oxford on my postdoc a little over 20 years ago, was to show that patients could consume bread over three days. If blood was collected six days after they began its inclusion, there is this remarkable expansion of T cells in blood, which could be then mapped using a list of assays. This allowed us to do very comprehensive mapping of essentially all of the then-known peptides in wheat, rye, barley, and also oats. Next slide, please. The result of that work, though, was a very detailed map showing that there were key peptides, and there were three that we identified along with the groups, and particularly in Oslo and the Netherlands who worked on T cell lines.
There was concordance really between the groups showing that the alpha-gliadin peptide you can see there, it's an 11 amino acid sequence with two overlapping nine- mer epitopes. Deamidated right there in the middle, you can see that E, that's glutamate. In the native sequence, that's gluten, glutamine. Transglutaminase modifies these peptides crucially to allow them to bind to HLA-DQ2 more effectively. You can see in the map on the left, the red areas indicate where T cell clones raised against the first peptide, alpha-gliadin, responded to a rather conserved region within many of the alpha-gliadins. For the omega-gliadin peptide response, it came up when patients ate any of the toxic cereals, and then one from barley, which is less important, but it still comes up.
The immunotherapy that I worked on in phase II consisted of three peptides, which had these three key immunogenic regions in them, and many groups subsequently have utilized these peptides together or sometimes the alpha-gliadin. I think the alpha-gliadin by itself is probably not ideal. The omega peptide is important. Next slide, please. Just to finish up, the areas where pharmaceutical development is focused is in these five main areas. There are a lot of drugs that are in preclinical. These are the ones that have made it into clinical development. The ones in blue are in phase II or beyond. The ones in B are in phase I. As you can see, the only drug that has been in phase III, larazotide, was discontinued earlier this year. That was a permeability agent.
There are, though, interesting precedents for antigen-specific immunotherapy. I would say we've learned most from the drug trials that have been focused on antigen-specific immunotherapy and transglutaminase 2 inhibitors. Many of the large pharma companies have taken an interest in celiac disease. Takeda is the most prominent, several of the other large pharmas are in this space, all learning the process of how to get regulatory approval. Currently, there's no drug with regulatory approval for treatment of celiac disease. I guess the key thing there with antigen-specific immunotherapies is that many of them have confirmed bioactivity in the phase I trial by showing cytokine release after the first dose.
Efficacy is shown in those early trials by showing suppression of the response to the drug itself, but also in some cases, suppression of the immune response and the histological response to eating gluten in a short-term gluten challenge. Very short gluten challenges are feasible. Giving the drug on several occasions can provide proof of concept. I guess the ones to watch out for, though, in the other areas are the transglutaminase inhibitors, which now are being pursued by GSK and by Takeda. A recent New England Journal paper on the TAK-227 indicated that reduced gluten- induced damage in the gut. A busy space, and it's emerged quite quickly in the last 10 years. I will stop there. Thanks for the opportunity of sharing this.
Okay, great. Dr. Anderson, really, really great discussion, and I'll go ahead and talk about what Barinthus is working on. If you could please advance to the next slide, please. Really, you know, what Barinthus is doing is building on a lot of the discoveries highlighted by Professor Jewell and Dr. Anderson to advance a candidate for celiac disease that leverages our platform referred to as SNAPvax. I really, you know, the goal of this program is really highlighted in this slide here. As discussed by Dr. Anderson and Professor Jewell, a major limitation of current treatments for autoimmunity, including celiac, is that they're nonspecific and often have dismal immune effects.
Therefore, a goal of our work in the tolerance SNAPvax tolerance program is to induce antigen-specific regulatory T cells that work by providing a specific and potentially more mild treatment that provides potentially durable protection from disease. The way that we're doing that, if you could advance to the next slide, please, is through use of our SNAPvax platform. Our approach to inducing Tregs is to co-deliver multiple peptide antigens and immunomodulators and self-assembly nanoparticles that target antigen-presenting cell populations that specifically prime regulatory T cells. Now, the important thing to emphasize is that our SNAPvax technology utilizes self-assembly, allowing for co-formulation of multiple peptide antigens and immunomodulators. I really emphasize this point is because going back to what Professor Jewell stated, is that really a key goal of nanotechnology is to provide control.
The way that we provide control is using self-assembly to bring together multiple peptide antigens and these immunomodulators. An immunomodulator is what provides the appropriate signals for really skewing the responses that we're generating towards the regulatory T cell population. If you could please advance to the next slide. The way this works is, I'll emphasize that the chemistry and mechanism of action underlying SNAPvax have been reported in recent publications, including a 2020 Nature Biotechnology particle paper that I've referenced below. In short, SNAPvax comprises a 20 nm size nanoparticles that are really an optimal size for targeting lymph node antigen-presenting cells, which recognize and take up particles. Within those antigen-presenting cells, the antigen and immunomodulator are co-delivered.
In the case of our tolerance program, the immunomodulator, excuse me, provides a context for promoting regulatory T cells that in the presence of antigen being processed and presented to naive CD4 T cells, helps to drive regulatory T cell responses, or what we refer to as inducing tolerance. Next slide, please. You know, an important point that I'll really emphasize that distinguishes what we're doing from some of the current approaches that are in advanced stages of clinical testing is that we aim to include the right antigens, but we're also co-delivering an immunomodulator that, at least in our work, we found is critical for efficiently priming regulatory T cells.
As shown in this data here, an antigen relevant to multiple sclerosis referred to as MOG, when provided alone, does not induce a significant number of Tregs above background in this assay, but when co-delivered with an immunomodulator, induces a significant increase in antigen-specific regulatory T cells. Next slide, please. You know, the other really important point to emphasize is that... Sorry, next slide, please. Okay, I just went over this one. One more slide, please. Okay. An important point to emphasize is that Vaccitech's lead SNAPvax utilizes an immunomodulator that has been shown to markedly improve Treg skewing as compared to rapamycin, which is considered a gold standard. This really emphasizes that not only is the antigen selection important, but the type of immunomodulator you use as well is key to helping prime regulatory T cells.
In this data set, you can see that SNAPvax with our so-called novel immunomodulator induces a high proportion of Tregs as compared with SNAPvax or rapamycin. Shown in this figure, as you can see on the right there's a higher proportion of Tregs as compared with another CD4 T cell population called a Th1. Really shows the importance of having the right immunomodulator together with antigen to efficiently prime regulatory T cell populations. Next slide, please. With our lead SNAPvax comprising the so-called novel immunomodulator, we've been able to show in mouse models of MS, referred to as EAE, that SNAPvax is efficacious by both the IV and IM routes of administration.
As seen in this figure, mice receiving vehicle develop a disease score of three which indicates partial limb paralysis and weight loss, which Professor Jewell showed in some of his slides, where SNAPvax by the IV route leads to near complete protection, and SNAPvax by the IM route, intramuscular route, completely abrogates disease in this model. This is important because many current tolerance strategies rely on IV administration, which can be cumbersome and potentially more likely to lead to toxicities as compared with IM route, which is likely preferred based on its simplicity, safety, and ease of implementation in outpatient pharmacies. Next slide, please. A final important point, rounding out our preclinical data, is that it appears that the protection we are getting is durable and may be related to immunological memory.
As shown in this data, SNAPvax with the MS antigen MOG leads to complete protection after disease onset, shown on the left side of this figure. As shown on the right, we then rechallenged protected animals two weeks after the final treatment, and the data show that all the mice have significantly improved protection, with four out of five completely protected. This data suggests that there's immunological memory that protects against rechallenge, which really is a goal of immunotherapies to get long-lived, durable immune responses that are protective against autoimmunity. This is some data, at least in the mouse EAE model, suggesting that that might be possible using the SNAPvax tolerance vaccine platform. Next slide, please. In sum, SNAPvax's tolerance is a modular peptide-based platform that can be programmed to promote antigen-specific tolerance.
Really a key point to emphasize is what Professor Jewell discussed earlier, is that this platform is really built to provide precise control over the antigens as well as immunomodulators, and really control the loading of those into particles of precise programmable composition. SNAPvax enables manufacturing and formulation of multiple key antigens and nanoparticles for efficient priming of regulatory T cells. This co-delivered novel immunomodulator has been shown to really improve the skewing towards the Treg population. Whereas many current approaches rely on IV administration, we've shown that SNAPvax is effective in preclinical models both by IV and IM routes, with the latter preferred for translation to patients. Next slide, please. We're now planning to leverage SNAPvax's tolerance platform for treating celiac disease with our candidate VTP-1000. Next slide.
Next. As Dr. Anderson discussed, the key epitopes derived from gluten have been identified and experimentally validated. We've then taken a bioinformatics approach to identifying a set of epitopes that is expected to give us near complete coverage of antigens derived from major grains, including wheat, barley, and rye, specific to the most important HLA allele, HLA-DQ2.5. These sequences will then be formulated with our novel immunomodulator and SNAPvax particles as discussed previously. Next slide. We're currently manufacturing VTP-1000 and undertaking key IND-enabling studies in advance of the clinical trial plan for this year that will evaluate safety, a proof of concept efficacy, and immunogenicity. The first part of the study will be a 3+3 dose escalation design, followed by an expansion part that will be double blind placebo-controlled.
Importantly, this, I believe, is also emphasized by Dr. Anderson. In this study, we'll be looking at a gluten challenge four weeks after four treatments. This will allow us to assess safety and determine a small subset of patients, if we're able to generate regulatory T cells that can reduce disease following re-challenge, and thereby providing a relatively near-term proof of concept efficacy readout. That concludes my portion of the discussion. I'll now hand it over to Bill Enright, our CEO, to close out the discussion here. Thank you.
Thanks, Geoff, Dr. Jewell, and Dr. Anderson for providing some insightful comments around this important disease. I'll take a few minutes to just give you an idea of where Vaccitech is going. Next slide, please. Our mission really is to become a global leader in immunotherapies and vaccines that leverage T-cell immune responses, both CD8 + T cells in the event of cancer and chronic infectious disease, as well as in the Tregs in the immune tolerance space that we've been focused on our discussion on today. Next slide, please. To do this, we leverage a number of different platforms.
In addition to the SNAPvax platform, which we discussed and we're utilizing on both, the tolerance platform, as well as on the infectious disease and chronic infectious disease and cancer pipe. We also have a number of viral-based platforms. One of the key things here is many people now have learned from COVID-19, is that utilizing these peptides in a heterologous prime boost or in a mixing and matching way, generates pretty significant T-cell responses. These viral-based platforms really been designed to utilize in that heterologous prime boost fashion. We can generate really high levels of CD8+ T cells that last for a long time.
You know, we've shown in, we and others have shown that when you can do that you have a potential impact on a number of different diseases. You can see from our pipeline on the next slide that we are going after a number of different diseases here. Our lead therapeutic candidate right now is a potential functional cure against hepatitis B. We presented some very interesting data this year at both EASL and AASLD, showing significant surface antigen response that is that lasts at least nine months, which was the last time point tested. We'll have final efficacy data from that study in the first quarter of next year. We've got a couple of phase IIs that are ongoing as well.
One that's looking at timing of low-dose checkpoint inhibitors in combination with VTP-300 and the other looking at combination with siRNA with a collaboration that we have with Arbutus. VTP-200 is a potential cure for HPV, so trying to eliminate HPV before it causes cancer. We've got a phase I/II trial that's ongoing for this study, with our first potential efficacy data in the first quarter of next year as well. A couple of programs in oncology, and prostate cancer and lung cancer, and then the VTP-1100 and VTP-1000, both derived from the SNAPvax platform, that we intend to get into the clinic next year.
We'll have INDs planned for the HPV cancer program in the first half of next year and in the celiac program the second half of next year. The focus really is on our therapeutic programs, although the technology, as we've shown, is very applicable in prophylactic indications. This is the platform that was behind AstraZeneca's COVID-19 vaccine that we outlicensed through the University of Oxford to AstraZeneca. Extremely large safety database in this program. We've got ongoing work going on in MERS and with our partners at CEPI and the University of Oxford, as well as with Zoster prophylactic with our partners in China, CanSinoBio. With that, I will turn it over to Tara for Q&A.
Great. Thank you, Bill. At this time, we'll be conducting a question- and- answer session with our speakers. As a reminder, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. Our first question comes from Matthew Harrison from Morgan Stanley. Please go ahead, Matthew.
Great. Good evening. Thanks for taking the question. I guess two for me. One, can you just talk about the range of immunomodulators that you've looked at in the platform, and sort of where the research side is there in terms of the immunomodulators that you plan on using with VTP-1000 versus some of the other programs you're thinking about? Second, just-
As you think about sort of the initial doses that you're looking at, what do you think is a clinical effect that you might see, or what do you think is clinically meaningful in terms of, gluten challenge? Thank you.
Geoff, you wanna take the first question?
Yeah. I'll go ahead and take the first question. Andrew, if you could take the second. The question is, which immunomodulators have we looked at, in essentially getting at how did we land on our, the novel immunomodulator that we mentioned. Really, you know, a few years back, we started taking a very broad look at what types of molecules would be useful for inducing regulatory T-cells. There's really three main classes that, you know, we focused on. Those are the mTOR inhibitors, the aryl hydrocarbon receptor agonist, and then also the scavenger receptor agonist. There's a lot of data supporting each of these three different classes of molecules.
It was within the mTOR inhibitor class that we found a novel agent that had not been used for tolerance previously. There was a lot of interesting biology underlying the molecule that we selected. We believed it could be effective for this purpose. Then, through several in vitro and then in vivo animal studies, we had identified a lead candidate based on this really extensive search, you know, about two and a half, three years back. That's how we landed on the molecule and the specific classes we looked at. Andrew, you wanna take the second part?
Sure. My name is Andrew Smith. I'm also a VP at Vaccitech and have been involved in the design of the clinical trial. We plan to do a single gluten challenge of either 3 g or 10 g of gluten for the initial first human clinical trial. We'll be looking at IL-2 and symptom scores in the immediate time period after that challenge. That's a pretty hefty dose of gluten. As Dr. Anderson said, the kinda daily exposure is about 16 g. We think we'll get a really excellent or the markers that we're looking at, the IL-2 signal specifically, is a very sensitive way to look at and evaluate efficacy in this model.
Subsequent studies, if that challenge is successful, that single dose challenge will look at multiple dose challenges in a subset of patients going forward. I'll just turn it over to ask Dr. Anderson, if he has any other comments on the size of the gluten challenge and how significant it is.
The size of the gluten challenge is important. As I highlighted earlier, the FDA is looking for adjuncts to gluten-free diet initially. In terms of gluten exposure that's likely to occur on a gluten-free diet, I mean, 3 g is still quite a hefty exposure. It's the same as about a bit over a slice of bread. You'd have to be pretty unlucky to get a slice of bread inadvertently. The 10 g is right up there. I mean, that's 2/3 of a daily intake of gluten in a normal, unrestricted diet. We use those doses really to push the system pretty hard, and some people do get quite sick with that. That's the data that I was showing you. About a quarter of the senior patients will vomit with that level of gluten.
If you give 3 g , some will vomit, but mainly it's gonna be nausea, a bit of tummy pain. I would highlight there, though, that the biomarkers are really the thing that are going to, I think, convince you that the drug is working. You have the interleukin-2 that can be measured within hours after eating gluten, three hours. There's the whole blood interleukin-2 release test, which is helpful in screening 'cause it tells you the patients actually have T cells recognizing the antigen in the compound. We know that about 1 in 10 patients are probably misdiagnosed. By combining these biomarkers, you can have a very efficient proof of concept early on in the program, which I think you're describing there, Andrew.
Okay. Thank you. Tara, are there other questions from the analysts?
Yes. Our next question comes from Peter Welford from Jefferies. Please go ahead, Peter.
Hi. Thanks for taking the question. Just two quick ones. First, is there any, or do we have any understanding of whether or not you will develop any long-term, I guess, immune modification due to this? I mean, I guess what I'm trying to understand is there a potentially you can actually, with a course of the vaccine, induce a permanent change, or is this likely to be a lifelong therapy? I don't know whether there's any data at all to suggest we can infer anything from that.
Equally, in the first phase I study, is there any suggestion that you can potentially rechallenge some of the patients a few days or perhaps weeks later to see what sort of residual or core benefit you have perhaps from the dose you do? Just secondly, just regard, so I can understand the manufacturing. Is there any, can you just sort of talk us through what, with regard to the SNAPvax, what manufacturing you have set up to get that to be able to be prepared, I guess, for potentially going into later-stage trials as well in the future? Thank you.
Thank you, Peter. Geoff, you wanna start with the preclinical data on memory?
I'll take the first part of this. Yeah. I'd say that Professor Jewell's really studied this extensively in his group. I'll say that in the preclinical data I showed earlier, we've shown that, you know, two weeks after the last treatment, you can then rechallenge animals. It suggests that it's not the ongoing treatment that is altering disease. It's possible that you've actually generated immunologic memory from prior treatments. Two weeks is not very long after treatment. This is a, you know, kind of earlier preclinical study. We do aim to push that and rechallenge at much later time points following last treatment. I will say in our own clinical trial design, we expect to challenge four weeks after last treatment.
All of the vaccine should be washed out by now. Anything, any response you're seeing should be, I'll say, should be immunological memory. That said, Professor Jewell also studied this. Professor Jewell, would you like to comment on potential of immunological memory?
Yeah. I think preclinically, I mean, there are a lot of tools to understand the durability and a lot more recognition of things like memory or at least maintenance capacity among Tregs. There's certainly, you know, the opportunities from everything we know about preclinical work. I think the idea of durability or the ability to create durable populations that, you know, kind of induce a lasting remission by controlling existing planetary populations is also something that, as Geoff said, is being studied clinically. Understanding what kind of biomarkers you can look at, you know, to understand if there are maintenance and survival signals being received by those cells in patients as you're drawing samples. You know, as that evolves, I think there'll be a lot more insight into what's gonna happen in the human case.
Certainly, preclinically, a lot of exciting developments in that area.
Could I just comment on that one, as well?
Mm-hmm.
We know something I did quite early on was to try gluten- challenging people soon after diagnosis, and I found that patients became much more symptomatic to gluten exposure when they excluded the gluten for at least two weeks. When many, many patients consume gluten regularly, they actually don't have many symptoms. When they exclude the gluten, they continue to have no symptoms to gluten challenge one week after they begin a gluten-free diet. From two weeks, they do become symptomatic when they have gluten. It suggests that there are processes going on in patients that probably downregulate the symptomatic response. The only other thing I'd just comment on that. In practice, people don't like having gluten challenges much in trials for celiac disease.
One of the real skills, I think, is designing the trial so that you do get an understanding of durability without necessarily re-exposing to gluten. The other conundrum is that exposing to gluten may confound the response to the next gluten challenge. Gluten challenge is great, but only once or twice during a trial. That's really why the blood tests are a very convenient way of understanding durability of the non-responsiveness or responsiveness. If it's allergy that you're inducing, that'll typically begin to unravel after about two weeks, and by four weeks you'll be back to normal. If it's something else more durable, you'd expect it to be going on for more than four weeks.
I think in the long term, it's the challenge is that the immune modulation changes with the number of doses and over the period that you give the dose. This is really why the trials in humans are so different from in mice. The other thing just to highlight is that the mouse experiments are in young mice and very soon after disease induction. We're talking about patients with celiac disease who've had the disease for over 30 years in most cases. There are tweaks that can be made to the experimental design that can give you a lot of information about durability, which is really the key issue as to whether you have a maintenance treatment or you have a more of a curative treatment.
Thank you. Thanks to everyone for answering those questions. The last thing I'll just add is, we do plan to build in an optional rechallenge for participants in the first-in-human clinical trial that will take place about 3- 6 months after the first challenge. We do hope to get durability data as well. Tara, I'm cognizant of the time. We're over 5:30 Eastern time already. Is there time for additional questions, or should we wrap up?
Yeah, we have time for one more question. Andy Hsieh from William Blair is in the queue, so we'll have him ask his question. Please go ahead, Andy.
Oh, great. Thanks for squeezing me in. I have an immunology question. In terms of, you know, kind of anti-tumor effect, I think we kind of are familiar with the idea of antigen maturation, and, you know, basically kind of honing in on what's really pertinent. I'm just curious if the same effect exists in terms of regulatory T cell biology. We've also kind of heard about kind of the original antigenic sin also from the, you know, the COVID vaccine realm. I'm just wondering if that's also, you know, relevant in terms of, you know, using the platform like this one. That's question number one.
Question number two, you know, in the paper you published before, I think you delineated between the sub-Q dosing and also the IV dosing, and you kind of attributed that to more stem cell-like in terms of the differences in efficacy. I'm just curious if that could also be expected from the IM dosing and also the IV dosing that you're thinking about in terms of the celiac disease? Thanks.
Okay. Could I turn it over to Geoff to answer we'll start with the second question first. That was how does the route of administration potentially impacts T cells?
Yeah. Andrew, I can also just answer the first one as well. I think the first question was getting at, you know, affinity maturation. I'd really say that's probably something we think more about in the antibody-mediated immunity context. For T cell-driven responses, we're really looking at a specific peptide MHC complex that's recognized by a specific T cell receptor clone. As far as I understand, there's no maturation of the T cell receptor that recognizes that peptide MHC complex. So, really the goal for immunological tolerance is to either prime a regulatory T cell response or take existing T cells that are pro-inflammatory, so these are their Th1- type CD4 T cells or Th17, and then either delete them, energize them, or transdifferentiate them towards the Treg population.
It's really giving that antigen to either induce Tregs or to change the Treg population. You know, having the immunomodulator present helps skew that population, but that's really the goal of T cell-based therapy versus the antibodies, where you're really trying to mature a response and trying to avoid off-target antibody responses, which you alluded to in COVID. Regarding the second question, Andrew, where was I going with that? If you could remind us?
Sure. It's, how the route of administration may affect-
Oh, right.
... the T cell quality.
Yeah. There's a couple factors for the cancer vaccine that I don't think we're facing here. One of the factors is the persistence of antigen pro-inflammatory stimulus. In the context of the cancer vaccine, we're including a toll-like receptor 7 agonist that creates a pro-inflammatory environment. Having that delivered locally provides persistent innate immune activation that, if it's too persistent, can lead to more of a kind of exhausted type T cell response. Having antigen delivered by the intravenous route actually gives you a more rapid clearance of the antigen by APC, antigen- presenting cells in the spleen and liver. We think that the pharmacokinetic differences may play a role there for the cancer vaccine.
For tolerance, you know, one of the big questions is how does the route of administration affects Treg induction and efficacy? There's a lot of earlier data suggesting that there's sickle inherent APC populations that may inherently promote tolerance localized in the spleen and liver. A lot of efforts were initially focused on IV route of administration. At least, you know, now with the some of these nanoparticle technologies that Chris Jewell's talked about, including our SnapVax platform, we've shown that we can effectively induce, in pre-clinical models, if you will, effectively induce Tregs by the IM route.
I think it's some of the mechanisms that make IV important for cancer we don't believe apply here, but there is still an unknown question in the field of, for tolerance, you know, really is IV or IM preferred for translation, based on some of the theoretical advantages of IV, given the APC populations that are localized in the spleen and liver. That's how we're thinking about it.
Great. Thank you so much.
Well, that's all the time we have for questions. I'll turn it over to Bill to close out the session.
Yes. Thank you very much, everyone. Really appreciate everybody joining us for this. Thank you for your time and attention. Thank you very much to both Dr. Jewell and Dr. Anderson for joining us as well.