Good afternoon, and welcome to the Vaccitech KOL event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentation. 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 your host, Nadège Pelletier, Chief Scientific Officer of Vaccitech . Please go ahead, Nadège.
Good morning, good afternoon, good evening, everyone. Welcome to the Vaccitech KOL webinar. Together with us today online, we have Bill Enright, Vaccitech CEO, Professor Ellie Barnes from the University of Oxford in the U.K., Professor Ed Gane from the University of Auckland in New Zealand. We will be talking about the current efforts that are being made across the board in the search of a functional cure for chronic hepatitis B. Our first speaker today is Ellie Barnes. Professor Ellie Barnes is a Professor of Hepatology and Experimental Medicine at the University of Oxford. She is leading a research group with a focus on applied immunology relevant to liver diseases, including chronic hepatitis B and hepatocellular carcinoma. Beyond this, Ellie is also leading international large consortium on stratified medicine in liver diseases.
She will be giving some background on chronic hepatitis B and, the HBV virus, and highlight the different treatment approaches that are currently either available or under development for chronic hep B. Our second speaker today is Professor Ed Gane. Ed is a Professor of Medicine at the University of Auckland in New Zealand, and Chief Hepatologist, Transplant Physician, and Deputy Director of the New Zealand Liver Transplant Unit, at Auckland City Hospital. Ed is an investigator for many clinical trial, international of new therapies for chronic viral hepatitis, and has been a long-standing high-profile figure in chronic hep B therapeutic strategy discussions. He will be talking about the value of combining different, therapeutic approaches, different MOAs, in, the goal of achieving functional cure for chronic hep B patients.
We will finish off with a short presentation of Vaccitech HBV asset, VTP-300, and how it fits the overall scheme of hep B functional cure. To start off, a little bit of background on Vaccitech, who we are. Vaccitech is a clinical stage company, a spin-out company from the Jenner Institute for Vaccine Research from the University of Oxford. We have a broad pipeline spanning across three therapeutic areas: chronic infectious diseases, autoimmunity, and cancer. At the core of all Vaccitech program, our technology platform, which are really highly specific antigen delivery platforms, either viral vector-based, with ChAdOx1 and MVA, and that's the program that you see in light blue on this slide, or fully synthetic with SNAPvax or more recently acquired platform, and that's the program that you see in dark blue on this slide.
So whether they are viral-based or fully synthetic, our platform have been specifically designed to guide disease-specific T cell responses back towards a healthy response, specifically in diseases where T cells are failed to protect. So in the context of chronic diseases like chronic infections or cancer, where T cells have lost their ability to fight the disease, so they are not able to kill the infected cells or the cancer cells, our immunotherapies are really aiming at restoring high numbers of high-quality disease-specific T cells, so they can fight the disease on their own.
On the contrary, in autoimmunity, where T cells have, on the other side, become a bit rogue, our approaches are aiming at dampening hyperactive T cells on the one hand, and on the other hand, increasing Tregs, so that we can reach a balance that is beneficial, a Treg to T effector ratio that's beneficial and in full control of the disease. So we will have a bit of time later on. Bill will take you into a bit more details of our pipeline. But in the meantime, let's start off with chronic hep B with our first speaker, Professor Ellie Barnes.
Okay. Thank you, Nadège, for the kind introduction. So, I'm going to focus my short presentation here on the treatment toolbox, and really highlight the difference in an innate approach and an antigen-specific immunotherapeutic approach, and explain what that means. My disclosures, I have consultancy and research grants for vaccines against viral hepatitis and liver cancer from AstraZeneca, Roche, and Vaccitech. Okay, so I'd like to start by highlighting the enormous size of the clinical problem that is hepatitis B virus infection. It's estimated that 300 million people are currently chronically infected with hepatitis B. I mean, I find it hard to imagine that number of people. And there's an estimated 1.5 million new infections every year. And in fact, hepatitis B is the eighth most frequent cause of mortality globally.
It actually causes more deaths per year than HIV and malaria combined. I think that's a fact that's frequently not fully appreciated. One point four million of these deaths per year come from acute infection, usually in adults. There's an estimated 820,000 annual deaths from the consequences of chronic hepatitis B virus infection, which is increasing scarring of the liver, which we call liver cirrhosis, and eventually transformation of the cirrhotic liver to hepatocellular carcinoma. In hepatitis B, liver cancer can also occur in the absence of liver cirrhosis, so an enormous global problem. If you look at how hepatitis B is distributed around the world, much of the infections is in Eastern Asia, Western Pacific, Southeast Asia and Africa. Even in the Americas and Europe, there's almost 20 million people infected.
The Polaris Observatory Group, which are an international group of epidemiologists, really have concurred with the WHO data. They estimate 275 million people are living with hepatitis B. Actually, this represents 3.5% of the world's population, which is an astounding figure, I think. The World Health Organization has set very ambitious global targets for hepatitis B that they hope to achieve by 2030. One point five million new cases of chronic hepatitis B, they would like to see that reduced by 90% to 150,000.
900,000 hepatitis B deaths reduced by 65%, and at the moment, only approximately 1.6% of people that are eligible for treatment receive that, and they hope we can increase that to 80% by 2030. There is an existing vaccine for hepatitis B. Most people will have heard of this, but just to be clear what this vaccine is, this is a protein-based vaccine that induces antibodies, and it's very good at actually preventing infection, so it's a prophylactic vaccine. However, it will not work at all in someone who already has persistent infection, because once the liver is infected, the virus can spread from cell to cell, and antibodies will not block that cell-to-cell transmission.
So this is a vaccine that does exist, that prevents infection, but does not treat the pool of people who are currently chronically infected. You could argue that we could just try to vaccinate everybody with this prophylactic vaccine, and that would solve the problem, but the estimates are that would take 90 years to eradicate hepatitis B if there was to be more than 90% coverage, which I would think would be highly unlikely. And in the meantime, we have this huge pool of people with chronic infection who are going to die from hepatocellular cancer, an estimated 80 million people. So at the moment, we have safe, effective oral drugs for hepatitis B to treat chronic infection. But the key point is that these drugs have to be given long-term.
Once you've started a patient on these nucleotide and nucleoside analogues, entecavir, tenofovir, we don't stop that therapy. And this means, as I've already highlighted, that only 1.5% of those who need to be treated actually are. And the reasons why uptake of these drugs is so low are really listed here. So most hepatitis B-infected patients who express hepatitis B surface antigen do not meet pre-specified starting criteria around things like HBV viral load. As I've already highlighted, once you've started, treatment is lifelong, and this is associated with cumulative costs and toxicity in some cases, and stopping those drugs allows the virus to come back, and I'll explain why that is in just a minute. And this can be associated with an immune reaction to that emerging HBV and inflammation in the liver, which can be clinically very, very serious.
For these reasons, once we've started patients on these therapies, they tend not to stop. Furthermore, these drugs do not remove the risk of liver cancer, and perhaps most importantly, they don't target the episomal HBV that sits in the nucleus of infected hepatocytes or the HBV that's integrated into the host's genome. I think to really understand this, I just want to briefly talk through the life cycle of hepatitis B to explain just what happens here, and this is my next slide. This is a hepatocyte. This is the nucleus. This is hepatitis B coming into the hepatocyte through its entry receptor, which was relatively recently identified, and it's transported into the nucleus, where it's uncoated, and it sits there as this cccDNA, covalently closed circular DNA. From there, it makes its messenger RNA through transcription.
That moves into the cytoplasm, and then the messenger RNA is translated into the hepatitis B proteins, and new viruses are made. If you properly understand this pathway, it's obvious that there's all these different parts of that pathway that could be identified for molecular targeting and new therapeutics. That is what's happened with these range of new molecular therapies, which Ed is going to talk about after me, entry inhibitors that block entrance, antisense oligonucleotides, RNAi inhibitors, capsid inhibitors, and nucleotide inhibitors that prevent this reverse transcription step here, but have no effect at all on the cccDNA that's sitting in the nucleus. Now you can understand why, when you stop those nucleotide inhibitors, the cccDNA is still active, and the virus just comes back again. That's the viral life cycle....
There's a whole other side to the story that's going on within an infected hepatocyte, and this is the immune response to the infecting virus. Broadly, we can categorize this response into the innate and the adaptive response. Inside the hepatocyte here, I've highlighted some key components of the innate immune response. Actually, not just hepatitis B. These are not specific responses, they're responses we see in all viral infections, in all cells. This includes the expression of interferons and the expression of toll-like receptors, which, through their pathways, go on to produce interferons. Actually, since 1990, we've used pegylated alpha interferon. It works in a really small subset of patients that have elevated liver function tests. It's pretty toxic therapy. It's the only current therapy that actually can provide some kind of cure for our patients.
And then on the other side, you've got the adaptive immune response with these CD8 cytotoxic killer T cells and CD4 positive T cells. We would argue that a better way to tackle this issue of persistent hepatitis B is try to harness the adaptive immune response, enhancing the CD8 and the CD4 specific T cells that specifically can kill infected hepatocytes. But there's one problem here, and this is the concept of T cell immune exhaustion. After a patient has been infected for many, many years with ongoing HBV antigen exposure, this has been demonstrated to lead to the exhaustion of these HBV-specific kind of T cells. And just to talk you, you know, briefly through that, you can imagine a naive CD8 T cell here that's never seen hepatitis B before.
When that's exposed to antigen, if you have appropriate antigen here and co-stimulation, you have a highly polyfunctional memory CD8 positive T cell response, and this is what happens in acute hepatitis B virus infection. With these cells that make interferon gamma, TNF, CTL with high proliferative potential. But if you have ongoing inflammation and that virus is not quickly eradicated, then you get an attenuated T cell response. You get downregulation of all of these and up, and up expression of these checkpoint modulators, for example, PD-1.
What we really want to do here is to take the immune response that we see in chronic HBV infection, so these deleted dysfunctional HBV-specific T cells, the overexpression of PD-1, and try to transform those into the kind of T cells that we see much more often in acute hepatitis B infection, so vigorous HBV-specific CD8 T cells against all the HBV antigen and the absence of inhibitory receptors like PD-1. A number of people now are working on novel immunotherapies to restore HBV immunity. These are listed here. You can aim to stimulate antiviral effector cells, so toll-like receptor 7 agonist, toll-like receptor 8 agonist. You can try to rescue exhausted cells with PD-1 inhibitors.
You can try to redirect non-HBV-specific T cells and turn them into HBV-specific T cells through quite sophisticated kind of technical, technological approaches, which, in my view, are not widely deployable to the millions of people infected around the world. Then there's therapeutic vaccines, which we're here to talk to you about today, which aim to generate new T cells. I do want to highlight this very nice data that comes from Michael Roggendorf's lab, published actually in 2014 now, but it looked at the only really good animal model of hepatitis B. And this is a combination approach using Entecavir, so an antiviral drug with a vaccine and then anti-PD-1. And in this model, with this combination, this particular research group was able to show that you could restore HBV-specific T cell immunity and clear cccDNA from the woodchuck.
So this was exciting, and it kind of led to some of the approaches that Ed's now going to talk to you about. So I'll stop there, and I'll hand over to Ed. Thanks very much.
Thanks, Ellie. I'm going to talk to you about functional cure, definitions, and the combination approach, which is currently entering clinical trials. Here are my disclosures. I'm obviously talking about investigational use of unapproved medications. Now, why do we need cure? We've heard a lot about functional cure, and that's really what I'm going to focus on today. We really want to be able to cure all patients who are surface antigen positive. This is the dream, regardless of their phase of infection. Obviously, we're going to take steps to get to that final goal, because there are many phases from the young person who's highly immune active, to the older person who has lower levels of replication, and as Ellie pointed out, immune exhaustion. The reasons for cure are really shown here. I should point out at the...
I'll put at the top, something which is often forgotten by some of the, by the clinicians and those in drug development, and that is the members of the affected community. At every meeting we go to, every hepatitis B forum, members of the community stand up and say: We really want you to achieve surface antigen loss because that's the only way to reduce the stigma and discrimination that patients face from day to day. It really would allow them to interact better with their workplace, their family, their friends. For them, the number one goal is getting rid of hepatitis B infection and markers of chronic infection. As Ellie pointed out, hepatitis B cure is associated with improved survival.
There's no doubt, and I'll give you some data for that. You will prevent liver cancer, in many patients, you will prevent liver failure, transplant, and death. You'll also improve the quality of life, and that comes with improved productivity and household income, in particular, in those countries with endemic hepatitis B. And by preventing ongoing transmission, in particular mother to child, you will, of course, hasten the progress towards the WHO goal of global elimination. So I'm just gonna define what cure is. I'll just come back, sorry. There are several definitions. What we are currently looking at is partial cure, and by partial cure, this is something which has been advocated by the NUC stop groups, where you're looking at finite treatment duration and cessation of lifelong entecavir or tenofovir.
And the patient doesn't have active liver disease but remains surface antigen positive. I think this is something which is being practiced at the moment. The issues with this approach is there's a very low success rate. I think you need to really try and predict those patients who would become inactive after you stop NUCs. There's usually ongoing low-level replication, which can clear up, and most patients will reactivate. And most of these NUCs stopping studies have shown that if you follow patients up for three or four years, the majority of them have active hepatitis B and need to restart their NUC therapy. So that's partial cure. That's the currently, I guess, attainable in a very small proportion of patients. What we're gonna talk about today is functional cure.
Functional cure is stopping all treatment, whatever that treatment may involve, and the patient remains negative for surface antigen and hepatitis B DNA in serum, and that is sustained off treatment. This is associated with no active disease, no active viral replication. cccDNA is still there in the affected hepatocytes, but it's transcriptionally inactive. There's a very low risk of reactivation. We do accept, however, that this is remission rather than complete cure. What is complete cure? I think this is something which, functional cure is the goal for drug development at the moment. Complete cure, you're looking at two possibilities. Where you clear cccDNA, that should reduce further the lifelong risk of liver cancer.
But patients with integrated HBV can still develop liver cancer, and the ultimate goal, of course, is sterilizing cure, where you clear all, hepatitis B DNA, both from, cccDNA mini chromosome and from integrated sequences. This goal and complete cure will only be acceptable when we have gene editing approaches to HBV, and for these to actually go into clinic, they need to be shown to be safe. Gene editing in a young person with hepatitis B is very different from gene editing in somebody with a fatal disease or malignancy. So functional cure is our current goal, and as I mentioned, that's sustained surface antigen loss after finishing treatment. This is a wonderful study from Korea where it was well-controlled.
These were over 5,000 patients on lifelong NUC therapy, and of those, only around 2%-3% lost surface antigen during follow-up. They matched them to a large number of similar patients at baseline in terms of disease and patient characteristics. And where they compared long-term outcomes to those who lost surface antigen, to those who remained surface antigen positive, and remember, these are patients with suppressed DNA, and you can see that surface antigen loss is associated with increased survival and reduced incidence of hepatocellular carcinoma. There is no doubt that functional cure, which is surface antigen loss, maintained off treatment, is associated with better long-term outcomes. Ellie has mentioned the challenges we have in achieving functional cure.
The person with chronic hepatitis B, these are largely people infected either at birth or shortly thereafter. They suffer from weak immune responses, so-called T cell exhaustion, but also a high viral burden, both in terms of replication and antigen burden. We need to address both of these issues if we are going to achieve functional cure. Huge advances in the knowledge of both immunology and molecular virology over the last decade has identified a large number of druggable targets. These are targets to inhibit viral replication, in the center, to lower viral antigen burden, and finally, to boost host immune response. If we look now at viral replication inhibitors, of course, we have the NUCs. The NUCs are very successful, but they are a lifelong treatment.
The other big area of development for replication inhibitors has been capsid assembly modulators or core inhibitors, and there are two classes of those. More than 20 capsid assembly modulators or CAMs have actually gone into clinical development. A small number have stopped because of liver toxicity. Some others have stopped because of lack of efficacy. These work, these are oral, once daily. They work by two mechanisms of action to reduce viral replication and also potentially reduce replenishment of cccDNA. They've been shown, certainly in the first generation of these drugs, to be potent inhibitors of viral replication. They've certainly achieved the primary mechanism of action of CAMs.
They reduce both these, HBV DNA, and also they reduce RNA, as shown on the right. While Nucs don't do that, CAMs are potent inhibitors of both, DNA and RNA. But unfortunately, even up to 72 weeks of CAMs plus Nucs, have had no effect on HBV surface antigen level. So up until this year, there was really no evidence that CAMs would achieve that secondary mechanism of action, which would be necessary to reduce hepatitis B surface antigen. However, there are new, what we call, next generation CAMs, one from Aligos, two from Assembly, and these have shown to be far more potent, 2-3 logs more potent in vitro compared to the CAMs I've just shown you.
We're seeing, for the first time, evidence not only of more potent anti-viral replication inhibition, but for the first time, we're seeing evidence of the secondary mechanism of action. This data was presented at EASL and showed that the Aligos CAM, and we expect the Assembly CAMs, which are equally potent, to finally provide an oral means of reducing surface antigen. The most recent data is showing 2-3 log reduction in surface antigen after six to 12 months... six to nine months of oral therapy. I mean, this gives you advantage of an oral translation inhibitor, really. I think CAMs are here, and they're looking as though they are going to continue in development. Let's look now at the other approach, and this will be an important approach for a combination with immunomodulators.
That's translation inhibitors, lowering the viral antigen burden to try and restore the host immune response. This is the biggest area of development for lowering it, are the two translation inhibitors, the siRNAs and the antisense oligos. What role will they have in cure? Well, the siRNAs, there are many in development, and there are five still going on to clinical development. These are given subcutaneously. They're not oral like CAMs. You have to give them every month or potentially every three months. The issues with this approach is, although they lower surface antigen, there appears to be a plateauing effect. After around 4-6 months of treatment, the declines in surface antigen and other proteins plateaus, and there's no further decline. This is very disappointing.
It wasn't expected, but it's seen throughout the class with every siRNA. We don't quite understand the actual mechanism for that, whether it's saturation of the RISC complex or some other intracellular issue. And so we really think that these are going to have to be co-combined with other agents. But where these do have a role, is they do cause quite a significant and predictable 2-3-log reduction in surface antigen, which may be very useful if you combine that with an immunomodulator. The antisense oligos have really become extremely of high interest because of the phase II results of bepirovirsen or Bepi from GSK. This is unconjugated antisense oligo. Again, it has to be given subcutaneously. Here, it's given weekly for 24 weeks.
The reason why I'm mentioning this is, this looks as though this will be the first agent to become registered for the treatment of hepatitis B since tenofovir alafenamide almost 10 years ago. So this is, you know, quite, quite an advance for hepatitis B. I should say, it is the phase two results, they're summarized in this graph here. They are not overwhelming. You are achieving around a 10% functional cure rate. So 24 weeks of weekly subcutaneous injections achieves around a 10% functional cure rate that sustains surface antigen loss. And it- this certainly is associated with ALT flares. This is an issue because this will prevent this being used in cirrhotic patients, which will limit its use.
It is a dose-related response, but the best responses are seen in patients with a low surface antigen. And the patients have a surface antigen level above 3,000, which is around 50% of our patients in clinic. The response rates, as you can see, are only around 6%. So I think although this is an advance, it's a small advance, and I do believe that if this Bepi does go, if this phase III registration study goes to registration, this will be used as a partner for future combination treatments, in particular with immunomodulators. Right. What about coming to immunomodulators? We've already had a very nice introduction from Ellie.
As I pointed out, there are a number of targets, both for the adaptive and the innate immune system, which are currently in development, many in phase I and a few entering phase II. I'd just like to talk about a couple of them, which may have relevance to subsequent discussion. This is the role of checkpoint inhibition or blocking the PD-1, PD-L1 pathway. As we've heard from Ellie, this is important in patients with lifelong chronic infection because of the association of immune exhaustion, really limiting the patient's HBV-specific immune responses.... I was involved in the first study, I guess, of using anti-PD-1 in patients. This was with Gilead. This was really a proof of concept study. I should point out for here, safety was the key.
We gave very small doses, one-tenth, a single dose of one-tenth the oncologic dose, and you can see that we saw in almost all patients who received that, a definite but small, modest reduction in surface antigen after a single dose. And this was really in patients suppressed on NUC as an additional monotherapy. And a single patient out of 22 achieved functional cure, and that really was, very, exciting. And this led to a number of other studies looking at giving repeated dosing and actually higher dosing. And I just want to mention this as a word of caution. This is the Ascletis study, presented in two parts. The first, cohort, which was the, similar cohort to us, so one-tenth the dose...
Sorry, and then a full, this is higher dose, about one-third the dose, and then they went up to full oncologic dose. Now, this showed that this appeared to work in patients with low surface antigen, and seven patients actually, three of the seven patients with low surface antigen achieved functional cure, but it came at a cost. If you give repeated doses of the monoclonal antibody, and these are 12 doses, you did see immune-related adverse events. And when they went up to the full oncologic dose, which was in the second cohort, and this is a full oncologic dose of 12 doses, every fortnight, no increase in efficacy, surprisingly, but a significant increase in immune-related adverse events, with 40% of patients having thyroid dysfunction.
I think there is some caution in using repeated dosing, and certainly, an argument against using oncologic dosing of the monoclonal antibodies, and a lot of interest in developing liver-targeting alternatives, such as small molecules. We've heard about therapeutic vaccines. The biggest issue with therapeutic vaccines, and they've been in development now for over 20 years, is they seem to be very immunogenic in healthy subjects, and very good in vaccine non-responders. When you put them into patients, the immunogenicity appears to be muted, and the results in terms of reduction in surface antigen, reduction in surface antibody, increase in T cell, HBV specific T cell responses, has been fairly disappointing to date, when compared to the results in healthy subjects.
And therefore, we have to look at ways to increase the efficacy of therapeutic vaccines, and this has been well summarized in this publication. Obviously, we need to improve the immunogenicity. I think an important aspect is lowering the viral antigen load prior to vaccination. We've heard about the addition of checkpoint inhibition to restore T cell responses from exhaustion, and also trying to develop liver-targeting approaches and the combined heterologous prime-boost strategies, which are being adopted by Vaccitech. I think we've seen a similar model from Ellie. This, of course, is Ulrike Protzer's study in the AAV mouse model, which showed clearly that this strategy of combining antigen reduction with an siRNA, with a therapeutic vaccine, was very successful in the mouse model.
Either strategy by itself really had no sustained responses, but when you use sequential antigen reduction followed by a therapeutic vaccine, all animals were cured of their chronic hepatitis B infection. What combinations do I think will work moving into the platform studies, which are currently underway? I do think you probably need to have representatives of at least two of these classes, possibly three, and you may need more than one replication inhibitor. They are a different class, such as a CAM, is shown to be at least additive. The question is: When do you combine them? Should they be simultaneous, or should we have sequential treatment? Certainly, there's some argument for sequential reduction of viral antigens, followed by immune modulators.
What duration of therapy, and I guess it's what duration of therapy is optimal and what is acceptable to the patient population? And finally, which patient population to include in these early studies, and how can we augment this to roll it out further? This cartoon here really summarizes the phase II studies currently. Or no, I should say phase Ib plus phase II studies currently out there in the HBV cure approaches. And you can see that most of them include a backbone of a viral replication inhibitor, and this is largely because it's got to be safer to add other agents in someone who has suppressed HBV on long-term NUCs.
Many of them are using one translation inhibitor to lower viral antigen burden, plus an immune modulator. There are a couple of studies using two agents to lower viral antigen burden, in particular, the GSK study. This is really early. I think they're using the new RNA destabilizers, but most of them... Then there's the Vir studies, which are using the monoclonal antibody approach, which may be both lowering viral antigen burden and also boosting immune response. All of these strategies are currently being evaluated in phase Ib and phase II in the clinic, in patients. I just want to summarize what I think is what we've learned from the studies of the various agents.
Certainly, as monotherapy, antivirals are profound suppressors of HBV DNA and RNA, but they really have no effect, up to date, up until the recent CAM results, on viral antigen production. The siRNAs and the antisense oligos, being translation inhibitors, they certainly profoundly suppress surface antigen and other viral proteins. The immune modulators, and there are a number which are being evaluated. Of course, we've heard about pegylated interferon, which is both an antiviral and an immune modulator, but the TLR7 and 8 agonists, the checkpoint inhibitors, and lastly, the therapeutic vaccines, these look to be effective in a small group of patients.
Certainly, to date, many of these have achieved the best results in patients who have a low baseline surface antigen titer, patients who are more immune reactive, are younger, and patients who do not have advanced fibrosis. Many of these agents' use to roll them out in the clinic will be limited by their tolerability. Many of these have specific on and off-target toxicities, such as the GI toxicities of TLR8 agonists, and I've mentioned the immune related adverse events of checkpoint inhibitors. So I think you will have to balance efficacy versus tolerability for some of the newer, more potent immunomodulators. I think we will need combination strategies.
Antivirals won't cure chronic HBV itself, and the immunomodulators are there to clear those infected hepatocytes, provide long-term surveillance for cccDNA, and thereby prevent late reactivation. I think that the next, really the next phase for drug, for cure development, will be to combine multiple agents from the different classes, which both inhibit replication, reduce viral antigen production, and restore host immune control. I'd just like to finish with a, really, a final slide. Whatever we develop has to be successful, but has to be acceptable to the patient population. We have to think of the route of administration. I think intravenous approaches will be difficult to roll out in the field, while subcutaneous and oral approaches are far more tolerable and convenient. Duration of therapy, I don't think we know what the optimal duration is.
I think it's likely to be 48 weeks or even longer to attain cure. Tolerability, I've talked about, the specific tolerability issues. We've been talking a lot about what is the acceptable surface antigen loss rate, when you get to phase III studies. And I think we'd like to see, I'm sure, at least 30%, not the 10% currently being mooted by the bepirovirsen programs. And then, of course, we need to have cure, which is accessible to many of those countries Alice mentioned at the beginning, who have endemic hepatitis B, who are now low or middle-income countries. And that's... Thank you very much. Happy to answer questions at the end.
Thank you, Ellie and Ed, for your insight into the therapeutic approaches that are currently being undertaken to bring a functional cure for chronic HBV patients. Given the time, I guess I'm not going to spend so much time on our pipeline as it stands now. So we have quite a few assets, as I was mentioning at the beginning, across different therapeutic areas: chronic infectious diseases, autoimmunity, and cancer. At different stage of development, we have our main two ones for HBV and HPV that will come with near-term proof of concept results in phase two. The two new ones are based on the newest platform that we have, SNAPvax, in the dark blue, celiac disease and HPV cancer, that are just in pre-clinical phase at the moment, going through IND soon.
Celiac disease at the end of the year, and HPV cancer hopefully sometime next year. The purpose of today, we're going to go a little bit deeper into our HBV assets, so VTP-300. What is VTP-300? It is based on our viral vector antigen delivery platform, ChAdOx1 and MVA, which are given sequentially, ChAdOx1 first and MVA second. This specific combination of ChAdOx1 and MVA really stem from the work of our scientific founders at the University of Oxford. They spent years working on these, looking at various technologies and combination of them, so viral-based DNA, RNA, protein, and so on. From all the different combinations that have been tried, they actually found that there is nothing more potent than this specific ChAdOx1 and MVA combination.
It really is very powerful in, most powerful of all, actually, in triggering not only the largest magnitude of disease-specific T cells, but also of the longest duration. So the T cells that are actually induced by that specific combination can take up to two years in some cases before going back to baseline levels. Beyond the numbers as well, from a quality perspective, these T cells are also very highly potent in killing the infected cells, and they are also polyfunctional in their release of soluble factors. So bottom line is that from a quantity, quality, and durability perspective, this specific combination, ChAdOx1 and MVA, is particularly well positioned, to treat chronic infectious disease and cancer....
VTP-300 specifically, it's the combination of ChAdOx1 and MVA, both of which are encoding the same disease antigen, covering both surface, polymerase, and core, HBsAg antigen, and they are being made out of a consensus genotype C sequence. We do believe that VTP-300 could be a critical component for functional cure regimen for chronic HB. As you heard from both Ellie and Ed just before, it is very likely that a functional cure will require a combination of different agents with complementary mechanism of action.
Inhibition of the viral replication to keep the viral activity down, something to decrease the viral antigen burden, so HBsAg, to give something like some breathing space to the immune system, so that it can recover a little bit from the exhaustion it's been through, and something that stimulates the host immune system. VTP-300 belong to that third category, in orange, and it has already been shown to be capable of inducing sustained HBsAg reduction in some patients in phase II studies. The goal of the ongoing and planned clinical trial that we have at the moment is to really evaluate VTP-300 in combination with other therapies as a component of a functional cure.
So on their new background, we are testing actually VTP-300 alone or in combination with another immunomodulator, so low-dose anti-PD-1, and with siRNA to decrease HBsAg load, or the combination of the three: siRNA, VTP-300, and anti-PD-1. So what you see on this slide is the design of the clinical trial for HBV002, which for which we presented final data at EASL earlier this year. So this study was a phase Ib/2a clinical trial, where we evaluated safety, tolerability, and immunogenicity of VTP-300 alone or in combination with low dose anti-PD-1 in chronic HBV patients under nuc treatment. And the key outcome of this trial are actually shown on this slide.
So maybe first off, the thing that we could see that was really reassuring is VTP-300 was administered with no treatment-related severe adverse event at all. Some infrequent transient ALT elevations have been observed. The key outcome that we saw as well is that across the board, we could see reduction of HBsAg, but those HBsAg reductions were actually most prominent in those people that started off with a very low baseline HBsAg, so below 100 or so international units per mL. The graphs that you see on the right side are actually the results of two of the groups that were evaluated, so group two and group three. Group two, the graph that you see at the bottom, is actually the monotherapy arm, so VTP-300 alone, in addition to NUCs.
The graph that you see at the top is VTP-300 in combination with low dose anti-PD-1. What you see there is the level of HBsAg with time after treatment for the entire duration of the trial, which lasted 9 months after the initial injection. So if you focus on the bottom graph at the moment, we could see VTP-300 alone, we could see significant and durable reduction of HBsAg that were starting as soon as we gave the MVA dose, and started to go down at 3 months and were sustained at that low level for the entire duration of the trial. And so that's the three line that you see, like the two greens and the and the red one at the end.
If we focus on group three, the top graph now, we could see actually a mean reduction of HBsAg that was higher than with VTP-300 alone, as we reach close to 1 log reduction in HBsAg. Again, it was more prominent in the group- in the, those patients with low HBsAg level to start with. And something that was quite interesting to actually observe there, is that among the 5 patients with a baseline of HBsAg below 100 at the beginning, two of those actually reached non-detectable HBsAg already at month 3, and that lasted for the entire duration of the study. So we got a very good meaningful, sustained reduction of HBsAg with VTP-300 observed.
From an immunogenicity perspective, when we looked at the T-cell response, we could actually robust T-cell responses against all encoded antigens in all patients. Something that is not shown on those slides is even though VTP-300 is based on a genotype C sequence, we could actually see cross-reactivity to genotype D clinically, as patients with genotype D HBV were also enrolled. And in vitro, we could also show that the T-cells that were in use could actually cross-react to all different genotypes from A to E. We still have two clinical trials ongoing for VTP-300. One is in collaboration with Arbutus, which is evaluating the combination of siRNA plus VTP-300.
So what you can see on this slide, on the left side, we have a lead-in phase with the siRNA only for 24 weeks, to decrease the HBsAg load in patients. Then we come in with VTP-300. Then we have the option to either add or not a low dose anti-PD-1. And what we have also in this trial-
I s we actually included eligibility criteria to discontinue nuc treatment, to test whether a specific combination can actually lead to functional cure in some patients. The other trial that we have ongoing at the moment is HBV003. This is a phase Ib study, or phase IIb study, sorry. This one is really building on HBV002, VTP-300 plus anti-PD-1, that we had before. In this one, we are actually evaluating additional dose of anti-PD-1, still low dose, and timing of that dosing when we actually give that anti-PD-1. To test whether we can improve on HBV002 results. In this trial as well, we also included an eligibility criteria for nuc discontinuation, to actually see whether we could achieve functional cure in some patients.
So before moving to the Q&A, something that I wanted to update you on. So we are expecting to update on data from HBV003, at AASLD later this year, as we have an award presentation for that one. And, Arbutus is actually currently submitting an abstract to present interim data for the ongoing trial. So hopefully some data to share on that one, as well, at the same time. So with this, we've reached the end of the presentation and we are open for questions.
Thank you. At this time, we'll be conducting a question and answer session with our speakers. As a reminder to our analysts, if you'd like to ask a question, please raise your hand. For the rest of the audience, 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. Please hold for a moment while we pull for questions. Our first question comes from Andy, from William Blair. Please go ahead and ask your question, Andy.
Great, thanks, everybody, and this has been tremendously helpful. So appreciate the time and sharing your perspective, especially on this emerging functional cure treatment paradigm. I am curious, you know, obviously the future lies within the combination therapy, as we kind of layer on top different modalities. One thing I think Vaccitech has done a good job is kind of teasing out different sequencing. So maybe from a clinician standpoint, what do you think from a scientific perspective is the best sequencing? Is there like a modality that you would want to use upfront or potentially in the middle or at the end? Just trying to understand if there is a logical sequencing here.
Shall I go first? Ed Gane here. Hi, Andy. Thanks for the question. I think certainly some of the preclinical models have suggested that reduction of viral antigen burden prior to the immunomodulator or prior to starting the therapeutic vaccine appears to be a very attractive strategy on the assumption that you may get some restoration of HBV-specific immune reactivity prior to starting the vaccine. The use of the checkpoint inhibitor or anti-PD-1, PD-L1, I think that's probably going to be delayed until after HBsAg antigen reduction, either with or towards the end of the vaccination. I'd be interested in Ellie's thoughts.
Yeah, thanks, Ed. I mean, I would agree with that regards to trying to lower the S antigen levels at the outset. I mean, as Ed explained very nicely, that our sustained responders in terms of S antigen loss were those that started with low levels. So, if we can kind of reduce those, it could be that we're able to most effectively induce further loss when we come in with our secondary strategies. I think the question as to when you give the anti-PD-1 is immunologically interesting. In the HBV002 study, you know, we had options there.
It was quite hard to design that trial, and in the end, we gave anti-PD-1 with the prime and the boost, and then we gave it only with the boost. Actually, our better responses were observed when we gave the PD-1 later on. I think maybe that's because if you give anti-PD-1 very early when you're trying to generate an immune response, you can kind of overdo it. So, in a way, it may be better to allow the vaccine to have some effect and then come in later with the anti-PD-1. Yeah, so I think lower the S antigen levels, then come in with your vaccine and then come in with anti-PD-1, if those are the three modalities that you're trying. So yeah, I think there is a sequence.
Got it. That's very helpful. I have a follow-up to that, which is, you know, in terms of measuring immune response, there's obviously standard ways of kind of quantifying that. One thing that would be interesting, at least for, from the perspective of, immune cells actually killing hepatocytes or infected hepatocytes. Are there standard assays or ways to kind of measure that, just to gauge, you know, even, you know, from a vaccine perspective and also from the checkpoint inhibitor perspective, they're actually resulting in immune cells, you know, actually, you know, eliminating these infected hepatocytes?
Mm-hmm. Yeah, that's, that's an excellent question. Do you-- Shall I take that? I mean, it's obviously very difficult to access the liver itself in a clinical trial. There are ways that we're trying to develop to do that with, with fine needle aspirations, but the number of cells you get are relatively low. I guess that's the first point to make. It's, it's actually a difficult organ to access, so, you can't actually obtain large numbers of, of functional hepatocytes in the middle of a trial like, you know, like these. I mean, we really are, on the whole, evaluating surrogate markers in the blood, where, where we can look to see how antigen-specific T cells recover in the peripheral blood. There are relatively standardized methodologies like ELISpot and intracellular cytokine stainings that we, that we, that we do.
In the old days, when we used to kind of biopsy lots of people with hepatitis C, one thing we did, actually, was to measure, and compare the immune response to that virus in the blood and in the liver. What we found was that we did get more responses in the liver in general, but they were kind of reflected proportionally in the blood measurements. I, you know, I think that does give me some confidence that what we measure in the blood, in terms of magnitude, to some extent reflects what's happening in the liver.
Okay. Great. Super helpful. And maybe last one. It's kind of a market sizing question. So, in terms of various surface antigen cutoffs, and obviously, this is the, you know, what we're showing is the HBV002 study, which has a cutoff of 4,000. But as you think about different cutoffs, so, you know, 100 or 5,000, how should we think about what proportion are these patients with different surface antigen cutoffs with respect to the entire population? So just, you know, from, you know, just for background, we're trying to you know, at least assess how big is the addressable market, right? So, these various cutoffs and how many patients are basically coming in at these cutoffs could be helpful in terms of our modeling.
I think that's obviously a very important point. GSK has looked at this in some detail, as are obviously targeting a smaller population, a population with surface antigen titers below 3,000, and presented modeling on looking at the denominator being the population of patients with chronic hepatitis B, who are currently being assessed for treatment according to the AASLD and EASL criteria. This isn't everyone with surface antigen positive, but people with active hepatitis. As pointed out, about 50% of patients have a surface antigen level below 3,000, and the lower you bring the cutoff, the lower the proportion.
I think they've shown in the modeling presented by the EASL, I think last year, was if you get down to 100, it's getting down to about 15%, I think. So it's... No, 500, 15%. So the lower you go, the smaller the proportion, and hence the attraction of artifactually reducing surface antigen with other approaches, such as we've talked about, siRNAs. But I think there are other approaches also, which are potent approaches, such as the monoclonal antibodies against surface antigen. So artifactually bringing down the surface antigen levels in anyone who's surface antigen positive to be a low level prior to introducing the immune modulator.
Great. Thanks so much for answering all my questions.
Pleasure.
Thank you.
Yeah, I would like to point out one other thing, Andy. You know, when you're looking at the assays for on the ELISpot, you know, you do have to pay attention to how those assays are actually done and whether or not you have overnight stimulation or long-term stimulation of those to actually look at real magnitude of response of the T cells.
Thank you, Andy, for the question. Our next question comes from Yi, from H.C. Wainwright. Yi, you may go ahead and ask your question now.
Thank you for taking my question. My first question is, based on the information presented, is it so that a functional cure can only be achieved with a combination of at least three therapeutics?
I'll attempt to answer that. I don't, I don't think we know the answer to that. I think, at the moment, most of the studies are recruiting patients who are already suppressed on nucs. I think there are other approaches where they are looking at what we call nuc-naive populations, or populations who have stopped their nucs. Certainly, it looks as though you need at least one antiviral, plus one immunomodulator. The ongoing studies, and there are many platform studies, are looking at whether you add multiple combinations from the three classes. I, I- it may be that a single replication inhibitor plus a single immune modulator may be sufficient to achieve cure in a proportion of patients.
Okay, thank you. How many therapeutic vaccines are competing with VTP-300 for presence in a functional cure combination?
I'm not sure-
Yeah, the slide that you showed, I think with the various combinations may be the closest that we're aware of, right?
Sure. I mean, in terms of therapeutic vaccines, and I by no means do I know the exhaustive list, but I know of two other therapeutic vaccines in development, but much earlier on than Barinthus, in terms of their development. I'm not sure whether someone from Barinthus wants to add to that, but I can think of possibly two other therapeutic vaccines under development, but these are much earlier on and certainly not in patients.
Got it. Thank you. And last question: are there data available currently to compare the efficacy of VTP-300 as a monotherapy versus the add-on efficacy of VTP-300 in a combination therapy?
I can make a start on that one. The HBV002 trial did have, did have an arm, which was add MVA prime boost, and then the same combination with anti-PD-1. It was compared with and without. Nadège, I think you actually showed that data, or you talked to that data.
Yeah, exactly.
So that's these two graphs here. And you can see that we did see some patients, so that's group two, that did lose S antigen with vaccine alone. But it looked, you know, more promising in those people with slightly higher S antigen levels when you added in the checkpoint modulator, the checkpoint inhibitor. And-
Would you say the efficacy as a monotherapy is similar to the add-on efficacy in a combination?
I think the evidence is from this relatively small study, at this point, that the add-on is beneficial.
Yeah. I think something to keep in mind is, like, indeed, it looks better with the add-on PD-1 in that study, but it's a small number of patients, so-
Yeah
... we will have to see with a larger number, if this is something that is holding on or if there is indeed higher benefits with the anti-PD-1 or not.
Thank you.
Yeah, I mean, I think the key messages that I took from this study was that you could, with this vaccine, lose S antigen. And I think that wasn't a given, and we've observed that. That's the first observation. The second observation, that we clearly saw maximum effect in the subgroup with lower S antigen levels. It seems really sensible now to combine this with strategies which are known to lower the S antigen. I think the data will be very exciting. Looking forward to the American Liver meeting. Yeah.
Thank you for the clarification.
Thank you for your question, Yi. Our next question comes from Maxwell, from Morgan Stanley. Maxwell, you may go ahead and unmute your line to ask your question.
Great. Can you hear me? This is Max.
Yep.
Thank you very much for holding this call event. It's very informative. I'd like to drill down a bit on the sterilizing versus functional cure, and your thoughts around the durability of a potential functional cure. Would this one vaccination potentially be enough, and how long would we assume efficacy would be maintained?
I think functional cure with clearance of surface antigen and DNA at the end of treatment, sustained after treatment, should be durable. It is... I mean, the equivalent is someone with natural immunity from spontaneous clearance of hepatitis B. We know that these people still have transcriptionally inactive cccDNA in their liver, but they won't get progressive liver disease. Their risk of liver cancer is markedly reduced following clearance, but they remain what we call core antibody positive. But they are not at risk of reactivation unless they undergo really very heavy immunosuppression with a B-cell agent such as rituximab used for some types of hematological and malignancies and autoimmune diseases. I think this would be durable.
I'm not sure about your question about re-vaccinating. If somebody does lose surface antigen following a course of treatment, then that person – that should be durable. Your question is, do they need to have protective surface antibody? Well, with an immunological approach, if you lose surface antigen, well, almost certainly you will have production of neutralizing antibody. But certainly, loss of surface antigen is usually very durable.
Okay, great. Just one more question. In regards to safety concerns going forward with these combination approaches, is there anything we should keep in mind as the data matures? Any insights into that would be greatly appreciated. Thank you.
I think my one comment was, I think, checkpoint inhibition rescuing T cells from exhaustion is a very attractive therapeutic approach. I think we just need to be cautious of how much therapy we use. Certainly there's good evidence that the approach Vaccitech was using, which we use with the Gilead proof of concept study, using low dose, one or two doses, is very safe. Very safe. And I think, but to give therapeutic dosing or oncologic dosing, repeated dosing, will come with a risk. But I think the approaches being advocated by Vaccitech and by other companies now, of using low dose, one or two dosing, is extremely safe.
Great. Thank you very much.
Thank you, Maxwell, for the questions. This concludes the Q&A session and today's call. Thank you for tuning in, and as a reminder, the replay will be made available on the Vaccitech website.
Thank you.