Key opinion leader event where we're going to discuss the progress that we've made with our VTP-300 in the development as a key component for a potential functional cure for chronic hepatitis B. Joining me today will be Dr. Agarwal, who is a Consultant Hepatologist and Transplant Physician at the Institute of Liver Studies at King's College Hospital, Viral Hepatitis Service Lead and Director of the NIHR South London Clinical Research Network.
Dr. Henry Chan, Head of the Division of Gastroenterology and Hepatology, Director of the Institute of Digestive Disease, the Center for Liver Health, and the Office of Global Engagement. As well as our Chief Scientific Officer at Vaccitech, Tom Evans. First, few words from our, the legal group here. We are a publicly listed company. There may be some forward-looking statements, and you can find additional information on our website or on sec.gov. I'll now turn it over to Dr. Chan.
Thank you very much, Bill. It's a pleasure to share with you some of my insights into the concepts of functional cure for hepatitis B. Hopefully, I can set the stage for our discussion today. The immediate goal of all new HBV treatment is functional cure, which is defined as a clearance of serum hepatitis B surface antigen.
We know that it is not a complete clearance of all the viruses in the liver, which may be a complete sterilizing cure, but all the long-term data of HBsAg clearance will be translated into good clinical outcome with fewer cirrhosis complications, HCC, and death. That's the reason why we want to achieve that. We have NA for a long time, and we know that it is insufficient to lead to HBsAg loss.
What I'm showing you is actually a study of 43 hepatitis B patients being put on NA with undetectable HBV DNA for six to 12 years, and all of them had three liver biopsies. You can see that cccDNA actually dropped by more than 99%, which means about one to two logs, but HBsAg reduction was less than one log.
The reduction of HBsAg is much less efficient than that of cccDNA on long-term NA therapy. The reason behind that is because a lot of HBsAg in [HBeAg-negative] patients are coming from integrated HBV DNA. This is a very nice study showing that this HBsAg are actually coming from host-virus chimeric RNA, which is derived from integrated HBV DNA, but not from cccDNA.
In other words, if you really want to clear HBsAg from [HBeAg-negative]] patients, then what we need to do is to clear both the cccDNA and also most of the intrahepatic integrated HBV DNA. This is much more difficult than just clearing cccDNA, and it may involve clearance of intrahepatic virus which may not be replicating. We have tried lots of strategies to achieve functional cure.
Combination of NA plus peg interferon has been tested by many, many centers and results have been controversial. There are lots of negative studies, and I'm showing you one important positive study, which is the combination of tenofovir with peg interferon. In this study there are four arms. There's a peg interferon monotherapy arm, which is in yellow. There are two combination arms with tenofovir plus peg interferon. The blue line is the 48-week combination.
You can see that it can achieve a higher HBsAg loss over two years, up to 9% as compared to peg interferon monotherapy. Of course, tenofovir monotherapy is the worst one with almost zero rate of S loss. It raised some hope that maybe combining viral suppression and an immunomodulator can increase the chance of S0 clearance. Obviously, 9% is too low to be recommended for clinical use.
This is actually a group of patients who are indicated for treatment, so these are ALT high, DNA high patients with active hepatitis. In fact, the success of this combination depends heavily on the selection of patients. This is a study on probably so-called immunetolerant patient or E-positive chronic infection.
These are all adults, HBe-positive, high HBV DNA more than seven logs and ALT less than 1.5x upper limit normal. It's a one-arm study from U of Toronto and Jordan Feld. The group actually used combination of entecavir plus peg interferon alpha, and they found that the S loss rate is 0%. Actually, none of the patients could achieve a sustained response even in terms of HBV DNA.
If you pick these patients to treat with common therapy, the result is very disappointing. On the other hand, if you pick another group of patients, which are patients who are again on entecavir but already achieve a low HBe antigen titer, which means that they might already have some immune clearance of the virus just with entecavir, and then we add on peg interferon.
This is a pretty famous study published in Journal of Hepatology from Wuhan Group. They compare peg interferon versus entecavir among patients who achieve low HBe antigen titer on ETV. You can see an S loss rate of 8.5% in the peg interferon group versus 0% in the entecavir group. This has already raised the appetite of the academia to test peg interferon in this particular group of patients.
To date, there are a few studies. I want to show you three important studies. The Ning et al study is actually a study I've just shown you. Another study from China, which is a bigger study, they tested peg interferon in patients with HBe loss. They must have lost the HBe antigen and not just a low HBe titer.
In Hong Kong, actually, I have published another study a few years ago among patients who have HBe conversion. They must have E antibody before we start the peg interferon. You can see the overall S loss rate increases from 8.5% in low E titer to 11% into E loss and 15% on HBe conversion.
Among those patients who had a low HBe level at the time of starting peg, let's say less than 1,500, all studies show about 20%-25% rates of S loss, which is pretty good. In our study, we had some patients with very low HBe level, less than 500, and half of them had lost their antigen. If we pick the right group patient to receive peg interferon, the result can be promising.
Another group of patients I want to show you is actually patients with inactive disease. These are HBe negative patients, untreated with low viral load and also inactive hepatitis. You can see the response rate varies from 3%, the lowest row, 3% in the Netherlands study, up to 94% in the study on the far right.
The key difference among these studies are the HBsAg level of these patients, the lower the higher conversion rate, and also [ HBsAg] status. The lower HBsAg level, the higher the rate of [ HBsAg] conversion. Again, HBsAg level and DNA level are important predictors of response to an immune modulator. Putting everything together, there are lots of hypothesis stating that HBsAg level, if it's low, it may restore the exhausted innate adaptive immunity.
As [HBeAg] clearance is an immune-mediated phenomenon that can be facilitated by low HBeAg level, and if we can lower the HBeAg level, it may help the future HBV cure strategy. There are lots of new molecules studied to lower HBeAg level. One is RNA interference.
This is one example using antisense oligonucleotide, and you can see a dose-response relationship on the drop of HBsAg and the use of the ASO. Of course, we do also have siRNA. The earliest siRNA tested is the Arrowhead molecule ARC-520. Of course, this development is discontinued because of its ineffectiveness in [HBeAg- negative] patients. We learned something from a few patients who have received multiple doses of this RNAi. This report had eight HBV patients receive up to nine doses of this RNAi with entecavir.
Two patients, one E positive, one E negative, achieved HBe clearance. You can see from the figure, which is an E positive patient who achieved HBe clearance. After multiple doses of RNAi, everything is dropped, and the patient has ALT elevation, which is the blue line, followed by dramatic reduction of HBsAg level.
The high ALT level probably reflects an immune-mediated flare, which leads to a dramatic reduction of S level and S loss. A suppression of HBe level for a long time after stop everything, it may trigger a immune clearance. Another piece of evidence is a very recent presentation at AASLD in Boston last year, is the siRNA by Vir Biotechnology, the VIR-2218, and peg interferon combination.
With the purple and the blue, the blue cohort, that is cohort three and four, those are the combination of peg and VIR-2218 simultaneously. They can achieve the highest mean change in HBe level through week- 24, and a few patients in each of the combination group had S loss.
This is much better than using siRNA alone. Combining immune modulator with something that can suppress HBe levels seems to be a strategy that we can consider to achieve functional cure. Now, one very impressive experiment is actually from the nucleic acid polymer, the REP- 2139 and 2165. It is a small study, though, but the result is very encouraging.
Combining these three molecules, NAP, TDF, and peg interferon in a different sequential manner. We see a dramatic reduction in HBsAg level once the nucleic acid polymer is introduced and a significant ALT flare, which may represent immune clearance, and 60% of these patients achieve an S loss even at post-treatment follow-up, which is still at 42% left.
We need bigger studies to confirm whether nucleic acid polymer is the molecule that we should use in the combination therapy, but obviously, its major role is to suppress HBsAg release from cells and reduction of HBsAg. To conclude my talk, I think virus suppression is needed to achieve functional cure. We have NA nowadays, which is very convenient and very safe to be used. I don't think we will omit this as part of the formula.
Capsid assembly modulator has been put in doubt, particularly after we read the [JADE] study results of NA/siRNA, that it may not help NA or a combination of NA/siRNA in functional cure. In my opinion, a low HBsAg level is good. We probably need something to reduce it if HBsAg level is high to start with, maybe RNA interference, maybe not, I don't know.
Ultimately, clearance of HBsAg is an immune-mediated event, so we need to enhance immune clearance, and definitely a lot of molecules are being studied. We have therapeutic vaccine. There are also some other therapeutic vaccines under development.
Anti-PD-1 and PD-L1 is also another hot molecule we can talk about. TLR8 and TLR7 agonists are under study, and in the old days and up to now, we still have interferon. This is what I want to say, and we can have some discussions after other presentation. I'll hand over the time to Bill. Thank you.
Great. I think it's me next, Henry. My name is Kosh Agarwal. I'm based in London, and I'm gonna walk you through some slides and really hope that we can have a useful and fun interaction and discussion at the end of this.
I'm gonna come to you as primarily a clinician, as a Clinical Trialist, but to let you know, we understand what an exciting field this is now for hepatitis B, but I will give you my independent view, but it's good to be at this meeting, thank you for the invite from the Vaccitech guys. These are my disclosures, as well as a quote that I like, which reflects really the world of hepatitis B for me.
I'm obviously gonna stay away from all the areas where I have CDAs, but I am involved in a lot of multiple early phase studies, and you can see with some of those disclosures that many of these companies have also therapeutic vaccine and immunomodulators in their portfolio as they go into clinical trials.
I guess my key from this M.C. [Escher] quote is that hepatitis B is still rather chaotic. I really want to emphasize that it is a global pandemic with about 300 million people in the world affected with hepatitis B, and that also affects obviously all areas of the globe, but also high-income countries.
I've just come from my clinic, and I've seen three or four patients with very significant disease, and I'm on for transplant, and we have patients on the ward with hepatitis B. This is an important disease, and in the 15 minutes that Henry was speaking, 30 people in the world died of hep B-related complications, which mainly are end-stage liver disease and HCC.
This is an important disease, and really does deserve our focus. I was involved in the EASL guidelines, these are European guidelines, and this is a slide really just to reflect that hepatitis B is a disease of years. Most chronic hepatitis B, as you all know, is from vertical transmission and is chronic.
Likewise, we see different phases of the disease with different nomenclature, which I think the traditional nomenclature has been very poor. I guess the reason for me showing you this is that we are currently focusing on those patients who are suppressed and who are E-antigen negative and non-cirrhotic.
Certainly when we start to think about immunomodulatory therapies, we may need to widen our perspective and think about those patients who may be younger, who may be in phase I, who may have more robust, intrinsic, although exhausted, immune system responses to hepatitis B. The other thing I want to highlight is that hepatitis B is really rapidly changing with regard to stratification and understanding not only of the immunology and life cycle, but particularly the biology.
There are a whole raft of HBV biomarkers such as HBV pre-genomic RNA and [HBcrAg] that are going to give us a better handle on the heterogeneity of the disease that we see within hepatitis B. I think this will refine our ability to select patients for different types of therapies and potentially select certain patients for maybe a predominantly antiviral approach.
More, and this is my personal view, more likely we'll be moving more towards a balance of introducing immunomodulatory approaches within a broader group of patients as we take forward the clinical trials and get to that place which we think will be functional cure of hepatitis B. This is really a sort of summation of the world of hepatitis B.
I would say the last three, 3.5, four years have been really a very exciting roller coaster. There's no doubt that the antiviral approaches that we have seem to be very well established with siRNAs now antisense oligonucleotides, capsids, other drugs such as entry inhibitors. Obviously we have good second generation NUCs that will be the backbone of most of the therapies that we think about, we hope.
The trials and the work that's been going on has been mainly based around antivirals. I'd say, and again, from my personal perspective, we're seeing more and more recognition of the immunomodulatory perspectives around hepatitis B and requirement to reconfigure, re-energize, or really just boost the host innate and T-cell specific T-responses that exist to try and help the host system get a hold and clear hepatitis B to get to that place of functional cure. Again, a slightly different view of that you can see on the right-hand side of the slide, drugs that we could think about or therapeutic targets in red that are antiviral predominantly.
Clearly we really look and thirst for those drugs that may target cccDNA, and there are lots of new platforms coming along, really based around the oncology field that may be applicable to viruses and particularly hepatitis B.
Really for me, and for the subject today and our discussion, hopefully, we're interested in the recovery of T-cell responses, a robust anti-envelope and neutralizing responses, and also boosting that innate immunity, and really reconfiguring and allowing the clearance of hepatitis B and a long-term control of hepatitis B. This takes it down a further notch.
This is from Journal of Hepatology, from a couple of years ago, and this is showing you, of course, the topic of today, which is therapeutic vaccines, which are coming into play and starting to come into prime time.
A broader stimulation of innate immunity. The VIR-3434 with antibody-mediated neutralization, and then other mechanisms of priming of drugs that we can talk about but probably won't have time to talk about. What do we really want from a therapeutic vaccination approach? We want a vaccine that clearly is going to be safe.
Currently everything we're focused on is safety. We want to incorporate all of the antigens that are relevant. We want to induce multi-specific, long-term, broadly cross-reactive T-cells. Likewise, it'd be nice to have B-cell memory work and immunomodulation to overcome that HBV-specific tolerance. Let's be very clear, we've been talking about this for a long time.
There've been studies that've been done previously, and there's no doubt that by and large they have demonstrated some responses with regard to T-cells, but really have not translated to meaningful decreases in surface antigen or meaningful clinical endpoints.
I think going back, I was involved in the Gilead's 4774 Tarmogen program, and in essence, a safe drug, in this study that I'm just highlighting from a few years ago, in comparison with tenofovir, which is our nuke, you can see that it provided T-cell responses, so it did what it was supposed to do, but it really did not deliver the same level of responses that we see after spontaneous resolution of infection, which clearly would be the sort of benchmark or the place we want to get to.
In reality, it really didn't do anything from any other clinical parameters that we were interested in. I didn't put the slide in because of time, and I actually thought Henry was going to talk to it, but we've guillotined it out.
There are further studies and a small study looking at this fairly old-fashioned vaccine in conjunction with a PD-1 checkpoint booster, where actually in a small group of patients, I think one out of nine patients actually cleared surface antigen. It may be that those vaccines were not robust enough, and likewise, they need an additional platform of help from another arm of the immune system.
I want to highlight this, interesting, piece of data which was published by Ulrike Protzer's group in gastroenterology in 2020, which really kinda encapsulates the paradigm that we might be seeking in this balance of, aspiration for cure, and the balance in the antiviral and immunomodulatory responses.
In essence, the combination of aggressive rapid decrease of surface antigen level in a mouse model of hepatitis B. Let me say this again, a mouse model, not humans, then accompanied by a therapeutic vaccine, actually, seemed to provide fairly stunning results and a reconfiguration of several arms, that are critical in the context of the immune system.
This has really driven, I think, this interest now back into therapeutic vaccines, not only because of the new platforms we have, not only because of the better science, but also to really see if we can use either boosting of the immune system or rapid drop in [HBsAg] surface antigen with whichever mode we want to try and allow and facilitate that host immune system to reconfigure and cause clearance of hepatitis B. This is just another picture. I'm not an immunologist, but you can see here it's demonstrating the drop in some of the top panels, an [ELISpot] in E.
Really if you focus on the histology in [F], you can see various models of the expression of hepatitis B molecules, the staining, and really to direct you to the right-hand end of those where they seem very clean and gray. This is where you see no evidence of hepatitis B in those mice who had both the siRNAs and then followed by the primed vaccination, therapeutic vaccination in this context. Also, there are thoughts that we could reconfigure underlying HBV T-cell dysfunction with mitochondrial issues that drive dysfunction via hepatitis B.
It's an area of interest for me, but this is just again, preclinical, in vitro data showing that you can get some restoration of CD8 responses in this context by facilitating and helping mitochondrial function in hepatitis B mouse model in vitro models. To come to the discussion that we will have as I hand over to Tom and Bill. There are different strategies in play with regard to therapeutic vaccines.
They may be used in conjunction with antivirals. This is the current trials, I think, late last year, looking at those trials using a heterologous boosting therapeutic vaccine in hepatitis B. You can see GSK, TherVacB, and obviously Vaccitech going through.
My conclusion slide, really to give you that overview, and I hope it's been fairly broad-based and high level, really to generate discussion. I think we must remember that this is a very significant pandemic which is ongoing, but there is still questions that we really need to understand about the heterogeneity of disease and the influence of the host virus interaction.
We may need to think about therapeutic vaccination and immunomodulators in non-treated patients or younger patients. The field of hepatitis B therapeutics is really very extensive, with a lot of focus and a lot of excitement. I have to reflect honestly that after three years, we're still lacking a clear roadmap. There's no doubt that the balance has moved to an interest much more in immunomodulators and reconfiguring an immune exhaustion.
I think they're here to stay, and will be in the studies and will get us to where we need to get to. When we talk about broad immunostimulation, we are worried about off-target effects and safety because liver cells are infected with hepatitis B, so safety is going to be key in the immunomodulator world.
It's interesting, we may tease it out in the discussion, but we look for a flare, and we wonder whether this will be a good flare, but we've got to be clear about whether that's something to do with safety and has clinical consequence. I think to date, in the older world view of therapeutic vaccine, it's done what it's supposed to do, but it's not really translated into any clinical endpoints for today's world or the biomarkers that we need to see.
This is a hot area and clearly vaccination in the world around COVID and clearly hepatitis B is something that's very interesting. I'm grateful for your attention. I leave you with a slightly cheesy quote because I think hepatitis B is a very different game to hepatitis C. It's gonna be harder and longer, but I remain relatively confident that there is enough for us to get us to this area where we can start to consider cure of hepatitis B. Thank you for your attention.
Thank you, Kosh. This is Tom Evans, and I'm gonna go through our Vaccitech program. I appreciate the introductions by Doctors Chan and Agarwal. We're gonna talk about VTP-300, where we are and our plans. Just to remind people, the Vaccitech platform, as Dr. Agarwal mentioned, we use a heterologous prime boost.
This has been known for over 20 years to give superior antibody and T-cell responses to homologous boosts. This is not a new finding from the COVID era. It's been known for a long time among vaccinologists. That prime boost methodology to get the highest CD8+ T-cells to date is to use an adenoviral prime followed by a poxvirus boost. This has generated T-cell levels that have been in the, using ELISpot assays, over 5,000 units, which is the highest level reported to date.
We use a chimpanzee adenovirus to get around prior immunity, and then we boost with the MVA. This also gets around the anti-vector immunity that is induced by the adenovirus itself. These generally encode exactly the same antigens, sometimes in slightly different order, to avoid any sort of what we call junctional responses.
We also use proprietary molecular adjuvants such as the invariant chain, which is used in this program. Our HBV vaccine is a full length sequence that includes the core region, the polymerase, the PreS1, PreS2 from a consensus genotype C virus. Bioinformatically, what we did is we looked at the consensuses for each of these proteins and then picked the virus of an actual viral sequence, which was then encoded into the chimpanzee adenovirus and encoded into the MVA.
These are given anywhere from two to eight weeks apart. In this program, they're given four weeks apart, as that has been shown in the past to be a very good way to boost the adenoviral CD8+ T-cell responses.
To date, we have two trials underway, one trial about to start, and another one about to start later this summer, possibly late second or early third quarter of this year. HBV001, which I'll go through, has 40 healthy participants and 12 chronic hepatitis B patients administered ChAdOx at two different doses. This is just the monotherapy to look at safety. It was also to look at genotypic cross-reactivity.
And 20 of the healthy patients, we are looking at the effect of prior COVID vaccines using the ChAdOx platform that is now out licensed to AstraZeneca versus those patients that have received mRNA vaccines to understand whether prior ChAdOx vaccinations will inhibit any of our responses in the chronic hepatitis B patients.
That study is almost fully enrolled. HBV002 is in chronic hepatitis B patients that are well controlled on nucleosides, where they're administered VTP-300 with and without low-dose nivolumab, and I'll go through that in some greater detail. As of today, we have 38 patients enrolled of a planned 52.
We had initially planned 64, but based on MRM data, we are closing two of the arms, and those closures are underway with our regulatory colleagues and in the countries where we are conducting the study. AB-729-202 is a study that we're doing in collaboration with Arbutus.
Arbutus is the sponsor, and this is using the approach that Dr. Agarwal talked about that was seen pre-clinically in mice, where we will use induction therapy with a very potent siRNA from Arbutus for six months, and then we will come back and use multiple doses of VTP-300, looking for those people to have complete loss of surface antigen. We have also written into that protocol the appropriate kind of nucleoside discontinuation therapies that could be very promising.
Then HBV003 is a program which we are getting off the ground right now at Vaccitech. It also looks at using low-dose nivolumab or other checkpoint inhibitors that could potentially be given subcut or orally. In that we're looking at a variety of boosting regimens and the timing of the checkpoint inhibition.
Despite checkpoint inhibition having been around a long time, the appropriate timing of the checkpoint inhibition with therapy vaccines has not been as thoroughly studied as one might expect, especially given the widespread use of checkpoint inhibitors in cancer therapy. These are the design of the HBV001 and HBV002 trial.
In the chronic hepatitis B patients, these cohorts are now fully enrolled, and we are now enrolling cohorts five and six, which are the cohorts to look at prior and healthy adults looking at prior therapy. More importantly, in HBV002 we have group one, which is MVA. These are patients that have DNA that has been suppressed for at least six months on nucleoside therapy.
They've been on nucleoside therapy for at least a year. Their surface antigen is less than 4000. In these patients we have group one, which we're closing, which has MVA followed by MVA, and you'll see the reason for the closure shortly. Group two, ChAdOx plus MVA. Group three, ChAdOx plus MVA plus low-dose nivolumab, given at the 28-day boosting time point. Group four, ChAdOx plus nivolumab at prime and MVA plus nivolumab at boost.
In the phase I study in the healthy adults, we showed that a single ChAdOx alone gave over 1,000 spots median, whether given at the low dose or at the high dose. This is extraordinarily high compared to, say, three doses of the Tarmogen vaccine that was mentioned by Dr. Agarwal, where they could not even achieve levels that were in the hundreds in healthy participants.
We're talking about responses that are somewhere, once we boost 10 to 50-fold higher, than those prior vaccines that have been studied. This is an overnight unstimulated assay. Well, stimulated with peptides just overnight. We also looked at cross-reactivity in that study and showed that we saw good cross-reactivity between genotype C and genotype D by using genotype-specific peptides.
That is, we made pools of peptides representing a consensus genotype D and took the cells from the patients that had been vaccinated and showed that these responses did cross-react to genotype D peptides, giving us hope that we would not need to make more than one specific vaccine product and we will not need to go into genotype-specific products as we move forward.
This is the phase II-A data by groups, the most important data, which is the surface antigen reduction. Again, to remind you, the vaccines are given at day zero. Then, at day seven, there's essentially very little difference between day zero or screen. The change in surface antigen over time is less than a few percent. As you can see, group one, MVA, that basically had almost no effect.
Group two, which was the ChAdOx MVA, which is the brown line, we saw two patients who had meaningful reductions in surface antigen, one of 0.7 logs and one of over 1.34 logs. Both of those patients started with surface antigen of less than 100.
Those patients that started with surface antigen greater than 400, we did not see reductions in surface antigen in those four patients given just ChAdOx plus MVA. However, in group three, in the ChAdOx MVA, plus giving nivolumab at the time of boosting, we saw reductions of greater than 0.3 logs in every patient, all six patients that we examined to date.
We had three patients that had greater than one log reduction, which is considered to be the gold standard for phase II trials, to have a one log reduction in 50% of the patients. Certainly small numbers to date. One of these patients went on to have complete loss of surface antigen.
Group four, interestingly, which also gave nivolumab at the boost, but had nivolumab also at the prime, the ChAdOx plus nivolumab, we saw that there was an ablation of the responses that we saw in group three. That's consistent with the biology because PD-1 is actually necessary for initial activation of the T-cells in the lymph node. We will not be using that arm again. Given that data that we've seen, we've closed groups one and three, one and four, and we are enrolling specifically into group three.
Groups two and three. This is the group three data in the six patients. You can see that one patient, the yellow patient, had a transient ALT flare on day 35 and has dropped over two logs. They have continued to drop at six months. They've dropped another half log at six months and are close to being non-detectable.
We had one patient with complete surface antigen loss that started off with a surface antigen that was slightly less than 100. But all the patients, even those patients that had very high starting surface antigen levels, we've seen at least 0.3 log reductions, at most down close to 0.5. Just to give a sense of where this hits against these PD-1 alone. These are the same scale. This is the GAIN study that was referred to by Dr. Agarwal.
On the left in brown is what happens when you give a PD-1 dose alone. As you can see, very few patients there got down to the 0.5 level. There was the only single patient who had clearance. All the rest of the patients were basically below what our lowest patient was, which is patient one on the right, which only had a 0.31 log reduction.
This is that day at week 12. This is comparing week 12. The blue on the left is nivolumab plus the Tarmogen or the GS-4774. As you can see on the right, for six patients we have had remarkably higher loss than those patients that are on the left. In terms of immunogenicity, we are still doing many of the assays.
We did do assays and six per six patients in group one and group two. What we saw is in group two, after giving the MVA boost, we see T-cell responses in these chronic hepatitis B patients that have a mean of over 100.
That's consistent with the fact that we expect there to be quite a bit of a drop between the healthy volunteers and the chronic hepatitis B patients. These are essentially in terms of ICS positive T-cell response, the highest ever reported for a therapeutic vaccine. We will be starting AB-729-202. This is a study that's being run by our colleagues at Arbutus.
This is a study design where we will have a lead in with the AB-729, and then we will randomize these 40 patients, 20 to receive VTP-300 and 20 to receive [sham] vaccine. We will follow them up and look at possible nucleoside discontinuation. The study start should be soon. We hope it's this first quarter, but certainly in the first half of 2022. Then lastly, as we do not appropriately know the timing, and we may need to give further boosts to the T-cell system than you are. You do get very decent boost back to the peak levels with giving multiple MVAs.
We've designed an HBV003 trial that's looking at a variety of nivolumab timing in the relationship to the therapeutic vaccine, as well as a number of boosts given at either month two or month three. In this trial, we are finalizing the regulatory documents as we speak with plans for submissions over the next couple of months. VTP-300 progress in validating this as a new mechanism of action.
We've shown best-in-class T-cell induction in terms of immunogenicity. We've shown cross-reactivities to genotype C. We have very small numbers of patients in our trial. However, we are quite optimistic given what we've seen responses by VTP-300 alone and even better when loaded with nivolumab is given at the boost time point with a mean 1.1 log reduction after these single two interventions.
We have been very impressed with safety. There have been two episodes of transaminase flares related to either the timing of the boost or nivolumab. Both of these flares have resolved quickly over one to three weeks. We have not seen any safety signals that are of concern yet.
Of note, one of the patients with the flare was one of the patients who had the best response. I will stop there. That's the last slide. We will open this up to questions for people on the phone, and then we will also take questions from the web. I will turn it over and see if there are questions from people who are actually on the phone first.
Thank you. We'll now be conducting a question-and-answer session. If you'd like to verbally ask your question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. If you'd like to ask a question over the webcast, please type your question into the Ask a Question feature on the left side of your screen.
Once again, if you're dialing in over the phone and you'd like to verbally ask a question, please press star one at this time. Or you can type your question into the Ask a Question feature on the left side of your screen on the webcast. One moment please while we poll for questions. Our first question today is coming from Andy Hsieh from William Blair. Your line is now live.
Oh, great. Thanks for taking my questions and thanks for putting this together. It's super helpful and informative. In terms of the presentation by Dr. Chan, I just wanted to clarify the S antigen drop you presented that was observed after therapy stopped. I just wanted to, you know, kind of clarify that graph.
And then, you know, just kind of the general topic of flare. You know, I think that's super interesting. Would be curious to kind of take a deeper dive on that. You know, also remind me of the pseudoprogression that you see a little bit with immunotherapy from the oncology field. Just curious, maybe generally, is flare necessary or maybe it's, you know, kind of sufficient for a functional cure?
You know, maybe this is not related to the previous discussion, but in terms of the S antigen levels, what is the field at right now? Does it need to be completely undetectable, low as possible or something like that? Is there kind of a linear correlation between the reduction and the potential for recurrence? You know, lastly,
If I can ask about the treatment discontinuation, I think Tom asked, you know, kind of brought up the idea in the Arbutus trial to kind of look into that. You know, it's kind of tricky to withdraw treatment all the time, but just curious about how you handle that issue as you know, kind of advance the HBV003 trial. Thank you.
Henry, you wanna-
Thanks a lot.
Yeah. Go ahead, Henry.
Yeah, thanks. I can address some of the concerns. There are lots of very interesting, important questions. The first one I wanna address is flare enough? Is it necessary or is it sufficient? I must say, we learn a lot about flares in the 10, 15 days, as well as there are some recent studies of discontinuation of NA and with flares.
It seems that for those patients who successfully clear S antigen, they do have flares. Flare is probably insufficient on its own because most patients have flare will not have HBsAg loss. It seems that those who have HBsAg loss, they also have flares. I think ALT flare probably cannot be avoided, but we have to handle it very carefully because it also links to the safety. If flare is too serious, then it will also kill the development of a drug. Maybe Kosh, you can supplement some of this, some information about flares. I'm sure you have a lot of experience on this too.
Okay. Thanks, Henry, and really good questions. That's like another 20 minutes discussion you just came out with in your first question. I guess my recollection was flare and then surface antigen level. Briefly, I think we are not fully aware of what we really need to achieve surface antigen loss.
I would come back to my comment about the heterogeneity we have in the world of hepatitis B. There's no doubt if we extrapolate from the data of just nuke discontinuation, and that's a whole other topic in itself, that the lower the surface antigen, lower than 100 by and large, the more chance that you're going to get sort of clearance of surface antigen at the end, which is why I think the Arbutus hookup is a good study.
Number two, flares specifically, I'm not sure we fully know. I think for this field it's really important to have good control over safety. I tend to agree with Henry. I think we're going to need to see some immune engagement with immunomodulators.
We want a reconfigured immune system to engage with the hepatitis B surface antigen and the capsid and the rest. So that should generate some hepatocyte loss, and that should generate some flare. But the differentiation between flare and safety is a really critical and topical issue, which clearly is the number one thing in early phase studies. I'm gonna stop there.
Lastly, you asked about the HBV003 study. We have not yet written discontinuation rules into that study. There are discontinuation rules written into the Arbutus study, where if you, at the time of, at 48 weeks, if you have achieved the surface antigen below a specific cutoff that has been agreed with the regulators.
Then we will discontinue the nucleotide and see if we can either get further surface antigen loss or consolidate the surface antigen loss we've seen or prolong it without the nukes. Those patients are followed very carefully weekly, as a matter of fact, to see if they recur because then they would need to be quickly put back on their nucleosides. That's where we are with those. Thanks. Next question.
Thank you. Our next question today is coming from Carter Gould from Barclays. Your line is now live.
Great. Good morning and thanks to the Vaccitech team for putting this on. I guess just two for me. First off, when we think about the appropriate timing of a T-cell induction agent, I guess or you know different immune modulators, the field seems to be sort of congregating around sort of six months after RNA you know suppression therapy. Is that sort of settled in your mind? I don't know if there are basic principles that sort of guide how you think about you know the appropriate timing to introduce an immune modulator.
I guess, sort of as a corollary to that, when we think about, sort of the hurdle for the field in terms of sustained S antigen loss, you know, I'm not so much interested in kind of, you know, what the hurdle is for approval, but more in the minds of the clinicians, kind of how do they think about that, and if that's different when we think about, you know, immune modulators versus the other therapies that have come before it.
Henry, you wanna take that last question about how you get to surface antigen loss and whether it changes your clinical opinion of what's going on?
Well, actually, I think this is a very important question again. Well, we know that if S [antigen] is lower then it gives you the better timing to reduce the immune clearance. Well, actually, I'm really quite interested in the siRNA before immune modulation, whether it's a right strategy. Of course, nobody knows if we reach the results.
But the study I showed you on the combination of the siRNA by Vir Biotechnology with pegylated interferon seems that the simultaneous starting of these two drugs may have a better response than a sequential one. But of course, that's a very small study, but at least it sheds a little bit of light in HBsAg reduction. So, I don't know. I really don't know whether a sequential use of these two drugs is better than simultaneous.
We know that the HBsAg reduction of siRNA is pretty long. After we stop siRNA, the HBsAg will not bounce up immediately, but it will only climb up very slowly. Even if we start the immune model at that time, the HBsAg level should still be low. We don't know why. Probably because of the half-life of the siRNA. I think we need more information about that before we know how to use it wisely.
Yeah. This is Tom. I would say I agree with Henry. We don't know if we should be giving therapeutic vaccines or immunomodulators after surface antigen reduction direct agents. Theoretically, it's appealing because people that have lower antigen tend to clear better, so it makes you look better potentially.
I can tell you from my TB days that transgenic did studies where they showed giving therapeutic vaccines before drugs was better than giving them after, which was completely contrary to what the field had assumed. They had assumed the same thing that we're assuming here. I think it is an open question. The only way it'll be addressed is to actually do the studies in humans. We're not planning to do that as an initial study, but I think at some point it is a reasonable thing to consider. Thanks. Thanks for that question. Next question.
No further audio questions. I'll turn the floor back over for the web questions.
Tom, can I just add something in to that really good question, if I may?
Yep, please do.
Okay.
Go ahead.
Really good question. I tend to agree, but I'd be a bit firm. I don't think we're settled on the concept of six months of dropping of [surf sanction] and then using an immunomodulator. I do think we're further along than we were, but I think there is no clear roadmap that we need to do certain things in certain orders. Priming an immune system and then dropping [HBsAg] may actually be something we need to do at some stage. Nobody knows anything really. I think we know a little, but I don't think the field is set on this.
You could argue that dropping [HBsAg] very rapidly might really jumpstart your immune system and get you added value from your immunomodulator, whatever that may be. The second question is a very good question as well about what do we feel clinically about loss of [HBsAg] and its durability.
I'm really happy you didn't use the term sustained virological response, which I think is not what we should be using in hepatitis B. Remember, our aspiration to lose [HBsAg] and to get core antibody or get antibody response still leaves us with a small risk of reactivation in certain settings. Number one, we need to see what the regulators think. I think that is important. Number two, more importantly than that is gonna be what patients are comfortable with.
Once you've achieved [HBsAg] loss, that is a binary endpoint that does improve your long-term outcome and your risk of HCC. Certainly if we have the odd patient who does that spontaneously and they're non-cirrhotic, we discharge them. That is cure. That will be a good benchmark to get to, but I still think it's where we should be aiming. Thank you.
Great.
Yeah, I would echo.
Do we have any more? Go ahead, Henry.
Yeah, sorry. I want to echo the functional HBsAg loss is pretty durable. There are more and more data on NA-induced HBsAg clearance, and it's actually very durable. As durable as spontaneous S loss, which probably 95% of patients do not have HBsAg reappear. Even with those who have HBsAg reappear, they tend to have very low viral load. It should be a good marker for functional cure.
Thank you for that. Do we have other questions on the phone?
Not at this time.
Okay. Henry and Kosh, there's a few here from the web. I'll start with you on this one. A really good question. Is there any evidence for functional cure that the strategy may depend on the HBV genotype, or you think once you have a regimen it's going to be pan-genotypic? A great question. What do you think about that one, Henry? Then we'll go to you, Kosh.
Well, I think. Of course we cannot everything and even these HBV genotypes are different, most of the immune epitopes are very similar, and there will be lots of cross-reactivity. Well, to me, I don't think we need to have everything and what we are doing by using HBsAg consensus full-genome S should be good enough.
Kosh, what do you think?
I think that's a really great question.
Do we need to worry about genotypes? Should we be doing specific things based on genotype or what's your sense here?
I think the heterogeneity of virus is still not fully understood. I think this is a really classy question. At one level, let's not think about hep B as hepatitis C. It's a completely different kind of issue with regards to hepatitis C genotyping.
Look where we are now, it's all pan genotypes. I do think genotype is wrapped up in racial background, and I have to highlight that, you know, most of the data we're seeing is from pan-Pacific Asian and Caucasian populations. We need a treatment that will serve the global population of hepatitis B. I tend to agree that it's not going to drive, really, genotype is gonna drive our strategy of cure.
What I think is going to be more important, to take the question just a touch further, is actually the phase of disease. For immunomodulators, the sort of philosophical question generated by some of my colleagues, Antonio Bertoletti, Patrick Kennedy, others, is maybe we should be treating those patients who are younger, who are treatment naive, who may generate a better immune response or may have, you know, more perky immune responses.
It's more to do with phase rather than genotype and whether we should be treating younger patients. It's what I alluded to about maybe we're going to need to mix and match the strategies depending on the phase of disease and the age of the patient. I think there are still those drivers that we don't know.
In drug development, and others know this better than I do, right now, the suppressed population, non-cirrhotic body is by far and away the safest, and that's where we should be starting to get into at the beginning.
Thank you for that. We have another interesting question here that I'll start off with, and then I'll turn it over to the two of you. It says, "What are the key differentiating factors between Vaccitech's ChAdOx MVA platform and other prime boosts under clinical development?" Just to clarify that, the prime boost done by GSK uses an adenovirus followed by MVA, followed by protein.
It is a triple combination. However, they are not doing their studies at the moment with PD-1 or with other agents, as far as we can tell. The vaccine coming from Ulrike Protzer's group, which is gonna enter the clinic shortly, is an antibody-based vaccine, so it's a surface antigen protein, then followed by an MVA vaccine. It will induce...
She has designed that to induce antibodies to try to lower surface antigen and then to come in with the MVA and hope that that will give a sufficient boost on the CD4-positive T-cell side and to some CD8s to allow clearance, but clearly will not give us high CD8s as we see with an adeno plus MVA. Two strategies that are somewhat similar.
The point then comes up, and I'll ask Henry and Kosh this, there are approaches of thinking that you can reconstitute the immune system merely by getting rid of surface antigen. That's not just the production, but the circulating surface antigen, which some people claim is immunosuppressive, is basically immunosuppressive. For example, the Vir antibody approach. What's your feeling about the need to have a potential antibody-based mechanism as part of a therapeutic vaccine?
Is it going to, in your mind, be required? Is it a smart thing to be doing? Or do you think that you can get away with just sort of the Vaccitech approach, which is to allow the immune system to come in and then boost mainly on the CD4 and CD8 positive T-cell side? Henry, that's a complicated question, but I'll turn it over to you and see what you think about the role of surface antigen and the need to clear it, potentially using monoclonals.
Thank you. Well, that's a very common question. Again, I don't have an answer, but I can give an educated guess on that.
Okay.
With surface antibody, again, what we want to do is to bind the surface antigen so that it will have a lower free surface antigen level, and hopefully it can restore the host immune response to work together with the therapeutic vaccine. Nobody has tested that strategy, although other strategies are being tested like mRNA and the NAP approach is to block the antigen production from liver cells.
Well, theoretically speaking, it may work, but it may depend on how durable is the antigen blockade by the antibody and how complete it can be. How low HBsAg you can drop with that. It all depends on how good PreS-binding antibody. Potentially, yes, it may help with the therapeutic vaccine.
With therapeutic vaccine together with, say, any PD-1, it can induce a bigger immune clearance. The only risk is flares. Of course, in our study it seems that the flare is transient and is not serious, but still it's an early phase study, it's a small scale study. I don't know whether it will expect to induce an exaggerated immune clearance that some patients may have a serious flare and that may be difficult for this combination to carry on.
Thanks. Kosh, what do you think about the role of reducing circulating surface antigens?
I have a different view. I have to give a disclosure. I'm sort of lead presenter for the VIR-3434 program. And I think it's a nice program. The public available data shows quite a significant drop in surface antigen, but they haven't and we haven't presented any subsequent data looking at mechanisms that are a vaccinal effect or anything else.
And certainly I've highlighted we need to get that data. I am going to say this because we're involved in the study with Vaccitech. I quite like the approach, and I think I don't think we need to specifically look at surface antigen, surface antibody generation. I think by focusing on CD4-CD8 T-cell responses, I think that should be enough with that heterologous boost.
I think it's going to be in conjunction with another antiviral that's rapidly changing markers such as surface antigen and allowing that broader reconstitution with an additional broader immune stimulator, such as a PD-1 or TLR7, TLR8, something like that, to get you there. I'm comfortable with this approach personally, as an outsider, and I thought the trial design was a reasonable trial design, so we were happy to do it and are involved in the trial with you.
Thank you. The last question here is the reason for the lack of dose-dependent immune response. I'll take that one on because it's something I'm very interested in. Adenoviruses have a gamma-shaped curve on the dose-response that's fairly flat at the top for T-cells.
For antibodies, you can see from the COVID vaccination strategies that the higher the dose you give, the higher the antibodies you get. That is not true for T-cells. In fact, if you push the dose of adenoviral vaccines, you will actually decrease the T-cell response.
I have three papers myself, Tom, that we've published on it. If you go to PubMed and look at those papers, you'll see that in general, adenoviruses have very flat dose-response curve on the T-cell responses.
Sometimes people actually use them at higher doses that are actually not as efficacious as lower doses. We were not surprised to see this lack of dose response. It's been seen in multiple trials in terms of the CD4, combined CD4 and CD8 positive T-cell response.
Great. That's the questions we have. Henry, any other comments you would like to make for the people on the phone in terms of where do you think the field's going and your... Do you think that we'll get there with a double combination? Do you think it's gonna be a triple combination, or do you think it's just too early to say?
In fact, in the beginning, say like two years ago, you asked me this question. I think probably we can suppress the virus and induce the host immune response is good enough. After looking at a lot of newer data, I do think that an immune booster is important.
Definitely therapeutic vaccine has its role. Actually, I don't know whether we need one more immune booster on top of the therapeutic vaccine because it seems that by just dropping our antigens in DNA is insufficient to induce, I mean, to restore the host immune response to clear the virus.
Kosh, what do you think? How do you see this field evolving? Do you see triple combinations, quadruple combinations, multiple combinations? Where do you think we'll be in two to three years?
I think it's a good question. Let me reflect before I look forward and forecast. It's a trite comment, and I've said it in these sorts of meetings before. hepatitis B is not hepatitis C. Hepatitis B is a different virus. It has the heterogeneity. It's a more complicated game to get into than hepatitis C, which is an interesting reflection given the challenges we had in hepatitis C.
We've had three to four years of this now, and we have a lot of antivirals with new modes of action. We seem to dismiss the Replicor data and of course, the REEF-1 data where we expected a synergy between a safe siRNA and a capsid really did not show an enhanced effect of combination. It showed a decreased effect compared to the siRNA alone.
I think the field is taking a step back and taking a deep breath. I agree with Henry that I think I'm confident, and I believe that we are going to need to have immunomodulators. I think this combination of multiple direct-acting antivirals, as we saw in hepatitis C, which I think is more and more an anomaly, is not going to fly in the world of hepatitis B.
How many sequential repeated, non-repeated? I think we're still, you know, in the pre-telaprevir, pre-boceprevir years of hepatitis B as we take that metaphor from hepatitis C. I think we're going to need to have a combination. I think we're gonna stratify as to the phase and to the sort of immune responsiveness of the patient.
I believe we're going to need to have probably two or three agents. The aspiration of a 24-week or a 36-week combination treatment is really where we want to be. I think we're going to be using, you know, three or four agents in combination in various ways yet to be defined. Very exciting, and a lot of work to do. Certainly, you know, no clear roadmap, and no clear paradigms, and a lot of work to do.
Well, thank you very much. Those are all the questions. For Vaccitech, I'd like to thank Dr. Chan and Dr. Agarwal for joining us today. I appreciate people joining us on the phone and through the web questions.
If you have further questions concerning the Vaccitech program, please send them to me, tom.evans@vaccitech.co.uk. Thanks, Bill, for the introduction as CEO, and I appreciate it. We'll be signing off now. Thanks to all. Henry and Kosh, thanks a lot.
Thank you.
Thank you very much.
I really enjoyed this meeting.
Thank you very much.
Thank you. That does conclude today's teleconference webcast. You may disconnect your line at this time and have a wonderful day. We thank you for your participation today.