Channel: Academic Medical Education clear
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| 1 | Academic Medical Education | Is immunomodulation really needed to cure HBV? | Harry Janssen, MD, Ph... | 846 | 6 | 25.4 | 17:15 | These are my disclosures. This is an old slide where we really show what has happened. And if you look at immunotherapy over the years, the only thing which has really been licensed is peck and tephyrum. And the only antivirals that have been licensed are nucleotide analogs. So there's not a lot of diversity at all in what we have been doing over the last decades. And it's very good that we see change now. So the question is, what can be considered as cure? I don't want to go into that too deeply because Fabian already mentioned that very nicely. But I think the consensus really now is to go to functional cure. I don't know exactly what partial cures which might be important for particularly development of drugs. But most people think that HPS-Sensitum loss is what we should aim for. So the treatment paradigm is really changing from an indefinite therapy with poor off-treatment response to a fine aduration of treatment where really these nasty endpoints that we don't want to have like liver cancer and liver cirrhosis and liver related deaths are prevented. So last year, like a year ago, we had a very interesting discussion. There was a group of biologists and a group of immunologists in the room. And at the round table discussion, it went back and forth what is the role of both. And there's something to say for both would be the virological approach enough. And even within companies, there are virologists who say, well, I don't know if we need immunologists at all. Because the virologists say that blocking viral replication at multiple steps might eventually eliminate CCD and eventually curates BV infection. There will be no infected hepatocytes left. It's very debatable if that's true. It would be important though that we need better assays to really detect a very low level of replication, which we don't have in our hands now. And the other things that is mentioned is that once you decrease the viral load or the protein load, that by itself might mountain immune response, which would not need any immunological treatment. And there's some examples of that. There's modification of antiviral therapy leading to an effective immune response. For an example, stopping treatment, I'll show you in a minute. And also long-term treatment. We know that long-term treatment that people do get S-antage in loss, not at a very high extent with antivirals. But if you stop the antivirals, it's sustainable in the vast majority of the patients. And on the other side, you have the immunologies. The virus integrates. It's very difficult to get rid of CCD, NAFABN, mentioned that very clearly. And the proof is obviously that even patients who have S-antage and loss of serum version once you give them, like, profound immune suppression, they will relapse. And they will even relapse with an assasero-reversion. So that is, and we've seen that in many cases. And we do have effective immune control by giving back and deferred, although it's in a limited proportion of patients. Here's an example of what stopping therapy could do from Thomas Berg, who did the first randomized study on this, other studies are ongoing. And in the vast majority, you have a relapse of HBVDNA. But if your courage is enough not to re-initiate treatment very quickly, you have patients in there, not many, but part, let's say, 20% of your patients, where you do see an ass antigen decline, and even an ass-antage in loss. Because here you see on the left side the patients who stopped treatment and the amount of ass-antage in reduction. And on the right side, patients who continued to know of treatment, whether it was virtually no ass-antage in loss of reduction. And it was the case in patients who stopped therapy. So this is just by modifying new therapy. So theoretically, obviously, it's a very attractive option to combine the two. The agents are complementary to each other's HBV in pairs in it in adaptive immunity. And if you load a viral replication and protein load, as I mentioned, that might, by itself, enhance an immune response. And the question is whether immune therapy, and this is what many people think, currently, might tip the balance towards secure or functional cure of hepatitis B. The problem with immunotherapy is that it might have a smaller therapeutic window. You have to be very careful on how to dose these agents, because if you under-dose it, you won't have any effect. But if you over-dose it, you could get cytokine storms and all kinds of nasty side effects that we don't want to have, particularly in this hepatitis B patients, with very good treatments in our hands. Because remember, it's very different to hepatitis C, where we had a lot of back to the wall patients, and hepatitis B patients have a good therapy, and we have to give them a better therapy, but without any side effects, really. And then there's a heterogeneous response, which is very often seen. I would say more so with host targeting therapy than with virus targeting therapy. So there's a lot of different options. And there's also a treatment in the EF population, as well as a huge warehouse of patients who are already suppressed, who are on antivirals for a long time, and they might want to be cured. And if you compare the two populations, they're different. So the treatment in EF population is typically younger, have active disease. HBVDNA can be used as a biomarker. There's no resistance. And they might be more likely to accept finite treatment. And we have the suppressed population who are already on an effective and a safe treatment. They might have a partial immune restoration, which might help immune modifying therapy. They're potentially better protected against flares, but they also might have more objections to accept the experimental therapy. But particularly if they're a bit elder and they take their antivirals and they think one pill a day will keep the hepatitis away. So it's really sometimes challenging to enroll these patients into studies. Well these are all the different targets that we have. And we'll hear a lot about that this afternoon. And I'll come back to some of that in the rest of my talk. Because I thought, how can I answer this question? And I said, well, let's, if you don't know how to answer a question in science, you just try to go back to the data which are there. And as a clinician, I would like to look particularly in clinical data, because there's a lot of work done in the lab and in animal models. But that doesn't always or very often does not translate into results that we have in clinics. So I looked at the different clinical trials, which give both antivirals and immune activators both on licensed as well as on new therapies. And if you look at one of the studies which was done, it's highly cited. Most of you will have seen this before. It's combining tinoffapherin pecan-tiferin versus tinoffapherin alone and versus pecan-tiferin alone. And the authors of this paper were pretty excited that the combination did do better than the monotherapy. But if you look at the actual difference, it's very, very limited. This is I think 9% here with the combination. Nothing with tinoffapherin alone. And then the combination arms or the pecan-tiferin only arm and the short-term combination are kind of in between. And also what was interesting is that they did see S-antage and serial reversions in this particular study. And Fabian just showed the sustainability of S-loss in here. So yes, there is a bit of a better response in the combination, but it's not something that we would start massively practicing and giving our patients tinoffapherin pecan-tiferin. The benefit is just too small, really. Then another strategy where a lot of people are working on is to first decline the viral load, as I mentioned, to get rid of t-cell exhaustion. And if you do that long enough and then come in with an immune modulator where you might be more effective. So this is what we did in this particular study where we gave t-cafe here for half a year and then, and we've also done it with longer treatment and then randomized patients in either pecan-tiferin add-on or in t-cafe or alone. And the result was that indeed in the combination arm we did see a higher response rate in patients being treated with pecan-tiferin and in t-cafe versus in t-cafe or alone. But again, the difference was very, very limited, not really something to be very enthusiastic about. The interesting part of this study, in particular, those that the quality of the response was interferon, so the sustainability of response seemed to be higher with pecan-tiferin than with t-cafe. So we had more patients who off-treatment remained to in a response once they had had pecan-tiferin versus dose. We only were treated with t-cafe. So that means that that might also be very relevant for future agents that a specific response for one drug might not be as sustainable as it is for another drug, really. So that is a very difficult point also when we're discussing endpoints. So what about novel compounds? What has been done to combine antivirals and immune activators? And this is a study where capsid inhibitors, formerly owned by Novira, now by Janssen, was combined with pecan-tiferin. And again, if you look in the different categories here of patients, first on the top panel, you see HPV DNA, and then in the lower panel, you see E-antigen decline. You do see that once you combine it, you get a better response. But again, the difference with pecan-tiferin alone is not mind-boggling, really. And the problem here is that they saw a very negligible effect on E-antigen, which you might not expect with this particular compound with the capsid modulators. Then there are the patent recognition receptors, the LR agonists, RIGI, et cetera. Here is a study where we treated patients who were already on antivirals and added an immune modulator in different doses and different lengths of treatment. And the drug was very well tolerated, but the effect was limited close to zero, really. So there was definitely an effect on interferon-stimulating genes. However, it was disappointing to see that we didn't see any SD-cline in these particular patients. Some holds truth of therapeutic vaccination. We've been working on therapeutic vaccination for decades. Almost all of these studies are unfortunately negative. And every time we come in with a new vector or new peptides, and it is an interesting concept. It is, however, very challenging for people who have had this disinfection with their viral load with a huge load of proteins for decades to tip the immune balance just with the vaccine. Anyway, so what we did here is we had enough of your only group, and we had this GS4774 vaccine with the yeast-based vaccine called tarmogen packed with different epitopes. We gave different doses of the vaccine in combination with Tenoffafer and Tenoffafer alone. And it looked pretty promising here at week 24. If you looked at HBS-centrogen decline from baseline, the treatment was given for 24 weeks with a better response rate in the groups who were treated with the vaccine. However, off-treatment, so only the last 24 weeks, only Tenoffafer was given, the response was really leveled out, and unfortunately we didn't see a lot of effect of this vaccine either. Then, just as the last example, we have the checkpoint inhibitor, so PD-1, PD-L-1, inhibition can reverse immune exhaustion of HPV-specific T cells. This is done, this is work done in Germany from Rockendorf-Skope, where he really combined in an animal model, in a Wuchok model, and Tekkerfer together with the DNA vaccine, and together with an anti-PD-1 antibody. And there seemed to be an additional effect of combining these three, if you look at this blue curve, which contains all of the three components where you would have the best effect. And again, this was also done in humans in a different setting, obviously, where therapeutic vaccine was given together with nucleoside analogs and an anti-PD-1 antibody. This was done with the volumpt in the low dose, I would say, two different doses. So one group was given the volumpt alone, and in 0.1 milligram, then there are 0.3 milligrams in between. And the third group got the vaccine that I just mentioned you about, and the endpoint was 16 weeks after treatment, really. And if you look at this combination of, again, antivirals and immune modifying agents, again, there's a very modest response overall. And if you combine the group of actually nivolumap together with the vaccines, actually two immune modifying agents, it's not really better than nivolumap alone. So there is very limited evidence yet that we need immune modifiers. But then again, the antivirals are also not sufficient enough to give us the answer to functional cure. So in conclusion, ladies and gentlemen, targeting the virus, I think the therapies targeting HPV directly are effective and will come in many flavors and interfering in different steps of the replication cycle. And change in the viral load has been shown in the minority of patients to induce functional cure with S-Loss, either by long-term nucleoside analog therapy or by stopping therapy. With targeting the immune system, we're making very small steps, and we just are at the beginning of the road. So don't be in despair. I mean, we started with hepatitis C with 5% response, and we eventually got there. But the first response to antivirals, at least in the clinic, have been negative or very modest. And it's also a reason that we started very slowly, very carefully, not to induce too many side effects. Because the, again, the therapeutic window is small. There isn't a heterogeneous response, and I do think we have a long way with immune modulators to go and combination therapy is most likely needed. So to come back to my question, our immune modulators really need it to cure HPV infection. The answers I really don't know. And I do think that a lot of companies also don't know because they're infesting in both and they're combining treatments. I would say probably yes, we might need these immune modulators over time because we have no functional cure with the approach targeting the virus thus far. And I personally doubt whether we will ever will. A slight problem is that we have not find the round immune modulator really thus far, and it will be very, it will be far from easy to find this. So hopefully next year, we'll have the answer to it all. So today we're discussing this. But I really would like you invite you to come back in June 2018 at the Global Hepatitis Summit here in Toronto. You have the flyers on top of your desks, so don't throw them away like you usually do, but use them and submit an abstract, I would say, because we do have, I would say, an outstanding faculty, both from a basic science perspective as well as from a clinical perspective. Thank you very much. | ↗ |