It is our great honor to have an in-depth interview with Professor zoulim invited after the meeting to share with us the progress of new drug research on hepatitis B, the key issues and the future directions for curing hepatitis B. The interviews are now collated in writing for the reader!
Prof. Zoulim: Regarding the new drugs that are in development, there is a lot of excitement with strategies that target viral RNAs, and mainly antisense oligonucleotides (ASOs) and siRNAs. We have seen very nice studies very recently in clinical trials, which show that with ASOs or siRNAs, with subcutaneous injection, we can induce HBsAg decrease by approximately 2-log, and that this decrease may be sustained. So this is really encouraging. These trials showed that from different companies and with different regimens, the overall message is that a few patients were even able to clear HBsAg to achieve a functional cure. These are small trials but having a couple of patients in each trial that clear HBsAg is very promising. The decline in HBsAg was associated with transient transaminase elevation, which were very well tolerated, but which suggested that this may be associated with a restoration of antiviral immune responses. So, clearly, there is great enthusiasm with antisense oligonucleotides and siRNAs. These drugs are now evolving to late stage phase II clinical trials, and even in phase III that may start in a few months from now. This is really promising. There are also drugs that are more in the exploratory stage, such as capsid assembly modulators. There were big trials with the first generation of capsid assembly modulators, which were not really satisfactory - there was a modest effect on HBsAg. But now there are new generations of capsid assembly modulators that are much more potent, so clinical development is starting again with a new generation of capsid assembly modulators. This is very interesting. There are also novel HBV polymerase inhibitors that are starting clinical trials. So it is a very interesting time for direct-acting antivirals. And there are also immune modulation strategies that are being explored in clinical trials. There are new therapeutic vaccines and different types of vaccines being explored, but many in the early stages of clinical development. They will progress to larger phase II trials in combination with antisense oligonucleotides or siRNAs. The concept will be to decrease HBsAg levels withASOs or siRNAs so we can restore some adaptive immunity, and then introduce the
therapeutic vaccine. These combination trials will start very soon in 2022. This will be very fascinating I think. We have also heard from a Chinese group using PD-L1 antibodies, a checkpoint inhibitor - not a PD-1 blockade, but a PD-L1 blockade - which was shown recently and with very interesting results. It was a small trial, but still, again, showing that in patients with lower HBsAg (<500), results with a PD-L1 blockade were much better. So, very promising compounds with direct-acting antivirals and immune modulatory approaches.
Prof. Zoulim: I just covered the new direct-acting antivirals. I think the way the field is evolving is towards combination trials. Monotherapy with direct-acting antivirals is so far not an option for two reasons. One is that for most of these direct-acting antivirals, for example, the capsid assembly modulators or the new polymerase
inhibitors that are upcoming, there is a risk of resistance. We really need to combine two modes of action to prevent resistance. The second reason is currently, and with all of the data we have from the different drugs in clinical trails, we haven’t seen sufficient effect on HBsAg levels or on cccDNA levels in the liver with monotherapy. So clearly we need to go for combination - either combinations of direct-acting antivirals, or combinations of antivirals plus immune strategies.
Prof. Zoulim: For future research, in terms of clinical application, we need to have biomarkers so that we can predict what is going on in the liver. When we have new drugs with novel modes of action, we need to know whether the modes of action are really affecting the reservoir of cccDNA and improving the antiviral immune
responses. Biomarkers will be very important. We need to have biomarkers to reflect cccDNA in the liver, and these biomarkers need to be non-invasive (a blood test). We know there are different assays being evaluated correlating to antigen levels and viral RNA in serum. There is a lot of excitement for these biomarkers, and we need to learn from these ongoing studies how to use them, what they mean and their clinicalrelevance. We also need biomarkers for immune responses or assays that allow us to measure adaptive immune responses to HBV infection. These are very important in my view to help the development of the new drugs. In terms of basic science, we need to develop more knowledge that will be important for future drug discovery that really targets cccDNA, either aimed at eliminating cccDNA or completely inactivating it. We really need to have a strong involvement in research on cccDNA biology and drug discovery to target cccDNA. The other point for the more mechanistic studies is understanding the pathways of T-cell exhaustion, so we can try to restore stronger and efficient adaptive immunity against the infected hepatocytes. That will be a very important point. The first aim of clinical development is obviously to try to improve the efficacy of new strategies compared to what is currently available. Clearly, we need to target chronic hepatitis patients. But the long term goal is to have strategies that provide the
opportunity to achieve a functional cure in a large number of patients, so we can apply these strategies to treat all infected patients. For me, the long term goal is treat all the patients, and this could be possible if we can achieve this high rate of cure with a finite duration treatment (six months to a year, the shorter the better), instead of
lifelong therapy. Then if we can provide high cure rates, we can treat everyone to prevent all the complications of HBV, liver cirrhosis and hepatocellular carcinoma. That would be the long term goal, and I think it would be very important to achieve this goal.
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