The reason it takes so long is the efficacy data is not there yet. For Nasvac, the 10% functional cure rate was something like 4 out of ~40 people, this is quite a small trial. And it’s not clear what the control arm looked like. Larger studies are needed and sometimes the effect of these drugs shrink dramatically when testing in more diverse populations (for many different reasons).
For TherVac, there may be promising data in mice, but this is not a 100% accurate model for a human chronic infection (again, for many different reasons).
This is the stringency and tough trials that all hep B drugs have to go through to make sure that these are safe and effective medicines. We are dealing with a pretty high bar at the moment; the currently available antivirals are just daily pills that can slow liver disease down with very rare side effects.
Any developing therapy that does not work as well or suddenly generates adverse effects are going to receive a lot of scrutiny to make sure it is worth it for people with Hep B.
I hope that gives you a bit of insight into why it takes so long.
There are many types of “cures” once you dive into the details. I’ll discuss the 2 most commonly considered types.
By “Cure”, you are probably referring to what scientists call a “sterilizing cure”. That is when all traces of HBV are eliminated from the body, drugs are no longer needed, and the risk of disease progression is no higher than for someone who never had HBV. The scientific community does not think this will be achievable due to HBV’s propensity for integrating its DNA into the patient’s DNA. However, this is not the only type of possible cure.
The goal of the scientific community now is to generate one or more “functional cures”. This is defined as having no detectable HBV DNA or HBsAg in blood six months after termination of treatment. As near as we can tell, that will provide essentially as much benefit to the patient as a sterilizing cure. However, it may be hard to identify everyone who has achieved a functional cure because the integrated HBV DNA can make HBsAg even if the “live” virus has been eliminated. That is a definition and measurement issue that we need to work out.
Personally, I really hope that people who achieve a functional cure either naturally develop anti-HBsAg antibodies, or that they can be vaccinated against HBV. That would help stop viral relapse and reinfection. However, development of antibodies is not part of the current definition for a functional cure.
Yes, I was at the Singapore HBV Cure meeting last week. I enjoyed it very much and learned a lot. There have been no breakthroughs in HBV cure yet, but there has been steady progress in increasing the functional cure rates through combinations of novel drugs. Most of the successful combinations that I heard about are giving 25-30% functional cure rates, which is a lot better than the <10% rates we have now. Most of the curative combinations still include interferon alpha and require extended treatment (1 year or longer), so we have a long way to go to get therapies to where we want them. But I was very heartened to see that the hard work of the scientific and patient communities is beginning to pay off! I’m sure further steady improvements will continue as we learn more. New data on the next wave of clinical trials will be released at the EASL meeting in Vienna later this month. Hopefully, those studies will show continued improvements.
While it is true that some phase II studies are reporting elevated rates of HBsAg loss after removal of treatment (i.e. bepirovirsen and VIR 2218 + pegIFN), these studies are recruiting patients with low baseline levels of HBsAg and are reporting the large majority of HBsAg loss in patients with HBsAg < 1000 IU/mL.
The average baseline HBsAg in chronic HBV is ~10,000 IU/mL. Patients with baseline HBsAg < 1000 IU/mL represent only 5-10% of patients. There has not yet been a single reported case of HBsAg loss with either of these agents in a patient with a more typical HBsAg load. As such, the results from these studies cannot be said to be applicable to the patient population in general. Unfortunately, this is a misleading way of reporting outcome data from these trials.
In these kind of patients, pegIFN achieves HBsAg loss and functional cure in up to 30% of patients. In patients with typical HBsAg load, pegIFN rarely achieves functional cure (except in the most easily treatable genotype A).
For a phase II clinical trial to provide a real estimate of clinical potential in the entire patient population, patients with HBsAg < 1000 IU/mL should be excluded and baseline spread should include patients with a more typical baseline HBsAg. This has not yet been done for any of these agents.
A cautionary tale regarding VIR 2218: this is a GalNAc conjugated siRNA. One of issues that investigators never mention when reporting results from GalNAc siRNA in HBV is that the GalNAc conjugation has been shown to act as a long lasting depot for siRNA the liver, allowing for dosing intervals as long as 6 months while maintaining the siRNA effect on other liver diseases. This has already been demonstrated with single doses of AB-729. Off-treatment results from this class of compounds need to be interpreted cautiously.
AB-161 is the latest in a series of compounds in development by Arbutus Biopharma which target the activity of host proteins involved in stabilizing pregenomic HBV RNA produced by cccDNA. The development of a previous RNA destabilizer, AB-454 was halted by Arbutus before it reached the clinic for reasons not disclosed.
NAPs work by preventing the assembly of the major form of circulating HBsAg (subviral particles) in cells with cccDNA (which also produce virus) and in cells with integrated HBV DNA (which do not product virus). The majority of HBsAg comes from integrated HBV DNA as chronic infection progresses.
It is unlikely that HBV mRNA destabilizers will work in cells with integrated HBV DNA (there is no pregenomic HBV RNA produced in these cells) meaning that mechanism producing the majority of HBsAg will not be targeted by this approach. The safety of this approach has not yet been examined in humans.
Preclinical evaluation of this approach in animal models showed relatively weak antiviral activity (see here) compared to other approaches (antisense and RNAi) which have failed to produce functional cure in human studies.
Based on the information provided above, it seems that genotype A is the most easily treatable. Therefore, my genotype is A and my doctor is reluctant to prescribe pegIFN and prefers to start nucleoside analogs (NA), and also i have invited for TherVacB clinical trial in the coming June . is it good to find a doctor experienced in treating with pegIFN or better to wait incase not recommend with the clinical trail of thervac B???
BR
You are correct, this HBsAg result is not informative. The lower your HBsAg level, the more likely pegIFN is to achieve functional cure.
Taking part in the TheraVacB trial will not be harmful to you but I advise to find a hepatologist who has more experience with pegIFN.
When you are in the TheraVacB trial, your HBsAg assay will be monitored by a quantitative assay. You will have a better idea of your potential therapeutic response to TheraVacB (and pegIFN). You can assess your potential for response by examining any changes in your HBsAg levels four months after the HBsAg expressing vaccine is administered (or the control).
