In my last topic i pondered about Gene Editing being a potential cure, which in my opinion is. We also touched on NAPs as @availlant provided great and detailed insight. Many thanks to him. This is a great place for us all involved in this disease. Thanks to @ThomasTu .
As a mean to brighten us all let me mention about another promising molecule developed by Dicerna in collaboration with Roche. This product is a short interfering RNA which can inhibit HBV gene expression for HBsAg production. This is already in Phase 2 Clinical trial as a combination therapy with others.
But what has been kept secret i dont know for what reason is another product in development by Roche. Im not sure whether they have scrap its development or maybe i have not been upto date with the latest info. I think in 2019 or earlier they discovered a small molecule that can destabilize the HBV cccDNA in mouse models.
Perhaps, and i hope, this molecule is still in secret development and one day Roche will provide the related information.
While it is at times suffocating for many of us, the end of our anxieties is in sight. Dont know when but it will come to pass and Hepatitis B, like Hepatitis C will be curable. Many products are currently in development simultaneously, atleast one of them will knock Hep B down.
These are indeed interesting molecules. In the interest of keeping the community well informed, the following should be noted:
RG6346 (aka RO7445482) is a GalNAc siRNA very similar to the three other compounds also in development: JNJ-3989, VIR-2218 and AB-729. The performance of RG-6346 was very similar to these other three GalNAc-siRNA in phase IIA studies and demonstrated that a significant proportion of HBsAg persists despite repeated dosing. Longer duration combination trials with NUCs + CAMs + GalNAc-siRNA, including a large phase IIB trial by J&J have not been able to achieve any functional cure.
A recent combination trial with VIR-2218 + pegIFN demonstrated 30% HBsAg loss after 48 weeks but in this trial, patients with very low HBsAg were enrolled and it is in these patients where most of the HBsAg loss occurred. We will also have to wait to see how durable these HBsAg losses are after removal of therapy. For some reason, a control group of pegIFN alone was not included in this study which is unfortunate since pegIFN can also achieve > 30% HBsAg loss in patients with low baseline HBsAg. As such is it difficult to understand the contribution that VIR-2218 made in the HBsAg loss observed in this study. The community also needs to be aware that HBsAg levels < 1000 IU/mL occur in ~5% of patients (the average is ~10,000 IU/mL) so HBsAg loss rates made in studies that include patients with low HBsAg cannot be extrapolated to the patient population at large. Hopefully subsequent trials which recruit patients with low baseline HBsAg and use pegIFN will include a control group with pegIFN.
It has indeed been ~4 years since we heard from Roche regarding ccc_R08.
I encourage community members to search for clinical trials at www.clinicaltrials.gov to see what trials are ongoing with these agents. J&J, Arbutus and Roche all have trials underway with their GalNAc-siRNA in combination with pegIFN. There are no current listings for ccc_R08.
@availlant
regarding the variability in HBsAg levels observed among patients diagnosed with Hepatitis B Virus (HBV) infection.
I am particularly interested in understanding the factors contributing to the differing HBsAg levels among patients. As I’ve come to learn, some individuals exhibit lower HBsAg levels while others display higher levels, with notable differences, such as counts reaching 10,000.
is that linked to immune system responses, the administration of nucleos(t)ide analog (NA) treatments, or other pertinent factors?
Regards
The average HBsAg level in patients with chronic HBV infection is ~10,000 IU/mL.
During acute or HBeAg positive infection, HBsAg can be > 125,000 IU/mL.
In patients with inactive HBV infection (where HBV DNA > 2000 IU/mL and normal ALT), HBsAg levels can be much lower than 10,000 IU/mL.
We also have differences in HBsAg secretion efficiency between the different HBV genotypes and also HBV secretion efficiency can be affected by mutations in the HBsAg gene (which are present in all patients due to the genetic variation present in HBV infection in all persons). These can all affect the HBsAg levels in patients.
Given that HBsAg is a HDL, there is also some data suggesting that lipid content in the diet can influence HBsAg levels. For instance, an Asian diet is associated with lower HBsAg levels while a higher fat diet (ie North American) even in Asians, is associated with higher HBsAg levels.
Recall that a large portion of HBsAg comes from integrated HBV DNA in liver cells (almost all HBsAg is derived from integrated HBV DNA in HBeAg negative HBV infection and in chronic HBV/HDV co-infection). This HBsAg production is completely disconnected from viral replication (which can can only occur in hepatocytes with cccDNA). Removal of liver cells with integrated HBV DNA can only occur with their removal. This in partial cure, we have a good portion of these liver cells integrated HBV DNA removed and in functional cure, almost all are removed.
1,Does the removal of infected hepatocytes/liver cells remove both cccDNA and integrated DNA?
2,Precision :- PBGENE-HBV is expected to be the first and only potentially curative gene editing program to enter the clinic that is specifically designed to eliminate cccDNA and inactivate integrated HBV DNA. is really this have a probability to eliminate cccdna ???
It depends on the mechanism of how you remove infected cells as to whether cccDNA and integrated forms are targeted.
My understanding is that this has been shown in preclinical models to be able to clear cccDNA. I guess we can only wait and look at the results before forming an opinion on its probability of eliminating all cccDNA.
So crisp has success stories in curing sickle cell disease, so same should be possible with hepb probably using crisp to eliminate cccdna in the liver cells. Thing is this cost 2 million usd, 🫨
Yes it is exciting, however the major difference between this approach for sickle cell disease and Hep B is the number of cells you have to target. With sickle cell disease, as long as you can change some percentage of cells to the correct form, then it’s OK. With Hep B, it is likely that you would have to target every single cccDNA otherwise the risk of reactivation is still there. This is very difficult at the moment.
In addition, there are some other deficiencies in CRISPR:
The do not target condensed chromatin (chromosomes) very well. Latent cccDNA is also in a similar condensed form and so will be poorly targeted by CRISPR methods.
CRISPR (and other sequence dependent technologies like RNAi and antisense) rely on the specific DNA sequence present to properly target DNA (or RNA). One or two miss matches between the guide sequence in these approaches and the target sequence will prevent these approaches from functioning properly. Since HBV infection is actually a collection of thousands of variants with genetic diversity along its entire genome, a large majority of these variants will be able to escape the action of these kinds of molecules.
