This looks simple but interesting. Repeated high doses of antibodies from immune donors to see if it allows people to regain immune control
Doe anyone have any thoughts regarding guesses as to how effective this may prove to be?
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Hi @bob ,
Unfortunately, the data from VIR-3434 (also an anti-HBsAg IgG like HBIG) already shows that only a fraction of HBsAg is targeted with this approach. This is due the presence of numerous HBsAg immune escape variants not targeted by these antibodies.
Best regards,
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That sounds reasonable
There’s a similar smaller study on humans happening with another form of HBIG,
https://www.cghjournal.org/article/S1542-3565(19)31089-4/pdf
and this one says that it does bing to most mutants:
“Lenvervimab binds S antigens of most drug-resistant mutants except for those with mutations at residue E164. Lenvervimab binding was also impaired by mutation at residue K160, which is unrelated to drug resistance but is considered to be an antigenic element.”
(from: A recombinant human immunoglobulin with coherent avidity to hepatitis B virus surface antigens of various viral genotypes and clinical mutants | PLOS ONE)
Would you rate the chances higher for that?
HI @bob ,
This kind of language is commonly found in write ups for these approaches from companies developing these kinds of approaches.
The HBsAg mutants they are talking about are the ones which appear in higher prevalence in patients but do not represent the bulk of variants which exist in lower (but still significant) proportions in the genome variant pool. These can only be observed with deep sequencing of individual HBV clones in the circulation. For example see here.
HBIG is actually anti-HBsAg IgG purified from the serum of persons with anti-HBs with no active infection (where genome variants will be very low).
VIR-3434 is an improvement on HBIG since it is engineered to last much longer than a traditional IgG (like HBIG).
Best regards,
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Thanks for clarifying everything
It looks like someone else is taking a shot with an oligonucleotide: AusperBio Announces First-in-Human Dosing of AHB-137, an Antisense Oligonucleotide Drug Candidate for the Treatment of Chronic Hepatitis B | BioPharma Dive
I’d never heard of them before, I can’t see any information about their candidate publicly available. If you have any comments it’d be interesting to hear
Hi @bob ,
The ASO approach (and siRNA for that matter) in HBV are well worn paths for futility.
Here are the abandoned ASOs so far:
Roche: RG6004 aka RO7062931
GSK: GSK3389404 aka IONIS HBV L-Rx
Aligos: ALG-020572
These ASO have all had little or no effect on HBsAg in clinical studies. This is because single and double escape mutants to ASO and siRNA already exist in significant proportions in most patients prior to therapy or evolve during therapy.
The lone ASO still left in development is bepirovirsen (GSK3228836 aka IONIS HBV-Rx) which derives all of its activity via stimulation of innate immunity, which only has interesting effects in ~5% of the HBV population (those with baseline HBsAg < 1000 IU/mL). Even in the phase IIB study with bepirovirsen, most of the HBsAg loss achieved during therapy has already disappeared by 24 weeks of follow-up.
In the the case of the three abandoned ASOs mentioned above, these were high efficiency ASOs that resulted in enrichment in hepatocytes (~70% of accumulated dose in the liver). Bepirovirsen is a “low efficiency” ASO with 30% of ASO in the liver accumulating in hepatocytes (where the infection resides) and 70% accumulaion in immunoreactive cells of the liver. This ASO actually has a sequence motif which stimulates the innate immune response.
Judging from the scheduled dosing on clinicaltrials.gov (see here), AHB-137 is also a “low efficiency” ASO. It is not surprising that AusperBio does not disclose the sequence of the ASO or its effects in the clinic could be easily predicted: either little to no HBsAg response or a short-lived HBsAg response restricted to a small niche population like that in bepirovirsen (if it contains a TLR9 stimulatory motif.
Best regards,
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Some AHB-137 trial update Dosing complete in Phase 2b trial of hepatitis B therapy AHB-137 does it matter that some people developed antibodies ? Does it prevent rebound when drug in not present in the liver after some time ?
Dear @sorte ,
Remember this Phase II study with AHB-137 is not enrolling typical HBV patients. The study will be highly enriched in unicorn (HBsAg < 1000) patients as HBsAg at enrollment is limited to HBsAg from 100-3000 IU/mL. This is just like the phase II study for bepirovirsen, where about 70% of patients were unicorn patients with similar enrollment criterion. The average HBsAg in patients is ~ 10,000 IU/mL (where both these drugs show little effect unfortunately). Results form this study should not be interpreted to be applicable to the patient population at large.
It is also troubling that patients are allowed to enroll if they stopped previous siRNA therapy 12 months ago. SiRNA has a very long residence time in the liver (1/2 life of 6 months) so significant residual immunotherapeutic effects (which give rise the the HBsAg effects with these drugs) will still be in the liver 12 months. They should have sent a minimum delay of 24 months from last siRNA dose before allowing patients with previous siRNA exposure to enroll.
Anti-HBs seroconversion does occur in a subset of patients who achieve functional cure naturally or from pegIFN. However, anti-HBs seroconversion is not a reliable marker for functional cure, especially in the presence of immunotherapeutic agents like AHB-137.
This is different from the the induction of anti-HBs by vaccination in infected individuals, which is highly effective in preventing the development of chronic HBV.
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Thanks for clarify, yep it’s bad that many studies does not provide HBsAg level info. So even high HBsAb tier and HBsAg und, does not prevent those people from rebound ? How it works that after successful interferon seroconversion I guess rebund is unlikely and after “successful” siRNA therapy it’s possible ?
Dear @sorte ,
The details of all studies are available to all patients at www.clinicaltrials.gov. I encourage all patients to familiarize themselves with this website since it can help demystify what is reported in press releases. If companies conducting clinical trials want to be able to publish the results of their studies in peer reviewed scientific journal (which is always the case), they must disclose the details of the study (including enrollment criterion). In the case of the phase II AHB-137 study we are taking about, see here.
We have seen in our NAP studies that anti-HBs greater than 100,000 IU/mL and undetectable HBsAg can revert after therapy is removed. With siRNA and bepirovirsen we have also seen HBsAg rebound following HBsAg loss during therapy (this will also happen with AHB-137 since is it essentially working by the same mechanism as bepirovirsen). This is for two reasons:
-
HBsAg derived from HBV DNA integration in the liver cannot be eliminated by the immunotherapeutic activities of oligonucleotides (siRNA or antisense). This requires removal of the cells containing this integrated HBV DNA by different a immunotherapeutic process (only stimulated by pegIFN). Once therapy is removed, if these cells are not removed, HBsAg will eventually rebound and remove any immunological control of cccDNA which was established during therapy.
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HBV is genetically diverse and thus has many different immunoreactive HBsAg variants which have evolved to escape the antibody response present in patients. So the appearance of anti-HBs can also occur while HBsAg is present because the anti-HBs being produced does not recognize the HBsAg being produced. This is observed naturally in a small proportion of patients and we have observed this with NAPs for many years. Some of the newer studies with these invesrtigational agents have also observed this.
In the case of persistent siRNA, its immunological effects can persist long after therapy. This has been clearly shown with all siRNA in HBV, with patients enjoying a suppression “holiday” after stopping therapy for upto 9 month after a single siRNA dose. This “holiday” can be much longer in patients who recieve 12 monthly doses (as is the case in all siRNA trials to date). The danger here is including patients who are still experiencing the immunostimulatory effects of siRNA in the liver and attributing outcomes from these effects only to the new therapy (in this case AHB-137).
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thank’s for detailed explanation 
“…anti-HBs can also occur while HBsAg is present because the anti-HBs being produced does not recognize the HBsAg being produced. This is observed naturally in a small proportion of patients and we have observed this with NAPs for many years” - but you’ve overcomed it or it still happens or is not relavant in case of NAPs ?
Dear @sorte,
NAPs are different from all other technologies in that they efficiently target SVP assembly and production from all sources (cccDNA and integrated HBV DNA) and rapidly clear HBsAg from the liver. So the HBsAg clearance with NAPs is qualitatively different from ASO / siRNA / HBsAg antibodies and occurs at high rates REGARDLESS of baseline HBsAg. Replicor is actually the only company which excludes unicorn patients from its trials. So in our case, the 56% rate of functional cure is applicable across the entire global HBV population.
So obviously the issue with the inability of the existing anti-HBs in a patient to control HBV infection is not an issue with NAP therapy. However we note that in all patients where we achieve HBV functional cure, anti-HBs persists for as long as we have been able to follow patients (currently more than 7 years). So what is going on here?
The key to HBV functional cure is the removal those cells in the liver with integrated HBV DNA. This is the component of HBsAg production which cannot be immunologically controlled like cccDNA. These cells must be removed or at least significantly reduced in number for functional cure to persist. Removal of these liver cells (which in most instances requires the action of immune cells which “pop” them open (we call these cells natural killer cells or NK cells) or by swallowing them whole (phagocytes which are stimulated by a HBsAg-specific T-cell response).
This removal of liver cells leads to a rise in the levels of liver enzymes found only inside these cells (eg ALT) in the blood during therapy. In chronic HBV which is NUC suppressed, these ALT elevations are always a sign of removal of infected cells in the liver (containing active cccDNA and integrated HBV DNA). When NAPs + pegIFN, we see 95% of patients with these beneficial ALT flares. So the HBV functional cure we obtain in 56% of patients persists because the HBsAg producing capacity of the liver (from integration) is mostly eliminated. In this scenario, the production of anti-HBs persists, however it does not provide the same protection as seen in infection naive patients, who do not have a previously established reservoir of genetically variable cccDNA. Because HBsAg loss is persistent in our patients, innate immunity remains fully potentiated in the liver and maintains efficient control of cccDNA. This is what HBV functional cure allows the removal of all antiviral therapy. This is highly analogous to the acute resolution of new HBV infection which has occurred in 80% of people who get their HBV infection from routes other than maternal transfer.
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thanks again for awesome and detailed explanation !
@availlant , this conversation is bit confusing and not easy to understand as a layman. Are you suggesting some one with low HbsAg and low HBV dna should undergo NAP therapy? Is there any approved therapy available? Kindly advise
Dear @bmj1982 ,
Yes HBV is one of the most complex viral infections.
First NAPs are still in clinical development for the treatment of HBV and HDV infections they are not yet available as an approved therapy.
However, the lowest risk of HCC and the lowest risk of reactivation to chronic HBV is obtained with functional cure (HBsAg loss in the absence of therapy).
We expect all patients with any detectable levels of HBV DNA and HBsAg will benefit from and should receive NAP therapy once it is approved.
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Thank you @availlant . That helps and thank you for your continued work with NAP and keeping hopes high for chronic HBV patients around the world. 
hello, dr. @availlant.
I would like to highlight how much I learn from your explanations. Thank you very much in advance for your attention.
I have a question regarding the results of rep-2139 and I don’t know if you, for privacy reasons, could answer… anyway, I will ask the questions and it will be ok if you can’t answer.
I would like to know if it was possible to detect why the medicine does not work for all patients? Could it be the mechanism by which the medicine works? or the type of virus or any specific condition of each patient?
And one more question: would it be possible in this scenario to modify the medication to achieve this effect we so desire in all patients?
Dear @La.sciamachie ,
Its a great question. For the community at large, @La.sciamachie is referring to the small proportion of patients who do not achieve HBsAg loss during therapy in previous clinical trials with NAPs.
I can discuss here what we have already discussed publicly at scientific conferences.
Like all other phosphorothioate oligonucleotides (i.e. antisense compounds), NAPs have to pass through the filtration apparatus of the liver before getting to hepatocytes. This filtration apparatus is comprised of non-hepatocyte liver cells which play a role in cleaning the blood and sensing foreign infections but are not infected by HBV and HDV. As a result, only about 30% of NAPs actually pass into the infected cells (hepatocytes) under optimal conditions. The rest accumulate in the filtration cells in the liver. In the case of NAPs, this actually provides important hepatoprotective effects which support the liver during the elimination of infected cells.
The factors governing how efficiently NAPs accumulate in hepatocytes are complicated and include how they interact with the blood and the status of liver disease present. I will not get into all these here but I will say that we know that in those patients with a suboptimal response, we know there is a sub-optimal accumulation of NAPs into hepatocytes. We have demonstrated that patients which have an initial poor response recover a better response with higher or more frequent dosing of NAPs. Or altering the route of administration of the drug to improve hepatocyte uptake.
The good news is that there is a workaround for this problem by (as you suggest) modifying the REP 2139-Mg drug formulation. These details unfortuanely cannot be revealed but this new formulation is expected to dramatically reduce (hopfully eliminating) the proportion of patients with a suboptimal response.
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Thank you very much again for responding, dr. @availlant .
It’s wonderful for me to know that this medication adjustment is being attempted for maximum effectiveness. I wish you and your entire team success in this noble mission! And, if you don’t mind, I would like to reveal that within my personal beliefs I pray to God for your life, that He will keep you, free from evil and give you the necessary wisdom not only in this activity but in all areas of your life.
And, if you are not going to abuse it, I would also like to know if the 56% who obtained a cure, over these seven years of observation, had their liver “cleaned” (with less and less integration with the virus’s DNA)? Or even as the years go by, the liver will continue to be “genetically modified”?
I’m very excited about this! You had previously mentioned that the formula was being optimized for uptake (sorry if I butchered the scientific meaning behind it).
Will the new formulations require starting trials at the beginning or be part of the 2b phase?