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?
1 Like
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,
1 Like
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,
1 Like
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,
1 Like