ClinicalTrials.gov no initial HBsAg quant info
As always counting on comments from specialists 
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This sounds pretty awesome. Would love to hear any scientists commentary on this
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Hi @sorte,
Great find and thanks for bringing this study up. These therapies are depending on a technology similar to CRISPR/Cas (originally found in bacteria), but these were first discovered in algae in the 70s. My understanding is that Precision are able to make different versions of the ARCUS enzyme and “evolve” it to target a particular sequence with increasingly high specificity. They have developed one to HBV and have used it to deliver into cells and animal models, with HBsAg-lowering effects to enough of a degree that they have begun clinical trials. This press release describes the first of these.
These appear to be trials evaluating dosage and reporting findings so far for the lowest of 3 doses in 3 patients. It’s hard to say much about this without the data, but it sounds like the therapy itself is not harming the patients at this dose and that they see some reduction in viral targets (unknown how many patients and how much).
There is a worry about what happens to the HBV DNA after it is cut up with enzymes such as this. The strand of DNA is theoretically able to insert into the host genome (it’s unclear how often this happens) or reform into another cccDNA (which may contain mutations or still be able to express some viral proteins, even if it can’t produce more virus). There are a lot of unknowns at the moment for this, which hopefully will be clarified during the year as they present the results.
Hope this gives some context.
Cheers,
Thomas
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thanks for explanation. I remember that crisp therepies causes concern about some off-target insertions, but anyway as I remember there was some late state trial. I hope that technology is way better ?
Dear @bob,
There are two issues here with the ARCUS approach which must be understood:
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It is a sequence dependent approach. HBV is genetically diverse and can change the sequence composition of its variant pool quickly (especially in response to selection pressure). The absence of sequence specific effects of antisense and siRNA has been well demonstrated in clinical trials (the effects of these oligonucleotide-based compounds in HBV work via stimulation of innate immunity instead through sequence specific effects) . We have already seen that most patients have the required genetic escape mutations for any antisense or siRNA even before treatment starts. This will be the same with ARCUS. Unfortunately, pre-clinical data with the ARCUS approach was only obtained from mouse models of HBV infection which do not model at all the genetic diversity of human infection.
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The ARCUS technology is also oligonucleotide based and because of its LNP formulation, is targeting this oligonucleotide to the liver. This undoubtedly will generate a similar stimulation of innate immunity - suppressing cccDNA activity but not targeting HBsAg production from integrated HBV DNA. This is part of the reason why so many iterations of ARCUS has to be tested for safety - because of the propensity of oligonucleotides to stimulate potentially dangerous pro-inflammatory reactivity (this caused the termination of SB9200 and ALG-020572). However many innunostimulatory reactivities of oligonucleotides are sequence independent and cannot be removed by even by the sequence modification in the current clinical ARCUS compound.
There is no reason to expect that ARCUS will perform any better than siRNA or antisense has. The idea of “cumulative viral editing” is a non starter. Selection pressure from ARCUS will actually ensure that ARCUS resistant mutants become rapidly fixed in the cccDNA pool. This has already been demonstrated in appropriate animal models (replicating the genetic diversity of HBV) with LNP-siRNA.
Unfortunately, press releases like this one are written for investors and are typically very vague in describing specific performance details important to assess true impact. In this specific case, there are also unfortunately some critical scientific errors.
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What proportion of unicorn patients (HBsAg < 1000 IU/mL) have been enrolled in this trial? This will be critical since most of the effects of ARCUS will likely be from stimulation of innate immunity in a multiple dosing scenario. Any results obtained in these patients (which only represent 5% of a patients globally) cannot be applied to patients in general.
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If HBsAg reductions in humans really limited to what was observed in ARCUS animal models, this is actually not exciting al all. HBsAg loss achieved at these doses has been very well demonstrated to be futile. HBsAg loss of > 5 log reduction from baseline (in non unicorn patients) during therapy is the requirement to achieve functional cure. This has been well demonstrated in the literature.
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HBsAg reduction CANNOT AND DOES NOT prove inactivation of integrated HBV DNA. HBsAg is derived from cccDNA and integrated HBV DNA. Early reduction of HBsAg is also observed with various antisense and oligonucleotide therapies (via their stimulation of innate immunity). In the case of HBsAg reductions with ARCUS, early HBsAg reductions are more likely to caused by immunostimulatory effects.
Companies like Ausper Bio (AHB-137) and Precision should disclose the sequence of their oligonucleotide-based compounds so that TLR-stimulatory motifs (which are assuredly there) that activate innate immunity can be identified. This poses no risk to them since these sequences have already been filed in patents. They should also perform deep sequencing of HBV genomes in non-NUC suppressed patients prior to therapy to show the presence of escape mutations for the sequence-dependent mechanisms for these compounds. This has already been done by J&J (for two different HBV siRNA), GSK (for a HBV antisense) and others.
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Thanks for the updates So what are we to look forward to if all these findings are not making good promising products to achieve this cure we all expect?
Is there any promising product in trail?
Dear @Tonyrog ,
Full disclosure here, I am the CSO of Replicor, who is developing nucleic acid polymers (NAPs) for the treatment of HBV and HDV.
Unfortunately, HBV infection one of the most complex infections. One of the goals of this community forum (and my primary goal in joining ) is to help educate patients so that they can decipher press releases like the one we have just discussed as well as the hyperbole that frequently comes from companies trying to develop therapies. This is to avoid the generation of false hopes. Patients should ignore words like"novel", “promising”, “breakthrough” and the like.
Most times, this education involves taking a look back at what has already been tried to give us a glimpse into what might be possible moving forward. With these new technologies, their proponents simply ignore the scientific facts from the past. For instance, we have known about the futility of sequence dependent approaches as antiviral agents in many viruses (including HBV) for more than two decades (viral infections were one of the first applications tried for antisense and siRNA). The off target immunostimulatory effects of oligonucleotides have been also been well described for more than two decades and are completely ignored by companies developing these drugs for HBV.
This has led to a lot of frustration and false hope in the HBV patient community (which is unacceptable).
Patients can learn how to gauge when to get hope for a new treatment for HBV using the following criteria.
- The therapy is not a sequence-dependent approach.
- The therapy directly and efficiently targets subviral particles (99.99% of HBsAg). **REGARDLESS OF THE LEVEL OF HBSAG PRESENT.
- The therapy can achieve HBsAg loss (< 0.05 IU/mL) during therapy.
- HBsAg loss is accompanied by a therapeutic ALT flare (a sign that integrated HBV DNA is being removed from the liver). This will likely require pegIFN - there is currently no other substitute immunotherapy.
- When treatment is removed, HBsAg remains undetectable. Many companies have used the term “maintenance of HBsAg suppression” to hide the fact that there is a slow or delayed rebound in HBsAg.
These are the steps which have led to functional cure with NUCs and pegIFN since their inception and also to the resolution of acute HBV infection, which has occurred in 80% of patients since we became aware of the existence of HBV.
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So that means ThervacB may not be a solution?
Dear @Tonyrog ,
Again here there is a long list of therapeutic vaccines with different adjuvant approaches which have previously failed or have been abandoned which include:
HB-110 (Dong-A-Pharm)
GS-4744 (Gilead)
TG-1050 (Transgene)
VBI-2601 (BRI-179) (Brii)
HBV mRNA vaccine (J&J)
GSK3528869A (GSK)
Even though these vaccines have stimulated the production of HBsAg-specific B-cells and anti-HBs, and in some cases, HBsAg reactive T-cells, they have all only been able to achieve at best weak (1 log) reduction in HBsAg in a few patients and no HBsAg decline in most. They also do not increase HBsAg decline when added to siRNA (VBI-2601 + VIR-2218).
The problem with the therapeutic vaccine approach is again the genetic diversity issue in established HBV infection. There are numerous immunological variants of HBsAg prexisting in chronic HBV infection which have undergone a selection process to escape the host immune response. Vaccines which propose to engender new immunity (including TheraVac B) use wildtype HBsAg as their antigen and the engendered host response does little to target the immune escape HBsAg circulating in the patient.
This is different from classic prophylactic vaccination of HBV. Although these approved vaccines (TwinRx, Energix B, Prehevbrio and others) also only engender a wild type HBsAg response, they provide an effective immunological advantage against a new infection which prevents the development of chronic infection.
There is an additional complication with TheraVac B: it uses a second adjuvant “boost” with an inactivated form of vaccinia virus following the first immunization . Although this virus cannot replicate, it also can stimulate innate immunity in the liver (just like oligonucleotide based medicines). As such, it is not possible to distinguish HBsAg declines observed with TheraVac B as derived from a specific immunological response produced by the initial vaccine or a non-specific (and temporary) inactivation of cccDNA via induction of innate immunity.
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Hummm this is not a good luck to be an effected person it seems there is no way out of this
We just keep our hope that a day will come and the will be a good news
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Precision presented safety data for PBGENE today at EASL. Safety looks good after 2 doses at the lowest level. I guess we have to wait to see efficacy after all 3 patients get their 3rd dose. What I noticed is that the three patients had a wide range of hbsag (as low as 500s and as high as 11000) with a mean of 4387 iu/ml.
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Dear, dr. @availlant
Do these published results also fit into the unicorn patient condition?
Dear @La.sciamachie,
Unfortunately, another misleading press release.
The details for this trial on Clinicaltrials.gov can be found here.
This trial is almost exclusively in unicorn patients. Also, these HBsAg declines have not predicted functional cure after withdrawal of AHB-137 in previous trials (even in unicorn patients).
AusperBio are already trying to develop a therapeutic vaccine to use in combo - this tells you they know they cannot achieve meaningful rates of functional cure with AHB-137 monotherapy. This combo approach has already with failed with siRNA.
It is important for patients to understand that there is essentially no difference between AHB-137 and bepirovirsen - we have already seen that most patients slowly rebound after removal of bepirovirsen (and GSK’s in house therapeutic HBV vaccine has been abandoned for lack of effect).
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Thank you for your continued attention, Dr.
When I saw the news, I suspected that these were unicorn patients.
In any case, we are moving forward. May God bless us.
Thank you for being active and always responding. Theoretically if lets say ARCUS or CRISPR method of removing a big portion of cccdna and integrated DNA but not 100% of it, would it be a possibility that using Pegylated Interferon after treatment of Gene Editing tool work? The way Im thinking about it is that if ARCUS gene editing does have 99% viral engagement like preclinical studies and removes lets say 90% of cccdna and I-DNA and lowers all viral markers by that amount but doesnt get a patient to SAG < LLOQ, would hitting them with Peg be beneficial since at that point Interferon would have a lot less work to do to finish the job?
Dear @Mike2,
These are great questions.
To start understanding this issue properly, one has to consider the immunological impact of these and other therapies.
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All siRNA = TLR3 stimulation = 2 log reduction in HBsAg (from inactivation of cccDNA)
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Bepirovirsen = TLR9 stimulation driving transient HBsAg loss only in unicorn patients.
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Therapeutic antibodies = stimulation of innate immunity from heterologous (foreign) antibodies = rapid 2 log HBsAg reduction. Note host antibodies induced from therapeutic vaccines not delivered by adenovirus (ie TherVac B) have no impact on HBsAg (because of the high prevalence of escape mutations). Adenoviral vectors have a known immunoostimulatory effect in the liver which explains the mild HBsAg response seen with therVacB (inactivation of cccDNA).
Even when pegIFN is added to these approaches (siRNA and bepirovirsen), no durable functional cure is achieved (or only in a very small proportion of unicorn patients). So we know that HBsAg declines of 2-3 log are useless for achieving functional cure, even in the presence of pegIFN.
Now consider ARCUS and CRPISR technologies:
Preclinical assessments are useless for predicting the clinical effects of sequence dependent approaches because the preclinical used models used do not model the enormous genetic diversity seen in human HBV infection. This has been well proven for siRNA and antisense where activity in human studies was MUCH weaker than in preclinical studies. This will be the case for ARCUS and CRISPR as well.
Most likely ARCUS and CRISPR (directed against a single wild type HBV sequence) will only target a small proportion of active cccDNA or integrated HBV DNA. Because of the super condensed nature of inactive cccDNA, wildtype inactive cccDNA will not be targeted by these approaches at all (or only very poorly).
It is also important to understand the immunostimulatory properties of the ARCUS and CRISPR approaches:
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ARCUS = LNP-mRNA (mRNA vaccine) = stimulation of innate immunity in the liver (TLR7) as has been demonstrated for previous mRNA vaccines (this is the basis for their adjuvant like effects).
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CRPISR = LNP-mRNA + gRNA (so a mRNA vaccine plus a small ssRNA) = stimulation of innate immunity in the liver.
Almost assuredly the bulk of early HBsAg response in the clinic with these these drug products will from immune inactivation of cccDNA, not direct targeting of cccDNA or integrated HBV DNA (asis the case for siRNA).
Once these immunostimulatory effects wear off in 1-2 months after exposure (as is the case for mRNA vaccines), HBsAg rebound will occur, even after combination exposure with pegIFN. There are also safety concerns with using pegIFN in combination with a mRNA vaccine.
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Thank you for claryfing!
I see last week capsids inhibitor called ZM-H1505R progress to phase 3 but we know it is not for functional cure. From what i understand it will inhibit formation of new cccDNA so with NA treatment we will have good viral suppression and in long term good or reasonable reduction of hbsag and existing cccdna will also reduce naturally in long term . So the question is 1, can this be approved because the advantage over NA is small when we consider the cost 2, if approved do you think adding This to NA+immune modulator/therapeutic vaccine +rep2139 will increase functional cure much much ???
Thank you
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Dear @lemlem,
Although there is some evidence to suggest capsid assembly modulators (CAMs) like ZM-H1505R inhibit the formation of new cccDNA in vitro, there is no clincial data which suggests this is also hapenning in the clinic. The experimental conditions are very different.
Even if this were the case, cccDNA decline with NUCs, which also have the ability to inhibit cccDNA activity via immunostimulation, is very slow and significant levels persist after more than a decade of therapy.
Given that CAMs have no impact on subviral production (the bulk of HBsAg), their impact on any combination therapy approach will be less than NUCs.
I dont see why any doctor would prescribe an expensive new CAM when excellent NUCs are already available cheaply as generics.
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