Not breakthrought but better results than any other commercialised thereapy or maybe even between clinical trials (except Replicor which has better results). I’m interested in specialists’ opinions.
Especially that in that study, unlike in many others recelty, Arbutus did not choose “easiest” HBsAg levels but between 100 and 5,000 IU/mL at screening. I hope they will be transparent and publish some poster with initial levels of patients who have achieved SVR and seroconversion.
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Hi all,
I heard Mike Sofia (chief scientific officer, Arbutus) speak recently at a meeting in Germany. He presented some data on this therapy, but not these results as they were embargoed until the EASL meeting. However, he did foreshadow good results.
My personal opinion is that this is very promising, with the normal caveats that this is a small, early-phase trial and followup is not complete. I’m quite enthusiastic about Arbutus as a company because they have some superb HBV expertise and as Mike was one of the major forces behind developing Sofosbuvir, a backbone of HCV curative treatments, so he really knows drug discovery well.
John.
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Thanks so much for such updates on current research, going on
This is reassuring
We need such information to keep hope alive
I hope the trial would be speed up for better outcome
Impressive for the A1. I was in the B2 cohort and did not qualify to stop my NA. It still looks like HBsAg quantitative was lowered for all at endpoint, which is a benefit in and of itself. In the US, we cannot test for HBsAg quant outside of clinical trials.
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@3kids4me do you know what was your HBsAg quant before and after or it’s not disclosed for the participants ?
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They did let us know at start of study, but after that it was completely blinded, even at end of study. I’m out of town, so can’t look where I know it’s written, but starting trial HBsAg quant was in the low 3K range. I can pinpoint which study I am based on B2 cohort and starting quant. It looks from the poster that of the 5 of us that did not qualify for NA discontinuation, the ending HBsAg quant was just under 1K for all 5. Still a benefit I think. Of course, I can’t test to see where it is now. It’s cool to see the cohort which was a complete standout was the A1 cohort, which does not surprise me. Cool to see and good for future studies to know the combination seems the way to go for a full 6 months!
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Hi @3kids4me,
HBSAg quantitative test is available to providers in the US and not only available in clinical trial settings. My provider at Johns Hopkins have been able to order this test whenever he needs to see whether there are any changes. It is not something that is ordered regularly by providers. But it is available as long as your insurance will cover the cost or the provider orders it Lab Corp can do this test. Thanks, Bansah1
Thanks for the information! My provider has tried several times, but next visit I actually scheduled with the head of Hepatology, so maybe I’ll get somewhere. I usually go through Sonora Quest but will ask about LabCorp, as I’d even pay out of pocket if needed. Thanks again for the information, it’s much appreciated!
Glad to help! Keep us posted on what happens and how much it costs without insurance. Thanks, Bansah1.
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To all on this thread,
It is important to remember that all GalNAc siRNA (like imdusiran) has a very long half life in the liver (at least 6 months). This has been known for some time in the oligonucleotide field. Alnylam (the company who has led the way in the clinical development of GalNAc-siRNA for more than a decade) now doses siRNA for other liver indications every 6 months and still maintains a potent siRNA effect.
So, for all HBV focused GalNAc siRNA in development (JNJ-3989 / ARO-HBV, VIR-2218 / ALN-HBV02 and AB-729 aka imdusiran), the end of of therapy does not mean the end of the pharmacologcial effects of the siRNA. The slow accumulation of a depot of GalNAC siRNA in the liver with monthly dosing was confirmed for JNJ-3889 by J&J in their REEF-2 study. Eventually, all patients in this study rebounded their HBsAg (even those who also received short duration pegIFN in combination) but it took a year or more for this to happen.
Without a doubt, this depot effect is also occurring with imdusiran and so the assertion that HBsAg is sustained off treatment with short follow-up is incorrect. We need to wait for at least one year before seeing if any patients can maintain HBsAg loss during the very slow washout of siRNA from their livers. This did not occur with JNJ-3989 + pegIFN.
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Thanks for clarification.
How about people who achieved HBsAg loss during that therapy and developed HBsAb, does it matter that drug still works more or less when that desired target has been reached ?
Is it possible that hbv dna/hbsag will rebound in presence of decent level of HBsAb ?
Other question, if it has such a long half life time, are there any contraidications of using it as long term therapy instead nucs ? Like one shot per few months instead daily tablets
Dear @sorte ,
As expected, these TWO patients were unicorn patients. These are patients where HBsAg is < 1000 IU/mL before therapy. These patients represent ~5% of patients worldwide are known to achieve up to 30% functional cure with pegIFN monotherapy because they respond much better to immunostimulation (because of the lower circulating levels of HBsAg). The benefit of AB-729 was likely negligible here (in any case it cannot be detemined since we are lacking a very important pegIFN monotherapy control in this trial.
Anti-HBs is expected to decline completely in these patients as AB-729 washout continues and cccDNA activity improves. To can already see this starting in these patients in these patients. Complete rebound was already reported in the J&J study with JNJ-3989 + pegIFN.
While there are no current contraindications to long term use of siRNA (based on historical data with other siRNAs over the past 15 years), injection site reactions tend to become more severe with chronic dosing. Additionally, most (if not all) if the HBsAg response with these siRNA are coming from TLR3 stimulation (not mRNA degradation). This is a common off target effect of all GalNAc-siRNA currently in development. This stimulation of the immate immune response is the likely driver of the cytokine production reported in these two patients. The long term safety of this effect is unknown.
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@availlant not a good news but that’s better than delusional expectations 
from our (non-expert) side it looked very promising. Thank again for detailed explanation.
But I still don’t understand why already obtained HBsAb is going to decline. If the same point would be obtained with just peginf the protective HBsAb would persist ? Why HBsAb obtained with that therapy is “worse” ? Not real immunity/seroconversion is achieved ?
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Hi @sorte ,
Unfortunately, this is another misconception about anti-HBs.
In a prophyactic setting (i.e in people who have never been previously infected), vaccination (and the anti-HBs engendered) provides a protective effect against developing chronic HBV. This is because the vast majority of the HBV innocculum contains wild type HBsAg and so is effectively recognized by the wild type anti-HBs present.
However, in a therapeutic setting this is very different. HBV infection, once chronic, gradually acquires thousands of mutations over the entire genome resulting in a diverse array of genetic (and immunological) variants, including for HBsAg. Additionally, most wild type HBsAg (being initially the most dominant during chronic infection) has the largest effect on suppressing (and even deleting) B-cells, which are responsible for producing specific variants of anti-HBs.
In studies with NAPs, we have shown that the very large levels of anti-HBs which are produced (more that 100x those in the Arbutus trial) do not interact with the circulating HBsAg during this clearance. We also have some patients who lost anti-HBs completely during follow-up despite having levels greater than 10,000 mIU/mL during therapy. This is becuase free anti-HBs can only exist when its target HBsAg is completely cleared from the circulation and in the absence of therapy is NO LONGER PRODUCED BY INTEGRATED HBV DNA in the liver. Thus it can disappear if the liver starts producing HBsAg again - this is what is happening already in the two patients in the Arbutus trial.
Other studies with therapeutic vaccines (e.g. VBI-2601) also achieved anti-HBs levels greater than those observed in the Arbutus trial but these had NO EFFECT on levels of HBsAg. Again this is because the wild-type anti-HBs produced by the vaccine did not interact with the circulating HBsAg present.
I suggest that you do not focus on the production of anti-HBs in clinical trials but instead ALT flares (which signal the removal of cccDNA and integrated HBV DNA) and which are now recognized to be an important event required for functional cure of HBV.
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Another great explanation, thanks so in case of people who lost HBsAg eg, on interferon, developing HBsAb is not so important and does not mean seroconversion is permanent ?
How about people who (rarely) lost HBsAg over the years without any thereapy. I have a friend in her 40s and she lost HBsAg recently, but her HBsAg since monitored was low, around 100 IU. Do they also experience cleaning flares ?
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Hey. Thank for your very detailed responses. We all appreciate you and your valuable input on the forum. I guess my question is if this is the case with the way SIRNAS work, why do scientists pursue an hbv FC knowing it will go back up eventually when administering it as part of a regimen? It makes no sense to me. Its not Arbutus only. Its a bunch of companies like you stated. Also why would GSK license JNJ3989/Arrowhead SIRNA to up to a 1 Billion deal to combine it with Bepirovirsen if they knew that they (SIRNAS) only work temporarily. Im no scientist obviously but if this knowlege is known in the HBV scientific community, why continue trying to use SIRNAS? Research and clinical trials are very expensive. If you can help explain I would greatly appreciate it.
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Hi @mike,
Great question. My understanding is that @availlant is not saying that siRNA responses will definitely be temporary, just that we need to look over longer periods of time to show that they actually are long-lasting. There indeed is hope that there will be sustained responses by shifting the equilibrium of the system towards immune control through the silencing as well as immune stimulation.
Thomas
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Dear @sorte ,
Correct, the most important aspects of functional cure are almost perfect suppression of the production of subviral particles from integrated HBV DNA which includes silencing of cccDNA and and clearance of sufficient hepatocytes from the liver with integrated HBV DNA (these cannot be silenced). Because of the immunologically diverse nature of chronic HBV infection (and its ability to genetically shift rapidly), the production of a immunologically narrow spectrum of anti-HBs reactivity cannot play a role in this process.
That being said, when functional cure is achieved, production of anti-HBs can be permanent simply becuase there is no longer HBsAg being produced from the liver to sequester these anti-HBs which are being made by the patients endogenous immune response. We have observed this universally with NAPs.
Your question about HBsAg loss and flares is an important one. One of the problems is that there is very limited data with high resolution ALT sampling in patients to catch ALT flares during therapy or in the absence of therapy. One interesting study here showed that when ALT is sampled more frequently, many patients either on NUC therapy or untreated developed very strong ALT flares without any other symptoms. My impression is the HBsAg suppression to such low levels involves ALT flares as hepaocytes with integrated HBV DNA are being removed. We need more clinical data to confirm this.
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Dear @Mike2,
Your confusion is very understandable. Unfortunately, in the HBV field, there is a limited understanding of how oligonucleotide-based therapies work and either an inability to understand or a lack of desire to acknowledge the meaning of the clinical responses observed with these agents since the earliest clinical data became available in HBV for these approaches. Additionally, I think here was some hope that partial reductions of HBsAg would be enough in combination with other agents to achieve functional cure. This has been clearly been shown to not be the case.
HBsAg responses to the siRNA and antisense therapies still in development (many have already been abandoned) have reproducibly been shown to be temporary in numerous clinical studies, most strongly by the failure of the large phase IIB trial by J&J with 48 weeks of siRNA and add on pegIFN to achieve functional cure in a single patient (with complete HBsAg rebound in almost all patients at 48 weeks of follow-up). Because all of the siRNA currently in development are working the same way, this failure with JNJ-3839 unfortunately informs on the likely failure of these approaches with other companies (such as we have seen recently with Arbutus).
The licensing of JNJ-3989 can be interpreted as an understanding by GSK that the current combination of bepirovirsen (now acknowledged by GSK to be an immunotherapy) and pegIFN will not be effective in achieving high rates of cure. In fact, the current phase III study by GSK (with bepirovirsen and pegIFN staged, not given simutaneously) is being conducted in a patient population with low baseline HBsAg. These patients represent a small fraction of the population of patients world wide who respond much more easily to immunotherapy. We call these patients “unicorn patients”. As such, such a study cannot provide meaningful data on performance in the average patient. For instance, in unicorn patients, pegIFN monotherapy can get functional cure in up to 30% of patients but in the patient population at large, only 6% and those restricted to the most easily treated genotype A.
Unfortunately, the recent studies by Arbutus and Vir were enriched in unicorn patients and the (few) patients who showed interesting off therapy results were all unicorn patients. The phase IIB study by J&J also contained unicorn patients. Until clinical studies start EXCLUDING unicorn patients, we cannot hope to get a picture of how these therapies can even work in the patient population at large. In the two most recent clinical trials with NAPs, unicorn patients have always been excluded.
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Great information and we appreciate your insight! Replicor still looks to be most impressive, but when I look up where they are currently (for only HBV) it’s hard to find current information. If and when you can, please share. Thank you again.