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Latest Results for cohort 4 ARB 1420
So guys top line results for ArB-1420 cohort 4 got announced today where 12 patients received a total of 5 bi weekly doses. 9/12 patiens achieved greater than 1 log reduction in HbsAg including 5 ending up with a titre lower than 50iu/ml.
I find these results very encouraging given that only 5 doses were enough to bring about such great reductions. Their next study would explore adding on interferon to these patients to see if they achieve HbsAg seroclearance. Fingers crossed!
I find these results very encouraging given that only 5 doses were enough to bring about such great reductions. Their next study would explore adding on interferon to these patients to see if they achieve HbsAg seroclearance. Fingers crossed!
Arbutus has set the position of its iRNA triggers in the right place to reach the messenger RNA of integrated hbsag sequences as well, something that arrowhead failed to do ,with the known bad consequences for their program.
Thus their effectiveness in reducing hbsag production in e ag neg patients is much better. However the levels are still too high for the hoped for immune activation. With the addition of interferon-alpha one can hope for further improvement.
However, I am concerned that there will still be no real effective mechanism to eliminate the integrated only cells. The reduction in the translation intensity of the hbsag will actually reduce the already limited visibility to the tcell system. Thus once the interference is removed at the end of treatment, the hbsag from these cells will likely rebound strongly, reversIng achieved hbsag seroconversion in most cases.
And any reduction in infected cell numbers will not be stable once the free hbsag antibody level is again down to minute by trapping with abundantly available hbsag, leading to a respreading of the infection after treatment end.
Thus their effectiveness in reducing hbsag production in e ag neg patients is much better. However the levels are still too high for the hoped for immune activation. With the addition of interferon-alpha one can hope for further improvement.
However, I am concerned that there will still be no real effective mechanism to eliminate the integrated only cells. The reduction in the translation intensity of the hbsag will actually reduce the already limited visibility to the tcell system. Thus once the interference is removed at the end of treatment, the hbsag from these cells will likely rebound strongly, reversIng achieved hbsag seroconversion in most cases.
And any reduction in infected cell numbers will not be stable once the free hbsag antibody level is again down to minute by trapping with abundantly available hbsag, leading to a respreading of the infection after treatment end.
11 Comments
Ahan. Could RNAi treatment synergize with NAP? And achieve levels of HBsAG <0.01iu/ml in all patients that are currently achievable in about 80% on rep only therapy? Replicor's studies continually demonstrate that HbsAg levels below this threshold are critical inorder for immunotherapy to work and achieve functional control.
It seems logical that RNA and naps could synergize in reducing circulating hbsag levels and help to bring further down such levels in the minority of patients that do not fully respond to nap therapy.
But considering the mechanism of ER accumulation of hbsag monomers as a critical component of marking these cells for enhanced elimination by further proapoptotic processes, this might not work out into a lasting reduction of these integrated hepatocytes, since the RNAi would reduce the amount of hbsag monomer translatiion and ER membrane insertion, preserving cell survival.
The power of mere hbsag reduction to very low levels to achieve "immune control" is likely overrated. This could clearly be seen in the first replicor trial with rep2055 only, where close to zero hbsag levels nevertheless were incapable of initiating immune control in the majority of patients.
And external immune modulation by ifn or thy alpha might not work very well on "nonprestressed " hepatocytes with hbsag only integration, since on light of the profound surface antigen specific immune tolerance there is little reason to attack those cells more than any noninfected, nonintegrated hepatocyte.
But considering the mechanism of ER accumulation of hbsag monomers as a critical component of marking these cells for enhanced elimination by further proapoptotic processes, this might not work out into a lasting reduction of these integrated hepatocytes, since the RNAi would reduce the amount of hbsag monomer translatiion and ER membrane insertion, preserving cell survival.
The power of mere hbsag reduction to very low levels to achieve "immune control" is likely overrated. This could clearly be seen in the first replicor trial with rep2055 only, where close to zero hbsag levels nevertheless were incapable of initiating immune control in the majority of patients.
And external immune modulation by ifn or thy alpha might not work very well on "nonprestressed " hepatocytes with hbsag only integration, since on light of the profound surface antigen specific immune tolerance there is little reason to attack those cells more than any noninfected, nonintegrated hepatocyte.
It seems like something that may work would be to take this new drug alongside NUCs, and then when hbsag is as low as you can get it take a small dose of nivolumab (or another pd-1 inhibitor perhaps). Don't you think?
As studyforhope rightly highlights, the critical step towards achieving a cure is elimination of genomically altered cells that transcribe ansd translate HbsAg. Such cells would fly under the radar of Tcells that could be potentiated as a result of checkpoint inhibitors like Nivolumab. Even if these Tcells attack and destroy cells harbouring cccdna, complete elimination of cccdna is unlikely since the presence of cccdna persists even in patients with a resolved acute infection. Upon cessation of treatment, HbsAg derived from genetically altered hepatocytes would quickly rebound and allow denovo infection of hepatocytes, reversing all the progress and re-establishing infection. In my opinion, in combo with RNAi, what we need is a treatment that could silence cccdna and/or eliminate the genetically altered cells so that induction of HBsAb could take care of the remnant cccdna. Replicor can reliably achieve the latter.
"since the presence of cccdna persists even in patients with a resolved acute infection."
That's right. If we could be functionally cured (ie be identical to someone who has naturally cured the disease) that seems to me like it'd be a great step forward and I'd gladly take that.
If you got to that stage, then why do you think a rebound would happen and you'd get reinfected? I ask this question because I think if you got to that stage where hbsag is close to 0, then your antibody level would go up. The pd-1 signal (the signal that says the infection is resolved and that antibodies are no longer needed) would cease to be output. So if the virus did start to rebound, your antibodies would actually develop properly this time just like an adult who had contracted acute infection.
That's right. If we could be functionally cured (ie be identical to someone who has naturally cured the disease) that seems to me like it'd be a great step forward and I'd gladly take that.
If you got to that stage, then why do you think a rebound would happen and you'd get reinfected? I ask this question because I think if you got to that stage where hbsag is close to 0, then your antibody level would go up. The pd-1 signal (the signal that says the infection is resolved and that antibodies are no longer needed) would cease to be output. So if the virus did start to rebound, your antibodies would actually develop properly this time just like an adult who had contracted acute infection.
The answer lies in how RNA inteference works. Rnai temporarily blocks translation of hbv antigens including sAg by destroying mRNA transcribed from cccdna and hepatocytes that are genomically integrated with hbv DNA. Tcells need a stimulus to spring into action, which in case of hbv is provided by viral antigens. So it is presumable that in the absence of surface antigen, even if tcells recover from immunosuppression in adjunct with a checkpoint/pd-1 inhibitor, they will fail to receive an effective stimulus to gauge an anti-HBV action, as production of all hbv-specific antigens is already inhibited and absent, an end result that tcells are meant to acheive from their action. Its like a negative feedback system.
In summary, in the absence of viral antigens, hepatitis B virus would likely evade detection by tcells. But in theory, as long as you stay on RNAi treatment, you're as good as functionally cured, something you cant say while being on NUCs since they only inhibit hbv dna and not hbv antigens. This is just my understanding. Studyforhope might want to add more.
In summary, in the absence of viral antigens, hepatitis B virus would likely evade detection by tcells. But in theory, as long as you stay on RNAi treatment, you're as good as functionally cured, something you cant say while being on NUCs since they only inhibit hbv dna and not hbv antigens. This is just my understanding. Studyforhope might want to add more.
Very good summary re the key problem if RNAi. The better it works, the less recognizable antigen will be produced.
It is really necessary to understand how immunity works. Only cells containing material from invading organisms or illegal proteins from cancer transformation must trigger an attack, cells without those PAMPs (pathogen associated molecular patterns) must not be touched.
It is like the infected and integrated cells become invisible to the immune system as long as the suppression lasts. But the functional cure has to be based on effective immune action.
Staying on RNAi treatment for long is not feasable. The side effects are quite strong. I am not sure, but I think to remember that the FDA halted all trials from arrowhead after they had a fatality from the treatment. Their delivery platform included to use a bee venom to rupture endosomes in the cytosol to release the RNAi cargo inside towards the site of action.
It is really necessary to understand how immunity works. Only cells containing material from invading organisms or illegal proteins from cancer transformation must trigger an attack, cells without those PAMPs (pathogen associated molecular patterns) must not be touched.
It is like the infected and integrated cells become invisible to the immune system as long as the suppression lasts. But the functional cure has to be based on effective immune action.
Staying on RNAi treatment for long is not feasable. The side effects are quite strong. I am not sure, but I think to remember that the FDA halted all trials from arrowhead after they had a fatality from the treatment. Their delivery platform included to use a bee venom to rupture endosomes in the cytosol to release the RNAi cargo inside towards the site of action.
@landloper: bravesouls remark re the cccDNA remaining even in the seroconverted acute or chronic "cured" patient was to demonstrate that no matter how hard you hit the virus, some genetic material ready to restart the infection will always be present.
Thus as long as hbsag integrated cells are remaining, the rebound after removing the therapeutic block of hbsag production in these cells would soon remove the antibody that protects against reinfection of the liver from even tiny remnants of cccDNA containing cells.
This develish mechanism will condemn all attempts to cure by blocking the viral system as such to failure once a larger amount of hbsag only integration is present in the evolution of the disease in the individual patient.
it needs to be noted in this context that even a protecting antibody is not totally sufficient to prevent reinfection long term. A tcell response is needed at the same time to inhibit the slow growth of local infected cell clusters that the antibody cannot entirely prevent.
Thus as long as hbsag integrated cells are remaining, the rebound after removing the therapeutic block of hbsag production in these cells would soon remove the antibody that protects against reinfection of the liver from even tiny remnants of cccDNA containing cells.
This develish mechanism will condemn all attempts to cure by blocking the viral system as such to failure once a larger amount of hbsag only integration is present in the evolution of the disease in the individual patient.
it needs to be noted in this context that even a protecting antibody is not totally sufficient to prevent reinfection long term. A tcell response is needed at the same time to inhibit the slow growth of local infected cell clusters that the antibody cannot entirely prevent.
@studyforhope I do wonder how chronically infected patients that are naturally functionally cured achieve elimination of these HbsAg yielding hepatocytes. Even cell turnover shouldn't translate into their eventual elimination since daughter cells from such cells too would harbour the same altered genetic material. As such their proportion should atleast remain the same if not increase, but they end up getting eliminated. What gives?
It is indeed an important and difficult question how the rare natural switch to stable hbsag seroconversion might occur.
i think there are several scenarios:
1. There is not much integration present at the time of conversion, so it is still similar to the "acute cure".
2. Integration proceeds verly slowly in some patients due to a low availability of these special repair systems that are needed for full double stand insertion.
3. The expansion of inserted clones is slow, since the integration did mostly not occur in cell replication activating sites.
4. Most integration included the core gene, not just the surface gene, or the large envelope protein with its preS1 sequence that can contain a good epitope. In these cases an enhanced Tcell immunity is still able to target the integrated hepatocyte.
5. The most proliferative clones will produce the most hbsag, but will also elicit anti oncogenic defense mechanisms, that might drive those cells into apoptosis in some cases.
6. A lucky anti hbsag epitope cd8 tcell clone is produced de novo from the thymus, actually able to eliminate the hbsag producing cell by the classical CTL pathway, before it gets tolerized by long term overstimulation from the circulating hbsag uptake by antigen presenting cells.
i think there are several scenarios:
1. There is not much integration present at the time of conversion, so it is still similar to the "acute cure".
2. Integration proceeds verly slowly in some patients due to a low availability of these special repair systems that are needed for full double stand insertion.
3. The expansion of inserted clones is slow, since the integration did mostly not occur in cell replication activating sites.
4. Most integration included the core gene, not just the surface gene, or the large envelope protein with its preS1 sequence that can contain a good epitope. In these cases an enhanced Tcell immunity is still able to target the integrated hepatocyte.
5. The most proliferative clones will produce the most hbsag, but will also elicit anti oncogenic defense mechanisms, that might drive those cells into apoptosis in some cases.
6. A lucky anti hbsag epitope cd8 tcell clone is produced de novo from the thymus, actually able to eliminate the hbsag producing cell by the classical CTL pathway, before it gets tolerized by long term overstimulation from the circulating hbsag uptake by antigen presenting cells.
Yes, cell turnover does not eliminate the inserted hbsag sequence, but actually duplicates it. Furthermore many of these cells proliferate already at a higher rate, long before overt cancer, increasing the hbsag output even more.
William Mason has just published another paper on the clonal nature of most hepatocytes in a long standing hbv infection.
William Mason has just published another paper on the clonal nature of most hepatocytes in a long standing hbv infection.
Wow. Those results look extremely interesting.
4 Comments
I know right. However the reduction in HbsAg doesn't correlate to a reduction in the transcriptional activity or quantity of cccdna as observed in the natural history of hbv infection. So resuming treatment would bump up the HbsAg back to baseline levels. The objective is to induce an immune response to kill the infected cells that would result in a cure. I hope and pray they're able to achieve just that
Stopping* treatment.
Isn't HBSAG level a hint of Cccdna? My doc tellls me that HBSAG is a marker of virus in liver. Is it wrong?
It is a very unreliable marker for intrahepatic viral load/activity in HBeAg negative patients. This is because a large quantity of HBsAG is made from our own modified DNA and the remaining from cccdna. HbcrAg is a much better marker for that.
All I can say is let us be a little more encouraging and hopeful. There is always a positive side to everything Hope, pray and predict for a cure
Sept 27 2017 press release from arrowhead :
Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) today announced results from studies of ARC-520, a prior-generation RNAi therapeutic candidate against chronic hepatitis B virus (HBV) infection, in a Phase 2 clinical study in HBV patients and a complementary study in chimpanzees chronically infected with HBV. These studies demonstrated that HBV DNA integrated into the host genome is an under-appreciated source of HBV surface antigen (HBsAg), a key protein implicated in maintaining chronic HBV infection.
In many patients, integrated HBV DNA appeared to be the dominant source of HBsAg production. The findings expand the understanding of HBV biology and host interactions, and could have important implications for future trial design and endpoint expectations for new therapies developed to cure chronic HBV. These data from study, "RNAi-based treatment of chronically infected patients and chimpanzees implicates integrated hepatitis B virus DNA as a source of HBsAg" were published inScience Translational Medicine.
Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) today announced results from studies of ARC-520, a prior-generation RNAi therapeutic candidate against chronic hepatitis B virus (HBV) infection, in a Phase 2 clinical study in HBV patients and a complementary study in chimpanzees chronically infected with HBV. These studies demonstrated that HBV DNA integrated into the host genome is an under-appreciated source of HBV surface antigen (HBsAg), a key protein implicated in maintaining chronic HBV infection.
In many patients, integrated HBV DNA appeared to be the dominant source of HBsAg production. The findings expand the understanding of HBV biology and host interactions, and could have important implications for future trial design and endpoint expectations for new therapies developed to cure chronic HBV. These data from study, "RNAi-based treatment of chronically infected patients and chimpanzees implicates integrated hepatitis B virus DNA as a source of HBsAg" were published inScience Translational Medicine.
8 Comments
Replicors study found exactly the same situation re the source of circulating hbsag.
Here is more from the arrowhead press release, all no surprise but worth mentioning to doubters of this absolutely critical insight. I can say, with a little pride, that I predicted this already 10 years ago. "The nastiest trick of the hbv virus is that after the elimination of its cccDNA genome it often leaves a seemingles harmless trace of its genetic material in the "cured hepatocyte" that will ensure its capacity to reinfection and is almost untouchable by the immune system. And, to boot, it is the main source of liver cancer due to often destabilizing insertions into the human genome."
"In the publication, several independent lines of evidence demonstrate that HBsAg is expressed not only from the episomal covalently closed circular DNA (cccDNA) minichromosome, but also from transcripts arising from HBV DNA integrated into the host genome. The latter was a large source of HBsAg production in HBeAg negative chimpanzees and presumed, by extension, in HBeAg negative and NUC experienced patients.
"This is an important finding with wide-reaching implications for the field because production of viral proteins was previously thought to depend only on transcription of viral cccDNA. We now understand that integrated HBV DNA is a means of producing circulating HBsAg that is not dependent on viral replication, which may contribute to sustained suppression of the immune system and allow for continued virion production," commented Christine I. Wooddell, Ph.D., lead study author. "Just a few cccDNA-containing cells able to escape immune surveillance can maintain chronic infection. Therefore, only complete immune control of HBsAg can be expected to prevent reinfection off therapy and result in a functional cure."
Here is more from the arrowhead press release, all no surprise but worth mentioning to doubters of this absolutely critical insight. I can say, with a little pride, that I predicted this already 10 years ago. "The nastiest trick of the hbv virus is that after the elimination of its cccDNA genome it often leaves a seemingles harmless trace of its genetic material in the "cured hepatocyte" that will ensure its capacity to reinfection and is almost untouchable by the immune system. And, to boot, it is the main source of liver cancer due to often destabilizing insertions into the human genome."
"In the publication, several independent lines of evidence demonstrate that HBsAg is expressed not only from the episomal covalently closed circular DNA (cccDNA) minichromosome, but also from transcripts arising from HBV DNA integrated into the host genome. The latter was a large source of HBsAg production in HBeAg negative chimpanzees and presumed, by extension, in HBeAg negative and NUC experienced patients.
"This is an important finding with wide-reaching implications for the field because production of viral proteins was previously thought to depend only on transcription of viral cccDNA. We now understand that integrated HBV DNA is a means of producing circulating HBsAg that is not dependent on viral replication, which may contribute to sustained suppression of the immune system and allow for continued virion production," commented Christine I. Wooddell, Ph.D., lead study author. "Just a few cccDNA-containing cells able to escape immune surveillance can maintain chronic infection. Therefore, only complete immune control of HBsAg can be expected to prevent reinfection off therapy and result in a functional cure."
Well done for speculating on it and being right before it was found. But I don't understand why people get so hung up on this being a source of hbsag. When you clear hepatitis b naturally you are also left with the same viral reservoir. So yes, you can potentially get reinfected, and you are at an increased risk for cancer, but overall you're still pretty much okay. I think that when you get hbsag down to close to 0, and therefore your antibody level rises to a significant level (because you always create antibodies, however they get "used up" quickly because there are more antigens than antibodies so therefore they're generally undetectable) then as soon as an antigen is created it is destroyed. Exactly the same way as someone who is naturally immune. I'd gladly take that. Why don't we just focus on that?
Yes, once the HbsAg seroconversion is achieved, the memory B cells can quickly respond to a re-infection by rapidly generating antibodies. But what if the viral rebound outpaces the rate of production of these antibodies? This would be the case should integrated hepatocytes not be eliminated.
The thing is that an infection doesn't establish with full force from the get-go, rather it's a gradual process where a small amount of virus upon entry infects cells and replicates to large enough numbers to cause symptoms/disease (incubation period). Eventually with an immune reaction, the infection is cleared and antibodies are produced. The mission of antibodies is to attack the virus that re-gained entry inside the host before it can incubate. The antibodies would always present in overwhelming numbers relative to virus that yet has infect cells and multiply.
In patients with a resolved hbv infection, the Antibodies would present in overwhelming numbers relative to HbsAg derived from the small pool of remnant cccdna so that all HbsAg is neutralised and phagocytosed. But this shall no longer be the case in a patient with millions of cells that are genetically altered to output HbsAg,the production of which is temporarily blocked by a treatment. The antibodies would no longer be able to handle the overwhelming proliferation of HBsAG upon the cessation of treatment and seroreversion would occur, providing the virus an opportunity to respread.
The thing is that an infection doesn't establish with full force from the get-go, rather it's a gradual process where a small amount of virus upon entry infects cells and replicates to large enough numbers to cause symptoms/disease (incubation period). Eventually with an immune reaction, the infection is cleared and antibodies are produced. The mission of antibodies is to attack the virus that re-gained entry inside the host before it can incubate. The antibodies would always present in overwhelming numbers relative to virus that yet has infect cells and multiply.
In patients with a resolved hbv infection, the Antibodies would present in overwhelming numbers relative to HbsAg derived from the small pool of remnant cccdna so that all HbsAg is neutralised and phagocytosed. But this shall no longer be the case in a patient with millions of cells that are genetically altered to output HbsAg,the production of which is temporarily blocked by a treatment. The antibodies would no longer be able to handle the overwhelming proliferation of HBsAG upon the cessation of treatment and seroreversion would occur, providing the virus an opportunity to respread.
Thanks Bravesoul. I see your point. But as you yourself have raised nearly 50% of people who were chronically infected clear the infection at about age 50 on average. While we may not understand the mechanism behind this and can only theorize (as studyforhope has been doing), it seems that ya'll are focusing on the worst-case scenario. It's not hard to imagine several scenarios whereby the virus is suppressed to a satisfactory degree. Take a look at my previous post: http://www.medhelp.org/posts/Hepatitis-B/Nivolumab-lowers-hbsag-and-cures-chronic-hepatitis-b/show/2973527
And following up on that comment, take a look at this. Very few CHB patients have been treated with a pd-1 inhibitor. But this guy was cured from it. I don't think it was a freak occurrence: https://www.omicsonline.org/open-access/seroconversion-of-hbsag-in-melanoma-patient-with-hepatitis-b-treated-withcheckpoint-inhibitors-a-case-report-2165-7920-1000951.php?aid=88890
In my opinion this is actually fantastic news for us: http://www.infohep.org/US-FDA-approves-nivolumab-immunotherapy-for-liver-cancer/page/3175886/
Because now that people with liver cancer are going to be taking nivolumab I predict that we are going to see a lot of cases where it makes them seroconvert to being hbsag negative while on treatment. So we'll effectively see a ton of people being cured from chronic hepatitis b infection by it. Irrespective of the fact that it may not be approved for use for curing chronic hepatitis b due to its toxicity, it will certainly raise my interest level even higher in taking multiple small doses (probably 0.3mg/kg or less) to treat it. Given that the general dose is 240mg/kg I would speculate that this is likely to be very safe too.
Because now that people with liver cancer are going to be taking nivolumab I predict that we are going to see a lot of cases where it makes them seroconvert to being hbsag negative while on treatment. So we'll effectively see a ton of people being cured from chronic hepatitis b infection by it. Irrespective of the fact that it may not be approved for use for curing chronic hepatitis b due to its toxicity, it will certainly raise my interest level even higher in taking multiple small doses (probably 0.3mg/kg or less) to treat it. Given that the general dose is 240mg/kg I would speculate that this is likely to be very safe too.
The dosis is 240mg per two weeks total, not 240mg/kg for melanoma patients!
0.3mg/kg is still a small dose compared to about 3mg/kg for the cancer patients.
0.3mg/kg is still a small dose compared to about 3mg/kg for the cancer patients.
at yeah, that's what I meant. So a 70kg person would have about 20 ml for hbv vs about 240 ml for cancer. So the dose is tiny.
Very encouraging result of monotherapy. Supressing hbsag is the mainstay of immune reactivation. Adding ifn to it will certainly give seroconverting results. Yes ofcourse finger crossed.
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