Aa
Hsbag presentation!
Absolute HBsAg Levels, Not Percent Decline May Be Goal of HBV RNAi
I just walked into an early morning session at the International Liver Congress in Vienna and may have learned the most important nugget of information regarding RNAi treatment for HBV.
During the discussion in the ‘Banishing B’ session, Dr. Joerg Petersen referred to clinical analyses to be presented this Saturday showing that patients who achieve HBsAg levels of less than 500, or even better 200 IU/ml and then are given an interferon have a much better chance of eventually losing HBsAg, i.e. being functionally cured, than those that do not.
Dr. Petersen has been involved in clinical studies combining nukes and an interferon, and data presented at last year’s American Liver meeting (AASLD) showed that 9% treated with the combination for 1 year lost HBsAg in the year following combination therapy compared to just 2.8% receiving interferon alone.
Note that currently only interferons are thought to give you a chance of functionally curing HBV by medication and that HBsAg seroconversion attributed to interferon treatment may occur in the years after cessation of interferon therapy. It will therefore be important to see whether this increase in seroconversion with combination treatment continues to hold up in subsequent years. The nukes are ‘only’ thought to protect the liver from the ongoing damage from HBV replication and may have to be given indefinitely.
I am not sure whether the new insight comes from a fresh clinical study or are the result of a more detailed subgroup analysis of the previous study. Regardless, it hammers home a message that can be heard again and again, even more so in Vienna this year than at the London meeting last year: it is all about HBsAg lowering.
Implications for HBV RNAi
The implications of the new analysis for RNAi approaches for the treatment of HBV is obvious: use RNAi to get HBsAg below the threshold. In other words, it may be less about getting a magical 1log knockdown, but more about getting patients below 500IU/ml.
For this, Dr. Petersen recommended using 2 nukes so that the tiny and very slow HBsAg declines observed on nukes continue ( < 0.1 log per year). With RNAi agents, you would likely achieve this goal for a patient with an HBsAg at baseline of 1000IU/ml within a month, even with a single 2mg/kg dose of ARC520 from Arrowhead Research as reported last year.
The absolute knockdown potency of an RNAi agent would determine which fraction of the HBV population fall within this sweet spot. With a 1log knockdown e.g. you could start RNAi with patients with as much as 5000IU/ml.
For the clinical development of RNAi agents for HBV, the first step will be to determine the HBsAg decline on a background of nukes (just what Arrowhead is doing right now). For pivotal trials, an immunostimulatory agent such as an interferon should be added to the nukeà RNAi/nuke treatment regimen to finish off the virus.
Stay tuned to learn about the fold benefit of HBV cures in patients falling below the 500IU/ml threshold, and the 3-4mg/kg single-dose results for ARC520 from Arrowhead Research to be reported later this quarter (note to Arrowhead PR department: next Monday may be a good time to do so).
Dirk Haussecker at Thursday, April 23, 2015
2 comments:
AnonymousApril 23, 2015 at 1:10 AM
WOW!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Reply
AnonymousApril 23, 2015 at 2:14 AM
my expection is to lower than 100. or even better 100-1000 times lower than original value
Reply
I just walked into an early morning session at the International Liver Congress in Vienna and may have learned the most important nugget of information regarding RNAi treatment for HBV.
During the discussion in the ‘Banishing B’ session, Dr. Joerg Petersen referred to clinical analyses to be presented this Saturday showing that patients who achieve HBsAg levels of less than 500, or even better 200 IU/ml and then are given an interferon have a much better chance of eventually losing HBsAg, i.e. being functionally cured, than those that do not.
Dr. Petersen has been involved in clinical studies combining nukes and an interferon, and data presented at last year’s American Liver meeting (AASLD) showed that 9% treated with the combination for 1 year lost HBsAg in the year following combination therapy compared to just 2.8% receiving interferon alone.
Note that currently only interferons are thought to give you a chance of functionally curing HBV by medication and that HBsAg seroconversion attributed to interferon treatment may occur in the years after cessation of interferon therapy. It will therefore be important to see whether this increase in seroconversion with combination treatment continues to hold up in subsequent years. The nukes are ‘only’ thought to protect the liver from the ongoing damage from HBV replication and may have to be given indefinitely.
I am not sure whether the new insight comes from a fresh clinical study or are the result of a more detailed subgroup analysis of the previous study. Regardless, it hammers home a message that can be heard again and again, even more so in Vienna this year than at the London meeting last year: it is all about HBsAg lowering.
Implications for HBV RNAi
The implications of the new analysis for RNAi approaches for the treatment of HBV is obvious: use RNAi to get HBsAg below the threshold. In other words, it may be less about getting a magical 1log knockdown, but more about getting patients below 500IU/ml.
For this, Dr. Petersen recommended using 2 nukes so that the tiny and very slow HBsAg declines observed on nukes continue ( < 0.1 log per year). With RNAi agents, you would likely achieve this goal for a patient with an HBsAg at baseline of 1000IU/ml within a month, even with a single 2mg/kg dose of ARC520 from Arrowhead Research as reported last year.
The absolute knockdown potency of an RNAi agent would determine which fraction of the HBV population fall within this sweet spot. With a 1log knockdown e.g. you could start RNAi with patients with as much as 5000IU/ml.
For the clinical development of RNAi agents for HBV, the first step will be to determine the HBsAg decline on a background of nukes (just what Arrowhead is doing right now). For pivotal trials, an immunostimulatory agent such as an interferon should be added to the nukeà RNAi/nuke treatment regimen to finish off the virus.
Stay tuned to learn about the fold benefit of HBV cures in patients falling below the 500IU/ml threshold, and the 3-4mg/kg single-dose results for ARC520 from Arrowhead Research to be reported later this quarter (note to Arrowhead PR department: next Monday may be a good time to do so).
Dirk Haussecker at Thursday, April 23, 2015
2 comments:
AnonymousApril 23, 2015 at 1:10 AM
WOW!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Reply
AnonymousApril 23, 2015 at 2:14 AM
my expection is to lower than 100. or even better 100-1000 times lower than original value
Reply
No, the effects of Interferon are multiple. Through the activation of certain ISG genes, Interferon can have antiviral effect, including epigenetically controlling the cccDNA within an infected liver cells. Therefore it can inhibit production of hbvdna and HBsAg. As a cytokine, it affects various types of immune cells, inhibiting or promoting their activities. The details are beyond me.
So why for example interferon works ? It hasn't direct impact on HBV but produces more T-cells ?
You are right. The HBV virus only evolved mechanisms to evade attacks by HBV specific immune actions. So when I say rekindle our immune system, I should say rekindle the HBV specific immune functions. Chronic Hepatitis B can evade but does not compromise our immune system. Actually, Prof Bertolotti reckoned in a recent paper that HBV infected babies have a more mature immune system.
Stephen: At some low level of hbvdna and hbsag immune system wakes up and starts to fight with infection ?
But why it fights other infections successfully for hbv person ?
For example I never had any serious illness, sometimes I had flu sympthoms but in one max 2 days I was ok without any medicines, maybe garlic and vit c sometimes.
But why it fights other infections successfully for hbv person ?
For example I never had any serious illness, sometimes I had flu sympthoms but in one max 2 days I was ok without any medicines, maybe garlic and vit c sometimes.
I still think Dirk is no expert of Hepatitis B. To me, the crucial point is not lowering of HBsAg, but why lowering HbsAg will lead to a cure. REP9AC showed us several years ago that deep reduction of serum HBsAg plus an immune stimulant like Interferon can lead to a functional cure, and REPLicor has provided a very plausible explanation. That the reduction of serum hbvdna and viral antigens can rekindle our immune system seems to be accepted by more researchers now.
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