Aa
Something has been changed nowadays
Here is a researcher's opinion from the HBV Knockdown Blog about the EASL 2014 meeting.
"Having attended the EASL European Liver Meeting last week and listened to some of the clinical thought-leaders and companies involved in HBV research and treatment, it confirmed the view that there is a GREAT hunger in the field for new approaches to achieve that elusive finite treatment goal for HBV. For this, all differentiated, potentially high-impact new treatment approaches are welcome, RNAi or not. And yes, following the successes in HCV, the industry now views HBV as an opportunity as big as HCV and is shifting its resources accordingly.
There were numerous, not very imaginative studies about trying various permutations of treating HBV with the old, and tired workhorses interferon and NUCs: treat with NUCs, then come in with interferon or vice versa, trying different interferons (alpha or lambda), trying different treatment times…without much, if anything to show for it to change current standard of care.
Where there was progress in HBV was in better understanding the kinetics of this complex disease and in the development of better animal and tissue culture model systems that I expect to greatly facilitate the development of drugs for HBV. For example, following the discovery of NTCP as the viral entry receptor, it is now possible to have HBV replicate in the petri dish. Similarly, there are now mice with not only human livers, but also human immune systems. This is critical for studying immune-based treatment approaches which are viewed as most promising, including HBsAg gene knockdown.
The fact that HBsAg has emerged as a very important biomarker should aid in garnering support for knockdown approaches, although awareness of them is not great yet. This also showed from the reactions to a talk on the ISIS/GSK antisense candidate that I attended. Although multi-log knockdowns were achieved in certain model systems, I did not see great potency at doses that are clinically relevant. For example, what point is a 3 log HBsAg knockdown when you need 200mg/kg oligos in mice (or don't even show the data)? Granted, Arrowhead Research has also advertised knockdown levels with dosages that will not be used in the clinic, but with 2mg/kg they are close to or even better than something quite potent in humans.
With regard to other new treatment approaches besides HBsAg gene knockdown, there is the HBV entry inhibitor Myrcludex which is receiving more widespread attention, although the downside to that approach is that it has no apparent immune angle and would largely work the way that NUCs do…reduce viral load. Finally, there is the idea of inhibiting the PD-1 pathway as discussed in an earlier blog entry, but I’m quite skeptical about the safety of an antibody/small molecule approach here due to potential toxicity arising from the systemic inhibition of this pathway, including autoimmunity. More interesting would be an RNAi Therapeutics approach that targets thepathway specifically in the liver."
"Having attended the EASL European Liver Meeting last week and listened to some of the clinical thought-leaders and companies involved in HBV research and treatment, it confirmed the view that there is a GREAT hunger in the field for new approaches to achieve that elusive finite treatment goal for HBV. For this, all differentiated, potentially high-impact new treatment approaches are welcome, RNAi or not. And yes, following the successes in HCV, the industry now views HBV as an opportunity as big as HCV and is shifting its resources accordingly.
There were numerous, not very imaginative studies about trying various permutations of treating HBV with the old, and tired workhorses interferon and NUCs: treat with NUCs, then come in with interferon or vice versa, trying different interferons (alpha or lambda), trying different treatment times…without much, if anything to show for it to change current standard of care.
Where there was progress in HBV was in better understanding the kinetics of this complex disease and in the development of better animal and tissue culture model systems that I expect to greatly facilitate the development of drugs for HBV. For example, following the discovery of NTCP as the viral entry receptor, it is now possible to have HBV replicate in the petri dish. Similarly, there are now mice with not only human livers, but also human immune systems. This is critical for studying immune-based treatment approaches which are viewed as most promising, including HBsAg gene knockdown.
The fact that HBsAg has emerged as a very important biomarker should aid in garnering support for knockdown approaches, although awareness of them is not great yet. This also showed from the reactions to a talk on the ISIS/GSK antisense candidate that I attended. Although multi-log knockdowns were achieved in certain model systems, I did not see great potency at doses that are clinically relevant. For example, what point is a 3 log HBsAg knockdown when you need 200mg/kg oligos in mice (or don't even show the data)? Granted, Arrowhead Research has also advertised knockdown levels with dosages that will not be used in the clinic, but with 2mg/kg they are close to or even better than something quite potent in humans.
With regard to other new treatment approaches besides HBsAg gene knockdown, there is the HBV entry inhibitor Myrcludex which is receiving more widespread attention, although the downside to that approach is that it has no apparent immune angle and would largely work the way that NUCs do…reduce viral load. Finally, there is the idea of inhibiting the PD-1 pathway as discussed in an earlier blog entry, but I’m quite skeptical about the safety of an antibody/small molecule approach here due to potential toxicity arising from the systemic inhibition of this pathway, including autoimmunity. More interesting would be an RNAi Therapeutics approach that targets thepathway specifically in the liver."
For someone who wants to be a guru in HBV therapy research the remark re myrcludex is naive and misleading.
I also read his contribution regarding the hbsag reduction not being a result of seroconversion, meaning that the hbsag reductions seen are not merely caused by an anti hbs AB. He was trying to emphasize that the hbsag reduction to be achieved by the ARC 520 will be an initiator of immune clearance.
The truth is that an hbsag AB internally produced or injected can indeed reduce the hbsag, but only to a very minor degree, in the order of a few IU at best.
Trials with HEPEX B, a dual Israeli monoclonal with extremely high doses, have achieved temporary trapping of de novo produced hbsag into immune complexes. The lowering effect was lost within 2 or 3 days.
I also read his contribution regarding the hbsag reduction not being a result of seroconversion, meaning that the hbsag reductions seen are not merely caused by an anti hbs AB. He was trying to emphasize that the hbsag reduction to be achieved by the ARC 520 will be an initiator of immune clearance.
The truth is that an hbsag AB internally produced or injected can indeed reduce the hbsag, but only to a very minor degree, in the order of a few IU at best.
Trials with HEPEX B, a dual Israeli monoclonal with extremely high doses, have achieved temporary trapping of de novo produced hbsag into immune complexes. The lowering effect was lost within 2 or 3 days.
No disrespect to the blogger but he misses the point about Mycrludex - its action is to prevent new infection thereby accelerating the clearance of cccDNA pool by liver cells turnover. However, the difficulty with Mycrludex, in my understanding, is the dosage question, as NTCP is important for bile absorption, a high dose will have serious side effect.
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