Thursday, April 23, 2015

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).


Anonymous said...


Anonymous said...

my expection is to lower than 100. or even better 100-1000 times lower than original value


sweet...cant wait

Anonymous said...

What do the results of Replicor and RGLS mean for the likes of ARWR, TKMR, ISIS, ALNY, BLT, AGX or any other hepatitis chasing company?

More importantly, what are the patent issues, if any, surrounding them? Meaning, whose foundation IP are they employing?

Dirk Haussecker said...

REPLICor...single agent they claim most/all rebound after treatment. In combination, they say all s-seroconvert. There is A LOT of skepticism around REPLICor. One questioner challenged them why they have not published the results 2 years after presenting similar data from the Bangladesh trial at AASLD. Reply was vague and indicated that there were doubts about mechanism of action (e.g. potential innate immune stimulation). So nothing really changed for me, except to see that also in the hepatology community (not only in the oligoRx community) there is this skepticism. is now about whether RG-101 can enable 4-week pangenotypic treatments. That's always been the base case.

Anonymous said...

Sounds like another Benetic. All the promises in the world reinforced with some clever PowerPoint slides and devoid of close scientific scrutiny.

Success said...

I own both ARWR & TKMR. Both companies have acknowledged that to achieve functional cure will require combinational therapy to knock down antigen along with other aspect of infection. I guess it's just matter of who can reach this goal first? Timing wise, isn't ARWR ahead of both TKMR & Replicor?

I'm holding on tight to ARWR & TKMR for now.

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