Monday, November 4, 2013

ARC520 for Chronic HepB: The Immune System…It’s Reactivating!

Usually, immune stimulation which manifest itself as flu-like symptoms and the like is something that you do not want to see with an RNAi Therapeutic.  Having said that, there are settings in which you want to see immune stimulations.  This is also the case for the treatment of chronic HBV with a HBsAg knockdown approach. 

ARC520 is the lead candidate in this effort and yesterday the sponsor, Arrowhead Research, presented very exciting data in a chronically infected chimpanzee that had been treated with the RNAi agent.  The data are not only exciting because they presumably represent the fastest reduction of the HBsAg antigen ever seen in a real infection (note: only the chimpanzee is thought to reflect human HBV infection), no, what is even more exciting is that the data are consistent with a HBsAg-specific T-cell immune response.  

As the success of an HBsAg knockdown approach for the treatment of chronic HBV hinges on the hypothesis that by knocking down HBsAg it might be possible for the body to re-activate an adaptive immune response against the virus, the data in my mind are the biggest de-risking event in the development of ARC520.

The data

At the 2013 Liver Meeting of the AASLD in Washington DC, Arrowhead Research presented more detailed data on the chimpanzee that had been treated with ARC520.  Before that we had known that two doses of ARC520 (one of 2.0mg/kg and one of 3.0mg/kg) spaced 14 days apart was able to knock down HBsAg by ~80%, HBeAg by over 90%, and serum HBV DNA by 1-2logs.  The important knockdown here is that of HBsAg, an otherwise ‘undruggable’ target.  Reverse transcriptase inhibitors such as entecavir are not able to meaningfully reduce HBsAg.

The discrepancy of the degrees of HBsAg and HBeAg/HBV DNA knockdowns is likely explained by the prolonged half-life of HBsAg.  Repeat dosing for an extended period of time should lead to even further reductions in HBsAg.  Moreover, the treated chimpanzee was an unusually tough challenge, because old (HBV for over 35 years alone), heavy and with extremely high viremia (>10exp10 genomes per ml). 

Importantly, as predicted by the HBsAg knockdown-immune reactivation hypothesis, there was an apparent T cell-mediated anti-HBsAg immune response shortly after peak HBsAg knockdown levels were reached.  The peak HBsAG knockdown occurred somewhere between ~days 25 and 38 and there was a flare-up in liver enzymes around day 43.   
A liver-enzyme flare-up would be expected when anti-HBsAg cytotoxic T-cells start to attack HBV-infected hepatocytes.  Consistent with it being due to a T-cell response, markers of T cell activation, most notably interferon gamma, were also up-regulated around the time of the flare-up.  Interestingly, liver enzyme levels did not fully revert back to normal, but remained somewhat elevated compared to base-line suggesting that the RNAi knockdown kicked into gear a more persistent immune response.

Such delayed dynamics are consistent with what is seen following successful treatment with interferons.  In the ~5-10% of cases where interferons are able to achieve the gold standard HBsAg elimination (in the presence or absence of HBsAg seroconversion), the elimination usually occurs after the ~52 week course of interferon, in many cases years afterwards.

Of course, the present chimpanzee data do not show an elimination of HBsAg.  While I do not exclude the possibility that Arrowhead Research will come back in another 3 months or so to report that the immune system has finally overcome HBsAg, I prefer to keep expectations for such an event low and instead consider the present data as a nice starting point that indeed ARC520 is able rekindle the desired immune response after only two doses over 14 days.

Why it is unlikely to be a non-specific immune response

It is very important here to emphasize that what we are seeing here was not due to a non-specific innate immune response triggered by an immunostimulatory RNAi agent.  Similarly, some RNAi delivery strategies run the risk of causing direct damage to hepatocytes which would also manifest itself by increases in liver enzymes.

The most convincing argument to me is in the timing of the flare-up and cytokine elevations.  While non-specific responses usually occur in the hours and days immediately following RNAi administration, in this case, they occurred 3-5 weeks after the second dose.

Consistent with a ‘clean’ safety profile of ARC520, no such liver enzyme and cytokine elevations were seen in the phase I volunteer study for which Arrowhead reported initial safety data a month ago (2mg/kg highest dose in that study).  Nevertheless, as those data only focused on the safety in the first few days following drug administration for the above reasons and the 30-day follow-up still remains to be reported, one formally cannot exclude the possibility that the unique DPC chemistry is associated with liver damage and the like only weeks after drug administration.  I consider this quite unlikely though.

Going along with this theme, I expect the phase IIa study which will involve infected patients in Hong Kong and is scheduled to initiate enrollment in early 2014 to be ARC520 on top of an RT inhibitor such as entecavir.  As RT inhibitors stabilize the liver of HepB patients and in light of the phase I data, any flare-ups that would be seen in that single-dose study would presumably be the result of HBsAg-specific immune reactivation.  

Lots of exciting catalysts ahead over the next 6 months and who knows, due to intrapatient variability, maybe there will be a cure or two in the phase IIa study already.  

PS: For more background on RNAi knockdown for HBV and ARC520, please visit my cureHBV companion blog


Anonymous said...

"The most convincing argument to me is in the timing of the flare-up and cytokine elevations. While non-specific responses usually occur in the hours and days immediately following RNAi administration, in this case, they occurred 3-5 weeks after the second dose."

First off, I would agree this is extremely encouraging data.

Second though, I would presume they were unable to treat a "healthy" chimpanzee(s) with ARC-520 following the EXACT same dosing regimen to provide a negative control, within the same study, further strengthening the argument that this was not "a non-specific innate immune response triggered by an immunostimulatory RNAi agent."

Stated another way, my understanding is that it is difficult, if not impossible, to conduct drug safety/tolerability studies with chimpanzees so I presume either that reason, or the extremely high cost, is why we did not see "healthy" chimpanzees treated with the exact same ARC-520 dosing regimen as the chronically infected chimpanzee.

Dirk Haussecker said...

I would add to this comment that today (after chimp drug studies are essentially banned) you can forget about controlled studies as you suggest. I look at the chimp as an in-depth study of a patient. The internal consistency of the data make it a very strong case that what we are seeing here is real.

As interest in orphan drug development increases, I also expect regulatory agencies to warm up to such detailed studies of individual subjects.

Bikerieder said...

If regulatory agencies don't like studies with chimps, is that the reason why Wallstreet don't like very much the new data?
The first data on the chimp in march got about the same «welcome» like yesterday. In the last 12 months, ARWR went out with more than a few news, but WS did not rewarded this. At this moment, WS don't like ARWR?

Latebloomer said...

Hi, Dirk.

I could use your help with understanding something:

It would follow that for chronic HBV patients, carrying this disease for so long (in many cases since birth), that a great many more of their liver cells would have been infected by the time of starting treatment... in comparison to the amount of liver cells infected within people who were able to mount a full immune response and, within 6 months or less after initial infection, be rid of the virus.

For example, I believe they said the chimp, after 30 some odd years of harboring the infection, suffered from almost 100% of her liver cells being infected.

If the immune system of a chronic HBV patient does actually kick in in response to this disease to an extent it's never been able to do before, how might that patient(s)' liver fair when most, if not all, of his/her liver cells have become infected?

I imagine there's some way for the body to calibrate itself, some way for it to "know" that it can't mount a full-on "attack" against nearly all of the body's liver cells at once, but I could use some help in understanding how the body's immune system might accomplish that necessary balance that might ultimately lead to a "functional cure."


tettrazini said...

We probably can exclude the possibility that Arrowhead Research will come back in another 3 months or so to report that the immune system has finally overcome HBsAg because the study seems to be finished. According to the poster, "The ALT remained modestly elevated through day 85, the end of the

Dirk Haussecker said...'s not that regulatory agencies don't like chimp studies, they should love their scientific value. It's just for ethical reasons that chimp research is being abandoned. We have young adult males in London for that.

Linda...the way it works is that the killed hepatocytes are replaced by new cells. During this replication, it is likely that most cccDNA gets lost, too! The liver has an amazing capacity to regenerate. But yeah, you raise an important point. My understanding is that this is also a small risk (decompensating liver) when a cure based on other treatments such as interferon occurs. I do not see any other way how you can control, and even cure (not just functionally) the disease.

Tet, I would be surprised if the chimp were not tested in the future for HBV, e.g. during routine blood draws. As long as there aren't too many confounding factors after the study concluded (e.g. other drugs taken for HBV), that should be good enough.

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