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.
