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Today, we learned about some hard HBsAg knockdown numbers from the phase IIa Hong Kong study
of ARC520 in chronically infected HBV patients. The data relate to the first 2 cohorts in
this ongoing dose escalation trial. Accordingly, the mean HBsAg knockdown at nadir for the
starting dose of 1mg/kg was 39% within a range of 22-57% (n=6) while it was 51% within a
range of 46-59% for the 2mg/kg cohort (n=6).
ARC520 was given as a single dose to patients already stably on polymerase inhibitor
entecavir.
It should be noted while numerically the improvement in knockdown from 1mg/kg to 2mg/kg was
only 12%, this is likely the result of the apparent high variability at the lower dose level
with the increased tightness of the knockdown range at 2mg/kg indicating that the RNAi
mechanism is starting to be solidly engaged with the expectation of a steepening dose
response going forward.
While clearly missing the company’s own guidance of a 1 log reduction at 2mg/kg, the good
safety profile-no SAEs at all in the study with all AEs rated to be unrelated to ARC520- in
addition to the steepening dose-response curve following 2mg/kg means that ARC520 is far
from being out of the HBV knockdown race. Still, the stock market over-reacted, punishing
ARWR stock with a percent decrease that matched the reported knockdowns.
Although even I ended up willing myself into believing that a 70-80% knockdown was possible
following a single ARC520 dose of 2mg/kg, revisiting the chimp study which involved 2 doses
of ARC520 (first one at 2mg/kg then one at 3mg/kg), it should be noted that at the time the
3mg/kg dose was administered, the HBsAg levels had only declined by 50%...about the same as
achieved in the phase IIa study. It is thus possible that Arrowhead gave the 2nd dose just
as HBsAg levels were about to go up again, consistent with the already rebounding levels of
HBV DNA and HBeAg in that study.
As a result, my expectations for the single 3mg/kg dose are now 70-75% based on the ~75-80%
peak HBsAg knockdown in the chimp study following the 2mg/kg and 3mg/kg doses. This also
means that in order to reach that 1log knockdown goal the company had set for itself, 4mg/kg
will most likely be needed. Importantly, in the concurrent phase I dose-escalating study in
healthy volunteers, this quite large amount of drug seemed to be well tolerated and the
company is awaiting approval to adopt this dose in the Hong Kong study.
This projection is not much off the 90% knockdown achieved in the ARC-AAT program at 3mg/kg
in non-human primates. The improvement of this 2nd DPC-based candidate about to enter the
clinic is possibly explained by progress in the potency of 2-molecule DPC delivery
technology. I add this as today many were confused about what the interim phase IIa results
meant for the platform and the value of the company.
Overall, as long as 4mg/kg is an acceptable dose from a tox point-of-view, ARC520 is still
in the game to be first-in-class in HBV knockdown. It would have been much worse if say a
70% knockdown had been reported, but worrisome safety signals emerged. On the other hand,
the continued need for a dose escalation would seem to delay Arrowhead’s broad-based phase
IIb study plans, meaning that the competition, in particular Tekmira's TKM-HBV is coming
closer.
At a market cap of ~$400M, the market has almost fully discounted the potential of ARC520
given the $150M+ in cash as well as the IND-ready, first-in-class ARC-AAT for which we can
expect solid knockdowns in the clinic. Interestingly, data for this candidate were selected
for an oral presentation at AASLD while the ARC520 data will be in less prestigious poster
form. Finally, should the single-molecule DPC which got me excited about the Arrowhead RNAi
platform in the first place finally reach the clinic, it would necessitate an upward
revision of the value of the company.
Disclosure: Long ARWR. I sold most of my holdings at $11 and change given the underwhelming
results and increasingly negative market reaction, but got back in below $6 when I
considered the sell-off to be a gross over-reaction and imminent 3mg/kg data having the
potential to surprise the market to the upside from now much lowered expectations. Add to
this ARC-AAT, the platform...
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楼主: 林伍伍
发表于 2014-10-9 11:32
