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.
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...
