Last Friday,
Arrowhead Pharmaceuticals presented first data from its phase I study of
ARO-AAT being developed for addressing liver disease in people with certain
mutations in the alpha-1 antitrypsin gene.
Based on the selective data release, Arrowhead has assumed the lead in
this indication as Alnylam struggles to regain its footing following apparent
off-target-related liver toxicity almost 2 years ago.
With a mean
maximal target gene knockdown of -87% between 6 to 8 weeks following a single subcutaneous injection of 100mg dose of the GalNAc-enabled ARO-AAT, Arrowhead has shattered the previous AAT knockdown record by
Alnylam’s ALN-AAT of -80% at a ~4x dose of ARO-AAT. The dynamics of the knockdown also suggests
that infrequent dosing should be feasible with ARO-AAT, although without seeing
the multi-dose data from this study, it is difficult to predict whether we are
talking about quarterly or semi-annual dosing here.
It will
also be interesting to find out whether the variation of knockdown in the 4
patients- ~-70% knockdown at 4 weeks for the 2 weaker responders and ~-90% for the 2 better
responders- had to do the polymorphism issues similar to those encountered by
Alnylam before.
Safety mystery
remains
When Arrowhead
announced on June 18 that it would terminate the healthy volunteer trial
prematurely given that it had escalated above doses at which maximal knockdown can be observed, I was hesitant in taking it at face value or whether this decision
also had something to do with the safety profile of ARO-AAT.
The Alpha-1
National Education Conference update only added to the impression. Firstly, because Arrowhead must already know the
knockdown from the 200mg and perhaps also the 300mg open-label cohorts since at least June
18, why didn’t the company simply show the data?
Regarding
safety, the company chose a cut-off date of June 11, that is a week before the June
18 decision. By June 11, there were only
2 drug-related injection site reactions among the 32 subjects that had received at least 1 dose of either ARO-AAT (n=20)
or placebo (n=12) per slide 17 of the presentation. Those happened to be in the 2 of 4 100mg
open-label subjects, the only subjects for which the knockdown had been
reported.
Confusingly,
the company also reported that 44 subjects
had received at least 1 dose (at least as of the trial termination decision
date of 18/6), meaning that 8 subjects had further received 300mg of ARO-AAT (4
open-label, 4 blinded) and 4 placebo (all blinded). Adding to the confusion, a company representative emailed
me in a response to a tweet of mine on the ISR frequency that the safety update referred to those 40 subjects that had received at least 1
injection as of 11/6, but- as I said- contrary to this statement the table on slide 17 only included 32
subjects. For all those others, the
safety data were missing entirely.
The
question now is whether the omission was intended as a teaser for the Liver
Meeting presentation in November, a minor math issue, or whether there was
something more nefarious to it. The
speed with which the company will move into patients (which already have or are
at risk for liver disease) will be an important indication whether liver toxicity
or the like has been observed subsequent to June 11.
