Arrowhead Achieves Robust Alpha-1 Antitrypsin Lowering As Grounds for Trial Termination Still Shrouded in Mystery

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.

The press release can be found here, the actual presentation here. 

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.