14 Nov 2016

Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) delivered a poster presentation with Phase 1 clinical data and an oral presentation with preclinical data on ARC-AAT, its investigational medicine for the treatment of liver disease associated with alpha-1 antitrypsin deficiency (AATD), at The Liver Meeting® 2016, the Annual Meeting of the American Association for the Study of Liver Disease (AASLD), in Boston. The data indicate that in a first-in-human clinical study, ARC-AAT was well tolerated and induced deep and durable reduction of the target AAT protein. The preclinical data suggest that treatment with ARC-AAT over time may improve liver health and prevent further damage.

Bruce Given, M.D., chief operating officer of Arrowhead Pharmaceuticals, said: "We showed some exciting data today indicating that ARC-AAT, both clinically and in a preclinical model, is doing precisely what it is designed to do. In these studies, ARC-AAT led to deep, durable, and dose-dependent silencing of the liver production of the AAT protein. Accumulation of the mutant Z-AAT is believed to be the cause of progressive liver disease in patients with AATD, and reducing the production is important as it is expected to halt the progression of liver disease. Specifically, in the clinical study ARC-AAT led to a maximum reduction of up to 90% in the highest dose group, which we believe to be near full suppression of the liver production of the protein, and a mean maximum reduction of 88%. We are also pleased that in the clinical study ARC-AAT was well tolerated at all dose levels studied (0.3 - 8 mg/kg), which is consistent with the tolerability profile of our other clinical programs that use the same DPCivTM (EX1) delivery vehicle."

The poster titled, "RNA interference (RNAi) with ARC-AAT provides deep and prolonged knockdown of alpha-1 antitrypsin levels in healthy volunteers," publication LB-24 in the late-breaking poster session, describes data from a Phase 1, multi-center, randomized, placebo-controlled, double-blind, single dose-escalation first-in-human study to evaluate the safety, tolerability, pharmacokinetics of ARC-AAT and the effect on circulating alpha-1 antitrypsin (AAT) levels. Key findings from the study include the following:

Dose-dependent reductions in serum AAT of up to 90% were observed
Duration of effect indicates that monthly, or less frequent, dosing is likely
Pharmacokinetic (PK) parameters were linear across dose levels with a constant half-life
There have been no drop outs due to adverse events (AE), no clinically significant changes in ECGs, DLCO or FEV1, and one serious adverse event (SAE) in a placebo subject
No clinically significant transaminase (ALT, AST) elevations were reported
The most frequently reported ARC-AAT related AEs were headache, nausea and rigor (each, 3 events in 36 [8%] subjects)

The oral presentation titled, "RNA interference therapeutic ARC-AAT prevents production of Z-alpha1 antitrypsin polymers and reverses liver disease phenotype in PiZ mouse model," publication 124 in the session Parallel 19: Pediatric and Metabolic Liver Diseases: Basic and Translational, describes data from a 33-week study of ARC-AAT in the PiZ mouse model. Key findings from the study include the following:

Cleared Z-hAAT protein from the cytoplasm and reduced by > 90% in serum
Prevented and reversed polymer accumulation, with Z-hAAT monomer reduced by 87% and polymer by 42% at week 33
Halted accumulation of Z-hAAT globules in the liver, with 61% less in ARC-AAT treated compared to saline controls and 24% less than at baseline
Improved liver health and prevented further damage based on histopathology improvements compared to baseline and saline controls
Prevented liver inflammation with fewer inflammatory foci and reduced total area of inflammation
Prevented liver tumors
Normalized gene expression associated with liver disease

A copy of presentation materials will be made available on the Events and Presentations page under the Investors section of the Arrowhead website.