Arrowhead Research Corporation, a biopharmaceutical company developing targeted RNAi therapeutics, announced that it dosed the first patient in part B of a phase 1 clinical trial of ARC-AAT, the company's RNAi-based drug candidate for the treatment of liver disease associated with the rare genetic disorder alpha-1 antitrypsin deficiency (AATD).

ARC-AAT was recently granted orphan drug designation by the United States Food and Drug Administration.

The clinical trial is currently enrolling patients at a single centre in Australia and the company intends to open additional sites for enrollment in Europe, pending regulatory permission to proceed. The company expects to complete enrollment of the phase 1 study by the end of 2015.

"Dosing the first alpha-1 patient with ARC-AAT is a milestone for Arrowhead and for patients with AATD. The goal of treatment with ARC-AAT is to halt progression and possibly reverse the liver injury and fibrosis associated with AATD, which currently has no approved therapy short of liver transplant. This is becoming a larger clinical problem that we believe ARC-AAT holds great potential to address," said Bruce D. Given, M.D., Arrowhead's chief operating officer. "We would also like to thank the Alpha-1 Foundation and The Alpha-1 Project, who have agreed to help support the development of ARC-AAT through funding and assistance with patient recruitment."

The ongoing phase 1 trial of ARC-AAT is a multi-centre, randomized, placebo-controlled, double-blind, single dose-escalation, first-in-human study to evaluate the safety, tolerability and pharmacokinetics of ARC-AAT and the effect on circulating AAT levels. The study has been enrolling in dose cohorts of six participants each, with participants randomized at a ratio of 2:1 (active:placebo) to receive a single intravenous injection of either ARC-AAT or placebo (normal saline). The study consists of two parts; part A in healthy volunteers, which has been completed, and part B to be conducted in patients with PiZZ genotype AATD. Dosing in patients begins at the highest dose level used in healthy volunteers and then continued dose escalation may proceed under the protocol. The study evaluates participants for 28 days following dosing, with additional follow-up if needed every 2 weeks until AAT levels return to baseline.

ARC-AAT is being investigated for the treatment of liver disease associated with alpha-1 antitrypsin deficiency (AATD), a rare genetic disease that severely damages the liver and lungs of affected individuals. The mean estimated prevalence of AATD in the US is 1 per 3000-5000, or approximately 100,000 patients. AATD is also an important cause of paediatric liver disease with an estimated prevalence in children of approximately 20,000 patients, and 50-80 per cent likely to manifest liver disease during childhood. It is a rare disease that appears to be frequently misdiagnosed or undiagnosed.

ARC-AAT employs a novel unlocked nucleobase analog (UNA) containing RNAi trigger molecule designed for systemic delivery using the Dynamic Polyconjugate delivery system. ARC-AAT is highly effective at knocking down the alpha-1 antitrypsin (AAT) gene transcript and reducing the hepatic production of the mutant AAT (Z-AAT) protein in animals. Reduction of liver production of the inflammatory Z-AAT protein, which is believed to be the cause of progressive liver disease in AATD patients, is important as it is expected to halt the progression of liver disease and potentially allow fibrotic tissue repair. Arrowhead is conducting a single dose phase 1 clinical study of ARC-AAT, with part A in healthy volunteers and part B in AATD patients.