Arrowhead Announces New Clinical Candidate ARC-AAT for Treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
- RNAi Therapeutic ARC-AAT Induces Dose Dependent Reductions in Mutant AAT Protein of Greater than 95 Percent in Preclinical Studies
- Long Duration of Effect with AAT Remaining Reduced by More than 80% at 6 Weeks after a Single Dose
-
Company Receives Funding from
The Alpha-1 Project to Support ARC-AAT
A panel of key opinion leaders will join Arrowhead management for the
presentation today. Included in the panel are:
"ARC-AAT is our second clinical candidate to use the DPC delivery
system, and we are excited to build on the success to date of ARC-520,
our clinical candidate against chronic hepatitis B infection, which is
currently in a Phase 2a study," said
Arrowhead has developed a novel unlocked nucleobase analog (UNA)-containing RNAi molecule designed for systemic delivery using the Dynamic Polyconjugate (DPC) delivery system. ARC-AAT is highly effective at knocking down the Alpha-1 antitrypsin (AAT) gene transcript and reducing the hepatic production of mutant AAT protein. The Company plans to file an Investigational New Drug (IND) application for ARC-AAT in the fourth quarter of 2014.
In PiZ mice, which are genetically modified to produce the mutant human AAT (Z-AAT), ARC-AAT induced a greater than 95 percent reduction in circulating AAT after a single dose. After eight weeks of treatment in multi-dose studies, soluble (monomeric) and insoluble (polymeric) forms of Z-AAT were greatly reduced in the livers of PiZ mice treated with ARC-AAT. In addition, liver globule burden was substantially reduced from baseline levels and in comparison to treatment with saline, which showed progressive globule formation.
The addition of chemical modifications, including UNAs, slowed the rebound in production of AAT compared to canonical siRNAs, and produced a substantially improved duration of effect. In primate studies, knockdown of AAT in serum persisted for over ten weeks with greater than 80 percent knockdown observed at the six-week time point.
"AATD is one of the most common genetically-based orphan diseases," said
The goal of treatment with ARC-AAT is prevention and possibly reversal of Z-AAT accumulation-related liver injury and fibrosis. Reduction of inflammatory Z-AAT protein, which has been clearly defined as the cause of progressive liver disease in AATD patients, is important as it is expected to halt the progression of liver disease and allow fibrotic tissue repair.
The Company anticipates that initial testing will be in adult patients with signs of liver injury, with the intention of preventing additional injury and improving liver histology. In the future, additional studies may be initiated to investigate treatment of children, including those with severe hepatic disease who may otherwise require liver transplant.
Arrowhead also announced that it has signed an agreement with
"On behalf of the Alpha-1 community, I am delighted to see this
collaboration between TAP and Arrowhead," said
About Alpha-1 Antitrypsin Deficiency (AATD)
AATD is an autosomal recessive genetic disorder associated with liver disease in children and adults and pulmonary disease in adults. Alpha-1 antitrypsin is a circulating glycoprotein protease inhibitor of the serpin family encoded by the AAT gene and primarily synthesized in the liver. The physiologic function is inhibition of neutrophil proteases to protect healthy tissues during inflammation and prevent tissue damage. The Z mutant is the most common disease variant and has a single amino acid substitution that results in improper protein folding causing severe impairment of secretion from hepatocytes. This lack of secretion leads to accumulation of mutant Z-AAT polymers, which form globules in the hepatocyte endoplasmic reticulum. This triggers continuous hepatocyte injury, leading to fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma.
In clinical practice, approximately 96-98% of AATD-related disease is due to the homozygous PiZZ genotype. PiZZ individuals have severe deficiency of functional AAT leading to pulmonary disease and hepatocyte injury and liver disease. Lung disease is frequently treated with AAT augmentation therapy. However, augmentation therapy does nothing to treat liver disease, and there is no specific therapy for hepatic manifestations. There is a significant unmet need as liver transplant is currently the only available cure.
The mean estimated prevalence of AATD in the U.S is 1 per 3000-5000, or approximately 100,000 patients. AATD is also an important cause of pediatric liver disease with an estimated prevalence in children of approximately 20,000 patients, and 50-80% likely to manifest liver disease during childhood. It is considered to be a relatively high prevalence orphan disease, and it is frequently misdiagnosed or undiagnosed. European prevalence is estimated to be 1 per 2500.
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