|[June 19, 2014]
Arrowhead Announces New Clinical Candidate ARC-AAT for Treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
PASADENA, Calif. --(Business Wire)--
Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical
company developing targeted RNAi therapeutics, today announced its next
clinical candidate ARC-AAT, an RNAi therapeutic designed to treat liver
disease associated with Alpha-1 antitrypsin deficiency (AATD). The
Company is hosting an analyst day today to discuss ARC-AAT and will
present preclinical data starting at 12:30 p.m. EDT. A live webcast of
the presentation and archive are available on the Company's website at www.arrowheadresearch.com.
To access an audio only live presentation, dial 844-825-4406 toll free
from the U.S. or 315-625-3230 for international callers and enter
Conference ID 54600551.
A panel of key opinion leaders will join Arrowhead management for the
presentation today. Included in the panel are: Jeffrey Teckman, M.D.,
professor of pediatrics and biochemistry and molecular biology, and
director, division of gastroenterology and hepatology, department of
pediatrics, St. Louis University School of Medicine; John Walsh,
co-founder, president and CEO, Alpha-1 Foundation; and, Jean-Marc Quach,
executive director, The Alpha-1 Project.
"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 Christopher Anzalone, Ph.D.,
Arrowhead's president and chief executive officer. "ARC-AAT is designed
to inhibit the production of mutant AAT protein in the liver and in
preclinical studies it has shown high levels of knockdown with long
duration of action. AATD patients express mutant AAT, which can
accumulate in hepatocytes and damage the liver. Liver disease associated
with Alpha-1 antitrypsin deficiency has no current treatment options and
patients can progress to cirrhosis, hepatocellular carcinoma, and may
require liver transplant."
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
Bruce Given, M.D., Arrowhead's chief operating officer. "In the absence
of specific therapy other than liver transplant, the liver disease goes
largely undiagnosed. As the lung disease is better recognizedand
treated, leading to longer life spans, the liver disease associated with
AATD is becoming a larger clinical problem, for which we believe RNAi
holds great potential."
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
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 The
Alpha-1 Project (TAP), the venture philanthropy subsidiary of the
Alpha-1 Foundation. TAP's mission is to support organizations in pursuit
of cures and therapies for lung and liver disease caused by Alpha-1
Antitrypsin Deficiency. Under the terms of the agreement, TAP will
partially fund the development of ARC-AAT. In addition to the funding,
TAP will make its scientific advisors available to Arrowhead, assist
with patient recruitment for clinical trials thanks to the Alpha-1
Foundation Patient Research Registry, and engage in other collaborative
efforts that support the development of ARC-AAT.
"On behalf of the Alpha-1 community, I am delighted to see this
collaboration between TAP and Arrowhead," said John Walsh, president and
CEO of the Alpha-1 Foundation. "This is an exciting effort to develop a
therapy that could provide a sorely-needed treatment for both adults and
children with liver disease due to Alpha-1."
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
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.
About The Alpha-1 Project
Mission statement: The Alpha-1 Project will work with patients,
academia, pharmaceutical and biotech companies, and public health
organizations in the relentless pursuit of cures and therapies for COPD
and liver disease caused by Alpha-1 Antitrypsin Deficiency. For more
information, visit www.thealpha-1project.com.
The Alpha-1 Project is a wholly-owned for-profit subsidiary of the
Alpha-1 Foundation. For more information on the Foundation, visit www.alpha-1foundation.org.
About Arrowhead Research Corporation
Arrowhead Research Corporation is a biopharmaceutical company developing
targeted RNAi therapeutics. The company is leveraging its proprietary
drug delivery technologies to develop targeted drugs based on the RNA
interference mechanism that efficiently silences disease-causing genes.
Arrowhead technologies also enable partners to create peptide-drug
conjugates that specifically home to cell types of interest while
sparing off-target tissues. Arrowhead's pipeline includes clinical
programs in chronic hepatitis B virus and partner-based programs in
obesity and oncology.
For more information please visit http://www.arrowheadresearch.com,
or follow us on Twitter (News - Alert) @ArrowRes.
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This news release contains forward-looking statements within the
meaning of the "safe harbor" provisions of the Private Securities
Litigation Reform Act of 1995. These statements are based upon our
current expectations and speak only as of the date hereof. Our actual
results may differ materially and adversely from those expressed in any
forward-looking statements as a result of various factors and
uncertainties, including our ability to finance our operations, the
future success of our scientific studies, our ability to successfully
develop drug candidates, the timing for starting and completing clinical
trials, rapid technological change in our markets, and the enforcement
of our intellectual property rights. Arrowhead Research Corporation's
most recent Annual Report on Form 10-K and subsequent Quarterly Reports
on Form 10-Q discuss some of the important risk factors that may affect
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