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

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 recognized and

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

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 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

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.

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 @ArrowRes.

To be added to the Company’s email list to receive news directly, please

send an email to ir@arrowres.com.

Safe Harbor Statement under the Private Securities Litigation Reform

Act:

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

our business, results of operations and financial condition. We assume

no obligation to update or revise forward-looking statements to reflect

new events or circumstances.

Arrowhead Research Corporation
Vince Anzalone, CFA
626-304-3400
ir@arrowres.com
or
The

Alpha-1 Project, Inc.
Jean-Marc Quach
Executive Director
888-920-0002
jmquach@thealpha-1project.com
or
Investor

Relations:
The Trout Group
Lauren Glaser
646-378-2972
ir@arrowres.com
or
Media:
Russo

Partners
Martina Schwarzkopf, Ph.D.
212-845-4292
martina.schwarzkopf@russopartnersllc.com

Source: Arrowhead Research Corporation

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