Arrowhead Begins Phase 1 Trial of ARC-AAT for Treatment of Liver Disease Associated with Alpha-1 Antitrypsin Deficiency

PASADENA, Calif.–(BUSINESS WIRE)–

Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical

company developing targeted RNAi therapeutics, today announced that it

has initiated dosing in a Phase 1 clinical trial of ARC-AAT, the

company’s candidate for the treatment of liver disease associated with

Alpha-1 Antitrypsin Deficiency (AATD), a rare genetic disorder that

severely damages the liver and lungs of affected individuals. Trial

initiation followed successful completion of the Clinical Trial

Notification (CTN) regulatory process in Australia. The study will be

conducted in two parts, with Part A in healthy volunteers and Part B in

patients with AATD. The primary objectives of the study are to determine

the safety and tolerability of escalating doses of ARC-AAT, evaluate the

pharmacokinetics, and determine the effect on circulating levels of

alpha-1 antitrypsin. Initial data from this study is expected in late

2015.

Christopher Anzalone, Ph.D., president and chief executive officer of

Arrowhead said, “The ARC-AAT Phase 1 trial is the first human study of

an RNAi therapeutic against liver disease associated with AATD, which

has no current treatment options, short of liver transplant. ARC-AAT is

our second clinical candidate using the DPC delivery system, after

ARC-520 targeting the hepatitis B virus, and it is the first candidate

that targets an endogenous gene to enter human trials. We expect the

Phase 1 study to primarily generate safety and tolerability data, but it

should also give a readout on the depth and duration of activity.”

The Phase 1 trial is a 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. The study plans to enroll

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 will

consist of two parts, with Part A planned to be conducted in healthy

volunteers and Part B planned to be conducted in patients with PiZZ

genotype AATD. In Part A, dose escalation will proceed until the

achievement of certain target knockdown parameters. When these AAT

knockdown parameters are achieved, dose escalation in healthy volunteers

(Part A) is planned to stop and dosing in patients with AATD (Part B) is

planned to begin at the highest dose level used in Part A and then dose

escalation will proceed. We expect participants will be evaluated for 28

days following dosing with additional follow-up every 2 weeks until AAT

levels return to baseline.

“The whole Alpha-1 community is excited to see this landmark clinical

trial begin for Alpha-1 liver disease,” said John Walsh, president and

chief executive officer of the Alpha-1 Foundation. “We’re proud that The

Alpha-1 Project, the Foundation’s venture philanthropy arm, is

collaborating with Arrowhead on the development of this potentially

lifesaving therapy for both adults and children with liver disease due

to Alpha-1.”

ARC-AAT is the second clinical candidate to use Arrowhead’s proprietary

Dynamic Polyconjugate (DPC) delivery platform and includes an optimized

RNAi-trigger design that contains an unlocked nucleobase analog (UNA)

and various chemical modifications that enhance activity and

substantially extend the duration of effect in non-clinical studies.

Arrowhead previously reported data from these studies at an analyst day

the company held in June 2014 and in a plenary presentation at the AASLD

Liver Meeting in November 2014. Injection of ARC-AAT in transgenic mice

expressing the inflammatory human Z-AAT protein resulted in prevention

and reduction of Z-AAT globules and, importantly, liver inflammation. In

primate studies, a 90% reduction of AAT in serum was observed after a

single injection, which persisted for over ten weeks with greater than

80 percent knockdown observed at the six-week time point. Multi-dose

studies in primates showed a sustained reduction of AAT with once every

six weeks dosing. The goal of treatment with ARC-AAT is to reduce the

hepatic production of Z-ATT, thereby preventing further accumulation of

Z-AAT in the liver and potentially reversing pre-existing liver injury

and fibrosis.

About ARC-AAT

Arrowhead’s 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. 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.

Reduction of liver production of the 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 potentially allow fibrotic tissue repair. The Company

is conducting a single dose Phase 1 clinical study, with part A in

healthy volunteers and part B in AATD patients.

About Alpha-1 Antitrypsin Deficiency (AATD)

AATD is a co-dominant 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

dysfunction 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 Arrowhead Research Corporation

Arrowhead Research Corporation is a biopharmaceutical company developing

targeted RNAi therapeutics. The company is leveraging its proprietary

Dynamic Polyconjugate delivery platform to develop targeted drugs based

on the RNA interference mechanism that efficiently silences

disease-causing genes. Arrowhead’s pipeline includes ARC-520 for chronic

hepatitis B virus, ARC-AAT for liver disease associated with Alpha-1

antitrypsin deficiency, and partner-based programs in obesity and

oncology.

For more information please visit http://www.arrowheadresearch.com,

or follow us on Twitter @ArrowRes.

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Source: Arrowhead Research Corporation

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

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