Arrowhead Begins Phase 1 Trial of ARC-AAT for Treatment of Liver Disease Associated with Alpha-1 Antitrypsin Deficiency
February 23 2015 - 6:30AM
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.
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This news release contains forward-looking statements within the
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Source: Arrowhead Research Corporation
Arrowhead Research CorporationVince Anzalone,
CFA626-304-3400ir@arrowres.comorInvestor Relations:The Trout
GroupTodd James646-378-2926ir@arrowres.comorMedia:Russo
PartnersMatt Middleman,
M.D.212-845-4272matt.middleman@russopartnersllc.com
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