Arrowhead Completes Dosing Healthy Volunteers and Initiates Transition to Patients in Phase 1 Study of ARC-AAT
May 05 2015 - 7:30AM
Business Wire
Arrowhead Research Corporation (NASDAQ: ARWR), a
biopharmaceutical company developing targeted RNAi therapeutics,
today announced that it completed dosing healthy volunteers and
will begin dosing patients in an on-going phase 1 study of ARC-AAT,
the Company’s clinical candidate for the treatment of liver disease
associated with Alpha-1 Antitrypsin Deficiency (AATD). AATD is a
rare genetic disorder that can severely damage the liver and lungs
of affected individuals. The study was designed to begin dose
escalation in healthy volunteers (Part A) and transition into
patients (Part B) when a predefined knockdown target is achieved.
That target is at least 30% reduction of serum AAT levels in 3
subjects or greater than 60% reduction in a single subject. This
was met during the third cohort. All three dose levels tested
appear to be generally well tolerated and the data safety committee
has cleared the study to move into patients with AATD. Dosing in
patients may now begin at the highest dose level used in Part A and
then continued dose escalation may proceed under the protocol. The
company expects to complete the Phase 1 study by the end of
2015.
"We are excited that Part A of the phase 1 study is complete and
that we can now begin studying ARC-AAT directly in patients with
PiZZ genotype AATD,” said Bruce D. Given, M.D., Arrowhead’s Chief
Operating Officer. “The lung disease associated with AATD is
frequently treated with AAT augmentation therapy. However, there is
a great need in the field to identify new treatment options for the
AATD-related liver disease. Currently, the only option for severe
cases is liver transplant, with all of its attendant risks and
availability issues. We think ARC-AAT is a very promising program
that may potentially provide a better option for patients and
physicians.”
ARC-AAT is comprised of novel unlocked nucleobase analog
containing RNAi trigger molecules (UNA) that are co-administered
with Dynamic Polyconjugates (DPCs) to enable the escape of the UNA
from endosomes. The ratio of UNA to DPC is 2:1 by weight. In Part A
of the study, three cohorts of six participants each received
ARC-AAT at doses of 0.38 mg/kg, 1.0 mg/kg, and 2.0 mg/kg of UNA,
and 0.19 mg/kg, 0.5 mg/kg, and 1.0 mg/kg of DPC, respectively.
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 and
pharmacokinetics of ARC-AAT and the effect on circulating AAT
levels. The study has been enrolling 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 consists of
two parts; Part A in healthy volunteers, which has been completed,
and Part B to be conducted in patients with PiZZ genotype AATD. The
study evaluates participants for 28 days following dosing, with
additional follow-up if needed every 2 weeks until AAT levels
return to baseline.
“The Alpha-1 Foundation and the entire Alpha-1 community are
excited to see this program move forward,” said John Walsh,
president and chief executive officer of the Alpha-1 Foundation.
“We and The Alpha-1 Project, the Foundation’s venture philanthropy
arm, will continue to work closely with Arrowhead on clinical trial
recruitment and provide additional assistance to get this
potentially life saving therapy to 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 treatment for severe liver manifestations.
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 an orphan
disease that appears to be frequently misdiagnosed or undiagnosed.
European prevalence is estimated to be 1 per 2500.
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 is likely a
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 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 and ARC-AAT for
liver disease associated with Alpha-1 antitrypsin deficiency.
For more information please visit
http://www.arrowheadresearch.com, or follow us on Twitter
@ArrowRes. To be added to the Company's email list and receive news
directly, please visit
http://ir.arrowheadresearch.com/alerts.cfm.
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
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Corporation's most recent Annual Report on Form 10-K and subsequent
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Source: Arrowhead Research Corporation
Arrowhead Research CorporationVince Anzalone,
CFA626-304-3400ir@arrowres.comorInvestor Relations:The Trout
GroupTodd James, 646-378-2926ir@arrowres.comorMedia:Russo
PartnersMatt Middleman,
M.D.212-845-4272matt.middleman@russopartnersllc.com
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