Arrowhead Presents Promising New Preclinical Data on ARC-F12 at AAAAI 2016
PASADENA, Calif.–(BUSINESS WIRE)–
Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical
company developing targeted RNAi therapeutics, today presented
additional preclinical data suggesting that ARC-F12, an RNAi therapeutic
that inhibits the production of Factor XII (F12), has the potential to
treat hereditary angioedema and to prevent thrombosis. Data presented in
a poster at the 2016 American Academy of Allergy, Asthma & Immunology
Annual Meeting (AAAAI), show that ARC-F12 had the desired effects of
significantly reduced swelling in a rat model of edema and inhibition of
blood clot formation in a mouse model of thrombosis, without the
undesired effect of increased bleeding risk.
In a carrageenan-induced paw edema model in rats, treatment with ARC-F12
seven days prior to carrageenan challenge led to a significant reduction
in edema (p < 0.001). The reduction in swelling in ARC-F12 treated rats is
similar to that seen in rats treated with a kallikrein-targeted
antibody. This supports Arrowhead’s position that F12 inhibition could
be an attractive target for the rare genetic disorder, hereditary
angioedema (HAE).
In a mouse model of thrombosis, a dramatic increase in occlusion times
was observed in mice receiving ARC-F12. The time to blood flow occlusion
is measured as a clinically relevant indicator of physiological response
to F12 knockdown and is a measure of the inhibition of thrombus
formation. Further, in multiple relevant models of bleeding risk,
ARC-F12 did not cause an increase in bleeding times or bleeding risk.
Anticoagulants can be used to reduce thrombus formation and
thromboembolism occurrence, but also can cause an increase in serious
bleeding risk. ARC-F12 may be able to reduce the risk of blood clot
formation, without the undesirable bleeding risk caused by
anticoagulants.
In vivo studies in wild type mice showed that a single 2 mg/kg dose of
ARC-F12 achieved greater than 95% knockdown of F12 levels. In multi-dose
primate studies, a 4 mg/kg dose resulted in greater than 90% knockdown
with even greater knockdown following subsequent doses. Knockdown was
also highly durable with greater than 80% reduction maintained between
monthly doses. ARC-F12 appeared to be generally well-tolerated and no
drug-related changes in toxicity markers were observed as measured by
clinical chemistry and hematologic parameters.
F12 is a key component of the contact activation pathway involved in
thrombosis and the kinin-kallekrein system involved in angioedema. It is
predominantly produced in the liver and circulates in plasma, so
Arrowhead believes that it is a uniquely suited target for an
RNAi-therapeutic delivered with the proprietary Dynamic PolyconjugateTM
(DPCTM) delivery system.
Consistent with its process for all of its RNAi-therapeutic candidates,
Arrowhead’s discovery of ARC-F12 followed a screening funnel process
that includes: bioinformatic selection of RNAi trigger sequences;
trigger synthesis and in vitro screening; synthesis of cholesterol-RNAi
triggers and in vivo screening; multiple iterations of
structure-activity relationship (SAR) studies and in vivo screening to
assess various chemical modifications to improve RNAi trigger activity;
in vivo screening in non-human primates; efficacy testing in disease
relevant models; non-GLP toxicology studies; and lastly, the selection
of a lead candidate.
About ARC-F12
Arrowhead’s RNAi-based candidate ARC-F12 is in preclinical development
as a potential treatment for factor XII (F12) mediated diseases.
Arrowhead sees clear unmet need in hereditary angioedema (HAE) and
thromboembolic diseases. The biology of factor 12 as part of the
coagulation cascade and the kinin-kallikrein system suggest that its
reduction through RNAi may present opportunities in both disease areas.
The company is currently conducting studies in order to advance ARC-F12
into clinical trials.
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 and ARC-521
for chronic hepatitis B virus, ARC-AAT for liver disease associated with
alpha-1 antitrypsin deficiency, ARC-F12 for hereditary angioedema and
thromboembolic diseases, ARC-LPA for cardiovascular disease, and
ARC-HIF2 for renal cell carcinoma.
For more information please visit http://www.arrowheadresearch.com,
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Litigation Reform Act of 1995. These statements are based upon our
current expectations and speak only as of the date hereof. Our actual
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Corporation.
Source: Arrowhead Research Corporation
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Arrowhead Research Corporation
Vince Anzalone, CFA
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