Arrowhead Presents Data on Potential RNAi Candidate Targeting Factor 12 Mediated Angioedemic and Thromboembolic Diseases
PASADENA, Calif.–(BUSINESS WIRE)–
Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical
company developing targeted RNAi therapeutics, today presented data at
IBC’s 17th Annual TIDES Conference in San Diego on the
preclinical development of an RNAi therapeutic as a potential treatment
for factor 12 (F12) mediated angioedemic and thromboembolic diseases.
The presentation included data from in vitro screenings, in vivo
evaluations, a disease model, and a multiple dose study in nonhuman
primates. These data support advancement of ARC-F12 as a potential new
candidate in Arrowhead’s growing pipeline of RNAi-based therapeutics
enabled by the company’s Dynamic Polyconjugate (DPC) delivery platform.
A copy of the presentation may be viewed on the Events and Presentations
section of the company’s website at http://ir.arrowheadresearch.com/events.cfm.
“We see factor 12 as an extremely attractive target to add to our
pipeline. There is clear unmet need in thrombosis and angioedema and 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,” said Christopher Anzalone,
Ph.D., president and chief executive officer. “We will be conducting
additional studies in relevant disease models shortly to provide us with
further data to decide on the advancement of ARC-F12 as a clinical
candidate and initiation of IND enabling studies.”
David Lewis, Ph.D., chief scientific officer, presented initial data
from wild type mice, showing that various RNAi triggers selected from in
vitro screening sets and co-administered with DPCs achieved significant
and sustained knockdown of F12 levels of greater than 99% at nadir for
most triggers. Strategic incorporation of various modifications to the
most potent RNAi trigger increased the depth and duration of F12
knockdown activity as shown in dose response studies. In a study in
mice, these modified triggers exhibited a dose-dependent increase in F12
knockdown. A single intravenous dose of 0.5 mg/kg reduced F12 by greater
than 80%. When the dose was increased to 2 mg/kg, the reduction
increased to greater than 95% at nadir, with greater than 70% knockdown
observed at the one month time point. The lead RNAi trigger was also
highly active in multiple dose nonhuman primate studies. With four
intravenous doses of 2 mg/kg given once every four weeks, approximately
90% F12 knockdown was achieved after the first dose with even greater
knockdown following subsequent doses. Knockdown was also highly durable
with greater than 80% reduction maintained between monthly doses. The
combination of RNAi trigger and DPC appeared to be generally
well-tolerated and no drug-related changes in toxicity markers were
observed as measured by clinical chemistry and hematologic parameters.
Dr. Lewis also presented data from a relevant disease model on the lead
RNAi trigger and DPC combination. In this mouse model, thromboembolism
is induced by exposure of carotid artery to ferric chloride. The time to
blood flow occlusion is then measured as a clinically relevant indicator
of physiological response to F12 knockdown. Animals were treated with
saline or the lead RNAi trigger and DPC combination 15 days prior to
ferric chloride challenge. Treated animals showed approximately 99%
knockdown in serum F12 levels at Day 15 relative to baseline, while
animals receiving saline showed no reduction. A dramatic increase in
occlusion times as a measure of the inhibition of thrombus formation was
observed in treated mice.
Arrowhead believes that ARC-F12 may present opportunities to target
multiple diseases, including in thrombosis. The company is currently
planning to investigate ARC-F12 in hereditary angioedema (HAE) as the
first target indication. HAE is a rare genetic disorder with a
prevalence of approximately 1/5,000-1/10,000 that is most commonly
caused by mutations in the complement factor 1 esterase inhibitor gene
(C1INH). Patients with HAE can experience recurrent and dangerous acute
inflammatory attacks in multiple tissues, with attacks of laryngeal
edema being particularly serious and potentially fatal. Current
treatments seek to reduce the severity, duration, and frequency of acute
HAE attacks, but frequent intravenous dosing of 1-3 times weekly is
required and many patients do not respond adequately. Arrowhead believes
the novel mechanism of ARC-F12 may fill an unmet need for patients and
physicians who desire long term prophylaxis and may view intravenous
dosing every 4-6 weeks as a significant advance.
The company is currently planning additional evaluation of ARC-F12 in
relevant HAE disease models including C1INH knockout animals and
captopril-induced vascular leak, among potential other studies to
support advancement of ARC-F12 into IND enabling studies.
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,
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Source: Arrowhead Research Corporation
Arrowhead Research Corporation
Vince Anzalone, CFA
626-304-3400
ir@arrowres.com
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