Arrowhead Pharmaceuticals Hosts R&D Day on Pipeline of RNAi Therapeutics
Presentations will begin at
Select R&D Day Highlights
ARO-APOC3
ARO-APOC3 is designed to reduce production of Apolipoprotein C-III
(apoC-III), a component of triglyceride rich lipoproteins (TRLs)
including very low density lipoprotein (VLDL) and chylomicrons and is a
key regulator of triglyceride metabolism. The company believes that
knocking down the hepatic production of apoC-III may result in enhanced
triglyceride metabolism and clearance of VLDL and chylomicron remnants.
Elevated triglyceride levels are an independent risk factor for
cardiovascular disease. Severely elevated triglycerides (often over
2,000 mg/dL) in patients with familial chylomicronemia syndrome (FCS), a
rare genetic disorder, can result in potentially fatal, acute
pancreatitis. Arrowhead has conducted work in multiple preclinical
models, including in transgenic mice, cynomolgus monkeys (cynos), and
high fructose fed rhesus monkeys that suggest ARO-APOC3 strongly reduces
the liver production of apoC-III and has a desired effect on serum
triglyceride levels. The company will present additional data, including
liver biopsy measurements in cynos, in an oral presentation at the
ARO-ANG3
ARO-ANG3 is designed to reduce production of angiopoietin-like protein 3
(ANGPTL3), a liver synthesized inhibitor of lipoprotein lipase and
endothelial lipase. ARO-ANG3 is being developed for the treatment of
dyslipidemias and metabolic diseases. ANGPTL3 inhibition has been shown
to lower serum LDL, serum and liver triglyceride and has genetic
validation as a novel target for cardiovascular disease. In multiple
animal models, ARO-ANG3 led to deep ANGPTL3 knockdown in both Western
diet or chow-fed mice and significant improvements in lipid parameters.
A CTA was recently filed to begin AROANG1001, a Phase 1 single and
multiple dose study to evaluate the safety, tolerability,
pharmacokinetics, and pharmacodynamic effect of ARO-ANG3 in adult
healthy volunteers and dyslipidemic patients. The study is designed to
enroll up to 70 subjects. Arrowhead will also present additional data at
the AHA meeting on
Targeted RNAi Molecule Platform (TRiM™)
Arrowhead’s Targeted RNAi Molecule platform, or TRiM™, utilizes ligand-mediated delivery and is designed to enable multi-tissue targeting, while being structurally simple. TRiM™ represents an evolution in RNAi therapeutics from biologic complexity to small molecule precision and execution. It was designed to optimize potency, activity, durability, and safety. Important differentiators of the TRiM™ platform include:
-
TRiM™ platform demonstrates versatility for both hepatic and
extrahepatic targets
- Potency, activity, durability and safety
- Speed and high success rates
-
Hepatocyte targets
- Expertise in RNAi chemistry and biology
- We have yet to encounter a hepatocyte gene that we could not knock down effectively and with a wide therapeutic index
-
Extrahepatic targets
- Requires all TRiM™ platform modules to be fully optimized
- Expertise in uncovering ligand/receptor pairs
- Expertise in ligand designs to enable maximal uptake through endocytosis
- Successful extrahepatic, systemic delivery of RNAi triggers via IV and subcutaneous administrations in ccRCC
- Expanding extrahepatic capabilities to now include delivery to the lung, tumor, and muscle tissue
ARO-ENaC Gen 1
ARO-ENaC is designed to reduce production of the epithelial sodium channel alpha subunit (αENaC) in the airways of the lung. In cystic fibrosis patients, increased ENaC activity contributes to airway dehydration and reduced mucociliary transport. ENaC inhibitors promise a genotype-agnostic therapeutic approach for potentially all CF patients, including those with Class I mutations that produce no CFTR protein. Inhaled small molecule inhibitors transiently improve lung mucociliary clearance, but they are rapidly absorbed and systemic exposure results in renal ENaC inhibition and hyperkalemia. Inhalation of aerosolized ARO-ENaC Gen 1 selectively and durably silences ENaC mRNA expression in the rat lung while sparing the kidney. In addition, improved mucociliary clearance was observed in sheep two weeks after inhalation of aerosolized ARO-ENaC Gen 1. Work on a next-generation ARO-ENaC is focused on further increasing potency to produce in vivo clearance increases similar to short-acting small molecule ENaC inhibitors. A CTA is planned for ARO-ENaC in 2019. The platform may also be adapted to additional therapeutic targets in the pulmonary epithelium, particularly those that are currently inaccessible to traditional small molecule or antibody approaches.
ARO-HIF2
ARO-HIF2 is designed to inhibit the production of HIF2α, which has been
linked to tumor progression and metastasis, for the treatment of clear
cell renal cell carcinoma (ccRCC). Arrowhead believes it is an
attractive target for intervention because most ccRCC tumors express a
mutant form of the Von Hippel-Landau protein that is unable to degrade
HIF-2α, leading to its accumulation during tumor hypoxia and promoting
tumor growth. ARO-HIF2 has demonstrated effective tumor delivery and
deep HIF2α mRNA knockdown in tumors. In addition, ARO-HIF2 led to
inhibition of tumor growth and improved overall survival in tumor
models. Initial rat exploratory toxicity studies predict that ARO-HIF2
may have a wide safety margin. Additional data is planned to be
presented as a late-breaking poster at the EORTC/AACR/NCI symposium
being held
About
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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 the safety and efficacy of our product candidates, the duration and impact of regulatory delays in our clinical programs, our ability to finance our operations, the likelihood and timing of the receipt of future milestone and licensing fees, the future success of our scientific studies, our ability to successfully develop and commercialize drug candidates, the timing for starting and completing clinical trials, rapid technological change in our markets, and the enforcement of our intellectual property rights. Our most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q discuss some of the important risk factors that may affect our business, results of operations and financial condition. We assume no obligation to update or revise forward-looking statements to reflect new events or circumstances.
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Source:
Arrowhead Pharmaceuticals, Inc.
Vince Anzalone, CFA
626-304-3400
ir@arrowheadpharma.com
or
Investors
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Brian Ritchie
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