Arrowhead Pharmaceuticals Corp (ARWR) Reports First Patient Dosing in Phase 1 Study of ARO-ANG3 for Treatment of Dyslipidemias and Metabolic Diseases

January 7, 2019 7:31 AM

Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) today announced that it has dosed the first subjects in a Phase 1 clinical study of ARO-ANG3, an RNAi-based investigational medicine targeting angiopoietin like protein 3 (ANGPTL3) being developed for the treatment of dyslipidemias and metabolic diseases.

Bruce Given, M.D., chief operating officer and head of R&D at Arrowhead, said: “We continue to advance our broad pipeline of RNAi therapeutics with the dosing of the first subjects in our Phase 1 study of ARO-ANG3. ANGPTL3 has emerged as a potentially important target to address dyslipidemias, such as elevated cholesterol and triglycerides that are not well-controlled with currently available medicines, and also metabolic diseases, such as NAFLD and NASH. The preclinical data for ARO-ANG3 have been promising, and our prior clinical results from the ARO-HBV and ARO-AAT programs, which also leverage the Targeted RNAi Molecule, or TRiMTM, platform, give us confidence in the potential for ARO-ANG3 to address significant unmet medical needs.”

AROANG1001 (NCT03747224) is a Phase 1 single and multiple dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ARO-ANG3 in adult healthy volunteers and patients with dyslipidemia. The study is designed to enroll up to 70 subjects.

The single-ascending dose (SAD) portion of the study is designed to include up to 4 cohorts of 10 adult healthy volunteers per cohort (6 active: 4 placebo). Each SAD subject will receive a single-dose administration of either placebo or ARO-ANG3 at dose levels of 35, 100, 200, or 300 mg. The multiple-dose portion is designed to include up to 4 patient cohorts, including patients with non-alcoholic fatty liver disease (NAFLD), patients on a stable statin treatment regimen with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides, patients with heterozygous or homozygous familial hypercholesterolemia, and patients with severe hypertriglyceridemia.

Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (Kersten, 2017). While the current standard of care is effective at lowering LDL-C, a large unmet medical need for lipid lowering and risk modifying therapies with novel mechanisms of action persists. Hypertriglyceridemia and elevations in triglyceride-rich lipoproteins represent causative risks for atherosclerosis, and elevated triglycerides also manifest in the form of metabolic syndrome, pancreatitis and hepatic steatosis. Metabolic syndrome is a complex of interrelated risk factors for cardiovascular disease and type II diabetes mellitus.

ANGPTL3 has emerged as an important regulator of plasma lipoprotein levels (including triglycerides, LDL-C, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol) by inhibition of enzymes including lipoprotein lipase and endothelial lipase. ANGPTL3 may also be involved in regulating apolipoprotein B particle containing synthesis and hepatocyte clearance of LDL-C through mechanisms independent of the low-density lipoprotein receptor (LDLR) (Xu et al., 2018). This LDLR-independent feature makes ANGPTL3 inhibition potentially applicable as a therapeutic for LDLR-deficient hypercholesterolemic patients.

Intrahepatic targeting of ANGPTL3 may also improve hepatic steatosis which can progress to nonalcoholic steatohepatitis (NASH). Additionally, human genetic studies indicate that ANGPTL3-deficient homozygotes show lower serum insulin, lower serum glucose, and improved measures of insulin resistance compared to non-carriers (Robciuc et al., 2013).

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