18 September 2019 - - US-based Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) has presented initial top-line clinical data at The Global Summit on Cardiology and Heart Diseases, being held in Dubai, UAE, the company said.

According to Arrowhead, the data demonstrate that, in two Phase I single-dose clinical studies in healthy volunteers, ARO-APOC3 reduced plasma Apolipoprotein C-III (apoC-III) and ARO-ANG3 reduced plasma angiopoietin like protein 3 (ANGPTL3), and both candidates reduced triglycerides without drug-related serious or severe adverse events.

These initial clinical data also indicate that ARO-APOC3 and ARO-ANG3 administration led to a long duration of effect that potentially enables once every three-month or once every six-month dosing intervals.

Top-line data from a single dose of 100 mg of ARO-APOC3 in healthy volunteers demonstrated mean maximal reductions of plasma triglycerides of 63% and APOC3 protein of 94% without serious or severe adverse events.

The most common adverse events observed to date, all mild or moderate, have been headache, upper respiratory infection and mild injection site findings.

Top-line data from a single dose of 200 mg of ARO-ANG3 in healthy volunteers demonstrated mean maximal reductions of plasma triglycerides of 66% and ANGPTL3 protein of 79% without drug-related serious or severe adverse events.

The most common adverse events seen to date, all mild or moderate, have been headache and upper respiratory infection.

ARO-ANG3 reduced triglycerides and LDL-C in LDL receptor knockout mice.

ARO-ANG3 also ameliorates steatosis and improves insulin sensitivity in diet-induced obese mice.

In mouse studies, ANGPTL3 has shown endocrine effects on triglyceride and LDL-C metabolism and apparent autocrine effects on hepatic steatosis and insulin sensitivity.

Published research also indicates that APOC3 and ANGPTL3 are strong potential targets for addressing cardiovascular disease.

Genetic studies indicate that plasma triglycerides are an independent risk factor for cardiovascular disease

Loss of function mutations of APOC3 or ANGPTL3 are associated with markedly reduced triglycerides and other lipid parameters without reported adverse phenotype.

AROAPOC31001 (NCT03783377) is a Phase 1 single and multiple dose-escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ARO-APOC3 in adult healthy volunteers, hypertriglyceridemic patients, and patients with FCS.

The study is designed to enroll up to 63 subjects.

The single-ascending dose portion of the study included 4 cohorts of 10 adult healthy volunteers with (6 active: 4 placebo).

Each SAD subject received a single-dose administration of either placebo or ARO-APOC3 at dose levels of 10, 25, 50, or 100 mg.

The multiple-dose portion is designed to include 3 cohorts of patients with severe hypertriglyceridemia and 1 cohort of patients with FCS. The multiple-dose cohorts will receive two monthly doses of ARO-APOC3.

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 82 subjects.

The SAD portion of the study included 4 cohorts of 10 adult healthy volunteers per cohort (6 active: 4 placebo).

Each SAD subject received 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 healthy volunteers, 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.

Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them.

Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes.

RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein.

Arrowhead's RNAi-based therapeutics leverage this natural pathway of gene silencing.