11 March 2019 - - US-based Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) has dosed the first subjects in a Phase 1 clinical study of ARO-APOC3, an RNAi-based investigational medicine targeting Apolipoprotein C-III (apoC-III) being developed for the treatment of hypertriglyceridemia, the company said.

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 is designed to include 4 cohorts of 10 adult healthy volunteers with elevated triglycerides.

Each SAD subject will receive a single-dose administration of either placebo or ARO-APOC3 at dose levels of 25, 50, 100, or 200 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.

ApoC-III has emerged as a therapeutic target for triglyceride reduction. ApoC-III regulates triglyceride-rich lipoproteins and is a known inhibitor of lipoprotein lipase activity and LPL-mediated lipolysis of TRLs. ApoC-III also delays the clearance of lipoprotein remnants by the liver by inhibiting hepatocyte receptor-mediated uptake.

Human genetic studies indicate that people with apoC-III loss-of-function mutations show reduced risk for cardiovascular disease, with reductions in plasma triglycerides levels, while appearing to be phenotypically normal.

FCS is a severe rare genetic disease, with a prevalence of 1 in 1,000,000, and is often caused by single gene mutations that lead to extremely high triglyceride levels, typically over 900 mg/dL, representing the top 0.1% of triglyceride values measured.

Such severe elevations lead to various serious signs and symptoms, including acute pancreatitis, which can be fatal, chronic daily abdominal pain, type II diabetes mellitus, hepatic steatosis, and cognitive issues.

There is no currently available therapy that can adequately treat FCS.

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.