Efficacy, Safety and Tolerability of ISIS 304801 in People With Partial Lipodystrophy With an Open-Label Extension

Background: Lipodystrophy is a rare disease of deficient adipose mass, characterized by severe hypertriglyceridemia as well as insulin resistance, diabetes mellitus, fatty liver disease, acute pancreatitis, and early cardiovascular events. Apolipoprotein C-III (apoC-III) regulates triglyceride metabolism, and apoC-III levels strongly correlate with serum triglycerides in a variety of patient populations. Patients with genetically low levels of apoC-III have lower triglycerides and reduced cardiovascular disease, while individuals with genetically elevated levels of apoC-III have higher triglycerides and increased non-alcoholic fatty liver disease and insulin resistance. Pharmacologic reduction of apoC-III using anti-sense oligonucleotides (ASOs) reduce triglycerides by \~60-70% in a tested patient populations. Aim: The purpose of this study is to determine if apoC-III reduction using an ASO to apoC-III (ISIS 304801) will reduce triglycerides and improve insulin resistance, diabetes, and hepatic steatosis in patients with lipodystrophy. The primary hypothesis to be tested is: 1. ISIS 304801will reduce log10 fasting serum triglycerides. Secondary and tertiary hypotheses to be tested are: 2. ISIS 304801will improve glucose metabolism by improving insulin resistance. 3. ISIS 304801 will reduce hepatic steatosis. 4. ISIS 304801 will improve cardiovascular risk markers. We will also explore the mechanism of action of apoC-III ASO by studying lipoprotein lipase activity and lipoprotein particle distribution. Methods: This study will enroll up to 20 patients with partial lipodystrophy with a goal of 10 study completers. The study will be conducted in two phases. The first is a 16-week, randomized, double-blind, placebo-controlled design. Subjects will be treated with ISIS 304801 at a target dose of 300 mg per week or placebo. Following this phase, all subjects will enter a 12 month open-label extension in which they will receive active drug. Patients who experience benefit (triglyceride lowering greater than or equal to 50%) may receive an additional 12 months of open-label drug (up to 24 months, total). Measurement of the primary outcome (serum triglycerides) and key secondary outcomes will be performed at baseline prior to the intervention, after 13 weeks (primary outcome only) or 16 weeks (primary and secondary outcomes) of blinded drug or placebo, and after an additional 4 months of active drug in subjects initially randomized to placebo.