Differential Effects of Volanesorsen on ApoC-III, Triglycerides and Pancreatitis in Familial Chylomicronemia Syndrome Diagnosed by Genetic or Non-genetic Criteria

Background: Familial chylomicronemia syndrome (FCS) is diagnosed by genetic or non-genetic criteria.

Objective: To assess responses to treatment of apolipoprotein (apo)C-III, triglycerides, and pancreatitis events in patients with FCS-based diagnostic methods.

Methods: APPROACH enrolled 66 patients with FCS randomized to volanesorsen or placebo for 12 months. In 50 participants, genetic confirmation of FCS was based on the presence of pathogenic bi-allelic variants in LPL, APOC2, APOA5, GPIHBP1, or LMF1 genes. In 16 participants without a genetic diagnosis, FCS was diagnosed using clinical criteria and post-heparin lipoprotein lipase activity ≤20 % of normal. Plasma levels of apoC-III, triglycerides and related variables were measured at 3, 6 and 12 months.

Results: No significant differences were present in mean apoC-III reductions with volanesorsen at 3, 6 or 12 months in patients with FCS diagnosed either genetically or non-genetically. In contrast, the triglyceride reductions were statistically less robust in patients with genetic diagnosis at each timepoint, with mean (95 % confidence interval) percent reduction in triglycerides of -68.7 % (-78.7, -58.6) vs. -84.0 % (-99.4, -68.6), p = 0.014 at Month 3; -58.2 % (-78.1, -38.2) vs. -84.5 % (-122.4, -46.7), p = 0.009 at Month 6; and -35.6 % (-57.7, -13.4) vs. -69.0 % (-105.0, -33.1), p = 0.005 at Month 12. Patients with a genetic diagnosis had significantly lower response rates for achieved triglycerides <500 mg/dL, <750 mg/dL, <880 mg/dL and <1000 mg/dL than patients with a non-genetic diagnosis. All 5 episodes of acute pancreatitis occurred in patients with a genetic diagnosis.

Conclusions: For a similar reduction in apoC-III in response to volanesorsen, triglyceride reduction is attenuated in patients with genetically versus non-genetically diagnosed FCS.