Differential effects of volanesorsen on apoC-III, triglycerides, and pancreatitis in familial chylomicronemia syndrome diagnosed by genetic or nongenetic criteria

Abstract

BACKGROUND

Familial chylomicronemia syndrome (FCS) is diagnosed by genetic or nongenetic 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 postheparin 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 nongenetically. In contrast, the triglyceride reductions were statistically less robust in patients with genetic diagnosis at each timepoint, with mean (95% CI) percent reduction in triglycerides of −68.7% (−78.7, −58.6) vs −84.0% (−99.4, −68.6), P = .014 at Month 3; −58.2% (−78.1, −38.2) vs −84.5% (−122.4, −46.7), P = .009 at Month 6; and −35.6% (−57.7, −13.4) vs. −69.0% (−105.0, −33.1), P = .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 nongenetic diagnosis. All 5 episodes of acute pancreatitis occurred in patients with a genetic diagnosis.

CONCLUSION

For a similar reduction in apoC-III in response to volanesorsen, triglyceride reduction is attenuated in patients with genetically vs nongenetically diagnosed FCS.