(41) Olezarsen and plozasiran in the treatment of familial chylomicronemia syndrome (FCS): Results from a matching-adjusted indirect comparison (MAIC)

Background: : FCS is a rare genetic form of primary hypertriglyceridemia with an increased risk of acute pancreatitis (AP). Alongside strict adherence to an extremely low-fat diet, emerging data support apolipoproteinC-III (apoC-III) inhibitors olezarsen and plozasiran as therapeutic approaches to reduce triglycerides (TG).

Objective: : To compare the efficacy and safety of olezarsen 80 mg to plozasiran 25 mg in the BALANCE and PALISADE phase 3 studies, respectively.

Methods: : Indirect treatment comparisons were made using an anchored MAIC to account for cross-trial differences, weighting BALANCE’s individual patient level data to match published baseline characteristics in PALISADE. Matching variables included fasting TG and variables that showed significant (p < 0.2) treatment-by-covariate interaction in BALANCE, indicating treatment effect modification, assessed per study outcome. Risk of AP was compared for olezarsen 50–80 mg and plozasiran 25–50 mg because dose stratified plozasiran data were not publicly available. Sensitivity analyses were conducted using different sets of matching variables to test the robustness of the results.

Results: : The MAIC included 22 patients receiving olezarsen 80 mg and 23 patients receiving placebo in BALANCE, and 26 patients receiving plozasiran 25 mg and 25 patients receiving placebo in PALISADE. Both trials enrolled patients with a fasting TG ≥880 mg/dL, and PALISADE enrolled clinically diagnosed in addition to genetically confirmed FCS patients. After weighting, patient characteristics were nearly identical between BALANCE and PALISADE, and BALANCE had an effective sample size (ESS) of 29.2–63.3 depending on the outcome.

At 52 weeks, olezarsen was associated with improvement in fasting TG (mean difference [MD]: −15.51%; 95% confidence interval [CI]: −76.21, 45.20; ESS: 29.2), apoC-III (MD: −8.36%; 95% CI: −69.71, 53.00; ESS: 31.6), and non-high-density-lipoprotein cholesterol (−16.26%; 95% CI: −77.63, 45.11; ESS: 30.2), however these differences were not statistically significant. Olezarsen was also associated with 30% lower risk of an AP event (risk ratio [RR]: 0.70; 95% CI: 0.07, 6.66; ESS: 63.3) and 50% lower risk of a serious adverse event (RR: 0.50; 95% CI: 0.10, 2.58; ESS: 42.8); results non-statistically significant. Results from sensitivity analyses were similar to the base case.

Conclusions: : Based on an MAIC, olezarsen was associated with non-statistically significant improvement in efficacy and safety at 52 weeks compared to plozasiran in the treatment of patients with FCS.

Sponsorship:: Ionis Pharmaceuticals Inc.