6503 A Randomized, Placebo-Controlled Phase 3 Study of Olezarsen In Patients With Familial Chylomicronemia Syndrome: The Balance Trial

Abstract Disclosure: E.S. Stroes: Advisory Board Member; Self; Amgen Inc, Sanofi, Novartis Pharmaceuticals, AstraZeneca, Novo Nordisk, Ionis Pharmaceuticals Inc., Merck, Daiichi Sankyo. Grant Recipient; Self; Ionis Pharmaceuticals Inc., Novo Nordisk, Novartis Pharmaceuticals, Sanofi. V. Alexander: Employee; Self; Ionis Pharmaceuticals Inc. E. Prokopczuk: Employee; Self; Ionis Pharmaceuticals Inc. R.A. Hegele: Consulting Fee; Self; Aegerion Pharmaceuticals, Ionis Pharmaceuticals Inc., Amgen Inc, Novartis Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Sanofi, Ultragenyx, Acasti, and HLS Therapeutics. M. Arca: Grant Recipient; Self; Amgen Inc, Ionis Pharmaceuticals Inc., Novartis Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Sanofi, Ultragenyx, Daiichi Sankyo, Alfasigma, Amryt, Sobi, and Viatris. C.M. Ballantyne: Consulting Fee; Self; 89Bio, Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma Inc, Merck, New Amster. Grant Recipient; Self; Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, Novartis, Novo Nordisk, Regeneron, Roche Diagnostic, NIH, AHA, ADA. H. Soran: Grant Recipient; Self; Akcea Therapeutics, Alexion, Amryt, Kowa, MSD, NAPP, Novartis, Pfizer, Sanofi, Synageva, and Takeda. T.A. Prohaska: Employee; Self; Ionis Pharmaceuticals Inc. S. Xia: Employee; Self; Ionis Pharmaceuticals Inc. H.N. Ginsberg: Research Investigator; Self; Ionis Pharmaceuticals Inc. J.L. Witztum: Consulting Fee; Self; Ionis Pharmaceuticals Inc. S. Tsimikas: Consulting Fee; Self; Novartis. Employee; Self; Ionis Pharmaceuticals Inc.. Stock Owner; Self; Kleanathi, Oxitope. Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder of lipoprotein lipase deficiency that results in severe hypertriglyceridemia and an increased risk of potentially life-threatening acute pancreatitis (AP). Decreasing high plasma levels of apolipoprotein C-III (apoC-III) reduces hypertriglyceridemia. Olezarsen is an investigational ligand-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to reduce triglycerides (TG). Methods: Balance is a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial in 66 patients with genetically confirmed FCS and fasting TG ≥880 mg/dL at screening. Patients were advised to consume <20g fat/day and randomized 2:1 to olezarsen (50 mg or 80 mg) or placebo sc every 4 weeks for 53 weeks. The two primary endpoints were the placebo-adjusted % change in fasting TG from baseline to 6-months for (1) olezarsen 80 mg and (2) olezarsen 50 mg. Secondary endpoints included change in 12-month TG and apoC-III levels, and incidence of independently adjudicated AP events. Results: At baseline, TG levels were ∼2600 mg/dL and 47/66 (71%) of FCS patients had a history of AP. Placebo-corrected TG levels at 6 months were significantly reduced in olezarsen 80 mg (-43.5%, P=0.0009), and were numerically lower in the olezarsen 50 mg group (-22.4%, P=0.0775). Placebo-corrected TG levels at 12 months were reduced -59.4% in the olezarsen 80 mg group and -43.8% in the olezarsen 50 mg group. ApoC-III levels were reduced in both dose groups at 6 months (olezarsen 50 mg: -65.5%; olezarsen 80 mg: -73.7%) and 12 months (olezarsen 50 mg: -77.1%; olezarsen 80 mg: -81.3%). During 53 weeks of randomized treatment, 11 episodes of AP were observed in 23 patients on placebo versus 2 episodes in 43 olezarsen-treated patients (1 in 50 mg and 1 in 80 mg group). A favorable safety and tolerability profile was noted with more treatment emergent adverse events (TEAEs) and serious TEAEs in the placebo group. No serious TEAEs were related to study drug. Conclusion: In patients with FCS, olezarsen 80 mg significantly reduced TG levels and both olezarsen 50 and 80 mg groups demonstrated a marked reduction in AP events with a favorable safety and tolerability profile. Presentation: 6/1/2024