Rationale and design of the balance study: a randomized, double-blind, placebo-controlled, phase 3 study of olezarsen in patients with familial chylomicronemia syndrome

Abstract Disclosure: V. Alexander: Employee; Self; Ionis Pharmaceuticals Inc. E. Karwatowska-Prokopczuk: Employee; Self; Ionis Pharmaceuticals Inc. E.S. Stroes: Other; Self; Akcea Therapeutics, Ionis Pharmaceuticals Inc., Amgen Inc, Novo Nordisk, AstraZeneca, Esperion. C. Ballantyne: Speaker; Self; Ionis Pharmaceuticals Inc. H.N. Ginsberg: None. S. Xia: Employee; Self; Ionis Pharmaceuticals Inc. J. Witztum: Consulting Fee; Self; Ionis Pharmaceuticals Inc. S. Tsimikas: Employee; Self; Ionis Pharmaceuticals Inc. Background: Familial chylomicronemia syndrome (FCS) is a rare genetic cause of severe hypertriglyceridemia associated with an increased risk of acute pancreatitis (AP). Currently, there are no approved therapies for the treatment of FCS in the United States, and the absence of lipoprotein lipase (LPL) activity in FCS limits the effectiveness of current treatment options. Olezarsen, a ligand-conjugated antisense oligonucleotide (ASO), inhibits hepatic production of apolipoprotein (apo) C-III, a key regulator of LPL-mediated triglyceride (TG) lipolysis and non-LPL-mediated TG-rich lipoprotein hepatic uptake. In a phase 2 study of non-FCS patients with fasting serum TG levels of 200–500 mg/dL, olezarsen demonstrated reduction in fasting TG levels of up to 60% vs placebo (PBO). The Balance trial (NCT04568434) will evaluate the efficacy and safety of olezarsen as well as the rates of AP in patients with FCS. Methods: Balance is a phase 3, randomized, double-blind, PBO-controlled trial. Key inclusion criteria are genetic confirmation of FCS, fasting TG ≥ 880 mg/dL, and possible history of pancreatitis. Key exclusion criteria include clinically significant abnormalities in medical history such as major surgery within 3 mos of screening and active pancreatitis within 4 wks of screening. Patients will maintain ≤ 20 g daily fat intake and most will receive lipid-lowering medications per local standard of care. Results: Eligible patients (N=66) were enrolled at 29 sites (across 11 countries) and randomized 2:1 to receive one of two doses of olezarsen or PBO over a 53-wk treatment period, followed by post-treatment evaluation or entry into an open-label extension study. Enrollment was monitored to ensure that ≥ 65% of patients had history of pancreatitis within 10 yrs. Reported baseline parameters are preliminary. Of enrolled patients, mean age is 45±13.4 yrs, 58% of the population are female, and mean body mass index is 24.0 kg/m2; 83% had a history of hospitalization for AP, or severe abdominal pain episode, or symptoms suggestive of pancreatitis, with a mean of 2.4 episodes over the last 5 yrs and 5.1 over the last 10 yrs. Median fasting TG level is 2334.5 mg/dL. The primary efficacy endpoint of the study is percent change in fasting TG from baseline (BL) at 6 mos with olezarsen compared to PBO. Secondary endpoints (olezarsen vs PBO) include percent change in fasting TG from BL at 12 mos, achievement of ≥ 40% or ≥ 70% fasting TG reduction at 6 mos, patient proportions ≤ 500 mg/dL or ≤ 750 mg/dL at 6 mos, and adjudicated AP event rates. Exploratory assessments include patient-reported symptoms such as abdominal pain and health-related quality of life. Safety and tolerability assessments include adverse events and laboratory tests. Conclusion: Balance is designed to determine whether the apoC-III ASO olezarsen, added to standard of care, safely reduces TG levels and the rate of AP in patients with FCS. Presentation: Friday, June 16, 2023