Olezarsen Shows Ability to Reduce Triglycerides for Patients with FCS in BALANCE Trial

Erik Stroes, MD, PhD
Credit: European Society of Cardiology

A phase 3 trial of olezarsen suggests the APOC3 inhibitor could prove useful in the management of familial chylomicronemia syndrome (FCS).

Results of the trial, called the BALANCE study, the olezarsen 80 mg monthly dose met the primary endpoint of significantly reducing triglycerides in patients with genetically validated FCS at 6 months, with further analysis demonstrating use was associated with a reduced incidence of acute pancreatitis events over 12 months relative to placebo.¹

"As a physician who has seen first-hand the struggles of people living with FCS and its serious complications, there is significant need for an effective therapy to lower triglycerides and reduce acute pancreatitis events," said lead investigator Erik Stroes, MD, professor of medicine, Amsterdam University Medical Centers.² "Olezarsen represents a potentially life-changing new medicine for these patients who experience debilitating chronic symptoms, including abdominal pain and cognitive symptoms, as well as hospitalizations associated with potentially fatal acute pancreatitis events."

Presented at the American College of Cardiology 2024 (ACC.24) Annual Scientific Session and simultaneously published in the New England Journal of Medicine, the BALANCE trial was a phase 3, double-blind, placebo-controlled trial launched to assess the effects of olezarsen at a dose of 80 mg or 50 mg against placebo therapy in patients with genetically identified FCS over the course of 53 weeks. The trial enrolled and randomized 66 patients, with 21, 22, and 23 individuals randomized to olezarsen 80 mg, olezarsen 50 mg, and placebo once monthly through the duration of the trial.¹

The cohort who underwent randomization had a mean triglyceride level of 2630 (Standard Deviation, 1315) mg/dL, the majority were female, were White, and had a normal BMI. Investigators pointed out 83% of the cohort had biallelic pathogenic variants in LPL, 17% had other causative genotypes, 71% had a recorded history of acute pancreatitis within the previous 10 years, and 39% had previously received volanesorsen.¹

The study had 2 primary outcomes of interest, which were the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months and the difference between the 50-mg olezarsen group and the placebo group. Of note, the difference between the 50 mg olezarsen group and placebo group occurred first to determine if it was significant. The trial also included multiple secondary endpoints, such as mean percent change from baseline in the APOC3 level and an independently adjudicated episode of acute pancreatitis.¹

Upon analysis, results revealed a significant reduction in triglyceride levels at 12 months with olezarsen 80 mg (−43.5%; 95% confidence interval [CI], −69.1 to −17.9; P <.001) relative to placebo therapy. However, this difference failed to achieve statistical significance when comparing the olezarsen 50 mg group against placebo therapy (−22.4%; 95% CI, −47.2 to 2.5; P = .08).¹

Analysis of secondary endpoints indicated use of olezarsen 80 mg was associated with a 73.7% reduction in mean APOC3 level from baseline to 6 months relative to placebo therapy (−73.7%; 95% CI, −94.6 to −52.8). With olezarsen 50 mg, use was associated with a 65.5% reduction in APOC3 relative to placebo at 6 months (−65.5%; 95% CI, −82.6 to −48.3). Investigators highlighted a single episode of acute pancreatitis was observed in each olezarsen group compared to 11 episodes of acute pancreatitis among the placebo (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66).¹

Safety analyses from the trial demonstrated the most common adverse events were coronavirus disease 2019, abdominal pain, and diarrhea, none of which occurred more frequently among the patients who received either dose of olezarsen than among those who received placebo. Further analysis indicated serious adverse events were reported among 14% of patients treated with olezarsen 80 mg, 19% treated with olezarsen 50 mg, and 39% treated with placebo. In their release, Ionis Pharmaceuticals called attention to an 84% reduction in all-cause hospitalizations from baseline to 12 months among olezarsen-treated patients.^1,2

"Balance is the first clinical study to validate the association of reduced triglyceride levels with reduced incidence of acute pancreatitis events in patients with severely elevated triglycerides. This important finding supports the potential for olezarsen to be the standard of care for patients with FCS, if approved. These data further strengthen our confidence for a successful outcome in the ongoing Phase 3 CORE studies evaluating olezarsen in the much more prevalent severe hypertriglyceridemia patient population," said Brett P. Monia, PhD, chief executive officer of Ionis Pharmaceuticals.²

References:

1. Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E, et al. Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome. N Engl J Med. Published online April 7, 2024. doi:10.1056/NEJMoa2400201
2. Ionis Pharmaceuticals, Inc. Ionis presents positive results from phase 3 balance study of Olezarsen for familial chylomicronemia syndrome. Ionis Pharmaceuticals, Inc. April 7, 2024. Accessed April 16, 2024. https://ir.ionispharma.com/news-releases/news-release-details/ionis-presents-positive-results-phase-3-balance-study-olezarsen.