FDA Grants Priority Review for Olezarsen in Familial Chylomicronemia Syndrome

The US Food and Drug Administration has accepted the New Drug Application (NDA) for olezarsen, an investigational RNA-targeted medicine from Ionis Pharmaceuticals, in familial chylomicronemia syndrome (FCS) for priority review, according to a company announcement.¹

Announced on June 25, 2024, the company notes the FDA has set a PDUFA date of December 19, 2024 and is not expected to require an advisory committee meeting for the agent. In the announcement, the company also pointed out the completion of enrollment for their phase 3 CORE, CORE2, and ESSENCE trials evaluating olezarsen in the treatment of severe hypertriglyceridemia, which are expected to return results in the second half of 2025.¹

The basis of Ionis Pharmaceuticals’ NDA for olezarsen in FCS is the BALANCE trial. Presented at ACC.24 and simultaneously published in the New England Journal of Medicine, the phase 3, double-blind, placebo-controlled BALANCE trial evaluated the safety and efficacy 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. A total66 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.²

The cohort who underwent randomization had a mean triglyceride level of 2630 (Standard Deviation, 1315) mg/dL, 58% 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.²

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.²

Results indicated use of olezarsen 80 mg was associated with a significant reduction in triglyceride levels at 12 months relative to placebo therapy (−43.5%; 95% confidence interval [CI], −69.1 to −17.9; P <.001). 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).²

Secondary endpoint analyses 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).²

In their release, Ionis Pharmaceuticals highlighted olezarsen had previously been granted a Fast Track designation for FCS in January 2023 as well as Orphan Drug and Breakthrough Therapy designations in February 2024.¹

"FCS is a debilitating, rare, genetic disease that causes significant physical, emotional and financial burden with no approved treatment options in the US," said Brett Monia, PhD, chief executive officer of Ionis Pharmaceuticals.¹ "The Priority Review underscores the urgent need people living with FCS have for a medicine that may help lower triglyceride levels and reduce incidence of life-threatening acute pancreatitis events. We look forward to partnering closely with the FDA during the review process as we work to bring this potentially breakthrough medicine to patients before the end of 2024. Separately, we are pleased with the progress of our now fully enrolled Phase 3 program investigating olezarsen in the much more common severe hypertriglyceridemia population."

References:

1. ^{Ionis Pharmaceuticals, Inc. Ionis announces Olezarsen FCS New Drug Application accepted for Priority Review and enrollment in phase 3 shtg program completed. Ionis Pharmaceuticals, Inc. June 25, 2024. Accessed June 25, 2024. https://ir.ionis.com/news-releases/news-release-details/ionis-announces-olezarsen-fcs-new-drug-application-accepted.}
2. ^{Campbell P. Olezarsen shows ability to reduce triglycerides for patients with FCS in balance trial. HCP Live. April 16, 2024. Accessed June 25, 2024. https://www.hcplive.com/view/olezarsen-shows-ability-to-reduce-triglycerides-for-patients-with-fcs-in-balance-trial.}