See my other posts. Think it through. Regarding olezarsen (Tryngolza), the drug’s development began with preclinical studies in the early 2010s, focusing on its mechanism as an antisense oligonucleotide targeting apolipoprotein C-III (apoC-III). The first human clinical trial, a Phase 1 study (NCT02098278), was initiated in March 2014 to evaluate its safety, pharmacokinetics, and pharmacodynamics in healthy volunteers. This marked the start of clinical investigation for olezarsen, formerly known as AKCEA-APOCIII-LRx or ISIS-APOCIII-LRx.
The FDA approval process for olezarsen followed a structured pathway for a new molecular entity addressing a rare disease. Ionis Pharmaceuticals submitted a New Drug Application (NDA) on April 19, 2024, under section 505(b) of the Federal Food, Drug, and Cosmetic Act. The FDA accepted the NDA on June 25, 2024, granting Priority Review, which shortened the standard 10-month review period to 6 months, with a Prescription Drug User Fee Act (PDUFA) target action date of December 19, 2024. Olezarsen had previously received Orphan Drug designation for familial chylomicronemia syndrome (FCS), Fast Track designation, and Breakthrough Therapy designation for FCS, facilitating expedited review.
The approval was based on data from the Phase 3 BALANCE trial (NCT04568434), a global, multicenter, randomized, double-blind, placebo-controlled study initiated in October 2020, which evaluated olezarsen in 66 adults with genetically confirmed FCS and fasting triglycerides ≥880 mg/dL. The trial met its primary endpoint, showing significant triglyceride reduction at 6 and 12 months.
On December 19, 2024, the FDA approved olezarsen as an adjunct to diet to reduce triglycerides in adults with FCS. Post-approval, on December 1, 2025, the FDA granted an additional Breakthrough Therapy designation for olezarsen in severe hypertriglyceridemia (triglycerides ≥500 mg/dL), with Ionis planning a supplemental NDA submission by the end of 2025 based on ongoing Phase 3 trials (CORE, CORE2, ESSENCE).
Post-marketing requirements include completing long-term safety studies (e.g., CORE/CORE2 extensions through 2028) to assess risks like chronic liver injury, with interim reports due in June 2026–2028 and final submission in June 2029. Labeling includes warnings for hypersensitivity reactions, and the drug is self-administered subcutaneously once monthly.
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