Long-term efficacy and safety of olezarsen in patients with severe hypertriglyceridemia
R Giugliano, N M Marston, B A Bergmark, V J Alexander, T A Prohaska, A Dibble, E Waldman, S Li, A Soto-Hermida, M N Magda, P Moulin, E Stroes, U Landmesser, T Tsimikas, M S SabatineAbstract
Background
Olezarsen, an antisense oligonucleotide that targets the mRNA for apolipoprotein C-III, reduced triglycerides (TGs) in patients with severe hypertriglyceridemia (sHTG, TG >500 mg/dL) by 50-72% at 6 months in two double-blinded placebo-controlled randomized clinical trials (RCTs, CORE-TIMI 72a, CORE2-TIMI 72b).
Purpose
To evaluate the longer-term efficacy and safety of olezarsen in patients with sHTG.
Methods
After 12 months in the parent RCTs in which patients were randomized 1:1:1 to olezarsen 50 or 80 mg, or placebo Q4W, eligible patients could enroll in an open-label extension (OLE) study in which patients received olezarsen 80 mg Q4W. Key efficacy measures were % change in TG and other lipids and lipoproteins, while key safety measures included drug tolerability and lab abnormalities. We report below preliminary results (median follow-up 288 days) through a maximum of 12 months in the OLE.
Results
Of 1061 randomized and treated in the parent trials, 884 patients (83%; 291, 298, and 295 having been allocated to olezarsen 80 mg, olezarsen 50 mg, and placebo, respectively, during the parent RCTs) were enrolled in the OLE. Their median age was 55 years and 23% were women. Median [25th, 75th] fasting TGs for these patients at baseline in the RCTs were 798 [593, 1277] mg/dL. At baseline in the OLE, median fasting TGs were 149, 199, and 611 mg/dL for patients who had been randomized to olezarsen 80 mg, olezarsen 50 mg, and placebo, respectively. Median achieved fasting TGs at week 53 of OLE were 142, 129, and 129 mg/dL for the 3 groups, respectively, representing 68-79% reductions from baseline prior to starting olezarsen (Fig). During OLE, levels of remnant cholesterol, Apo-CIII, and non-HDL were reduced from baseline levels prior to initiation of olezarsen, similarly to reductions observed with olezarsen in the RCTs. Treatment emergent adverse events related to olezarsen led to discontinuation in 2.0% of patients. ALT>3x ULN occurred in 2.4% and >5x ULN in 0.5%, platelet counts <100K in 2.4% and <75K in 0.9%.
Conclusions
Long-term olezarsen treatment resulted in clinically meaningful, durable reductions in TG with low rates of adverse events.TGs Over Time During the RCT and OLE