BRIDGE-TIMI 73a: Olezarsen halves triglyceride levels

The antisense oligonucleotide olezarsen lowered triglycerides by up to 53% at 6 months compared with placebo in patients with hypertriglyceridaemia and elevated cardiovascular risk in the phase 2b BRIGDE-TIMI 73a trial. Moreover, the agent led to reductions in apolipoprotein B and was generally well tolerated.

“Treatments to reduce high triglycerides are an unmet clinical need,” said Dr Brian Bergmark (Brigham and Women's Hospital, MA, USA) [1]. Rare mutations that disrupt apolipoprotein C3 (ApoC3) function are associated with lower levels of plasma triglycerides and ApoC3, and carriers of these mutations were found to have a reduced risk of coronary heart disease [2].

A previous study found that olezarsen, an antisense oligonucleotide that targets ApoC3 mRNA, significantly reduced levels of both triglycerides and ApoC3 in patients with moderate hypertriglyceridaemia. The objective of the BRIDGE-TIMI 73a trial (NCT05355402) was to assess the efficacy and safety of olezarsen in patients with moderate hypertriglyceridaemia (150 to <500 mg/dL) and elevated cardiovascular risk or in patients with severe hypertriglyceridaemia (≥500 mg/dL) [1]. All 154 participants were already receiving standard-of-care anti-lipid medication. They were randomised to receive either 50 mg (n=58) or 80 mg olezarsen (n=57), or a placebo (n=39), subcutaneously every 4 weeks.

At month 6, the primary endpoint of placebo-adjusted change in triglyceride concentrations was -49.3% with 50 mg olezarsen (95% CI -59.0 to -39.5; P<0.001). The corresponding number in the 80 mg group was -49.3% (95% CI -62.7 to 43.3; P<0.001).

The secondary endpoint of ApoC3 protein levels at 12 months dropped by -64.2% in participants in the 50 mg group and by -73.2% in the 80 mg group (P<0.001 for each comparison). Moreover, “if you want to reduce a patient’s risk for a heart attack or stroke, you would like to see a reduction in apoB. And we did see that in this study [by 18% on both doses], which is very encouraging,” Dr Bergmark commented.

At 6 months, 85.7% of the participants treated with 50 mg and 93.3% of those treated with 80 mg olezarsen achieved a triglyceride goal of <150 mg/dL, another secondary outcome. This was 11.8% in the placebo group (P<0.001 for both comparisons). As Dr Bergmark pointed out, this triglyceride effect was greater than is possible with currently available treatments.

No major safety concerns emerged during the study and follow-up period. Additional trials of olezarsen including participants with severe hypertriglyceridaemia are ongoing.

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   1. Bergmark BA, et al. Efficacy and safety of olezarsen in patients with hypertriglyceridemia and high cardiovascular risk: Primary results of the BRIDGE-TIMI 73a trial. LB2, Session 405, ACC 2024 Scientific Session, 6–8 April, Atlanta, USA.

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Posted on 16 May 202417 May 2024