Vupanorsen

Zimerman A, et al. Journal of Clinical Lipidology, 18(2), e261-e268.

Vupanorsen has emerged as a promising therapeutic agent for hyperlipidemia. By inhibiting ANGPTL3 protein synthesis, Vupanorsen effectively reduces triglyceride levels, achieving reductions of up to 57% in a phase 2b clinical trial. However, its effects on hepatic fat fraction (HFF) warrant careful consideration.
In the TRANSLATE-TIMI 70 randomized, placebo-controlled trial, 227 adults with hyperlipidemia were analyzed for changes in HFF over 24 weeks of treatment. Results demonstrated a dose-dependent increase in HFF, with relative increases of up to 76% and absolute increases of up to 7.0% at the highest dose (p < 0.001). Baseline characteristics, such as elevated HFF, body mass index, triglycerides, and diabetes, amplified this effect.
Additionally, Vupanorsen induced dose-dependent elevations in liver enzymes, including aspartate transaminase (AST) and alanine transaminase (ALT), which were moderately correlated with HFF changes (rho = 0.49-0.50, p < 0.001). This moderate correlation indicates that liver enzyme elevations may not fully capture hepatic fat accumulation, emphasizing the need for direct HFF monitoring during clinical evaluations.
The findings underscore both the therapeutic potential and the metabolic trade-offs of Vupanorsen. While its lipid-lowering efficacy addresses significant unmet needs in hyperlipidemia management, the observed HFF progression highlights potential hepatic side effects. This dual impact necessitates vigilant HFF assessment in future clinical trials targeting intracellular ANGPTL3 inhibition, particularly with liver-directed therapies.