Obicetrapib Treatment Increases Pre-Beta1 HDL and Lipophilic Antioxidants in the Ocean and Rose2 Studies

Abstract

Background and Aims: Non-lipidated ApoA1 (pre-beta1 HDL) captures cholesterol and lipophilic antioxidants via ABCA1. HDL particles transport antioxidants to tissues such as retina and brain. The effect of HDL raising interventions on pre-beta1 HDL levels and the distribution of lipophilic antioxidants amongst lipoproteins is unknown. CETP-inhibition was hypothesized to reduce the antioxidant capacity of HDL, although direct evidence was never presented. This is now addressed in phase II studies of the novel CETP-inhibitor obicetrapibMethods: Plasma samples from two phase II studies with obicetrapib were used to measure changes in pre-beta1 HDL by ELISA with a selective antibody to ApoA1 aa 137-144 (LQEKLSPL).. Lipophilic antioxidants were quantified in plasma, non-HDL, and HDL-fractions by ULPC ms-ms.Results: In both studies, no significant changes occurred in placebo groups but, in the obicetrapib treated groups, plasma pre-beta1 HDL increased by 12% (p<0.04) and 24% (p<0.03). In OCEAN, plasma ApoA1 and HDL-C levels correlated with increasing levels of antioxidants in the HDL fraction.In ROSE2, α-tocopherol was raised in plasma by 16% (p<0.003) and in HDL by 58% (p<0.00003). In both studies pre-beta1 HDL in obicetrapib treated patients was correlated with α-tocopherol in plasma.Conclusions: CETP inhibition with obicetrapib increases pre-beta1 HDL, impacts excess cholesterol efflux, and also raises important HDL antioxidants. Thus, these results support the potential therapeutic use of obicetrapib in diseases with high unmet medical need that are associated with low HDL and low levels of lipophilic antioxidants in plasma and tissues, such as AMD, neurodegenerative disorders, and sickle cell anemia.