The Phase III BROOKLYN trial, presented at the American Heart Association (AHA) 2024 Annual Scientific Sessions, revealed that obicetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, significantly reduces low-density lipoprotein cholesterol (LDL-C) in patients with heterozygous familial hypercholesterolemia (HeFH). The study, which evaluated obicetrapib as an adjunct to maximally tolerated lipid-modifying therapies, met its primary endpoint, offering a promising new approach to managing dyslipidemia.
Significant LDL-C Reduction with Obicetrapib
In the BROOKLYN trial (NCT05425745), patients were randomized in a 2:1 ratio to receive either obicetrapib 10mg or a matching placebo orally once daily for 52 weeks. The results, presented by Professor Stephen Nicholls, director at the Victorian Heart Hospital and Victorian Heart Institute, demonstrated a significant placebo-adjusted LDL-C reduction of 36.3% at day 84 and 41.5% at day 365. Notably, 34% of patients treated with obicetrapib achieved LDL-C reductions greater than 50%.
Achievement of Treatment Goals
Obicetrapib also facilitated the attainment of treatment goals for familial hypercholesterolemia (FH). According to the study, 77% of patients reached the primary prevention target for FH of 100mg/dL, 51% achieved the 70mg/dL target, and nearly 25% met the target of 55mg/dL for very high-risk FH patients.
Impact on Other Lipid Parameters
Beyond LDL-C, obicetrapib demonstrated favorable effects on other lipid parameters. Placebo-adjusted reductions were observed in non-HDL cholesterol by up to 37.5%, and apoB decreased by 25.8%. As expected with CETP inhibitors, HDL cholesterol increased, with obicetrapib showing a placebo-adjusted increase of up to 138.7%. Triglycerides showed a modest placebo-adjusted reduction of 11.7%. Obicetrapib also led to a placebo-adjusted reduction in Lp(a) of 54.3%, independent of its effects on lowering atherogenic lipid levels and increasing HDL cholesterol. Nuclear magnetic resonance (NMR) analysis revealed a 52.5% reduction in total LDL particle concentration and a 102.3% reduction in small atherogenic LDL particles at day 180.
Safety and Tolerability
Professor Nicholls reported that obicetrapib was well-tolerated, with no serious adverse events or clinically significant changes in vital signs, electrocardiograms, or other laboratory values. Unlike previous CETP inhibitors, obicetrapib did not show any changes in diastolic or systolic blood pressure throughout the study.
Unmet Needs and Future Directions
Key opinion leaders (KOLs) have emphasized the significant unmet need for therapies targeting Lp(a) in dyslipidemia, as elevated Lp(a) levels are a known risk factor for cardiovascular diseases. Currently, standard dyslipidemia treatments like statins are not effective in reducing Lp(a) levels. Obicetrapib's ability to lower Lp(a) levels by up to 54.3% presents a potential advancement in managing dyslipidemia and reducing cardiovascular risk.
Limitations of the study include the 365-day evaluation period and the inclusion of a cohort not specifically required to have elevated Lp(a) levels at study entry. Future studies will focus on evaluating the impact of obicetrapib in individuals with elevated Lp(a) levels. The longer-term effect of obicetrapib on cardiovascular outcomes is currently being evaluated in the PREVAIL trial. GlobalData forecasts that obicetrapib will generate the highest sales among pipeline drugs across the seven major markets, with projected sales reaching $1.40 billion by 2032.
