Obicetrapib Treats Hypercholesterolemia, Phase 3 Trail Results Suggest

Results from the BROOKLYN phase 3 trial have indicated the safety and efficacy of obicetrapib in treating heterozygous familial hypercholesterolemia (HeFH).

Presented at the 9th Annual Heart in Diabetes Conference, these data indicate the significant low-density lipoprotein cholesterol (LDL-C) lowering capabilities of obicetrapib as an adjunct to maximally tolerated lipid-modifying therapies.1

Despite being extremely common, HeFH remains relatively underdiagnosed, affecting roughly 1 in 220 individuals worldwide. HeFH is an autosomal dominant disorder characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C), which can lead to early-onset atherosclerosis and an increased risk of cardiovascular events. Untreated men and women affected by HeFH have a 30-50% risk of a fatal or nonfatal cardiac event by ages 50 and 60, respectively.2

Previous trials of early cholesteryl ester transfer protein (CETP) inhibitors have been largely unsuccessful in demonstrating reduced atherosclerotic cardiovascular disease (ASCVD) risk for a variety of agent-specific reasons. Obicetrapib is an oral CETP inhibitor, which reduces concentrations of atherogenic lipid parameters and increases high-density lipoprotein cholesterol (HDL-C) when added to statins.1,3

To investigate the efficacy and tolerability of obicetrapib 10 mg in patients with HeFH, Stephen Nicholls, MD, PhD, professor of cardiology and leader of the Victorian Heart Hospital at Monash University, and colleagues conducted the phase 3 BROOKLYN trial, a randomized, double-blind, placebo-controlled study with a 1-year follow-up.1

The trial enrolled a total of 354 patients across 70 sites, all of whom were on maximally tolerated LLT and had fasting LDL-C ≥70 mg/dL and triglycerides ≤400 mg/dL. Patients were excluded if they had experienced a cardiovascular event in the last 3 months, had homozygous familial hypercholesterolemia, or had uncontrolled hypertension.1

Nicholls and colleagues randomly assigned patients 2:1 to receive either 10 mg obicetrapib per day (n = 236; average age standard deviation [SD], 57 years) or placebo (n = 118, average age SD, 56.6 years) for 52 weeks. A collective 22% of the placebo group had diabetes compared to 19.9% in the obicetrapib group, and 83.9% of the placebo group used statins versus 88.6% of the obicetrapib group.1

The primary endpoint was least squares (LS) mean percent change from baseline to week 12 in LDL-C; secondary endpoints included percent change from baseline in apolipoprotein B (ApoB), non-HDL-C, total cholesterol, HDL-C, triglycerides, and lipoprotein (a), as well as safety measures required.1

Patients treated with obicetrapib saw a sharp decline in LDL-C over the first 30 days, averaging a total percent change of -39.6%. LDL-C then exhibited relative stability through day 365. The placebo cohort, however, saw a brief decrease in LDL-C by day 84, followed by a gradual increase above baseline through follow-up. Days 84 and 365 saw a 36.3% difference and a 41.5% difference between the two groups, respectively (both P = .0001).1

Investigators noted obicetrapib was also well-tolerated with no serious adverse events. In the placebo group, 70.3% of participants exhibited treatment-emergent adverse events, compared to 63.7% of the obicetrapib group. Listed adverse events of special interest included new diabetes or worsening glycemic control, which impacted 19.5% of the placebo cohort and 16.7% of the treatment cohort, and hemoglobin A1c increase >0.5% from baseline, which impacted 6.8% of the placebo group and 9.8% of the treatment group.1

“Obicetrapib holds promise for patients with HeFH who are unable to attain their LDL-C treatment targets with available lipid-lowering agents,” Nicholls and colleagues wrote.1

References

1. Nicholls J, Stephen. Safety and Efficacy of Obicetrapib in Patients With Heterozygous Familial Hypercholesterolemia. Abstract presented at the 9th Heart in Diabetes Conference in Philadelphia, PA from June 6 – June 8, 2025.

2. McGowan MP, Hosseini Dehkordi SH, Moriarty PM, Duell PB. Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia. J Am Heart Assoc. 2019;8(24):e013225. doi:10.1161/JAHA.119.013225

3. Kastelein JJP, Hsieh A, Dicklin MR, Ditmarsch M, Davidson MH. Obicetrapib: Reversing the Tide of CETP Inhibitor Disappointments. Curr Atheroscler Rep. 2024;26(2):35-44. doi:10.1007/s11883-023-01184-1