Treatment with obicetrapib, a CETP* inhibitor, significantly reduced low-density lipoprotein cholesterol (LDL-C) levels for up to 1 year in patients with heterozygous familial hypercholesterolaemia (HeFH), despite being on maximally tolerated lipid-lowering therapy, according to the BROOKLYN trial presented at AHA 2024.

The BROOKLYN trial met its primary endpoint of achieving a mean percent reduction in LDL-C of 36.3 percent (p<0.0001) from baseline to day 84 with obicetrapib, with a further decrease of 41.5 percent (p<0.0001) at day 365, compared with placebo. [AHA 2024, abstract 4171281]

“Within the HeFH patient community, it is common for patients to be on multiple lipid-lowering therapies, and given the efficacy and safety profile observed to date, we believe obicetrapib has the potential, if approved, to provide physicians with a new tool to address unmet needs in these patients,” said lead author Dr Stephen Nicholls from Monash University in Melbourne, Australia.

This phase III, double-blind, placebo-controlled study included 354 patients (mean age 56 years, >50 percent female) with HeFH who were randomized in a 2:1 ratio to receive either oral obicetrapib 10 mg once/daily (n=236) or matching placebo (n=118), as an adjunct to maximally tolerated lipid-lowering therapies, for 52 weeks.

At baseline, the mean LDL-C level was 123.4 mg/dL in the obicetrapib group, despite most patients being on high-intensity statin (78.8 percent), with 53.8 percent on ezetimibe and 14 percent on PCSK9 inhibitors.

By day 84, a higher percentage of patients treated with obicetrapib attained an LDL-C goal of <100 mg/dL, the primary prevention target for FH, than those treated with placebo (77 percent vs 40 percent).

More obicetrapib recipients also attained an LDL-C goal of <70 mg/dL (51 percent vs 11 percent) and <55 mg/dL (24 percent vs 1 percent) than placebo recipients.

Other lipid parameters

Obicetrapib reduced lipoprotein(a) (Lp(a)) levels by 45.9 percent at day 84 and 54.3 percent at day 365 compared with placebo, with 38 percent of obicetrapib-treated patients achieving an Lp(a) reduction of >50 percent.

Similarly, reductions in non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B levels were observed with obicetrapib than with placebo at day 84 (34.5 percent and 24.4 percent, respectively), which were sustained through day 365 (37.5 percent and 25.8 percent).

Additionally, HDL-C levels increased at days 84 and 365 (placebo-adjusted mean percent change from baseline, 138.7 and 121.4, respectively), though this “was expected, with CETP inhibitors producing HDL rising,” Nicholls noted.

“For the first time, we used nuclear magnetic resonance analysis to assess lipid particles in patients treated with obicetrapib,” said Nicholls. Obicetrapib reduced LDL particles by 52.5 percent (total) and 102.4 percent (small) at day 180, as well as high-sensitivity C-reactive protein levels by 16.8 percent at day 84 and 8.8 percent at day 365.

In terms of safety and tolerability, the rates of treatment-emergent adverse events did not differ between the treatment groups, and so did adverse events related to the study drug or led to treatment discontinuation. Obicetrapib was well-tolerated with no safety concerns, Nicholls noted.

“We believe the additional data presented today underscore obicetrapib’s potential to significantly reduce not only LDL-C but also Lp(a), LDL particles, both total and small, along with several other biomarkers in HeFH patients when compared with placebo,” said Nicholls.

“The findings suggest that obicetrapib has considerable promise as an approach to more effective lipid control in high CV risk patients,” he concluded.

*CETP: Cholesteryl ester transfer protein