Obicetrapib: A Promising CETP Inhibitor for LDL and Lp(a) Reduction

Introduction

Obicetrapib, a cholesteryl ester transfer protein (CETP) inhibitor developed by NewAmsterdam Pharma, has emerged as a promising lipid-lowering therapy. Unlike previous CETP inhibitors like anacetrapib, evacetrapib, torcetrapib, and dalcetrapib, which failed due to safety concerns, obicetrapib has shown impressive results in the BROADWAY and TANDEM trials. These studies, presented at the 2025 European Atherosclerosis Society Congress and published in the New England Journal of Medicine and The Lancet, highlight the potential of obicetrapib as a novel oral agent for managing low-density lipoprotein (LDL) and lipoprotein(a) [Lp(a)] in high-risk patients.

Background on CETP Inhibitors
CETP inhibitors have long been explored as a therapeutic option for cardiovascular disease, initially aiming to raise high-density lipoprotein (HDL) levels. However, this approach fell out of favor as studies like the ILLUMINATE trial demonstrated increased cardiovascular events and mortality with torcetrapib. The failure of earlier CETP inhibitors shifted the focus toward LDL reduction, which has proven to be a more effective strategy for reducing major adverse cardiovascular events (MACE).

BROADWAY Trial Findings
The BROADWAY trial enrolled 2,530 patients with heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD) who were already on maximally tolerated lipid-lowering therapy. Key results include:

• LDL Reduction: A 29.9% reduction in LDL at day 84 versus a 2.7% increase in the placebo group (P < 0.001). This effect was maintained through 1 year.

• Lp(a) Reduction: A 33.5% reduction in Lp(a) levels, highlighting its potential as a dual-action lipid-lowering therapy.

• Adverse Events: Comparable overall adverse event rates between obicetrapib (59.7%) and placebo (60.8%), with low rates of liver-enzyme (0.6%) and muscle enzyme (0.3%) abnormalities.

TANDEM Trial Findings
The TANDEM trial further tested obicetrapib in 407 patients with heterozygous FH or ASCVD, including those at high risk but not on statins. Key results include:

• Combination Therapy: Fixed-dose combination with ezetimibe achieved a 48.6% LDL reduction compared to placebo, a 27.9% reduction compared to ezetimibe monotherapy, and a 16.8% reduction compared to obicetrapib monotherapy.

• Adverse Events: Low rates of serious adverse events (3-7%) across all study arms, reinforcing the safety profile seen in BROADWAY.

Clinical Implications and Future Directions
The promising results from the BROADWAY and TANDEM trials position obicetrapib as a potentially important addition to the lipid-lowering toolkit. The PREVAIL study, expected to report outcomes in 2026, will be crucial for determining the long-term cardiovascular benefits of this agent. If successful, obicetrapib could fill a critical gap for patients with elevated LDL and Lp(a) levels who may not qualify for existing injectable therapies.

Key Takeaways

• Obicetrapib offers significant reductions in both LDL and Lp(a), addressing a critical need in lipid management.

• Safety profile appears favorable, with low rates of serious adverse events.

• The upcoming PREVAIL trial will provide crucial long-term efficacy data.

Conclusion
Obicetrapib represents a promising step forward in lipid management, potentially providing clinicians and patients with a novel oral option for comprehensive cholesterol control. With further validation, it could become a mainstay in the management of ASCVD and heterozygous FH.