Cardiovascular diseases, linked to high cholesterol, are a significant global health concern. Many individuals struggle to achieve optimal cholesterol management, increasing their risk of heart attacks and strokes. New, effective treatment options are needed to further reduce harmful cholesterol levels. Obicetrapib is a promising investigational therapy addressing this medical need.
A New Approach to Cholesterol Management
Obicetrapib is an investigational cholesteryl ester transfer protein (CETP) inhibitor. CETP is a plasma protein primarily synthesized in the liver that facilitates the exchange of lipids between different lipoprotein particles in the bloodstream. Its function involves transferring cholesteryl esters from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL), while moving triglycerides in the opposite direction.
By inhibiting CETP, obicetrapib reduces the transfer of cholesteryl esters from HDL to LDL and VLDL, resulting in higher HDL cholesterol and lower LDL cholesterol. The drug effectively enhances HDL’s capacity to remove excess cholesterol, transporting it to the liver for excretion. This dual action offers a distinct mechanism for lipid modification.
Obicetrapib also decreases apolipoprotein B (ApoB) and non-HDL cholesterol, recognized markers of cardiovascular risk. Inhibiting CETP may lead to increased LDL receptor expression and LDL clearance from the bloodstream. This suggests obicetrapib alters cholesterol distribution and promotes the removal of atherogenic particles.
The Evidence: Clinical Trial Results
Clinical trials have demonstrated obicetrapib’s effectiveness in modifying lipid profiles. Early Phase 2 studies (ROSE and ROSE2) showed significant reductions in LDL-C and increases in HDL-C when added to high-intensity statin therapy. In these patients, 10 mg obicetrapib reduced LDL-C by up to 50.8% and increased HDL-C by up to 165% compared to placebo.
Phase 3 trials have further supported these findings. The BROOKLYN trial, in patients with heterozygous familial hypercholesterolemia (HeFH), met its primary endpoint, showing a 36.3% reduction in LDL-C at day 84, sustained at 41.5% at day 365 compared to placebo. This trial also observed reductions in lipoprotein(a) (Lp(a)) by up to 54.3%, an independent cardiovascular risk factor.
The BROADWAY study, a multinational, placebo-controlled trial with over 2,500 patients (ASCVD or HeFH), yielded positive results. Patients receiving obicetrapib experienced a 29.9% reduction in LDL-C at day 84, compared to a 2.7% increase in the placebo group (a 32.6 percentage point difference). Additionally, 51% of obicetrapib-treated patients achieved LDL-C levels below 55 mg/dL, a recommended target for very high-risk individuals. An exploratory analysis in BROADWAY also indicated a 21% relative reduction in major adverse cardiovascular events (MACE), including heart attack, stroke, and revascularization, favoring obicetrapib.
Understanding Side Effects and Availability
Obicetrapib’s safety profile has been a central focus, especially given challenges faced by earlier CETP inhibitors. Across multiple Phase 2 and Phase 3 trials, obicetrapib demonstrated a safety profile comparable to placebo. Common adverse events, such as COVID-19, hypertension, and upper respiratory tract infections, occurred with similar incidences in both obicetrapib and placebo groups.
Clinical trials have not shown an increase in blood pressure with obicetrapib, a concern that affected some previous CETP inhibitors. Rates of liver and muscle enzyme abnormalities were low and comparable between treatment and placebo groups. Treatment discontinuation rates due to side effects have been similar to or lower in the obicetrapib arms compared to placebo.
Obicetrapib is currently in late-stage clinical development. NewAmsterdam Pharma completed enrollment for its pivotal Phase 3 BROADWAY, BROOKLYN, and TANDEM trials, and the PREVAIL cardiovascular outcomes trial, which enrolled over 9,500 patients. Topline data from BROOKLYN were announced in July 2024, with BROADWAY data published in May 2025. PREVAIL results, assessing major adverse cardiovascular events, are expected in early 2026. These studies are crucial for determining long-term cardiovascular benefits and potential regulatory filings with agencies like the FDA and EMA.