Cardiovascular disease (CVD) is a major global health concern. Managing cholesterol levels is important, as abnormal lipid profiles are linked to CVD progression. New therapeutic options to improve lipid profiles and reduce cardiovascular risk are a high priority. Obicetrapib is an investigational drug being developed for lipid management.
Understanding Obicetrapib
Obicetrapib is an investigational oral medication that belongs to a class of drugs known as cholesteryl ester transfer protein (CETP) inhibitors. These inhibitors are designed to modify lipid metabolism in the body. They aim to increase high-density lipoprotein cholesterol (HDL-C), or “good” cholesterol, and lower low-density lipoprotein cholesterol (LDL-C), or “bad” cholesterol. Developed by NewAmsterdam Pharma, obicetrapib is investigated for its effects on dyslipidemia, a condition of abnormal blood lipid levels.
How Obicetrapib Works
Obicetrapib works by inhibiting cholesteryl ester transfer protein (CETP). CETP is a plasma protein that exchanges cholesterol esters and triglycerides between lipoproteins like HDL, very-low-density lipoprotein (VLDL), and LDL particles. It facilitates the transfer of cholesterol esters from HDL to other lipoproteins, particularly LDL.
By inhibiting CETP, obicetrapib disrupts this transfer. This inhibition leads to an increase in HDL-C levels, as HDL retains more cholesterol esters. Concurrently, it results in a reduction in LDL-C and non-HDL-C levels. This dual action of increasing HDL-C and decreasing LDL-C contributes to a more favorable lipid profile, beneficial for cardiovascular health.
Clinical Applications and Efficacy
Obicetrapib is investigated for dyslipidemia and reducing cardiovascular risk, especially in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) who have not achieved optimal lipid levels with existing therapies. Clinical trials show promising results in modulating lipid parameters.
For instance, the Phase 2 ROSE trial indicated that obicetrapib 10 mg, when added to high-intensity statin therapy, reduced median LDL-C levels by up to 51% from baseline. It also decreased apolipoprotein B (ApoB) by up to 30% and non-HDL-C by up to 44%, while significantly increasing HDL-C by up to 165%.
The Phase 3 BROADWAY trial showed obicetrapib 10 mg reduced LDL-C by 33% compared to placebo at day 84 in patients with ASCVD and/or HeFH. This reduction was statistically significant and similar to findings in two previous Phase 3 trials. The PREVAIL trial, a Phase 3 cardiovascular outcomes study, assesses obicetrapib’s potential to reduce major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, and stroke. An exploratory analysis from the BROADWAY trial also indicated a 21% reduction in MACE favoring obicetrapib at one year.
Safety Profile and Current Status
Obicetrapib’s safety and tolerability have been evaluated in clinical trials, showing a favorable profile. Across various Phase 2 studies, obicetrapib, as monotherapy or in combination with ezetimibe, demonstrated LDL-C lowering with side effects similar in frequency and severity to placebo. For example, in the ROSE trial, no serious adverse events were reported in the obicetrapib cohorts.
Common adverse events in trials included COVID-19, hypertension, and upper respiratory tract infections, with similar incidences between obicetrapib and placebo groups. Liver and muscle abnormalities also occurred at low, comparable rates. Unlike some earlier CETP inhibitors with safety concerns, obicetrapib has not shown similar off-target effects, such as increases in blood pressure. Obicetrapib is undergoing Phase 3 clinical trials, including the PREVAIL cardiovascular outcomes trial, with topline data expected in 2026. NewAmsterdam Pharma plans to discuss regulatory filings with U.S. regulators following these results.