CETP inhibitor reduces LDL-c on top of high-intensity statin

EAS 2022 Treatment with the CETP inhibitor obicetrapib resulted in a dose-dependent reduction of LDL-c after 8 weeks in patients enrolled in the ROSE trial. Obicetrapib had a good safety and tolerability profile.

Presented at the EAS congres 2022 by: Kausik Ray, MD - London, UK.

Introduction and methods

Background

Previous studies with the CETP inhibitor obicetrapib have shown that monotherapy or in combination with low statin therapy reduces LDL-c by 45%. More recently, evidence has emerged resulting in increased interest in the potential of inhibiting CETP for CV protection.

First, genetic studies have shown that polymorphisms associated with reduced CETP are cardioprotective without raised HDL-c levels, but with lower LDL-c levels. Mendelian randomization studies have demonstrated a 16% reduction in CV risk for every 10 mg/dL decrease in LDL-c in patients with loss-of-function CETP genotypes. This CV risk reduction is equivalent to that observed in patients with loss-of-function genotypes in each of the proteins targeted by statins, PCSK9 targeted therapies, and ezetimibe.

Second, the REVEAL study demonstrated that CETP inhibition anacetrapib reduced MACE. The 9% reduction in MACE after 4.1 years follow-up was exactly predicated by the 11 mg/dL reduction in LDL-c and not associated with the increase in HDL-c.

The objective of the ROSE study was to evaluate the lipid-lowering efficacy, safety and tolerability of obicetrapib 5 and 10 mg in patients treated with high-intensity statin therapy compared to placebo.

Study design

120 Patients on a stable high intensity statin with fasting LDL-c levels >1.8 mmol/L were randomized to placebo, obicetrapib 5 mg or obicetrapib 10 mg for 8 weeks and followed for efficacy, safety and tolerability.

Primary outcome

The primary efficacy outcome was the percent change from baseline in LDL-c compared to the placebo group. There was a pre-specified assessment of LDL-c levels by preparative ultracentrifugation or Friedewald calculation.

Main results

• When analyzing the data of LDL-c obtained by preparative ultra-centrifugation, there was a dose-dependent decrease in LDL-c by obicetrapib (42% reduction in the 5 mg group and 51% reduction in the 10 mg group).
• Looking at the LDL-c data by the Friedewald method, a similar pattern was observed (43% reduction in the 5 mg group and 46% in the 10 mg group).
• When patients were stratified by LDL-c baseline, comparable effects on LDL-c lowering by obicetrapib were observed, with a slightly higher LDL-c reduction in those with baseline LDL ≥100 mg/dL than in those <100 mg/dL.
• Waterfall plots showed that almost all patients had some degree of LDL-c lowering with obicetrapib.
• Dose-dependent lowering of ApoB (up to 30%) and non-HDL-c (up to 44%) was observed with obecitrapib.
• HDL-c was dose-dependently increased by obecitrapib (up to 165%), as was ApoA1 (up to 48%).
• There was a reduction in Lp(a) and triglyceride levels in the obecitrapib groups.
• Addition of obecitrapib to high-intensity statin resulted in a greater proportion of patients achieving lipid goals.
• Obecitrapib was well-tolerated, and there was no increase rate of adverse events or serious adverse events.

Conclusion

Obicetrapib 5 and 10 mg in addition to high intensity statin therapy lowered median LDL-c levels from baseline by 42% and 51%, respectively in patients enrolled in the ROSE trial. Obicetrpib was well-tolerated. The investigators concluded that obicetrapib can be a valuable addition for high risk ASCVD patients who do not achieve their target LDL-c goals despite high intensity statin therapy.

Obicetrapib is currently being evaluated in phase 3 lipid lowering and CV outcome trials.

- Our reporting is based on the information provided at the EAS congress 2022 -

Watch a video on the ROSE trial