Dose-dependent reduction of LDL-c levels by CETP-inhibitor
ROSE: A Placebo-Controlled, Double-Blind, Randomized, Phase 2 Dose-Finding Study to Evaluate the Effect of Obicetrapib 5 and 10 mg as an Adjunct to High-Intensity Statin Therapy
Presented at the American Heart Association’s Scientific Sessions 2021 by: Stephen Nicholls, MD - MonashHeart in Melbourne, Australia.
Introduction and methods
Previous studies with the CETP inhibitor obicetrapib have shown that monotherapy with this agent 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.
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.
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.
- 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.
- Obecitrapib was well-tolerated, and there was no increase rate of adverse events or serious adverse events.
- No increase in SBP or DBP was observed in a pooled analysis of studies with obecitrapib (ROSE, TULIP, OCEAN).
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.
In response to the question on difference in characteristics of obicetrapib vs. other CETP inhibitors, Stephen Nicholls answered that obicetrapib is more potent; only a few mg result in strong effects on lipid parameters. Furthermore, he said, the first member, torcetrapib had toxic effects. The CV outcome trial with torcetrapib was stopped early due increased rate of CV and non-CV events, and all-cause mortality. Torcetrapib had off-target effects, and with the development of other CETP inhibitors it has been important to demonstrate that they lacked these effects. Three studies thus far with obicetrapib look promising and provide the foundation to move forward.
- Our reporting is based on the information provided at the American Heart Association’s Scientific Sessions 2021 -
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