CEPT Inhibitors Finally Show Potential With Obicetrapib CEPT Inhibitors Finally Show Potential With Obicetrapib

MILAN — Adding the cholesteryl ester transfer protein (CETP) inhibitor obicetrapib to high-intensity statins significantly lowers cholesterol levels and substantially increases the number of patients achieving cholesterol targets, suggest data from the ROSE trial.

The latest results are something of a reversal for the CEPT inhibitor, after a series of disappointments led to many writing them off, and the original developer of obicetrapib, Amgen, discontinuing development in 2017.

However, as reported by theheart.org | Medscape Cardiology, a team of academics led by experts from the Universities of Amsterdam and Chicago acquired the drug and set up New Amsterdam Pharma to develop it further.

Now, a trial comparing two doses of obicetrapib with placebo in 120 patients already on high-intensity statin therapy has shown that it significantly reduces low-density-lipoprotein (LDL) cholesterol by up to 51% over baseline and improves many other lipid parameters.

The drug was also associated with up to 82.5% of patients achieved an LDL cholesterol target of 55 mg/dL to 70 mg/dL, all while being well tolerated.

Consequently, “this could obviously be a valuable addition for high-risk atherosclerotic cardiovascular disease patients who don’t achieve current levels of guideline recommendations, despite the use of high-intensity statins,” said presenter Kausik K. Ray, MD, PhD.

The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 23.

Ray, from the Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, who is president of EAS, told theheart.org | Medscape Cardiology that the current findings should allay fears over CETP inhibitors as a class.

He acknowledged that there were safety concerns torcetrapib, efficacy concerns with dalcetrapib, and investigations of evacetrapib were “stopped early” and represent a “wasted opportunity.”

Moreover, although anacetrapib “showed that LDL lowering via CETP inhibition worked,” retention of the drug in fat tissue meant it had an extended half-life.

Ray said that, in contrast, obicetrapib is the “most potent” drug in the class, has “none of the off-target effects of torcetrapib and, after stopping, is not retained in the body,” making it a “viable option.”

He emphasized that cost limits the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and small-interfering (si)RNA drugs, “so there is a huge unmet need globally in order to get patients to goal.”

“If the drug is cheap,” Ray added, “which it should be, it will be a better option” than bempedoic acid with or without ezetimibe as an add-on to statins, “thus picking up the lions share.”

Largest LDL Reduction

Alberico L. Catapano, MD, PhD, professor of pharmacology, University of Milan, who is past president of the EAS and was not involved in the study, agreed with Ray’s assessment of obicetrapib.

“Provided the safety is okay,” which will be better determined in a large, randomized outcomes trial, he said, “I am quite positive because the reduction of LDL is the largest” for the class.

Catapano told theheart.org | Medscape Cardiology that he therefore believes that there is hope for the drug, although where it will fit into the treatment pathway is “a different story.”

He underscored that with a huge number of trials and experience in the treatment of “hundreds of millions” of people, statins will remain the “cornerstone” of lipid management, particularly given that they are generic.

“After that,” Catapano said, there will be combination therapy, starting with bempedoic acid and ezetimibe, followed by PCSK9 inhibitors, siRNA drugs, and CETP inhibitors, all competing for the same space.

Combination Therapies

Ray began his presentation by explaining that any update to risk-based goals for LDL cholesterol “inevitably means” the greater use of combination therapies in addition to high-intensity statins.

As the cost of “potent but expensive” injectable therapies has limited their uptake, he noted, “there remains a high unmet need for new effective, safe therapies.

Noting that obicetrapib has previously demonstrated LDL-cholesterol reductions of 45% against low or no statin therapy, Ray said the ROSE study set out to examine the drug in addition to high-intensity statin therapy.

All patients had to be on a stable statin dose 8 weeks prior to screening and had to have fasting LDL-cholesterol levels above 1.8 mmol/L (32.4 mg/dL). However, they were required to be free of significant cardiovascular disease, diabetes mellitus, or uncontrolled hypertension.

They were randomized in a 1:1:1 ratio to obicetrapib 5 mg or 10 mg or placebo, and were assessed at baseline and weeks 4, 8, 12, 16, and 23.

Of 195 patients, 120 were randomized, and all but one completed treatment. Mean age of the study cohort was 61.1 to 62.9 years, and between 35.7% and 52.5% of participants were female. Mean baseline LDL-cholesterol levels ranged from 88.0 mg/dL to 95.0 mg/dL.

Compared with baseline, the addition of obicetrapib 5 mg to high-intensity statin therapy reduced LDL-cholesterol levels by 42%, whereas the addition of obicetrapib 10 mg was associated with median reductions of 51%. Both reductions were significantly greater than the 7% reduction with placebo (P < .0001 for both).

Patients taking the lower dose of obicetrapib also saw reductions in their apolipoprotein (apo)B levels, compared with baseline, of 24%, which increased to 30% with the higher dose, compared with 3% for placebo. Reductions in non-high-density-lipoprotein (HDL)-cholesterol levels were 39%, 44%, and 4% respectively.

Lipoprotein(a) levels fell by a median of 33.8%, compared with baseline, in patients in the obicetrapib 5 mg group and by 56.5% in those in the 10 mg group; in the placebo group, levels remained unchanged.

Triglycerides also were reduced by a median of 11%, compared with baseline, with obicetrapib 5 mg and by 8% with obicetrapib 10 mg, but rose by 2% with placebo.

In contrast, HDL-cholesterol levels increased by a median of 135%, compared with baseline, with obicetrapib 5 mg and by 165% with obicetrapib 10 mg; in contrast, levels decreased by 5% with placebo.

The results also showed that apolipoprotein A1 levels increased with the 5 mg and 10 mg doses of obicetrapib, by a median of 45% and 48%, respectively, compared with baseline, whereas levels remained unchanged with placebo.

Ray showed that the LDL-cholesterol target of 55 mg/dL to 70 mg/dL was achieved by 82.5% of patients in the higher-dose group, 75.0% in the lower-dose group, and just 15.0% in the placebo group.

A similar picture was seen for a target of 85 mg/dL to 100 mg/dL for non-HDL cholesterol, with 90.0% of patients in the 10 mg group and 82.5% in the 5 mg group achieving the target, compared with 25.0% in the placebo group.

For an apoB target of 65 mg/dL to 80 mg/dL, target attainment was 92.5% with obicetrapib 10 mg, 80.0% with obicetrapib 5 mg, and 37.5% with placebo.

Ray said that “one side of the coin is efficacy” and the other is safety, and “there is a safety profile that is broadly comparable with placebo, with no excess of adverse events or serious adverse events.”

In fact, obicetrapib was associated with a lower rate of adverse events overall, at 32.5% with the 5 mg dose, 20.0% with the 10 mg dose, and 47.5% with placebo.

There were only two serious adverse events in total, both in the placebo group, and only one adverse event that led to discontinuation, again in the placebo group.

The study was sponsored by New Amsterdam Pharma. Ray declares relationships with Amgen, Sanofi, Regeneron, Daiichi Sankyo, Pfizer, Viatris, Abbott, AstraZeneca, Lilly, Kowa, Novo Nordisk, Boehringer Ingelheim, Esperion, Cargene, Resverlogix, SCRIBE, Novartis, Silence Therapeutics, CRISPR, Bayer, New Amsterdam. Catapano declares no relevant financial relationships.

European Atherosclerosis Society (EAS) 2022. Presented May 23, 2022.

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