CEPT Inhibitors Finally Show Potential With Obicetrapib

Milan – Addition of the cholesterol ester transporter protein (CETP) inhibitor obicetrapib to high-density lipoprotein statins significantly reduces cholesterol levels and significantly increases the number of patients achieving cholesterol goals, suggested data from Has risen Experience.

The latest findings are a reversal of a CEPT inhibitor, after a series of disappointments led to it being delisted, and obicetrapib’s original developer, Amgen, discontinuing development in 2017.

But as mentioned by theheart.org | Medscape HeartIn this study, a team of academics led by experts from the Universities of Amsterdam and Chicago obtained the drug and created 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 shows 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 who achieved an infection rate Low-density lipoprotein cholesterol Aim for 55 mg/dL to 70 mg/dL, with good tolerance.

Thus, “this could obviously be a valuable addition to the higher risk Atherosclerosis, cardiovascular disease Patients who do not achieve current levels of guideline recommendations, despite using HDLs,” said presenter Kausik K. Ray, MD.

The research was presented in European Arteriosclerosis Community Conference (EAS) 2022 on May 23.

Ray, from the Imperial Center for the Prevention of Cardiovascular Diseases, Imperial College London, President of EAS . told Ray theheart.org | Medscape Heart The current findings should allay concerns about CETP inhibitors as a class.

He acknowledged that there were safety concerns for torcetrapib, and efficacy concerns with dalcetrapib, and evacuation investigations were stopped early and represented a ‘missed opportunity’.

Furthermore, although anacetrapib “was shown to lower LDL by inhibiting CETP,” retention of the drug in adipose tissue means it has an extended half-life.

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

He stressed that cost limits the use of subtilisin/kexin type 9 (PCSK9) inhibitors and small interfering (si) RNA drugs, “so there is a huge unmet need globally to drive patients to the target.”

“If the drug was cheap, which it should be, it would be a better option” than bempedoic acid with or without, Ray added. ezetimibe As an addition to statins, “thereby picking up the black stake.”

Biggest LDL Reduction

Alberico L. Catapano, MD, PhD, professor of pharmacology, University of Milan, who was the former head of the EAS and was not involved in the study, agreed with Ray’s evaluation of obicetrapib.

“Provided that safety is OK,” which will be better defined in a large randomized outcome trial, he said, “I am completely positive because the LDL reduction is the greatest” for the class.

Catapano said theheart.org | Medscape Heart So he believes there is hope for the drug, although where it fits into a course of treatment is a “different story.”

He stressed that with a large number of trials and expertise in treating “hundreds of millions” of people, statins would remain a “cornerstone” in fat managementespecially given that it is generic.

Next, there will be a combination therapy, starting with bempedoic acid and ezetimibe, followed by PCSK9 inhibitors, siRNAs, CETP inhibitors, all competing for the same space,” Catapano said.

Combined treatments

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

Because the cost of “robust but expensive” injectable treatments has limited their uptake, he noted, “there remains a significant unmet need for new, effective and safe therapies.

Noting that obicetrapib has previously shown a 45% reduction in LDL cholesterol versus low or no statin therapy, Ray said the ROSE study aimed to examine the drug in addition to high-intensity statin therapy.

All patients must be on a stable dose of a statin 8 weeks prior to the examination and must have fasting LDL cholesterol levels above 1.8 mmol/L (32.4 mg/dL). However, they were required to be free of cardiovascular disease, diabetes mellitus or Uncontrolled high blood pressure.

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

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

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

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

Lipoprotein(a) levels decreased by a mean of 33.8%, compared to baseline, in patients in the obicetrapib 5 mg group and by 56.5% in the 10 mg group; In the second group, the levels remained unchanged.

Triglyceride It also decreased by a mean of 11%, compared to baseline, with obicetrapib 5 mg and by 8% with obicetrapib 10 mg, but increased by 2% with placebo.

In contrast, HDL cholesterol levels increased by an average of 135%, compared to baseline, with obicetrapib 5 mg and by 165% with obicetrapib 10 mg; In contrast, levels decreased by 5% with the placebo.

The results also showed that lipoprotein A1 levels increased with 5 mg and 10 mg doses of obicetrapib, averaging 45% and 48%, respectively, compared to baseline, while levels remained unchanged with placebo.

Ray showed that a target LDL cholesterol 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 only 15.0% in the placebo group.

A similar profile 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 the apoB target of 65 mg/dL to 80 mg/dL, target reach was 92.5% with obicetrapib 10 mg, 80.0% with obicetrapib 5 mg, and 37.5% with placebo.

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

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

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

The study was sponsored by New Amsterdam Pharma Company. Ray announces his relationship with Amgen, Sanofi, Regeneron, Daiichi Sankyo, Pfizer, Viatris, Abbott, AstraZeneca, Lilly, Kowa, Novo Nordisk, Boehringer Ingelheim, Esperion, Cargene, Resverlogix, SCRIBE, Novartis, Silence Therapeutics Amsterdam, CRISPR, CRISPR Catapano does not advertise any related financial relationships.

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

More from theheart.org | Medscape Cardiology, join us Twitter And the Facebook.

.