Conference Coverage

New CETP inhibitor impresses in LDL lowering


 

FROM AHA 2021

A new lipid-lowering agent in a class that had been written off by many is being developed by a group of academic experts, with new data showing large LDL reductions on top of high-intensity statins.

Obicetrapib is a member of the cholesteryl ester transfer protein (CETP) inhibitor class, which had fallen out of favor after several disappointments with previous drugs in this class.

These agents were initially developed for their ability to raise HDL cholesterol, which was thought to be beneficial. But that approach has now been virtually abandoned after several studies failed to show a link between raising HDL and a reduction in subsequent cardiovascular events.

However, obicetrapib, which is said to be the most potent CETP inhibitor to date, has been shown to produce impressive LDL reductions, and it’s this important data that has caused several lipid experts to want to continue its development.

New data, presented at the recent American Heart Association scientific sessions, show that obicetrapib reduces LDL by 50% when given in addition to high-intensity statins, which could place it as competition for PCSK9 inhibitors or the new agent, inclisiran, but with the advantage of oral dosing.

The drug was in development by Amgen, but the company decided to discontinue its development in 2017 after disappointing results had been seen with several other CETP inhibitors and interest in this class of agent was waning.

But academic experts in the lipid field, led by John Kastelein, MD, PhD, professor of medicine at the Academic Medical Center, University of Amsterdam, and Michael Davidson, MD, clinical professor of medicine at University of Chicago, believed the drug had potential and have acquired obicetrapib from Amgen.

Dr. Kastelein and Dr. Davidson have set up a new company – New Amsterdam Pharma – to further develop obicetrapib, and have raised $200 million from venture capital funding to complete phase 2 and phase 3 studies.

The company has a heavyweight academic advisory board including Stephen Nicholls, MD, Monash University, Clayton, Australia; Kausik Ray, MD, Imperial College London; and Christie Ballantyne, MD, Baylor College of Medicine, Houston.

“We wanted to develop obicetrapib further because of its amazing LDL-lowering properties,” Dr. Kastelein said in an interview.

“No one has paid much attention to CETP inhibitors after the HDL hypothesis was disregarded, as everyone thought these drugs were just about raising HDL. But actually, they can also lower LDL, and this particular agent reduces LDL very effectively,” Dr. Kastelein said.

ROSE study

Dr. Nicholls presented the latest data on obicetrapib at the AHA meeting.

“Despite the use of high-intensity statins, two-thirds of patients do not reach their target LDL level, so we have a need for new therapies that lower LDL and can be used in combination with high-intensity statins,” he explained.

Dr. Stephen Nicholls of Monash University, Clayton, Australia

Dr. Stephen Nicholls

He noted that earlier studies with obicetrapib showed a 45% lowering of LDL with monotherapy.

Dr. Nicholls reported that recent evidence has emerged that increases interest in inhibiting CETP to be potentially cardioprotective.

To begin, genetic studies have shown that genetic polymorphisms associated with lower levels of CETP appear to be cardioprotective, and this is associated with lower levels of LDL rather than higher levels of HDL.

Furthermore, the REVEAL cardiovascular outcomes trial with anacetrapib (also a CETP inhibitor) in 2017 showed a significant 9% reduction in major adverse cardiac events (MACE) after 4 years of follow-up. “This was exactly predicted by the 11 mg/dL drop in absolute LDL cholesterol level. It was not predicted or associated with the increase in HDL level observed with that agent,” Dr. Nicholls said.

The objective of the current ROSE study was to evaluate the lipid-lowering ability, safety, and tolerability of obicetrapib in patients on high-intensity statins.

The study included 120 patients who had been treated on a stable dose of high-intensity statins (atorvastatin at a dose of at least 40 mg daily or rosuvastatin at a dose of 20 mg daily) for at least 8 weeks. All patients were required to have a fasting LDL of at least 70 mg/dL and the median baseline LDL was 90 mg/dL. They were randomly assigned to obicetrapib (5 mg or 10 mg daily) or placebo.

The primary endpoint was the difference between groups in percentage change in LDL from baseline to week 8, with LDL levels measured by two different techniques.

Results showed a “robust” 51% reduction in LDL with the 10-mg dose of obicetrapib, and a 42% reduction with the 5-mg dose, Dr. Nicholls reported.

These effects were comparable regardless of baseline LDL and were similar with both methods of LDL measurement.

Almost all patients demonstrated some degree of LDL cholesterol lowering, with only three patients on the 5-mg dose and one patient on the 10-mg dose not showing any reduction in LDL.

Other results showed a dose-dependent lowering of Apo B of up to 30%, and a reduction of non-HDL cholesterol of up to 44%.

“Predictably, there were also increases of HDL cholesterol,” Dr. Nicholls said. “At the 10-mg dose, we see a 165% increase in HDL levels. That is associated with a 48% increase in Apo A1 levels. This is very consistent with findings from the previous monotherapy study.”

There was a 56% reduction in Lp(a) levels, and a modest 11% reduction in triglycerides.

Both doses of obicetrapib were well tolerated, with no increase in the rate of adverse events. Only one patient discontinued the study drug because of an adverse event and that patient was in the placebo group, Dr. Nicholls noted.

“Blood pressure is an important adverse event to look at in the CETP class given the challenges seen with the first CETP evaluated – torcetrapib,” Dr. Nicholls said. “But in the three clinical trials with obicetrapib conducted to date, reassuringly, we see no increase in either systolic or diastolic blood pressure with either the 5-mg or 10-mg dose.”

He concluded that obicetrapib “could be a valuable addition to high-risk patients with atherosclerotic cardiovascular disease who do not achieve their target LDL level despite use of high-intensity statin therapy.”

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