Obicetrapib: CETP Inhibitor Impresses in LDL Lowering

November 24, 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 also 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 2021, 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, the Netherlands, and Michael Davidson, MD, clinical professor of medicine at University of Chicago, Chicago, Illinois, believed the drug had potential and have acquired obicetrapib from Amgen.

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

"We wanted to develop obicetrapib further because of its amazing LDL-lowering properties," Kastelein told | Medscape Cardiology.

"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," Kastelein said.

ROSE Study

The latest data on obicetrapib were presented at the AHA meeting by Nicholls.

"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.

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

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 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," 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, 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," 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, 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," 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."

Differences From Other CETP Inhibitors

Asked how obicetrapib differs from other agents in the CETP inhibitor class, Nicholls replied that obicetrapib is much more potent, evidenced by the large lipid changes seen with very small quantities of this drug, 5 mg or 10 mg, whereas prior CETP inhibitors showed smaller changes with much higher doses.

"We are giving very small amounts of obicetrapib and seeing very robust effects on both atherogenic and lipid parameters," he commented.  

"The other major point with this class of agent is that the first drug, torcetrapib, had toxicity, which resulted in increased cardiovascular events. But it has now been established that torcetrapib had a number of off-target effects that have not been seen with subsequent agents in this class," he said.

Studies so far show that obicetrapib does not have torcetrapib-like effects. "That is encouraging. This, and the impressive LDL lowering effects, certainly lay the foundation for larger studies moving forward," he added.

"This has been an intriguing field to many of us involved from the start. We started with a very disappointing result with torcetrapib. Then a couple of studies looked to be clinically futile, but we were encouraged by the REVEAL study which suggested that there might be benefit," Nicholls said.

"If we combined the REVEAL results with the genetic data, it has actually flipped the whole CETP story upside down. We started thinking that inhibiting CETP was all about raising HDL, but it turns out that it is about LDL lowering," he said. "And that is not only important in terms of the lipid effects but also the trials and the way they are designed.

"I think you'll find that the future trials in this class and with this agent will have LDL very much in mind and that will very much influence the study design," he said, adding that a larger cardiovascular outcome trial is now being planned. 

"The regulatory perspective is that LDL is a pretty trusted surrogate…but I think an outcomes trial will be important to reinforce and reassure on safety and outline cost-effectiveness, which will help us understand where the sweet spot for using this agent in the clinic will be," Nicholls noted.  

Kastelein explained that it has taken some time to realize that CETP inhibitors may be valuable for reducing LDL.   

"The first agent, torcetrapib, had an off-target toxicity that led to increased blood pressure but a specific part of the torcetrapib molecule was subsequently identified that was responsible for that, and subsequent agents in the CETP inhibitor class did not have such adverse effects," he said.  

"The next agent, dalcetrapib (Roche), raised HDL but didn't move LDL, and an outcomes trial with evacetrapib (Lilly) was stopped after 2 years because of futility, but we now believe that lipid lowering trials need longer term follow-up — up to 5 years — to see a benefit," he noted.  

Kastelein reports that anacetrapib (Merck) has been the most powerful CETP inhibitor until now, giving an LDL reduction of about 20%, which was associated with a 10% reduction in cardiovascular events in first 4 years of follow-up. 

"Oxford academic researchers decided to continue follow up in this trial without Merck and showed a 20% reduction in cardiovascular events by 6 years. This has been the strongest rationale for our investors," Kastelein commented.   

He points out that obicetrapib is much more potent than anacetrapib. "Obicetrapib reduces LDL by 50% at just a 10 mg dose, whereas anacetrapib was used at a dose of 100 mg to give a 17%-20% LDL reduction."

Could HDL Increase Be Beneficial After All?

Although increasing HDL is currently not thought to bring about a direct reduction in cardiovascular events, there is new evidence emerging that increasing HDL may confer some benefit in protecting against the development of type 2 diabetes, Kastelein noted.

"We know that statins can increase risk of developing type 2 diabetes, and post-hoc analyses of previous trials with CETP inhibitors suggest that these drugs have the opposite effect," he said. "We will investigate this protectively in our phase 3 outcomes trial. If this is a true effect, it should eventually translate into a reduction in cardiovascular outcomes, but this could take a longer time to see than the benefits of lowering LDL."

Commenting on the current data for Medscape, Steven Nissen, MD, Cleveland Clinic, Cleveland, Ohio, said: "The results are truly impressive — a nearly 50% LDL reduction on a background of statins with a once-daily oral agent. While PCSK9 inhibitors can achieve similar results, they are injectable and costly.

"Since anacetrapib, a much weaker CETP inhibitor, was successful at reducing major adverse cardiac events, the likelihood that obicetrapib would reduce MACE even more substantially is very high," he added.

Nissen said he has been aware of this drug for some time and has advised the company about development options and regulatory strategy. "I have encouraged this company to develop this very promising drug," he said.

The current study was funded by New Amsterdam Pharma. Nicholls reports grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron and LipoScience, and honoraria from New Amsterdam Pharma, AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Kastelein is chief scientific officer of New Amsterdam Pharma.  

American Heart Association (AHA) Scientific Sessions 2021: Abstract FS02. Presented November 13, 2021.

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