Obicetrapib Effective When Added to Statins and Ezetimibe: ROSE2

Obicetrapib, a Lazarus-like cholesteryl ester transfer protein (CETP) inhibitor currently on its second life, checked another box in its development program with investigators showing the drug could be safely used in combination with a high-intensity statin and ezetimibe.

When obicetrapib was used in combination with these other medications, nearly 88% of patients lowered their LDL-cholesterol levels to less than 55 mg/dL, according to the ROSE2 study published May 31, 2023, in the Journal of Clinical Lipidology.   

“It makes sense today to be testing drugs in combination with other therapies, just like with blood-pressure medications,” lead investigator Christie Ballantyne, MD (Baylor College of Medicine, Houston, TX), told TCTMD. “With obicetrapib, we wanted to look at it with ezetimibe to see if you get the extra benefit, and results came out as predicted. It’s highly effective.”

In the first ROSE study, obicetrapib 10 mg reduced LDL-cholesterol levels by as much as 50% without any evidence of harm when combined with high-intensity atorvastatin or rosuvastatin. In ROSE2, adding obicetrapib to ezetimibe and high-intensity statin therapy cut LDL levels by 63.4%, non-HDL-cholesterol levels by 55.6%, and apolipoprotein B (apoB) levels by 34.4%.

ROSE2, said Ballantyne, “is another piece of the development program” that shows obicetrapib is safe and effective. He added that he’s been surprised by its turnaround given that it was part of a drug class largely considered one of the costliest failures in cardiovascular medicine. But the data, thus far anyway, look solid.

The big test, said Ballantyne, will be whether obicetrapib can safely lower the risk of major adverse cardiovascular events in a large outcomes trial. That study, known as PREVAIL, has begun. Investigators led by Stephen Nicholls, MBBS, PhD (Monash University, Victoria, Australia), plan to randomize approximately 9,000 patients with high-risk atherosclerotic cardiovascular disease with elevated LDL-cholesterol levels despite treatment with lipid-lowering therapy to 10 mg obicetrapib or placebo, on top of their other lipid-lowering meds.

The CETP inhibitors were initially developed to increase HDL-cholesterol levels to prevent major cardiovascular events, but more than 15 years ago Pfizer’s torcetrapib rattled researchers when data from ILLUMINATE showed the CETP inhibitor increased the risk of death among treated patients. Other CETP inhibitors including evacetrapib in ACCELERATE and dalcetrapib in dal-OUTCOMES didn’t prove harmful, but were largely ineffective.

Anacetrapib only modestly reduced the risk of MACE when added to statin therapy in REVEAL, and drug development was halted. Later, Ballantyne pointed out, anacetrapib demonstrated a more-potent reduction in CVD outcomes in extended follow-up. The treatment effect, he said, was likely not attributable to changes in HDL-cholesterol levels, but rather the result of reductions in non-HDL cholesterol levels.

Obicetrapib, originally developed by Amgen, was most the potent of the drug class for reducing LDL cholesterol. NewAmsterdam, a company created by lipid experts John Kastelein, MD, and Michael Davidson, MD, acquired it and, since then, has received several rounds of funding to continue its development as an LDL-lowering medication.

Getting Down to Target

In ROSE2, 119 men and women with LDL  levels > 70 mg/dL were randomized to placebo, obicetrapib 10 mg, or obicetrapib 10 mg plus ezetimibe 10 mg. All were treated with atorvastatin 40-80 mg or rosuvastatin 20-40 mg for at least 8 weeks prior to screening.

At 12 weeks, LDL-cholesterol and non-HDL-cholesterol levels were reduced 43.5% and 37.5% with obicetrapib alone and by 63.4% and 55.6% with obicetrapib and ezetimibe. These reductions were statistically significant when compared with those treated with statins alone. In the obicetrapib/ezetimibe arm, 87.1% achieved an LDL target of less than 55 mg/dL while 93.5% got down to less than 70 mg/dL. With obicetrapib alone, 42.3% and 73.1% achieved the targets of less than 55 and 70 mg/dL, respectively. In terms of safety, obicetrapib was well tolerated, say investigators.

To TCTMD, Ballantyne said any new therapy needs to demonstrate safety and effectiveness on top of statin therapy. “We have excellent generic agents out there,” he said. “Not everybody is able to take the highest doses, but they should be taking a statin.”  

Today, combination therapy is currently underutilized in clinical practice, said Ballantyne. The reason, he said, harkens back to 2013 when the American College of Cardiology/American Heart Association cholesterol guidelines moved away from LDL-cholesterol targets to a strategy that recommended prescribing statin intensity based on patient risk.  

Data, said Ballantyne, continue to support “lower is better” when it comes to LDL levels, and this will require the use of combination therapy in some patients. If obicetrapib is successful in clinical testing, it might be a new agent that could offset some of the difficulties that have emerged with patient access to newer medications.  

“The concept of lower is better has lots of support in terms of scientific evidence, but what has been one of the issues is cost and side effects,” said Ballantyne. “The PCSK9 inhibitors are being used more now and they’re really effective agents, but there have been barriers with prescribing. Prior authorization, lots of denials, and it takes time. It consumes a lot of energy. One of the keys with obicetrapib, as well as with the oral PCSK9 inhibitors in development, is whether these agents will be more available. Can you set a different price point? It’s going to be a question of access.”