ROSE Trial: CETP Inhibitor Shows Promise as Oral Add-on for LDL-Lowering

MILAN, Italy—Obicetrapib, an investigational agent belonging to a drug class that has been largely dismissed by cardiovascular researchers, can reduce LDL-cholesterol levels when added to high-intensity statin therapy, the ROSE trial showed this week at the European Atherosclerosis Society (EAS) Congress 2022.

At a dose of 10 mg, the cholesteryl ester transfer protein (CETP) inhibitor reduced LDL-cholesterol levels by as much as 50% without any evidence of harm when combined with high-intensity atorvastatin or rosuvastatin.

“We’ve heard a lot at this meeting and elsewhere that the change in risk-based guidelines towards lower LDL-cholesterol levels inevitably means that we will need to use more combination therapy,” said lead investigator Kausik Ray, MBChB, MD (Imperial College London, England), during a late-breaking trial session. “The question, then, is what will that look like?”

Current oral lipid-lowering drugs, such as ezetimibe and bempedoic acid (Nexletol; Esperion), cut LDL cholesterol by 25% when added to high-intensity statin therapy, said Ray. Injection-based therapies, such as the PCSK9 inhibitors alirocumab (Praluent; Sanofi/Regeneron) and evolocumab (Repatha; Amgen), as well as the small interfering RNA molecule inclisiran (Leqvio; Novartis), are much more powerful, capable of reducing LDL cholesterol by 50% to 60% on top on statin therapy.

However, the “expense of these injectable therapies has limited their uptake,” said Ray. For these reasons, obicetrapib might be an attractive option for physicians treating high-risk or very-high-risk patients who need to further reduce LDL-cholesterol levels. “There is a need for further options,” said Ray. “Another shot at goal.”

The Comeback Kid

Still, that obicetrapib is being tested at all is surprising considering that a host of other CETP inhibitors have fallen by the wayside after disappointing clinical trials.  

Pfizer’s torcetrapib was the first high-profile failure, with the ILLUMINATE study stopped prematurely due to a higher risk of death among treated patients. The adverse outcomes seen in that trial were attributed to off-target effects of the drug, such as an increase in blood pressure and electrolyte changes.      

While the other CETP inhibitors didn’t prove to be harmful, they were largely ineffective. The ACCELERATE trial with evacetrapib in high-risk vascular patients didn’t show any benefit on clinical outcomes, and neither did the dal-OUTCOMES trial with dalcetrapib in patients with recent ACS. Anacetrapib came the closest to succeeding, with data from the REVEAL trial showing the CETP inhibitor modestly reduced the risk of MACE when added to statin therapy.

However, the CETP inhibitors were initially developed to test the hypothesis that increasing HDL-cholesterol levels could prevent major cardiovascular events. They were not developed to lower LDL-cholesterol levels, although some of the drugs did.  

To TCTMD, Ray explained the rationale for bringing back obicetrapib as an LDL-lowering therapy, noting that genetic studies have validated CETP as a therapeutic target worth pursuing. Dalcetrapib increased HDL cholesterol, but didn’t alter apolipoprotein B (apoB) or LDL-cholesterol levels. Evacetrapib reduced LDL cholesterol in dal-OUTCOMES, but that trial was halted prematurely. With anacetrapib, the 9% reduction in major coronary events observed in the outcomes trial was proportional to the magnitude of LDL cholesterol- and apoB-lowering, said Ray. That drug is retained in the fat long term, though, and as such might not be best for long-term development.

“Obicetrapib is the most-potent comparable to injectables for LDL-cholesterol-lowering,” Ray told TCTMD. “It increases clearance of LDL via the LDL receptor, and all drugs that have done that have been effective in reducing cardiovascular disease to date. Hence, this is a target worth pursuing.”

Past studies with obicetrapib have shown that the drug lowered LDL-cholesterol levels by 45%, but those studies included patients treated with a low-dose statin or no statin at all. Ray said that for the drug to be useful, it will need to be effective when given on top of optimized lipid-lowering therapy.    

Big Reduction on Top of Statin Therapy

The ROSE investigators randomized 120 patients to treatment with obicetrapib 5 mg or 10 mg or placebo. All patients were treated with atorvastatin 40/80 mg or rosuvastatin 20/40 mg for at least 8 weeks prior to randomization. Mean LDL-cholesterol levels at baseline were 90.0, 95.0, and 88.0 mg/dL in the placebo and 5- and 10-mg treatment arms, respectively.

After 8 weeks of treatment, obicetrapib 5 and 10 mg reduced LDL cholesterol 42% and 51% from baseline (P < 0.001). The treatment effect was consistent across baseline LDL levels.

ApoB, a marker of total atherogenic lipoproteins, and non-HDL cholesterol also were reduced in a dose-dependent manner. Lipoprotein(a) was reduced by 33.8% and 56.5% with the 5- and 10-mg doses of obicetrapib, respectively. There was a modest reduction in triglycerides. HDL-cholesterol levels increased significantly, up 135% and 165% with 5- and 10-mg doses, respectively. Among patients treated with the 10-mg dose, 82.5% of patients achieved an LDL-cholesterol target of less than 70 mg/dL, while 90% achieved the non-HDL-cholesterol target of less than 100 mg/dL.

In terms of safety, there was no significant difference in the risk of adverse events compared with placebo. There were no serious adverse events in the treatment arms and no withdrawals due to study drug.

Like all other drugs, obicetrapib must prove it can safely lower the risk of major adverse cardiovascular events in a large outcomes trial. That study, known as PREVAIL, has begun, and 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 LDL-cholesterol levels not at the guideline-recommended target despite treatment with lipid-lowering therapy.

Risks of Age-Related Macular Degeneration

During the Q&A following the presentation, Anne Tybjærg-Hansen, MD, DMSc (University of Copenhagen, Denmark), highlighted her group’s recent study suggesting there might be risks associated with CETP inhibition. Published in JAMA Cardiology, the study showed that a genetic deficiency in CETP—which the researchers say mimics pharmacologic CETP inhibition—was associated with a lower risk of cardiovascular morbidity and mortality, but also a higher risk of age-related macular degeneration (AMD).

While the mechanism behind the higher risk of AMD is not known, Tybjærg-Hansen suspects it may be the result of high HDL cholesterol.

“We know that genetically high HDL-cholesterol levels cause AMD,” she told TCTMD. “There’s a direct causal relationship. We don’t know exactly what the explanation is, but we know part of it. With these types of [CVD] studies, you don’t have enough observation time and people aren’t necessarily, on average, old enough. [AMD] is a disease of the elderly and you need to have a long observation time. I’m really worried about it.” 

Børge Nordestgaard, MD, DMSc (University of Copenhagen), who was part of the JAMA Cardiology study, said the LDL-cholesterol reduction observed in the ROSE trial is impressive, but that he is also worried about the large increase in HDL-cholesterol levels with CETP inhibition. When torcetrapib failed in ILLUMINATE, several analyses showed the drug was associated with off-target effects, but it’s also possible the high HDL-cholesterol levels played a role.

“That’s just a personal thought,” he told TCTMD. “The research world was very HDL-centric for a while. We now have some genetic evidence showing that it causes age-related macular degeneration, which is the most common cause of blindness.”

In response, Ray noted that one of the advantages with the CETP class is that the drugs were tested in very large trials. For example, REVEAL included more than 30,000 patients with more than 5-year follow-up, and there was no signal of harm in that trial. He also pointed out that there may be differences in AMD risk based on the age of patients in the genetic studies, who were older, versus those who would be candidates for lipid-lowering therapy. Regardless, investigators plan to watch for AMD as an adverse event in the ongoing PREVAIL trial, he said.

Obicetrapib was initially developed by Dezima Pharma but was acquired by Amgen when it bought the company. In 2017, Amgen discontinued further development of obicetrapib and licensed the rights to NewAmsterdam Pharma, a company created by lipid specialists Michael Davidson, MD, and John Kastelein, MD, PhD.