Precision Medicine Gamble Fails for CETP Inhibitors in ACCELERATE Analysis

ORLANDO, FL— A pharmacogenetic fishing expedition has failed to land a benefit for evacetrapib, dimming hopes that using the investigational agent in a more targeted population might yield positive results.

Evacetrapib—a cholesteryl ester transfer protein (CETP) inhibitor—came up short in the ACCELERATE trial, but investigators for the study elected to delve back into their data to see whether pharmacogenetic profiling might identify a subset of patients in whom the drug might successfully lower the risk of cardiovascular events. That idea stemmed from the signal of cardiovascular benefit observed among patients with a ADCY9 single nucleotide polymorphism (SNP) treated with dalcetrapib, another of the CETP inhibitor drug class, in the dal-OUTCOMES study.

Steven Nissen, MD (Cleveland Clinic, OH), who led ACCELERATE as well as the latest pharmacogenetic analysis, explained the rationale to TCTMD.

“We really wanted to confirm it because in genetic studies replication is critical,” Nissen said. “If you study a million genes, there’s a statistical probability you’re going to find something. It’s a little like throwing spaghetti at the wall. Something is going to stick. So we did the replication study and we had about three times the number of events [seen in dal-OUTCOMES] and we didn’t see what they saw.”

Nissen presented results from the new pharmacogenetic analysis earlier this week at the American College of Cardiology 2018 Scientific Session; it was published simultaneously in JAMA Cardiology.

Precision Medicine or a Risky Gamble?

For cardiologists, the CETP inhibitors have been a massive disappointment, as well as a costly investment for their manufacturers. The drugs do a fantastic job raising HDL cholesterol and lowering LDL cholesterol levels, but the clinical outcome trials have all failed to live up to the early hype. The heartbreaks include torcetrapib in ILLUMINATE, dalcetrapib in dal-OUTCOMES, and evacetrapib in ACCELERATE. The REVEAL study with anacetrapib was the only positive trial, but the benefit was largely attributed to the effect on LDL lowering and Merck abandoned the agent.   

While most researchers and physicians had given up on the drugs, a flicker of hope emerged in 2016 when investigators conducted a genome-wide association study of 5,749 patients in the dal-OUTCOMES trial.

The post hoc pharmacogenetics substudy found that when dalcetrapib was used in patients with the AA genotype in ADCY9, there was a significant 39% reduction in the risk of major adverse cardiovascular events. With the alternate GG genotype, there was a 27% increase in the risk of MACE among patients treated with dalcetrapib.

Given the genetic findings, a startup company secured the rights to dalcetrapib and raised $150 million dollars in 2016 to launch the dal-GenE study, a trial currently randomizing 5,000 patients with ACS and the AA genotype to treatment with dalcetrapib or placebo. Results of that study are expected in 2020.

If you study a million genes, there’s a statistical probability you’re going to find something. It’s a little like throwing spaghetti at the wall. Steve Nissen 

Given that background, Nissen and colleagues performed a similar pharmacogenetic analysis of evacetrapib-treated patients in ACCELERATE. Overall, genotyping was performed in 1,427 patients with clinical events and 1,532 matched controls.

For evacetrapib-treated patients with the AA genotype, there was no reduction in the risk of a composite of cardiovascular death, stroke, MI, coronary revascularization, or hospitalization for unstable angina (OR 0.88; 95% CI 0.69-1.12). There was also no reduction in the risk when the composite endpoint was confined to cardiovascular death, stroke, or MI among evacetrapib-treated patients with the AA genotype (OR 0.92; 95% CI 0.67-1.27).

Also in contrast with the dal-OUTCOMES analysis, the ACCELERATE researchers did not observe an increased risk of MACE among evacetrapib-treated patients with the GG genotype (OR 1.18; 95% CI 0.98-1.41).

Looking at the relationship of the various SNPs with biomarkers, they also observed no relationship between the AA genotype and LDL cholesterol, HDL cholesterol, high-sensitivity C-reactive protein (hsCRP), and systolic blood pressure.

Glass Half Full

Jean-Claude Tardif, MD (Montreal Heart Institute Research Center, QC), who is leading the dal-GenE study testing dalcetrapib in patients with the AA genotype, took another view of the data entirely. He told TCTMD the ACCELERATE analysis is “encouraging.”

Even though Nissen and colleagues did not observe a statistically significant reduction in the risk of events among evacetrapib-treated patients, there was a trend toward a reduction in cardiovascular events among patients with AA genotype and an increased risk in those with the GG genotype.

“These results support out initial discovery,” he said in an email. “There are obviously other differences that pertain to chemical structure and study design that may lead to different results.”

Tardif said there is a lot of agreement across different studies showing genotype-dependent effects of dalcetrapib not only on clinical outcomes, but also on atherosclerosis in imaging studies, cholesterol efflux, and hsCRP, as well as genetic evidence showing interactions between CETP and ADCY9. All of this, he said, “sets the stage well for Dal-GenE.”     

Nissen agreed that the drugs are different and cautioned that their findings do not necessarily mean the forthcoming dal-GenE study will be negative. He also agreed that the only way to get an answer about the potential benefit of CETP inhibition in patients with the AA genotype is to complete the study.

“I’m like everybody else, I’m frustrated the CETP inhibitors didn’t work and I would love for there to be a group where they do work but that’s not what we found,” he said.

Nissen pointed out that the initial finding of benefit among dalcetrapib-treated patients with the AA genotype was based on very small numbers. Just 38 dalcetrapib-treated patients with the AA genotype had clinical events compared with 59 placebo-treated patients. In the ACCELERATE analysis, 125 evacetrapib-treated patients with the AA genotype had an event compared with 143 placebo-treated patients.

As such, making a decision to chase after a potential benefit among patients with the AA genotype—approximately 1 in 5 patients according to the dal-OUTCOMES investigators—based on a small number of events and without replication is a gamble, said Nissen.   

“I think there’s a lesson in all of this for people who do large trials,” he told TCTMD. “More and more companies are doing GWAS studies, and they’re going to find things, but I think before we pursue those we need to have replication. It’s the way we avoid going down blind alleys and studying things that aren’t going to work out. At the end of the day, we’ll find out if their original study was right or wrong, but I think we wanted to put up a cautionary note that we really have to be careful about precision medicine.”