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Pharmacogenetic analysis fails to find benefit for evacetrapib
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ORLANDO, Fla. — In the ACCELERATE cohort, a pharmacogenetic analysis did not find that evacetrapib improved outcomes for patients with a certain genetic variant, according to findings presented at the American College of Cardiology Scientific Session.
As Cardiology Today previously reported, main results of the ACCELERATE trial of the CETP inhibitor evacetrapib (Eli Lilly) showed that the drug did not reduce major adverse CV events in 12,092 patients at high vascular risk.
In a previous analysis of another CETP inhibitor, dalcetrapib (F. Hoffmann-La Roche), although its outcome trial was neutral, patients with the single nucleotide polymorphism rs1967309 on the ADCY9 gene (AA genotype) had a reduction in major adverse CV events when assigned that drug.
“In patients with the AA genotype, dalcetrapib was associated with a 39% reduction in morbidity and mortality,” Steven E. Nissen, MD, MACC, chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic’s Sydell and Arnold Miller Family Heart and Vascular Institute, told Cardiology Today. “When we studied this in the ACCELERATE population, we did not find the same benefit with evacetrapib.”
The researchers conducted a nested case-control study of selected patients from the ACCELERATE cohort, matching 1,427 patients with the AA genotype with 1,532 controls without the variant. The primary outcome was major adverse CV events, defined as CV death, stroke, MI, coronary revascularization or hospitalization for unstable angina. The results were simultaneously published in JAMA Cardiology.
The treatment effect of evacetrapib was not significantly better in patients with the AA genotype than in those with the AG genotype, which had no relationship to outcomes from dalcetrapib, or the GG genotype, which had evidence of harm from dalcetrapib (OR for AA genotype = 0.88; 95% CI, 0.69-1.12; OR for AG genotype = 1.04; 95% CI, 0.9-1.21; OR for GG genotype = 1.18; 95% CI, 0.98-1.41; P for interaction = .17; P for trend = .06), Nissen said.
The trends were less favorable after adjustment for CV risk factors (OR for AA genotype = 0.93; 95% CI, 0.73-1.19; OR for AG genotype = 1.05; 95% CI, 0.91-1.22); OR for GG genotype = 1.02; 95% CI, 0.85-1.24; P for interaction = .71; P for trend = .59), Nissen and colleagues found.
“Unfortunately, what we found was not encouraging,” Nissen told Cardiology Today.
The results should not produce any assumptions about the benefit of dalcetrapib, Nissen said during his presentation.
“Genome-wide association studies are now commonly performed for large outcome trials,” Nissen, a Cardiology Today Editorial Board Member, said. “The large number of evaluated single nucleotide polymorphisms creates the potential for therapeutic insights, but also raises the risks of false discovery. Replication of the results is a key component required to determine preliminary findings. Whether the pharmacogenetic relationships reported for dalcetrapib represents a paradigm-shifting discovery or a false signal awaits the results of the current outcome trial in patients with the AA genotype.” – by Erik Swain
References:
Nissen SE, et al. Featured Clinical Research II: Interventional. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.
Nissen SE, et al. JAMA Cardiol. 2018;doi:10.1001/jamacardio.2018.0569.
Disclosures: The study was funded by Eli Lilly. Nissen reports he received grants and nonfinancial support from Eli Lilly during the conduct of the study, and that he has no relationship with the dal-OUTCOMES trial. He does not accept personal fees or honoraria from drug and device companies.
Perspective
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Robert H. Eckel, MD
This analysis was not confirmatory about the importance of this mutation relating to outcomes in CETP inhibitors. This appears to be unique to one drug in one study, and not to a similar drug in the same class in another study. It is difficult to say whether another CETP inhibitor would “break the tie.” I’m not sure if anyone knows what this gene does. In any case, the AA genotype does not appear to predict success on evacetrapib.
The question now arising is whether this class of drugs is going to have a future. Merck has decided not to promote anacetrapib and the other three compounds have been discontinued or have little planned going forward. This is interesting science, and may identify some genetic marker that leads to success with dalcetrapib, but it does not take us to the next level of understanding whether this class of drugs is ever going to see the light of day.
If this line of research is pursued with anacetrapib, it could lead to modifications of trial designs for people with certain genetic dispositions, and maybe the drug could find a home. This mutation is not rare, so whatever this gene does, the AA genotype is fairly prevalent, which suggests it may be worthwhile to pursue the science further. But at this time, that promise remains remote.
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