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GWAS Finds Genetic Predictor of Response to Cardio Drug; Prospective Follow-up Planned


NEW YORK (GenomeWeb) – By reanalyzing samples from previous studies in which the cholesterol drug dalcetrapib, developed by Hoffmann–La Roche, failed to show clinically meaningful efficacy, researchers have identified a genetic subgroup with a much higher response, resurrecting the chance for approval of the drug for a genetically defined group.

The results, published last week in the journal Circulation Cardiovascular Genetics, have spurred plans for a new prospective trial examining the efficacy of the drug in reducing cardiovascular disease outcomes specifically in those patients who have the genotype associated with response.

Although there is a wealth of biochemical and mechanistic evidence that higher levels of HDL are associated with better cardiovascular outcomes, Jean-Claude Tardif, one of the study's lead authors and director of the Montreal Heart Institute Research Center told GenomeWeb that HDL-raising drugs have so far yielded disappointing results.

In the dal-OUTCOMES study, published in 2012 in the New England Journal of Medicine, for example, dalcetrapib successfully increased HDL cholesterol levels but failed to improve clinical outcomes among the 15,871 studied patients.

Tardif and his colleagues hypothesized that there may be a genetic determinant of response to HDL-raising therapy that could help explain the discordance between this negative result and the epidemiological, clinical, and molecular studies that support HDL as a therapeutic target.

Based on their results, which showed that patients homozygous for a variant in the gene ADCY9 had almost a 40 percent reduction in outcomes like heart attack and stroke, the group is now planning a prospective PGx-guided trial with Hoffman-La Roche to begin in September of this year. They are also partnering with a diagnostics device company, Tardif said, to simultaneously develop a test that will be used to select patients for the trial. 

The researchers plan to work with regulators, including the FDA, he added, to make sure the plans for the trial are appropriate for establishing evidence to support approval of the drug and companion test.

In their retrospective study, Tardif and his colleagues analyzed more than 6,000 samples from patients who received dalcetrapib or placebo in two clinical studies, dal-OUTCOMES and another trial, dal-PLAQUE-2.

First, the group performed a broad GWAS using the Illumina Infinium HumanOmni2.5Exome-8 v1 BeadChip on a total of 5,749 patient samples from the dal-OUTCOMES trial. This revealed a variant in the gene ADCY9 associated with improved outcome in the dalcetrapib arm of the trial.

Patients homozygous for the rs1967309 variant had a 39 percent reduction in cardiovascular endpoints, including heart attacks, strokes, unstable angina, coronary revascularizations, and cardiovascular deaths, with dalcetrapib compared to placebo. In contrast, homozygous wild-type patients had a 27 percent increase in events with dalcetrapib versus placebo. Heterozygous patients had an intermediate response.

Several other polymorphisms in the ADCY9 gene also showed an association with response to dalcetrapib, but with less dramatic effects.

Using a Sequenom panel to genotype a more targeted set of variants in the ADCY9 gene, the group confirmed these associations, and then also evaluated another 386 samples from a second cohort, the dal-PLAQUE-2 trial, which also initially failed to demonstrate efficacy for dalcetrapib. 

Complementing the results from the dal-OUTCOMES cohort, patients homozygous for rs1967309 in dal-PLAQUE-2 also appeared to benefit from a reduction in the amount of atherosclerosis present in their blood vessels, based on imaging data.

"We wanted to make sure it was not a false positive signal, and we had access to this second supporting study and the results were unbelievably concordant," Tardif said. "Patients with the [sensitive] genotype had regression of disease on imaging while those with a [wild-type genotype] showed progression … so we clearly seem to have a marker that identifies responsive patients."

Based on these results, the team is now gearing up for a new study of the Hoffman-La Roche drug, which they hope to begin in September. This trial will be similar to dal-OUTCOMES, but will be limited to patients homozygous for the predictive allele the researchers identified in their retrospective GWAS, Tardif said.

Though he did not name the company that will be involved, Tardif said that the plan is to work with an established diagnostics firm to develop an assay that will determine patient eligibility for the trial. That assay will be advanced as a companion to the drug as the group seeks regulatory approval. 

"We hope that when the data are out there that this could eventually be on the market with an accompanying diagnostic test," Tardif said. "That would be a first for cardiovascular drugs. 

If the researchers are successful in this, their achievement could also serve as a catalyst for the investigation and development of other individualized drugs in the cardiovascular field, he added.

"Everyone is talking about personalized medicine, but [before this] there has not been a single cardiovascular drug whose effects have been shown to be determined by genetics when it comes to cardiovascular outcomes like death, MI, and strokes," Tardif said. "Now we may have opened the way, so this could be a paradigm shift whereby people now believe that this can work."