By Turna Ray

CHICAGO Data from a prospectively designed, randomized study involving patients who have undergone a percutaneous coronary intervention suggests that individuals who are carriers of the CYP2C19*2 allele experience lower platelet aggregation, and therefore greater response, to standard-dose Effient than they do to high-dose Plavix.

In the study, called RESET, University of Rome's Gennaro Sardella and colleagues also identified a possible platelet aggregation cutoff above which patients may be more likely to harbor genotypic variations in CYP2C19 that compromise their ability to respond to Plavix.

Although the US Food and Drug Administration has placed a "black box" warning on Plavix to note that patients with certain CYP2C19 genotypes may not respond to the drug, physicians have been reluctant to adopt testing without more specific guidance on how genotypic information can guide dosing. Preliminary data from the RESET trial, presented here this week at the American College of Cardiology's annual meeting by Sardella, may further inform such a genotype-driven dosing strategy.

The data confirms results from other trials suggesting that patients who have undergone PCI and harbor certain CYP2C19 alleles respond better to Daiichi Sankyo/Eli Lilly's Effient (prasugrel) than they do to Plavix (clopidogrel), marketed by Bristol-Myers Squibb and Sanofi-Aventis. Specifically, the findings in RESET corroborate results from a retrospective gene substudy of the GRAVITAS trial, in which Matthew Price and colleagues from the Scripps Clinic found that CYP2C19*2 carriers compared to those with the normal allele experienced increased platelet reactivity despite a double dose of Plavix (150 mg/day).

Meanwhile, a prospective study published by researchers at Brigham and Women's Hospital last November in the Journal of the American Medical Association genotyped more than 300 patients with cardiovascular disease and reported the most detailed genotype-guided dosing data for Plavix to date. In that study, called ELEVATE-TIMI 56, the researchers found that patients with CYP2C19*2 genotypes given triple the maintenance dose of clopidogrel (225 mg/day) experienced the same level of platelet reactivity as patients without the CYP2C19*2 allele who received a 75 mg/day dose of the drug. However, the researchers, led by Jessica Mega, found that in patients who carried two copies of the *2 allele, "doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition."

While the Mega study investigated the influence of genotype on response to increasing doses of Plavix, the Sardella study compared the influence of genotype on response to high-dose Plavix and standard-dose Effient. Also, the Meta study broke down Plavix response by whether patients had one or two copies of the *2 allele, whereas Sardella's study only considered *2 carriers versus non-carriers. The retrospective GRAVITAS genetic substudy, meanwhile, also found that *2 homozygous patients fared worse on Plavix than did heterozygous *2 patients.

It is currently controversial in medical practice to use genetic testing to determine whether patients should be treated with Plavix, since a number of studies have come to divergent conclusions about the association between CYP2C19 genotypes and Plavix response, depending on whether researchers focused on surrogate markers of response, such as platelet reactivity, or patient outcomes in terms of cardiovascular events. Many of these studies have been retrospective in design, involved heterogenous disease populations, or been too small to provide definitive answers. Most doctors are waiting for the FDA to provide more definitive dosing recommendations by genotype before deciding whether to adopt genetic testing in this setting.

RESET

In RESET, the study investigators used a crossover, randomized design to compare the antiplatelet effect of standard-dose Effient (10 mg/day) versus high-dose Plavix (150 mg/day) in patients who were stable after a PCI, but had high on-treatment antiplatelet activity upon receiving moderate- to low-dose Plavix. Researchers looked at the relationship between platelet reactivity and CYP2C19*2 genotype when patients were on Effient and then switched to Plavix, or were first on Plavix and then given Effient.

Original post:
Study: Higher Plavix Dose Doesn't Improve Response for CYP2C19*2 Carriers; Effient May Be Best Option

By Turna Ray

CHICAGO A recent analysis of genotype and clinical data from more than 700 heart failure patients found that individuals who are homozygous for the wild-type allele Ser49 in the beta 1-adrenergic receptor gene experienced prolonged survival when they received treatment with beta-blockers compared to Ser49 homozygotes who didn't receive such treatment.

The study, led by researchers from the University of North Carolina, Chapel Hill, also found that carriers of one or two copies of the Gly49 allele in the beta1-AR gene did not experience a survival advantage when treated with beta-blockers compared to Gly49 carriers who didn't receive such drugs.

Beta-blockers inhibit beta-adrenergic substances that regulate the nervous system of the heart and are often prescribed to control high blood pressure, to manage irregular heart rhythms, and to treat heart failure patients. There are several beta-blockers on the market approved by the US Food and Drug Administration, including AstraZeneca's Toprol XL and GlaxoSmithKline's Coreg.

Based on data from past studies, UNC researchers Jasmine Talameh, Kirkwood Adams, and others hypothesized that Ser49 allele status "will be associated with beta-blocker survival benefit in a large, heterogeneous, US heart failure population," said Talameh, who presented data from this study at the American College of Cardiology meeting here this week.

Study investigators reviewed beta-blocker use and survival for heart failure patients enrolled in the United Investigators to Evaluate Heart Failure Biomarker Registry from 2000 to 2002. The current analysis involves more than 700 patients in the registry for whom there was information on beta-blocker use, survival, and genotype.

"The UNITE-HF DNA Registry was started by Kirkwood in 1999 as a way to promote clinical registry, biomarker, and genomic research in heart failure," Talameh said during her presentation. "These prospective, multicenter, observational registries were designed to study medication use, long-term outcomes, and the genomics of heart failure patients seen in US heart failure specialty clinics."

Patients in the registry had a history of heart failure and could have been asymptomatic at the time they were enrolled. According to Talameh, the majority of patients in the registry had received Coreg and Toprol.

Study investigators used mass spectrometry to genotype patients for the Gly49 and Ser49 alleles in the lab of Howard McCleod, director of UNC's Institute for Pharmacogenomics and Individualized Therapy. During the follow-up period, researchers collected patients' clinical information at the study sites and then periodically with the Social Security Death Index.

Among the study participants, 68 percent were Ser49 homozygous and 32 percent were Gly49 carriers. Using the Social Security Death Index, researchers found that more than 340 patients died after an average follow up of seven years, of which 52 percent were Gly49 carriers and 47 percent were Ser49 homozygous.

More:
UNC Analysis Finds Beta1-AR Alleles Impact Survival in Patients Treated with Beta-Blockers

The Broad Institute and Sanger Institute announced yesterday (March 28) details from their separate cancer cell line databases, the largest such repositories of genomic and drug profiling data to date. With preliminary results published in two Nature papers, the databases should help researchers identify which drugs to use against which cancers to streamline drug development efforts.

This continues to move us towards cancer being understood as a molecular disease instead of an anatomical disease, said Eileen Dolan, who studies pharmacogenomics at the University of Chicago and was not involved in either study. It will help us understand our existing drugs, as well as new drugs, to make more informed decisions in phase I and phase II trials.

In recent years, researchers have become increasingly aware that whether a tumor will respond to a given drug treatment depends on its genomic profile. But because of the vast number of cell lines and variety of drug options, researchers in smaller labs often dont have the resources to identify the best fit for the cancer type or drug theyre studying.

For any variety of cancer drugs that are being developed, we cant necessarily know in advance which cancers are going to be vulnerable, said Levi Garraway, a cancer biologist at the Dana Farber Cancer Institute who spearheaded the Broad project. If you have a large collection of cell lines that are deeply annotated genetically and molecularly, you can probe the biology linked to many types of genetic alterations of interest.

Four years ago, Garraway and his colleagues began a massive screen of 947 cancer cell lines, sequencing cancer-associated genes, profiling drugs, collecting RNA expression data using microarrays, and combing the cancer genomes for repeated regions. And they werent too far along when they learned of a parallel project at the Sanger Institute, led by genomicist Mathew Garnett.

The projects arent identical; they screen different genes and different drugs using slightly different methods. For this reason, Garnett views the two databases as complementary. There was sufficient non-overlap that it was possible to make different observations, agreed Garraway. (See table for details.)

Plus, having two separate databases rather than pooling the data, as previous databases have done, could lend more weight to certain findings. I think having two independent resources is a good thing, said Jian Ma, a computational genomicist at the University of Illinois, who did not participate in the research. If two different groups have the same result for one cell line, it would be more reliable.

The two Nature papers, submitted as a pair, describe how the data for each project were collected, and include confirmatory experiments to demonstrate how the databases could enhance cancer drug development. Garnetts project, called the Cancer Cell Line Encyclopedia, identified a mutation in Ewings sarcoma cells that is highly sensitive to PARP inhibitors, for example. Meanwhile, Garraways database, the Genomics of Drug Sensitivity in Cancer project, includes data suggesting that MEK inhibitors, a class of cancer drugs that target the RAS oncogene, may have increased efficacy in cancers with a mutation in another gene, AHR.

The ultimate hope is that the databases will be used to help people with cancer by better matching a cancer type to a drug, and identifying which patients to enroll in clinical trials based on their genetic flavor of cancer. Often, drugs fail [in clinical trails] simply because theyre not tested in the right people, said Garnett. A better understanding of how drugs respond to genetic mutations, helped by the databases, could help clinicians single out what populations are most likely to respond.

Continued here:
Collecting Cancer Data

The annual meeting of the American College of Cardiology held this week in Chicago featured a number of pharmacogenomically guided studies related to treatments for cardiovascular disease.

The following is a roundup of some of the meeting's pharmacogenomics highlights.

Lack of Association in SLCO1B1 Polymorphisms and Clinical Myalgia after Crestor Treatment

Researchers led by Jacqueline Suk Danik from Brigham and Women's Hospital investigated whether individuals who are carriers of SCLCOB1 rs4363657C and rs4149056C have increased incidence of myopathic complaints when taking AstraZeneca's Crestor (rosuvastatin) compared to non-carriers. In past studies, researchers have seen a similar influence in patients taking Merck's Zocor (simvastatin).

Danik et al. retrospectively genotyped patients receiving Crestor in the JUPITER trial. The original study randomized 4,400 people without heart disease or diabetes to Crestor or placebo. "Among those allocated to active rosuvastatin, there was no difference in [the] rate of myalgia among carriers of the rs4363657C allele or the rs4149056C allele when compared to non-carriers," the researchers found. The researchers had similar findings even after expanding their definition of myalgia to include complaints of muscle weakness, stiffness, or pain.

"In contrast to data for simvastatin, there appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C allele or the rs4149056C allele in the SLCO1B1 gene," Danik et al. concluded.

AstraZeneca, the National Cancer Institute, and the National Heart, Lung, and Blood Institute provided funding for this study.

Impact of CYP2C19 and CYP3A5 Genotypes in Patients Undergoing Stent Procedures, Treated with Maintenance Dose Plavix

Studies have shown that patients with high platelet reactivity after being treated with Bristol-Myers Squibb's Plavix (clopidogrel) may be at increased risk of stent thrombosis after undergoing a stent procedure. Researchers led by Tadasuke Chitose of Kumamoto University examined CYP2C19 and CYP3A5 genotypes, as well as platelet aggregation, in 62 patients. Platelet reactivity was measured twice, after patients received a loading dose (300 mg/day) of Plavix, and then after they received a maintenance dose (75 mg/day) of the drug.

In the study, 31 percent, 42 percent, and 27 percent of patients were extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively. After patients received 300 mg/day of Plavix, platelet reactivity was 4,069 +/-1,383; 4,407 +/-1,755; and 5,301 +/-807 AU*min in the extensive, intermediate, and poor metabolizer groups, respectively. After receiving the maintenance dose of Plavix, platelet reactivity levels were 2,948 +/-1,427; 3,068 +/-1,656; and 4,465 +/-1,557 AU*min in the extensive, intermediate, and poor metabolizer groups, respectively.

See more here:
PGx Highlights from American College of Cardiology Annual Meeting