Originally published Aug. 9.
The International Serious Adverse Events Consortium this week announced the launch of a new project in collaboration with researchers at the Royal Devon & Exeter Hospital in England to gauge genomic markers associated with treatment-related inflammatory bowel disease.
At the same time, the iSAEC also said it had finished enrolling participants in two other projects launched in 2010: an effort to characterize genetic alterations linked to drug-induced liver injury and another study to gauge genetic markers linked to treatment-related hypersensitivity skin rashes.
Tariq Ahmad, consultant gastroenterologist at the Royal Devon & Exeter Hospital, is leading the Predicting Serious Drug Side Effects in Gastroenterology, or PRED, study, launched this week. In the last 18 months, researchers have enrolled 900 patients with inflammatory bowel disease, drawing from a network of more than 50 leading research and gastroenterology centers worldwide.
According to Arthur Holden, CEO of iSAEC, the consortium plans to enroll 1,500 participants into the PRED4 project as part of an initial recruitment push by year end. Researchers will conduct standard genome-wide analysis to gauge markers of interest in the study.
The PRED4 study will specifically look for gene markers linked to nephrotoxicity, a type of kidney damage, caused by the anti-inflammatory drug 5ASA; inflammation of the pancreas and low white blood cell count due to the leukemia treatment thiopurine; a kidney disorder caused by proton pump inhibitors for treating stomach acid where the spaces between kidney tubules swell; and a nervous system disease that complicates anti-TNF therapy for rheumatoid arthritis, called demyelination.
Founded in 2007, the iSAEC is a multidisciplinary effort that joins drug developers, regulatory organizations, and academic centers with the aim of conducting research to uncover the genomic underpinnings of drug-related serious adverse reactions. The consortium's research efforts around liver toxicity and hypersensitivity reactions have been ongoing for several years now.
In 2009, iSAEC published findings from a study conducted with the US Food and Drug Administration, which found that those treated with the antibiotic flucloxacillin and with variations in HLA-B and HCP-5 genes were at greater risk for liver injury than those without these gene variations (PGx Reporter 6/3/2009).
The consortium announced this week that it had finished enrolling patients in the liver toxicity and hypersensitivity studies, with around 1,300 participants in each cohort. The genetic analysis for the liver toxicity study will be led by Tom Urban at Duke University and Paola Nicoletti at Columbia University. The hypersensitivity study data will be analyzed by researchers at Columbia.
For these studies, Holden explained that researchers will perform genotyping to gauge gene mutations associated with the adverse events, and then conduct custom genotyping and sequencing to validate their findings. The major drugs included in the hypersensitivity reaction study include amoxicillin-clavulanate, other beta-lactam antibiotics, carbamazepine, and anti-AIDS drugs. The drugs implicated in the liver toxicity study are amoxicillin-clavulanate, other major antibiotics, statins, NSAIDs, anti-TB drugs, and anti-TNF drugs.
The study investigators expect to have results in the next six months.
Although iSAEC is mostly applying GWAS techniques to gauge gene variants linked to drug related adverse events, the consortium two years ago launched pilot projects to apply exome sequencing to several of their studies. With Duke University, iSAEC used exome sequencing to identify rare variants predictive of clozapine-induced agranulocytosis, a failure of the bone marrow to produce sufficient neutrophils that leads to a reduced immune response. In another pilot effort, iSAEC and the Broad Institute used exome sequencing to look at rare variants associated with Augmentin-induced liver injury (IS 10/19/2010).
According to Holden, drug-related inflammatory bowel disease, liver toxicity, and hypersensitivity reactions are "quite rare" across drug groups. "In most cases, less than 2 percent of patients taking a given drug at proper dosing are at risk," he said.
Given the rarity of these adverse events, recruiting large study cohorts requires collaboration between multiple stakeholders and time. According to Holden, for the liver toxicity and hypersensitivity studies, approximately 20 centers were involved in the recruitment effort. Researchers also used data in electronic medical records to retrospectively identify patients for enrollment who had good phenotype data about their adverse reactions.
For the hypersensitivity study, in which researchers have enrolled precisely 1,330 patients, the majority of the cohort is of European descent. However, the study also contains "significant numbers" of patients of African descent, iSAEC noted in a statement.