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SAEC Joins with Two UK Universities to Expand PGx Research on Liver Injury, Hypersensitivity Reactions

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By Turna Ray

This article was originally posted on Sept. 10.

The International Serious Adverse Events Consortium last week announced separate collaborations with two UK academic research institutions to expand recruiting capabilities for studies on the pharmacogenetics of drug-induced hypersensitivity reactions and liver injury.

SAEC is partnering with the University of Liverpool's Wolfson Center for Personalized Medicine on the hypersensitivity research project, and the consortium is working with investigators at Newcastle University's Institute of Cellular Medicine to study liver injury.

SAEC is a non-profit consortium formed in October 2007 between industry, academia, the Wellcome Trust, and the US Food and Drug Administration to identify genetic variants associated with serious adverse events (PGx Reporter 06/03/09).

"Our fundamental challenge is scale," SAEC CEO Arthur Holden told PGx Reporter this week. Holden explained that prior pilot studies on drug-induced liver injury and hypersensitivity reactions conducted by the consortium were limited by the lack of diversity in study participants' ethnicities and geographic distributions. As such, these new efforts will aim to scale up recruitment of people from different parts of the world and validate risk alleles in subsets of patients treated with a particular drug or a class of drugs.

Research on drug-induced liver injury and hypersensitivity reactions is already a major focus of the consortium. Earlier this year, the SAEC released its third data set on these two areas (PGx Reporter 02/24/10).

For the hypersensitivity project with the University of Liverpool, SAEC and university researchers will form the International Hypersensitivity Consortium, or ITCH, which will be led by Munir Pirmohamed, National Health Service Chair of Pharmacogenetics at the university. ITCH will recruit patients with drug-induced hypersensitivity reactions within its collaborative network of more than 20 leading research centers through the world, and investigate risk alleles linked to a number of drugs.

"The aim is to identify genetic predisposing factors that would allow for prospective identification of susceptible patients, and insights into the mechanisms of these serious adverse reactions, which are associated with a number of drugs," said Pirmohamed. "Because of the relative rarity of these reactions, a global approach with multiple partners is the only solution," which is why the collaboration with SAEC is key, he noted.

For the liver injury project with Newcastle University, the partners will form the International Drug Induced Liver Injury Consortium, or IDILIC, which will be co-directed by Ann Daly, professor of pharmacogenetics at the university, and Guru Aithal, deputy director of the Digestive Diseases Center at Nottingham University. IDILIC will be responsible for recruiting patients with drug-induced serious liver injury reactions for a study to validate previously identified genes linked to liver injury.

"Our aim is to develop simple genetic tests so that treatment can be personalized and those at risk of these liver reactions prescribed other medicines instead," Daly said in a statement.

SAEC previously studied liver injury in partnership with the US Food and Drug Administration. The agency and SAEC reported their findings from that study in Nature Genetics last year, concluding that some people treated with the antibiotic flucloxacillin — a drug widely used in Europe and Australia, but not approved in the US — had greater risk for drug-induced liver injury if they had variations in the HLA-B and HCP-5 genes (PGx Reporter 06/03/09).

Flucloxacillin is a drug marketed by CSL Limited under the brand name Flopen and by GlaxoSmithKline under the name Floxapen in the UK, Europe, and Australia as a treatment for staphylococcal infections and infections caused by other gram-positive bacteria. GSK is a member of the SAEC consortium.

In addition to these collaborations, SAEC is also attempting to integrate sequencing data with data from genome-wide association studies in several PGx projects.

One such study announced earlier this year by SAEC and Duke University's Center for Human Genome Variation aims to investigate rare genetic variants associated with adverse events in people taking the antipsychotic drug clozapine. Researchers are expanding on published data on associations between the chromosome 6 HLA region and clozapine-induced agranulocytosis using a whole-genome sequencing approach (PGx Reporter 01/28/10).

Although the FDA and several drug companies are part of the consortium, Holden said that it will likely be several years before SAEC's research translates into commercial products or drug labeling changes. Although the impulse of most observers of the genetics field is to conjecture about the commercial viability and regulatory implications of a particular body of research, Holden doesn't entertain such questions.

"The genetics field is covered with failure. The science hasn't developed enough in a substantive way to support" commercialization of genetic tests, Holden told PGx Reporter. "We haven't even done the science yet." According to Holden, the aim of SAEC's partnerships with these UK universities is to facilitate the kind of in-depth and complex analyses on subpopulations necessary to derive validated gene targets that confer risk to certain drugs.

"It's way too early to jump to commercialization. It's going to take us a while to do this research," he added. "In three to five years, after the data generation is complete, maybe we can get closer to that. But right now, we're building the knowledge set to be able to do that."

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