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EU s GenoSept Project, SIRS-Lab Aim To Bring Sepsis Dx to Market by 2007


A large new European research project is starting to investigate the genetics of sepsis and septic shock, and, like a recent multi-institutional US effort, it aims to yield risk factors and markers of variation in treatment response that may interest drug makers and diagnostic companies.

The 14-institution GenoSept (Genetics of Sepsis and Septic Shock) project was begun by the European Society of Intensive Care Medicine with the goal of identifying genotypes predisposing some patients to sepsis or septic shock. The project also plans to explain gender-related differences in the development of sepsis, Roberto Wolfer, manager of operations for Jena, Germany-based SIRS-Lab, told Pharmacogenomics Reporter. After seeking out risk- and treatment-variation genotypes, the study aims to standardize protocols for sample-gathering in genotyping and gene expression analysis, Wolfer said.

The project's laboratory work — the expression profiling — will be finished by the end of the year, followed by data integration and bioinformatics analysis, with a diagnostic product available as soon as 2007, Wolfer said.

The total amount of funding was not available on the project's website. Wolfer did not know the amount.

Studies like GenoSept and the US National Institutes of Health's Inflammation and Host Response to Injury consortium promise benefits for drug makers and clinicians alike. As the genetics of these diseases are sorted out, pharma will be able to use genotypic variation to stratify clinical trials, while clinicians can use prognostic tests to prescribe more aggressive treatments.

But that is still pretty far down the road. The first phase of the GenoSept study began in February as researchers started working to identify SNPs related to sepsis morbidity and mortality, said Wolfer. The entire first phase, including lab work and analysis, could last as long as three years, he said. Only then will the next phase, the search for SNPs explaining variation in treatment response, begin, he said.

SIRS-Lab's role is to use its medium-density expression array to identify genes likely to be related to sepsis in more than 6,000 patients whose samples have been gathered from hospitals throughout Europe, said Wolfer. The project partners will then try to identify polymorphisms in these genes that may serve as morbidity and mortality markers, he said.

Results from the project ultimately have to be commercialized, said Wolfer. "This is one prerequisite from the EU grant — that there should be a partner from the commercial side" who is able to develop products from the data, he said. SIRS-Lab is "the only commercial partner in this project," he added.

In particular, Wolfer hopes that the gene expression and genotyping data will allow drug makers to stratify patients during clinical trials of sepsis-related drugs. "This would be one piece of the puzzle," he said. The study might also yield new targets for pharma to target with new compounds. But in general, "the earlier that you are able to diagnose" sepsis and septic shock, the earlier "you are able to give [appropriate] antibiotics and therapeutics," which will reduce the cost of treatment, the risk of adverse drug events, and slow the spread of antibiotic resistance among bacteria.

SIRS-Lab has not yet decided whether it will develop its own sepsis-related diagnostic using data gathered from the study, although "this is one option" for product development in the next three to five years, Wolfer said. Alternatively, the firm may attract a business partner capable of translating SIRS-Lab's data into a diagnostic product for determining risk or judging treatment response, he said. The company specializes in gene expression systems, protein arrays, and microorganism detection, and not SNP genotyping, he said.

Few drugs exist for sepsis-related areas. The only drug approved to treat sepsis itself, Xigris, generated $201.8 million for Eli Lilly in 2004, according to company documents. According to Stephen Kingsmore, director of the National Center for Genome Resources, about 750,000 patients contract sepsis annually in the US, and the infection-related systemic inflammation has an annual healthcare burden of about $20 billion in the United States [see Pharmacogenomics Reporter 3/31/2005.

According to the Interdisciplinary German Competence Network for the Study of Severe Sepsis and Septic Shock, 154,000 patients suffer from sepsis annually in Germany — where SIRS-Lab is based — and half of them die.

"Early goal-directed therapy," a low-technology support regimen for sepsis patients, drops the disease's mortality rate by 15 percent — "but it's very intense — it involves intensive monitoring and support," Kingsmore said. Furthermore, that therapy is very effective in only a small subset of patients.

If initiatives like GenoSept and the NIH Inflammation and Host Response to Injury study deliver on their promise, Xigris, which costs on average more than $7,000 per patient, may perhaps be prescribed only to those individuals with high-risk prognostic markers, said Kingsmore. The drug "gives a 12-percent reduction in mortality … but it's not something you can give to everybody" because of its high cost and possible side effects, he said.

GenoSept "will hopefully improve the way patients are treated," with therapy organized and decided for each patient depending on genotype and other clinical factors, said Wolfer. "Xigris has a problem because it affects patients differently, which is why [the manufacturer Eli Lilly has] to involve more and more patients from the regulatory point of view to [understand how] to use Xigris in the right way," he said. "But that's only one example."

— Chris Womack ([email protected])

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