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With New Coalition in Place, PGx Takes Aim at Trauma Setting, ICU

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A large multi-institutional research project funded by the US National Institutes of Health aims to identify the genetic and other factors that determine the broad range of outcomes seen in trauma and critical care patients.

The research project is a long-term, 19-institution collaboration, known as the Inflammation and the Host Response to Injury program, that seeks to understand the causes and progression of systemic inflammation through clinical, genomic, proteomic, and bioinformatic analyses. Should the program successfully identify prognostic markers and clinically relevant proteins, drug makers may find themselves with a ready supply of surrogate endpoints to aid drug development, in addition to a new supply of drug targets to use in preventing the progression of systemic inflammation.

Still, even describing the problem is difficult, meaning that devising new diagnostic and prognostic tests — and eventually therapeutics — based on pharmacogenomics lie years in the future.

"There's no question that [molecular medicine is] coming, and to be honest, the critical care people are becoming quite excited," Stephen Chanock, principal investigator of the US National Cancer Institute's Advanced Technology Center, and a speaker at the upcoming Functional Genomics in Critical Illness and Injury meeting in Bethesda, Md., told Pharmacogenomics Reporter this week.

"I'm curious to see at this meeting [which will be held on April 21] who says, 'We're now in the early phases of a study where we're using microarray [profiles] or SNPs to be able to make therapeutic or prognostic decisions" in the trauma setting or intensive care unit, said Chanock. "I think we're moving in that direction, but we're not quite there," he added. The field is "very much in the discovery phase."

But getting there is the hard part. For example, comparing data between disparate research groups is difficult because of differences in technology platforms and variations in the definition of diseases, such as sepsis or respiratory failure, common in the critical care setting, Chanock said. "The hard part is that the accrual is always going to be small in any center, compared to what you can do in an out-patient clinic for cancer or mental health or diabetes or what have you. So they face the question of how to do multi-institutional studies," he added.

The Inflammation and the Host Response to Injury network recently jumped that first hurdle when it developed a standardized system that could compare expression data. The group is now ready to begin enrolling patients for true molecular profiling studies.

Nearly halfway through its 10-year lifespan, the 4-year-old project will begin looking at large patient groups to find prognostic markers for critical care diseases, which it hopes will lead to diagnostic products, drug targets, and, ultimately, new pharmacogenomics-based therapeutics.

To be sure, drug makers will have plenty of time to prepare — the use of microarrays and other pharmacogenomic technologies is fairly new to critical care. "Certainly there's a lot of work looking at how individuals respond differently to a similar injury or a similar disease, like sepsis," said Scott Somers, a program director at NIGMS in trauma, burns, and perioperative injury who oversees the grants funding the IHRI project. "Maybe as an offshoot of that, in the future as answers become available, we'll see more and more people dealing with pharmacogenomics" in critical care, he said.

The IHRI's research is published in the March 29 issue of the Proceedings of the National Academy of Sciences.

The Project

In an effort to confront "big problems" in genomics it identified, the NIGMS put together a program to fund multi-institutional studies through its Large-Scale Collaborative Research Project grants, said Perren Cobb, the lead author of the recent IHRI paper and one of its 70-odd principal investigators.

"These are big grants — they're $25 million direct over five years," and renewable once, said Cobb, who is also an associate professor of surgery and genetics at Washington University School of Medicine. The grants amount to about $30 million when indirect funding is included, according to NIGMS.

"The big problem that we [the IHRI] tackle is systemic inflammation" — the release of inflammatory mediators into the bloodstream due to a number of different conditions, including trauma and sepsis, that can lead to organ failure and death, Cobb said. Specifically, the group investigates responses to blunt trauma and burn-injury trauma by examining patients "at the blood level with regard to the immuno-inflammatory mediators," he said.

According to 2003 figures from the US Centers for Disease Control and Prevention, 5 million critically injured Americans are admitted to intensive care units each year. Trauma is the number one cause of death for Americans between the ages of 2 and 40, and it is the fifth-most common cause of death overall.

In the near term, the consortium's goal is to identify markers that can help distinguish patients who will have the most difficulty surviving systemic inflammation, and to develop a diagnostic to be used in critical care, said Cobb. To that end, the group plans to collect samples from 250 patients for expression profiling. Later, these markers may provide novel therapeutic targets, he added.

But in the present day, precious little overlap exists between therapeutics and molecular diagnostics in the trauma setting or ICUs. "I know of nothing by any drug maker or diagnostic company working in critical care or trauma right now that is relevant to pharmacogenomics," said Somers, who is responsible for a "fairly large research portfolio" concerning trauma and critical illness, in addition to the IHRI grants. "If you're not seeing it in academics, you're not seeing it in industry" either, he said.

Simply separating trauma and critical-care patients into risk groups would be a big step, said Somers. "So little is known about the physiological responses and the disease process, that targeting interventions is really hard," he said. "What's out there right now are some fairly simple-type interventions that need to be tested that no drug company is going to touch, because they're cheap, commonplace interventions," he added.

The Sepsis Example

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

"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," but that therapy is very effective in only a small subset of patients, said Kingsmore.

Although prognostic indicators may eventually become surrogate endpoints useful to drug makers, it is possible that the economic incentives to develop a sepsis drug may diminish, at least temporarily. 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.

But the eventual development of prognostic biomarkers and later surrogate endpoints may smooth the way for new therapies, if only in the long term. Newer therapies for sepsis are "not really well-proven. … [F]or the last 15 years people have thrown everything at this problem — every biologic that's come down the pike," including steroid therapy and intensive sugar-control therapy using insulin, said Kingsmore. "There have been a whole bunch of innovative therapies that potentially could be expedited" using surrogate endpoints, he said.

— CW

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