By Karen Pihl-Carey

DeCode genetics Inc. says it identified a gene contributing to cerebrovascular disease.

GlaxoSmithKline plc says it knows the genes associated with migraine, Type II diabetes and psoriasis.

Genset SA says it uncovered genes involved in prostate cancer and schizophrenia.

The list goes on and on, and will continue to grow. The mapping of the human genome last year was merely the gunshot at the start of the race. It gave companies the go-ahead to find effective therapies for deadly and debilitating diseases.

But will it pay off?

That is the focus of a report put out this month by The Boston Consulting Group (BCG) called "A Revolution in R&D Part II: The Impact of Genetics." The report is the second part of a three-part series that is exploring the impact of genomics and genetics. The first part, published in June, illustrated how genomics technologies can make things more efficient for the research and development company. But the second part shows how genetics can have an even greater impact.

"The promise of disease genetics is too good to ignore and you don't want to get left behind," said Peter Tollman, a BCG vice president in Boston, and the leader of the firm's biopharmaceutical R&D practice. "On the other hand, you could get caught up in a lot of debt."

It's a high-stakes game that many R&D companies are willing to play. DeCode, for example, signed an agreement with Affymetrix Inc. just last week to develop DNA-based tests to predict the responsiveness of patients to treatments for high cholesterol, depression, asthma, hypertension, breast cancer, schizophrenia and migraines.

"DeCode, they do what are called linkage studies in disease genetics. Up until now, there has been no real evidence that linkage studies work," Tollman said. "It might work."

But DeCode is not the only company sailing for a new world. More and more companies are exploring disease genetics, the search for genes that make people susceptible to particular diseases, and pharmacogenetics, which involves predicting the efficacy and side effects of candidate drugs. They are researching polymorphisms, or common variants found in more than 1 percent of the population, as well as single nucleotide polymorphisms (SNPs), which are more rare and consist of just a single altered letter in the genetic code.

The application of disease genetics and pharmacogenetics could save hundreds of millions of dollars in developing a drug ¿ half of what it costs now, Tollman told BioWorld Financial Watch. Some of those savings would come from improved efficiency in discovery, but most of it would come from a better success rate in the clinic.

"Today, companies that are spending $4 billion on their R&B budget, $3 billion of that $4 billion is basically what their rejects are costing them," Tollman said.

While estimates of the financial impact of genetics on research and development are merely guesses, it is clear that genetics can shorten the time it takes for a product to reach the market, in some estimates by as much as two years, the report says. Companies will be able to tailor their clinical trials to achieve the desired outcome when focused on a specific group of people known to carry a particular marker of the disease.

Genentech Inc., for example, knew that its breast cancer treatment Herceptin was effective in 25 percent to 30 percent of patients whose tumors overexpressed the HER2/neu oncogene. The company screened the patients and eliminated nonresponders early in the clinical trial.

"If you were working with a group of people and only a third of them respond, and you don't know who that third is, it's much harder to prove your point," Tollman said.

Without eliminating the nonresponders, Genentech would have needed nine times as many patients in the Phase III trial in order to show efficacy. In that case, Herceptin would not have been an economically viable product for Genentech, the report says.

Pharmacogenetics, however, has been "over-hyped," Tollman said, because sometimes drugs that fail are not due only to genetic reasons. Certain environmental factors may contribute to the patient's response to the therapy. For instance, grapefruit juice, the report says, is known to modify the effect of certain drugs in certain people, "sometimes raising the uptake to dangerous levels."

Therefore, companies that design a trial based only on genetic factors may get themselves in trouble. From a marketing standpoint, however, both genetics and pharmacogenetics could have an impressive impact, Tollman said.

Companies can focus their efforts better when they know the frequency of a causal polymorphism. For example, there are rare variants in PS1, PS2 and APP that are almost certain to cause Alzheimer's disease, but the ApoE4 polymorphism of the ApoE gene, which sometimes causes Alzheimer's, is much more common, and a therapeutic targeting it would have a larger market.

With pharmacogenetics, companies also can determine which patients might suffer adverse effects from a particular drug. That could mean more sales for a company if patients know ahead of time that they are not susceptible to the side effects. They may even be willing to pay more, the report says.

The same advantage, however, that allows a company to narrow in on a subset of patients also can be a disadvantage for the company because the market then becomes smaller. Once approved, the therapy will be marketed only to people with the specific gene marker responsible for the disease, and those people not expected to experience the side effects, instead of the entire disease itself.

Also, being able to identify a SNP associated with a disease does not necessarily mean that target will be "druggable," the report says. CFTR was a disease gene discovered long ago for cystic fibrosis, but a successful therapeutic is yet to be developed. And while Ceredase, a drug for Type I Gaucher's disease, was created through disease genetics, it is one of only a few success stories.

Another disadvantage to disease genetics is that studies focus on a subset of genes and risk missing other potential causes. The BRCA1 breast cancer susceptibility gene may be pinpointed in certain families, for example, but it may show a low prevalence in other families also known to develop breast cancer.

And finally, recruiting for clinical trials may not be quite as easy using disease genetics. A company would now have to find patients ¿ not just with a particular disease, but patients that carry certain genetic variants associated with the disease.

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