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Emboldened by Research, Roche Said It Will Shoot for Molecular Dx, Tx for Osteoporosis

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Encouraged by research linking a gene with bone mass density, Roche Palo Alto plans to develop what the Swiss company hopes will become the first molecular diagnostic for osteoporosis risk, SNPtech Pharmacogenomics Reporter has learned.

The company said it also hopes to develop a therapeutic that would target the product of that gene, Alox15, and help delay or even reverse the onset of osteoporosis — a disease that costs US health-care facilities $17 billion a year to treat, according to the National Osteoporosis Foundation.

“What we want to do is develop genetic tests that would predict who is at risk for developing osteoporosis,” said Gary Peltz, head of genetics and genomics at the Roche unit.

The new diagnostic would be based in part on research published in the Jan. 9 issue of Science by scientists from Roche, Oregon Health and Science University, and the Veterans Affairs Medical Center. In this study, researchers found that bone mineral density in mice is low when Alox15 is highly expressed. This gene encodes the 12/15-lipoxygenase enzyme. Low BMD is a hallmark of osteoporosis.

Although researchers must still prove whether Alox15 contributes to BMD loss — and thus the onset of osteoporosis — in humans, a test for its expression may one day predict who is at greater risk for the disease. Indeed, Peltz said Roche is currently trying to identify mutations of the Alox15 gene that may trigger increased expression. Bob Klein, associate professor of medicine at Oregon Health and Science University and a lead author of the Science study, said his group has already found SNPs within Alox15, but do not yet know which of them leads to increased expression.

However, other genes that are part of the Alox15 pathway may also contribute to osteoporosis predisposition — and may become part of a future diagnostic. “We are in the middle of studies looking at that,” Peltz told SNPtech Pharmacogenomics Reporter.

Alox15 isn’t the only gene or pathway associated with increased osteoporosis risk. Late last year, for instance, researchers at Decode Genetics said they linked variants of the bone morphogenetic protein-2 gene to osteoporosis in humans — giving the Icelandic company a distinct lead over its Swiss counterpart. And Klein’s group has found at least four other loci in mice that probably represent different pathways contributing to BMD.

Because of this variety, Klein said a diagnostic would likely cover a panel of genes. “You would be looking at a variety, and not simply BMP2 or simply something in the Alox15 pathway,” he said.

Eventually, Roche would like to couple a diagnostic with a therapeutic and offer a prophylactic drug to patients that test positive in a molecular diagnostic for osteoporosis susceptibility. “The ideal situation would be to identify who is at risk in particular, based on that gene and pathway, and have a fairly selective and targeted therapeutic,” Peltz said.

There doesn’t appear to be a shortage of compounds. In the Science article, for example, researchers treated two mouse models of osteoporosis with compounds “known from the literature” to inhibit 12/15-lipoxygenase, according to Peltz. Mice given the compounds experienced increased bone density and strength.

Peltz said Roche does not intend to pursue these compounds. Rather, the company is currently working to develop its own 12/15-lipoxygenase inhibitors, he said. He stressed that a therapeutic based on the Alox15 pathway is at least 12 years away, while a diagnostic may be marketed “a lot sooner.”

According to Klein, between 60 percent and 80 percent of the variations in bone mineral density is due to genetic factors. “One can imply from there that a good deal of osteoporosis will be genetically predetermined,” he said. However, it is not yet clear how many genes would be responsible. “You may be talking as small as five or maybe as high as 20-50 different genetic variations that could be contributing to that.”

The market for an osteoporosis predisposition test could be considerable: According to a 2000 report by the National Institutes of Health, 10 million Americans suffer from osteoporosis, and 18 million more have low bone mass, putting them at increased risk.

And the prevalence of bone fractures triggered by the disorder is also great: Half of all women and a quarter of all men over age 50 will have an osteoporosis-related fracture in their lifetime, according to the National Osteoporosis Foundation. The disorder is responsible for more than 1.5 million fractures annually, including 300,000 hip fractures, 700,000 vertebral fractures, 250,000 wrist fractures, and 300,000 other fractures. US-based hospitals and nursing homes spent $17 billion to treat osteoporotic and associated fractures in 2001, the NOF estimates.

The high prevalence of osteoporosis, the enormous cost of treating its effects, and a dearth of sophisticated diagnostic or therapeutic tools — physicians today rely on traditional X-rays to confirm the disease — has made osteoporosis a prime candidate for pharmacogenomic intervention.

A few weeks ago, Procter & Gamble Pharmaceuticals licensed from Sequenom an undisclosed number of osteoporosis targets against which the drug company hopes to develop new therapeutics. P&G will validate targets in biological and animal models in osteoporosis to identify screening candidates.

In November, Decode’s identification of the BMP2 mutations showed that approximately 30 percent of individuals in a recent Icelandic study had one of three versions of the gene that put them at three times greater risk for developing osteoporosis.

Two months earlier, Interleukin and UCSF researchers began studying mutations linked to bone fractures in patients with osteoporosis. The partners said they hope to use the data to develop a home-brew test that Interleukin would market. Interleukin CEO Philip Reilly said he expects a home-brew test to be ready for marketing in less than one year, and said it would cost between $100 and $200.

— JK/KL

 

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