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Diagnostics Eye Fragile-X Market After Wide Adoption of CF-Screen

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At least four pharmacogenomics companies are currently working on a diagnostic test for fragile-X syndrome, with the apparent goal of replacing the expensive, time-consuming, and awkward existing test with assays that are simple enough or cheap enough to be used in clinical screening.

“We’re looking very hard at some new methods,” said Michael Watson, executive director of the American College of Medical Genetics, who sits on an advisory committee involved in developing newborn screening for fragile-X. The committee reviewed a test as recently as last week, said Watson, but “the first test that they thought was going to work didn’t have a hope.”

Watson declined to name the company responsible for the failed prototype test, but more candidates are appearing on the horizon. “We’re looking at a few other options,” said Watson. “Tm Bioscience is looking at it pretty hard,” as are a few academic labs, he added.

Today’s fragile-X test hasn’t changed much since the 1991 discovery of its related gene, FMR-1. It is a two-part test consisting of a PCR amplification of sometimes very long sequences, followed by a Southern blot, which must reveal both the number of repeats in the amplified region and the gene’s methylation status to determine a patient’s fragile-X status.

The target market of fragile-X testing is essentially the same as that of cystic fibrosis — the four million Americans born every year and their parents, according to Ed Highsmith, associate professor of laboratory medicine and pathology and co-director of the molecular genetics lab at the Mayo Clinic in Rochester, Minn. Like fragile-X tests, CF testing is mediated by an ob-gyn. “Clearly you would like to target people before their pregnancy,” but people don’t often think about genetics ahead of time, said Highsmith.

“There is probably on the order of 60,000-70,000 CF tests being done per month in the US, and that probably represents about a 30 percent penetration into the 3,000 or so Caucasian pregnancies,” said Highsmith. “We’re still in sort of an implementation phase.”

Cystic fibrosis is more common in Caucasians and Ashkenazi Jews than other ethnic groups.

Companies whose fragile-X programs have been disclosed include Third Wave Technologies and Celera Diagnostics, according to spokespeople from both companies.

“We believe the market for fragile-X testing exceeds the market for CF testing today. It is a significant, significant market opportunity,” Third Wave spokesman Rod Hise told Pharmacogenomics Reporter. The test Third Wave is working on “could be used for both” population screening and as a typical diagnostic “just like CF [tests],” said Hise.

In fact, the “most significant” product in feasibility at Third Wave Technologies is a fragile-X diagnostic, according to a company statement. “When we bring a product to market, we want to be as assured as we can be that it’s a competitive and compelling product,” said Hise.

With a poster presented at the Association for Molecular Pathology meeting last week in Los Angeles, Celera Diagnostics introduced its fragile-X test, but spokesperson Robert Bennett was not able to disclose by press time whether the company had decided to pursue the project as a new product.

Among molecular geneticists familiar with the implementation of population-based carrier screening for cystic fibrosis, fragile-X testing often “comes up” as a likely candidate, said Highsmith.

Genzyme Genetics is a big player in the fragile-X market. Of the approximately 50,000 prenatal patients that the company sees every year, about 8 percent consent to fragile-X testing, said Vivian Greenblatt, the firm’s northern regional manager. Companies like Genzyme and LabCorp offer diagnostic services using homebrew tests — usually for patients in well-described categories.

Newborn population screening of fragile-X syndrome is not done routinely today. “The test is way, way, way too expensive for such a system,” said Watson. “It’s probably 10 to 20 times more expensive than current tests run.”

However, Greenblatt estimates that molecular-based CF tests cost about $270 apiece. Because the American College of Obstetricians and Gynecologists issued a statement recommending CF testing for all Caucasian and Ashkenazi Jewish patients that are pregnant or considering pregnancy, CF tests are performed much more often than fragile-X tests, Greenblatt said.

The existing fragile-X test — based on the difficult amplification of a long DNA segment and a time-consuming Southern blot — now costs between $200 and $500, according to several sources. By contrast, a tandem mass spectrometer test of particular metabolites can cost less than $10, said Watson. The unsuccessful fragile-X test submitted by the unnamed company was an “inexpensive amplification-based test they thought they could do for $25,” said Watson.

The expensive and cumbersome existing fragile-X tests already have a position in the marketplace into which molecular diagnostics companies likely hope to move.

“It is clearly part of the standard of care for the workup of a child with proven environmental delay,” a market segment that will probably continue to grow, said Paul Billings, senior geneticist and vice president for biotechnology and healthcare strategy at LabCorp. “I think more and more biological workups of developmental delay are occurring — I think you’re going to find a greater market for this test,” he said. The test is also in common use in infertility workups, Billings added.

But parts of the fragile-X test’s market are fraught with ethical issues, such as its use in amniocentesis. “Some OB/GYNs do it, others don’t; it’s certainly not paid for by third-party payors, but there is certainly some uptake of it,” said Billings.

“The growing part of the market is its use in selection of embryos in [in vitro fertilization] settings,” Billings said. LabCorp does not perform these tests, he said.

Customers who use the test to determine carrier status are, “for the most part,” people who are easily able to afford it, said the ACMG’s Watson. “However, when you move toward the newborn screening side and it’s state mandated, money becomes a major issue,” he said.

Fragile-X testing is not yet mandated by any state. By way of comparison, the cheaper and easier cystic fibrosis tests are mandated for newborns by several states, and “several [more] are moving that way,” Watson said.

Aside from the issues of cost and convenience, other parameters become important in newborn screening. The discovery of fragile-X enables physicians to intervene, but with only incremental improvement in outcome, said Watson. “You should be able to treat it to make a difference in the infant for having screened them in the first place — you need a good, sensitive, cheap test and you have to know the natural history of the disease pretty well,” he added.

“There’s no test that I’m aware of that would meet the needs of a newborn screening type of test,” said Watson.

Fragile-X is the leading inherited cause of mental retardation. One of every 4,000 males and one of every 6,000 females are affected by fragile-X, according to Liane Abrams, a genetic counselor who works occasionally with the Fragile-X Foundation. About one in 800 males and one in 259 females carry the premutation that can lead to fragile-X in offspring, she said.

— CW

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