Full article reprinted from "The Gray Sheet" - November 3, 2008
Find out how Sequenom has made progress towards being first-to-market with a blood test to replace invasive prenatal Down syndrome diagnostics despite a challenge along the way from an upstart group out of Stanford University.
Down Syndrome Diagnosis: Sequenom Moves Closer To Noninvasive Test
Full article reprinted from "The Gray Sheet" - November 3, 2008
Sequenom has made progress towards being first-to-market with a blood test to replace invasive prenatal Down syndrome diagnostics despite a challenge along the way from an upstart group out of Stanford University.
In September, Sequenom announced positive results for its SEQureDx Trisomy 21 Down syndrome assay. The market reacted strongly; the firm's stock price moved up 35% on the news to $27.76. This is almost triple what the stock's value was in early June just before the company first released data on the test.
Then, on Oct. 28, Sequenom announced the launch of a 10,000-patient study of the assay, which the firm hopes will ultimately drive adoption among obstetricians caring for the approximately 3 million pregnant women in the U.S. who annually elect to have noninvasive risk assessments for Down.
But between the data release and the study launch, potential competition reared its head. The San Diego firm's stock tumbled after results were published online Oct. 6 from Stanford researchers demonstrating a different prenatal blood diagnostic technique for Down syndrome and other abnormalities.
Stanford is filing for a patent for that test and says it has two company licensees in mind.
Sequenom played down the results from the Stanford team, questioning whether their test could feasibly be developed into an affordable clinical diagnostic that didn't infringe on Sequenom patents.
In any case, the company plans to launch SEQureDx out of its clinical laboratory next year. When that happens, it will be the first assay available to directly measure fetal chromosomal abnormalities in the mother's blood.
The hunt for such a non-invasive prenatal diagnostic has been a long one, according to Allan Bombard, an obstetrician, clinical geneticist, and chief medical officer at Sharp Mary Birch Hospital in San Diego.
"When I was in medical school and a fellow [in the 1980's], this was the hot topic," Bombard said at a Sept. 23 event organized by Sequenom. "Unfortunately, it has not really progressed very far over the past 25 years." Until now, he affirms.
New Blood Tests Fit Nicely With Clinical Guidelines
The American College of Obstetricians and Gynecologists (ACOG) recommends that all pregnant women, independent of age, be offered screening for Down syndrome.
Women can be non-invasively assessed in the first trimester with a test consisting of two blood markers and a "nuchal translucency" ultrasound measurement; or in the second trimester with a four blood marker test; or with a combination of these options to arrive at results identifying whether a fetus has a greater-than-average probability of having Down.
If the risk is judged to be elevated, the patient can elect to have chorionic villus sampling - analysis of placenta tissue during the first trimester - or an amniocentesis - analysis of amniotic fluid during the second trimester. Both of these tests offer definitive results for the presence of an extra chromosome 21 - the cause of Down - but they both come with a small risk of miscarriage.
Both Sequenom's and Stanford's assays also directly measure for the extra chromosome, but they do so non-invasively from a sample of the mother's blood.
The current version of SEQure Dx relies on two freely floating genes pinpointed by researchers to derive from a growing fetus. They are not present in a woman's blood before pregnancy or after delivery. By quantifying the ratios of certain mutations in these genes, the assay can detect an extra chromosome 21.
Internally, Sequenom has collected data from about 400 patients in the first and second trimesters at different risk levels. As reported in September, the test correctly identified six cases of Down's, with no false positives or false negatives.
The current version of the test will not give results in about 7% of women from the general pregnant population who do not have certain mutations. These patients will yield a definitive "no call" outcome that will trigger a physician to suggest conventional blood and ultrasound screening, according to the firm.
Based on its findings so far, the company expects less than a 1% false positive rate and 99% sensitivity in the upcoming trial.
Bombard says that the test is particularly appealing because it is simple and can be employed with equivalent accuracy at any time of pregnancy after 10 weeks. Results for current non-invasive and invasive Down tests, on the other hand, are highly dependent on gestational age, he explained. "This technology really provides, in a direct fetal test, an opportunity to bypass the biggest problem we have, and that is inaccurate gestational dating."
"Given the level of improvement in detection rate, sensitivity and specificity, once there is sufficient data out there, my personal opinion is [the test] will be very widely adopted," Bombard said. "There will be a strong demand from patients."
Test Service Launch Planned For June
Brown Medical School researchers will lead the 10,000-patient observational RNA-based Noninvasive Aneuploidy (RNA) study evaluating SEQureDx against amniocentesis or chorionic villus sampling.
The RNA study will enroll 5,000 women in the first trimester of pregnancy and 5,000 in the second trimester, all of whom have already been judged to be at an elevated risk and referred for CVS or amnio. Each individual will be tested with SEQureDx and the results will be compared with the subsequent CVS/amnio findings.
"This is quite simply a major step forward if it works at all like we expect," said Jacob Canick, a professor of pathology and laboratory medicine at Brown, during the Sept. 23 Sequenom briefing. Canick is the co-lead investigator for the RNA study.
Results from the study will not be published before 2010, after Sequenom plans to make the test available in June 2009.
In September, the firm announced a definitive agreement to acquire the Center for Molecular Medicine, a Michigan-based clinical laboratory with expertise in genetic testing and, most importantly, a certification under the Clinical Laboratory Improvement Amendments as a "highly complex" lab (see sidebar: "1"Not An IVDMIA"").
Sequenom plans to launch SEQureDx as a service from the CMM lab (which has started to recruit a sales force to market the service to obstetricians), but not before collecting and releasing data from another 3,000 to 5,000 samples to validate the CLIA lab.
The combination of the validation data and the RNA study "should support early as well as broad, long-term adoption," said Harry Stylli, CEO of Sequenom.
The RNA data will also be used to support eventual FDA approval of a SEQureDx test kit; the firm plans on initiating discussions with the agency on the Down syndrome test by the end of the year.
Further, the RNA investigators will bank the 10,000 patient samples as tools to help develop the assay as one that could truly displace amniocentesis by testing for additional, rarer, abnormalities. This will include, in the near term, trisomy (third chromosome) 18 and 13 disorders. Sequenom has already developed prenatal assays for rhesus D and fetal XY syndromes that will be offered out of the CMM lab in the first half 2009.
Stanford Test Relies On Sequencing
Despite the market reaction to the Stanford results, Sequenom's Down syndrome test is likely to beat the Stanford assay to market.
Stephen Quake, the Stanford professor of bioengineering whose lab published the data in the Oct. 21 issue of the Proceedings of the National Academy of Sciences (posted online Oct. 6), says it will take the test two to three years to reach the clinic.
Instead of monitoring for specific genes and mutations, Quake's test simply employs a rapid biochemistry platform to sequence the entire genome in the pregnant woman's blood and identify specific sequences associated with each chromosome. By counting the sequence tags, the researchers measured for over-representation, which is a sign, they say, of an extra chromosome.
In 18 subjects, the team successfully identified nine cases of Down syndrome, two cases of trisomy 18, and one case of trisomy 13, with no false negatives.
Quake and colleagues say their test has an advantage over assays like SEQureDx because it does not require subjects to have specific mutations and, thus, can theoretically work for everyone. The researchers are now looking to confirm their results in a several-hundred-patient study.
Sequenom Defends Its Competitive Advantage
For its part, Sequenom says its scientists have identified additional mutations to include in the assay that will increase the test's coverage to greater than 95% of the general U.S. population and it is considering including a new gene that could increase the applicability rate further.
The company has initiated studies in Asia to find better mutations for that population; Sequenom's current test can only provide "yes or no" results in about 65% of that ethnic group.
Shortly after the Stanford paper came out, Sequenom issued a "2fact sheet" that is highly critical of the Quake test's prospects to be a serious competitor. "The testing methodology described in the Quake manuscript is still only of academic interest and is far from being commercially feasible," the document notes.
Sequenom says the method used by the Stanford researchers to quantify fetal material infringes patents exclusively licensed by the firm.
Further, Sequenom points out that the earliest-stage pregnancy in the Stanford study was 14 weeks, in the second trimester. The firm says it has demonstrated yes-or-no Down syndrome accuracy at 12 weeks and is currently refining its sample preparation so the launched version can get the needed signal at 10 weeks.
The fact sheet also suggests that the cost of the sequencing assay on top of predicted royalty obligations would not be feasible for a clinical lab test. The PNAS paper identified the sequencing cost per sample in the study as $700, but said that the "cost of sequencing is expected to continue to drop dramatically in the near future."
Sean Lavin, an analyst with Lazard Capital Markets, says SEQureDx costs about $80-$150 to run, according to numbers he has seen. Sequenom says it plans to price the Down syndrome assay at about $800 and then add to that when additional chromosomal markers are added to the panel.
Lavin tends to agree with Sequenom's view of its competitive advantages, calling the Quake assay a "good science experiment" but "not a viable diagnostic mechanism" in an Oct. 22 research note.
"Sequenom's advantages include its strong IP portfolio, being first to market, its very low [cost of goods] and high efficiency, and the fact that it will likely be the first with both an ACOG recommendation and FDA approval - all significant barriers," he writes.
- David Filmore
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