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Sequenom s Latest Dx Plan Focuses On Fetal DNA; Hopes to File 510(k) in 5 Years

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Armed with new intellectual property, Sequenom is continuing to advance its plan to produce molecular diagnostics for its MassArray platform with a test that uses fetal DNA found in maternal blood.

Last week, the company announced that it had licensed patents from Isis Innovation, the technology transfer company of the University of Oxford, covering the United States, the United Kingdom, and other countries in Europe. The patents protect prenatal genetic diagnostic testing on fetal nucleic acids derived from plasma or serum "on any platform including mass spectrometry and real time polymerase chain reaction amplification platforms," the company said in a statement. The patents cover tests for cystic fibrosis, hemoglobinopathies (such as sickle cell anemia), and chromosomal aneuploidies (such as Down syndrome).

"The IP is not restricted to MassArray," Harry Stylli, Sequenom's CEO, told Pharmacogenomics Reporter this week, adding that the company has the right to "where appropriate, use whatever is the best platform to tackle these problems, so we're not tied to any particular platform."

Despite the broader applicability of the IP rights, the agreement is in line with the company's new strategy, announced in mid-September, to focus its efforts on MassArray's utility in diagnostics.

In its latest stab at the molecular diagnostics market, the company is modifying the MassArray for the relatively undeveloped area of non-invasive fetal diagnostics. The traditional method of testing for fetal abnormalities — such as Rhesus D incompatibility, cystic fibrosis, and Down syndrome — is through amniocentesis or chorionic villus sampling, both of which are invasive and potentially harmful techniques.


"The first one to reach the finish line will be really well off, let's say, because it's a test that the government and the public [have] been waiting for, and screening tests are just not good enough for the moment."

Sequenom plans to produce a test for RhD incompatibility on its Compact MassArray to begin with, and to follow that up with a test for RhD fitted to its high-throughput platform, according to a company spokesperson. These tests involve identifying an RhD-positive genotype from fetal DNA in the blood of an RhD-negative mother.

The company will provide homebrew information on the tests to CLIA labs for their own in-house testing within approximately two years, and use the labs' experiences to accrue clinical data to support an application for US Food and Drug Administration 510(k) clearance "in maybe five years, plus or minus a year or two," Stylli said. Sequenom plans to use this route for all of its tests on fetal DNA, applying for FDA premarket approval for those tests without a predecessor, he said.

For the next test after RhD incompatibility, Sequenom is "deciding between two or three tests," including thalessemia, cystic fibrosis, and aneuploidy-related disorders, Stylli said.

For future tests, the company may sublicense its fetal-DNA intellectual property and partner with other firms. "Before this IP was made public, [other companies] were approaching us because of the MassArray's potential in this area," said Stylli. Sequenom believes its MassArray is the best platform for RhD incompatibility, but the choice of platform for other fetal-DNA applications would depend on the needs of that test, he said.

Amniocentesis and CVS, which are nearly 99-percent accurate, can cause miscarriages in one out of every 200 or 300 procedures, said Ronald Wapner, director of the Division of Maternal Fetal Medicine at New York-Presbyterian Hospital. Stylli characterized Sequenom's non-invasive diagnostics as likely complements to amniocentesis and CVS, but would not go so far as to call them replacements.

The hunt for alternatives to amniocentesis is "a big area right now," said Bischoff. "The first one to reach the finish line will be really well off, let's say, because it's a test that the government and the public [have] been waiting for, and screening tests are just not good enough for the moment," she said. "To be honest, I think for any paternal sequences, [DNA testing from blood samples] should be done now."

At the moment, the only testing on fetal DNA in mothers' blood is conducted in Europe, said Bischoff. Although Sequenom's intellectual property seems to cover the gamut of testing in this area, there is still room for competition, she said. "I actually put in the IP [for a patent] last week," she said. "This is through Baylor [College of Medicine], but Biocept in San Diego will probably license it. The method we have here may be used to not only distinguish circulating DNA, but also cells," increasing the representation of fetal DNA, she added.

Sequenom's Plans for RhD

In RhD incompatibility, an Rh-negative mother's immune system attacks Rhesus D-positive fetal cells. Sequenom estimated that there are around 20,000 "high-risk" births out of about 420,000 RhD-incompatible pregnancies in the US annually. Currently, all Rh-negative mothers are given an injection of Rhogam, an anti-Rh antibody that suppresses the immune response to Rh-positive fetal cells, but only about half of them really need it, according to a Sequenom spokesperson. Real-time PCR tests are currently used in some European countries to identify Rh-positive fetuses, but this approach suffers from a higher rate of false-negative results than the company's MassArray platform-based tests are expected to, the spokesperson said.

If a DNA test identifies functional RhD genes in an RhD-negative mother's blood, those genes would therefore belong to an Rh-positive fetus, but in the case where a test finds no functional RhD genes, it's necessary to prove that fetal DNA was indeed tested.

Sequenom has been working on fetal DNA detection with Dennis Lo, a researcher at the Chinese University of Hong Kong who has investigated both genetic and epigenetic methods of distinguishing maternal and fetal DNA. In July 2004, Lo and colleagues reported in the Proceedings of the National Academy of Sciences that they were able to detect four common Southeast Asian beta-thalassemia mutations in at-risk pregnancies using the MassArray platform. A month later, Sequenom announced it had placed a Compact MassArray system at the Chinese University's Department of Chemical Pathology, where Lo heads a research team examining fetal nucleic acids in maternal blood, to support "large-scale" studies to "accelerate the introduction of non-invasive prenatal tests … into the clinical diagnostic market."

Asked whether Sequenom would eventually move beyond genotyping and venture into probing fetal gene expression from maternal blood samples, Stylli said that tests measuring fetal RNA levels in maternal blood are not currently planned, but "if you look at methylation markers, they're involved in gene regulation." The company's intellectual property covers any technique used for non-invasive prenatal diagnosis based on fetal nucleic acids in plasma or serum, he added.

Any methylation-related tests will probably happen much further down the line than the company's nucleic acid tests, however. "All near-term applications are genetic, not epigenetic, fetal markers in maternal plasma or serum," Dereck Tatman, the company's vice president of business development, said in an e-mail exchange. "Epigenetic markers can be used for some of the same applications (or other tests), but are not required for what we have planned," he said.

Like Sequenom's RhD effort, there are other genetic conditions lending themselves to a simple approach based on the detection of a disease gene different from any carried by the mother. "[Researchers] have proven this now for cystic fibrosis, for Huntington's [disease], for achondroplasia, for myotonic dystrophy," said Bishchoff. "All of these severe disorders, where if you could detect the paternal allele, you basically could perform a diagnostic test and determine if the fetus is affected versus [becoming] a carrier," she said. However, "you could never rule out the maternal contribution," unless methylation or other differences are detected, she said. "But you could certainly rule out an affected homozygous case."

While there is certainly an incentive to find replacements for current fetal diagnostics, the immediate investor reaction to Sequenom's latest deal has been uninspiring.

Since the company announced its licensing agreement with Isis on Oct. 20, its stock price has continued to hover between $.60 and $.70 per share, representing no diversion from a decline that began in July. The company said on Sept. 20 that it had received a warning letter from Nasdaq's listing qualifications department because its shares did not comply with Nasdaq's $1 minimum bid price requirement for 30 consecutive business days.

Sequenom has until March 15, 2006, to regain compliance by closing at or above $1 per share for at least 10 consecutive business days. If the company does not regain compliance by this deadline, its common stock will be delisted.

— Chris Womack ([email protected])

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