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Prenatal Sequencing Becoming Standard of Care in Increasingly Litigious Market

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Since Sequenom launched the first noninvasive prenatal sequencing test for Down syndrome and other fetal aneuploidies in October 2011, the field has exploded.

For instance, just last week, Illumina said it planned to acquire Verinata Health for up to $450 million. Verinata markets a noninvasive sequencing-based fetal aneuploidy test, Verifi (CSN 1/9/2013).

Other companies, such as Ariosa Diagnostics and LifeCodexx have also launched tests.

In addition, two technology assessment committees have green-lighted the tests and insurance companies are increasingly reimbursing for them.

With Sequenom alone running an estimated 60,000 MaterniT21 Plus tests in 2012, some observers include sequencing-based prenatal tests among the fastest-adopted clinical tests in the US.

However, because the market is so lucrative — potentially several billion dollars per year, according to some estimates — the field is rife with patent disputes. Currently, all the US-based companies are caught up in lawsuits. LifeCodexx, which is based in Germany, has licensed intellectual property from Sequenom to launch its test and has so far avoided being sued. Additionally, China's BGI, which has begun offering its NIFTY test through partnerships with Prague-based GENNET, Inex Innovations Exchange in Singapore, and Pregnicare in Israel, has managed to avoid lawsuits despite using a very similar methodology as Sequenom and Verinata.

A number of academic groups are also developing methods for noninvasive prenatal sequencing, including a team from Johns Hopkins University that is working on a method for aneuploidy detection dubbed Fast-SeqS (CSN 8/8/2012). In addition, teams from Stanford University, the University of Washington, and the Chinese University of Hong Kong have been developing techniques to sequence the entire fetal genome deeply enough to detect SNPs (CSN 7/11/2012, GWDN 6/6/2012, and IS 12/14/2010).

Test Adoption Picks Up

At last week's JP Morgan Healthcare conference in San Francisco, Sequenom said that it had run more than 60,000 of its MaterniT21 Plus tests in 2012, beating its latest goal of 50,000 tests, and that its annualized run rate had topped 120,000.

During its first full year of testing, through October 2012, the company ran 37,000 tests, and had increased its testing volume to an average of 1,700 per week.

LifeCodexx, which offers its test in German-speaking countries, had received around 1,000 samples as of the end of November 2012 since its launch last August.

Verinata Health has not disclosed the number of tests it has run.

Ariosa reported at last week's JP Morgan Healthcare conference that it has reached an annual run rate of 100,000 tests, with more than 22,000 sold in the fourth quarter of 2012.

In addition, Ariosa's executive director, John Stuelpnagel, previously estimated that these prenatal tests were among the fastest adopted clinical tests in the US.

BGI has also run tens of thousands of its test to analyze fetal aneuploidies. As of the end of 2011 it had offered a Down syndrome test to more than 10,000 women (CSN 11/30/2011), and it recently published a study of its expanded NIFTY test, which screens for trisomies 21, 18, and 13, in the Journal of Maternal, Fetal, and Neonatal Medicine.

There are multiple reasons for the quick adoption. First, in each of the company's validation studies, the tests have all had high rates of specificity and sensitivity, ranging from around 92 percent for trisomy 13 to 100 percent for trisomy 21.

Second, the tests can be performed relatively early in a pregnancy, at around 10 weeks, which gives women time to plan ahead.

Third, the tests are noninvasive, unlike amniocentesis and chorionic villus sampling, which both carry about a 1 percent risk of miscarriage.

And finally, a study published last year in the Journal of Managed Care Medicine evaluating the cost-effectiveness of Verinata's Verifi test found that while the economic impact was moderate, resulting in a 1 percent cost savings over the standard of care, the use of the test as a follow-up to initial screening could reduce the number of invasive tests by 72 percent and thus reduce the number of test-induced miscarriages by 66 percent (CSN 5/2/2012).

Ariosa, meantime, has begun studies of its Harmony Prenatal test in not only high-risk pregnancies, but the general population as well, and has begun enrolling average-risk women into a clinical study to compare its test with standard first-trimester combined screening for trisomy 21 (CSN 12/19/2012).

Sequenom has been in discussions with the US Food and Drug Administration about applying for 510(k) clearance for its assay, as well as for implementing its test in the general population, and has also begun a clinical trial to evaluate test performance in low-risk pregnancies, which it expects to complete by the end of the year.

Payors, Tech Assessment Groups, Professional Organizations Approve

Key endorsements have given further strength to these tests' acceptance in the market. Two technology assessment organizations, the California Technology Assessment Forum and the Blue Cross and Blue Shield Association Medical Advisory Panel, concluded that noninvasive prenatal tests meet their criteria. CTAF issued draft guidelines recommending the tests as advanced prenatal screening for trisomies 21 and 18 in high-risk pregnant women (CSN 10/24/2012).

The BCBS panel concluded that sequencing-based testing of fetal trisomy 21 meets its criteria for both high-risk and average-risk pregnancies, as long as positive results are followed up with confirmatory testing.

In November, the American College of Obstetricians and Gynecologists issued an opinion that such testing can be offered to patients at an elevated risk for fetal aneuploidies, which it defined as "women aged 35 years or older, fetuses with ultrasonographic findings that indicate an increased risk of aneuploidy, women with a history of a child affected with a trisomy, or a parent carrying a balanced Robertsonian translocation with increased risk of trisomy 13 or trisomy 21."

Finally, payors have been increasingly reimbursing the tests. The companies have said that reimbursement is typically won on a case-by-case basis, but recently, several plans have started putting policies in place to cover the tests.

Most recently, WellPoint revised its policy regarding noninvasive fetal aneuploidy screening, suggesting that it would cover such tests for high-risk women. Additionally, Tufts Health Plan began covering Sequenom's test in October.

And, according to a research note by Jefferies that surveyed 20 regional and two national insurers representing 15 percent of the insured US population, Sequenom, Verinata, and Ariosa have captured in-network agreements serving 60 percent, 13 percent, and 15 percent of covered lives, respectively.

Patent Disputes

With 4.1 million live births each year, 750,000 of which are considered to be high risk, the market for these tests could potentially be several billion dollars per year if they are adopted in the general population.

Ariosa's test is the cheapest at $795, while Verinata markets its test for $1,200. Sequenom offers its test to uninsured patients for $1,700, but charges a copay of $235 to insured patients, while taking on the responsibility of securing the remaining costs from the payor. It bills insurance companies $2,900.

The market opportunity for these tests — and the fact that they all use similar technology — has led to a history of litigation in the sector since Sequenom first launched its test.

The lawsuits primarily concern a broad patent in the field, US Patent No. 6,258,540, which Sequenom licensed from Dennis Lo at the Chinese University of Hong Kong.

Most recently, Ariosa filed a petition with the US Patent and Trademark Office for an inter partes review of the '540 patent (CSN 9/19/2012).

Sequenom has sued Ariosa, along with Verinata and Natera, claiming the companies infringe on the patent.

Ariosa, Verinata, and Natera are also suing Sequenom for being overly aggressive in its enforcement of the patent, claiming the company is interpreting it too broadly.

Additionally, in October, Verinata sued Ariosa, claiming it infringes US Patent No. 8,296,076 entitled, "Noninvasive diagnosis of fetal aneuploidy by sequencing." Verinata licensed the '076 patent from Stanford's Stephen Quake (GWDN 10/25/2012).

And in December, the USPTOwithdrew a patent that it planned to issue to Sequenom, US Patent No. 8,340,916, due to an anticipated interference between it and another company with a similar patent.

Sequenom has also licensed that patent, titled "Diagnosing Fetal Chromosomal Aneuploidy Using Massively Parallel Genomic Sequencing," from Lo.

While the USPTO did not mention the competing firm, analysts speculated that it was likely Verinata, which holds a similar patent that it licensed from Quake (GWDN 12/17/2012).

Future

However the patent disputes play out, it's clear that noninvasive prenatal testing is here to stay. Researchers from these companies and academia are already looking beyond fetal sequencing for aneuploidy detection and are considering other diseases, as well.

At the American Society of Human Genetics meeting in San Francisco last November, a number of researchers reported that they are looking to expand the technique to other genetic disorders, such as sub-chromosomal aberrations and single-gene disorders (CSN 11/14/2012).

Before these future tests become reality, a number of technical and ethical hurdles will have to be overcome. For instance, moving into single-gene disorders will be tricky because there is still so much uncertainty and variability in clinical presentation even of known pathogenic mutations, Mary Norton, a professor of obstetrics and gynecology at Stanford University, said at the time.

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