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As Rivals Vie for Share of Noninvasive Trisomy Testing Market, Physicians See Value for Screening

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This story has been revised to clarify the tests' different no-call rates.

Over the past year, three different companies in the US have launched noninvasive sequencing-based prenatal trisomy tests, competing furiously for what could be a multi-billion dollar market.

Each company is attempting to grab market share by distinguishing itself from its competitors through various criteria, including test quality, price, turnaround time, and the number of disorders for which the test screens.

In the meantime, early adopters in the obstetrics and gynecology community are reporting positive experiences with tests from all three vendors, but stressed that these tests should only be used for screening tools in high-risk pregnancies, not as trisomy diagnostics.

Sequenom broke first ground last October when it launched its MaterniT21 test, which now screens for trisomy 21, 18, and 13. The test is based on massively parallel shotgun sequencing and uses an algorithm that essentially looks at the proportion of reads from chromosome 21 compared to a control chromosome to call trisomy.

Verinata Health's Verifi, which launched this March, uses a very similar technique and, like MaterniT21, screens for trisomy 21, 18, and 13. This week, however, the company also added a Turner syndrome option to Verifi.

Ariosa's Harmony Prenatal Test, meantime, uses a slightly different technique. Instead of whole-genome sequencing, it uses a targeted sequencing approach. It currently assesses only trisomy 21 and 18, but the company is planning to expand it to include trisomy 13.

In Europe, GATC Biotech subsidiary LifeCodexx will be the first to enter the market when it launches its PrenaTest for trisomy 21 this month in Germany, Austria, and Switzerland (CSN 5/23/2012). LifeCodexx licensed IP from Sequenom in order to develop its test, which is based on the same technology.

Performance, Price Differences

All three US-based tests have similar performance metrics for sensitivity and specificity.

In a study of more than 4,000 women published in Genetics in Medicine in February, including 212 cases of trisomy 21, 59 cases of trisomy 18, and 12 cases of trisomy 13, Sequenom achieved sensitivities of 99.06 percent, 100 percent, and 91.67 percent, respectively; and specificities of 99.94 percent, 99.7 percent, and 99.05 percent, respectively.

Verinata published results in the journal Obstetrics and Gynecology in May from a study of 2,882 subjects, including 89 cases of trisomy 21, 36 cases of trisomy 18, and 14 cases of trisomy 13. It achieved sensitivities of 100 percent, 97.2 percent, and 78.6 percent, respectively; and specificities of 100 percent for all three trisomies.

Ariosa has so far only published results from trisomy 21 and trisomy 18 cases. In a 4,000-person trial published in the American Journal of Obstetrics and Gynecology in June that included 81 cases of trisomy 21 and 38 cases of trisomy 18, the test achieved sensitivities of 100 percent and 97.37 percent, respectively; and specificities of 99.77 percent and 99.93 percent, respectively.

Where the tests showed some difference is the number of samples that were not called, either due to not having enough fetal DNA or because the analysis did not yield a definitive answer.

In Sequenom's study, 17 samples out of 1,988, or 0.86 percent, could not be analyzed due to low fetal DNA. The company did not report any samples that were sequenced but did not yield a test result.

In Verinata's study, 16 out of 532 samples, or 3 percent, did not contain enough fetal DNA. Additional samples were removed that had complex karyotypes, leaving between 501 and 503 samples. Of those, the assay could not call 14 samples as either trisomy or normal. In total, excepting the samples that were excluded due to a complex karyotype, around 5.6 percent of samples did not yield a result.

In Ariosa's validation study, out of 3,228 samples analyzed, 148 samples, or 4.58 percent, did not yield a result. Of those, 57 were due to low fetal DNA and 91 were due to assay failure.

The tests also differ in price. Sequenom bills insurance companies $2,900, offers the test to uninsured patients for $1,700, and charges a $235 copay for insured patients while taking responsibility for securing the remaining costs from the payor. Verinata's test, meantime, is priced at $1,200. And because Ariosa uses a targeted sequencing approach, it is able to offer the lowest priced test in the market at $795.

Market Potential

It still remains to be seen how these differences in performance, method, and price will impact the companies' ability to penetrate the still-nascent market for noninvasive prenatal trisomy testing.

In the US, there are some 4.1 million live births each year, of which 750,000 are considered to be high-risk pregnancies — the segment of the market that these companies are currently targeting.

For its first full year of sales, Sequenom has set an internal goal of conducting 40,000 tests, although many analysts believe the company will sell significantly more. In its most recent estimate, investment bank William Blair projected the company could sell 70,000 tests in 2012.

Neither Verinata nor Ariosa have disclosed test sales projections, although in May, Verinata said that it had processed more than 1,100 tests during its first three months of launch and that its run rate was continuing to increase on a weekly basis. These numbers are comparable to the 1,000 tests that Sequenom reported conducting from its October 2011 launch through the end of the year.

Nevertheless, William Blair analyst Brian Weinstein projects that Sequenom's first-mover advantage will enable it to capture 55 percent of the noninvasive prenatal trisomy testing market in 2013.

Ariosa's partnership with Laboratory Corporation of America for the sale of its test, signed in May, will help boost its position in the market, Weinstein said, but will likely have more of a negative impact on Verinata than Sequenom, he said.

Oppenheimer analyst David Ferreiro also doubted that Ariosa's agreement with LabCorp would have a major impact on Sequenom given the "uncertainty" over Ariosa's commercial infrastructure. The company's "internal capabilities in terms of sales force, reimbursement team, customer support, and capacity capabilities remains unclear," he wrote in a recent report.

Details of the agreement have not been disclosed, but LabCorp's Genzyme Genetics organization will be responsible for much of the commercialization of Ariosa's test. Weinstein said that the 150 representatives that have been trained by Genzyme will "give Ariosa an immediate presence in a market where land grabs are becoming increasingly important."

Additionally, Ariosa could "benefit from reimbursement expertise and possibly contracts that LabCorp has in place," noted Weinstein. Sequenom's experience has demonstrated that the reimbursement front is tricky — shortly after announcing a contract with Coventry Health Care in May, the payor canceled the deal. Afterwards, Sequenom said it would no longer announce individual contracts, only the number of lives covered. Currently, it has around 26 million lives covered for the MaterniT21 test.

Verinata has not yet announced any deals with insurance companies or other commercial partners.

Physician Acceptance

Importantly, physicians seem to be buying into the capabilities of non-invasive trisomy testing. All three tests available in the US have high sensitivities and specificities, and due to their non-invasiveness, physicians across the country have started offering them to women considered to be at high risk of aneuploidy either because of age, an abnormal ultrasound, or a positive serum screening test.

In a survey of 25 Ob/Gyns conducted in April, analysts from Oppenheimer found that more than 24 percent of those surveyed were already offering Sequenom's MaterniT21 and 68 percent had heard of it, even though only 8 percent had been visited by a Sequenom sales rep.

Herb Barr, a gynecologist who was involved with Ariosa's Non-Invasive Chromosomal Evaluation, or NICE, clinical trial, told Clinical Sequencing News that he has been offering the Harmony test to his patients since its launch, and that so far his experience has been "very positive." Around several dozen patients per week receive the test, he said, and turnaround time has averaged about two weeks.

He said that prior to the launch of the Harmony test, he offered both Sequenom's MaterniT21 test and Verinata's Verifi test, but the turnaround times were longer and the tests were more expensive. Additionally, he said the LabCorp partnership has made Ariosa's test "more readily available" due to LabCorp's network of draw stations.

While Ariosa's reported no-call rate in the published NICE study was 4.58 percent, Barr said that so far he has not had any no-calls.

He offers the test to women who are considered to be at high risk of having a baby with aneuploidy. If the test is positive, it is followed up with an invasive procedure like amniocentesis or chorionic villus sampling. "Even though the [Harmony] test has a high sensitivity and high specificity, it is currently still considered a screening test," he said.

Lee Shulman, medical director and professor of obstetrics and gynecology at Northwestern University's Feinberg School of Medicine, agreed with Barr that all three tests are currently screening tests, not diagnostic tests, and does not think that they will replace amniocentesis or CVS anytime soon.

Nonetheless, Shulman, who also serves on Sequenom's clinical advisory board, has been offering the MaterniT21 test since the beginning of the year to high-risk women and said that the test has been well-accepted among his patients.

While it's a "far better screening protocol, with higher specificity and higher sensitivity in a high-risk population," he said, "it's not a diagnostic test."

Shulman said that he has had three false positives with the test so far. "I've not had three false positives with CVS in 25 years."

As such, Shulman said he only offers the test to those women who fit exactly the population that was studied in Sequenom's clinical validation study. Such patients must be either 35 or older, have had an abnormal ultrasound, or have had a positive serum screen. Additionally, every woman who tests positive with MaterniT21 has gone on to receive an invasive test to validate the results.

Shulman has not tried either Verinata's or Ariosa's tests, but said that he thinks those "validation studies are even less robust than those from MaterniT21."

Anthony Odibo, the director of the Division of Ultrasound and Genetics and co-director of the Fetal Care Center at Washington University School of Medicine, has been offering patients Verinata's test. He has been happy with the test, and said that it has helped reduce the number of invasive procedures that have to be performed.

He hopes the test will eventually replace invasive procedures altogether. "The more the test is used and the more the lab gets experience, amniocentesis and CVS will become unnecessary," he said.

IP Uncertainty

One major question mark for the noninvasive trisomy testing sector is the contentious legal landscape. All three US-based companies are currently embroiled in lawsuits with each other, along with Natera, which has not yet launched a trisomy test, but plans to (CSN 1/18/2012).

The major patent in question is US Patent No. 6,258,540, a broad patent assigned to Dennis Lo of the Chinese University of Hong Kong, to which Sequenom holds exclusive rights. Sequenom has said that any test that uses sequencing to analyze fetal DNA from maternal plasma would be infringing on this patent.

However, both Verinata and Ariosa are seeking declaratory judgments that their respective tests do not infringe on the '540 patent (CSN 2/29/2012 and CSN 12/21/2011). Verinata also holds IP in the space that it has licensed from Stanford University (CSN 9/7/2011).

Sequenom has also sued Ariosa for patent infringement and is seeking an injunction against the company to halt the use and development of its Harmony test (CSN 2/29/2012 and CSN 1/25/2012).

The outcome of these various lawsuits could ultimately impact which company or companies gain market share. Currently though, trial dates have not been set.

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