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Aria Plans Clinical Trial of T21 Dx in 25K Women; Says Test Does Not Infringe Sequenom IP

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By Monica Heger

This story was originally published Jan. 17.

Aria Diagnostics is planning to launch a clinical trial of its noninvasive sequencing-based trisomy 21 test in 25,000 women.

Aria's CEO Ken Song told Clinical Sequencing News last week that the company plans to launch its test in the US in the first half of this year for under $1,000 with a turnaround time of about one week.

The company will be able to reach this sub-$1,000 price point because it is using a targeted sequencing approach that will allow it to pool up to 96 samples per sequencing lane. However, Song said that the company could pool fewer samples if necessary, and would not need to wait until it collected 96 samples before running the test.

The targeted sequencing approach differs from Sequenom's MaterniT21 test, which uses a shotgun sequencing approach. In Aria's test, only certain regions of the chromosomes of interest are sequenced.

Additionally, it uses an internally developed automated process to target the regions of interest, which helps reduce complexity and cost of the test, Song said.

As a result, Aria does not believe that its test infringes a patent held by Sequenom covering noninvasive prenatal testing. Aria has already filed a suit against Sequenom, alleging that the firm is overaggressive in its patent enforcement. In the suit, Aria requested a declaratory judgment that its test does not infringe the IP (CSN 12/21/2011).

Aria will run its test from its CLIA-certified lab in San Jose, Calif., on the Illumina HiSeq 2000, though Song said that the company is "platform agnostic," and also has Life Technologies' SOLiD and Ion Torrent PGM machines, which it will evaluate.

Song did not disclose the company's current testing capacity, but said that within its existing facility it could, in a "straightforward" manner and "short period of time," scale up to process 1,500 samples per day.

Aria also recently completed a $52.7 million fundraising effort, which will be enough to support the company "through profitability," and will be used in part to expand its sales and marketing force, Song said. He declined to disclose how large the company's workforce currently is or what its plans are for hiring, but said that "the largest growth area will be the commercial team," as it expands its "sales force, customer service, and reimbursement efforts" in the upcoming months.

Song said the company has already completed a number of studies validating its protocol, the first of which was published recently in Prenatal Diagnosis. That study evaluated the test in 298 pregnancies, including 39 cases of trisomy 21 and seven cases of trisomy 18.

Aria has "several additional clinical studies that we have completed, as well as others that are still underway," Song added. Over the next several months, a number of those studies will be published in peer-reviewed journals, he said.

In its upcoming blinded, multicenter clinical trial, Aria will compare its test to standard first-trimester screening — serum screening and nuchal translucency ultrasound, alone and in combination — for detecting trisomy 21. Women 18 years of age or older will be enrolled, and blood samples will be collected between 10 and 14 weeks of pregnancy. In addition, the company will follow the patient for the entire pregnancy through birth.

Aria's Targeted Approach

Aria's targeted sequencing approach uses an internally developed assay, called digital analysis of selected regions, or DANSR, which targets 384 loci each on chromosome 21 and chromosome 18.

The company tested three different sequencing depths on the Illumina HiSeq 2000 generating 204,000 reads per sample, 410,000 reads per sample, and 620,000 reads per sample. At the lowest depth, one normal case was incorrectly called as trisomy 21, but at medium depth it was called as normal. All trisomy 21 and trisomy 18 cases were correctly called at all read depths, and the highest coverage did not significantly increase statistical significance.

Song noted that this is significantly less sequencing than is required from the shotgun sequencing approach, which requires around 2 million aligned reads per sample to accurately diagnose trisomy 21.

As a result, Song said Aria plans to multiplex up to 96 samples per sequencing lane, compared to Sequenom, which multiplexes four samples. He said this would allow Aria to launch its test at a much lower cost.

Like Sequenom, Aria uses a Z statistic to call aneuploidies, with a Z score above three called as aneuploidy.

The difference is that Sequenom sequences the entire genome and compares the number of reads from chromosome 21 to the number of reads from a separate chromosome. Aria, meantime, sequences only chromosomes 18 and 21 and compares them to each other, which is feasible, said Song, because the likelihood of a fetus having both trisomy 21 and 18 is "so rare, it is not relevant."

Dennis Lo of the Chinese University of Hong Kong, who developed the technique behind Sequenom's test, said that while he found Aria's approach "intriguing," the normalization procedure described in the Prenatal Diagnostics study was very complex, so it would have been more convincing if the "authors had separated their samples into two groups," developing "the normalization procedure on the first group and then validating the procedure using the second group."

IP Issues

Sequenom has said publicly on several occasions that it believes anyone offering a noninvasive sequencing-based trisomy test infringes US Patent No. 6,258,540, "Non-invasive prenatal diagnosis" (CSN 7/27/2011). Sequenom holds an exclusive license to the broad patent, which is assigned to Lo.

Song, however, thinks that the method Aria has developed does not infringe the IP.

"We started the company in light of knowing the IP landscape and spent a considerable amount of our own resources evaluating the patent and developing our own test," Song said. "Our position is that … our processes and methods do not infringe on [Sequenom's] patent."

Additionally, he cited Aria's latest $52.7 million fundraising effort as evidence that investors, too, are comfortable with the company's IP position.

A number of other companies are also developing sequencing-based prenatal trisomy tests, including Natera, which, like Aria, recently filed a pre-emptive suit against Sequenom seeking a judicial declaration that its test does not infringe the '540 patent (CSN 1/11/2012).

Verinata Health is also planning to launch a sequencing-based fetal aneuploidy test this year.

Verinata holds a patent that it licensed from Stephen Quake at Stanford University, No. 8,008,018, titled "Determination of fetal aneuploidies by massively parallel DNA sequencing." The patent's claims cover a method for determining fetal aneuploidy in maternal tissue using next-gen sequencing (CSN 9/7/2011).

Verinata recently published an abstract describing its test in the American Journal of Obstetrics and Gynecology for February's annual meeting of the Society for Maternal-Fetal Medicine. The prospective, blinded study with an analysis cohort of 532 pregnant women showed that the company's sequencing-based test "provides superior sensitivity and specificity to diagnose trisomies 21 and 18, compared to screening by serum analytes and ultrasound, and is capable of detecting trisomy 13 and monosomy X," according to the authors.

Aria's Song noted that the fact that "at least a half a dozen other companies" are pursuing sequencing-based aneuploidy tests "should be informative [about] how others, including us, view the IP landscape."


Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.

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