Non-invasive prenatal testing remained the biggest clinical application of next-gen sequencing in 2013, and its largest clinical market, as the technology made inroads into oncology, rare disease diagnosis, and other areas.
During the year, NIPT providers expanded the indications for their tests and insurers started to reimburse for them, resulting in increased testing volumes, a trend that is likely to continue.
In the meantime, testing companies forged alliances with international distributors to offer their tests abroad, and several firms continued to fight each other in court over intellectual property rights to the test technologies.
According to a report by market research firm DeciBio, the majority of the $100 million worldwide next-gen sequencing molecular diagnostic market in 2012 consisted of non-invasive prenatal testing, and the NIPT market will grow to around $600 million, or half the estimated total NGS MDx market, by 2015, following by oncology testing, which it predicts to make up about a third of the market, and tests in areas such as infectious disease, HLA typing, idiopathic diseases, preventive medicine, and pharmacogenomics.
Professional societies, including the American College of Obstetricians and Gynecologists, currently recommend NIPT as an option for women at high risk of carrying a fetus with trisomy, but several studies to evaluate the tests for average-risk women, a significantly bigger market, are either underway or have already been published.
Although more expensive than current screening methods – prices for NIPT range from $800 to $3,000, compared to $50 for nuchal translucency and serum screening, according to one study – the new tests are more sensitive and result in fewer false positive results.
However, the fraction of fetal DNA in the mother's blood, which hinges on factors such as maternal weight and pregnancy stage, appears to be crucial for the tests' success, and some incorrect test reports have resulted from mosaicism of either the mother or the placenta.
In a policy statement issued in April, the American College of Medical Genetics and Genomics pointed out several limitations of NIPT, recommending obstetric care providers become familiar with the pros and cons of the approach.
Test numbers soar in 2013
While the overall number of non-invasive prenatal tests performed in the US and elsewhere is difficult to estimate, several companies indicated growth over the last year has been significant.
Sequenom, for example, conducted its MaterniT21 PLUS test on 111,600 patient samples during the first three quarters of 2013 alone, almost twice the number of tests, 61,000, it ran in all of 2012.
The company, which was the first to launch a NIPT in October 2011, is believed to be the market leader in the US, covering more than 60 percent of the high-risk pregnancy market in the country.
Ariosa Diagnostics, one of Sequenom's main rivals in the US, also released some data on its market position in 2013. The company launched its Harmony test in May of 2012, offering it through LabCorp. In the third quarter, Ariosa tested more than 40,000 pregnant women, more than Sequenom, which tested 38,600 samples during the same quarter. Since launching Harmony, Ariosa has tested more than 150,000 samples in total, and has been offering the test in more than 50 countries.
In the meantime, Berry Genomics, a Beijing-based NIPT company, said a year ago that it had performed more than 50,000 of its BambniTests since its launch in late 2011, and expected to run more than 100,000 tests in 2013.
BGI, whose clinical spin-off BGI Health offers the NIFTY non-invasive prenatal test, said in September that it had administered more than 200,000 tests in total in 22 countries, which does not include in the US.
Two other companies, Verinata Health and Natera, are also competing with Sequenom and Ariosa in the US NIPT market but have not released test numbers so far.
Verinata offers its Verifi test through PerkinElmer, while Natera has been making its Panorama test available through Quest Diagnostics and Bio-Reference Laboratories' GenPath in the US. All three partnerships were announced in early 2013.
In a move that surprised many in the industry, research equipment maker Illumina acquired Verinata last February, turning Illumina into a competitor to some if its own customers, as it provides sequencing systems and reagents to a number of NIPT firms, including Sequenom, Ariosa, Natera, BGI, and Germany's LifeCodexx.
Illumina is seeking approval from the US Food and Drug Administration to offer Verifi as an in vitro diagnostic test, and said in July that it had begun discussions with the agency on a trial design.
Insurance coverage
Reimbursement for non-invasive prenatal testing from national health insurance companies continued to grow in 2013, with some challenges along the way.
Following WellPoint's decision in late 2012 to start covering NIPT, Aetna said in February that it would also consider such tests medically necessary in pregnant women who meet a set of criteria demonstrating an increased risk for fetal aneuploidy. UnitedHealthcare followed suit in March, issuing a note in favor of NIPT for women meeting similar criteria.
However, none of the three payors guarantees reimbursement for the tests at this point, and none have contracts with NIPT providers yet.
Sequenom said in November that it had secured additional contracts with third-party payors and now has 90 million covered lives under contract. But it has experienced reimbursement challenges from changes in CPT codes by the Centers for Medicaid and Medicare Services, which prompted some insurance firms to initially deny payment.
The company said it has been particularly difficult to obtain reimbursement from Medicaid under the new coding system, leading the firm to implement a program to reduce the volume of uncompensated Medicaid tests.
New indications for NIPT
Sequencing-based non-invasive prenatal tests were originally launched to gauge the risk of fetal chromosomal trisomies, in particular Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Patau syndrome (trisomy 13).
But two research groups demonstrated last spring that the technology can also be used to look for sub-chromosomal aberrations, and several NIPT providers expanded the use of their tests to new indications last year.
Sequenom said in February that following a clinical validation study, Materni21 Plus can now also report on sex chromosome aneuploidies, including Turner syndrome, Triple X syndrome, Klinefelter syndrome, and another Y-chromosomal syndrome.
After conducting a method validation study, the company expanded the test further in October, so it now also reports on trisomies 16 and 22, as well as on select subchromosomal microdeletions, including DiGeorge syndrome, Cri-du-chat syndrome, Prader-Willi/Angelman syndrome, and 1p36 deletion syndrome.
Ariosa expanded the applications for its Harmony test last January to include IVF pregnancies, and in March to include Y-chromosome analysis, allowing for fetal sex determination and to assess the risk for Y chromosome aneuploidy. Later in the spring, it added the analysis of twin pregnancies as well as the evaluation of fetal sex chromosome conditions, such as Turner and Klinefelter syndrome.
Like Ariosa, Verinata Health in October also expanded its Verifi test to include twin pregnancies. The test currently detects Down syndrome, Edwards syndrome, and Patau syndrome, and looks for the presence of a Y chromosome.
Natera launched its Panorama test in March, initially for Down syndrome, Edwards syndrome, Patau syndrome, and select sex chromosome abnormalities, such as Turner syndrome. In October, following a validation study, it expanded the test to include the detection of triploidy, a fatal condition where a fetus has three copies of every chromosome.
Legal quarrels continue
As NIPT companies pushed into the market in 2013, their legal quarrels over patents continued beneath the surface.
In April, the US Patent and Trademark Office agreed to an inter partes review of a key patent held by Sequenom, following a request from Ariosa. The patent, No. 6,258,540, is assigned to Dennis Lo of the Chinese University of Hong Kong and licensed by Sequenom.
Then, in October, in a lawsuit between Sequenom and Ariosa, a federal court declared the patent invalid, saying that it covers a phenomenon of nature, which is unpatentable. Sequenom is appealing the decision.
In addition to litigation surrounding the '540 patent, which also involves Natera and Verinata, several lawsuits regarding other patents are pending, including one in which Verinata sued Ariosa over alleged infringement of two US patents, and several others between Sequenom and Verinata.