NEW YORK ─ Arcedi Biotech is rolling out a noninvasive prenatal test that relies on detecting rare fetal cells in maternal blood. The Vejle, Denmark-based firm claims the test can provide an overview of all 22 chromosome pairs and sex chromosomes and can detect syndrome-causing abnormalities. It can also determine the sex of the baby from week 12 of pregnancy.
The blood-based test is being positioned as an alternative to invasive prenatal diagnostic tests like chorionic villus sampling, which relies on obtaining placenta tissue samples with a needle and can result in miscarriage. The assay is being marketed under the name Evita Test Complete.
CEO Palle Schelde said that after rare fetal cells are obtained from maternal blood via Arcedi's enrichment method, they are analyzed using array comparative hybridization using 4x180K microarrays produced by Agilent Technologies. He said that Arcedi is planning to migrate the test this year to a next-generation sequencing platform and is currently reviewing Illumina and Thermo Fisher Scientific as prospective vendors.
"We haven't set our minds on which is the better one but of course it is interesting to take this from an array CGH platform to an NGS platform," said Schelde.
"It will definitely be this year," he said of the transition. "We have already tested a fair amount of technologies, library preps, and things like that. We know the technology is working, so now it's a matter of just getting the agreement together and having pricing everyone sees as a good deal."
Established in 2005, Arcedi Biotech has sought to commercialize technology developed in collaboration with Aarhus University Hospital, about 40 miles away. The company currently employs around 30 people and is backed by Bagger-Sørensen, a family-owned Danish investment company, also based in Vejle. Its longstanding goal has been to develop a test that could provide a full overview of any chromosomal abnormalities from a blood draw from any expectant mother, replacing the need for invasive CVS, which can result in loss of pregnancy.
There are numerous noninvasive prenatal tests in the market as well, but these rely on cell-free DNA and can detect only a limited number of abnormalities.
Arcedi's underlying method, described in a 2016 paper with Baylor College of Medicine, uses antibodies against cell surface markers to enrich and stain trophoblasts, cells present in the placenta, from about 30 ml of blood. First red blood cells, then white blood cells are subsequently removed, leaving behind only fetal cells. These are identified using a fluorescence scanner and selected for analysis, followed by whole-genome amplification of pooled DNA from several cells.
"We then do short tandem repeat [analysis] to distinguish the origin of the cells," said Schelde of the approach. "That makes it possible to send DNA from only pure fetal cells for downstream analysis at the department of clinical genetics" at Aarhus University Hospital.
Arcedi is not the only company developing such tests. Illumina-backed Cradle Genomics, for instance, raised $17.1 million in 2019 to develop an NIPT based on the analysis of fetal cells. Researchers at Baylor College of Medicine and Columbia University have also been developing similar approaches, and Houston-based Luna Genetics is also working on a cell-based noninvasive prenatal test.
For Denmark first
Arcedi's initial users will be private fertility clinics in Denmark. The first adopter of Evita Test Complete is the Aargaard Fertility Clinic, also in Aarhus, which began offering the test service earlier this month. Schelde said that more Danish clinics will likely adopt the test later this year, liaising with Aargaard to offer the test.
In regards to regulation of the test, Schelde noted that the analysis portion of Evita Test Complete is conducted at Aarhus University Hospital's department of clinical genetics, which is regulated by Danish authorities. Arcedi's approach fits between the blood draw obtained at the clinic and the downstream analysis, he noted.
The current price for the test is DKK 12,000 out of pocket, or about $1,930. This includes the blood draw at the fertility clinic, Arcedi's preparation of fetal cells for analysis, as well as array CGH and reporting of results. Schelde claimed the coverage of Evita Test Complete makes it competitive with other NIPTs on the market, which rely on cell-free DNA and pivot to invasive testing in case an abnormality is identified.
"Cell-based NIPT reports on all chromosomes and includes smaller chromosome aberrations not picked up by other NIPT offerings that could lead to severe impact for the coming child and the entire family," he noted. He said the "certainty and comfort that risk-free cell-based NIPT brings throughout the pregnancy is value for money."
In Europe, pricing and reimbursement for cell-free NIPT costs can vary from about $150 up to $1,000, depending on the test used and the health system, according to a study last year in Acta Obstetricia et Gynecologica Scandinavica, although prices continue to decrease.
Johnny Hindkjær, scientific director at the Aargaard Fertility Clinic, said that uptake of cell-free NIPT has been limited in Denmark to date, though some use Roche's Harmony, Natera's Panorama, or BGI's NIFTY. "To my knowledge, these are not used very much in Denmark," Hindkjær said.
He said there are about 60,000 births per year in the Scandinavian country, which has a total population of about 5.8 million people. In about 3 percent of pregnancies, fetuses with one or more genetic defects are detected, meaning that about 1,800 women per year undergo invasive diagnostic testing or cell-free NIPT.
Hindkjær said that the Aargaard Fertility Clinic has not recommended cell-free NIPT to patients in the past because it believes those tests provide limited information and only scan a few chromosomes for abnormalities. He said the clinic opted to adopt Evita Test Complete because it provides information on all chromosomes, including microdeletions and duplications.
That being said, he does not feel the test will entirely replace CVS at the moment. In Denmark, CVS is the standard of care, while amniocentesis is a reflex test if CVS reveals mosaicism. Aargaard will offer Evita to all fertility patients, especially those who do not wish to risk miscarriage due to an invasive test, as well as those at low risk who are seeking peace of mind. But it will continue to offer CVS alongside Evita to high-risk patients, in part because the resolution on DNA obtained via CVS is still higher than on DNA obtained from the blood draw.
"CVS can still be used in cases where there is a known inherited disease," Hindkjær commented. "But in a few years, I believe that the Evita test can be used instead of CVS, when the DNA amplification and sequencing techniques improve and we have more experience and more data."
Arcedi's Schelde said that the test's resolution is to some extent dependent on amplification that is equal over the full genome, or has as little bias as possible. The current resolution is 1 Mb, compared to 90 kb for CVS, but the company has decided on a threshold of 5 Mb. "For optimizing the resolution, we are testing different enzyme systems as well as downstream analysis applications," Schelde said.
Hindkjær noted that the availability of Evita will make diagnostic prenatal testing more widely available in the country, where low-risk pregnancies often do not undergo such rigorous testing. "When no chromosomal analysis is offered to this group of pregnant women, several children are born with abnormalities from women considered to have a low risk," said Hindkjær. "My hope is that with the noninvasive Evita test, every pregnant woman can be offered a risk-free chromosome screening."
Hindkjær added that Arcedi's offering could be used to test fetuses in cases where the mother has undergone in vitro fertilization and has a known chromosomal rearrangement. He reiterated that in the future, the clinic might also move to using Evita Test Complete in lieu of CVS for all cases.
Rest of world to come
According to Hindkjær, his clinic does not only see cases from Denmark but also throughout the region, with women from Germany, Norway, and Sweden frequently visiting Danish fertility clinics, often due to long queues for testing in their home countries. Arcedi's Schelde noted that the company intends to make Evita Test Complete available outside of Denmark and is planning a study of the test with a Dutch partner to introduce it to the Netherlands.
The US is also of interest, and Schelde said Arcedi has been working with consultants in San Francisco to set up a CLIA lab in the US to offer Evita Test Complete. "Of course, we need financing to make that happen and hope that it will be financed by the end of the year," Schelde said.
There are also murmurings of other application areas. Schelde said that Arcedi has a test for cystic fibrosis in its pipeline that will be based on the same method. The company is also interested in looking at Fragile X Syndrome using its test approach. On top of that, it is collaborating with MOMA, the department of molecular medicine at Aarhus University Hospital, to use its cell-based screening method in cancer research. This work is preliminary, however.
"We thought that having a technology that can detect and isolate rare fetal cells might also be useful in detecting circulating tumor cells," noted Schelde. But for now, he said, the company's primary focus is making Evita Test Complete widely available in the US, UK, and Europe.