This article has been corrected to reflect that Euclidean Capital is not an investor in Celmatix.
NEW YORK (GenomeWeb) – Women's reproductive health company Celmatix is poised to expand its business next year, betting on a combination of genetic testing and predictive clinical data analysis to help women and their doctors make choices related to having children and treating infertility.
Late last week, the company, which is headquartered in the financial district of New York City — literally on Wall Street — and has labs in New York and New Jersey, was awarded $4.5 million from the New York City Regional Economic Development Council to expand its offices and to add more than 3,000 square feet of lab space. Celmatix said it plans to share more details about the headquarter expansion in the new year. According to the state's funding announcement, the entire project will cost $12.5 million and is expected to start in early 2018.
The new funding adds to $57.1 million the company has raised so far. The firm, which has grown to about 110 employees, was founded in 2009 by Piraye Yurttas Beim, the firm's CEO, who holds a PhD in molecular biology and mammalian embryology from Cornell University, and Laura Towart Bandak, a company director with a master's in neuroscience from Cornell. Among the company's funders is venture capital firm Topspin Partners, its main investor.
In addition, Celmatix last month won approval from the New York State Department of Health for its Fertilome infertility genetic panel test, which analyzes 49 variants in 32 genes that have been associated with a number of reproductive conditions. To obtain approval, the company had to demonstrate analytical and clinical validity for the test. According to Celmatix, doctors can use the test, together with other clinical data and family history, "to create a more personalized fertility plan that addresses your family-building goals." The self-pay test, which needs to be ordered by a physician, currently costs $950.
Beim said that the Fertilome test is meant for two types of patients. One is women of younger age who want to gauge their risk of developing conditions that might lead to fertility problems later in life, when they are ready to build a family. Based on the results, they might consider freezing their eggs or not waiting as long to have children. The other group is women already struggling with fertility problems whose doctors might use the genetic risk data to guide treatments and recommendations.
So far, the company has marketed the Fertilome test mainly to reproductive specialists, but starting in 2018, it plans to market it more broadly to OB/GYNs as well as patients, Beim said.
In addition to its genetic test, the company offers a web-based data analytics platform, Polaris, that helps reproductive medicine centers manage and counsel their patients. The platform includes predictive models for the success of fertility treatments that are based on clinical and outcomes data from de-identified electronic health records of patients treated at the 10 US-based centers that currently use Polaris. So far, Polaris has been used to collect data from more than 88,000 patients, including more than 670,000 fertility treatment cycles, which the company claims is "the world's largest fertility dataset."
Though Celmatix offers the Polaris platform and the Fertilome test separately — Beim said there are centers that use one, the other, or both — the goal is to use them together to improve predictions. "Where we are going, and we're not that far away, is to bring the report that powers the Fertilome genetic test and the report that powers the treatment navigator function of Polaris together into an integrated clinical report," she said.
Celmatix first launched the Fertilome test in January of this year, offering it under New York's non-permitted laboratory test request process, which allows the use of a test on a case-by-case basis. The test runs on an Illumina MiSeq Dx sequencing platform and is performed by Celmatix's own CLIA-certified laboratories. The company opened its first lab in Brooklyn, New York, and recently built a second one in New Jersey that it wants to use to scale its business.
Since January, the test has been prescribed by more than 80 physicians in the US for hundreds of patients, Beim said, and several patients who had the test are now pregnant. "Physicians have gotten in touch with us because they feel that without the insight from the genetic test, that individual would not currently be pregnant," she said.
However, some have questioned the clinical utility of Fertilome, or how actionable the test results are for patient management, and have cautioned that patients may not understand the genetic risk information they receive.
The current test looks for 49 variants associated with five conditions: premature menopause (or primary ovarian insufficiency), endometriosis, polycystic ovary syndrome (PCOS), recurrent pregnancy loss, and unexplained infertility.
The prevalence of these conditions differs between different age groups and populations, Beim said, and ranges from about 1 percent for premature menopause and recurrent pregnancy loss to about 10 percent for endometriosis and PCOS.
Beim said that Celmatix went through an almost two-year extensive analysis of the medical literature to get to those variants. It started by mining the 24 million or so papers in PubMed, using natural language processing, for those that associate a genetic locus with 11 of the most common reproductive conditions. That lead to about 25,000 peer-reviewed papers that the company manually curated, leaving it with just under 5,000 studies. It then used two independent reviewers to extract data points from these papers — a minimum of 137 for each one — and arrived at about 1.1 million annotations that were unique between the two experts. On the genomic level, it ended up with about 1,700 genetic loci that were linked to one of the reproductive conditions, either statistically or through functional data.
They then used a qualitative framework that they based on the framework developed by the ClinGen resource for evaluating genetic variants to rank the genetic loci according to how strongly they are associated with a particular condition. "What came out of it is, there are actually 201 of those genetic loci that fall into the category of strong evidence," Beim said. They then looked at which variants in those genes came up in multiple studies and identified 427. Further analysis of these variants to define their statistical significance left them with the 49 variants, in 32 genes, that are on the current panel.
Celmatix has not published a list of the variants, but physicians and patients can access them in the report. The company continues to refine the list by mining the research literature and might add or drop variants over time as new evidence emerges, Beim said, and plans to stay ahead of the competition that way.
Several other companies have started to offer genetic infertility testing panels of various sizes, but she said they differ from Celmatix in how they selected their variants and because they do not have access to a large patient database.
It is unclear how exactly the Fertilome test reports the risk associated with its variants — according to the company's website, the report "will outline which genetic variant, if any, are present in your DNA, which reproductive condition(s) those variants are associated with, and the strength of association of those variants to a reproductive condition(s)."
While Celmatix stresses that the results are not diagnostic but provide risk information, it states that "you and your doctor can use this information to help create a fertility plan that's tailored to your biology and your specific family-building goals. For instance, you might choose to get pregnant sooner, seek fertility treatment earlier on, freeze your eggs, or change nothing at all."
However, others do not believe that the results have much clinical utility. In an article published in the Journal of Assisted Reproduction and Genetics in May, for example, Stephen Collins, a research fellow in the Division of Reproductive Endocrinology and Infertility at the Yale School of Medicine, wrote that the majority of alleles included in infertility gene panels — including Fertilome's — do not have outcomes data available for interventions doctors took as a result of the test.
In addition, patients may find it challenging to understand that the absolute risk conferred by many of the variants on multigene infertility panels is small. For example, a specific variant raises the absolute risk of developing primary ovary insufficiency from 1 percent to 1.5 percent. "While additional studies could be done to characterize the cost-effectiveness of fertility preservation for patients with this allele, the low absolute risk it confers suggest that it is unlikely to be of clinical utility," he wrote.
In a commentary published in the same journal in October, Beim and her colleagues countered that considering other risk factors that result in a small absolute risk "have made significant clinical and societal impacts." As an example, they pointed to the practice of putting infants to sleep on their stomachs, which slightly increases the small risk of sudden infant death syndrome (SIDS), yet prompted most parents to put their babies on their backs for sleeping.
However, the fact that patients can easily misunderstand genetic risk information makes it important for patients to receive pre- and post-test counseling for such tests, Collins wrote. Celmatix says on its website that it offers patients a free phone or video call with a certified genetic counselor to discuss their test results.
According to Collins, one key improvement for multigene infertility risk panels would be to develop polygenic risk scores that integrate the impact of several genetic variants into a single disease risk. "The polygenic risk score may increase the utility of identifying even low- to moderate-risk alleles, provided that they contribute to a net risk of disease that is more clinically relevant," he wrote. "With continued research on polygenic risk scores, genotype-phenotype correlations, and pharmacogenomics applications, it is likely that multigene test panels will eventually serve an important role in bringing precision medicine to the treatment of infertility."
In the meantime, doctors are already using the Fertilome test. Aimee Eyvazzadeh, a reproductive endocrinology and infertility doctor in San Ramon, California, for example, has prescribed the test dozens of times for her patients since January.
She has found the test useful, for example, to advise patients about egg freezing for use at a time when their fertility may have declined. "Now with this genetic information, you can take a patient's age, her genetics, her family history, and her hormone levels, and then give her an accurate picture of what their fertility might look like in the future," she said.
She has also used the test for patients who have gone through several in vitro fertilization cycles without success, even with genetically screened embryos. "I can see what their variants are and then decide, based on their variants, whether they should consider different protocols that actually may be more suitable," Eyvazzadeh said.
The test results can also suggest further diagnostic tests, she added, for example a test for endometriosis if Fertilome reveals an increased risk for that condition.
She cautioned, though, that the test may not be suitable for every patient because some might react negatively to the results, and she provides counseling to her patients to discuss the test before she orders it. "You want to make sure this person actually views these results as actionable items for them and sees that this knowledge is very powerful," she said.
For Celmatix, it appears that the Millennial generation in particular — typically defined as those born between the early 1980s and the early 2000s — will be most receptive to its offerings. Beim said that according to market research conducted in the US, more than half of Millennial women plan to have children after the age of 30, and 20 percent after the age of 35, which is considered advanced maternal age. In addition, 60 percent said they would be willing to use IVF to get pregnant, and 60 percent said they would consider freezing their eggs. More than 80 percent said they were interested in genetic testing to find out about risks to their reproductive health. "What we're seeing is, whereas generations before them felt the pressure to live their lives in a certain way based on their biology, the Millennial women are saying 'I want to live my life by my own plan, and technology should fix the biology part,'" Beim said.