InVitro Fertilization
[Source: Maciej Frolow / Getty Images]

Startup Orchid is launching the first preconception test that the company contends predicts a couple’s chances of conceiving a child with high risk of common illnesses, such as heart disease, stroke, schizophrenia, and several types of cancer. The test applies whole-genome sequencing (WGS) to a saliva sample from each partner, and is based on polygenic risk scores (PRSs), rather than the standard carrier-type of test for single-gene, or monogenic, mutation screening for hereditary disorders. The company says it plans to offer similar PRS-based WGS testing for IVF-generated embryos soon as well.

Although the seed round of financing is a modest $4.6M, the investors include high profile names, such as: 23andMe’s Anne Wojcicki; co-founder of Counsyl and former general partner at Andreessen Horowitz, Balaji Srinivasan; co-founder, former CEO of Flatiron health Nat Turner; and MacArthur award-winning Stanford geneticist Carlos D. Bustamante. Notably, 23andMe paved the pathway for medically-related direct-to-consumer product approval.

This is a new angle in a thriving market. Non-invasive prenatal testing (NIPT) is set to reach more than $10 billion over the next few years, besides monogenic diseases it covers common aneuploidies. On its own, carrier testing, which typically screens just for heritable genetic diseases, is expected to exceed $1.3 billion. Most of the growth in the carrier and NIPT testing is generated by more thorough single-gene disorder testing and geographic expansion.

Orchid's couples report
Orchid believes prospective parents will find value in their test that provides a “couples report” of genetic disease risk of their offspring.

Currently, carrier screening is used mostly by people with a family history of illness to find out if they have a high risk of passing on severe conditions such as cystic fibrosis, sickle cell disease, or spinal muscular atrophy. Most often carrier testing involves just one or a few tests, and is relegated to the leading rare diseases or to people, such as Ashkenazi Jews, whose ethnicity puts them at particular risk for certain inherited conditions.

But the push to offer screening for a larger number of disorders has accelerated. LabCorp’s Integrated Genetics, for example, offers screening for one-to-500 heritable genetic diseases. And as these panels have expanded, a wider array of patients have started using them.

There’s science supporting wider testing. For example, Myriad, through its 2018 acquisition of Counsyl, gained a foothold in expanded carrier screening (ECS). In a 2020 paper in Genetics in Medicine, Myriad researchers reported that in a study of more than 93,000 people “Self-reported ethnicity was an imperfect indicator of genetic ancestry, with 9% of individuals having more than 50% genetic ancestry from a lineage inconsistent with self-reported ethnicity. Limitations of self-reported ethnicity led to missed carriers in at-risk populations.”

Myriad says its exome-based Foresight 176-condition ECS panel can identify 30% more carriers of cystic fibrosis than typical tests and offers a 99% detection rate for Alpha Thalassemia across ethnicities.

Sema4 also offers ECS based on exome sequencing. Their Sema4 ECS screen detects up to 280 diseases, with sequencing technology the company describes as “99% accurate.” They also see potential for expansion. “Looking forward, we could foresee that, when applied across the whole genome, this industry could potentially realize near 95% detection rate on thousands of genes. Advances in RNA sequencing in studies of germline cancer will evolve to contribute to increased understanding in carrier screening as well,” says Bridget Winders, SVP and general manager, Women’s Health, Sema4.

So, for now it seems to be a numbers game, who can offer the most coverage with the greatest accuracy across the most ethnicities.

Orchid’s gamble is on whether parents will pay up to take the additional step of finding out how their genetics could influence their future offspring’s risk of common diseases. It also brings PRS testing, which is slowly entering the clinic, further into the already booming prenatal testing field, which is expected to grow at a CAGR of more than 13% per year for the next few years.

“This is not for the rare genetic diseases,” Noor Siddiqui, Orchid founder and CEO told Clinical OMICs. “These are the most common health conditions and we are aggregating millions of data points about every risk.” The company says its test is based on six billion data points, from published studies, and those will be added to and updated as new data is gathered in the now rapidly-moving field of genetic risk score assessment.

One of the references Orchid cites is Khera, A.V. et al’s 2018 Nature Genetics paper “Genome-Wide Polygenic Scores for Common Diseases Identify Individuals with Risk Equivalent to Monogenic Mutations.” These authors developed and validated genome-wide polygenic scores for five common diseases. They reported that their approach identified 8.0%, 6.1%, 3.5%, 3.2% and 1.5% of the population at greater than three-fold increased risk for coronary artery disease (CAD), atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively.

PRS in the clinic

The hope is that PRS scores will allow clinicians in to use genomic sequence information for more than just diagnosing chromosome abnormalities and rare diseases.

The key question is whether this approach is ready for application in this particular market. Specialists in PRS have expressed skepticism about healthy parents using such a tool, since these scores provide a relative risk, rather than an absolute risk score. The data sets used are so non-specific that it can be difficult to narrow down their implications, even with input from experts.  A common complaint is that they are not yet large enough to cover a wide range of ethnicities, but there are other problems.

‘We don’t have large enough data sets to have confidence in these scores in many applications,” says Nicholas Schork, Ph.D., deputy director and Distinguished Professor of Quantitative Medicine at the Translational Genomics Research Institute (TGen). “To use these properly you need to know other data, such as a patient’s medical history and age.” For example, someone who is elderly, has smoked all their lives, and has an elevated cholesterol level will likely have a different risk level than a much younger person with the same PRS score.

The UK Biobank, he notes, has data from more than 400,000 individuals. These include more than 20,000 cancer cases and it recently published a study showing that a PRS with family history “measurably improves prediction accuracy for most cancers, but the magnitude of this improvement varies substantially.” (Kachuri, L., et al. Nature Communications, November 2020).

However, he also points to Myriad Genetics’ MyRisk test for women who have a family history of breast cancer but have tested negative for BRCA1 or BRCA2.  Myriad famously pioneered the first commercial test to identify carriers of mutations in these two genes, which are linked to hereditary cancer. The company’s MyRisk panel was first launched in 2013 as a 25-gene panel to identify elevated risks for eight hereditary cancers. It currently includes mutations in 35 genes and is available to people of all ancestries.

Thomas Slavin
Thomas Slavin, M.D., senior vice president, Oncology, Myriad Genetics

Thomas Slavin, M.D., says “Myriad is in the process of presenting data at ASCO that further validates the company’s PRS in breast cancer, called riskScore, across all major ancestries.” Slavin is senior vice president of Oncology at Myriad.

Another expert with reservations is, Genevieve L. Wojcik, Ph.D., assistant professor at the Johns Hopkins Bloomberg School of Public Health. Wojcik was a post-doc in Bustamante’s lab and is the senior author on a recent (March 2021) landmark paper in Nature on improving reporting standards for polygenic scores in risk prediction studies.

“Out-of-the-box, a lot of these scores are not as clinically useful as people think they are,” says Wojcik. “I do not think carrier testing or embryo selection is the right application for PRS scores at this time.”  Since the calculations involve two parents, and the embryo’s risk is a range, that’s not very useful information, she says.

But help is on the way. Clinical trials are being pursued and the paper on PRS standards that Wojcik co-authored was a collaboration between the Clinical Genome Resource (ClinGen), the ComplexDisease Working Group, and the Polygenic Score (PGS) Catalogue.

That publication presents standards for PRS score reporting. The authors note that the weighted sums of allele counts used to estimate a risk of a trait or disease for a PRS can include millions of variants, so a structured format in publishing these is crucial. They point out that more than 900 publications mentioning PGS or PRS have been published in the last decade. Reporting standards, they write, could “boost predictive performance” of these scores.

At least one company, Genomic Prediction, is offering PGS-based testing for embryos. Its LifeView PGT-P test identifies an embryo’s lifetime risk of developing conditions including schizophrenia, type 1 or type 2 diabetes, several causes of heart disease, and a variety of cancers including basal cell carcinoma, malignant melanoma, and breast or prostate cancer. But this is clearly just the beginning for PRS in prenatal testing, and clinical use overall.

Genevieve L. Wojcik
Genevieve L. Wojcik, Ph.D., Johns Hopkins Bloomberg School of Public Health

It’s not clear whether the Orchid test will be direct-to-consumer or, like most carrier tests, will require a physician’s sign off. The company is marketing to consumers, and inviting them to join its wait list. It’s notable, however, that one of Orchid’s investors is Anne Wojcicki, a co-founder of 23andMe. Her company has been one of the few, if the only, that has stayed the course in getting FDA approval for direct-to-consumer medical tests.

After a flurry of DTC genomic tests were launched, FDA put the brakes on the field in 2010. But with diligence and evidence from 23andMe, by 2017 the agency announced that it had allowed that company to market the “first direct-to-consumer tests that provide genetic risk information for certain conditions.” Those conditions include Parkinson’s disease, late-onset Alzheimer’s, celiac, Gaucher type 1, and several others.

A 23andMe spokesperson says the company’s offerings include some PRS, including some wellness reports such as the Type 2 Diabetes Report within their Health Predisposition category. “These reports are developed and validated completely on 23andMe research data,” the spokesperson said. “They fall under the FDA’s enforcement discretion.”

InVitroFertilization
[Source: Visual Mozart / Getty Images]
An Orchid spokesperson says their test is, “…a patient initiated, physician ordered test, results are reviewed and released with a board certified genetic counselor.” While the FDA will neither confirm nor deny if an application is in process, the Orchid spokesperson says that tests like this one are classified as laboratory developed tests (LDTs).”

Skeptics abound

While the Orchid preconception test may be attractive to patients, the company still faces many skeptics, especially for its use among healthy would-be parents.

“For prenatal testing, this is still very controversial,” says Schork. “It’s very unlike evaluating a 40-year-old where you have other data. And then there are a really deep set of issues relating to the whole idea of creating ‘super embryos’.” He adds that this is a disruptive technology and medical education will need to step up to meet the demands it creates to make it truly useful for patients.

Julian Savulescu
Julian Savulescu, Ph.D., professor in Philosophy, University of Oxford

Julian Savulescu, a professor in Philosophy at the University of Oxford, says, “For IVF, it’s reasonable to use whatever means you have to select the healthiest embryo, in fact, it can be seen as a moral obligation,” he says.  “Afterall, if you have only 10 embryos and are choosing one, you just have to do better than chance in making that selection.” Natural reproduction, Savulescu points out is relatively inefficient. “One-out-of-five fertilized eggs go on to produce an embryo, and 5% of babies have some chance of having an abnormality.”

But it is a separate question whether you should do this type of testing if you are not at risk of having any of these diseases and you are not doing IVF,” he adds. “The accuracy and reliability is just not there yet.”

Nonetheless, Savulescu sees the use of such tests as “Becoming more and more common.” After all, he points out, “If parents want to use it, why shouldn’t they?”

 

The Orchid Couple Report Launched

Orchid’s test aims to provide even people without a family history of disease a means to determine their future offspring’s likelihood of serious common ailments. The test requires only a mailed-in saliva sample from each prospective parent, and is based on genetic risk scores calculated by testing for genetic variations.  Its “Couple Report” reveals if either partner is at elevated risk of passing on 10 diseases: heart disease, stroke, atrial fibrillation, schizophrenia, Alzheimer’s Disease, breast cancer, prostate cancer, type 2 diabetes, type 1 diabetes, and inflammatory bowel disease.

Orchid advanced preconception screening
Skeptics abound, but startup Orchid believes there is a market for their pre-conception testing product for parents that uses polygenic risk scores to indicate the future risk of their children developing common ailments such as heart disease, stroke, schizophrenia, and several types of cancer.

The report comprises data from both partners’ whole genomes and models of how that DNA could combine in a child, providing simulations of both the lower- and higher-likelihood scenarios. If the result is a “high likelihood” for one of more conditions, there are genetic counselors on hand and advice available about how to mitigate whatever disease is involved.

Orchid’s leadership emphasize that one of most prospective parents’ key concerns is their children’s health.

“Up until now, parents could only genetically screen for the rare events with a one-in-1,000 or even one-in-a-million chance of happening. Yet there was no way for prospective parents to measure their future child’s genetic predispositions to much more common chronic, debilitating diseases based on their combined genetics alone,” said Orchid advisor Jacques Cohen, Ph.D., in a press release, adding that “Orchid now makes this at-home test a reality.”

Cohen is director of the ART Institute of Washington, which runs the joint National Institute of Health and Walter Reed National Military Medical Center IVF program. He was a founder of Reprogenetics, now called Cooper Genomics, and other reproductive science-related firms.

There is evidence supporting their claim. Over the last few years, the market for prenatal testing has grown dramatically. Further, a March 2019 survey of just over 800 pregnant women in Obstetrics and Gynecology found that when it came to prenatal testing “Respondents generally preferred to receive all categories of genetic results pertaining to medical conditions.”

Noor Siddiqui
Noor Siddiqui, founder, Orchid

A typical preconception genetic screening, Siddiqui said, analyzes only 2% of just one partner’s genome and is only capable of detecting rare genetic disorders affecting approximately 1% of the population. By contrast, Orchid analyzes the entirety of both partner’s genomes and assesses genetic predispositions to diseases that affect more than 60% of the population.

For couples who find they are at elevated risk based on Orchid’s test, one strategy is to elect to pursue IVF and have further analyses of their embryos. Later this year, Orchid plans to launch an Embryo Report that will provide genetic risk information related to IVF embryos.

Investors in the seed round include Refactor Capital, Village Global, Day One Ventures, Olive Capital, and Boom Capital. The round also includes participation from the founders of 23andMe, Counsyl, Clover Health, Coinbase, Eventbrite, Flatiron, Oscar Health Insurance, and Stellar.

“Having children is the most consequential choice most of us make, yet parents go into pregnancy with zero visibility into how genetic risks could impact their future child,” said Siddiqui. “With Orchid’s ultra-high-resolution reports, prospective parents can now conceive with confidence, prepared with information and guidance to give their children a better chance at a healthy life.”

Orchid is now inviting couples to join a waitlist to get early access to Orchid’s Couple Report. Each test provides a risk-analysis report for each partner as well as an estimate of their potential offspring’s risk. Along with their report, couples also receive health and wellness guidance from professionals including genetic counselors and fertility experts as part of the service. That includes advice on how to prevent or mitigate any risks detected.

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