Natera building

Originally named the Gene Security Network, clinical molecular testing company Natera was founded in 2004 by Jonathan Sheena and Matthew Rabinowitz. Both of the co-founders came from outside the life sciences industry: Sheena from mobile search engine technology company PhoneSpots, which pioneered the ‘send to mobile’ feature, and Rabinowitz at which offered users real-time interactive product suggestions.

It seems a far cry from a molecular testing company, but the formation of Natera was forged from a personal family tragedy when Rabinowitz’s sister unexpectedly gave birth to a child with Down syndrome, who died six days later. The baby’s condition had not been picked up by then-current screening methods.

From this, the pair set out to create better neonatal testing methods in the nascent field of pre-implantation testing for in vitro fertilization and, eventually, noninvasive prenatal testing (NIPT) that can screen for a number of genetic anomalies via the capture of fetal cell-free DNA (cfDNA) circulating in the mother’s blood during gestation.

About four years after opening its doors, the company launched its first test called Spectrum aimed at the preimplantation market, and in 2013 launched its Panorama NIPT offering.

Getting a foothold in prenatal testing

It’s not a stretch to say that, to date, NIPT has made the most significant impact and inroads to regular clinical practice of all genetic testing methods. OB-GYN’s were keen to use these tests as they were non-invasive procedures for expectant mothers and didn’t carry some of the risks associated with other prenatal testing methods such as amniocentesis. Estimates vary, but the market for NIPT today is roughly $3 billion and is expected to more than double to about $6.5 billion in the next seven years, according to Polaris Research.

But when Natera first launched Panorama, the test was not covered by payers in the U.S. According to Paul Billings, chief medical officer of Natera, the company invested heavily in clinical studies to prove the test’s worth and published them in leading journals such as Nature, JAMA, and Science. This work is now paying dividends.

“Natera’s investment in generating high-quality clinical data has now led to the American College of Obstetrics and Gynecology recommending NIPT for all women, regardless of age or maternal risk,” Billings points out. “This will allow us to grow from testing roughly 25% of all pregnancies in the U.S. and equitably deliver important results to all pregnant women.”

Solomon Moshkevich
Solomon Moshkevich, GM,
Oncology, Natera

While Natera was the fourth company to launch an NIPT to the market, it was a tough competitor because it took a different approach with its assay. “We were the only ones to take a SNP-based approach. Everyone else was doing massively parallel shotgun sequencing,” says Solomon Moshkevich, general manager, oncology with Natera. “It allowed us not only to be more accurate, more sensitive and specific, but also to report qualitatively certain features that nobody else could see.”

As an example, Moshkevich notes that the Panorama test can distinguish identical twins and non-identical twins, something that is not just an interesting tidbit for parents, but could have clinical implications.

It’s the power of the test and the testing approach that has propelled Natera into the leading NIPT company in the U.S. Over time, it has refined its NIPT and the analysis of cfDNA using a patented multiplex PCR technology. “Multiplexing PCR is not something we invented, but something I think we’ve perfected,” Moshkevich notes, adding that in the research setting some groups have been able to multiplex from dozens to perhaps hundreds of targets in a single reaction. At Natera, the company can currently reliably query 13,000 targets in a single reaction and has even pushed it as far as 30,000 targets in internal testing.

As company management surveyed the business landscape, it wasn’t long before they recognized the company had created a powerful technology platform suitable for other diagnostic and screening applications, beyond NIPT.

“We’re in the beginning stages of what’s possible with genetic testing, which will play a much larger role in health care as we move forward,” says Steven Chapman, company CEO. “Looking across each of our business units, we have an enormous opportunity to help millions of additional patients while rapidly growing our business.”

Minimal residual disease and cancer recurrence testing

Moving into oncology testing with its patented PCR multiplexing platform was the next most logical extension for the company, and in 2017 it launched—as research use only—its Signatera test, a tumor-informed cfDNA assay designed for minimal residual disease monitoring and for cancer recurrence monitoring. In 2019 it made the test available for clinical use when it received a breakthrough device designation from the FDA.

Natera lab
Natera is a leading provider of pregnancy health and screening tests, and now is making inroads in cancer and organ rejection testing.

As a tumor-informed assay, Signatera is customizable to each patient based on the molecular profile of their solid tumor, meaning only the relevant molecular markers for that specific patient will be included on their testing panel. Its two main capabilities—measuring either for minimal residual disease (MRD) after surgery or neoadjuvant therapy, or for earlier detection of disease recurrence—both have major implications in how cancer patients will likely receive care in the future.

In the case of MRD, the test can accurately look for traces of the primary cancer after resection to determine whether the surgery successfully cleared the patient’s cancer. If the test still detects whispers of the cancer, it can provide a platform for an oncologist not only to begin adjuvant therapy sooner than they would under current clinical practice, but even provide information on which targeted therapies could be most effective.

There are also implications in the neoadjuvant setting, when leading up to surgery oncologists will provide a therapy designed to shrink the tumor to make it easier to remove.

Alexy Aleshin
Alexy Aleshin, VP, Natera

“For many cancers, we give systemic therapy before surgery to try to downstage the tumor or to shrink it to make it more easily operable, or even try to avoid surgery immediately,” says Alexy Aleshin, a vice president at Natera. “In this setting, sometimes it’s hard to know if somebody is responding to therapy or not. So Signatera can really be beneficial for tracking neoadjuvant treatment response.”

But there’s more. In the adjuvant setting, by monitoring MRD, doctors can know soon after the initial treatment whether it has been effective. MRD negative at this stage is the hoped-for testing outcome, but patients with MRD positive results can be moved to an adjuvant therapy quickly.

“To me, as an oncologist, it almost seems like science fiction,” Aleshin notes. “Because, for the first time, you can identify somebody who’s MRD positive and know that you’re going to have close to 100% risk of recurrence. You know that this patient most likely should be treated with some type of systemic adjuvant therapy.”

It also provides the opportunity for “multiple shots on goal” Aleshin says, meaning that monitoring MRD can tell a clinician whether or not a therapy is working. If it isn’t, the oncologist can pivot quickly to another treatment to see if it will be more effective.

In cancer recurrence, early studies have shown that using cfDNA from liquid biopsies in cancer patients can detect the return of cancer as much as two years earlier than current imaging techniques—and the implications are significant. First, the early detection can allow for lower dosing, and because Signatera is designed for each patient based on the analysis of their solid tumor, it can also help inform targeted treatments.

“In the future, we may see a day where you get your tumor sequence at diagnosis and if you develop molecular recurrence, because you have [a particular] mutation, we’ll give you a targeted therapy to prevent your ‘recurrence’ from ever occurring,” Aleshin concludes. “That is the future that we’re starting to work towards today.”

With the treatment paradigm bound to change to reflect these testing capabilities being developed by Natera and other companies, the market opportunity is significant.

“In oncology, we’re just scratching the surface of what’s going to be a more than $20 billion total market opportunity,” contends company CEO Chapman. “Our Signatera test has been approved by Medicare for use in stage II and III colorectal cancer, which we estimate enables about a million blood draws per year. This approval makes Signatera one of the largest specialty diagnostics ever approved, and that’s only for colorectal cancer. We have plans to expand further and go pan-cancer.”

The runway has been cleared for these other indications, Chapman notes, as Medicare has also issued a draft local coverage determination that proposes expanded coverage of the Signatera test in a broad range of additional solid tumor types and indications.

Better transplant care

While Signatera represents perhaps the larger opportunity for Natera, its organ health tests Prospera and Renasight promise to provide molecular insights into allograft rejection using the same, non-invasive blood-based analysis of cfDNA. Where Natera stands apart in this market is, again, the company’s core PCR multiplexing technology.

To test whether it could create a viable product in this space, Moshkevich approached an old colleague at University of California, San Francisco (UCSF), which he knew had a large biobank of tissue from UCSF organ transplant patients. An early study with a prospective product, led a to a clinical validation study with UCSF with the hoped-for results.

“[It] demonstrated that our multiplex PCR technology detects rejection with high sensitivity and high specificity without needing the donor DNA sequence,” Moshkevich says. “That is a very big deal.”

Being able to detect the first signs of organ rejection in transplant patients has the potential to improve what are currently dismal rates of organ rejection. Currently, in kidney transplants, between 20% and 30% of all patients experience a transplant failure within five years and nearly 50% experience failure within 10 years. According to Natera, its blood test has a 95% negative predictive value and misses roughly three times fewer kidney failures than the standard serum creatinine test used in most clinical settings.

“With our technology, we’re detecting organ rejection early, so that the patient and physician can alter the treatment course and potentially save the kidney,” says Chapman.

Today as it eyes its three firmly established testing lines, Natera has its eyes firmly on the future.

“We will continue to provide novel tests for risk, the diagnosis of diseases, and the monitoring and response to treatment of underlying conditions that affect pregnancy health, cancer care, and organ failure/transplantation management,” Billings concludes. “We will always assess unmet medical needs worldwide and waste in clinical care systems. Then by applying our expertise and proprietary methods, we will seek to improve individuals’ health.”

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