Natera Announces Publication of Kidney Transplant Validation Study, Demonstrating Superior Data in Detection of Clinical and Subclinical Rejection

Represents Successful Achievement of All 2018 Commercialization Milestones, on Path to 2019 Launch

Natera, Inc.a leader in cell-free DNA, today announced clinical validation study results published in the Journal of Clinical Medicine,¹ demonstrating the highly accurate performance of its donor-derived cell-free DNA (dd-cfDNA) test for active allograft rejection in kidney transplant recipients, including higher sensitivity and nearly 18% higher area under the curve (AUC) than the competitive dd-cfDNA assay.^1,2 The study also reports the first accurate detection of T-cell mediated rejection (TCMR) and subclinical rejection. This marks the successful completion of all 2018 commercialization milestones, and is in line with the company's plan to secure Medicare coverage and commercially launch its test in 2019.

The blinded study, conducted in collaboration with the University of California, San Francisco (UCSF), leveraged Natera's massively-multiplexed PCR (mmPCR) technology to measure dd-cfDNA levels in plasma collected on the same day as a kidney biopsy from 193 unique kidney transplant recipients. The primary analysis focused on 217 plasma samples from 178 unique kidney transplant patients, including 38 cases of histologically-confirmed active rejection (AR), making it the largest published study of its kind, with approximately two times more patients and 40 percent more affected cases of AR than the next largest study.² Another strength of the study is its broad ethnic diversity, which is important because kidney transplant assessment and biomarker performance are known to vary by ethnicity.

In the study, Natera's assay detected AR with 89% sensitivity and 0.87 AUC. This test performance compared favorably to the current standard of care, eGFR (estimated glomerular filtration rate), which is a clinically accepted but inaccurate biomarker for AR. The study results also showed higher sensitivity (89% vs. 59%) and higher AUC (0.87 vs. 0.74) than the competitive dd-cfDNA assay.² This superior data may be due to differences in the analytical performance and underlying technology behind the assays. 

The new study also had two novel, clinically significant findings:

• TCMR detection: Test performance was independent of rejection type, inclu ding antibody-mediated rejection (ABMR, 16 cases), T-cell mediated rejection (TCMR, 10 cases), and combinations of the two (ABMR/TCMR, 12 cases). By contrast, previous dd-cfDNA studies reported a poor ability to detect TCMR, which represents approximately one third of all AR diagnoses, and more than half of the AR cases in certain patient subgroups.³

• Subclinical AR detection: Test performance was also independent of clinical presentation, demonstrating high accuracy in detecting both clinical and subclinical AR. The study was unique in that 13 of the 38 AR cases were diagnosed using protocol (or surveillance) biopsies, in contrast to the other 25 cases diagnosed using for-cause (or clinically-indicated) biopsies. The 13 cases are considered "subclinical AR," because the patients otherwise had stable renal function based on serum creatinine, showing no clinical signs of rejection. In the study, Natera's assay detected the subclinical AR cases with 92% sensitivity and 75% specificity. No other dd-cfDNA assay has been validated to detect subclinical AR, which occurs in 20-25% of patients in the first two years post-transplant,⁴ and which is considered a major driver of graft failure.

According to Paul Billings, M.D., Ph.D., Natera's Chief Medical Officer and Senior Vice President of Medical Affairs, Natera's dd-cfDNA-based assay is designed to help physicians detect active rejection events earlier, avoid unnecessary biopsies, and better optimize immunosuppression levels. "This published study adds to the mounting body of evidence showing the validity of dd-cfDNA in detecting active allograft rejection," Billings said.

"With this publication, we have achieved all of the company's 2018 milestones related to our transplant business, including the attainment of a Z-code, completion of analytical and clinical validation studies, and completion of the CLIA validation," said Steve Chapman, Natera's CEO. "This is in line with Natera's history of successful execution with regard to commercializing novel clinical assays."

There are more than 190,000 people living with a kidney transplant in the U.S.⁵ and roughly 20,000 new kidney transplant surgeries performed each year.⁶ It is estimated that 20-30 percent of organ transplants fail within five years and approximately 50 percent fail within 10 years.^7,8  The current tools for diagnosing organ transplant rejection are either invasive (biopsies) or inaccurate (serum creatinine), creating a strong unmet need for better diagnostic tools to improve patient management and outcomes.

About Natera's dd-cfDNA Organ Transplant Assay

Natera's organ transplant rejection assay is designed to detect active allograft rejection in patients who have undergone renal (kidney) transplantation. The assay works by measuring the fraction of donor-derived cell-free DNA (dd-cfDNA) in the recipient's blood, which can spike relative to background cfDNA when the transplanted organ is injured due to immune rejection. The assay leverages Natera's core single nucleotide polymorphism (SNP)-based massively multiplexed PCR (mmPCR) technology, to more accurately measure dd-cfDNA levels without the need for donor genotyping, and it has been clinically validated for test performance independent of donor type, rejection type, and clinical presentation.

About Natera

Natera is a global leader in cell-free DNA testing. The mission of the company is to transform the management of diseases worldwide. Natera operates an ISO 13485-certified and CAP-accredited laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA) in San Carlos, Calif. It offers a host of proprietary genetic testing services to inform physicians who care for pregnant women, researchers in cancer including bio pharmaceutical companies, and genetic laboratories through its cloud-based software platform. For more information, visit natera.com.  

Forward-Looking Statements

All statements other than statements of historical facts contained in this press release are forward-looking statements and are not a representation that Natera's plans, estimates, or expectations will be achieved. These forward-looking statements represent Natera's expectations as of the date of this press release, and Natera disclaims any obligation to update the forward-looking statements. These forward-looking statements are subject to known and unknown risks and uncertainties that may cause actual results to differ materially, including with respect to our efforts to develop and commercialize new product offerings, our ability to successfully increase demand for and grow revenues for our product offerings, whether the results of clinical studies will support the use of our product offerings, our expectations of the reliability, accuracy and performance of our tests, or of the benefits of our tests and product offerings to patients, providers and payers. Additional risks and uncertainties are discussed in greater detail in "Risk Factors" in Natera's recent filings on Forms 10-K and 10-Q and in other filings Natera makes with the SEC from time to time. These documents are available at www.natera.com/investors and www.sec.gov.

Contacts

Investor Relations: Mike Brophy, CFO, Natera, Inc., 650-249-9090 
Media: Andrea Sampson, Sullivan & Associates, 714-374-6174, asampson@sullivanpr.com

References

1.Sigdel TK, Archila FA, Constantin T, et al. Optimizing Detection of Kidney Transplant Injury by Assessment of Donor-Derived Cell-Free DNA via Massively Multiplex PCR. J. Clin. Med. 2019, 8, 19.

2.Bloom RD,  Bromberg JS, Poggio ED,  et al. Cell-free DNA and active rejection in kidney allografts. J Am Soc Nephrol. 2017 Jul;28(7):2221-2232. doi: 10.1681/ASN.2016091034. Epub 2017 Mar 9.

3.Wehmeier C,  Amico P,  Minkowski, PH, et al. Acute Rejection Phenotypes in the Current Era of Immunosuppression: A Single-Center Analysis. Transplantation Direct 2017;3: e136; doi: 10.1097/TXD.0000000000000650. Published online 9 February, 2017.

4.Choi BS, Shin MJ, Shin SJ, et al. Clinical significance of an early protocol biopsy in living-donor renal transplantation: Ten-year experience at a single center. Am J Transplant 2006; 5: 1354-1360

5.Kidney Disease Statistics for the United States. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease. Published Dec. 1, 2016.

6.Organ Donation Statistics. U.S. Department of Health and Human Services. U.S. Government Information on Organ Donation and Transplantation. https://www.organdonor.gov/statistics-stories/statistics.html. Published March 31, 2016.

7.Stegall MD, Gaston RS, Cosio FG, Matas A. Through a glass darkly: seeking clarity in preventing late kidney transplant failure. J Am Soc Nephrol. 2015; 26(1):20-9.

8.Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant. 2011; 11(3):450-62.