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With 510(k) Clearance for Prosigna, NanoString Targets Early 2014 Commercial Launch

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After receiving 510(k) clearance this week from the US Food and Drug Administration for its Prosigna Breast Cancer Prognostic Gene Signature Assay, NanoString will take the next few months to make agency-requested changes to the test report and engage in discussions with potential early adopters ahead of launching the test early next year.

"Prosigna is the first breast cancer prognostic assay to be cleared by the FDA as an in vitro diagnostic kit for decentralized testing," NanoString CEO Brad Gray told investors and analysts during a call to discuss the milestone.

Prosigna uses the PAM50 gene signature to gauge patients' breast cancer subtype and characterize their risk of breast cancer recurrence. The test runs on NanoString's nCounter Dx Analysis System and analyzes FFPE. The nCounter technology uses colored "barcodes" and single molecule imaging to count hundreds of transcripts in one hybridization reaction. Each barcode is attached to a probe that corresponds to a gene of interest. The predicate device for 510(k) clearance was Agendia's microarray-based MammaPrint breast cancer recurrence test.

The assay is intended to be used in conjunction with patients' clinical factors to assess their distant recurrence-free survival at 10 years. Only postmenopausal women with hormone receptor-positive breast cancer who are Stage I/II lymph node-negative or Stage II lymph node-positive should receive Prosigna testing. Candidates for testing should also have undergone surgery and standard-of-care locoregional treatment.

"The assay is not intended for patients with four or more positive nodes, for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients," Gray said during the call with investors.

When NanoString commercially launches its test in the first quarter of 2014, Prosigna will enter a breast cancer recurrence testing market currently dominated by Genomic Health's Oncotype DX, which doesn't have FDA clearance and is administered out of a centralized, CLIA-certified lab. Agendia also competes in this market with its MammaPrint test, and has been pushing to cut into Genomic Health's market share in this space in recent months. Although Agendia has received 510(k) clearance from the FDA for MammaPrint, the laboratory-developed test is also performed at a centralized lab.

NanoString highlighted as a competitive advantage the fact that Prosigna is cleared by the FDA as a kit. The workflow for the Prosigna test begins with the treating oncologist sending the patient's tumor sample, fixed in FFPE, to the clinical lab for basic pathology tests, such as staging and assessing hormone and HER2 status. Based on the results, the pathologist discusses with the treating oncologist whether Prosigna testing is needed. If testing is decided upon, then the pathologist can run Prosigna on the tumor sample either on a kit within an in-house laboratory or send the sample out for testing at a reference lab.

"By eliminating the need to shift the tumor sample to a specialized testing laboratory, the Prosigna assay offers the potential to report results more quickly than first-generation breast cancer assays," Gray said. The turnaround time for the Prosigna test is three days. The turnaround time for Oncotype DX and MammaPrint is around 14 days.

As a developer of a second-generation breast cancer recurrence test, it seems NanoString has been preparing for a highly competitive landscape and has tried to cultivate published data around Prosigna with this in mind. In July, researchers from NanoString and elsewhere published data in the Journal of Clinical Oncology showing that the Prosigna score provides more information than Genomic Health's Oncotype DX in gauging the risk of recurrence for women with ER-positive, early stage breast cancer (PGx Reporter 7/10/2013).

Analyst Vamil Divan from the investment bank Credit Suisse wrote in a note this week that the fact that NanoString's test can be performed as a kit in house will likely be attractive to larger medical centers. However, Divan pointed out that the majority of breast cancer assays are ordered by community physicians, who look to see if the test can predict whether patients can benefit from chemotherapy, if it is included in treatment guidelines, and if it has broad reimbursement coverage.

Prosigna doesn't have a predictive claim for assessing whether a patient with benefit from chemotherapy treatment. And since Oncotype DX has been on the market for nearly a decade, Genomic Health has established reimbursement contracts for the test with the majority of insurers in the US, particularly for the node-negative population. As such, NanoString will have to battle Genomic Health's established presence with payors in proving the value of Prosigna.

Test report

For 510(k) clearance, one of the main issues that NanoString had to work out with the FDA was how risk information was going to be presented in the Prosigna report.

The test report characterizes patients' risk of recurrence in two ways. First, the report issues a Prosigna score of between 0 and 100 that denotes the patient's likelihood of distant recurrence in 10 years. Originally, NanoString had referred to this as the risk of recurrence, or ROR, score. However, the FDA was concerned that physicians might wrongly interpret the value in the report to mean that that is the actual percent probability of the patient's disease returning.

After discussions with the agency, NanoString decided to rename this data point "the Prosigna score," in an effort to minimize the risk that physicians will inaccurately interpret the test report. "The FDA may have done us a favor here," Gray added. "The Prosigna score is a more differentiated and more branded way to report our individualized risk information." Genomic Health characterizes the Oncotype DX result as a risk of recurrence score.

In addition to the Prosigna score, the test report also categorizes the patient of being at low, intermediate, or high risk of recurrence if her cancer hasn't spread to the lymph nodes, and as either low or high risk if her cancer has spread to the lymph nodes. "Prosigna's risk categories are reported based on the patient's Prosigna score and cutoffs, which differ based on whether the patient is lymph node-negative or lymph node-positive," Gray explained.

Node-positive breast cancer patients with Prosigna scores greater than 80 are automatically considered to be at high risk of recurrence. As such, reports for such high-risk patients will just state the score as being "greater than 80," Gray said.

Gray highlighted as "one of the distinctive features" of the Prosigna test its ability to identify node-positive patients at low risk of recurrence. During the submission process with the FDA, NanoString reevaluated its risk category cutoffs based on data from a clinical validation study.

"It became clear that node-positive patients who would have been categorized as intermediate risk by our original cutoff points actually had quite low risk," he noted. "Therefore, we made the decision in collaboration with the FDA to merge the previous low and intermediate risk groups to create a new, larger low-risk group." This larger low-risk group contained 41 percent of the node-positive patients in the clinical validation study, with an average distant recurrence rate of 6 percent.

This change in how the test report presented risk groups for node-positive patients came about after discussions with the FDA, which went on right up until the agency issued the 510(k) clearance, Gray said. As such, NanoString will now have to go back and revalidate the Prosigna test to ensure that the report it issues will reflect the new risk categories.

"We have to go back and write software code and validate the software code to actually generate the report in an automated way on the instrument," Gray said. "So, that's a step we will be taking in the next few weeks."

Reimbursement traction

In the coming months, NanoString will begin discussion with early adopters, which the company has identified as cancer centers and large commercial labs. Gray noted that the company aims to ready a small number of nCounter systems for shipment to high-volume, high-complexity clinical labs by late in the fourth quarter of this year.

With the nCounter system, NanoString can run 10 patient samples in a single run, 30 samples per eight-hour work day, and 7,500 samples per year. The company estimates that 10 nCounter systems could fulfill the current US market demand for breast cancer recurrence testing.

Ultimately, NanoString is betting that all the effort to garner's FDA's nod for Prosigna will pay off when it comes time to drive test adoption and garner reimbursement. In the coming months, the company will ramp up discussion with guideline-setting bodies and with payors.

NanoString is planning eventually to apply for a CPT code for Prosigna within the American Medical Association's multi-analyte algorithm assay category. However, because getting an MAAA code can take a few years, NanoString in the interim will discuss alternate coding strategies with payors.

NanoString will be present at the San Antonio Breast Cancer Symposium in December to promote the availability of Prosigna early next year.

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