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Startup Guardant Health Developing NGS-based Assays to Assess Circulating Tumor DNA

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Guardant Health, a startup company formed in 2012 by two former Illumina employees, recently announced its first product — a targeted next-gen sequencing-based assay that assesses circulating tumor DNA.

The test, Guardant 360, analyzes 54 oncogenes and tumor suppressor genes. It requires a patient blood sample and uses a proprietary target capture to zero in on the specified genes. Sequencing is done on Illuumina's HiSeq 2500 and turnaround time is two weeks. The company has not yet disclosed a price for its test, which is currently available via early access.

The firm was founded in 2012 by CEO Helmy Eltoukhy and President and CTO AmirAli Talasaz, and currently has around 15 employees. It recently raised $10 million in a financing round led by Sequoia Capital to support technical development, clinical validation, and early commercialization of the test.

Eltoukhy and Talasaz both did postdoctoral work at Stanford University's Genome Technology Center. Eltoukhy founded the company Avantome in 2007, where he worked on developing sequencing technology on disposable CMOS chips. Talasaz cofounded a company called Auriphex Biosciences, which was working to develop technology to isolate rare blood cells.

Illumina purchased Avantaome and Auriphex in 2008 and 2009, respectively, and both Eltoukhy and Talasaz began working for Illumina. Eltoukhy most recently served as senior director of Illumina's advanced technology group and Talasaz was most recently senior director of scientific research.

Eltoukhy told Clinical Sequencing News that he and Talasaz decided to start Guardant Health because they felt that although "sequencing costs have come down dramatically … there still weren't very many killer apps based on low-cost DNA sequencing" and, aside from the success that sequencing has seen in the NIPT market, "sequencing and genomics have yet to make a true dent in major disease."

Guardant Health is betting that its method for analyzing circulating tumor DNA will change cancer treatment by enabling rapid and noninvasive diagnostics and disease monitoring that will also pinpoint effective treatment options.

The key to the Guardant 360 test, which analyzes around 54 cancer-related genes in a patient's blood, is the company's proprietary sample prep and bioinformatics, Eltoukhy said. While he declined to provide additional details, he said that the sample preparation method essentially "converts the molecules to something that is sequenceable yet resistant to the errors and bias that sequencing introduces." Using bioinformatics, the firm is able to convert the output from the sequencer back into the original molecule, he said.

The combination of the sample prep and bioinformatics reduces the error rate by about 1,000-fold, he said, which is essential for detecting point mutations in ctDNA.

Even though sequencers such as Illumina's HiSeq have accuracy rates above 99 percent, when looking for just a handful of true actionable mutations among several thousand bases of sequence data, there can be thousands of false positives, Eltoukhy said.

"That's a big problem right now, and what we've been able to solve," he said.

Currently, Guardant Health is working with several unnamed cancer centers.

At last month's Molecular Medicine Tri-Conference in San Francisco, Dave Hoon, the director of the John Wayne Cancer Institute's sequencing center and an advisor to the company, presented a validation study he is doing with the company, results of which have been analyzed in around 250 patients so far.

The study seeks to verify that the assay detects the same mutations in a patient's blood as can be detected in the patient's tumor. In a pilot of 19 colorectal cancer patients and 21 melanoma patients, the assay found at least one mutation in the patients' blood that was also present in the tumor in 36 out of the 40 patients.

Looking at 250 patients, he said that the assay found that 89 percent of patients had at least one alteration and between 60 percent and 70 percent of those patients had at least one actionable alteration.

Currently, Hoon said that it is important to verify that the mutation found in the circulating tumor DNA is also present in the primary tumor, before the information can be used to make treatment decisions. Eventually though, he said the assay could be valuable for identifying targetable mutations in tumors that are difficult to biopsy or present at subclinical levels.

The assay has two features that Guardant Health believes make it "quite a powerful tool," he told CSN in a follow-up interview. Because it analyzes blood rather than tumor tissue, the test is noninvasive and can be done repetitively to monitor a patient's response to therapy, for instance, or to identify residual disease or monitor recurrence. "It adds a new dimension," he said.

Guardant Health's test will initially be used for late-stage patients that have failed the standard of care, Eltoukhy said. Currently, there are guidelines for patients at the time of diagnosis, he said, and oncologists will work within those guidelines, but "as soon as a patient fails therapy, there are a lot of open questions," he said. While tumor sequencing is starting to be adopted as a means to find an alternative therapy, "perhaps an even better solution will be sequencing circulating tumor DNA."

Aside from identifying the next course of treatment, the test can be used throughout treatment to see whether, after treating a patient, those mutations have gone down or whether new mutations have arisen.

The firm plans to publish a paper on its technology in the near future, Eltoukhy said.

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