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Inivata to Open Clinical Labs in North Carolina and UK With First ctDNA Test for NSCLC

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NEW YORK (GenomeWeb) – Startup liquid biopsy firm Inivata plans to open two new clinical laboratories — a CLIA-certified lab in the Research Triangle area of North Carolina and an ISO-accredited lab in Cambridge, UK — later in the second quarter, CEO Michael Stocum told GenomeWeb this week.

In addition, he said that the firm has completed the analytical validation of its 35-gene next-generation sequencing-based circulating tumor DNA assay and is conducting clinical validation studies, which it expects to complete in about one year.

Inivata spun out from Nitzan Rosenfeld's laboratory at the University of Cambridge in 2014 based on technology called targeted amplicon sequencing (TAm-seq), developed by Tim Forshew and Muhammed Murtaza. The Rosenfeld lab published a proof of principle in 2012 of a six-gene version of TAm-seq in Science Translational Medicine, demonstrating that it could detect mutations in ctDNA that were present at frequencies of between 1 percent and 2 percent.

In January, Inivata raised £31.5 million ($46 million) in a Series A financing round. In addition, it expanded the assay to 35 genes from six and improved on its limit of detection to be able to detect mutations present at 0.1 percent frequency.

Inivata plans to commercialize the test initially for late-stage non-small cell lung cancer patients.

Stocum said that the firm would initially use its US-based lab to conduct clinical validation studies in collaboration with partners using samples from the US, and to identify "any emerging commercial opportunities." Meantime, it will initially use the UK clinical lab for European clinical samples.

In the original proof of principle of TAm-seq, the researchers demonstrated a two-step amplification process where they first created primer sets to generate amplicons from regions of interest and then performed a limited-cycle pre-amplification to capture all the starting molecules, followed by individual amplification to select targets. They then used Fluidigm's Access Array to amplify the targeted regions and sequenced them on an Illumina sequencing instrument.

John Beeler, vice president of product development, told GenomeWeb that the updated version of the assay, which it is now calling "enhanced TAm-seq," has been modified on both the front and back ends to increase sensitivity. It still uses a two-step amplification process, he said, but it has improved on primer design and library prep methods and has designed bioinformatics. He declined to disclose additional details of the improvements that confer greater sensitivity.

In the majority of the 35 genes included in the assay, TAm-seq analyzes hotspot regions, while for a few genes of interests, like TP53, it targets all of the exons. The firm will also screen for CNVs in a handful of those genes.

Separately, it is developing a method to detect gene fusions by "exploring the use of a hybrid capture technique,", Beeler said.

At Cambridge Healthtech Institute's Molecular Medicine Tri-Conference in San Francisco last month, Forshew described a clinical collaboration the firm is doing with the Institut Gustave-Roussy in Paris.

The group looked at 20 individuals with non-small cell lung cancer, including 18 samples from patients prior to being treated and two patients post-treatment. For 10 patients, the researchers were also able to collect samples 21 days after starting treatment.

Out of the 20 individuals, they were able to detect mutations in 19 down to a mutation allele frequency of 0.1 percent. In addition, by comparing the pre- and post-treatment samples and looking at patient outcomes, they demonstrated that ctDNA levels dropped for patients who had a clinical response to treatment.

Forshew also highlighted one specific patient who had a metastasis in the bone from which it was difficult to get a tissue biopsy. Instead, they took a blood sample and ran the TAm-seq assay, which detected a mutation for which there is a compound being developed by Astra Zeneca to treat. They were able to get the drug for the patient, who had a good clinical response and also showed dropping levels of the mutation in circulation. However, throughout the course of the patient's treatment, one mutation to the TP53 gene has remained stable. "We're following this individual because there is a good likelihood that the cancer will come back" due to that TP53 mutation, Forshew said.

Aside from offering its test as an alternative to tissue biopsy in NSCLC patients, Inivata also plans to launch it for other tumor types and other applications. Stocum said the firm is looking to validate its test in breast and colorectal cancer, while Beeler added that the firm thought the "immediate need is to provide molecular profiles," but that there are many points along the continuum of cancer care where a noninvasive genomic assay would be useful. A logical next application, he said, would be to monitor patients' response to treatment, including any development of resistance mutations that would impact their treatment plan. He said the firm is currently trying to determine whether and when it makes sense to develop the assay for these other applications.

Inivata will be entering an increasingly crowded market when it launches its test, and will have to compete with firms like Guardant Health and Foundation Medicine. Guardant Health already markets a 70-gene ctDNA test, Guardant360, and last year published an analytical validation of the test, demonstrating that it could detect mutant alleles down to a 0.1 percent frequency.

Meantime, Foundation Medicine plans to launch its 61-gene ctDNA assay, FoundationAct, this quarter. The test will be able to detect SNVs at a 0.5 percent allele frequency and indels and CNVs at a 1 percent frequency.

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