NEW YORK (GenomeWeb) – Admera Health recently expanded the number of genes covered in its next-gen sequencing liquid biopsy assay, making it possible for the company to give a readout of microsatellite instability (MSI), which has become a crucial biomarker for cancer immunotherapies such as Merck's PD-1/PD-L1 inhibitor Keytruda (pembrolizumab).
Admera, originally a pharmacogenomics company, began expanding several years ago, first branching out to offer cardiovascular risk testing and tissue-based cancer tests in 2015 and 2016, and more recently developing a set of liquid biopsy services that include both the firm's newly-expanded NGS panel, which detects more than 170 variants across 17 genes compared to 10 in the previous-generation test, and qPCR assays providing even higher sensitivity for four genes.
Like many in the growing field of noninvasive cancer testing, the company is leveraging a set of purpose-built methods to make it possible to detect the minute amounts of mutated DNA in a large background of normal genomic material.
Various players have cited proprietary techniques for barcoding, correcting sequencing errors, and/or selectively amplifying mutant DNA while suppressing wild-type molecules.
Admera's liquid biopsy special sauce is similar to competing techniques but the company believes it has unique advantages, Admera R&D Manager Chris Kasbek, who led development of the LiquiGx test, said this week.
For its qPCR assays — for ALK, BRAF, EGFR, and KRAS mutations — the company employs what Kasbek described as a "blocking system," and abstracts have referred to as blocking oligos, which help preferentially enrich "very, very low-frequency mutations."
"Some other companies have similar technologies, but I think … with the R&D and development we've done it's possible in the future we can multiplex them a little bit better," he added.
With its NGS panel, Kasbek cited three aspects that he believes gives Admera's test advantages over some other approaches. First, he said, though the firm uses a standard amplicon-based method on Illumina's technology, it adds " a unique molecular tagging [method] … to remove a lot of the background of the NGS system — a lot of the error."
"Other people are doing this too, but I think our advanced bioinformatic system can get our LOD to be even a little bit lower," he added. The company calls its informatic pipeline AGIS (Actionable Genomic Interpretation System).
According to Kasbek, the company's decision to keep its panel relatively small and focused is also a differentiator from the very broad approaches at companies like Guardant Health and Foundation Medicine — albeit one that some other companies like Resolution Biosciences have also adopted.
"We focus on these 17 genes because by [professional guidelines] and other metrics, these are the only ones that are really clinically actionable and have approved drugs or very late stage drugs [associated with them,]" Kasbek argued. "Focusing on that allows us to get very high uniformity, whereas with a lot of [larger] panels, they're so broad that there may be many of the spots where they aren't reaching their claimed sensitivity."
Finally, he said, the company's NGS approach also combines both DNA and RNA sampling, which he said helps maintain high sensitivity for the detection of fusions.
Data the firm has shared publicly over the past few years include a poster presented at the American Association for Clinical Chemistry meeting in 2017, which reported an assessment of its NGS and qPCR tests in a cohort of lung cancer patients — with 210 individuals tested using the NGS panel, and 173 of these also tested with the firm's qPCR assays.
According to Admera, the mutations identified by the tests closely mirrored published lung cancer tissue biopsy data, and its two assays exhibited 93 percent concordance with each other with discordances explained by the greater detection limit of qPCR (0.01 percent) compared to sequencing.
In new data that the company expects to share at this year's annual meeting of the American Association for Cancer Research, investigators studied the ability of the expanded NGS panel to identify single nucleotide variations, indels, fusions, copy number variations, and MSI.
Using spike-in experiments, researchers reported that the assay's limit of detection for CNVs could go as low as 2.2 to 2.5 total gene copies. The LOD for MSI detection was 2 to 4 percent, authors added.
Measuring patients' likelihood of responding to immunotherapy based on MSI is something that the company was excited to be able to add with the new expansion of its test, and was partly spurred by customer interest, said Admera Associate Director of Strategy and Marketing Jeffrey Mitchell.
"Were getting a lot of questions about whether we could do anything with PDL or PDL 1 … And that being a protein marker, you really can't do that with ctDNA. But we found with the [new] panel size we had, that the most appropriate solution or analogue to that that was MSI," Mitchell said.
Tissue biopsies have previously been the mainstay of MSI testing, but Admera is not alone in adapting noninvasive tests to read out the biomarker. Guardant Health, Personal Genome Diagnostics, and Foundation Medicine have all moved to provide MSI status as part of their comprehensive sequencing reports, following the pan-cancer approval of Merck's Keytruda, for example.
Unlike Guardant, Foundation, and PGDx, Admera's NGS panel is not large enough, however, to measure tumor mutational burden, another immunotherapy biomarker that has recently received great attention from drugmakers and diagnostics firms that hope to offer associated tests.
Mitchell declined to provide details about the company's sales volume in the liquid biopsy space, or for its older tissue-based cancer offering, but he said that the firm is "running the tests regularly."
A draw for customers, he also argued, is Admera's ability to provide not just cancer mutation testing, but also to potentially add on pharmacogenomics information. In that vein, the firm offers a PGx tool specifically geared toward cancer patients called PGxOnco.
"No other company also has the PGx component where they can incorporate supportive care — looking for things like the right pain management drugs, the right antidepressants or anxiety drugs, and also chemotherapeutic selection," he said.
As the company has built up is oncology business, Mitchell said that its international presence has grown, with about half of its business outside the US. Ex-US testing is performed with distribution partners, he added, something the company also does in the states, though it saw a setback last year with Rosetta Genomics' bankruptcy filing.
"That was unfortunate for us. They were, as a brand name, one of our larger partners," Mitchell said.
As the liquid biopsy field evolves, Kasbek said that Admera plans to continue to align its test with the most actionable genes.
"As more drugs are developed and late-stage trials appear, obviously we'd want to expand some, but I don't think we will ever get to a really huge panel," he said.
"We hear it a lot … [that] people think that they might want a large panel and they get a large panel, but there's a contingency … who might have a little buyer's remorse that they get all this information that they don't know what to do with — information that might even be more academic in nature than clinical in nature … so we're focused on just providing that option for physicians to have a more actionable panel." Â