ArcherDx Focuses on CDx and IVD Development Based on Patented Target Capture Tech

R. Kulesus | 17 Nov, 2016

New York (GenomeWeb) Nov,17 2016—ArcherDx has been developing new products for cancer research and other applications over the past year and has established additional partnerships, including for companion diagnostic and in vitro diagnostic development. Last week, the company and its customers presented several posters at the American Molecular Pathology annual meeting on research involving many new assays. In addition, the firm was recently granted a US patent for its core technology, which enables open-ended capture of target sequences from a single primer for next-gen sequencing analysis.

ArcherDx presented six posters at the American Molecular Pathology conference, including evaluations of an assay for cystic fibrosis mutations and a B- and T-cell immune repertoire assay. The firm also presented an evaluation of an assay for detecting copy number variations in formalin-fixed paraffin-embedded samples, data showing its assays enable NGS-based detection of all modes of MET aberrations in cancer samples, and evidence for comprehensive detection of acute myeloid leukemia driver mutations, including internal tandem duplications.

ArcherDx is also branching into liquid biopsy testing with the recently-launched circulating tumor DNA kit that detects 28 genes in a one-day workflow, and one of its posters focused on that.

An additional 15 posters at the conference — describing assays for gene fusions in a range of cancers and validating several the firm's tests — were presented by ArcherDx customers, including authors at Baylor College of Medicine, Emory University Hospital, Dartmouth-Hitchcock Medical Center, Nationwide Children’s Hospital, and Dana-Farber Cancer Institute.

All of the firm's assays use the newly-patented anchored multiplex PCR (AMP) technology. Importantly, none of the kits are for diagnostic use. However, Archer partnered with Illumina earlier this year to co-develop in vitrodiagnostics.

"We think the technology was purpose-built for clinical use,"

— Jason Myers, Ph.D., Chief Executive Officer of ArcherDX

Myers told GenomeWeb, adding that the firm plans to take the Archer assay portfolio and create IVDs. Illumina had initially contacted the firm about distributing ArcherDx products outside of the US, he said, and Archer in turn proposed IVD co-development.

The firm has also created a program to certify outside labs to run its workflow, in particular to support pharma partnerships — so far, it has certified reference laboratory PathGroup, Cancer Genetics and Admera Health, and the Molecular Pathology Laboratory Network this year — and has a direct sales team focused on marketing to pharmaceutical companies.

One such pharma endeavor is with Ignyta, developer of entrectinib, a selective inhibitor for all three Trk receptor tyrosine kinases encoded by the three NTRK genes, as well as the ROS1 and ALK receptor tyrosine kinases. Entrectinib received orphan drug designation in 2015 and is currently in Phase II clinical trials. The firms released a co-developed clinical trial assay in June of 2015 for the purpose of identifying potential patients for trial enrollment.

Ignyta's initial approach to CDx aims for single site premarket approval, Myers said, adding,

"They built that on top of our technology, and we've worked very closely with them."

Jason Christiansen, Ignyta's vice president of diagnostics, said that the firm has been a strong partner with ArcherDx in its diagnostic development efforts.

"When we were considering the design of the companion diagnostic program for our lead drug candidate, entrectinib, we evaluated our requirements for the test and looked for a technology that could provide robust results and represent a leading-edge technology — we found that the ArcherDx technology provided what we needed to meet these needs," Christiansen said in an email.

Ignyta has an integrated "Rx/Dx" approach that combines precision medicines with in-house molecular diagnostics, Christiansen noted. The firm currently uses the Archer technology in its clinical laboratory and has had positive interactions with regulatory agencies as the program has moved forward, he added.

Other ArcherDx partnerships of note are with GenomeOncology, PerianDx, and Sofia Genetics, for creating data automation, annotation, and reporting packages. The firm is also working with Memorial Sloan Kettering Cancer Center, and two assays from this collaboration have been granted conditional approval from the NY State Department of Health for clinical use at MSKCC.

Founded in 2013 and based in Boulder, Colorado, ArcherDx's products are built around the the AMP technology. The company was acquired by Enzymatics in September of 2013 for $50 million. At that time, Myers told GenomeWeb that the firm was targeting development of diagnostic assays that could be brought through the US Food and Drug Administration approval process. Through its partnership with Illumina, the company now plans to work with pharmaceutical companies to bring a next-generation sequencing-based companion diagnostic through FDA approval.

Enzymatics was in turn acquired by Qiagen in January of 2015, for an undisclosed amount, and Qiagen entered a partnership with ArcherDx at the time, whereby Archer re-formed as an independent company focusing on the development of its own line of NGS products.

The AMP chemistry was originally developed at Massachusetts General Hospital by Long Phi Le, Zongli Zheng, and John Iafrate. As described in Nature Medicine in 2013, the method was intended to address the escalating demand for gene rearrangement testing.

The chemistry was also invented with the idea of overcoming the shortfalls of other sequencing chemistries in dealing with nucleic acids that may have been mangled by formalin fixing and paraffin embedding, or handling low-input samples.

Archer was subsequently co-founded by Le, Iafrate, and Myers, who was previously a senior scientist and group leader at Ion Torrent Systems, now part of Thermo Fisher Scientific. The company licensed the AMP technology exclusively from Massachusetts General Hospital.

Myers told GenomeWeb that he believes the new AMP patent will prove to be a seminal patent in molecular biology. Standard PCR-based methods, he explained, involve designing forward and reverse primers, but the AMP method only requires one primer.

"If you just have to know one specific region of a gene, you can actually leverage the power of the sequencer to identify what is next to it," Myers said.For example, the ALK gene can fuse to other genes and drive cancer, but its fusion partners can be highly variable. "If you're going to use just standard PCR, you have to make a primer pair for every partner — gene fusions are a relatively new field, so the problem is, if you don't know what the partner is and don't put a primer in, you'll never be able to discover it."

— Jason Myers, Ph.D., Chief Executive Officer of ArcherDX

The AMP method, on the other hand, uses random start sites and a combination of gene-specific primers and universal adapters that contain a universal primer binding region, a molecular barcode, and an index region to generate a library for the MiSeq sequencer. A first PCR step uses an anchored gene-specific primer which amplifies against the primer in the adapter. A second enrichment amplification employs a nested gene-specific hybrid primer that also contains another primer region and an additional index region. Two sample indexes are thus added to every enriched DNA molecule, and the availability of a variety of unique indexes enables a high degree of multiplexing. In this way, the method can capture "unknown information" in a quantitative way, Myers said.

Interestingly, the strand-specific priming method also prevents false positive single-nucleotide variant calling due to formalin-induced deamination events. This is because the adapters are ligated to the DNA prior to amplification, unlike with standard PCR. The AMP method also sees a fourfold improvement in accuracy over standard PCR if there is a SNP in the primer-binding region, Myers said.

Archer has several product lines that rely on the newly-patented AMP technology.

The FusionPlex line can be used to detect gene fusions, single nucleotide variants, and insertions and deletions from RNA. VariantPlex assays can detect copy number variations, single nucleotide variants, and indels from DNA. These workflows can be performed concurrently on FFPE samples, for example, to yield high-quality results from low amounts of starting sample.

Archer has also launched kits for comprehensive tumor profiling, including one for thyroid and lung cancer called the Comprehensive Thyroid and Lung Assay (CTL) and a solid tumor panel. The CTL kit uses both the FusionPlex and VariantPlex lines to create libraries from RNA and DNA, and it detects relevant exons in 44 genes implicated in lung and thyroid cancers from 20 nanograms of total nucleic acid. The VariantPlex solid tumor kit, meanwhile, identifies fusions and other mutations associated with 67 genes genes involved in solid tumors, using 10 to 200 nanograms of DNA.

In addition, the firm manufactures a qPCR-based method to determine the quality of DNA prior to targeted sequencing library prep using the VariantPlex system, called the PreSeq DNA QC Assay.

The company has also developed three blood cancer tests with partially overlapping targets, referred to as the myeloid panel, the heme V2 panel, and the acute lymphoblastic leukemia or ALL panel. Its recently launched T-cell receptor repertoire kit uses primers that target the constant regions and are extended into the variable regions, Myers said.

About ArcherDX

ArcherDX addresses the bottlenecks associated with using NGS in translational research by offering a robust platform for targeted sequencing applications.

By combining proprietary AMP chemistry and easy-to-use, lyophilized reagents, Archer NGS assays generate highly enriched sequencing libraries to detect gene fusions, point mutations, CNVs and RNA abundance. Complemented by the Archer suite of bioinformatics software, ArcherDX technology dramatically enhances complex mutation identification and discovery.

ArcherDX is headquartered in Boulder, Colorado.

Note: Archer kits and analysis software are for research use only and not for use in diagnostic procedures.