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Invivoscribe Aiming to Bring CDx, MRD Tests for Hematological Cancers Through FDA Clearance


NEW YORK (GenomeWeb) – Invivoscribe Technologies is developing a suite of companion diagnostic and minimal residual disease tests for acute myeloid leukemia, and plans to bring its tests through US Food and Drug Administration clearance.

In addition, the company, which operates clinical testing laboratories in San Diego and Germany, plans to open a third lab, in Japan, by the end of the second quarter, Invivoscribe CEO Jeffrey Miller told GenomeWeb this week.

Currently, Invivoscribe's primary business is FLT3 and NPM1 testing in AML to stratify patients, and its largest customers are pharmaceutical companies. However, the firm also has a number of other tests, including a 194-gene NGS panel currently being used for biomarker discovery in AML, as well as NGS-based tests for minimal residual disease tracking that have CE marking for in vitro diagnostic testing in Europe.  In addition, Miller said Invivoscribe is developing an NGS-based MRD test to identify AML-associated FLT3 mutations in patients. The test could be used to monitor a patient's response to therapy, predict relapse, or determine whether or not a patient would benefit from a bone marrow transplant.

Invivoscribe's NGS-based tests are designed to run on either Illumina's MiSeq or Thermo Fisher's Ion Torrent PGM. Miller said that while the firm is technology agnostic, when it submits its test for 510(k) clearance, it would have to do so on a specific platform. The company is still deciding which tests would be submitted on which platforms, he said.

However, in February, Invivoscribe formed a strategic partnership with Thermo Fisher to develop NGS-based cancer diagnostics on its Ion PGM Dx system for diagnosing and monitoring MRD in hematological cancers.

Companion diagnostics

Invivoscribe's FLT3 CDx assay uses PCR and capillary electrophoresis sequencing. The firm has agreements with both Astellas Pharma and Novartis to develop and commercialize the CDx, which uses what's called a signal ratio test that compares the signal from the mutant to the wild type to distinguish patients with FLT3 mutations from cytogenetically normal ones.

Miller said that the company has been working to develop a standardized assay that can work as a CDx for multiple pharmaceutical companies' drugs and for patients all over the world.

"The assay is locked down and can be used to stratify patients on an international basis," Miller said.

Without such standardization, Miller said, there are different thresholds for mutant allele signals that are utilized to stratify patients, he said. If different thresholds are used to define what is positive, patients will not be stratified in a coherent manner and the clinical trial "data will be sloppy."

Although companies like Illumina are looking to develop multi-gene panels that can serve as a universal companion diagnostic, Miller said that Invivoscribe is not going that route, despite its experience with NGS. Instead, he said, the company is taking a "more focused approach that will pay off in the short term and addresses the specific needs of our partners."

MRD testing and gene panels

Bringing a FLT3 companion diagnostic through FDA clearance will be a big push for Invivoscribe over the next year, but the company is also concurrently pushing to bring a test for monitoring MRD through FDA clearance.

This test will also assess FLT3 mutations, although it will use next-gen sequencing as opposed to PCR and CE sequencing, enabling it to detect lower frequency variants. Miller said the firm is validating it to detect mutations down to a frequency of 1 in 10,000 from 700 nanograms of input DNA. The test will look at SNVs as well as indels up to 120 base pairs.

Invivoscribe is also developing a number of NGS-based panels to run on either the PGM or MiSeq.

The company already offers CE-IVD marked assays in Europe to detect clonality in hematological malignancies, including one that assesses T-cell receptor gamma rearrangements and another that looks at immunoglobulin heavy chain gene rearrangements. Both tests are CE marked to run on either the MiSeq or PGM.

Miller said that a version of those tests would be brought through FDA clearance. "We may tweak them" in the process of developing them for FDA standards, he said, but they will be almost identical.

In addition, he said, specific assays would be submitted to the FDA on specific platforms, although he declined to disclose which ones. These assays are currently being used for both diagnostic purposes and to track a patient's disease over time, analyzing DNA taken from bone marrow aspirates. Miller said that the company would initially submit them to the FDA with diagnostic claims, but said that the firm would later seek to expand the designation so that it could be used for monitoring disease, as well.  

In order to do that, he said the firm would need to do software and clinical validation, for instance, running a trial demonstrating the assay's ability to monitor disease using a different set of samples than it does for the diagnostic claim.

The tests can also work with peripheral blood in most cases, Miller said, but bone marrow tends to yield more robust results because there is more tumor material.

Finally, the firm offers a 194-gene AML panel for discovery and is working on a smaller panel that will assess around 30 driver genes.

Pharmaceutical companies use the 194-gene panel in both prospective and retrospective analyses of early-phase trials to "let them think more carefully about the patients to include in subsequent trials," Miller said. In addition, he said, the larger panel enables biomarker discovery as well as the ability to track how clones disappear or emerge throughout treatment, giving "pharma good ideas of what they have to look for," and "helping them identify mutations that correlate with outcome."

Miller said that pharmaceutical companies have also expressed a desire for a more limited panel — one that looks at between 10 to 30 AML driver genes — and the firm is in the midst of developing that panel now. Most likely, that panel will include some customization ability so that customers can analyze a range of genes.

In the future, Miller said that Invivoscribe will continue to focus on hematological diseases and developing products for the entire range of drug development pipelines from discovery, to developing products for a regulated environment as IVDs or MRD tests. "That's our goal for the next decade or so," he said.