NEW YORK – Morgan and Mendel Genomics has developed functional genomics tests that they believe can lead to faster and more accurate results for determining germline variants related to hereditary cancer than sequencing.
The company's products come out of research done at the Albert Einstein College of Medicine and use flow cytometry-based functional variant assays to measure protein changes in DNA repair pathways that could indicate the presence of pathogenic variants leading to cancer.
The Bronx-based company, founded in 2016, currently has two tests in the works: Cancer Risk B (CR-B), which evaluates the risk of a patient developing breast or ovarian cancer based on the presence of variants in BRCA1, BRCA2, and other genes; and Cancer Risk C (CR-C) for Lynch Syndrome, a genetic disorder that increases the risk of colorectal cancer and is caused by heritable pathogenic variants in the DNA mismatch repair (MMR) pathway.
According to Harry Ostrer, a professor of pathology and pediatrics at Albert Einstein and a member of the company's scientific advisory board, the technology was originally used to annotate variants, but the team realized it had the potential to work with any genetic pathway, meaning it could meet the diagnostic need that arises when gene panel sequencing finds variants of unknown significance or no variants, and patients are "left worrying because [they] have no idea what that means."
A paper published late last month in Genetics in Medicine lays out the development process for the CR-C test, which measures functional activities in the MMR pathway to determine the presence of variants indicating Lynch Syndrome. The test is based on functional variant assays for the nuclear translocation of repair proteins — MLH1 and MSH2 — and nuclear phosphorylation of the DNA damage-sensing kinase ATR and creates a risk classification score that combines the results of the three assays to determine the risk of MMR pathway deficiencies.
Running the test requires the isolation of white blood cells from a patient's blood sample, which are then treated with DNA damaging alkylating agents, Morgan and Mendel Senior Scientist Ishraq Alim said. The cells are then fixed by treating the sample with methanol, and the protein activity of the repair process is measured with fluorescently labeled antibodies. That activity indicates whether there are deficiencies in the MMR pathway, and those deficiencies determine the patient's risk classification score.
After developing the test with 40 patient samples, as described in the Genetics in Medicine study, the remaining 140 samples included in the research were used as a replication cohort — 40 patients had pathogenic or likely pathogenic variants in MMR-related genes; 60 patients had a variant of unknown significance in MMR genes and a colorectal tumor; and 40 were family members of patients with known pathogenic or likely pathogenic variants who didn't have the variants themselves. Within that cohort, the test's risk classification score in the first and third groups of patients was 100 percent sensitive and 98 percent specific. For the second group with MMR deficient colorectal cancer — as judged by microsatellite instability and variants of unknown significance — 73 percent of patients had a positive risk classification score.
Although the test showed high sensitivity and specificity, Ostrer noted that there is still a need to prove the assay's clinical utility, since the ultimate goal is to measure a patient's cancer risk in a clinical setting. When both the CR-C and CR-B tests are fully validated, Ostrer said that they could be used as an alternative to sequencing, because sequencing "detects germline defects in only 15 to 20 percent of patients" and has a long turnaround time and high cost compared to the two-to-three-day turnaround time of the CR-B and CR-C tests.
Morgan and Mendel's tests rely on flow cytometry instruments that are present in most commercial labs, and the goal for the company is to ensure the test can be used on instruments that have already been cleared by the US Food and Drug Administration so there's no additional cost or regulatory burden for a lab to implement the assays. While the workflow could be "quite different" than what clinical laboratorians are used to, most of the test — triggering the pathways, prepping the cells — is automated, and the company has developed software to help facilitate the interpretation of results.
While other companies have developed tests for Lynch Syndrome, such as Promega with its OncoMate MSI Dx Analysis System and Biocartis with its Idylla MSI test, the CR-C test is unique because, according to Alim, a lot of the tests for Lynch syndrome are intended for use after a patient has already developed a tumor. The CR-C assay is specifically for pre-tumor testing, and there's "really not anything out there" for pre-tumor testing with Lynch syndrome, he said.
The firm also has plans in place for the future of its products in the US, Alim said. The CR-B test is further along the commercialization route than the CR-C assay, as the company has already had conversations with the FDA about CR-B's future de novo clearance. Currently the firm is collecting clinical data for the CR-B regulatory submission, and it is planning a larger clinical study to determine the clinical utility of the CR-C test that will be used for that test's regulatory submission. Ostrer said the company expects FDA clearance for CR-B in 2023, with CR-C nine to 12 months later.
He also noted that Morgan and Mendel has explored reimbursement pathways with the US Centers for Medicare and Medicaid Services and Medicare Administrative Contractor Palmetto GBA. The tests would most likely have their own CPT codes for payment and would not be covered under an existing local coverage determination, so a new coverage decision would need to be created for their technology.
The firm has patented CR-B in the US, EU, Britain, and China and is currently waiting on a patent in Canada. For the CR-C test, the company has submitted a fast-track patent application in the US and plans to apply for patents outside the US later this year or early next year, Ostrer said.
Outside the US, he said there has been interest from both academic and commercial collaborators in France who'd like to do their own studies on the technology to show its analytical validity.
Although cancer risk determination has been the focus of the company so far, the technology could also be used to measure a patient's potential response to cancer therapies, such as increased sensitivity to PARP inhibitors, Ostrer said. That use case is something the firm has considered, but most of its funding and grants — about $5 million in grant money so far — have been for cancer risk.
As for using the technology for other types of cancer, once the first test has been brought on board and to market, it becomes "so much easier" to move forward with other tests, Ostrer said. The company has its eye on cardiac disease and other rare diseases listed by the American College of Medical Genetics and Genomics as recommendations for reporting incidental findings in clinical exome and genome sequencing.
However, the main goal for the company right now is ensuring it can prove the clinical utility of its technology in cancer risk. "The debate that we have with reviewers, both for grants and manuscripts is, 'Is it just a test for annotating variants, or is it a test for predicting cancer risk?'" Ostrer asked. "We'll know that from the studies we're doing right now."