NEW YORK (GenomeWeb) – With its acquisition this week of Seattle-based Integrated Diagnostics, Biodesix has positioned itself to bring to market one of the first molecular tests to aid identification of early-stage lung cancers, with aims at solving the commercialization puzzle Indi had faced after expending its own resources in development and validation of the test.
The second generation of a multiplex proteomic test that Indi previously called Xpresys Lung, the XL2 assay measures two plasma proteins — LG3BP and C163A. Combined with pathologic and clinical factors, the protein readout is intended to improve the identification of cancers in individuals who have had a lung nodule detected via imaging.
More than identifying nodules that are likely to be cancer, the assay is designed to help reduce unnecessary biopsies by helping to rule out those who have a low risk of malignancy.
For Biodesix, the acquisition extends its presence in the lung cancer space from later-stage disease, where it offers two assays — the proteomic VeriStrat prognostic assay, and the GeneStrat liquid biopsy test, which noninvasively detects actionable mutations in advanced lung cancer patients — to the increasingly well-attended realm of early detection.
"Our strategy is to own the continuum of care, from screening to therapy guidance, so this bookends our existing products nicely," said Biodesix CEO David Brunel.
On the other side of the deal, Indi's CEO Albert Luderer said that as his company neared completion of its validation work for XL2, and the finalization of its Medicare coverage determination, it was clear that it would either need new funding, or a merger or acquisition to support the move into the clinic.
He noted "the paucity of molecular diagnostic investors" and said, "Biodesix, as a lung company from inception, was clearly a good fit." .
Indi had struggled in years past to gain adoption of the XL2 test's predecessor Xpresys Lung. The original test, which used multiple-reaction monitoring mass spec to quantify the levels of 11 proteins in patient blood samples, posted only modest sales, with around 2,000 total tests sold during the roughly three years it was on the market after a 2013 launch.
One hurdle that the company hoped to overcome with the second generation of the test was to focus more narrowly on stratifying patients who are considered moderate-to-low-risk based on existing clinical and other factors — recognizing that physicians already feel confident in their ability to pick out high-risk individuals who should get further testing.
The positive coverage determination for XL2 by Medicare contractor Noridian last year reflects this — outlining coverage for the test in assessing patients who have a pre-test cancer risk of 50 percent or lower based on the Mayo Clinic Model for Solitary Pulmonary Nodules.
Results of Indi's Panoptic study, which supported the CMS coverage decision for XL2, were published in full this March in the Chest Journal.
Investigators studied 178 low-to-moderate risk subjects — 29 diagnosed with malignant lung nodules and 149 with benign lung nodules. Among those with benign nodules, 42 underwent at least one invasive procedure to further assess the nodule. Of the 29 malignant nodules, 13 were moved on to surveillance, as opposed to biopsy or other procedures.
In the 178-subject cohort, XL2 demonstrated a sensitivity of 97 percent, specificity of 44 percent, and negative predictive value of 98 percent in distinguishing benign from malignant nodules.
Analyzing patients diagnoses and outcomes in light of the results of the XL2 test, researchers concluded that if the results had been used to guide treatment decisions, it would have reduced the number of benign patients receiving invasive procedures by 36 percent and reduced the number of malignant nodules passed on to surveillance to 3 percent.
According to Noridian's determination for XL2, continued CMS coverage for the test is contingent on the ability of Indi, and now Biodesix, to confirm the implied clinical utility offered by the retrospective analysis in Panoptic with prospective data.
The coverage determination mandates that patients who receive the test must have a record kept of their clinical risk factors, PET results if used, physician pre-test risk assessment, physician post-test lung nodule management recommendation, any subsequent procedures, and their clinical diagnosis based on those procedures.
In addition to utility data already collected by Indi, Brunel said that Biodesix is planning its own registry study to further validate the test later this year, which will involve about 500 patients.
Demonstrating clinical utility will also depend on the willingness of physicians to implement the results of the test in their practice, something that may have also played into Indi's challenges in gaining adoption for the prior Xpresys assay.
Researchers have reflected previously on the fact that pulmonologists may be hesitant to forego biopsies even if test results indicate they aren't necessary lest they miss a cancer. Because of this, building confidence in the test and its accuracy will require educational and outreach efforts that Indi did not have resources for, but Brunel said Biodesix is prepared to furnish.
While the promise of the XL2 test was central in Biodesix's decision to acquire Indi, Brunel said that other proteomic methodologies and sample sets that Indi has developed are going to be strategically valuable, and are expected to help Biodesix push forward with optimization of the XL2 test itself, and in further discovery efforts for new tests.
He didn't specify that there would be a platform change, but said that Biodesix is going to be working to simplify XL2 and make it cheaper to run. One way to do that may be to transition from a mass-spec platform to immunoassay for the two measured proteins.
Although it has focused mainly on proteomics, Biodesix also offers one genetic test currently —  the GeneStrat liquid biopsy test — which uses BioRad's Droplet Digital PCR to detect therapeutically relevant mutational biomarkers like EGFR, ALK, and ROS alterations.
But according to Brunel, although there are also genomic strategies that have been developed for lung nodule stratification, Biodesix was confident that XL2 holds the most promise for commercial implementation.
While XL2 is the first blood-based test in this pulmonary nodule indication to garner CMS coverage, it may likely face market competitors in the future from at least one genetic alternative.
OncoCyte, for example, is in the end stages of validating a gene expression-based assay it calls DetermaVu, and is working to lock in the platform on which it intends to launch the test.
Although the company has recently had to push back its commercial timeline, it said yesterday that researchers had collected new results supporting moving the test from the Nanostring platform OncoCyte had been using to an NGS technology (both Thermo Fisher and Illumina platforms were tested). The company also said that the addition of new biomarkers to its panel seems to offer equal or even better accuracy than it has reported previously, potentially without the inclusion of clinical information like nodule size.
Although it remains to be seen how previously reported sensitivity and specificity numbers for DetermaVu hold up in the company's final validation experiments, the 73 percent specificity that OncoCyte has claimed represents a significant improvement over the 44 percent reported for XL2, although sensitivity lags slightly behind the proteomic test.
OncoCyte has said that it hopes to complete a planned clinical validation study — a last step before a commercial launch — during the first half of 2019