NEW YORK – Having recently announced the launch of its first clinical assay, French biotech firm Genfit is looking to move further into the diagnostics business.
Genfit developed its first test, a blood-based assay for nonalcoholic steatohepatitis, or NASH, offered as of this month in the US and Canada by the Laboratory Corporation of America, using resources from an ultimately unsuccessful NASH drug development program.
While the Loos, France-based company is still focused on the development of therapeutics for liver conditions, it also plans to continue biomarker discovery and development and has indicated that it will likely create a wholly owned subsidiary that will house its diagnostics work, said Suneil Hosmane, global head of diagnostics at Genfit.
Labcorp licensed Genfit's NASH test, called NASHnext, through its Covance drug development business for clinical research in 2019 and licensed it as a diagnostic for use in NASH patients in 2020.
The test integrates blood-based measurements of miR-34a-5p, alpha-2-macroglobulin, YKL-40, and HbA1c to detect patients with high-risk NASH, meaning they are at risk of progressing to more severe conditions including liver cirrhosis, cancer, and potentially the need for a liver transplant.
Labcorp announced the commercial launch of the test last week. In an email, Brian Caveney, chief medical officer and president of Labcorp Diagnostics said the test would be used in patients considered at risk of having high-risk NASH because they have "multiple metabolic risk factors such as type 2 diabetes, obesity, dyslipidemia, hypertension, hepatic steatosis, with or without elevated alanine aminotransferase or aspartate aminotransferase results."
He noted that NASHnext offered an advantage over existing assays like FIB-4, APRI, and the Enhanced Liver Fibrosis test in that while those tests assess risk of liver fibrosis, they don't identify patients with NASH specifically.
"NASHnext identified patients with NASH and significant liver fibrosis with a single score," he said.
Hosmane said that many of the tests used for assessing NASH today have been repurposed from other liver indications — for instance, as tools to identify fibrosis in patients with hepatitis C.
"Those tests, while they are used somewhat for NASH, it was clear that people wanted something more specific to" NASH, he said.
Imaging tools to assess fibrosis are, likewise, general tools intended for use "across the spectrum of all liver diseases," Hosmane said. "And generally, the feedback that we have seen and heard is that they like to combine that with blood-based testing to get a full view of what is happening."
Genfit scientists and collaborators published a study detailing the performance of the test last year in The Lancet Gastroenterology & Hepatology to rule in and rule out patients with at-risk NASH, which they defined as NASH with a nonalcoholic fatty liver disease activity score of 4 or greater and fibrosis of stage 2 or higher.
In a validation cohort of 702 patients, the test ruled out patients as not having at-risk NASH with 82 percent sensitivity and 63 percent specificity, and a negative predictive value of 78 percent. Using a different cutoff, the test performed as a rule-in assay with specificity of 87 percent and sensitivity of 51 percent, and a positive predictive value of 79 percent.
Hosmane said that in its market research it had learned that false positives were a particular concern for payers and physicians when diagnosing at-risk NASH "because these patients will go on to unnecessarily receive therapy, have a bunch of referrals, and it is a lot of emotional burden for the patients."
He said that one of the most effective interventions for halting or reversing fibrosis from NASH is significant weight loss.
"The issue, though, is that it requires commitment, and it is actually not cheap from an intervention standpoint, because there is a behavioral element to it, there is a nutritional element to it," Hosmane said. "So, who should receive that care? We can say in an ideal world that everyone should, but if you know that this subset of patients is more likely to progress, then it warrants that level of intervention."
There are also drug therapies that have shown effectiveness, "but the issue is, they aren't without their own risks," he said.
Given these concerns, the company targeted a high specificity at the rule-in cutoff while maintaining a sensitivity of around 50 percent that Hosmane said "is not so dissimilar from a lot of tests in the metabolic space."
He noted that false negatives were less of a concern than they might be for other conditions because the patient population targeted by the test would likely still be in frequent contact with their doctor due to the need to manage the larger metabolic conditions that made them a candidate for the test in the first place.
"You're not really ruling them out of the system altogether," he said. "The thinking is that you keep them in the system, and there is some periodic follow-up, albeit less frequent than, say, a positive patient."
NASH is an area of growing interest among test developers, Hosmane said, noting that "there's going to be a lot of opportunity for a lot of innovation in this space."
In March, Palo Alto, California-based diagnostics firm DiscernDx presented data at the 2021 NASH-TAG annual meeting in Park City, Utah, on a rule-out test for NASH designed to identify patients with nonalcoholic fatty liver disease who are unlikely to progress to NASH.
In December, Renown Institute for Health said that it was partnering with Foster City, California-based Gilead Sciences and Erlangen, Germany-based Siemens Healthineers to offer the ELF test to patients at risk of NASH who are participating in the Health Nevada Project genetic population health study.
Also last year, Cambridge, Massachusetts-based Glympse Bio launched studies using its nanosensor-based platform to measure patient response to NASH treatment.
Genfit's NASH diagnostics program emerged from its efforts to develop therapeutics for the condition, Hosmane said, noting that the company had a large number of well-annotated clinical samples well suited to test development.
"In the course of drug development you are collecting blood samples, you are collecting clinical information on these individuals, you are collecting biopsy results, and we used all of that to explore different biomarkers," he said. The company explored roughly 100 potential markers drawn from medical literature and input from clinicians, ultimately arriving at the four used in the NASHnext test.
While Genfit ultimately abandoned its NASH therapeutics program, Hosmane said that several other drug developers have used the test within clinical trials run in collaboration with Labcorp's Covance business. He added that he believes those trials will begin releasing data from the test toward the end of this year.