NEW YORK (360Dx) – New York City-based Glycotest is preparing a clinical trial to validate a multimarker antibody ELISA test for early detection of hepatocellular carcinoma (HCC), the most common form of liver cancer.
The panel and others like that are in development for early detection of liver cancer have the potential to broaden screening in an area where mortality rates have increased while rates for other cancers have simultaneously fallen, Amit Singal, clinical chief of hepatology and medical director of liver tumor program at UT Southwestern in Dallas, Texas, said in an interview.
Singal, who is working with Glycotest to launch the biomarker validation study, said that he and other physicians are hopeful that early biomarker tests for liver cancer, now in preliminary trials in a few companies, will emerge in clinical practice over the next few years.
Glycotest's platform leverages antibody testing technology designed to measure two disease signals. First, it calculates the amount of monosaccharide fucose that appears abnormally on specific serum glycoproteins that are associated with the likelihood of disease, the firm said. Second, the system measures the pattern of glycoproteins that are abnormally fucosylated and that are associated with specific diseases such as HCC.
The firm uses a double sandwich antibody-based ELISA platform consisting of antibodies to six biomarkers that are indicators of the presence of disease. They consist of three proprietary glycoproteins as well as AFP and liver enzyme biomarkers aminotransferase (AST) and alanine aminotransferase (ALT).
An algorithm developed by Glycotest's researchers combines measurements from the biomarkers with age and gender in calculating a score and indicating whether the patient has cancer. Among the antibodies incorporated into its test, the firm has integrated an engineered recombinant lectin as a detector molecule associated with levels of fucosylated proteins.
"If your score is above the cut-off, we demonstrated it's very likely that you have liver cancer," Glycotest CEO Lawrence Cohen said in an interview. A physician would use a CAT scan or MRI to confirm the test's results in clinical practice, so it would be useful as a method of surveillance rather than to confirm a diagnosis, Cohen said.
Among the most important benefits of a biomarker panel such as the one being developed by Glycotest is that it could replace the current use of ultrasound in combination with alphafetoprotein (AFP), a blood biomarker, to diagnose HCC, but only if it can achieve similar sensitivities in large cohort studies to the levels it has achieved in smaller controlled studies, Singal said.
The current standard for HCC screening is use of abdominal ultrasound with or without the blood biomarker test called AFP. "If you use that approach, the best you can do is to find about 60 percent of people with HCC at an early stage, so you still miss more than one third of them until it becomes more advanced, and that is why we desperately need a better test to improve early detection," Singal added.
In January 2019, Glycotest anticipates kicking off its validation trial by testing its assay and platform in 600 patients as part of a multicenter clinical trial, and to simultaneously obtain CLIA lab certification that permits the firm to run a laboratory-developed test for physicians. If all goes according to plan, Cohen said, the lab, operated by an undisclosed Glycotest partner, should be up and running in 2020.
In the clinical trial, the firm anticipates using a few hundred of the samples to train an algorithm that it would eventually use in a commercial platform.
Glycotest has already completed three IRB-approved studies, Cohen said, with hospitals and academic medical centers that used archived samples from patients with hepatitis and cirrhosis of the liver, conditions that could progress to liver cancer. He said that the firm has obtained results that show that the test is "significantly more accurate" than the current blood test used for detection of liver cancer, which uses a single AFP biomarker along with imaging.
In the first trial with samples from 208 patients with cirrhosis, Glycotest's platform detected early-stage liver cancer with an area under the receiver operating curve (AUROC) of .98, while AFP exhibited an AUROC of .79 for the same stage of disease progression, he said.
In a second study, the firm's platform exhibited an AUROC of .95 for early-stage detection and .96 for detection in all stages in a mix of samples from 127 patients with cirrhosis of the liver or hepatitis.
This past January, the firm announced that it had successfully completed a clinical evaluation of its HCC panel in China. In a blinded evaluation of 149 HCC patient and control samples, the test achieved an AUROC of 0.97 with a sensitivity of 93 percent and specificity of 92 percent, the firm said. Further, in a cohort of patients whose sample results were negative for the AFP biomarker, the HCC panel achieved an AUROC of 0.93 and identified 8 percent of the HCC patients undetected by AFP. In an early-stage HCC cohort, the HCC panel achieved an AUROC of 0.96 and identified 78 percent of the HCC patients undetected by AFP.
The prevalence of nonalcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), or liver disease that arises from alcohol consumption are drivers of an accelerating rate of liver cancers and associated deaths in recent years. Further, mortality rates for liver cancers have risen dramatically in part because many cancers continue to be found at a late stage when effective therapies are not available.
"If we find HCC at an early stage, we can treat it with surgical resection or liver transplantation, and we see five-year survival rates exceeding 70 percent," Singal said. "If we find it an intermediate or advanced stage, the survival rate is one to three years."
China has a particularly high prevalence of liver conditions that could lead to cancer, Cohen noted. The firm recently announced that it inked an agreement to raise $10 million in a Series A round of financing from Chinese healthcare firm Shanghai Fosun Pharmaceutical.
Upon completion of the round, Shanghai Fosun will hold a 40 percent stake in Glycotest. It will also receive the exclusive rights to manufacture and market the HCC test in China in exchange for an undisclosed royalty to Glycotest.
Meanwhile, British investment firm NetScientific said its stake in Glycotest will fall to 51.1 percent following the close of the Series A. NetScientific, an investor in early-stage technology companies, founded Glycotest in 2012 after licensing technology from Philadelphia-based Baruch S. Blumberg Institute and Drexel University College of Medicine.
Cohen joined the firm as CEO in 2016, and with colleagues at the company began working with undisclosed contract research organizations to move the technology closer to commercialization.
He noted that the firm anticipates using the results of its validation study to not only apply for CLIA certification, but also to publish the results that it will use to market the test to physicians. The company plans to hire its own sales and marketing team to target major academic medical centers. As the firm expands, it could change course and collaborate with another firm to help market the test, he said.
The firm might eventually apply for clearance of the test from the US Food and Drug Administration, but that is not in its immediate plans.
Cohen said that he and his colleagues have not yet established a price for its anticipated laboratory-developed test service, and it could be available at a premium to the price of an ultrasound and existing AFP blood biomarker test. However, the firm is conducting health economics studies to demonstrate how its test can save money for health systems stemming from its early detection capabilities, Cohen said.
In the beginning, patients will pay for testing, but the firm hopes to be able to get reimbursement from third-party payors in a few years, Cohen said.
Biomarker panels, such as that being developed by GlycoTest, have the potential to broaden access to screening for HCC, which is "underused in clinical practice because of the difficulty associated with doing an ultrasound every six months" requiring a few appointments when a blood test could be done in a single day in a large health facility, said Singal, who has previously worked with Anand Mehta, a professor at the Medical University of South Carolina and Glycotest's chief technology officer.
Seeing opportunity and clinical need, a handful of additional companies are also developing diagnostic tests for NASH.
Massachusetts Institute of Technology spinout Glympse Bio recently announced it had raised $22 million in a Series A financing round to support clinical trials for its technology platform based on activity sensors within the body to detect human diseases and monitor drug responses.
French biopharma company Genfit said it has successfully completed the feasibility stage in the development of its biomarker-based in vitro diagnostic for NASH. The company's test uses standard biochemistry test parameters, such as liver enzymes and glucose, and other biomarkers such as alpha-2 macroglobulin, HbA1c, YKL-40, and the microRNA miR-34a.
Bristol-Myers Squibb and Denmark's Nordic Bioscience have announced a collaboration to develop biomarkers to help diagnose and monitor scar-tissue related to diseases of the liver, and they aim to develop biomarkers and diagnostics to evaluate NASH in pre-clinical models of fibrotic diseases and in clinical settings.