A promising biomarker for diagnosing liver disease

Owlstone study pinpoints limonene for early diagnosis of NASH and NAFLD

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CAMBRIDGE, U.K.—Owlstone Medical, known for its Breath Biopsy technology for early disease detection and precision medicine, recently announced the promising results of a patient study that supports exhaled limonene as a breath biomarker to measure liver function and to stage liver disease.

This inhalation method, if approved, could replace the more costly and invasive liver biopsy, the current gold standard.

The positive results, published in peer-reviewed journal Clinical and Translational Gastroenterology, reportedly validate Owlstone Medical’s EVOC Probe strategy for the development of breath-based diagnostic and prognostic tests for non-alcoholic fatty liver disease (NAFLD) in general, as well as non-alcoholic steatohepatitis (NASH) specifically.

NAFLD is one of the most common causes of liver disease in the United States. Experts estimate that about 20 percent of people with NAFLD have NASH, and between 30 and 40 percent of adults in the United States have NAFLD.

“This study is an important step for the business as it successfully demonstrates the use of exhaled limonene as a breath biomarker to measure liver function and stage liver disease,” says Chris Claxton, head of Investor Relations at Owlstone Medical. “Owlstone Medical’s Exogenous Volatile Organic Compound (EVOC) Probes are compounds which undergo metabolism in the body and are excreted via breath, offering a read-out of metabolism by enzymes and organs.

“Where possible, EVOC Probes are designed utilizing GRAS [generally recognized as safe] compounds, which are largely food additives. This approach enables high levels of exogenous compounds to be administered, such that changes in levels are much more visible with substantially improved signal-to-noise ratios over those that come from endogenous sources.”

The concept is similar to PET scans or glucose challenge studies where a probe is administered to the body to elicit a clear and unambiguous response, Claxton explains, noting, “This can be a powerful approach, best deployed in applications where the underlying biology is well understood, operating through known metabolic pathways so that measurement of their breakdown or the triggering of another biochemical marker provides direct insight into the functioning of that pathway.”

Studies have suggested that metabolic dysfunction in liver disease is reflected in the composition of exhaled breath, with limonene—a naturally occurring chemical that is found in citrus foods—being particularly promising, Claxton tells DDN.

“Currently, the only way to diagnose NASH/NAFLD is through liver biopsy; however, for obvious reasons, this isn't feasible or desirable for a large part of the population,” he comments. “We envision Breath Biopsy will be used to screen individuals who are at increased risk of NAFLD and NASH due to risk factors such as diabetes and obesity, and would become part of their regular check-up. We also see a test being deployed to monitor progression of and recovery from liver disease.”

Billy Boyle, Owlstone Medical’s CEO and co-founder, says, “This study represents a major milestone for Owlstone Medical, as it is the first proof of the value of our EVOC probe approach for the development of breath tests in areas of high clinical need.”

Boyle adds that the company has identified a number of additional highly promising compounds that they  are working to validate as biomarkers for EVOC Probes for liver disease. He also thinks that the EVOC Probe approach can be applied to other disease areas, including lung cancer.

“When a probe with higher levels of limonene optimized for this application is used along with other markers to measure liver function, the potential for this approach to non-invasively stage liver disease and to measure the progression or recovery from disease is excellent,” asserts Dr. Chris A. Mayhew, who is a professor of molecular physics at the University of Birmingham, director of the Institute for Breath Research at the University of Innsbruck in Austria, and an Owlstone Medical scientific advisory board member.

Limonene was identified as a biomarker for liver disease in a paper by Mayhew et al. at the University of Birmingham in 2015.

Key to the work by Mayhew et al. is that pre- and post- liver transplant breath samples were investigated, which unambiguously allowed the researchers to assign limonene as a distinct biomarker for liver disease.

In the published study, entitled “Breath Biopsy Assessment of Liver Disease Using an Exogenous Volatile Organic Compound—Toward Improved Detection of Liver Impairment,” patients were recruited from the clinical research facility at Cambridge University Hospitals or through the Cambridge BioResource. Cirrhotic hepatocellular-carcinoma patients had an established diagnosis prior to entry into the study.

In the study, exhaled breath from 32 cirrhosis patients and 12 cirrhotic hepatocellular-carcinoma patients was compared with 40 controls. Breath samples were analyzed by Owlstone Medical’s Breath Biopsy platform, with the results (sensitivity of 73 percent and specificity of 77 percent) demonstrating that limonene levels are associated with alterations in liver function.

These tests will initially be offered in research settings, including to pharma companies developing NAFLD/NASH drugs, with their launch as clinical tests to follow after appropriate testing and regulatory approval.

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