NEW YORK ─ Diagnostic test developer Owlstone Medical recently announced findings from a study with Cambridge, UK-based Addenbrooke's Hospital that measured patients' levels of exhaled limonene, an ingredient in citrus fruits, as part of a breath diagnostic test to detect liver disease.
According to the Cambridge, UK-based company, the study provides further evidence of the potential of its breath biomarker-based diagnostic platform, which is already part of a number of long-term clinical studies to validate its potential to detect cancers using breath testing.
The results of the new study, published in Clinical and Translational Gastroenterology, are preliminary, and limonene as a biomarker will need to be validated in additional, broader clinical studies. But, Owlstone Medical hopes to launch a research-use version of the test in late 2021 and an IVD version with US Food and Drug Administration clearance and CE marking sometime thereafter, Chris Claxton, the firm's head of investor relations, said in an interview.
"In the study, the question we posed was whether we can see differences in limonene levels between individuals who are healthy and those who have advanced liver disease, including cirrhosis," Claxton said. "We saw those differences, and while these study results are early, it gives us tremendous comfort about the potential of this approach to be able to deploy these probes for liver disease in the future."
Owlstone Medical's Breath Biopsy platform is based on the detection of volatile organic compounds as metabolic markers of cells undergoing biochemical reactions. The firm uses a device called the ReCiva Breath Sampler and analyzes the samples in its clinical laboratory in Cambridge using Thermo Scientific Q Exactive GC Hybrid Quadrupole-Orbitrap mass spectrometers and gas chromatography field asymmetric ion mobility spectrometry (GC-FAIMS). Sets of volatile organic compounds, or exogenous volatile organic compounds in the case of the recent liver disease study, are tied to many medical conditions, including cancers.
In the recent study, Owlstone Medical along with Addenbrooke's clinical investigators collected exhaled breath from 32 patients with cirrhosis, 12 with cirrhotic hepatocellular-carcinoma, and 40 who were healthy. The breath test demonstrated 73 percent sensitivity and 77 percent specificity, showing that limonene levels are associated with alterations in liver function, Owlstone said.
A future version of the diagnostic test incorporates additional volatile organic compounds made by the body as well as others that come from external sources, including limonene, which will be optimized as a probe, Claxton said. "Ultimately, we want to include cocktails of probes to increase the performance of this diagnostic approach," he said.
It intends to offer the tests initially for use in academic and pharmaceutical research, including by companies developing drugs for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
Though the firm sees a need to increase levels of performance, current levels far surpass that of standard blood tests and provide a method that is less invasive than biopsy, the most sensitive and specific approach for determining liver deterioration, Claxton added.
Victoria Snowdon, an investigator in the Owlstone study and a transplant hepatology consultant at UK-based Addenbrooke's Hospital, noted in an interview that the findings reveal that Owlstone Medical's exogenous volatile organic compound (EVOC) probes could be used in breath tests to improve the diagnosis of NAFLD and NASH.
"One of our aims is to try to identify patients with a deteriorating liver function that has not yet manifested in blood testing, because we can then define a suitable intervention for them," said Snowdon, who is involved in the diagnosis and treatment of patients with liver disease and cancers at Addenbrooke's Hospital.
Snowdon noted that to evaluate liver health and liver disease stages, she and her colleagues use a standard approach, involving blood tests and an assessment of symptoms that contribute to a classification called the Child Pugh score. The score provides an indication of how to best treat a patient, and the most severe cases can require a liver transplant. To obtain a score, the clinicians measure levels of bilirubin, albumin, and prothrombin time.
The approach has its challenges, however, because the liver can deteriorate without blood tests detecting it. The Owlstone Medical breath test ─ after further validation and potentially the use of additional breath biomarkers ─ "could add to the overall analysis" and enable clinicians to detect liver deterioration earlier, Snowdon said. "This would be an accessible test in areas where it is difficult to perform blood tests, and it could be used when blood test results are normal, but the liver function is deteriorating."
Such a test could be used by a large population of patients with nonalcoholic fatty liver disease, some of whom remain healthy while others progress to liver cancer and liver failure, Snowdon added.
Her group believes the breath-biopsy probe could also be useful in the testing of patients with liver cancer who require surgery. "We need a way to determine that the patient's liver is functioning well despite the presence of cancer," Snowdon said. "A breath test that indicates the patient's limonene clearance is good could enable us to proceed with resection."
Commercially available diagnostic tests that use the breath to diagnose liver health are a long time in the future and require extensive clinical trials as well as regulatory clearances. However, if they could be launched commercially, they wouldn't require a blood draw or more invasive means of sample collection.
The various detection technologies in development that use breath as a sample include mass spectrometry, gas chromatography, ion mobility spectrometry, and electronic sensing.
A number of entities are looking to develop breath-based diagnostic tests, including the Cleveland Clinic and Thermo Fisher Scientific, which have ongoing collaborations with Owlstone Medical. Further, Cambridge, UK-based Rapid Biosensor Systems is targeting the clinical need for more rapid and affordable tuberculosis screening by combining breath sampling with evanescent-wave optical sensing. Using a breath test being developed by Reeuwijk, Netherlands-based Breathomix, clinical investigators have reported accurate results in identifying whether lung cancer patients responded to the anti-PD-1 immunotherapies nivolumab (Bristol-Myers Squibb's Opdivo) and pembrolizumab (Merck's Keytruda).
Given that liver disease is difficult to diagnose and is an area of unmet medical need, the Massachusetts Institute of Technology spinout Glympse Bio has entered clinical studies to validate a nanosensor-based platform that doesn't use breath as a sample but measures dysregulated protease activity associated with NASH, specific cancers, and infectious diseases.
For Owlstone Medical, the recent study with Addenbrooke's Hospital is another in a series of investigations that aim to validate its breath biopsy platform for disease diagnostic testing. The firm has been participating since 2018 in a clinical trial with clinical investigators at Cancer Research UK and University Cambridge Hospitals NHS Foundation, including Addenbrooke's.
The PAN Cancer Early Detection observational study is evaluating whether its breath biopsy clinical workflow and technology could effectively differentiate between patients with and without different types of cancers. The current study to validate its breath diagnostic test for liver disease was initiated as a result of findings from the cancer study, the firm said.
Owlstone Medical is further participating in the Lung Cancer Indicator Detection (LuCID) study that seeks to assess the ability of its approach for diagnosing lung cancer, aiming to identify breath-based biomarkers that would enable detection of stage I and stage II cancers and differentiate between benign and malignant nodules.
The firm is generating revenue by working with large academic institutions and pharmaceutical companies such as AstraZeneca, GlaxoSmithKline, and Actelion, part of Johnson and Johnson.
Claxton noted that the firm is initiating a new study with Addenbrooke's Hospital involving exhaled limonene as a biomarker. The study aims to enroll about five times the number of patients compared to the recent investigation.