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Breath Diagnostic Platform Developers Exploring a Selection of Technologies in Commercial Push

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NEW YORK – The drive to develop breath diagnostic systems may eventually lead to non-invasive tests that patients and their physicians can use at the point of care, but commercial diagnostic devices are not likely to make an impact in the market for several years, according to researchers familiar with breath diagnostic technologies in development.

For many reasons, breath is appealing as a non-invasive sample medium that can be analyzed directly in a physician's office or collected by a patient and sent to a laboratory for analysis. A flurry of research and development, collaboration, and investment into companies developing breath-based diagnostic technologies has surfaced in the past year, emphasizing the promise of such products.

But the use of breath as a sample is still many years away from deployment for clinical diagnostic purposes. "Our vision is that [point-of-care] breath diagnostic devices can become part of routine wellness testing in about 10 years," Anthony Giordano, an innovation manager at the Cleveland Clinic and a proponent of breath diagnostics, said in an interview. Breath tests that provide results at the point of care may have a long horizon for adoption, but those that provide results based on analysis in laboratories are likely to come to market faster and could be available in about five years, he added.

Researchers are using an array of technologies to develop breath diagnostic testing for clinical applications, Beniam Ghebremedhin, a specialist in microbiology, virology, and infection epidemiology at Helios University Hospital Wuppertal, Germany, said during a presentation at the Medica world medical forum in Dusseldorf, Germany, last week.

"Volatile organic compounds (VOCs), the chemical compounds of interest in exhaled breath, are found in trace concentrations, which makes analysis very complex," Ghebremedhin said.

The various technologies in development that use breath as a sample include mass spectrometry, gas chromatography, ion mobility spectrometry, and electronic nanosensing. To be accepted commercially, they need to show that they can perform with high accuracy in testing for the many diseases for which they are being developed, including lung and liver cancers, tuberculosis, and other conditions.

Developing instruments that may one day be available at the point of care is an objective of many current studies, but use of laboratory-based techniques, including gas chromatography-mass spectrometry has the advantage of high sensitivity, detecting trace volatile organic compounds in sizes ranging from parts per million to parts per trillion. Gas chromatography-mass spectrometry enables identification, detection, and quantification of volatile organic compounds, Ghebremedhin said. However, the techniques require large, immovable equipment and specific technician training, and they are expected to be expensive compared to other techniques, such as use of nanosensor-based electronic noses.

Electronic nose technologies in development also have a disadvantage, Ghebremedhin said. They don't currently allow identification of specific volatile organic compounds. On the other hand, they have potential to be applicable at the point of care and to be inexpensive compared to laboratory techniques, he added.

Wieland Voigt, a professor of medical innovation and management at Steinbeis Transfer Institute Berlin, said in a separate presentation at Medica that VOCs represent "an endpoint of gene transcription and protein expression." Therefore, they provide "a powerful way to detect, diagnose, and monitor" disease. Exhaled breath testing is showing "meaningful performance" in detecting some conditions, he noted, but added that "further research and standardization of methods are required for large-scale routine application."

The Cleveland Clinic is working toward routine application of breath diagnostics. The innovation team is taking a long-term view of a recently announced collaboration with Cambridge, UK-based Owlstone Medical to establish a Center for Early Disease Detection, Giordano said. The partners aim to investigate the use of tests that measure and quantify VOCs in exhaled breath in combination with noninvasive biomarkers from saliva and blood, among other body fluids. In a first project, they will focus on the discovery of breath biomarkers for chronic liver diseases and liver-related cancers.

Led by Raed Dweik, chair of the Cleveland Clinic's Respiratory Institute, the clinic has been evaluating the use of selected ion flow tube mass spectrometry (SIFT-MS) to identify metabolic markers associated with disease, including diabetes, liver cancer, and Helicobacter pylori, a type of bacteria that can live in the digestive tract. In preliminary testing, the system has performed better in detecting liver disease than alpha-fetoprotein, a standard liver disease biomarker, Giordano said.

In searching for a partner to do breath-diagnostic platform development, the Cleveland Clinic "looked at various systems" and concluded that Owlstone Medical's, based on published reports, had the most potential. "We're hopeful that their system is going to be at least as sensitive as SIFT-MS," Giordano said. "We'll compare the systems and see whether we get similar results or whether the different systems give us different information."

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's CE-marked ReCiva Breath Sampler provides a means of capturing breath samples for analysis. Owlstone Medical analyzes the breath samples in its clinical laboratory in Cambridge, using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) and gas chromatography field asymmetric ion mobility spectrometry (GC-FAIMS). Patterns of VOCs are tied to cancers and other conditions.

Altough its CE-marked ReCiva Breath Sampler, part of the breath diagnostic system, is not being applied not for clinical diagnostics, researchers are using it for development and validation of the overall platform.

The collaboration with Cleveland Clinic is a "great exemplar for the type of project we want to do a lot more of," Chris Claxton, Owlstone Medical's head of investor relations, said in an interview. "The impact of the collaboration for us in the short term is that it provides great credentialing for our business and for the breath space that we are involved in. And longer term, hopefully, some great discoveries will come out of this research, including novel breath-based biomarkers and tests."

Owlstone Medical is participating in several clinical validation studies for use of its platform in the screening and detection of cancers, asthma, chronic obstructive pulmonary disease, and other diseases.

"These are long term trials and they are proceeding well, but there's nothing announced yet in published data in terms of clinical performance or hitting milestones," Claxton said. "We're currently generating revenue by working with large academic institutions, such as the Cleveland Clinic and others, and we've announced deals with pharmaceutical companies such as AstraZeneca, Glaxo Smith Kline, and Actelion, part of Johnson and Johnson."

For those organizations, the firm supplies breath diagnostic products and services, mostly for biomarker discovery.

"We've estimated that market at being worth more than $1 billion globally," Claxton said. "In terms of the addressable market for tests themselves, a lot depends on which tests get to market. The test development focus areas for us are asthma, respiratory disease, oncology, liver disease, drug metabolism, and environmental exposure. The addressable market in each of those areas is the upper tens to hundreds of millions of dollars."

Point of care

Claxton acknowledged that new companies are emerging as potential market entrants. "It just validates that breath can have a potentially powerful impact on healthcare," he said.

Among the breath-based electronic nose technologies showing promise, Reeuwijk, Netherlands-based Breathomix uses metal oxide semiconductor sensors to measure the mixture of molecules in exhaled breath and employs advanced signal processing to create individual breath profiles. These breath profiles, together with clinical patient characteristics, are stored in an online reference database. Using molecular pattern recognition and machine-learning algorithms the breath profiles of new patients are compared to the reference database in order to achieve a diagnostic or phenotypic answer.

Separately, a consortium of nine European and Middle East partners is developing a platform consisting of a nanosensor attached to a smartphone for screening gastric cancer at the point of care. They've developed a prototype, called the SniffPhone, as part of a four-year, €5.8 million ($6.6 million) European Union Horizon 2020 Funding Programme.

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. The company has said that its test, currently a pre-production prototype, has shown promise in detecting early-stage active TB during preliminary field trials involving 1,000 patient samples, and demonstrated both sensitivity and specificity values between 95 and 96 percent.

Funding and collaboration

In September, Oakland, California-based Hound Labs announced it had closed a $30 million Series D financing round to support faster manufacturing and commercial availability of its alcohol and marijuana breathalyzer. Intrinsic Capital Partners, a private equity firm that funds businesses in the cannabis industry, led a group of investors that also included NFP Ventures, Main Street Advisors, Icon Ventures, and Benchmark.

In November, Bristol, UK-based Rosa Biotech said it had raised £760,000 ($984,000) from angel investors to commercialize an artificial intelligence-based biosensing technology that mimics mammals’ sense of smell, with a potential application for medical diagnostics and pharmaceuticals.

Meanwhile, Owlstone Medical and the University of Manchester announced in March that they have partnered on the development of a breath-based diagnostic for asthma with funding from British research organizations Asthma UK and Innovate UK. The partners are using a £249,950 ($327,498) grant to conduct a three-year study that uses the Breath Biopsy platform to collect samples from asthmatic patients and healthy controls.

That marked one of a series of announcements this year from Owlstone. One such announcement revealed a collaboration with Renji Hospital to conduct a clinical study into the early detection of lung cancer in China.

The firm also noted that it has entered into a collaborative partnership with Thermo Fisher Scientific to advance the early diagnosis of cancer and other diseases through the discovery and validation of biomarkers by noninvasive breath sampling. That alliance intends to integrate Thermo Fisher's Q Exactive GC Hybrid Quadrupole-Orbitrap, a gas chromatography mass spectrometer (GC-MS), into Owlstone Medical's Breath Biopsy platform.

In addition, Mayo Clinic Laboratories and Louisville, Kentucky-based Breath Diagnostics they are collaborating to develop clinical diagnostic tests that use patient breath samples to identify biomarkers that can predict a spectrum of diseases.

At Medica, Ghebremedhin said that standardization and harmonization associated with the multiple steps involved in testing is needed to move systems closer to commercialization. Among different systems, there are different sampling techniques, different ways to do preconcentration of exhaled breath, and different ways to conduct measurements, making comparisons among products difficult.

"Nowadays, each lab has its own algorithm to define a signal or signature of disease related to a VOC profile," he said. "We have to harmonize these analyses by having a community of bioinformatics specialists developing algorithms and tools so that you can [compare results among platforms]."