Diagnosis of liver disease using Magnetic Resonance

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1 20 Perspectum s first product, LiverMultiScan, is a software addition to a standard MRI system that makes it possible for the first time to look at the whole liver and see and quantify patchy liver disease, and to measure improvements in the liver after treatment of the disease. Perspectum has developed a way to use magnetic resonance imaging (MRI) to determine the state of a person s liver by measuring the amount of fat, iron and scar tissue ( fibrosis ). Currently, diagnosis of fibrosis in fatty liver and other conditions can only be achieved by undergoing a biopsy test, which is painful, costly, and unreliable, especially for patchy disease. supervision of Professor Stefan Neubauer who is a world-leading imaging scientist at Oxford University. To run alongside his academic research, he obtained funding from the Oxford NHS Trust to carry out a trial which could test the effectiveness of imaging the liver using MRI techniques. Key facts/data: Perspectum Diagnostics Ltd Technology: Quantitative MRI for visceral organs to help diagnose disease Established: 2012 Type: Start up Location: Oxford Employees: 8 CEO/Co-Founder: Dr Rajarshi Banerjee Having worked for the NHS for over a decade, Dr Rajarshi Banerjee, together with Professor Stefan Neubauer and Dr Matthew Robson in the Oxford Centre for MR Research, pioneered the use of quantitative imaging to enable medical diagnosis. The Channel Islands It was while Dr Banerjee was studying cardiology at university in the 1990s that he noticed people with liver problems often died early of heart disease. In 2007, he was appointed as a cardiologist to the Channel Islands. Whilst there he found that liver disease was a major problem, even in an affluent population. To understand the link between liver and heart disease better he secured a grant from the British Heart Foundation (BHF) to investigate the links with excess body weight. When someone asked why expensive and relatively painful biopsies were the only way to characterise liver conditions he started to think about how to use MRI techniques to image the organ non-invasively. Up to this point doctors had only been able to use MRI to look at the anatomy of internal organs, what Dr Banerjee proposed was to analyse the properties of a specific organ, such as the signals from iron and water, and the ratio of fat to water. Investigation The opportunity to investigate the use of MRI was made much easier by the fact Dr Banerjee was studying for a D.Phil on the Effects of excess body weight on the heart and liver, under the

2 21 Intellectual Property The Oxford trials for the Rapid Image Assessment of the Liver (RIAL) tested the predictive ability of an MR scan successfully. This led to the filing of two patents in 2011 (now exclusively licensed by Perspectum in exchange for giving equity in the company to the University) which were granted in In essence, the patents cover the type and combination of MR scans and analysis that accurately measure fat, water and iron simultaneously. Oxford luminaries Professor Stefan Neubauer and other senior academics in the Radcliffe Department of Medicine at the University actively supported the research. They were joined by Sir Michael Brady, Professor of Oncological Imaging in the Department of Oncology, who has helped launch several companies from the University. Prof Brady became Chairman after the company was established in Initial investment into the company was from the founders, Oxford University and the Oxford University Hospitals NHS Trust. A friends and family investment round was conducted in November 2013 and following on from that in December 2013 the company was awarded a 1.2 million grant from the Technology Strategy Board to work in partnership with the Universities of Birmingham and Edinburgh to complete a multi-centre clinical trial. Motivation An important motivation to establish a company, rather than continue the research within the university, was to speed up the adoption of the technology. Dr Banerjee had seen developments in cardiac MRI and other branches of medicine take over a decade and still make little progress beyond academia and was determined to address the emerging liver epidemic in a shorter time span. Healthcare costs Liver disease is the 5th largest cause of death in the UK and is the only disease where mortality is increasing year on year. A major factor is the epidemic of non-alcoholic fatty liver disease (NAFLD) in Western countries which affects about 20-30% of the general population, and leads to annual healthcare costs in the UK of around 4.2 billion. It can progress to a more severe form non-alcoholic steatohepatitis (NASH), associated with liver scarring (fibrosis) and the risk of cirrhosis (end stage fibrosis) and liver cancer. There are also no effective ways of detecting liver disease at an early stage. Movements in mortality Deaths per million of population n Liver n Diabetes n Cancer n Respiratory n Road n Heart n Stroke Relative growth of mortality from liver disease in the UK. The British Liver Trust.

3 22 60m UK population is approx 60 million 15m Number in the UK with fatty liver disease 4m Number in the UK with fatty liver disease steatohepatitis (ie fatty liver with inflammation) is 4 million. Fatty liver Deposits of fat cause liver enlargement UK BioBank Perspectum expects the importance of earlier liver diagnosis to become better recognised as a result of a mass population study, called UK Biobank, which will involve one million participants, of whom 100,000 will have detailed MRI examinations. According to Perspectum this is one of the largest and most detailed studies ever undertaken in medical science. One expected outcome is that it will establish the true prevalence of liver disease in the UK, and raise the profile of research in the field, which is still largely neglected. Liver biopsies The usual method for the diagnosis and staging of liver disease is a liver biopsy. However, it has many disadvantages, including the length of time, discomfort, and cost to the provider. Also, it is only able to look at a very small Fatty fibrosis Scar tissue forms. More liver cell injury occurs. Cirrhosis Scar tissue makes liver hard and unable to work properly sample of the liver; and is not necessarily accurate; often the only way to tell if a treatment is working is to do repeated biopsies, but this is painful as well as inconvenient and expensive (9% of patients complain of chronic pain afterwards). Non-invasive alternatives There are several non-invasive methods to diagnose the liver. A good overview is provided on Perspectum s web site at: but all the different methods, in Perspectum s view, have fundamental flaws (see box below). Dr Banerjee adds that many of the alternatives worked better before the obesity epidemic when most liver disease was related to gallstones, for which ultrasound and MRI are both very good. The alternatives are better able to identify more obvious problems (for example, large tumours or severe disease). However, with the rise of NAFLD and NASH conditions, many patients with suspected early liver disease are left un-diagnosed. Perspectum s view of alternative non-invasive diagnoses n Traditional ultrasound can assess liver size and blood flow, and in extreme cases can identify some patients with liver disease, but does not provide information about liver fibrosis, fat or iron content. n Newer ultrasound-based tools, such as transient elastography, claim to discriminate normal from severe disease by measuring the stiffness of the liver. However, poor sensitivity (<50%) and the inability to look at the whole liver are limitations to clinical use. Ultrasound is even less effective in overweight patients because accuracy depends on the proximity of the ultrasound probe to the organ being examined. n Serum markers are similarly non-specific, and do not inform the clinician of the extent or nature of liver injury.

4 23 Commercial opportunity Changing the diagnostic pathway n X-ray based techniques, such as contrast-enhanced CT, cannot identify diffuse fibrosis, and their use is limited by the risk of cancer associated with exposure to ionising radiation, especially in young and overweight patients. Drug evaluation Given the constraints on health budgets and the slowness of decision making Dr Banerjee believes it will take several years before liver screening becomes a standard procedure. However, there are several areas where better scanning techniques can be useful for the medical profession. For example, 90% of new drugs evaluated for commercial use fail to gain FDA approval because of suspected hepatic toxicity. Also, clinical trials often fail because patients drop out after the first biopsy due to the inconvenience and discomfort of the process (a 50% drop out rate is not unusual). This has prompted interest from pharma companies in using Perspectum s software in clinical trials. GSK was the first company to contract to use Perspectum s service. Strategy Perspectum is considering several revenue earning options. For example: n An R&D service where a pharma company requests a particular piece of contracted research such as a drug trial using Perspectum s MRI technique; n Clinical lab service where hospitals send the MRI data to Perspectum to analyse smaller hospitals already do this for a variety of imaging services; n Product sales where hospitals pay a license fee to 'own' the software for a given period, and are then free to use it within the terms of the End-User License Agreement. LiverMultiScan The software will be sold as a package under the name LiverMultiScan adapted for use with different makes of MRI scanner. A Beta version was sold in May to a teaching hospital. It then formally launched the product in Boston on November 8th 2014 at a meeting of the American Association for the Study of Liver Diseases. The objective is to have the product available for use on both sides of the Atlantic within a year. Symptoms/abnormal blood tests Repeat blood tests Liver ultrasound Liver clinic appointment Liver biopsy Liver clinic appointment for diagnosis Symptoms/abnormal blood tests LiverMultiScan Same day diagnosis

5 24 For the production of the software it has partnered with another Oxford medical imaging software company, Mirada Medical Ltd. The founder of Mirada, Sir Michael Brady, is also Chairman of Perspectum. The relationship is described as open ended and benefits now from mutual learning based on each other s expertise. Liver scans Drawing on data from a Thompson report in 2007, Perspectum estimates the number of people who could be eligible for an MRI liver scan as 175,000 in Europe, 100,000 in the USA, and 50,000 in the Rest of the World. LiverMultiScan could also replace an increasing percentage of the 650,000 liver biopsies that are performed annually. Sales Sales will be via distributors in specific geographic regions, while it will be direct to academia and pharma companies in cases where the company can take advantage of the Board s high level connections in the medical world. In the future the majority of sales are likely to be through OEMs, primarily the major imaging companies. Perspectum s software works currently with Siemens MR scanners; by the end of 2014 it will work with GE s scanners; a version for Philips and others will follow. Other organs There are many opportunities for MR in other abdominal organs, including the spleen, kidney, and pancreas. The challenges are the same. A pilot clinical study has begun with the University of Oxford for the assessment of the kidney and pancreas in vivo. Major innovation According to Perspectum s Head of Research, Dr. Michael Gyngell (who studied at Nottingham University where early research on MRI was pioneered) there is typically a major innovation in MRI every five years. His experience he says suggests that Perspectum s technology could be the next. n