Personalised medicine with state-of-the-art MR image analysis

Transcription

1 Personalised medicine with state-of-the-art MR image analysis

2 Biomarkers as tests

3 Diagnostic pathways in chronic disease Heart failure EKG BNP Echo/cardiac MRI COPD CXR Pulmonary function tests Chest CT Renal failure Serum urea and creatinine Ultrasound Blood panels

4 History and founders Dr Rajarshi Banerjee CEO Professor Stefan Naubauer CMO Professor Sir Michael Brady, FRS Chairmn Professor Matthew Robson CTO

5 Iron (T2*) Inflammation & fibrosis indicator (T1) Fat

6 FDA cleared and CE marked Enables diagnosis of early liver disease with multiparametric quantitative MRI Suitable for use in obese patients Requires no additional hardware reducing capital expenditure

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9 LIVERMULTISCAN EVIDENCE BASE Validation in clinical studies

10 Multi-parametric MRI stages adult patients with chronic disease (n=79) The first non-invasive test to clearly identify even early fibrosis AUROC is 0 94 (95% CI ) to detect any disease in a general population (viral hepatitis n=31, FLD n=31, other n=17); sensitivity 86%, specificity 93%. *The LIF scale represents the range of focus for ct1 values in the liver Banerjee et al. (2014) Journal of Hepatology

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12 LIF score accurately predicts clinical outcomes (n=112) Pavlides et al. (2015) Journal of Hepatology

13 Same Day Reporting

14 Changing the diagnostic pathway for patients Repeat blood tests Liver ultrasound Liver clinic appointment Liver biopsy Appointment for diagnosis Symptoms / abnormal blood tests 2-6 weeks 4-8 weeks 4-8 weeks 2-6 weeks 4 weeks weeks Multiparametric MR to diagnose and stage disease Same day diagnosis Saving up to 32 weeks per patient - diagnosis & management begin earlier Saving patients from unnecessary and painful liver biopsy Less disruptive to the patient s life, fewer visits to hospital, less anxiety Saving over $2000 in cost per patient

15 Nodular Fibrosis 27 F Referred to gastroenterology department for unexplained weight loss, under lower GI team, for 2 week inpatient stay. Investigations: Normal OGD & colonoscopy Fibroscan unrecordable Ultrasound showed ascites Referred for a liver biopsy 1 H MRS showed she has moderate steatosis Histology showed severe nodular fibrosis, haemosiderosis and steatosis

16 NO TREATMENT, NO UTILITY Why bother?

17 How big is the potential market for NASH treatments? Diabetes market worth $41.5 billion - Set to increase to >$57 billion a year over the next 5 years - Fastest growing condition in Asia No approved therapies in NASH - Estimated R&D to reach $1.6 billion a year by Demand for non-invasive diagnostics - Approximately 40m US people with NASH, with 4-fold that number for NAFLD A new or retasked compound has the potential to transform treatment landscape for NASH

18 LEAN study evaluating GLP-1 analog as promising NASH candidate Phase 2 study in 26 patients with NASH vs. 26 placebo 48-week treatment, once-daily injections Trial initiated 2010 Reported 2015 FIVE YEARS TO ESTABLISH EFFICACY

19 Accelerating and enriching clinical trials Precision medicine for chronic liver disease Patient Recruitment Liver biopsy Baseline LiverMultiScan for enrichment LiverMultiScan for efficacy indication Liver biopsy Primary endpoint weeks LiverMultiScan as a surrogate endpoint Follow-up Phase progression / Regulatory submission Several P2 trials have failed to complete or had unsatisfactory results: MRC FELINE losartan Raptor Procysbi Mochida Ethyl EPA Shire SHP625 De-risk trial design Patient stratification Early efficacy indication Faster recruitment & lower drop-out Reduces timeline to approval Companion diagnostic

20 BIG PROBLEMS NEED SCALABLE SOLUTIONS Scalability, and stratified medicine

21 Partner in the UK Biobank Imaging Study Detailed MRI imaging scans to be performed in >100,000 participants LiverMultiScan selected as the only liver imaging technique

22 Population Prevalence of NALFD and NASH Using Non-Invasive Multi-Parametric MRI Kelly et al. (2015) Hepatology

23 Scalability Liver Imaging with UK Biobank Liver fat Liver Iron Liver inflammation and fibrosis Liver fat (%; <2% is 'healthy'; >5% signifies disease) Liver iron content (mg/g dry weight) LIF score (>2 signifies disease) From 3203 patients recruited: 3160 datasets acquired 3071 fully analysed and QCed data in all three domains (95.9% complete success) 2 0 Liver fat content 0 Liver iron 0 LIF

24 Population Prevalence of NALFD and NASH Using Non-Invasive Multi-Parametric MRI 4 Steatohepatitis = 70 (2.3%) 3 LIF (0-4) 2 1 Steatosis = 548 (17.8%) Population imaging (n = 3071) Fat (%) 96% Imaging Success Rate

25 Answering the clinical problem What is the burden of fatty liver disease in the UK? Assuming UK population 60 million 78.9% 20.1% 2.3% 0.6% 47.3m 12m 1.38m 360,000 Healthy Using UKBB, we have measured the prevalence of liver disease in the UK, and with outcomes data can support demand forecasting.

26 CAN WE MEASURE CHANGES IN INDIVIDUALS? Accuracy

27 Pre op ct1 = ms Histology showed 90% of hepatocytes had lipid inclusions, and an ISHAK score of 3, with marked pericellular fibrosis as well. Diagnosis = NASH Pavlides et al, J Hepatology 2014 Visible, quantifiable, accurate changes

28 34 patients (purple) from original 2014 J Hep study with suspected steatohepatitis as indication for biopsy, and 30 healthy volunteers (blue). 3/34 patients had normal biopsies (ie no steatosis, fibrosis, ballooning or lobulitis). Bonferroni's Multiple Comparison Test Mean Diff. t Significant? P < 0.05? Healthy vs Normal No Healthy vs Mild Yes Healthy vs Moderate Yes Healthy vs Severe Yes Normal vs Mild Yes Normal vs Moderate Yes Normal vs Severe Yes Mild vs Moderate Yes Mild vs Severe Yes Moderate vs Severe No

29 Pre op ct1 = 996.1ms Clear change in ct1/lif. No follow-up biopsy; no clinical indication After weight loss ct1 = 783.5ms

30 Liver Segmentation Whole liver statistics and vessel extraction

31 What size study group is required? Study type: Metric: Sources of variation: Two-treatment parallel design (1:1 randomisation) ct1 Test-retest (individuals imaged on subsequent days) CoV in healthy volunteers familiar to imaging is 1.75%. In an untrained patient population, this may be up to 5%. Assuming an average initial ct1 of 950ms, the standard deviation at CoV = 5% will be 42.5ms Eligibility Randomisation n = 44 Question: How many trial participants are required to detect a 5% change in ct1? To have a 90% chance of detecting, with significance level 1%, a decrease in the primary outcome measure from 950ms in the control group to 900ms in the experimental group over time requires 44 trial participants (22 in each group) Note: Bariatric surgery study ct1 change over 11 months: 213ms; other interventions may be less Placebo n = 22 Treatment n = 22

32 Measure change, quantify response to drug treatment Case Study February 2012 October 2012 October 2013 LIF: 3.4 LIF: 2.7 LIF: 1.4 Pre Treatment ct1: ± 12ms After Treatment ct1: ± 46ms After Treatment ct1: ± 24.7ms 22 yr old Oxford man with PSC and AIH overlap syndrome Response to prednisolone and azathioprine over one year Data acquired on 3T scanner

33 Healthy liver biopsy could have been avoided 30M Unwell for 2 weeks, after a chest infection, treated with penicillin. Drinks very little alcohol. Persistently raised liver enzymes on two clinic visits. No other medical history. Was sent for biopsy but histology was all normal. Investigations: Negative hepatitis serology Ultrasound showed normal liver Fibroscan 8.1kPa Normal iron and no fibrosis.

34 Early Fatty Liver Disease 38, M This individual is young, but is developing early signs of fatty liver disease as highlighted by the fat levels in the statistical summary. The LIF score of 1.7 is raised compared to normal, but early identification gives time for lifestyle change.

35 Advanced NASH 65, M High fat % and a LIF score >2 may predict a poor prognosis for this patient and suggests a diagnosis of advanced NASH In a normal MRI scan, you don t get anything at all. You don t get to see anything. You have to wait to go back to your consultant, and they tell you well, that was okay or it wasn t okay. You still don t ever get to see it.

36 Non Alcoholic Fatty Liver Disease, Cirrhosis 52 M Severe disease, likely florid steatohepatitis, or autoimmune hepatitis. On transplant list. ct1 (ms)

37 Using Quantitative Spleen Imaging to Measure HVPG N=19; median age of 57 years Paired spleen ct 1 and HVPG Spleen ct 1 vs HVPG There was a strong correlation between spleen ct 1 and HVPG (r=0.66, R 2 =0.43, p=0.0021). Patients without clinically significant portal hypertension (CSPH; HVPG<10mmHg, n=10) had a lower mean spleen ct 1 than patients with CSPH (HVPG 10mmHg, 1235ms vs 1385ms, p=0.0009). The area under the receiver operating characteristic curve for the diagnosis of patients with CSPH was Spleen ct 1 (m s) r=0.66 p= R 2 = H VPG (m m Hg)

38 CHILDREN S LIVER DISEASE Early intervention in metabolic syndrome

39 Children s liver imaging seeing steatohepatitis Normal 12 year old with NASH by MRI (LIF 2.9, fat 19%), prior to the onset of T2DM NASH precedes T2DM in adolescence Population-specific studies needed to determine natural history and value of screening

40 Comparison of hepatic steatosis in adults (n=148) and children (n=22) and 20 patients with biopsy-proven steatohepatitis Bars and whiskers show mean ± SEM for each category. Obesity in adults and children is associated with marked hepatic steatosis. Hepatic lipid content is shown on a logarithmic scale. Of note, all the steatohepatitis patients (SH) had histologically significant steatosis, but there were many obese adults and children who had similar levels of steatosis to these confirmed adult cases.

41 Steatohepatitis in children 1000 None of the children were diabetic Three children have clear evidence of NASH Liver T1 (milliseconds) [ECF] These children have no significant evidence of increased hepatic extracellular fluid of NASH. Note that the obese children still have more steatosis. LEAN OBESE Log 10 Hepatic Lipid Content as % of water signal The extent of steatosis is the only current predictor of future progression of NASH. Systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. Pais et al, J Hep 2013

42 Images from (top) a normal weight child with low levels of abdominal visceral, subcutaneous fat, and hepatic triglyceride, with a normal aortic pulse wave velocity (PWV) and (bottom) an obese child with higher levels of abdominal visceral, subcutaneous fat, and hepatic triglyceride, with a higher PWV. Oliver J. Rider et al. Arterioscler Thromb Vasc Biol. 2016;36: Copyright American Heart Association, Inc. All rights reserved.

43 The proposed liver fat arterial stiffening pathway, showing the indirect effect of hepatic fat acting via increasing circulating triglycerides (TG) to influence aortic pulse wave velocity (PWV). Oliver J. Rider et al. Arterioscler Thromb Vasc Biol. 2016;36:

44 The correlations between increasing hepatic fat content and aortic pulse wave velocity in adults and children. Oliver J. Rider et al. Arterioscler Thromb Vasc Biol. 2016;36:

45 Moving forward Summary Open minded approach to a complex organ NASH is a risk factor and a disease, like hypertension Imaging is a safe, easy-to-use, organ-specific test-bed Build pathways, not one ring to rule them all Enrichment Efficacy signalling Diagnosis Utility of testing for NASH in the US still debated