Perspectum Ltd.
April 2020
Measuring fibrosis in NASH:Sorting Fact from Fiction
Perspectum Ltd.
Perspectum Ltd.
NAFLD World Prevalence
Adapted from: Younossi et al. Hepatology, 2016
Global prevalence of overweight and obesity: 39%
Global prevalence of NAFLD: 25%NAFLD: Nonalcoholic fatty liver disease
Perspectum Ltd.
Measuring fibrosis in NASH: Sorting Fact from Fiction
MYTH:FibroScan is reliable
to monitor liver disease and response
to treatment.
MYTH:FibroScan
measurements are reliable.
MYTH:FibroScan is
reproducible.
MYTH:FibroScan can
diagnose NASH.
MYTH:FibroScan can
monitor treatment response in NASH.
MYTH:FibroScan can
distinguish between simple steatosis and
NASH.
MYTH:FibroScan can
stratify NASH patients
by risk.
NASH: Non-Alcoholic Steatohepatitis
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FACT: A large retrospective analysis of paired liver stiffness by FibroScan revealed significant operator- and patient-related factors that make FibroScan unreliable for these goals
MYTH 1:FibroScan is reliable
to monitor liver disease and
response to treatment.
Measuring fibrosis in NASH: Sorting Fact from Fiction
Perspectum Ltd.
Large retrospective analysis of paired liver stiffness revealed significant operator- and patient-related factors
Nascimbeni, et al. Clinical Gastroenterology and Hepatology Radiology 2015;13;763-771
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MYTH 2:FibroScan
measurements are reliable.
FACT: Significant variations in FibroScan measurements have been flagged by experts as a concern to clinicians using FibroScan to make decisions
Measuring fibrosis in NASH: Sorting Fact from Fiction
Perspectum Ltd.
Significant variations in FibroScan measurements flagged as concern to clinicians using LSM to make decisions
• LSM measure is associated with >30% false positives in early fibrosis, even after cut-off adjustment. There is an over-estimation of liver fibrosis in NASH:
• Jung IL. (2019) World J Gastroenterol.
• Variation in cut-off selection in the clinic as well as between diseases and studies decreases FibroScan’s reliability:
• Pavlov CS, et al. (2015) Cochrane Library; Talwalkar JA, et al. (2017) Clin Gastroenterol and Hepatol
• Fibroscan is mediocre to diagnose moderate fibrosis:• Xu X-Y, et al. (2019) World J Clin Cases.
• Fibroscan performance is decreased in obese patients and those with ALT >100 IU:• Petta S, et al. (2019) Am J Gastroenterol.
• Fibroscan fails to detect good response to treatment as proven by biopsy in both Hep B and Hep C patients
• Wu SD, et al. (2018) Clin and Exp Med; Salvati et al. (2018).
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Significant variations in FibroScan measurements flagged as concern to clinicians using LSM to make decisions
Vuppalanchi & Sanyal. (2016) Clin Gastroenterol Hepatol.
Lee JI. (2019) WJ Gastroenterology
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MYTH 3:FibroScan is very
reproducible.
FACT: FibroScan shows poor reproducibility with a very high coefficient of variation
Measuring fibrosis in NASH: Sorting Fact from Fiction
Perspectum Ltd.
Monitoring & Response to Treatment
Perspectum Ltd.
Sera i SD, et al. Radiology 2017; Loomba et al. Hepatology 2019; Harrison, et al, PLOS1, 2018; Yin, et al. Radiology 2016; 278:114-124Ahmed, et al. Clin Exp Gastroenterol 2018; Lazo & Clark. Ann Intern Med 2008; Lee, et al. K J Radiol 2017; McDonald N, et al. Scientific Reports 2018
cT1 has best-in-class repeatability
Monitoring & Response to Treatment: Fibroscan suffers of a very high Coefficient of Variation
Comparative performance with other NILTs
CoV (%)
MRE (kPa) 11-22 %
FibroScan (kPa) 40-44 %
ALT 20.4 %
AST 13.9 %
LiverMultiScan cT1 (ms) 1.4-3.1 %
Liver Biopsy 55.0 %
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LiverMultiScanQuantitative MRI metrics that correlate with histology
1. Idilman et al., 2013; Reeder et al., 2017.2. Wood et al., 2005; Hoad et al., 2015.3. Banerjee et al., 2014; Pavlides et al., 2016; Pavlides et al., 2017.
Hepatic iron concentration2
Fibroinflammation315 minutes from start to finish
3 metrics for liver disease
In a single MRI scan
Corrected T1 is a patent protected technologyUS20140330106A1
GB2498254B
MRI-PDFF (%)
T2* (ms)
cT1 (ms)
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LiverMultiScanQuantitative MRI metrics that correlate with histology
Fibrosis
• LSM
• ARFI
• MRE
Steatohepatitis?
Steatosis• CAP• PDFF
Perspectum Ltd.
LiverMultiScanQuantitative MRI metrics that correlate with histology
Fibrosis
• LSM
• ARFI
• MRE
Steatohepatitis?
Steatohepatitis(steatosis, inflammation and ballooning)
• LiverMultiScan• cT1
• PDFF• T2*
Steatosis• CAP• PDFF
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MYTH 4:FibroScan
can diagnose NASH.
FACT: FibroScan is not a diagnostic-of choice in NASH clinical trials
Measuring fibrosis in NASH: Sorting Fact from Fiction
Perspectum Ltd.
FibroScan is not a diagnostic-of-choice in NASH trials
• NASH trials have used FibroScan for pre-screening with limited success
• Clinical trials have not reported FibroScan results to measure treatment response
Trial Phase Drug Name Mechanism of ActionFibroScan Endpoint
ApplicationTrial status
FibroScan result reported?
II Cilofexor FXR Agonist Secondary Completed No
II GRMD-02 Galectin 1 & 3 Inhibitor Primary Completed No
II Solithromycin 23S rRNA Inhibitor Secondary Completed No
II PXL-770 AMPK Activator Primary Completed No
Adapted from Celerion White Paper (The FibroScan® Advantage in Early NASH Clinical Studies)
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MYTH 5:FibroScan can
monitor treatment response in NASH.
FACT: FibroScan is not reliable for monitoring treatment response in NASH trials or in Hep C patients.
Measuring fibrosis in NASH: Sorting Fact from Fiction
Perspectum Ltd.
•Phase 2a study of Gilead’s GS-0976 (an allosteric acetyl-CoA carboxylase inhibitor) reported a significant change in MRI-PDFF
•No significant change in stiffness (MRE or FibroScan)
•MRE and FibroScan reported conflicting trends in stiffness with treatment
Endpoint (Week 12)
GS-097620
mg(n=49)
GS-09765 mg
(n=51)
Placebo(n=26)
P-values
20 mg vs.
Placebo
5 mg vs.
Placebo
MRI-PDFF -28.9 -13.0 -8.4 0.002 0.142
≥30% reduction in MRI-PDFF, % (n/N)
48%(22/46)
23%(11/47)
15%(4/26)
0.004 0.433
MRE-stiffness -5.5 -9.6 -12.5 0.100 0.743
Liver stiffness by FibroScan
-11.1 -8.4 -3.1 0.212 0.364
ALT -20.5 -9.8 -6.7 0.176 0.765
TIMP-1 -7.9 -2.9 -1.5 0.022 0.301
PIII-NP -13.9 -7.0 -0.5 0.107 0.605
Relative (%) Changes in Imaging, ALT and Serum Fibrosis Markers at Week 12
% Change in MRE kPa % Change in Fibroscan kPa
FibroScan is not reliable for monitoring treatment response in NASH trials
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• 54 chronic hepatitis C subjects enrolled in an observational pilot drug study
• Interim analysis of 30 subjects:All patients showed week-12-SVR (aviremia)
• Significant reductions occurred for:cT1, TE, AST, ALT, GGT, HOMA
• PDFF did not decrease significantly
• cT1 reduction occurred in all subjects
• Overall TE median levels showed a significant reduction,but TE did not decrease in 14 out of 30 subjects
Salvati et al. (2018); Wu SD, et al. (2018) Clin and Exp Med
Even in Hep C patients, FibroScan cannot be used as a reliable non-invasive measure of treatment response
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MYTH 6:FibroScan can
Distinguish between simple steatosis and
NASH.
FACT: cT1 is superior than FibroScan for distinguishing NASH from simple steatosis
Measuring fibrosis in NASH: Sorting Fact from Fiction
Perspectum Ltd.
Adapted from Pavlides, M. et al. Liver Int, 2017.
LiverMultiScan gave reliable data more frequently than FibroScan.Advantage of LiverMultiScan to assess both necroinflammatory and fibrotic components of NASH.
• Prospective study in 71 subjects with suspected NASH/NAFLD.
• LiverMultiScan (MR) overall success rate was 95% vs 59% for FibroScan (TE); p <0.0001.
Liver stiffness (n=38) and cT1 (n=71)
vs histological ballooning grade
ROC curves of liver stiffness (n=38) and cT1 (n=71) for diagnosing
ballooning vs no ballooning
AUROC: 0.61 AUROC: 0.84Se
nsi
tivit
y (
%)
0
50
100
50 1000 50 1000
0
50
100
Se
nsi
tivit
y (
%)
100% - Specificity (%) 100% - Specificity (%)Ballooning gradeBallooning grade
Liv
er
stif
fne
ss
(kP
a)
0
40
60
1 20
20
cT
1 (
ms)
600
1000
1200
1 20
800
1400
FibroScan LiverMultiScan (MR) FibroScan LiverMultiScan
LiverMultiScan is superior to FibroScan for distinguishing simple steatosis from NASH
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MYTH 7:FibroScan can
Stratify NASH patients by risk.
FACT: cT1 is superior than FibroScan and MRE for identifying high-risk NASH (NAS≥4, F≥2)
Measuring fibrosis in NASH: Sorting Fact from Fiction
Perspectum Ltd.
Strong and statistically significant correlation between cT1 vs inflammation and ballooning cT1 is superior to FibroScan and MRE with high specificity
for identifying high-risk NASH (NAS≥4 & F≥2)
Assessment of NASH compared to liver biopsy
Advantage of LiverMultiScan vs FibroScan and MRE for assessment of NASH and high-risk NASH.
Aslam, F. et al. Manuscript in preparation.
NASH activity(Prevalence, %)
Quantifier AUROC 95% CI Cut-off Sens (%) Spec (%)
NAS≥4(56%)
LMS-cT1 0.76 0.68 - 0.84 875 67 79
MRE-LSM 0.56 0.46 - 0.66 2.88 83 31
VCTE-LSM 0.57 0.47 - 0.68 5.8 88 27
NAS≥4 & F≥2(46%)
LMS-cT1 0.71 0.63 - 0.80 875 66 69
MRE-LSM 0.65 0.56 - 0.74 3.54 67 49
VCTE-LSM 0.66 0.56 - 0.76 7.0 90 42
cT1 FS-LSM*
rs= 0.500, p <0.0001 rs= 0.237, p <0.01
Inflammation + Ballooning Inflammation + Ballooning
cT
1 (
ms
)
VC
TE
-LS
M (k
Pa
)
0 1 2 3 4 5
0
20
40
60
VC
TE-L
SM
(kP
a)
0 1 2 3 4 5600
800
1000
1200
00 1 2 3 4 5
20
40
60
*Note: No patients with grade 0 (inflammation+ballooning) due to unreliable/failed reading.FS-LMS: FibroScan Liver Stiffness Measure; MRE: Magnetic Resonance Elastography
cT1 is superior to FibroScan and MRE with high specificity for identifying high-risk NASH (NAS≥4, F≥2)
Perspectum Ltd.
Summary
• FibroScan suffers of significant operator- and patient-related factors that explain in part it’s very high coefficient of variation that make this technology unreliable to monitor liver disease and response to treatment in patients with NASH and in Hepatitis C patients
• Significant variations in FibroScan measurements have been flagged by experts as a concern to clinicians using FibroScan to make medical decisions
Corrected T1 is superior than FibroScan for distinguishing NASH from simple steatosis
Corrected T1 is superior than FibroScan for identifying patients with high-risk NASH (NAS≥4, F≥2)
Perspectum Ltd.
References
MYTH References
FibroScan is reliable to monitor liver disease and response to treatment
Nascimbeni, et al. (2015) Clinical Gastroenterology and Hepatology
FibroScan measurements are reliable Vuppalanchi & Sanyal. (2016) Clin Gastroenterol Hepatol; Lee JI. (2019) World J Gastroenterol; Jung IL. (2019) World J Gastroenterol; Pavlov CS, et al. (2015) Cochrane Library; Talwalkar JA, et al. (2017) Clin Gastroenterol Hepatol; Xu X-Y, et al. (2019) World J Clin Cases; Petta S, et al. (2019) Am J Gastroenterol; Wu SD, et al. (2018) Clin and Exp Med; Salvati et al. (2018)
FibroScan is reproducible Serai SD, et al. (2017) Radiology; Loomba et al. (2019) Hepatology; Harrison, et al, (2018) PLOSONE; Yin, et al. (2016) Radiology; Ahmed, et al. (2018) Clin Exp Gastroenterol; Lazo & Clark. (2008) Ann Intern Med; Lee,et al. K J (2017) Radiol; McDonald N, et al. (2018) Scientific Reports
FibroScan can diagnose NASH Adapted from Celerion White Paper (https://www.celerion.com/wp-content/uploads/2019/06/Celerion_FibroScan-Advantage-in-Early-
NASH-Clinical-Studies_WP_011419-1.pdf)
FibroScan can monitor treatment response in NASH
Loomba R, et al. (2018) Gastroenterology; Salvati et al. (2018); Wu SD, et al. (2018) Clin and Exp Med
FibroScan can distinguish between simple steatosis and NASH
Pavlides M, et al. (2017) Liver Int.
FibroScan can stratify NASH patients by risk
Aslam F et al. Manuscript in preparation.
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