measuring fibrosis in nash: sorting fact from fiction · 1. idilman et al., 2013; reeder et al.,...

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April 2020

Measuring fibrosis in NASH:Sorting Fact from Fiction

Perspectum Ltd.

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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

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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.


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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


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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


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Monitoring & Response to Treatment

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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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Fibrosis

• LSM

• ARFI

• MRE

Steatohepatitis?

Steatosis• CAP• PDFF

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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


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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.


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•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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Distinguish between simple steatosis and

NASH.

FACT: cT1 is superior than FibroScan for distinguishing NASH from simple steatosis


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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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Stratify NASH patients by risk.

FACT: cT1 is superior than FibroScan and MRE for identifying high-risk NASH (NAS≥4, F≥2)


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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)

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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)

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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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measuring fibrosis in nash: sorting fact from fiction · 1. idilman et al., 2013; reeder et al.,...

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