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In advanced
fibrosis
due
to NASH

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Advanced Fibrosis
Due To NASH
Noninvasive Tests
For Identifying
Advanced Fibrosis
Identifying NASH
Without A Biopsy
Advanced Fibrosis
Due To NASH
Noninvasive Tests
For Identifying
Advanced Fibrosis
Identifying NASH
Without A Biopsy
 

FIBROSIS STAGE exponentially INCREASES THE RISK OF
LIVER-RELATED MORTALITY1

Patients with Advanced Fibrosis are at the greatest risk.1*

MRR (mortality rate ratio)
(95% CI)

50
40
30
20
10
0
REF
1.41
9.57
 
 

F0

F1

F2

F3

F4

95% confidence intervals
(0.17–11.95)
(1.67–54.93)
(2.92–95.36)
(3.51–510.34)
Risk of Liver-
Related Mortality
Increases exponentially
with increasing
fibrosis stage1
17xHigher
Risk
42xHigher
Risk
Liver related mortality increases exponentially by fibrosis stage
Liver related mortality increases exponentially by fibrosis stage

Risk of Liver-Related Mortality Increases exponentially by fibrosis stage4*

Ratio vs F0

Early Fibrosis – F1 1.41X higher risk, F2 9.57X higher risk

Advanced Fibrosis – F3 17X higher risk, F4 42X higher risk

*From a meta-analysis of 5 multinational cohorts (1,495 NAFLD patients with 17,452 PYF). Liver-related mortality was a secondary outcome and was defined by investigators.

 

FIBROSIS IS ASSOCIATED WITH REDUCED TRANSPLANT-FREE
SURVIVAL

In patients with fibrosis, survival is reduced regardless of the presence or absence of NASH; therefore, when assessing long-term prognosis of patients, the focus should be on fibrosis stage.2†

chart for cumulative survival(%) vs Years of follow-upchart for cumulative survival(%) vs Years of follow-up

From a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand, who underwent laboratory and liver biopsy analysis. NASH includes borderline NASH plus definitive NASH (n=284).2

 

IN ADVANCED FIBROSIS DUE TO NASH, SOME PATIENTS MAY
PROGRESS QUICKLY

The natural history of Advanced Fibrosis due to NASH may be more rapid than previously thought. In a study of patients with histologically confirmed NASH, 48 of 217 (22%) patients with stage 3 fibrosis (F3) progressed to cirrhosis at median follow-up of 29 months.3‡

1 IN 5 PATIENTS

May progress from
F3 to cirrhosis in
just ~2.5 years3

Analysis used data from 2 large, randomized, placebo-controlled, phase 2b studies of patients with F3 fibrosis and compensated cirrhosis due to NASH in which patients underwent biopsy at screening, Week 48, and Week 96.

 

GIVEN THE INCREASING RISK OF ADVANCED FIBROSIS DUE TO NASH, IT IS IMPORTANT TO IDENTIFY THESE PATIENTS AND TAKE ACTION

At F4 cirrhosis, the disease state may not be fully reversible.4 For patients with F3, preventing progression to cirrhosis and monitoring for other sequelae is a principal objective.5,6

Distribution of NASH population by fibrosis stage in the US using a Markov population model7§

Early Fibrosis
Advanced
Fibrosis
Patients with advanced fibrosis due to NASH have elevated risk and urgent action is needed.Patients with advanced fibrosis due to NASH have elevated risk and urgent action is needed.
liver graphic representing distribution of fibrosis stage in the NASH population using a Markov population model
F3 12%
F4 8%
without cirrhosis
with cirrhosis
Patients with advanced fibrosis due to NASH have elevated risk and urgent action is needed.
Patients with advanced fibrosis due to NASH have elevated risk and urgent action is needed.

Depiction of “early fibrosis” and “advanced fibrosis” for graphical purposes; based on modeling of the annual estimated number of incident NAFLD cases in 2015.

 

BIOPSY HAS TRADITIONALLY BEEN USED FOR IDENTIFICATION OF NASH and/or Advanced Fibrosis BUT IS ASSOCIATED WITH NUMEROUS LIMITATIONS8-13

variability

Only analyzes 1/50,000 of the liver and interpretation may differ between pathologists, therefore serial biopsies may provide inconsistent findings9-13

Cost

Costly procedure9 which may require additional cost and time of an interventional radiologist12

Adverse
events

Invasive procedure with a risk of rare but life-threatening complications, not ideal for monitoring patients over time9,13,14

Patient
Reluctance

Patient concerns related to the invasive nature of biopsy, as well as the potential for pain, discomfort, and complications13,14

According to claims data, ~7% of patients newly diagnosed with NASH (without cirrhosis) received a liver biopsy in the prior 12 months15¶

Noninvasive tests for
Identifying Advanced FibrosisIdentifying NASH
Without a Biopsy
Based on a retrospective cohort study using administrative claims data from a national payer (study period: January 1, 2017 through September 30, 2019): 5,459 patients received a new ICD-10 diagnosis of NASH (without cirrhosis), of whom 362 patients underwent a liver biopsy in the prior 12 months, including the index date.
 

For patients with Advanced Fibrosis without cirrhosis, halting progression is an important goal16

HALT or REVERSE
FIBROSIS

PREVENTPROGRESSION TOCIRRHOSIS

Managing advanced fibrosis due to nonalcoholic steatohepatitis (NASH)
Managing advanced fibrosis due to nonalcoholic steatohepatitis (NASH)
 

With no indicated pharmacological treatments, management options are currently limited5,8

Lifestyle
Modification

  • Lifestyle modification, including changes such as diet, weight loss, and exercise, is recommended as a first-line treatment17
  • Lack of patient compliance may be a key limitation of this approach8

Nonindicated
Pharmacological
Treatments

  • Nonindicated treatments, such as vitamin E or pioglitazone, may be considered in select patients8,9
  • Data are limited and risks and benefits should be discussed with each patient before starting therapy8

There is an urgent need for options for
patients with Advanced Fibrosis due to NASH17

“Currently, there are no approved drugs for the treatment of NASH.”
– FDA-US, 201818

“No specific therapy can be firmly recommended [for NASH].”
– EASL-EASD-EASO, 20169

Noninvasive tests for
Identifying Advanced FibrosisIdentifying NASH
Without a Biopsy

 

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NASH, nonalcoholic steatohepatitis; PYF, patient years of follow up; NITs, non-invasive tests; NAFLD, nonalcoholic fatty liver disease; AUROC, area under the receiver operating characteristic curve; FIB-4, fibrosis-4; URL, Uniform Resource Locator; AASLD, American Association for the Study of Liver Diseases; CI, confidence interval; F0–F2, stage 0–2 fibrosis; F2, stage 2 fibrosis; F3, stage 3 fibrosis; F4, stage 4 fibrosis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; NFS, NAFLD fibrosis score; APRI, aspartate aminotransferase/platelet ratio index; US, United States; ELFTM, enhanced liver fibrosis; NICE, National Institute for Health and Care Excellence; IFU, instructions for use; LSM, liver stiffness measurement; TE, transient elastography; MRE, magnetic resonance elastography; kPa, kilopascal; EASD, European Association for the Study of Diabetes; EASL, European Association for the Study of the Liver; EASO, European Association for the Study of Obesity; FDA, Food and Drug Administration.

References: 1. Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 2017;65(5):1557-1565. 2. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389-397. 3. Sanyal AJ, Harrison SA, Ratziu V, et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials. Hepatology. 2019;70(6):1913-1927. 4. Servin-Abad L, Schiff ER. The treatment of hepatic fibrosis: reversal of the underlying disease process. Gastroenterol Hepatol (NY). 2006;1(1):819-825. 5. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64(6):1388-1402. 6. Loomba R, Lim JK, Patton H, El-Serag HB. AGA clinical practice update on screening and surveillance for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: expert review. Gastroenterology. 2020;158(6):1822-1830. 7. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123-133. 8. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-357. 9. European Association for Study of Liver. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2015;63(1):237-264. 10. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD; American Association for the Study of Liver Diseases. Liver biopsy. Hepatology. 2009;49(3):1017-1044. 11. Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014;20(2):475-485. 12. Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med. 2017;23;377(21):2063-2072. 13. Anstee QM, Lawitz EJ, Alkhouri N, et al. Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials. Hepatology. 2019;70(5):1521-1530. 14. Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L. Current guidelines for the management of non-alcoholic fatty liver disease: a systematic review with comparative analysis. World J Gastroenterol. 2018;24(30):3361-3373. 15. Data on file, Intercept Pharmaceuticals. US-NAS-MED-00826. 16. Schuppan D, Surabattula R, Wang XY. Determinants of fibrosis progression and regression in NASH. J Hepatol. 2018;68(2):238-250. 17. Oseini AM, Sanyal AJ. Therapies in non-alcoholic steatohepatitis (NASH). Liver Int. 2017;37(1):97-103. 18. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment. Guidance for industry. Effective December 2018. Accessed October 2022. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM627376.pdf