All Rights Reserved, Duke Medicine 2007
Biomarker Workshop 2018
Defining Therapeutic Response in
Precirrhotic and Cirrhotic NASH
Manal F. Abdelmalek, MD, MPH, FAASLD
Professor of Medicine
Division of Gastroenterology & Hepatology
All Rights Reserved, Duke Medicine 2007
DISCLOSURE(S)• Research Support
– NIH / NIDDK (NASH CRN) - Prometheus
– Gilead Sciences - Galmed
– Genfit Pharmaceuticals - Galactin
– Conatus Pharma - Shire
– TaiwanJ - Intercept
– Bristol Meyers Squibb - NGM Biopharma
– Immuron - Madrigal
– Allergan - Excelanz
• Consultant /Scientific Advisory Board
- Bristol Meyers Squibb - TaiwanJ
- Allergan - NGM Pharma
- Lexicon - Medimmune
- NGM Biopharma - Immuron
• Speaker’s Bureau
– Alexion
I have no conflict of interest or financial disclosures
pertaining to content of today’s presentation.
Estimated US Prevalence
Many companies with clinical
development programs
80-100M 24-30M
Compensated Decompensated
Stage 1 Stage 2 Stage 3 and 4
No varices Varices Bleeding, ascites, HE, SBP
Portal Pressure (mmHg)
Low 1 year mortality (1-3%) 50% 1 year mortality
≥ 6 > 10 ≥ 12
1.5-2M 1.5-2M
Few companies with clinical
development programs
No FDA Approved Treatments for NASH or Cirrhosis
Estimated US Prevalence
Drug Development Regular Approval Pathway: Clinically Meaningful Benefit
• Based on how a patient feels:
• Symptoms (caveat: majority of patients asymptomatic)
• Quality of life
• Based on how a patient functions:
• Functional status (impairment or improvement in ability to lead a normal active life)
• Based on how a patient survives:
• Survival
• Liver-related outcomes
• Rates of hospitalization (resource utilization)
Drug Development Accelerated Pathway
• Accelerated pathway (Subpart H)• Based on use of surrogate endpoints that are
reasonably likely to reflect changes in clinically meaningful outcomes
• Requires post-approval completion of long-term study to objectively document improvement in clinically meaningful outcomes or changes in surrogates generally accepted to reflect changes in clinically meaningful outcomes.
Surrogate Endpoints
Generally accepted• Substantial body of literature
available
• Quality of data is strong
• Surrogate should reflect:• Survival• Other clinical outcomes
• Surrogate should have:• Content and face validity• Sensitivity to change
Reasonably likely • Less amount of data available
• Quality of data not as strong
• Surrogate should have:• Reasonable likelihood of reflecting
change in health status based on its relationship to biology of disease
• Sensitivity to change
Biomarkers that are still under development are not currently accepted as endpoints
Defining Therapeutic Response for
Precirrhotic NASH
Challenges in identifying therapeutic response in early stage disease• Long natural course of the disease:
• clinical outcomes largely linked to cirrhosis
• Even progression to cirrhosis takes years to develop• however, careful selection of the population may help reduce
the time course to a few years• although HCC can develop in the absence of cirrhosis, the
denominator of all subjects at risk is very high and does not lend itself to easy study design.
• Thus, the need for surrogate short-term histological endpoints
Analysis of endpoints that are practical
Metric Reversal of steatohepatitis Decrease in NAS
Linkage to clinically meaningful benefit
Reduced risk of cirrhosis Potential reduction in cirrhosis risk
Is it measurable Yes Yes
Impact on study duration 6-24 months 6-24 months
Impact on study size 200-300 200-300
Can it be used to provide guidance post approval
Yes, but multiple biopsies needed
Yes, but multiple biopsies needed
Population of interest= NASH with enough histological activity to measure improvement
How much improvement in NAS is clinically meaningful?
Resolution of NASH May Improved Fibrosis
Stage 2-3 Stage 3-4
A DECREASE IN STEATOSIS , INFLAMMATION AND BALLOONING COULD THEORETICALLY
REFLECT DISEASE PROGRESSION- thus reversal of steatohepatitis or drop in NAS. Should be accompanied by improvement or no worsening of fibrosis scores
Potential endpoints in a subpart H program in early stage studies• Short-term surrogate:
• Reversal of steatohepatitis (without worsening of fibrosis)
• Decrease in NAS with improvement in multiple components (without worsening of fibrosis)
• Decrease in NAS with improvement of fibrosis (Co-primary endpoint)
• Endpoint for long-term trial:
• Reduction in progression to cirrhosis
• May be defined by biopsy or non-invasive methods approved by FDA for diagnosis of cirrhosis
Defining Therapeutic Response for Cirrhotic NASH
Angulo P, et al. Gastroenterology. 2015.
In Compensated HCV Cirrhosis, Presence of Varices is Associated with Greater Probabilities of Decompensation and Death
Bruno et al. Am J Gastro. 2009. 104: 1147.
Outcomes of Cirrhosis is Determined by Portal Hypertension 1-year Outcome Probabilities According to Clinical Stages
D'Amico G1, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006 Jan;44(1):217-31.
Child-Pugh Score as an Surrogate Endpoint
D'Amico G1, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006 Jan;44(1):217-31.
Subjective assessment of HE and ascitesInsensitivity of serum albumin
MELD as a Surrogate EndpointPros Cons
• Relates to mortality• Well known to clinicians• Widely available• Easy to measure• Threshold value of 10 or 14
identifies a important stage in clinical course
• Inter-lab variability• Related to 3 month mortality• Rate of progression of MELD
score not linear• Most patients with
compensated cirrhosis have a MELD < 10
MELD ≥14 strongly reflects mortality, and risk for decompensation Increase in MELD to > 10, ≥ 14, or delta MELD can be a potential surrogate
Study Designs
HVPG, hepatic venous pressure gradient.Sanyal A, Harrison S, et al. EASL 2017, abstr GS-004
Key inclusion criteria• Histologically confirmed NASH with bridging fibrosis (F3) or compensated cirrhosis (F4)• Randomization stratified by diabetes and HVPG ≥10 mmHg (F4 only)
Study Endpoints
Sanyal A, Harrison S, et al. EASL 2017, abstr GS-004
Results—Demographics
* No difference between treatment groups between studies
Results: Hepatic Collagen Content
P-values for comparison of mean change (SD) between baseline (BL) and week 96 (W96) vs placebo
▪ SIM had no effect on hepatic collagen content
RESULTS: NASH CRN Fibrosis Stage (W96)
▪ SIM had no effect on fibrosis stage at week 96
Results: Clinically Significant Portal HTN (HVPG ≥ 10)
SIM had no effect on portal pressures
Mean HVPG at entry was 12 mmHg68% had CSPH
Analysis restricted to cirrhotic patients with HVPG ≥ 10 at baseline and week 96. P-values for comparison with placebo adjusted for stratification factors.
Progression to CirrhosisBridging Fibrosis
Progression to CirrhosisBridging Fibrosis
• Greater hepatic collagen, FIB4, ELF, and alpha-SMA at baseline and worsening over time increased the risk of disease progression.
• Conversely, lowest tertile alpha-SMA had histological improvement• No patient with Ishak stage improvement had clinical deterioration
Results: Impact of Fibrosis on Clinical EventsCirrhosis
Increased risk of clinical events with:• Higher baseline hepatic collagen content and ELF• Worsening of fibrosis by Ishak stage, collagen content, ELF
* Separate multivariate models run for baseline and change from baseline for each variable
Compliments of Dr. Peter Traber
• Clinical outcome (ascites, HE, development of varices) are leading complications of cirrhosis which can be readily ascertained in phase 2 studies.
• Knowledge of event-rate data facilitates design and powering of phase 3 studies
• Collagen content and fibrosis markers are associated with risk of clinical outcomes in advanced fibrosis / cirrhosis.
What have we learned...
ACKNOWLEDGEMENTS
• Dr. Arun Sanyal—guidance and sharing slides
• Gilead Sciences –Dr. Rob Myers
• Galactin Pharmaceuticals—Dr. Peter Traber
• Special Thanks: Dr. Brent Tetri
and Dr Michael Middleton
THANK YOU