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