Lessons learned from NASH clinical trials · 12/07/2019 · Lessons learned in published placebo controlled Phase 2 studies 7/12/2019 3 PIVENS FLINT GOLDEN NGM Centaur Central pathology

Lessons learned from NASH clinical trialsMary E. McCarthy Rinella, MD, FAASLDProfessor of Medicine, Division of Gastroenterology & Hepatology

Northwestern University Feinberg School of Medicine

2 | FORUM FOR COLLABORATIVE RESEARCH | CATALYZING CLINICAL RESEARCH TO IMPROVE GLOBAL HEALTH

2010

Improvement

in NAS,

fibrosis no

worsening

‘NASH

resolution’

no ↑F

NASH

resolution

refinement

Evolution of NASH inclusion criteria and histological endpoints

PIVENS GOLDEN 505

Stellar 3

FLINT

REGENERATE

RESOLVE-IT

2014 2015 2016

AURORA

2017

NASH

resolution/

↓fibrosis co-

primary

Fibrosis

improvement

as primary

Initiation of Phase 3 non-cirrhotic trials

NAS>4 if def NASH, >5 if not* F1-3 Focus on F>2

20192018 2020

NAS>4


Lessons learned in published placebo controlled Phase 2 studies

7/12/2019 3

PIVENS GOLDEN CentaurFLINT NGM

Central pathology critical

First trial to show fibrosis can improve with metabolic MoA

ALT can predict histological response

Higher Placebo response: milder disease, looser endpoint

Fibrosis improves when NASH improves

Center effect

Steatosis and ALT can improve quickly and dramatically

Appealing MoA may have been offset by redundant pathways or limited target engagement

High screen fail rate…50%

Resolution of NASH strongly tracks with fibrosis improvement (Brunt, Hepatology 2019)


Endpoints in early stage disease: ALT and PDFF – is one enough?


Endpoints in early phase 2 development

ALT• ↑ALT associated with ↑

mortality• Every 10 U/L ↓ in ALT: OR 1.3

for histological improvement or resolution of NASH

• >17 U/L ALT ↓ predicted response in FLINT

(PIVENS, TONIC)Ruhl and Everhart Gastroenterology 2009; Lee et al. Hepatology 2008, Ruhl et al. Hepatology 2016; Vuppalanchi et al. CGH 2014; Patel et al. Therap Adv Gastro 2016; Middleton et al. Gastroenterology 2017; Loomba et al. Gastroenterology 2019

MRI PDFF

•> 5% absolute reduction*

•> 30% relative reduction*

•Associates with histological improvement

* Targets for efficacy are based on limited data

Validity of ALT and MRI PDFF to assess efficacy is MoA dependent


Pros

• Easy to measure• Good agreement on histology

• Accurate non-invasive measurement

• Degree of steatosis associated

with increased metabolic risk

• ?Link to fibrosis progression 1

Steatosis as an endpoint

Cons

• Improvement not linked to outcomes

• Steatosis lessens as disease progresses

Stage 2-3 Stage 3-41 Ajmera et al baseline PDFF and fibrosis progression. Gastroenterology 2018


Association between significant improvements in liver fat, ALT and histology in NASH trials

Study Drug/MoA Steatosis ALT GGT NASH res Fibrosis

Wt loss N/A + + + + +

PIVENS Pio/PPAR𝛾 + + + +* +

PIVENS Vit E + + + Trend,p=0.05 -

FLINT OCA/FXR + + + Trend,p=0.08 +

LEAN Liraglutide/GLP-1 - + (trend) + + +

REGENERATE OCA/FXR - + + +* +

GOLDEN Elafibranor/PPAR⍺,ẟ +/- + + + (NAS>4)

Madrigal THRβ + + + + +**

NGM (no Pbo) NGM282/FGF19 + + + + +

ARREST Aramchol/SCD-1 modulator + + + -

*By gestalt diagnosis** By Histoindexonly


Seladelpar Phase 2b Study in NASH Discordance between PDFF response and ALT

PDFF Relative Change from Baseline

8

Cymabay Press release, June 11, 2019

⍏Average placebo PDFF relativechange (Viking, MGL, Pegbelfermin, GS4997, Aramchol): -5.25%

Placebo 10 mg 20 mg 50 mg

-30

-20

-10

0

Me

an

R

ela

tiv

e C

ha

ng

e in

LF

C (

%)

p=NS

p=NSp=NS

⍏ -5.25%

0 4 8 12

-50

-40

-30

-20

-10

0

Weeks

Re

lati

ve A

LT

(%

, S

E)

Placebo (n=27)

10 mg (n=53)

20 mg (n=51)

50 mg (n=50)

9 | FORUM FOR COLLABORATIVE RESEARCH | CATALYZING CLINICAL RESEARCH TO IMPROVE GLOBAL HEALTHPresented at EASL, April 10-14, 2019; Vienna, Austria 9

Precedent for liver chemistry improvement independent of steatosis

Placebo OCA 25mgOCA 10mgYounossi et al. ILC, Vienna 2019


The impact of the placebo response and importance of placebo control

11 | FORUM FOR COLLABORATIVE RESEARCH | CATALYZING CLINICAL RESEARCH TO IMPROVE GLOBAL HEALTH11

Ratziu, et al. Gastroenterology. 2016

Protocol defined vs. modified NASH resolution Response according to baseline fibrosis

b - all patients; c- those with EOT biopsy


Expected placebo response depends on the endpoint

FLINT, PIVENS, GENFIT, LEAN,

REGENERATE, MGL, ARREST

0

5

10

15

20

25

30

NASH resolution NAS improvement >2, noworse fibrosis

Fibrosis improvement >1 stage

28%

16%

12%

FLINT, PIVENS, EPA, CVC,

MGL, REGENERATE

(6.4-21%)

FLINT, CVC ,MGL, STELLAR 3,

REGENERATE *varies based on F1

inclusion

(19-40%)

(12-23%)


Factors influencing placebo response

▪ Disease activity at baseline

▪ Endpoint

▪ Weight loss

▪ Surreptitious Vit E use (intentional or non-intentional)

▪ Dietary macronutrients: e.g. Fructose, olive oil, coffee

▪ Change in activity level, intensity of exercise

▪ Alcohol intake

✓

✗

✗

✗

✓

✓

✗


The pitfalls of current histologic endpoints


Currently accepted endpoints for non-cirrhotic NASH

Stage 2-3 Stage 3-4

Resolution or improvement of NASH could reflect disease progression

•Resolution of NASH, no worsening of fibrosis

• Reduction in fibrosis, no worsening of NASH

- Fibrosis linked to hard clinical outcomes

- Needs to not adversely impact metabolic or inflammatory activity


Gestalt: Resolution of Definite NASH With No Worsening of Fibrosis

Placebo OCA 10 mg OCA 25 mg0

10

20

30

40

% P

ati

en

ts

16.3%

23.1%

(n=311) (n=308)

p=0.0004

12.2%

(n=312)

p=0.14

Younossi et al. ILC, Vienna 2019


10

20

30

40

% P

ati

en

ts

11.2% 11.7%

(n=311) (n=308)

p=0.13

8.0%

p=0.18

(n=312)

NASH Resolution With No Worsening of Fibrosis by criteria

Endpoint defined as (i) resolution of definite NASH (i.e., absence of steatohepatitis) based on pathologist overall diagnostic assessment and (ii) no worsening of fibrosis stage from baseline. P values are nominal.ITT population (N=931).

Primary endpoint definition: (i) pathologist overall histopathologic assessment of “no fatty liver disease” or “fatty liver disease (simple or isolated steatosis) without steatohepatitis”; (ii) NAFLD Activity Score (NAS): hepatocellular ballooning = 0 and lobular inflammation = 0 or 1; and (iii) no increase in fibrosis stage from baseline


0

10

20

30

40

50

60

70

51.8 52.3

43.6

47.846.0

34.1

43.342.0

28.6

p=0.03

p=0.0008

% P

ati

en

ts

Steatosis Lobular

Inflammation

Hepatocellular

Ballooningp=0.07

p=0.33p=0.38

p=0.19

43.342.0

28.6

0

10

20

30

40

50

60

70

44.0

36.3

30.8

p=0.004

NAS Improvement 2

with No Worsening of Fibrosis

p=0.19

30.8

Placebo (n=224) OCA 10 mg (n=226) OCA 25 mg (n=218)

Improvement by NAS ≥2 and individual components

P values are nominal.

Per protocol population (N=668).

≥1 Point Improvement in



Inter- and Intra-rater Agreement on Major Categories

Inter

(adult)

Inter

(ped)

Intra

(adult)

Steatosis 0.79 0.64 0.83

Fibrosis 0.84 0.62 0.85

Lob. Inf. 0.45 0.28 0.60

Ballooning 0.56 0.22 0.66

Mallory’s 0.58 0.69 0.64

Diagnosis 0.61 0.33 0.66

(All values are grouped, weighted Kappa values)


NAFLD Activity Score Discriminates Among Steatohepatitis Diagnoses In Adults

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Activity Score

% o

f A

ll S

co

res

No

Probable

Yes

Steatohepatitis


Criteria: Blond hair - likely dyed and modified, orange skin, small hands and CANNOT be diplomatic

Is this NASH Donald Trump?✗



✗

Is this Donald Trump?



✗ ✗✗




✗

✗ ✗✗


✗



✗

✗ ✗✗


✗✗


Gestalt: You know him when you see him

✗

✗

✗✗ ✗



Fibrosis Improvement by ≥1 Stage with No Worsening of NASH (ITT, F2/3)

Primary endpoint definition: • Improvement in fibrosis by ≥1 stage (NASH

CRN) AND• no worsening of lobular inflammation,

hepatocellular ballooning or steatosis


10

20

30

40

% P

ati

en

ts

17.6%

23.1%

(n=311) (n=308)

*p=0.0002

11.9%

p=0.04

(n=312)



Week 36: MGL-3196 impact on Fibrosis

27

>=1 pt reduction in fibrosis on liver biopsy (SHG)

Using traditional staining, fibrosis was reduced by ≥ 1 point in 29% of MGL-3196 treated patients vs. 23% in placebo (F1-3, ≅ 50% F1))

Those with F2/3 had more marked response

Second Harmonic Generation (SHG) microscopy: Automated quantification of fibrosis on liver biopsy that correlated with pathologist read (baseline, r=0.76).

120

32

47

0

10

20

30

40

50

All F3

p=0.03 p=0.05

% b

iop

sie

s

Placebo MGL-3196

Week 36: Change in Fibrosis Score on Liver Biopsy

13

n Second Harmonic Generation (SHG) microscopy provides automated fully quantitative assessment of fibrosis on liver biopsy slides based on unique architectural features of collagen

n SHG score was generated and aligned with the pathologist baseline score (baseline, r=0.76),

(left panel), blinded to treatment code

n Using SHG, MGL-3196 treated compared with placebo showed a statistically significant ≥1-pt reduction in fibrosis score at Week 36. Based on pathology score, fibrosis was reduced by ≥ 1 point in 29% of MGL-3196 treated patients vs. 23% in placebo

≥1 pt reduction in fibrosis on liver biopsy (SHG)

Pathologist Score

SHG

(q

fib

rosi

s)

https://doi.org/10.1371/journal.pone.0199166Week 36 pathology scores and treatment code were not provided to SHG readers.

3

2

1

0

SHG Score

0 1A 1B 2 30.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

12

32

0

47

0

10

20

30

40

50

Placebo MGL-3196 Placebo MGL-3196

p=0.03 NA p=0.05

% o

f b

iop

sie

s

F3

Variability in collagen burden within fibrosis stage

Histology courtesy of Elizabeth Brunt

Both are technically stage 3 fibrosis

Baseline Post-treatment

Liver Collagen Burden is not Linear Across Fibrosis Stages

0

5

10

15

20

25

30

35

0 1 2 3 4

METAVIR Fibrosis Stage

Co

llage

n P

rop

ort

ion

al S

urf

ace

Are

a (%

)

Chen et al., Medicine 2016 Aug; 95(35): e4736

N=274

Liver Collagen Burden is not Linear Across Fibrosis Stages

0

5

10

15

20

25

30

35

0 1 2 3 4

2.8

6.3

27.5

METAVIR Fibrosis Stage

Co

llage

n P

rop

ort

ion

al S

urf

ace

Are

a (%

)

Chen et al., Medicine 2016 Aug; 95(35): e4736

N=274

CV and Hurst Index decrease with increasing

burden of fibrosis0.07 for cirrhosis, 0.29

for F0


Limitations of current histologic endpoints

▪ Discrepancy between gestalt and quantitative assessment for NASH resolution

▪ Inter-observer variability (between local and central as well as between experts)

▪ Fibrosis stages may not accurately reflect the burden of fibrosis as a continuous measure


Studies evaluating efficacy in cirrhosis


Challenges in trials using endpoints to define clinically meaningful benefit

• Prolonged compensated phase

• More advanced patients (decompensated) may reach outcomes more quickly…but may be out of therapeutic efficacy window

0 5 10 15 20 250

25

50

75

100

HCV

NASH

p< 0.04

years

% s

urv

ival

Sanyal et al, Hepatology 2006, 43:682-689


SIM had no effect on portal pressure compared to placebo in patients with CSPHTN (HVPG >10mmHg)

34

Analyses restricted to cirrhotic subjects with HVPG ≥10 mmHg at baseline and Week 96 HVPG data. P-values for comparisons with placebo group adjusted for

stratification factors.

27.3

20.0

29.1

20.4 18.9 20.4

34.0

12.3

35.8

0.0

10.0

20.0

30.0

40.0

50.0

Pat

ien

ts, %

16/55 10/49 19/5378 7511/55 6/49 10/5315/55 10/49 18/53

≥20% ↓ ↓ to <10 mmHg≥20% ↓ and/or↓ to <10 mmHg

SIM 700 mg SIM 200 mg Placebo

P=0.52 P=0.13 P=0.87 P=0.36 P=0.51 P=0.086

Harrison, et al. Hepatology. 2019

Mean HVPG at entry was 12 mm, 68% had CSPH


Progression to cirrhosisBridging Fibrosis

• Median follow-up 24.9 months (range, 0.3–41.4)

Sanyal, et al. Hepatology. 2019

Change in hepatic collagen content ELF

• 47 patients (21.5%) progressed to cirrhosis• 89% (n=42) histologic progression

• 11% (n=5) clinical events


Liver related clinical events in patients with cirrhosis

Time, months

36

Pro

gre

ssio

n to

Cirrh

osis

, %

Sanyal, et al. Hepatology. 2019

– Ascites (n=19)

– Encephalopathy (n=13)

– Variceal hemorrhage (n=6)

– Newly-diagnosed varices (n=4)

• Median follow-up 24.9 months (range, 0.3–41.4) – ≥2-point increase in Child-Pugh score and/or MELD ≥15 (n=6)

– Death (n=1)

HVPG Baseline ELF


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 with baseline and change from baseline for each variable.

Hazard Ratio * 95% CI p-value

Ishak stage 5 vs 6 (baseline) 1.25 0.68, 2.29 0.48

No improvement vs improvement 9.63 1.33, 69.81 0.025

Hepatic collagen (baseline), per 5% 1.39 1.15, 1.69 <0.001

Change from baseline, per 5% 1.20 1.03, 1.39 0.017

ELF (baseline) 2.37 1.69, 3.31 <0.001

Change from baseline 1.54 1.10, 2.15 0.002

0 1 2 3 4 5 6 7 8 9 10 11

37


Subclassification of cirrhosis is important

Emricasan 5mg v Pbo

–3 –2 –1 0 1–4

Emricasan 25mg v Pbo

Emricasan 50mg v Pbo

-2.16 -3.8 -0.52

-2.26 -3.84 -0.67

-2.02 -3.76 -0.29

Favors emricasan ← → Favors placebo

Post hoc analysis HVPG>16

Post hoc analysis cirrhosis no varices (post hoc)Absolute change from baseline HVPG

p=0.01

p=0.36

PLB GR2 GR8

Ab

so

lute

Ch

an

ge

in

HV

PG

fro

m

ba

se

lin

e t

o w

eek 5

4 (

mm

Hg

)

+0.80

-1.08

+0.15n=33

n=25

n=23

Mean ± SEM

Mean HVPG: 10.6mmHg vs 12.22mmHgGarcia-Tsao G, et al. EASL 2019, Vienna, Austria. #LB-01Chalasani et al 2018

Emricasan: ITT no reduction in portal pressure vs Pbo

Galectin: ITT no reduction in portal pressure vs Pbo

Least squares mean difference

95% lower CL

95% upper CL


New lessons learned from NASH trials

7/12/2019 39

MGL, others STELLAR 3/4, GAL, EMR, CVC

REGENERATEEarly phase trials

• Success can be achieved in phase 3 trial of NASH• Histological endpoint of NASH resolution needs further refinement

• Better mechanisms to measure fibrosis improvement on a linear scale are needed

• Steatosis and ALT can predict histological response• Thus far, ALT has been more consistently predictive of histological improvement

• More appraisal of evidence prior to phase 3.• Adaptation of stopping rules should be developed.• Cirrhosis populations

SIMTUZUMAB

• Natural history of NASH in F3 and F4 patients• Increased collagen burden and ELF predictive


Thank you for your attention

Documents

Lessons learned from NASH clinical trials · 12/07/2019 · Lessons learned in published placebo controlled Phase 2 studies 7/12/2019 3 PIVENS FLINT GOLDEN NGM Centaur Central pathology