RELATIONSHIP BETWEEN BASELINE HEPATIC DISEASE … · 2017-11-27 · RELATIONSHIP BETWEEN BASELINE HEPATIC DISEASE SEVERITY AND THE CARDIOMETABOLIC AND ANTI-INFLAMMATORY EFFECTS OF

RELATIONSHIP BETWEEN BASELINE HEPATIC DISEASE SEVERITY AND THE CARDIOMETABOLIC AND ANTI-INFLAMMATORY EFFECTS OF ELAFIBRANOR IN PATIENTS WITH NASH

Sven M. Francque1, Stephen A. Harrison2, Arun Sanyal3, Pierre Bedossa4, Lawrence Serfaty5, Manuel Romero-Gomez6, Jerome Boursier7, Manal Abdelmalek8, Stephen Caldwell9, Joost Drenth10, Quentin Anstee11, Dean Hum12, Remy Hanf12, Alice Roudot12, Sophie Megnien12, Bart Staels13,14, Vlad Ratziu15,16

1 Department of Gastroenterology Hepatology, University Hospital Antwerp, Antwerp, Belgium – 2 Department of Medicine, Gastroenterology & Hepatology Service, Brooke Army Medical Center, Houston – 3 Virginia Commonwealth University, Richmond, United States - 4 Department of Pathology, Hôpital Beaujon, University Paris-Denis Diderot – 5 Service d'Hépatologie, Hôpital Saint-Antoine, APHP, UPMC Paris 6, Paris, France – 6 Unit for the Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain – 7 Hepatology Department, University Hospital & LUNAM University, Angers, France – 8 Duke University, Durham NC – 9 Gastroenterology & Hepatology Division, University of Virginia, Charlottesville, United States – 10 Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, Netherlands –

11 Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom – 12 Genfit SA – 13 Université Lille 2 - 14 INSERM U1011, Europena Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille – 15 Université Pierre et Marie Curie, Hospital Pitié Salpêtrière – 16 Institute of Cardiometabolism and Nutrition (ICAN), INSERM, UMRS 938, Paris, France

INTRODUCTION / AIM

CONCLUSION

REFERENCES

EFFECTS OF ELAFIBRANOR-120 ON LIVER FUNCTION MARKERS

EFFECTS OF ELAFIBRANOR-120 ON PLASMA LIPIDS

EFFECTS OF ELAFIBRANOR-120 ON GLUCOSE HOMEOSTASIS

BASELINE CHARACTERISTICS IN SUBGROUPS EFFECTS OF ELAFIBRANOR-120 ON INFLAMMATION/FIBROSIS MARKERS

DEMOGRAPHIC, CO-MORBIDITIES AND PNPLA3 HAPLOTYPE

BASELINE HISTOLOGICAL SCORES

GOLDEN505 DESIGN

GOLDEN505 RESULTS: EFFECT OF ELAFIBRANOR ON THE PRIMARY OUTCOME

BASELINE VALUES

Elafibranor induced histological improvement increases with NASH baseline severity.

Patients treated with Elafibranor-120mg displayed an overall improvement of the cardiometabolic risk profile.

The extent of dyslipidemia at baseline was independent of NASH severity and/or fibrosis at baseline. The favorable effects of Elafibranor-120mg on plasma lipids were comparable irrespective of NAS and/or fibrosis score.

Patients with marked histological lesions (NAS≥6 and NAS≥4; F2-F3) had increased levels of hepatic markers, marked impairement of glucose homeostasis and increased levels of inflammatory and fibrosis markers at baseline.

Under treatment with Elafibranor-120mg, patients with marked histological lesions showed pronounced reductions of hepatic markers, glucose homeostasis and inflammation/fibrosis markers compared to less severe patients.

Considering the role of hepatic insulin resistance in the inflammatory and fibrosis cascade leading to intra-hepatic lesions in NASH, this post-hoc analysis suggests that the histological efficacy of Elafibranor in patients with high NAS might be linked to its insulin-sensitizing effects[2].

Compared to patients with NAS=3-5, those with NAS≥6 had significantly higher levels of fibrosis markers: TIMP1, PIIINP and PAI1.

Compared to patients with NAS≥4; F0-F1, patients with NAS≥4; F2-F3 had significantly higher levels of fibrosis markers: Alpha2- macroglobulin, TIMP1, PIIINP.

This confirmed that levels of liver fibrosis markers were consistentlyassociated with the extent of intra-hepatic lesions.

-100

-80

-60

-40

-20

0

20

40

NAS=3-5 NAS≥6 NAS≥4; F0-F1 NAS≥4; F2-F3

Effe

ctsi

ze v

s pl

aceb

o (n

g/m

L)

TIMP1

-7

-6

-5

-4

-3

-2

-1

0

1

2


Effe

ctsi

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o (n

g/m

L)

PIIINP

-5

-4

-3

-2

-1

0

1

2

3


Effe

ctsi

ze v

s pl

aceb

o (n

g/m

L)

PAI1

-0,7-0,6-0,5-0,4-0,3-0,2-0,1

00,10,20,3


Effe

ctsi

ze v

s pl

aceb

o (lo

g)

hsCRP (log)

******

***

*

** * *

LSMean±Standard Error. *p<0.05; **p<0.01; ***p<0.001 vs placebo

EFFECT SIZE VS PLACEBO (LSMEAN±SE)

BASELINE VALUES


Elafibranor is a dual PPARα/δ agonist that has demonstrated efficacy on resolution of NASH without worsening of fibrosis in a recently published randomized, placebo controlled trial[1]: GOLDEN505.

One year treatment; 3 parallel groups: Placebo, Elafibranor-80mg, Elafibranor-120mg.

Patient population: NAS≥3 with at least 1 in steatosis, ballooning and inflammation scores.

Primary outcome: % Resolution of NASH without worsening of fibrosis.

NASH resolution = Score of 0 for ballooning and 0-1 for inflammation

Worsening of fibrosis = any progression ≥1 stage

n Placebo Elafibranor 120 mg OR RR p-value

NAS≥3 274 92 (12%) 89 (19%) 2.31 1.9 0.045

NAS≥4 234 76 (9%) 75 (19%) 3.52 2.42 0.013

NAS≥6 90 31 (0%) 30 (13%) - - 0.012 (Khi2)

NAS≥4; F0-F1 116 35 (11%) 37 (24%) 3.99 2.76 0.05

NAS≥4; F2-F3 118 41 (7%) 38 (13%) 18.46 4.29 <0.001

Patients who completed the study in the Elafibranor-120 and placebo groups were selected and sub-grouped according to NASH severity (NAS) and/or fibrosis score.

Baseline biochemistry and responses to Elafibranor-120 vs placebo after 1-year treatment were compared in:

the subgroup of patients with NAS=3-5 vs the subgroup of patients with NAS≥6

the subgroup patient with NAS≥4 and no or minimal fibrosis F0-F1 vs the subgroup patient with NAS≥4 and fibrosis F2-F3

Baseline biochemical values in various subgroups were compared using unpaired t-test.

In each subgroup of patients, results vs placebo are expressed as Effect size vs placebo (Lsmean±SE).

NAS=3-5 NAS≥6 NAS≥6 vs NAS=3-5

NAS≥4; F0-F1

NAS≥4; F2-F3

NAS≥6 vs NAS=3-5

N=165 N=72 p-value N=103 N=99 p-value

Age, years; mean (SD) 53 (12) 53(10) 0.850 50 (12) 55(11) 0.0015 Male, % 56% 49% 0.383 (Khi2) 46% 54% 0.260 (Khi2)

Race, Caucasian, % 88% 90% 0.301 (Khi2) 89% 89% 0.06 (Khi2) BMI, kg/m², mean (SD) 31 (5) 32 (5) 0.06 31 (5) 31 (4) 0.794 Weight, kg; mean (SD) 89 (16) 91 (17) 0.302 89 (16) 88 (15) 0.584

Waist circ., cm, mean (SD) 105 (11) 107(12) 0.09 105 (12) 105 (10) 0.690 Type 2 diabetes 37% 46% 0.255 (Khi2) 30% 49% 0.007 (Khi2)

GG PNPLA3 haplotype 22% 40% 0.029 (Khi2) 21% 38% 0.020 (Khi2)

Mean Baseline (SD) or %

NAS=3-5 NAS≥6 NAS≥6 vs NAS=3-5 NAS≥4; F0-F1 NAS≥4; F2-F3 F0-F1 vs

F2-F3


Hepatocyte Ballooning score 1.2 (0.4) 1.8 (0.4) <0.001 1.3 (0.5) 1.6 (0.5) <0.001

Lobular Inflammation score 1.1 (0.3) 1.9 (0.5) <0.001 1.2 (0.4 1.7 (0.6) <0.001

Steatosis score 1.9 (0.7) 2.8 (0.5) <0.001 2.4 (0.6) 2.5 (0.5) 0.606

NAS 4.3 ( 0.8) 6.5 (0.5) <0.001 4.9 (0.9) 5.6 (1.1) <0.001

Fibrosis score 1.3 (1.0) 2.1 ± 0.9 <0.001 0.8 (0.4) 2.5 (0.5) <0.001

Mean Baseline (SD)

PATIENT DISPOSITION

ScreenedN=351

RandomizedN=276

PlaceboN=92

CompletersN=77

NAS=3-5 (N=55)

NAS≥6 (N=22)

NAS≥4; F0-F1 (N=31)

NAS≥4; F2-F3 (N=32)

Not treatedN=0

Elafibranor-80mgN=93

CompletersN=82

NAS=3-5 (N=59)

NAS≥6 (N=23)

NAS≥4; F0-F1 (N=39)

NAS≥4; F2-F3 (N=33)

Not treatedN=0

Elafibranor-120mgN=91

CompletersN=78

NAS=3-5 (N=51)

NAS≥6 (N=27)

NAS≥4; F0-F1 (N=33)

NAS≥4; F2-F3 (N=34)

Not treatedN=2

Screening failuresN=75

BASELINE VALUES NAS=3-5 NAS≥6 NAS=3-5 vs NAS≥6 NAS≥4

F0-F1 NAS≥4 F2-F3

F0-F1 vs F2-F3


ALT (U/L) 54 (30) 78 (54) <0.001 60 (35) 69 (48) 0.133

AST (U/L) 35 (17) 54 (37) <0.001 36 (18) 50 (33) <0.001

GGT (U/L) 68 (77) 78 (78) 0.344 61 (54) 81 (94) 0.07

Alkaline phosphatase, (U/L) 77 (23) 74 (19) 0.404 75 (22) 76 (24) 0.939

CK18-M65 428 (543) 782 (806) <0.001 438 (574) 704 (771) 0.006

CK18-M30 430 (368) 664 (462) <0.001 450 (411) 604 (444) 0.011

Mean Baseline (SD)Baseline ALT and AST, GGT and CK18 fragments levels were significantly higher in NAS≥6 than in NAS=3-5.

Baseline ALT and AST and CK18 fragmentslevels were higher in NAS≥4 with F2-F3 thanin NAS≥4 with no or minimal fibrosis (F0-F1).

These results showed that levels of hepatic markers at baseline are associated with the extent of liver lesions.


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0

10

20


Effe

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o (U

/L)

ALT

-35

-30

-25

-20

-15

-10

-5

0

5

10

15


Effe

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/L)

AST

*****

-70

-60

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-40

-30

-20

-10

0


Effe

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o (U

/L)

GGT

-40

-35

-30

-25

-20

-15

-10

-5

0


Effe

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aceb

o (U

/L)

ALP

*

****

**

*** ******

***

******

-600

-500

-400

-300

-200

-100

0

100

200


Effe

ctsi

ze v

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aceb

o (U

/L)

*

P=0.07

CK18-M65


BASELINE VALUES


There were more patients with T2D and GG PNPLA3 haplotype in NAS≥6 than in NAS=3-5.

There were more patients with T2D and GG PNPLA3 haplotype in NASH patients with fibrosis (F2-F3) compared to NASH patients with no or minimal fibrosis (F0-F1).

NASH patients with fibrosis (F2-F3) were older than NASH patients with no or minimal fibrosis (F0-F1).

NAS=3-5 NAS≥6 NAS=3-5 vs NAS≥6

NAS≥4 F0-F1

NAS≥4 F2-F3

F0-F1 vs F2-F3


Triglycerides, mmol/L 1.8 (1.1) 1.9 (0.9) 0.564 1.9 (1.2) 1.9 (0.9) 0.615

Total cholesterol, mmol/L 4.9 (1.2) 4.9 (1.0) 0.713 5.1 (1.2) 4.8 (1.0) 0.017

HDL-cholesterol, mmol/L 1.3 (0.3) 1.2 (0.3) 0.300 1.3 (0.3) 1.2 (0.3) 0.298

LDL- cholesterol, mmol/L 2.8 (1.0) 2.9 (0.9) 0.638 3.0 (1·0) 2.7 (0.9) 0.027

ApoA1 (mg/dL) 150 (26) 147 (24) 0.479 151 (27) 148 (26) 0.439

ApoB (mg/dL) 101 (29) 105 (27) 0.236 107 (31) 100 (27) 0.06

Mean Baseline (SD) Baseline lipid levels were comparable in NAS≥6 and NAS=3-5.

Baseline TG, HDL-C and apolipoproteins levels were comparable in NAS≥4; F0-F1 and in NAS≥4; F2-F3. A slight but statistically significant lower level of total cholesterol and LDL-cholesterol was observed in NAS≥4; F2-F3 vs NAS≥4; F0-F1.

Together, these results suggested that NASH dyslipidemia at baseline was independent of NASH severity and fibrosis score.

-1

-0,8

-0,6

-0,4

-0,2

0

0,2

0,4


Effec

tsiz

e vs

pla

cebo

(m

mol

/L)

TG Total-Chol LDL-Chol HDL-Chol

**

** **

*****

* **

*

** **



NAS≥4 F0-F1

NAS≥4 F2-F3

F0-F1 vs F2-F3


Fasting glucose, mmol/L 5.7 (1.5) 6.4 (2.1) 0.003 5.5 (1.3) 6.4 (2.1) 0.006

Fasting insulin, pmol/L 168 (165) 199 (141) 0.162 157 (121) 200 (92) 0.058

HOMA-IR 6.6 (8.2) 8.5 (7.8) 0.100 6.0 (6.4) 8.6 (9.6) 0.027

HbA1c (all), % 5.9 (0.8) 6.4 (1.0) <0.001 5.8 (0.6) 6.3 (1.0) <0.001

HbA1c (T2D), % 6.5 (0.9) 7.1 (1.2) 0.009 6.3 (0.8) 7.0 (1.1) 0.003

C-peptide (nmol/L) 1.2 (0.6) 1.4 (0.5) 0.03 1.2 (0.5) 1.4 (0.7) 0.041

Fructosamine (µmol/L) 236 (34) 252 (51) 0.004 227 (26) 253 (50) <0.001

FFA (mmol/L) 0.5 (0.2) 0.6(0.2) 0.110 0.6 (0.2) 0.6 (0.2) 0.514

Mean Baseline (SD)

Effects of Elafibranor on plasma lipids (TG, Total-cholesterol, LDL-cholesterol and HDL-cholesterol) were comparable in NAS≥6 and NAS=3-5.

Effects of Elafibranor on plasma lipids (TG, Total-cholesterol, LDL-cholesterol and HDL-cholesterol) were comparable in NAS≥4; F0-F1 and in NAS≥4; F2-F3.

These results suggested that the favorable effects on Elafibranor on plasma lipids were independent on initial intra-hepatic lesions.

Compared to patients with NAS=3-5, those with NAS≥6 had significant impairment of glucose homeostasis and insulin resistance.

Compared to patients with NAS≥4; F0-F1, patients with NAS≥4; F2-F3 had significant impairement of glucose homeostasis and insulin resistance.

This suggests that the severity of hepatic lesions at inclusion was positively associated with a marked degradation of glucose homeostasis and insulin resistance.

-2,5

-2

-1,5

-1

-0,5

0

0,5

1


Effe

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o (m

mol

/L)

FPG

-6

-5

-4

-3

-2

-1

0

1

2

NAS=3-5 NAS≥6 NAS≥4; F0-F1NAS≥4; F2-F3

Effe

ctsi

ze v

s pl

aceb

o

HOMA-IR

-

45-

40-

35-

30-

25-

201510-50


Effe

ctsi

ze v

s pl

aceb

o (µ

mol

/L)

Frustosamine

* *

***

*

-0,25

-0,2

-0,15

-0,1

-0,05

0

0,05

NAS=3-5 NAS≥6 NAS≥4; F0-F1NAS≥4; F2-F3

FFA

*

-1,6

-1,4

-1,2

-1

-0,8

-0,6

-0,4

-0,2

0


Effec

tsiz

e vs

pla

cebo

(%

)

HbA1c T2D

-1,6

-1,4

-1,2

-1

-0,8

-0,6

-0,4

-0,2

0


Effe

ctsi

aze

vs p

lace

bo (%

)

HbA1c (Non-T2D + T2D)

*

*


REFERENCES

[1] Vlad Raziu et al. 2016 « Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. » Gastroenterology. 2016 Feb 11. doi: 10.1053/j.gastro.2016.01.038.

[2] Cariou et al. 2013 « Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects » Diabetes Care. 2013, 36(10):2923-2930.


NAS≥4 F0-F1

NAS≥4 F2-F3

F0-F1 vs F2-F3


Alpha2-macroglobulin (g/L) 2.2 (0.9) 2.5 (0.8) 0.073 1.9 (0.9) 2.7 (0.9) <0.001 Fibrinogen (g/L) 3.3 (0.8) 3.3 (0.7) 0.713 3.2 (0.7) 3.3 (0.6) 0.352 Haptoglobin (g/L) 1.2 (0.5) 1.3 (0.5) 0.528 1.3 (0.5) 1.2 (0.5) 0.481 TIMP1 (ng/mL) 242 (49) 269 (53) <0.001 236 (44) 265 (55) <0.001 PIIINP (ng/mL) 8.3 (3.3) 10.3 (4.8) <0.001 7.8 (2.5) 9.9 (4.6) <0.001 PAI-1 (ng/mL) 6.4 (3.9) 8.7 (4.6) <0.001 7.1 (4.0) 7.3 (4.6) 0.728 hsCRP 3.7 (10.8) 4.2 (4.5) 0.711 3.4 (3.5) 3.6 (4.1) 0.754

Mean Baseline (SD)

METHODS

Elafibranor-120 induced comparable reduction of plasma alpha2-macroglobulin and haptoglobin in all subpopulations (data not shown).

Beneficial effects of Elafibranor-120 on major inflammatory (hsCRP) and fibrosis markers (TIMP1, PIIINP and PAI1) were observed in patients with NAS≥6 but not in NAS=3-5.

Beneficial effects of Elafibranor-120 on major inflammatory (hsCRP) and fibrosis markers (TIMP1, PIIINP) were observed in patients with NAS≥4; F2-F3 but not in NAS≥4: F0-F1.

These results showed that effects of Elafibranor on major inflammatory and fibrosis markers increased with NASH severity and fibrosis score at baseline.

The histological improvement induced by Elafibranor-120mg increased with baseline NASH severity.

Concomitant to histological improvements, Elafibranor treatment had favorable effects on multiple circulating cardiometabolic risk factors including plasma lipids, glucose homeostasis and insulin resistance, liver enzymes and inflammation markers[1].

Beneficial effects of Elafibranor on hepatic markers (ALT and AST, GGT, ALP and CK18-M65) were more pronounced in patients with NAS≥6 than in NAS=3-5.No significant effect on CK18-M30 (data not shown).

Benefical effects of Elafibranor on hepatic markers (ALT, AST, GGT, ALP and CK18) were more pronounced in patients with NAS≥4; F2-F3 than in patients with NAS≥4; F0-F1. No significant effect on CK18-M30 (data not shown).

In line with a better histological efficacy of Elafibranor in patients with most advanced lesions at inclusion, these results showed that effects of Elafibranor-120mg on hepatic markers increased with baseline NASH severity and fibrosis.

As expected, hepatocyte ballooning, lobular inflammation and steatosis scores were higher in NAS≥6 than in NAS=3-5.

The fibrosis score increased with the NAS severity at baseline (NAS≥6 vs NAS=3-5).

Patients with fibrosis (F2-F3) had higher NAS than patients with no or minimal fibrosis (F0-F1).

Higher NAS in F2-F3 patients is due to higher necroinflammation (hepatocyte ballooning + lobular inflammation) while steatosis score was comparable to that in patients with no or minimal fibrosis.


--

-----

-

0,05

0

-0,05

-0,1

-0,15

-0,2

-0,25

Beneficial effects of Elafibranor-120 on markers of glucose homeostasis and insulin resistance were observed in patients with NAS≥6 but not in NAS=3-5.

No statistically significant effect of Elafibranor on markers of glucose homeostasis and insulin resistance was observed in NAS≥4; F0-F1 and NAS≥4; F2-F3. No difference was seen between the two populations.

When considering both non-diabetic and diabetic patients, the effects of Elafibranor on glucose homeostasis and insulin resistance increased with NASH severity (NAS≥6 vs NAS=3-5). Elafibranor induced non-significant improvement of glucose homeostasis and insulin resistance in patients with NAS≥4 whatever the extent of fibrosis.

In NASH patients with type 2 diabetes, Elafibranor consistently reduced HbA1c in all sub-populations considered. This anti-diabetic effect of Elafibranor is particularly marked and significant in patients with NAS≥6: -0.94±0.4%, p=0.03.

The aim of this post-hoc analysis is to evaluate the influence of NASH severity and fibrosis score at baseline on the biochemical responses to Elafibranor-120mg.

AIM

LSMean±Standard Error. *p<0.05; ***p<0.001 vs placebo

TIMP1: Tissue Inhibitor of MetalloProteinase-1PIIINP: amino terminal type III pro-collagen peptidePAI-1: Plasminogen Activator Inhibitor-1hsCRP: high sensitive C-Reactive Protein

Documents

RELATIONSHIP BETWEEN BASELINE HEPATIC DISEASE … · 2017-11-27 · RELATIONSHIP BETWEEN BASELINE HEPATIC DISEASE SEVERITY AND THE CARDIOMETABOLIC AND ANTI-INFLAMMATORY EFFECTS OF