1. CENTAUR Study: cenicriviroc in NASH (phase 2b)
Design
Randomisation *
2:1:1
Double-blind
Year 1
Year 2
Adults
NASH (liver biopsy)
+ NAS ** ≥ 4 (≥ 1 in each component)
+ Liver fibrosis (NASH CRN stages 1 to 3)
+ ≥ 1 of the following: diabetes mellitus,
BMI > 25 kg/m2 + ≥ 1 component of
metabolic syndrome, bridging fibrosis (NASH CRN stage 3), NAS ≥ 5
CVC 150 mg
N = 289
Placebo
CVC 150 mg
Placebo
Placebo
** NAS (NAFLD Activity Score): steatosis (0 to 3), lobular inflammation (0 to 3), ballooning (0 to 2)
* Randomisation was stratified by NAS (4 or ≥ 5)
and fibrosis stage (≤ 2 or > 2)
Cenicriviroc: oral dual antagonist of CCR-2 and CCR-5
Objective
Primary: hepatic histologic improvement at year 1 (≥ 2 point in NAS with ≥ 1 point in lobular inflammation or ballooning) with no worsening of fibrosis ; superiority of CVC vs placebo, 80% power
Cenicriviroc - Phase 2b
Friedman SL, Hepatology 2018;67: , Ratziu, EASL 2018, Abs. GS-002

2. CENTAUR Study: cenicriviroc in NASH (phase 2b)
Baseline characteristics and disposition
CVC, N = 145
Placebo, N = 144
Mean age, years 55 54
Female
50%
55%
Mean BMI, kg/m2
33.6
34.1
Diabetes mellitus
57%
44%
≥ 3 criteria of metabolic syndrome, % 72
Liver histology
NASH CRN fibrosis stage 1 / 2 / 3
NAS
Mean
≥ 5, %
Mean steatosis
Mean lobular inflammation
Mean ballooning
32% / 29% / 39%
5.3
73.1%
1.4
2.4
1.5
33% / 28% / 38%
5.4
75.0%
Discontinued before end of Year 1, N
For adverse event
Withdrew consent 20
9 10 18
8 7
Entered Year 2 of the study, N
Early withdrawal, N / for adverse event, N
121
12 / 5
CVC = 61
2 /1
PCB = 60
2 /0
Cenicriviroc - Phase 2b
Friedman SL, Hepatology 2018;67: , Ratziu, EASL 2018, Abs. GS-002

3. CENTAUR Study: cenicriviroc in NASH (phase 2b)
Primary endpoint at Year 1:
improvement in NAS and no worsening of fibrosis, ITTm 10 20 30 40 50
15.9
18.8
OR = 0.82 ( )
p = 0.52
CVC
N = 145
Placebo
N = 144 %
Cenicriviroc - Phase 2b
Friedman SL, Hepatology 2018;67:

4. CENTAUR Study: cenicriviroc in NASH (phase 2b)
Key secondary endpoint at Year 1: improvement in fibrosis by ≥ 1 stage
and no worsening of steato-hepatitis by baseline characteristics
All patients
By NAS 10 20 30
21.6
18.8
p = 0.77
OR = 1.2 (0.37 ; 3.9)
23.6
9.6
p = 0.013
OR = 2.92 (1.26 ; 6.78) 37 32 89 94
NAS = 4
NAS > 5
N = % 10 20 30
10.4
OR = 2.20 (1.11 ; 4.35)
p = 0.023 %
CVC
Placebo
By Fibrosis stage (NASH CRN)
By ballooning grade
13.6
4.8
p = 0.175
OR = 3.16 (0.6 ; 16.62)
22.9
8.8
p = 0.123
OR = 3.06 (0.74 ; 12.71)
31.9 20
p = 0.183
OR = 1.88 (0.74 ; 4.73) 28
15.5
p = 0.049
OR = 2.2 (1.0 ; 4.7) 44
Stage 1 10 30 40
N = 42 35 34 47 50 82 84
Stage 2
Stage 3
Pooled
stage 2 and 3 %
17.7
15.8
p = 0.78
OR = 1.15 (0.44 ; 3.02)
28.1
8.7
p =
OR = 4.1 (1.51 ; 11.2) 62 57 64 69
Grade 1
Grade 2 10 20 30 40
N = %
Cenicriviroc - Phase 2b
Friedman SL, Hepatology 2018;67:

5. CENTAUR Study: cenicriviroc in NASH (phase 2b)
Improvement in fibrosis by ≥ 1 stage and no worsening of steato-hepatitis
15/126 (12%)
6/32 (19%)
9/94 (10%)
2/42 (5%)
3/34 (9%)
10/50 (20%)
9/57 (16%)
6/69 (9%)
7/61 (12%)
10/81 (12%)
4/41 (10%)
5/45 (11%)
4/28 (14%)
3/19 (16%)
5/69 (7%)
10/57 (18%)
29/126 (23%)
8/37 (22%)
21/89 (24%)
6/44 (14%)
8/35 (23%)
15/47 (32%)
11/62 (18%)
18/64 (28%)
17/66 (26%)
11/54 (20%)
8/31 (26%)
7/32 (22%)
8/51 (16%)
6/22 (27%)
7/19 (37%)
15/52 (23%)
17/74 (23%)
Overall mITT population
NAS = 4
NAS > 5
Stage 1
Stage 2
Stage 3
Grade 1 (few ballon cells)
Grade 2 (prominent ballooning)
Grade 2 (2-4 foci/200x)
Grade 3 (> 4 foci/200x)
Grade 1 (5-33 %)
Grade 2 (> %)
< 30 kg/m²
> 30 - < 35 kg/m²
> 35 - < 40 kg/m²
> 40 kg/m²
Not present
Present
NAS
Fibrosis stage (NASH CRN)
Hepatocellular ballooning
Lobular inflammation
Steatosis
BMI
Type 2 diabetes status
Favors placebo
Favors CVC
Cenicriviroc - Phase 2b
Friedman SL, Hepatology 2018;67:

6. CENTAUR Study: cenicriviroc in NASH (phase 2b)
Change in liver biopsy at year 1 (IPP population)
CVC
N = 123
Placebo
Improved
No change
Worsened
Steatosis
19.5
74.0
6.5
25.2
61.8
13.0
Lobular inflammation
31.7
43.9
24.4
27.6
49.6
22.8
Ballooning
26.8
54.5
18.7
35.0
50.4
14.6
Biomarkers of inflammation
Marked reductions in circulating biomarkers of systemic inflammation (high-sensitivity C-reactive protein, interleukin-6, interleukin-8, fibrinogen, and IL-1ß) and of monocyte activation (sCD14) were observed with CVC (vs placebo). Persistence of systmeic anti-inflamamtory activity at Year 2, without no metabolic disturbances
Cenicriviroc - Phase 2b
Friedman SL, Hepatology 2018;67: , Ratziu, EASL 2018, Abs. GS-002

7. CENTAUR Study: cenicriviroc in NASH (phase 2b)
Main outcomes at Year 2
Improvement in fibrosis (≥ 1 stage)
Improvement in fibrosis (≥ 1 or ≥ 2 stages) and no worsening of NASH
Maintenance of antifibrotic response from Year 1 to Year 2 (groups with 2 years CVC vs 2 years of placebo)
Effects of 2 years of CVC treatment (groups with 2 years CVC vs 2 years of placebo)
Effects of 1 year of CVC treatment (immediate or deferred CVC vs placebo)
Safety and tolerability of CVC vs placebo during Year 2
Cenicriviroc - Phase 2b
Ratziu, EASL 2018, Abs. GS-002

8. CENTAUR Study: cenicriviroc in NASH (phase 2b)
Antifibrotic response at year 2, ITTm
CVC
Placebo 10 20 30 40
N evaluable =
N enrolled = 26 22
p = 0.63 15 17
p = 0.94 11 3
p = 0.13 99
145 54 72 65 86 34 50
Stage 2 or 3 %
Improvement in
fibrosis by ≥ 1 stage
and no worsening of NASH
fibrosis by ≥ 2 stages
Cenicriviroc - Phase 2b
Ratziu, EASL 2018, Abs. GS-002

9. CENTAUR Study: cenicriviroc in NASH (phase 2b)
Adverse events and laboratory abnormalities, %
CVC 1st year
N = 144
Placebo 1st year
N = 145
CVC 2nd year
N = 182
Grade 3-4 drug-related adverse event
8.3
6.3
12.1
Serious adverse event
11.1
6.9 NA
Discontinuation for adverse event
2.7
Most common adverse events of grade ≥ 2
Fatigue
Diarrhea
Headache
ALT increase ≥ grade 2
1.4
0.7
3.5
7.1
Grade 3-4 laboratory abnormalities
Fasting serum glucose > 250 mg/dL
ALT > 5 x ULN
AST > 5 x ULN
Triglycerides grade 3 / grade 4
Gamma-GT grade 3 / grade 4
Creatine kinase grade 3 / grade 4
Uric acid grade 3 / grade 4
Amylase > 2-5 x ULN
Phosphorus < 2-1 mg/dL
Absolute neutrophil grade 3 / grade 4
11.9
11.8
4.9
3.5 / 2.1
5.6 / 0.7
4.2 / 1.4
6.3 / 7.6
4.2
1.4 / 1.4
9.2
4.9 / 2.1
4.2 / 0.7
4.9 / 1.4
6.3 /
2.1 / 0.7
Cenicriviroc - Phase 2b
Friedman SL, Hepatology 2018;67: , Ratziu, EASL 2018, Abs. GS-002

10. CENTAUR Study: cenicriviroc in NASH (phase 2b)
Summary
CVC showed a significant antifibrotic benefit at year 1 and was well tolerated
Although the primary endpoint of the study was not met, the fact that the CENTAUR year 1 study results showed that CVC provided clinically meaningful benefits and resulted in twice as many subjects achieving improvement in fibrosis by 1 stage and no worsening of steato-hepatitis as compared to placebo suggests that the study did, in fact, show proof of concept, warranting phase 3 development of CVC
Year 2 analyses corroborate CVC antifibrotic activity in adults with NADH and liver fibrosis
Effect more pronounced in stage 3 fibrosis
Cenicriviroc - Phase 2b
Friedman SL, Hepatology 2018;67: , Ratziu, EASL 2018, Abs. GS-002