1. Selonsertib in NASH: phase 2
Design
Randomisation *
2:2:1:1:1
Open-label
W24
Selonsertib 6 mg
18-70 years
Liver biopsy within 3 months with NASH
+ stage 2 or 3 fibrosis or NAS ** ≥ 5 with a score ≥ 1 for each 3 components
+ ≥ 3 components of metabolic syndrome
ALT ≤ 5 x ULN
Fibroscan ≥ 7 kPa
Selonsertib 18 mg
N = 72
Selonsertib 6 mg
+ simtuzumab 125 mg
Assessment
Selonsertib 18 mg
+ simtuzumab 125 mg
** NAS (NAFLD Activity Score): steatosis (0 to 3), lobular inflammation (0 to 3), ballooning (0 to 2)
Simtuzumab 125 mg
* Randomisation was stratified by diabetes mellitus (yes or no)
Selonsertib (PO): selective inhibitor of ASK1 (apoptosis signal-regulating kinase 1)
Simtuzumab (SC): humanized monoclonal antibody directed against lysyl oxidase-like molecule 2
Assessment at W24
Paired pre- and post-treatment liver biopsies, magnetic resonance elastography, MRI-estimated proton density fat fraction, quantitative collagen content, and non invasive markers of liver injury
Selonsertib - Phase 2
Loomba R, Hepatology 2018;67:549-59

2. Selonsertib in NASH: phase 2
Baseline characteristics
SEL 18 mg + SIM
N = 32
SEL 6 mg + SIM
N = 30
SIM
N = 10
Median age, years 55 54 57
Female, % 69 73 60
Diabetes mellitus, % 66 80
Non invasive measures (median)
MRI-PDFF (proton density fat fraction), %
MRE, kPa
FibroScan kPa 18
3.7
10.4 17
11.0 16
3.4
13.5
Liver histology, %
NASH CRN fibrosis stage 3
NAS 6-8
Steatosis grade 2-3
Lobular inflammation grade 3
Hepatocyte ballooning grade 2
Hepatic collagen content, %
3.8
4.3
3.5
Selonsertib - Phase 2
Loomba R, Hepatology 2018;67:549-59

3. Selonsertib in NASH: phase 2
Fibrosis change at W24
Worse
No change
Improved ( ≥ 1 stage of fibrosis [NASH CRN]) 20 40 60 80
100
Selonsertib 18 mg + simtuzumab N = 30
Selonsertib 6 mg + simtuzumab N = 27
Simtuzumab N = 10
7 %
50 %
43 %
30 %
56 %
15 %
40 %
20 % %
Selonsertib - Phase 2
Loomba R, Hepatology 2018;67:549-59

4. Selonsertib in NASH: phase 2
Changes in histology and imaging at W24
SEL 18 mg + SIM
N = 32
SEL 6 mg + SIM
N = 30
SIM
N = 10
Histology
Improvement in fibrosis, %
Progression to cirrhosis, %
Median change in hepatic collagen content
NAS
≥ 1 point reduction
≥ 2 points reduction
≥ 1 point reduction in steatosis
≥ 1 point reduction in lobular inflammation
≥ 1 point reduction in ballooning 43 52 23 32
32 16 30 7
- 8.2
20 20
2.1
Imaging
MRDI-PDFF
Median % change
≥ 30% reduction
MRE
≥ 15% reduction
Fibroscan, median change in kPa
- 4.55
26% %
0.2
- 6.67
13% %
- 0.80
10%
2.06
- 0.50
Selonsertib - Phase 2
Loomba R, Hepatology 2018;67:549-59

5. Selonsertib in NASH: phase 2
Factors associated with fibrosis improvement 1 2 3 4 5 6 7 8
7.52
2.50
1.45
1.20
2.66
1.44
1.25
1.12
0.04
< 0.001
< 0.01
0.08
0.02
NAS, improved/no change vs worse
Hepatic collagen, per 1% decrease
Alpha-SMA, per 1% decrease
Fibroscan, per 1-kPa decrease
MRE, per 1-kPa decrease
GGT, per 10 U/L decrease
Cytokeratin-18 M30, per 100 U/L decrease
Cytokeratin-18 M65, per 100 U/L decrease
Histology
Imaging
Laboratory
Odds ratio (adjusted for baseline values)
95% CI p
SMA: smooth muscle actin ; MRE: magnetic resonance elastography
Changes in body weight, MRI-PDFF and grades of steatosis and ballooning were not associated with fibrosis improvement
Selonsertib - Phase 2
Loomba R, Hepatology 2018;67:549-59

6. Selonsertib in NASH: phase 2
% changes in MRE and MRI-PDFF at W24
MRE stiffness
MRI-PDFF
-50
100
p = 0.17 50
Non responder N = 36
Responder N = 18
Median
150
p = 0.01
-100
-50 50
100
Non responder N = 47
Responder N = 18
Fibrosis response:
 ≥ 1 stage of fibrosis [NASH CRN]
Steatosis response:
 ≥ 1 grade of steatosis
Selonsertib - Phase 2
Loomba R, Hepatology 2018;67:549-59

7. Selonsertib in NASH: phase 2
Changes in serum and metabolic biomarkers at W24
SEL 18 mg + SIM
N = 32
SEL 6 mg + SIM
N = 30
SIM
N = 10
Enhanced liver fibrosis test
0.02
- 0.07
- 0.13
FibroSure/FibroTest
- 0.01
0.01
AST, U/L
- 8
- 6
- 3
ALT, U/l
- 5
- 4
Gamma-glutamyl-transferase, U/L
- 7
- 2
Triglycerides, mg/dL
- 21 12
- 30
Total cholesterol, mg/dL
- 10
- 13
High-density lipoprotein, mg/dL 1 2
Low-density lipoprotein, mg/dL
- 25
HOMA-IR
0.98
2.17
- 0.22
Hb A1c, %
- 0.2
0.2
Cytokeratin-18 fractions
M30, U/L
M65, U/L
-110
- 222
- 34
- 162
- 89
- 185
Selonsertib - Phase 2
Loomba R, Hepatology 2018;67:549-59

8. Selonsertib in NASH: phase 2
Adverse events and laboratory abnormalities, %
SEL 18 mg ± SIM
N = 32
SEL 6 mg ± SIM
N = 30
SIM
N = 10
Grade 3-4 adverse event 9 13 10
Serious adverse event 7
Discontinuation for adverse event 6 3
Most common adverse events
Headache
Nausea
Sinusistis
Nasopharyngitis
Upper abdominal pain
Fatigue 28
19 13 16
Grade 3-4 laboratory abnormalities
Alkaline phosphatase > 5 x ULN
ALT > 5 x ULN
AST > 5 x ULN
Gamma-glutamyltransferase > 5 x ULN
Serum glucose > 250 mg/dL
GFR < 30 mL/min
Triglycerides > 500 mg/dL 17
0 0 3
0 0 40 20
Selonsertib - Phase 2
Loomba R, Hepatology 2018;67:549-59

9. Selonsertib in NASH: phase 2
Summary
In this phase 2 exploratory trial, selonsertib appeared to improve liver fibrosis in a substantial proportion of patients with NASH and stage 2 or 3 fibrosis
This suggests that selonsertib has the potential to help address an important unmet medical need for an effective antifibrotic therapy for patients with NASH and advanced fibrosis
Rationale for phase 3 studies of selonsertib in patients with NASH and bridging fibrosis (STELLAR-3) and compensated cirrhosis (STELLAR-4)
Selonsertib - Phase 2
Loomba R, Hepatology 2018;67:549-59