1. NGM282, NAS and fibrosis in NASH: a phase 2 study
Design
Follow-up
Liver biopsy with NASH
NAS * ≥ 4 with a score
≥ 1 for each component
Stage 1-3 of fibrosis
Liver fat content ≥ 8% (MRI-PDFF)
NGM282 1 or 3 mg
NGM282 1 or 3 mg Rosuvastatin (if needed)
D-28 D1 W2 W4 W6 W8
W12
W18
MRI-PDFF X
Liver MultiScanTM
Liver biopsy
* NAS (NAFLD Activity Score): steatosis (0 to 3), lobular inflammation (0 to 3), ballooning (0 to 2)
NGM282: engineered variant of human FGF19
Rosuvastatin: started at W2 if LDL-cholesterol rise ≥ 10 mg/dl
Endpoints
Primary: decrease in absolute liver fat content (MRI-PDFF) ≥ 5% at W12
Exploratory: change in liver histology at W12
NGM282-phase 2
Harrison SA, AASLD 2018, Abs. 104 1

2. NGM282, NAS and fibrosis in NASH: a phase 2 study
Baseline characteristics, mean (SD)
NGM282 1 mg
N = 24
NGM282 3 mg
N = 19
Age, years (SD)
49.4 (10.7)
51.4 (12.6)
Male/ Female, N
5 / 19
4 / 15
Liver fat content, MRI-PDFF
(proton density fat fraction), %
19.2 (7.1)
17.1 (5.6)
AST, U/L
70 (39)
64 (32)
ALT, U/L
92 (53)
82 (39)
Fibrosis stage
2.3 (0.8)
2.5 (0.8)
NAFLD activity score
5.4 (1.5)
5.7 (1.5)
LDL cholesterol, mg/dL
103 (24)
97 (27)
Statin naïve/experienced
20 / 4
13 / 6
7α-hydroxyl-4-cholesten-3-one (C4), ng/mL (SD)
35.6 (27.0)
35.1 (24.2)
NGM282-phase 2
Harrison SA, AASLD 2018, Abs. 104 2

3. NGM282, NAS and fibrosis in NASH: a phase 2 study
Mean C4 levels (ng/ml)
Mean total serum bile acids (µmol/L) 40 10 35 30 25 20 15 5
NGM282 1 mg
Baseline W6
W12 *
NGM282 3 mg 40 10 35 30 25 20 15 5
Baseline W6
W12 *
NGM282 1 mg 6 2 5 4 3 1
Baseline W6
W12 *
NGM282 3 mg 6 2 5 4 3 1
Baseline W6
W12 *
* p < vs baseline
NGM282-phase 2
Harrison SA, AASLD 2018, Abs. 104

4. Primary endpoint: mean absolute liver fat content at W12, %
NGM282, NAS and fibrosis in NASH: a phase 2 study
Primary endpoint: mean absolute liver fat content at W12, % 40 5 15 10
Baseline W6
W12
***
NGM282 1 mg
NGM282 3 mg 40 5 15 10
Baseline W6
W12
***
Absolute and relative changes in LFC at W12: % and -67% (3 mg) ; -10.9% and -57% (1 mg)
100% (3 mg) and 92% (1 mg) of subjects achieved primary endpoint of ≥ 5% absolute LFC reduction
100% (3 mg) and 92% (1 mg) had a relative decrease in LFC ≥ 30% at W12
63% (3 mg) and 33% (1 mg) of subjects normalized LFC (≤ 5%) by W12
NGM282-phase 2
Harrison SA, AASLD 2018, Abs. 104

5. Mean transaminases (IU/L)
NGM282, NAS and fibrosis in NASH: a phase 2 study
Mean transaminases (IU/L)
NGM282 1 mg
100
Baseline 80 60 40 20 W2 W4 W6 W8
W10
W12
NGM282 3 mg
100 80 60 40 20
Baseline W2 W4 W6 W8
W10
W12
ALT
AST
NGM282-phase 2
Harrison SA, AASLD 2018, Abs. 104

6. Histological parameters, %
NGM282, NAS and fibrosis in NASH: a phase 2 study
Histological parameters, %
NGM282 1 mg
NGM282 3 mg
Improved
No change
Worsened
-1.9 (1.7) 20 40 60 80
100
-1.0 (0.9)
-0.4 (0.6)
-0.5 (0.9)
Mean change at W12 (SD)
NAS
Steatosis
Inflammation
Ballooning 8%
17%
75%
33%
67%
46%
42%
12%
NAS
Steatosis
Inflammation
Ballooning
-2.3 (1.8)
-1.1 (0.9)
-0.4 (0.7)
-0.7 (0.9)
84%
74%
26%
53%
42% 5% 20 40 60 80
100
11%
NGM282-phase 2
Harrison SA, AASLD 2018, Abs. 104

7. Fibrosis at baseline and W12 in the NGM282 1 mg group
NGM282, NAS and fibrosis in NASH: a phase 2 study
Fibrosis at baseline and W12 in the NGM282 1 mg group
Fibrosis Stage at baseline, %
Fibrosis Histologic Response at W12, %
Mean fibrosis stage = 2.3 F4 F1 F2 F3
38 %
42 %
16 %
4 %
Improved
No change
Worsened (1 point)
Mean change from baseline in fibrosis stage: - 0.1
One subject had a 2-stage improvement in fibrosis: F2 to F0
NGM282-phase 2
Harrison SA, AASLD 2018, Abs. 104

8. Mean LDL-cholesterol changes during treatment, mg/dL
NGM282, NAS and fibrosis in NASH: a phase 2 study
Mean LDL-cholesterol changes during treatment, mg/dL
Baseline
200
100 50 W2 W4 W6 W8
W10
W12
150
NGM282 1 mg
NGM282 1 mg + rosuvastatin (if needed, titration at W4, W8)
NGM282 3 mg
NGM282 3 mg + r0osuvastatin (if needed, titration at W4, W8)
LDL-C levels drop below baseline with rosuvastatin
Decreased C4 and increased LDL-cholesterol reflect potent CYP7A1 inhibition
Lipid particle change primarily driven by increase in large LDL particles
Significant reductions in serum triglycerides: -25 % (1 mg) and -34 % (3 mg) at W12
NGM282-phase 2
Harrison SA, AASLD 2018, Abs. 104

9. Safety and tolerability
NGM282, NAS and fibrosis in NASH: a phase 2 study
Safety and tolerability
Favorable safety and tolerability profile consistent with other NGM282 studies: no new safety signals identified
Mild gastrointestinal symptoms (loose/frequent stools) were the most common treatment emergent adverse events
Majority were mild and resolved during treatment phase
No subject withdrew from treatment due to any drug-related AEs
Gastrointestinal symptoms were largely mitigated with separating the timing of injection around meals and decreasing meal size
Five severe adverse events, all unrelated to study drug:
Pneumonia
Pleurisy
Chest tightness
Cardiac arrest (non myocardial infarction)
Renal mass
NGM282-phase 2
Harrison SA, AASLD 2018, Abs. 104

10. NGM282, NAS and fibrosis in NASH: a phase 2 study
Summary
Potent C4 and bile acid suppression consistent with FGF19 hormone activity
Significant and clinically meaningful reductions across non-invasive markers of NASH-related disease
Large percentage of patients demonstrated histological improvement at W12
Statin co-administration rapidly mitigates LDL-cholesterol elevations
Treatment was safe and well tolerated
NGM282-phase 2
Harrison SA, EASL 2018, Abs. GS-014