1. NGM282 in NASH: 3 mg vs 6 mg QD (phase 2)
Design
Randomisation *
1:1:1
Double-blind
W12
18-75 years
Liver biopsy with NASH at screening or previous 6 months
NAS * ≥ 4 with a score ≥ 1 for each component
Stage 1-3 of fibrosis
Liver fat content ≥ 8% (MRI-PDFF)
N = 27
NGM282 3 mg
N = 28
NGM282 6 mg
N = 27
Placebo
* Randomisation was stratified by diabetes (yes or no)
* NAFLD Activity Score: steatosis (0 to 3),
lobular inflammation (0 to 3),
ballooning (0 to 2)
Type 2 diabetes and lipid lowering treatments
had to remain stable during the study
NGM282: engineered variant of human FGF19, administered subcutaneously QD
Endpoint
Primary: decrease in absolute liver fat content ≥ 5% (MDRI-PDFF) at W12 (power based on reduction ≥ 6% with NGM and ≤ 1% with placebo)
NGM282 - Phase 2
Harrison SA, Lancet 2018;391: 1

2. NGM282 in NASH: 3 mg vs 6 mg QD (phase 2)
Baseline characteristics and disposition
NGM282 3 mg
N = 27
NGM282 6 mg
N = 28
Placebo
Mean age, years
52.0
56.4
52.8
Male, % 41 43 26
BMI, mean, kg/m2
34.0
34.7
35.6
Diabetes mellitus, % 56 61 63
HbA1c, mean, %
6.5
6.7
Hyperlipidemia / Hypertension, %
37 / 56
54 / 64
30 / 78
On statins / other antilipidaemic %
44 / 30
50 / 29
26 / 30
Fibrosis stage: F1 / F2 / F3, %
41 / 26 / 33
36 / 43 / 21
NAFLD activity score, mean
5.1
Liver fat content (MRDI-PDFF), mean, %
18.1
19.5
16.8
Pro-C3, mean, ng/mL
19.2
14.9
18.9
ELF score, mean
Hyaluronic acid, mean, UG/L
PIIINP, mean, UG/L
TIMP-1, mean, UG/L
Discontinuation: AE / patient choice, N
3 / 0
3 / 1
0 / 2
NGM282 - Phase 2
Harrison SA, Lancet 2018;391: 2

3. NGM282 in NASH: 3 mg vs 6 mg QD (phase 2)
Change in liver fat content (MRDI-PDFF) at W12
 ≥ 5% (treatment response)
Absolute change
Relative change
Placebo (N = 27)
NGM282 3 mg (N = 27)
NGM282 6 mg (N = 28) %
p <
p = 0.144
p <
p = 0.112
p <
NGM282 - Phase 2
Harrison SA, Lancet 2018;391:

4. NGM282 in NASH: 3 mg vs 6 mg QD (phase 2)
Outcomes at W12
NGM282 3 mg
N = 27
NGM282 6 mg
N = 28
Placebo
 ≥ 30% in liver fat content (MDRI-PDFF)
85% *
86% * 7%
ALT normalisation
37% **
36% ** 4%
C4, mean change at W12, ng/mL * *
11.7
Mean change in fibrosis biomarkers at W12
Pro-C3, ng/mL
 > 15% in pro-C3
ELF score
Hyaluronic acid, UG/L
PIIINP, UG/L
TIMP-1, UG/L
- 5.4
74% ¶
- 0.3 ¶¶¶
- 5.5
- 2.9 §
- 3.6 ***
76% ¶¶
- 0.1
22.6
- 1.5 §§
- 1.21
24%
7.0 0
5.2
Mean change in lipids at W12, mmol/L
Triglycerides
Total cholesterol
HDL-cholesterol
LDL-cholesterol
- 0.4
1.1 *
1.2 *
- 0.5 §§§
0.8 ¶¶ *
0 0 0
Hb A1c, mean change at W12, %
HOMA-IR, mean change at W12
BMI, mean change at W12, kg/m2
- 0.2
- 0.9
0.7
- 0.9 ✔
1.13
C4 : 7α-hydroxy-4-cholesten-3-one
vs placebo : *p < ; **p = ; ***p = ; ¶p = ; ¶¶p = ; ¶¶¶p = ; §p = ; §§p = ; §§§p = ; ✔p = 0.024
NGM282 - Phase 2
Harrison SA, Lancet 2018;391:

5. NGM282 in NASH: 3 mg vs 6 mg QD (phase 2)
Most common adverse events
NGM282 3 mg
N = 27
NGM282 6 mg
N = 28
Placebo
Adverse event in > 10% in either group
Injection site reactions
Diarrhoea
Abdominal pain
Nausea
Headache
Abdominal distension
Vomiting
Frequent bowel movements
Increased appetite
Constipation
Injection site brushing
Weight decreased
11 (41%)
8 (30%)
9 (33%)
3 (11%)
2 (7%)
15 (54%)
10 (36%)
5 (18%)
4 (14%)
1 (4%)
6 (22%)
5 (19%)
Serious adverse event
1 (4%) *
Discontinuation / transient interruption for AE, N
3 / 2
3 / 6
0 / 1
Treatment-related adverse events by severity
Grade 1
Grade 2
Grade 3
Grade 4
18 (67%)
2 (7%) **
23 (82%)
12 (43%)
2 (7%) ***
14 (52%)
4 (15%)
* Acute pancreatitis ; ** Aggravated abdominal pain, acute pancreatitis ; *** Nausea or abdominal pain, depression
NGM282 - Phase 2
Harrison SA, Lancet 2018;391:

6. NGM282 in NASH: 3 mg vs 6 mg QD (phase 2)
Summary
In patients with NASH, 3 mg and 6 mg doses of NGM282 significantly and rapidly (over 12 weeks) reduced
liver fat content, as measured by MRI-proton density fat fraction
as well as markers of liver inflammation (ALT, AST)
and fibrosis, as assessed by non-invasive biomarkers (pro-C3, enhanced liver fibrosis score)
Significant decreases in serum C4 concentrations, and the ensuing increases in LDL-C were recorded with NGM282, consistent with potent target engagement and inhibition of CYP7A1
Both doses were generally well tolerated
In view of the similar efficacy of NGM282 3 mg and 6 mg in lowering liver fat content, doses lower than 3 mg should be evaluated to better characterise the efficacy and tolerability profile
NGM282 - Phase 2
Harrison SA, Lancet 2018;391: