NGM313, a Novel Once-Monthly Activator of bKlotho-FGFR1c, Significantly Reduces Hepatic Steatosis and Key Biomarkers of Non-Alcoholic Steatohepatitis: Results of a Randomized, Active-Controlled Clamp Study in Obese Insulin-Resistant Patients with NAFLD

Sudha Shankar1, Mustafa R. Bashir2, Bryan A. Baxter1, Van Phung1, Andrew Z. Yan1, Stephen J. Rossi1, and Alex M. DePaoli1

1NGM Biopharmaceuticals, South San Francisco, CA 2Duke University, Durham, NC

1. NGM data on file; 2. Lan et al., Cell Metab. 2017;26:709-718; 3. Kliewer et al., Am J Clin Nutr.2010;91:254S-257S; 4. Sanyal et al., EASL 2017 (LBO-02); 5. Sanyal et al., AASLD 2017; 6. Belfort etal., N Engl J Med. 2006;355:2297-307; 7. Cusi et al., Ann Intern Med. 2016;165:305-15

Twenty-five insulin-resistant patients with NAFLD wererandomized 2:1 to either a single dose of NGM313 240 mg SC(n=17) or pioglitazone 45 mg QD (n=8) for 36 days

Primary objectives

– Change in insulin sensitivity from baseline to Day 29

– Change in liver fat content from baseline to Day 36

MRI-PDFF was performed at Day 1 (baseline), Day 23 and Day36, and read centrally by radiologists blinded to treatmentassignment

Hyperinsulinemic-euglycemic clamp and associated metabolicstudies were performed at Day 1 and Day 29

NGM313 is a once-monthly, humanized, monoclonal antibodydirected to bKlotho and modulates activity of the bKlotho-FGFR1c receptor complex

– Highly specific, no signaling through other receptors

– Does not compete with endogenous FGF21/FGF19 bindingto bKlotho-FGFR1c

– Favorable effects on lipids and glucose metabolism, with agood safety profiles in obese healthy volunteers1

FGF21 signals through the bKlotho-FGFR1c, FGFR2c and FGFR3creceptor complexes to regulate glucose, energy and lipidhomeostasis2-3

FGF21 analogues have demonstrated changes in imaging andlaboratory parameters supportive of improvements in patientswith non-alcoholic steatohepatitis (NASH)4-5

This study aims to compare the effects of a single dose ofNGM313 vs. daily pioglitazone (45 mg), an insulin-sensitizerwith modest efficacy in NASH6-7, in insulin-resistant patientswith NAFLD

This study was funded by NGM Biopharmaceuticals, Inc.Author disclosures on file at AASLD

RESULTSBACKGROUND AND AIMS

METHODS

Liver Fat Content

ALT, AST and Weight CONCLUSION

Safety

All AEs were mild in severity

No SAEs or Grade 3/4 AEs

No pattern or organ system AEs of note

Most common AEs (>10%) were injection site reaction (12%) andincreased appetite (12%)

No evidence of safety issues that were associated with FGF21 analogues inclinical development

NGM313 was safe and well tolerated in obese, insulin-resistant, non-diabetic subjects with NAFLD

Administration of a single dose of NGM313 resulted in robust reductionsin liver fat content in obese, insulin-resistant, non-diabetic subjects withNAFLD

– 6.3% reduction in absolute liver fat content on Day 36

– 37% relative reduction in liver fat content on Day 36

NGM313 has also demonstrated robust metabolic effects on insulinsensitivity and lipid homeostasis

– Improved insulin sensitivity

– Reduced HbA1c and fasting glucose levels

– Reduced ALT and AST

– Lowered triglycerides and LDL-C

– Raised levels of HDL-C

Data support once-monthly dosing of NGM313

These data support Phase 2b studies of NGM313 in patients with biopsy-proven NASH with or without type 2 diabetes

Significant decreases in alanine aminotransferase (ALT) and aspartateaminotransferase (AST) were recorded in both the NGM313 and thepioglitazone groups

63% patients in the NGM313 group achieved ≥30% reduction in liver fatcontent after a single dose

NGM313 Selectively Targets bKlotho-FGFR1c

FGFR1c FGFR2c FGFR3c FGFR4

KLB KLB KLB

NGM313

KLB

D-35 D-1 D29 D70Screening

Pioglitazone 45 mg daily PO

(n=8)

MRI-PDFF

NGM313 240 mg (single dose)

SC

D1 D28 D36

CLAMP

Follow up

MRI-PDFF

CLAMP

D23

MRI-PDFF

(n=8)

(n=17)

Baseline Patient Characteristics

ParameterNGM313 (n=17)

mean±SDPioglitazone

(n=8) mean±SD

Age (years) 41.9 ± 11.8 47.0 ± 10.2

Weight (kg) 106.0 ± 15.4 100.4 ± 18.7

BMI (kg/m2) 36.8 ± 3.1 33.7 ± 3.2

Fasting Glucose (mg/dL) 101.7 ± 9.6 101.5 ± 10

Fasting Insulin (μU/mL) 27.0 ± 13.9 20.0 ± 5.9

HbA1c (%) 5.81 ± 0.37 5.70 ± 0.33

Hepatic Fat Fraction (%) 18.5 ± 6.4 17.3 ± 7.7

LDL-C (mg/dL) 105 ± 25 111 ± 41

HDL-C (mg/dL) 39 ± 8 42 ± 10

Triglyceride (mg/dL) 148 ± 91 136 ± 61

ALT (IU/L) 30.7 ± 14.0 43.0 ± 24.4

AST (IU/L) 20.7 ± 6.3 23.0 ± 10.9

Change in Liver Fat Content from Baseline

Relative Change in Liver Fat Content from Baseline

Summary

Ab

solu

te C

han

ge (

%, L

SMe

an±

SE)

Day 23Day 36

***

***p<0.0001**p<0.001*p<0.01

**

***

# (%) of Subjects with Absolute

Reduction≥ 5% HFF

6 / 16(38%)

10 / 16(63%)

1 / 8(13%)

2 / 8(25%)

NGM313

Day 23 Day 36 Day 23 Day 36

PIO

Pe

rce

nt

Ch

ange

(LS

Me

an±

SE)

Day 23Day 36

***

***p<0.0001**p<0.001*p<0.01

*****

# (%) of Subjects with Relative Reduction in

HFF≥ 30%

8 / 16(50%)

10 / 16(63%)

1 / 8(13%)

2 / 8(25%)

NGM313

Day 23 Day 36 Day 23 Day 36

PIO

HbA1c

HbA1c

HOMA-IR

Inclusion criteria included males and females 18-65 years of age,fasting glucose ≤125 mg/dL, fasting insulin ≥10 mU/mL, BMI 30-43 kg/m2, waist circumference >40 inches in males or >35 inchesin females, NAFLD with ≥8% liver fat content as measured bymagnetic resonance imaging-proton density fat fraction (MRI-PDFF)

Fast

ing

HO

MA

-IR

NGM313, 240 mg Pioglitazone, 45 mg QD

***p<0.0001 vs. baseline

******

(kg,

LS

me

an±

SE)

Body Weight Change from Baseline to Day 36

**

*

(me

an±

SE)

BaselineDay 28

#p<0.05*p<0.01

**p<0.001***p<0.0001

vs. baseline

*****

**#

Lipids

A single dose of NGM313produced a favorable lipidprofile in patients withNAFLD

– ↓Triglycerides (48%)

– ↓LDL-C (14%)

– ↑HDL-C (20%)

# p<0.05vs. baseline

Triglycerides(mg/dL)

HDL-C(mg/dL)

LDL-C(mg/dL)

Liver fat content was measured by MRI-PDFF at Day 1, Day 23 and Day 36

A single dose of NGM313 resulted in reductions from baseline in absoluteliver fat content of 6.3%, and relative reduction of 37%, at Day 36

NGM313 appeared to exert greater effects on steatosis reduction thandaily pioglitazone

Index of homeostatic model assessment-insulin resistance(HOMA-IR) was assessed as a measure of insulin resistance(an apparent mediator of abnormal fat deposition in the liverand the Metabolic Syndrome)

At Day 28, significant reductions in HOMA-IR were observedin the NGM313 and the pioglitazone groups

Hemoglobin A1c (HbA1c) was reduced following treatment with asingle dose of NGM313

Day 23§ or 28^ Day 36

NGM313 240 mg, x1

PIO45 mg, QD

NGM313 240 mg, x1

PIO45 mg, QD

D MRI-PDFF (absolute)§ -5.1%*** -1.2% -6.3%*** -4.0%**

% pts with ≥5%↓ 38% 13% 63% 25%

D MRI-PDFF (relative)§ -30%*** -7% -37%*** -25%**

% pts with ≥30%↓ 50% 13% 63% 25%

D Triglycerides (mg/dL)^ -72* -21* -49* -38*

D LDL-C (mg/dL)^ -15* -8 -3 5

D HDL-C (mg/dL)^ 8* 5* 10* 10*

Patients receiving NGM313 did not experience hemodilution or edema

*p<0.05, **p<0.01, ***p<0.001

BaselineDay 28

#

#

#

(me

an±

SE)

(me

an±

SE)

(me

an±

SE)

Day 23 Day 36 Day 23 Day 36

NGM313 PIO

Day 23 Day 36 Day 23 Day 36

NGM313 PIO

Day 28Day 28Bsl Bsl

NGM313 PIO

Day 28Day 28Bsl Bsl

NGM313 PIO

Day 28Day 28Bsl Bsl

NGM313 PIO

ALT (IU/L) AST (IU/L)

Day 28Day 28Bsl Bsl

NGM313 PIO

Day 28Day 28Bsl Bsl

NGM313 PIO

NGM313 PIO

***

** #

#

#p<0.05*p<0.01

**p<0.001***p<0.0001

vs. baseline