Sorafenib Improves Efficacy in the Treatment of Cirrhotic …...Combination Therapy with a Liver Selective Acetyl CoA Carboxylase Inhibitor ND-654 and Sorafenib Improves Efficacy in

Combination Therapy with a Liver Selective Acetyl CoA Carboxylase Inhibitor ND-654 and Sorafenib Improves Efficacy in the Treatment of Cirrhotic Rats with Hepatocellular Carcinoma

Lan Wei1, Omeed Moaven1, Geraldine Harriman2, Sarani Ghoshal1, Wenyan Miao2, Jennifer Rocnik2, Jeremy Greenwood3, Sathesh Bhat3, William F. Westlin2, H. James Harwood2, Rosana Kapeller2, Kenneth K. Tanabe1, Bryan C. Fuchs1

1Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 2Nimbus Therapeutics, Cambridge, MA, 3Schrodinger, New York, NY,

Abstract#3781

1. ND-654 Targets Allosteric Site in Biotin Carboxylase Domain

ACC: An Emerging Tumor Metabolism Target

2. ND-654 is Well-Tolerated in the DEN Rat ModelOVERVIEW

CONCLUSION3. ND-654 Results in Marked Reduction of Tumor Nodules

4. ND-654 Decreases Tumor Proliferation and Increases Tumor Necrosis

5. ND-654 Significantly Improves Survival in the Aggressive DEN Model

6. ND-654 Decreases Markers of Fibrosis and Inflammation

7. ND-654 Decreases Markers of Fibrosis and Inflammation in Primary Human Stellate Cells in vitro

8. ND-654 Improves the Efficacy of Sorafenib

• Current treatment options for HCC are limited, and as such, prognosis is extremely poor with a 5-year survival less than 12%

• Metabolic attenuation is a promising approach to cancer therapy, and rate-limiting steps in key biosynthetic pathways are particularly attractive targets. Hepatospecific ND-654 is a potent allosteric inhibitor of the lipid master regulator Acetyl CoA Car-boxylase (ACC)

• ND-654 demonstrates excellent PK/PD relationships in the target tis-sue, the liver (exposure vs Malonyl CoA reduction), and is effective at modifying cirrhotic and HCC rele-vant endpoints in the DEN model

• ND-654 demonstrates the ability for tissue targeted ACC inhibition to decrease tumor burden, liver fibrosis and prolong survival in the highly aggressive rat DEN model of HCC

DEN DEN + ND-654 10PBS

Alpha-Smooth Muscle Actin

CD68 InflammationMarker

Collagen 1A1 Marker(Fibrosis)

DEN + ND-654 30

a-S

MA

Tric

hrom

e

• Only potent BC domain inhibitor: Soraphen A

• Industry efforts on analoging Soraphen proved unsuccessful

• Allosteric binding site implicated in dimerization of ACC

• Highly lipophilic binding site• Inhibitors bind to active site• Past programs exhibited poor

drug-like properties

Challenges in Drugging ACCTarget potency• ACC1 IC50 = 3 nM• ACC2 IC50 = 8 nM• HepG2 EC50 = 4 nM (serum free) = 14 nM (10% serum) Pharmacology• Rat FASyn ED50 = 0.3 mg/kg PO• Rat Malonyl-CoA ED50 = 0.3 mg/kg (liver) PO• Rat DEN HCC MED = 10 mg/kg PO

ADME• Moderate multispecies intrinsic clearance

(human, mouse, rat, dog, monkey)• P450 inhib >50 μM• Highly selective across broad panel (>1000x)

Exposure at 10 mg/kgHep-G2 Cell FASyn Inhibition[14C]acetate incorporation into FA

Liverp < 0.01

Muscle(Gastrocnemius)

n.s.

784 Memorial Dr, Cambridge, MA 02139, USA • www.nimbustx.com • Tel: 857.999.2009 • info@nimbustx.com

ND-654

• ND-654 preferentially biodistributes to the liver where it inhibits ACC activity without generating liver toxicity

• ND-654 inhibits HCC development by decreasing tumor proliferation and causing tumor necrosis

• ND-654 reduces markers of fibrosis and inflammation in the liver of DEN rat in vivo efficacy model and in primary human stellate cells in vitro

• ND-654 improves overall survival and the efficacy of sorafenib in the DEN rat model

• Our results therefore provide further evidence that de novo fatty acid synthesis is an important mediator of hepatic carcinogenesis

• Selective inhibition of hepatic ACC is a potential therapeutic strategy for hepatocel-lular carcinoma

a-SMA TIMP1

DEN + ND-654 DEN + SorafenibDEN DEN + Combination

Study Design

OTHERS

COO-

Acetyl CoA Malonyl CoA

BC CT

Acetyl-CoA

Acetyl-CoA

Acetyl-CoA

Malonyl-CoA

Citrate

Very long chain fatty

acids

ACC1

ACC2

Fatty Acids

Fatty Acids

FAO

Pyruvate

Oxaloacetate

Krebs Cycle

ETC NADH

NADH +

FADH2

FAO

MITOCHONDRION

PEROXISOME

Phosphoinositides

Eicosanoids

Sphingolipids

Phosphoglycerides

CELL GROWTH SIGNALING MEMBRANE BIOGENESIS

AMPK

LKB1

CPT1

0.000001 0.0001 0.01 10

5000

10000

15000

cpm

ND-654 (µM)

0.01

0.1

1

10

100

Plasma Liver Muscle Tiss

ue C

once

ntra

tion

(µM

)

0

2

3

6

Vehicle 0.3 3 30

mg/kg

1

5

4

Mal

onyl

-CoA

(n

mol

/g ti

ssue

)

0

4

5

Vehicle 0.3 3 30

mg/kg

1

2

3

Mal

onyl

-CoA

(n

mol

/g ti

ssue

)

012345

9

Live

r Wei

ght

(% B

ody)

PBS DEN DEN +ND-654

0

10

15

20

25

Tum

or N

odul

es

PBS DEN DEN +ND-654

5

#

*678#

**

PBS DEN DEN + ND-654

PCNA

Actin

DEN DEN + ND-654

Tumor

PBS DEN DEN + ND-654

Liver

PCNA

Actin

DEN DEN + ND654

H&

EPC

NA

Cle

aved

C

aspa

se-3

ND-65410 mg/kg qd po

50mg/kg DEN

13 18

50mg/kg DEN

Weeks 0 8

Cirrhosis HCC

50mg/kg DEN

Fibrosis

Vehicle qd po

ND-65430 mg/kg qd po

0

10

20

30

40

50

60

70

80

90

100

90 95 100 105 110 115 120 125 130 135 140 145 150 155

Perc

ent S

urvi

val

Time (Days)

Vehicle

ND-654 10

ND-654 30

Vehicle/

DEN ND-654

10 mg/kgND-654

30 mg/kg

MEDIAN SURVIVAL 114 days 126 days 129 days

P VALUE 0.02 0.009

#

DEN +ND-654

#

#

#

**

#

ND-65410 mg/kg qd po

Control (PBS)

13 18

Sacrifice

50mg/kg DEN

Weeks 0 8Cirrhosis HCC

50mg/kg DEN

X

Fibrosis

0

100

200

300

400

500

600

Bod

y W

eigh

t (g)

PBS DEN

0

20

40

60

80

100

140

ALT

(IU

/L)

PBS DEN DEN +ND-654

0

100

150

200

250

300

350

AST

(IU

/L)

PBS DEN DEN +ND-654

120

50

0

1.52

2.53

3.5

4.5

Alb

(g/d

L)

PBS DEN DEN +ND-654

4

1.5

0

0.2

0.3

0.4

0.5

0.6

0.7Sp

leen

Wei

ght

(% B

ody)

PBS DEN DEN +ND-654

0.1

0

1

2

3

4

5

6

TBIL

(mg/

dL)

PBS DEN DEN +ND-654

020406080

100

160

TG (m

g/dL

)

PBS DEN DEN +ND-654

120140

#

** *

DEN DEN +ND-654

DEN +Sorafenib

DEN +Combination

#

*

DEN DEN +ND-654

DEN +Sorafenib

DEN +Combination

0

5

25

Tum

or N

odul

es

0

400

500

600

700

Tota

l Bod

y W

eigh

t (g)

300 10

15

20

200

100

0

0.40

0.80

1.20

RQ

TKL4.1Control

10 µMND-654

30 µMND-654

0

0.40

0.80

1.20

RQ

TKL4.1Control

10 µMND-654

30 µMND-654

0

0.00005

0.0001

0.0003

PBS DEN DEN + 10ND-654

DEN+ 30ND-654

mg/kg

0.0002

0.00025

0.00015

0

0.00005

0.0001

0.0003

PBS DEN DEN + 10ND-654

DEN+ 30ND-654

mg/kg

0.0002

0.00025

0.00015

0

0.00040.0005

0.0009

PBS DEN DEN + 10ND-654

DEN+ 30ND-654

mg/kg

0.00070.0008

0.0006

0.00010.00020.0003

*

*

**

* *

Gen

e Ex

pres

sion

(AU

)

Gen

e Ex

pres

sion

(AU

)

Gen

e Ex

pres

sion

(AU

)