Endpoints 28-day rat DIO study high sucrose diet with 4w diet run-in 14-day rat DIO study high fat diet with 4w diet run-in Body weight i i Food intake — — Hepatic triglycerides i i Hepatic cholesterol — i Insulin Sensitivity (oGTT) h h Plasma leptin i i Plasma triglycerides i — Plasma free fatty acids i nd Plasma cholesterol i — Plasma ketone bodies h nd Plasma insulin — i Plasma glucose — — ACC1 ACC2 Mitochondrion Acetyl- CoA Fatty acid synthesis Fatty acid oxidation Malonyl -CoA Malonyl -CoA ACC Inhibitor ACC inhibitor leads to: Fatty acid synthesis Tissue triglycerides Body fat and weight Fatty acid oxidation Insulin sensitivity OTHERS COO - Acetyl CoA Malonyl CoA BC CT 0.001 0.01 0.1 1 10 0 10000 20000 30000 40000 ND-630 CP-640186 (3μM) cpm ND-630 (μM) 0.001 0.01 0.1 1 10 Plasma Liver Muscle Cmax (μM) 0 1 2 3 Triglycerides (mg/g Tissue) 0 1 2 Lean DIO 3 10 30 Triglycerides (mg/g Tissue) ND-630 (mg/kg) Vehicle Lean DIO 3 10 30 ND-630 (mg/kg) Vehicle p < 0.01 vs. vehicle ** ** 0 10 20 30 40 Vehicle 0.5 1.5 5 BID (mg/kg) Triglycerides (mg/g) * *** *** 0 5 10 15 Insulin (ng/mL) Lean DIO 3 10 30 ND-630 (mg/kg) Vehicle 0 100 200 300 400 500 600 700 800 Fatty Acid Lean DIO 3 10 30 ND-630 (mg/kg) Vehicle 0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 100 120 Plasma Cholesterol (mg/dL) Lean DIO 3 10 30 ND-630 (mg/kg) Vehicle Lean DIO 3 10 30 ND-630 (mg/kg) Vehicle Plasma Triglycerides (mg/dL) 0 1 2 3 4 5 6 7 8 9 10 Plasma Leptin (ng/mL) Lean DIO 3 10 30 ND-630 (mg/kg) Vehicle 25 30 35 40 45 50 55 60 Body Weight Gain (%) Vehicle 3 10 30 mg/kg 330 340 350 360 370 380 390 400 1 3 5 7 9 11 13 15 17 19 21 23 25 27 0 20 40 60 80 100 120 140 2 4 6 8 10 12 14 16 18 20 23 25 27 Body Weight (g) Day Food Intake (% of baseline) Vehicle 3 mg/kg 10 mg/kg 30 mg/kg Vehicle 3 mg/kg 10 mg/kg 30 mg/kg Day 0 10 20 30 40 50 60 Vehicle 0.03 0.1 0.3 1 3 0 1 2 3 Vehicle 0.3 3 30 0 1 2 3 4 5 6 Vehicle 0.3 3 30 Malonyl-CoA (nmol/g Tissue) mg/kg mg/kg mg/kg Malonyl-CoA (nmol/g Tissue) DPMs/mg Tissue 0.7 0.8 0.9 1 1.1 1.2 -60 0 60 120 180 240 RQ Time (min) Vehicle 3 mg/kg 10 mg/kg 30 mg/kg ABSTRACT CONCLUSIONS 1. Acetyl CoA Carboxylase (ACC): Master Regulator of Fatty Acid Synthesis & Oxidation 2. Nimbus Solves ACC Druggability Challenge by Targeting Allosteric Site in BC Domain 3. ND-630: Hepatotropic ACC Inhibitor for NASH/Metabolic Disease 4. ACC1/2 Allosteric Inhibitor ND-630 Favorably Modulates Key Metabolic Parameters In Vivo 5. Data Summary of ND-630 in High Fat and High Sucrose DIO Rat Studies 6. Weight Neutral Profile; Well Tolerated. Reduction in Weight Gain at High Dose 7. ND-630 Favorably Modulates Key Metabolic Parameters In Vivo 8. Liver Triglycerides Lowered Across14-Day DIO and ZDF Studies 28-day Rat DIO Study High Sucrose Diet with 4w Diet Run-in 28-day Rat DIO Study High Sucrose Diet with 4w Diet Run-in A B C D ND-630, a Potent and Liver-Directed Acetyl-CoA Carboxylase Inhibitor, Reduces Hepatic Steatosis and Improves Dyslipidemia in Diet-Induced Obese and Diabetic Rat Models of Non-Alcoholic Fatty Liver Disease Geraldine Harriman, Jeremy Greenwood*, Sathesh Bhat*, William F. Westlin, Rosana Kapeller, and H. James Harwood Jr. Nimbus Therapeutics, Cambridge MA and Schrodinger*, New York NY (USA) 25 First St #404, Cambridge, MA 02141, USA • www.nimbustx.com • Tel: 857.999.2009 • [email protected] Simultaneous inhibition of the acetyl-CoA carboxylase isozymes, ACC1 and ACC2, results in concomitant inhibition of fatty acid synthesis (FASyn) and stimulation of fatty acid oxidation (FAOxn) and may favor- ably affect fatty liver diseases such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Using state-of-the- art structure-based drug design technologies and crystal structures of human ACC biotin carboxylase (BC) domain, we identified a unique se- ries of allosteric inhibitors that binds to the BC domain of the enzyme to prevent dimerization and inhibit enzymatic activity, distributes pref- erentially to the liver (the pharmacologic target organ), and exhibits functional activity in cultured cells and acute and chronic in vivo effica- cy in experimental animals. The representative series analog, ND-630, inhibited human ACC1 & ACC2 (IC 50 2.0-7.0 nM), inhibited HepG2 cell FASyn (EC 50 66nM), stimulated C2C12 muscle cell FAOxn (2-fold at 200nM), distributed preferentially to the liver (135:10:1 liver:plas- ma:skeletal muscle at T max ), inhibited rat liver FASyn (ED 50 0.14mg/kg), and stimulated rat whole body FAOxn (MED 3mg/kg). When admin- istered chronically by once-daily oral gavage, ND-630 demonstrated dramatic and dose-dependent reductions in hepatic steatosis in high- fat diet-induced obese (DIO) rats, high-sucrose DIO rats, and Zucker diabetic fatty (ZDF) rats. When evaluated chronically in high-sucrose DIO rats, ND-630 also markedly and dose-dependently reduced plas- ma triglycerides, free fatty acids, and cholesterol. These observations suggest that ND-630 and related analogs may favorably affect the he- patic steatosis, dyslipidemia, and sequalae of fatty liver diseases such as NAFLD and NASH. • ND-630 is a potent ACC1/2 inhibitor with good drug-like properties • It is well tolerated and effective in three models of hepatic steatosis and dyslipidemia • ND-630 was also effective at modulating several parameters of met- abolic syndrome • ND-630, designed to have hepatoselective bio-distribution, was shown to reduce hepatic steatosis and improve dyslipidemia in DIO and ZDF diabetic rat models of non-alcoholic fatty liver disease • Beneficial effects on lipids, insulin sensitivity, weight, and potentially diabetes and CV risk • Nimbus: first small molecule allosteric inhibitor successfully targeting BC domain ND-630 was evaluated in three rat models of target engagement. (A,B) ND-630 shows a dose de- pendent reduction in the formation of the enzymatic product of acetyl coA carboxylase, malonyl coA. This reduction occurs in both the liver and muscle tissues. In alignment with the hepatoselec- tive nature of the bio-distribution of ND-630, the ED 50 in muscle proved to be lower. (C,D) ND-630 demonstrates its effectiveness at inhibiting the production of fatty acids in the liver (C, ED 50 = 0.14 mg/kg) and modulating respiratory quotient (D, MED = 3 mg/kg). • 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 1. Novel class of ACC inhibitors 2. Prototype for modulating protein-protein interactions Nimbus inhibitors prevent ACC dimerization ND-630 binds to the same site as Soraphen A Nimbus Breakthrough Challenges in Drugging ACC Target potency • ACC1 IC 50 = 2 nM • ACC2 IC 50 = 7 nM • HepG2 EC 50 = 9 nM (serum free) = 66 nM (10% serum) • C2C12 FAOxn stim. = 2x @ 200 nM Pharmacology • Rat FASyn ED 50 = 0.14 mpk PO • Rat RQ MED = 3 mpk PO • Rat Malonyl-CoA ED 50 = 0.8 mg/kg (liver) • Rat Malonyl-CoA ED 50 = 3 mg/kg (muscle) ADME • Low multispecies intrinsic clearance (human, mouse, rat, dog, monkey) • Eliminated predominantly as parent • P450 inhib >50 μM • Protein binding (98%) Toxicology • GLP toxicology supports clinical development ND-630 Hep-G2 Cell FASyn Inhibition [ 14 C]acetate incorporation into FA Exposure at 3 mg/Kg PO MC in Saline • Nimbus’ allosteric inhibitors show promise for diabetes, metabolic disease, and fatty liver disease • Profound hepatic triglyceride lowering in ZDF study at day 37 • Weight neutral, with weight gain reduction at high dose • No change in food intake • No differences in fed blood glucose • Animals healthy Liver Muscle Decreases Fatty Acid Synthesis Increases Fatty Acid Oxidation During QD Dosing of ND-630 in DIO SD Rats Day 28 Body Weight Gain Daily Change in Mean Food Intake vs Baseline Decreases Free Fatty Acids ... and Plasma Triglycerides Normalizes Plasma Insulin Levels … and Decreases Plasma Cholesterol Reduction in Whole Body Fat Leptin as a Surrogate Marker (Day 20 in Rat DIO Study) Day 14 (High Fat Diet) Day 14 (High Sucrose Diet) Day 37 ZDF Rat Study 14-day Rat DIO Study 28-day Rat DIO Study • Similar changes in liver cholesterol & free fatty acid Data are mean values for n=8 animals per group ± SEM
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Endpoints 28-day rat DIO study high sucrose diet with 4w diet run-in
14-day rat DIO study high fat diet with 4w diet run-in
Body weight i iFood intake — —Hepatic triglycerides i iHepatic cholesterol — iInsulin Sensitivity (oGTT) h hPlasma leptin i iPlasma triglycerides i —Plasma free fatty acids i ndPlasma cholesterol i —Plasma ketone bodies h ndPlasma insulin — iPlasma glucose — —
ACC1 ACC2
Mito
chon
drio
n
Acetyl-CoA
Fatty acid synthesis Fatty acid oxidation
Malonyl-CoA
Malonyl-CoA
ACCInhibitor
ACC inhibitor leads to:
Fatty acid synthesisTissue triglyceridesBody fat and weightFatty acid oxidationInsulin sensitivity
OTHERS
COO-
Acetyl CoA Malonyl CoA
BC CT
0.001 0.01 0.1 1 100
10000
20000
30000
40000 ND-630 CP-640186 (3μM)
cpm
ND-630 (μM)
0.001
0.01
0.1
1
10
Plasma Liver Muscle
Cm
ax (μ
M)
0
1
2
3
Trig
lyce
rides
(m
g/g
Tiss
ue)
0
1
2
Lean DIO 3 10 30Trig
lyce
rides
(m
g/g
Tiss
ue)
ND-630 (mg/kg) Vehicle
Lean DIO 3 10 30
ND-630 (mg/kg) Vehicle
p < 0.01 vs. vehicle
** **0
10
20
30
40
Vehicle 0.5 1.5 5
BID (mg/kg)
Trig
lyce
rides
(m
g/g)
*
******
0
5
10
15
Insu
lin (n
g/m
L)
Lean DIO 3 10 30
ND-630 (mg/kg) Vehicle
0
100
200
300
400
500
600
700
800
Fatt
y A
cid
Lean DIO 3 10 30
ND-630 (mg/kg) Vehicle
020406080
100120140160180
0
20
40
60
80
100
120
Plas
ma
Cho
lest
erol
(mg/
dL)
Lean DIO 3 10 30
ND-630 (mg/kg) Vehicle
Lean DIO 3 10 30
ND-630 (mg/kg) Vehicle
Plas
ma
Trig
lyce
rides
(mg/
dL)
0123456789
10
Plas
ma
Lept
in (n
g/m
L)
Lean DIO 3 10 30
ND-630 (mg/kg) Vehicle
25
30
35
40
45
50
55
60
Bod
y W
eigh
t Gai
n (%
)
Vehicle 3 10 30
mg/kg
330340350360370380390400
1 3 5 7 9 11 13 15 17 19 21 23 25 27
020406080
100120140
2 4 6 8 10 12 14 16 18 20 23 25 27
Bod
y W
eigh
t (g)
Day
Food
Inta
ke
(% o
f bas
elin
e)
Vehicle 3 mg/kg 10 mg/kg 30 mg/kg
Vehicle 3 mg/kg 10 mg/kg 30 mg/kg
Day
0
10
20
30
40
50
60
Vehicle 0.03 0.1 0.3 1 3
0
1
2
3
Vehicle 0.3 3 300
1
2
3
4
5
6
Vehicle 0.3 3 30 Mal
onyl
-CoA
(nm
ol/g
Tis
sue)
mg/kg
mg/kg mg/kg
Mal
onyl
-CoA
(nm
ol/g
Tis
sue)
DPM
s/m
g Ti
ssue
0.7
0.8
0.9
1
1.1
1.2
-60 0 60 120 180 240
RQ
Time (min)
Vehicle 3 mg/kg 10 mg/kg 30 mg/kg
ABSTRACT
CONCLUSIONS
1. Acetyl CoA Carboxylase (ACC): Master Regulator of Fatty Acid Synthesis & Oxidation
2. Nimbus Solves ACC Druggability Challenge by Targeting Allosteric Site in BC Domain
3. ND-630: Hepatotropic ACC Inhibitor for NASH/Metabolic Disease
4. ACC1/2 Allosteric Inhibitor ND-630 Favorably Modulates Key Metabolic Parameters In Vivo
5. Data Summary of ND-630 in High Fat and High Sucrose DIO Rat Studies
6. Weight Neutral Profile; Well Tolerated. Reduction in Weight Gain at High Dose
7. ND-630 Favorably Modulates Key Metabolic Parameters In Vivo
8. Liver Triglycerides Lowered Across14-Day DIO and ZDF Studies
28-day Rat DIO Study High Sucrose Diet with 4w Diet Run-in
28-day Rat DIO Study High Sucrose Diet with 4w Diet Run-in
A B
C D
ND-630, a Potent and Liver-Directed Acetyl-CoA Carboxylase Inhibitor, Reduces Hepatic Steatosis and Improves Dyslipidemia in Diet-Induced Obese and Diabetic Rat Models of Non-Alcoholic Fatty Liver DiseaseGeraldine Harriman, Jeremy Greenwood*, Sathesh Bhat*, William F. Westlin, Rosana Kapeller, and H. James Harwood Jr.Nimbus Therapeutics, Cambridge MA and Schrodinger*, New York NY (USA)
25 First St #404, Cambridge, MA 02141, USA • www.nimbustx.com • Tel: 857.999.2009 • [email protected]
Simultaneous inhibition of the acetyl-CoA carboxylase isozymes, ACC1 and ACC2, results in concomitant inhibition of fatty acid synthesis (FASyn) and stimulation of fatty acid oxidation (FAOxn) and may favor-ably affect fatty liver diseases such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Using state-of-the-art structure-based drug design technologies and crystal structures of human ACC biotin carboxylase (BC) domain, we identified a unique se-ries of allosteric inhibitors that binds to the BC domain of the enzyme to prevent dimerization and inhibit enzymatic activity, distributes pref-erentially to the liver (the pharmacologic target organ), and exhibits functional activity in cultured cells and acute and chronic in vivo effica-cy in experimental animals. The representative series analog, ND-630, inhibited human ACC1 & ACC2 (IC50 2.0-7.0 nM), inhibited HepG2 cell FASyn (EC50 66nM), stimulated C2C12 muscle cell FAOxn (2-fold at 200nM), distributed preferentially to the liver (135:10:1 liver:plas-ma:skeletal muscle at Tmax), inhibited rat liver FASyn (ED50 0.14mg/kg), and stimulated rat whole body FAOxn (MED 3mg/kg). When admin-istered chronically by once-daily oral gavage, ND-630 demonstrated dramatic and dose-dependent reductions in hepatic steatosis in high-fat diet-induced obese (DIO) rats, high-sucrose DIO rats, and Zucker diabetic fatty (ZDF) rats. When evaluated chronically in high-sucrose DIO rats, ND-630 also markedly and dose-dependently reduced plas-ma triglycerides, free fatty acids, and cholesterol. These observations suggest that ND-630 and related analogs may favorably affect the he-patic steatosis, dyslipidemia, and sequalae of fatty liver diseases such as NAFLD and NASH.
• ND-630 is a potent ACC1/2 inhibitor with good drug-like properties
• It is well tolerated and effective in three models of hepatic steatosis and dyslipidemia
• ND-630 was also effective at modulating several parameters of met-abolic syndrome
• ND-630, designed to have hepatoselective bio-distribution, was shown to reduce hepatic steatosis and improve dyslipidemia in DIO and ZDF diabetic rat models of non-alcoholic fatty liver disease
• Beneficial effects on lipids, insulin sensitivity, weight, and potentially diabetes and CV risk• Nimbus: first small molecule allosteric inhibitor successfully targeting BC domain
ND-630 was evaluated in three rat models of target engagement. (A,B) ND-630 shows a dose de-pendent reduction in the formation of the enzymatic product of acetyl coA carboxylase, malonyl coA. This reduction occurs in both the liver and muscle tissues. In alignment with the hepatoselec-tive nature of the bio-distribution of ND-630, the ED50 in muscle proved to be lower. (C,D) ND-630 demonstrates its effectiveness at inhibiting the production of fatty acids in the liver (C, ED50 = 0.14 mg/kg) and modulating respiratory quotient (D, MED = 3 mg/kg).
• 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
1. Novel class of ACC inhibitors
2. Prototype for modulating protein-protein interactions
Nimbus inhibitors prevent ACC dimerization
ND-630 binds to the same site as Soraphen A
Nimbus BreakthroughChallenges in Drugging ACC
Target potency• ACC1 IC50 = 2 nM• ACC2 IC50 = 7 nM• HepG2 EC50 = 9 nM (serum free) = 66 nM (10% serum)• C2C12 FAOxn stim. = 2x @ 200 nM
Pharmacology• Rat FASyn ED50 = 0.14 mpk PO• Rat RQ MED = 3 mpk PO• Rat Malonyl-CoA ED50 = 0.8 mg/kg (liver)• Rat Malonyl-CoA ED50 = 3 mg/kg (muscle)
ADME• Low multispecies intrinsic clearance
(human, mouse, rat, dog, monkey)• Eliminated predominantly as parent• P450 inhib >50 μM• Protein binding (98%)
Toxicology• GLP toxicology supports clinical development
ND-630 Hep-G2 Cell FASyn Inhibition[14C]acetate incorporation into FA
Exposure at 3 mg/KgPO MC in Saline
• Nimbus’ allosteric inhibitors show promise for diabetes, metabolic disease, and fatty liver disease
• Profound hepatic triglyceride lowering in ZDF study at day 37
• Weight neutral, with weight gain reduction at high dose• No change in food intake• No differences in fed blood glucose• Animals healthy
Liver Muscle
Decreases Fatty Acid Synthesis Increases Fatty Acid Oxidation
During QD Dosing of ND-630 in DIO SD Rats Day 28 Body Weight Gain
Daily Change in Mean Food Intake vs Baseline
Decreases Free Fatty Acids ... and Plasma Triglycerides
Normalizes Plasma Insulin Levels … and Decreases Plasma Cholesterol
Reduction in Whole Body Fat Leptin as a Surrogate Marker
(Day 20 in Rat DIO Study)
Day 14 (High Fat Diet) Day 14 (High Sucrose Diet) Day 37ZDF Rat Study14-day Rat DIO Study 28-day Rat DIO Study
• Similar changes in liver cholesterol & free fatty acid
Data are mean values for n=8 animals per group ± SEM
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