Slide 1: PXL770, a novel direct AMPK activator, improves metabolic disorders in a diet-induced mice model
PXL770, a novel direct AMPK activator, improves metabolic disorders in a diet-induced mice model of obesity and diabetes Sébastien Bolze1; Sophie Hallakou-Bozec1; Michael Roden2, 3,4 ; Julien Roux5 1Poxel SA Lyon, France 2Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute
Slide 2: Disclaimer
DISCLAIMER IMPORTANT: You must read the following before continuing. By receiving and using this presentation and/or accepting a copy of this document, you agree to be bound by the following limitations and conditions and, in particular, will be taken to have represented, warranted and undertaken th
Slide 3: Presenter Disclosure Information
Presenter Disclosure Information ¡ Sébastien Bolze, Pharm D, PhD, is an employee of Poxel SA 3 EASD 2016 – OP19 – 113
Slide 4: Why Activating AMP Kinase is of Interest for the Management of Metabolic Disorders?
Why Activating AMP Kinase is of Interest for the Management of Metabolic Disorders? Glucose Uptake Glycolysis Fatty Acid Uptake Fatty Acid Oxidation Mitochondria Biogenesis P Treatment and Thr 172 Thr 172 Thr 172 AMPKK AMP AMP Prevention of: ATP ATP ADP/ATP AMPAMP LKB1, CaMKK, TAK1 g a AMP/ATP g a a
Slide 5: PXL770, a Novel Agent for Treating Type 2 Diabetes
PXL770, a Novel Agent for Treating Type 2 Diabetes ¡ PXL770 is a direct and potent AMPK activator1 P Thr 172 AMP AMP } b1 containing heterotrimers: EC50 ~ 50nM a g } b2 containing heterotrimers: EC50 ~ 1µM CBM b PXL 770 ¡ PXL770 inhibits de novo lipogenesis in vitro and in vivo in mice2 ¡ PXL770 imp
Slide 6: PXL770 Effect in a High Fat Diet Fed Mouse Model
PXL770 Effect in a High Fat Diet Fed Mouse Model Study Design SD Standard Diet (SD) ; n=10 HFD HFD (60% Fat) ; n=10 HFD + PXL770 HFD + PXL770 75 mg/kg BID orally ; n=10 HFD Pair-fed HFD pair-fed ; n=10 same daily caloric intake as PXL770 treated mice 10 weeks 5 weeks Indirect calorimetry 3 weeks OGT
Slide 7: Induced a Steady Body Weight Loss Despite Similar Caloric Intake Compared to the Pair-fed Group
PXL770 Induced a Steady Body Weight Loss Despite Similar Caloric Intake Compared to the Pair-fed Group HFD mice – 5 weeks of treatment – Mean daily caloric intake (Kcal) Chow diet HFD control HFD Pair fed HFD PXL770 Days post treatment HFD mice – 5 weeks of treatment – Mean body weight gain (g) & to
Slide 8: PXL770 Decreases Respiratory Exchange Ratio With an Increase in Fat oxidation in HFD Mice
PXL770 Decreases Respiratory Exchange Ratio With an Increase in Fat oxidation in HFD Mice HFD mice – 3 weeks of treatment – indirect Calorimetry Respiratory Exchange Ratio Fat Oxidation Carbohydrate Oxidation Chow diet HFD Pair fed HFD control HFD PXL770 WD: whole day; NP: nocturnal period; DP: diur
Slide 9: PXL770 Strongly Reduces Fat Mass in HFD Mouse
PXL770 Strongly Reduces Fat Mass in HFD Mouse HFD mice – 5-week treatment – White Adipose Tissue Weight Epidydimal White Adipose Tissue Weight Perirenal White Adipose Tissue Weight Chow diet Mean ± SEM. HFD control ££ P<0.01, £££ P<0.001 vs. Chow diet group * P<0.05, ** P<0.01, vs. HFD control group
Slide 10: PXL770 Decreases Basal glycemia in HFD Mouse
PXL770 Decreases Basal glycemia in HFD Mouse HFD mice – 2 & 5-week treatment – 3h Fasting glycemia 3h-fasting blood glucose (mg/dl) 200 ££ 180 ££ ££ ££ £££ ££ ££ £££ $$ $ Fasting bloo glucose (mg/dl) 160 ** * NC-fed group Chow diet 140 HFD control 120 Veh s.c.HFD Pair fed HFD PXL770 100 80 Pair-fe
Slide 11: PXL770 Improves Glucose Tolerance in HFD Mouse While Normalizing AUC Insulin
PXL770 Improves Glucose Tolerance in HFD Mouse While Normalizing AUC Insulin HFD mice – 4-week treatment – OGTT A B OGTT AUC 120min A 400 Glucose B AUC 120min AUC Glucose 45000 OGTT £££ 400 45000 * £££ 350 40000 £££ * PXL770 75mg/kg 40000 AUC 120 min (mg/dl/min) 350 35000 ££ -23% vs. control AUC 120
Slide 12: Conclusion
Conclusion In a model of diabetes and obesity: ¡ PXL770 induces a weight loss ¡ PXL770 increases energy expenditure and fat oxidation leading to a decrease in fat mass ¡ PXL770 decreases basal glycemia and improves glucose tolerance These results } have been consistently observed in different animal
Slide 13: Thank you
Head Office: 259/261 avenue Jean Jaurès 69007 Lyon France Tel: +33 4 37 37 20 10 Fax: +33 4 37 70 88 15 Thank you contact@poxelpharma.com 13 EASD 2016 – OP19 – 113