pxl770 a novel direct ampk activator improves metabolic

PXL770, a novel direct AMPK activator, improves metabolic disorders - PowerPoint PPT Presentation

PXL770, a novel direct AMPK activator, improves metabolic disorders in a diet-induced mice model of obesity and diabetes Sbastien Bolze 1 ; Sophie Hallakou-Bozec 1 ; Michael Roden 2, 3,4 ; Julien Roux 5 1 Poxel SA Lyon, France 2 Institute for

  1. PXL770, a novel direct AMPK activator, improves metabolic disorders in a diet-induced mice model of obesity and diabetes Sébastien Bolze 1 ; Sophie Hallakou-Bozec 1 ; Michael Roden 2, 3,4 ; Julien Roux 5 1 Poxel SA Lyon, France 2 Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; 3 German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Germany; 4 Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany 5 Biomeostasis SAS Marseille, France

  2. 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 that you have read and agree to comply with the contents of this disclaimer including, without limitation, the obligation to keep this document and its contents confidential. The information and opinions presented herein are based on general information gathered at the time of writing and are therefore subject to change without notice. Poxel S.A. (the “ Company ”) accepts no obligation to update any information contained herein. While the Company has accurately reproduced and sourced such information from publicly-available information that the Company believes to be reliable, the Company has not independently verified such information and cannot guarantee its accuracy. Some of the statements contained in this presentation constitute forward-looking statements. Statements that are not historical facts are forward-looking statements. Forward-looking statements generally can be identified by the use of forward-looking terminology such as “may”, “will”, “expect”, “intend”, “estimate”, “anticipate”, “believe”, “continue” or similar terminology. These statements are based on the Company’s current strategy, plans, objectives, assumptions, estimates and projections. Investors should therefore not place undue reliance on those statements. The Company makes no representation, warranty or prediction that the results anticipated by such forward-looking statements will be achieved, and such forward-looking statements represent, in each case, only one of many possible scenarios and should not be viewed as the most likely or standard scenario. Forward-looking statements speak only as of the date that they are made and the Company does not undertake to update any forward-looking statements in light of new information or future events. Forward-looking statements involve inherent risks and uncertainties. The Company cautions that a number of important factors could cause actual results to differ materially from those contained in any forward-looking statement. This presentation does not constitute an offer or invitation to sell, or any solicitation of any offer to subscribe for or purchase any securities and nothing contained herein shall form the basis of any contract or commitment or investment decision whatsoever. This presentation does not constitute an offering document in relation to any securities. No reliance may be placed for any purposes whatsoever on the information contained in this presentation or on its completeness, accuracy or fairness. No representation or warranty, express or implied, is made as to, and no reliance should be placed on, the fairness, accuracy, adequacy, completeness or correctness of the information or opinions contained herein or any further information supplied. This presentation is not directed to, or intended for distribution to, directly or indirectly, or use by, any person or entity that is a citizen or resident or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would require any registration, licensing or other permission within such jurisdiction. The distribution of this presentation in certain jurisdictions may be restricted by law and, accordingly, recipients of this presentation represent that they are able to receive this presentation without contravention of any unfulfilled registration requirements or other legal restrictions in the jurisdiction in which they reside or conduct business. Nothing in this presentation should be construed as legal, tax, regulatory, accounting or investment advice. You should not rely on any representations or undertakings inconsistent with the above paragraphs. EASD 2016 – OP19 – 113 2

  3. Presenter Disclosure Information ¡ Sébastien Bolze, Pharm D, PhD, is an employee of Poxel SA EASD 2016 – OP19 – 113 3

  4. 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 Prevention of: Thr 172 Thr 172 AMPKK AMP AMP ADP/ATP ATPATP AMPAMP LKB1, CaMKK, TAK1 a AMP/ATP g a a g Diabetes g Cardiovascular PP2a Disease Gluconeogenesis PP2c CBM b b CBM CBM b Glycogen Synthesis Fatty Acid Synthesis AMPK AMPK AMPK Triglyceride Synthesis Allosterically Activated Allosterically Activated Protein Synthesis & Phosphorylated Cell Cycle EASD 2016 – OP19 – 113 4

  5. PXL770, a Novel Agent for Treating Type 2 Diabetes ¡ PXL770 is a direct and potent AMPK activator 1 P Thr 172 AMP AMP } b 1 containing heterotrimers: EC50 ~ 50nM a g } b 2 containing heterotrimers: EC50 ~ 1µM CBM b PXL 770 ¡ PXL770 inhibits de novo lipogenesis in vitro and in vivo in mice 2 ¡ PXL770 improves glycemic control, lipid profile and hepatic steatosis in ob/ob mice 1 ¡ PXL770 is currently in phase I – SAD part completed showing a very good tolerability with no safety signal 1 Poster 081, World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease, 19th–21st November, Los Angeles, CA, USA 2 Poster 724, European Association for the Study of Diabetes, 12th–16th September 2016, Munich, Germany EASD 2016 – OP19 – 113 5

  6. 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 OGTT 4 weeks Organ collection 5 weeks EASD 2016 – OP19 – 113 6

  7. 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) & total energy expenditure 160 from baseline (kcal/min/kg 0,75 )x10 -2 * 140 Mean change TEE AUC 120 100 80 60 40 20 0 Diurnal Period EASD 2016 – OP19 – 113 7

  8. 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: diurnal period Mean ± SEM. * P <0.05, ** P<0.01, vs. HFD control group. $$ P <0.01, $$$ P<0.001 vs. HFD pair-fed group EASD 2016 – OP19 – 113 8

  9. PXL770 Strongly Reduces Fat Mass in HFD Mouse HFD mice – 5-week treatment – White Adipose Tissue Weight Perirenal White Adipose Tissue Weight Epidydimal White Adipose Tissue Weight Chow diet Mean ± SEM. ££ P<0.01, £££ P<0.001 vs. Chow diet group HFD control * P <0.05, ** P<0.01, vs. HFD control group. HFD Pair fed $$ P <0.01, $$$ P<0.001 vs. HFD pair-fed group HFD PXL770 EASD 2016 – OP19 – 113 9

  10. PXL770 Decreases Basal glycemia in HFD Mouse HFD mice – 2 & 5-week treatment – 3h Fasting glycemia 200 ££ 180 ££ ££ ££ £££ ££ £££ ££ $$ Fasting bloo glucose (mg/dl) $$$ 160 * ** Chow diet 140 HFD control 120 HFD Pair fed HFD PXL770 100 80 Mean ± SEM. ££ P<0.01, £££ P<0.001 vs. Chow diet group 60 * P <0.05, ** P<0.01, vs. HFD control group. 40 $$ P <0.01, $$$ P<0.001 vs. HFD pair-fed group 20 0 D56 T0 T15 T35 2-week 5-week § PXL770 induced a significant decrease in basal glycaemia, contrary to the pair-fed animals that remained hyperglycemic throughout the experiment. EASD 2016 – OP19 – 113 10

  11. PXL770 Improves Glucose Tolerance in HFD Mouse While Normalizing AUC Insulin HFD mice – 4-week treatment – OGTT Glucose AUC Glucose OGTT £££ * £££ 400 40000 PXL770 75mg/kg AUC 120 min (mg/dl/min) 350 ££ 35000 -23% vs. control 300 -32% vs. pair-fed Blood glucose (mg/dl) Chow diet $$$ 30000 ** 250 HFD control 25000 200 HFD Pair fed 20000 150 HFD PXL770 15000 100 50 10000 0 5000 -30 0 30 60 90 120 Time (min) 0 Insulin AUC Insulin A OGTT : plasma insulin (pM) 600 500 Plasma insulin (pM) 400 Chow diet 300 HFD control HFD Pair fed 200 HFD PXL770 100 0 0 10 20 30 40 50 60 Time (min) Mean ± SEM. ££ P<0.01, £££ P<0.001 vs. Chow diet group EASD 2016 – OP19 – 113 11 * P <0.05, ** P<0.01, vs. HFD control group. $$ P <0.01, $$$ P<0.001 vs. HFD pair-fed group

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