Société Médicale des Hôpitaux de Paris Le diabète quels enjeux ? 14 janvier 2011

DIABETE DE TYPE 2 NOUVELLES PISTES THÉRAPEUTIQUES

Alain Ktorza Institut de Recherches Servier (IdRS) THE AIMS OF TREATMENT OF TYPE 2 DIABETES

To prevent early death and improve quality of life

To prevent micro- and macro vascular complications

•Lipid profile •Cardiovascular Optimal glycemic control function •Atherogenesi s CURRENT ORAL AGENTS USED IN THE TREATMENT OF TYPE 2 DIABETES

THIAZOLIDINEDIONES SULFONYLUREAS INSULIN GLINIDES

Pancreas INCRETINES (GLP-1)

 Gut

White adipose  tissue METFORMIN

Muscle Liver ACARBOSE

6/7 different approaches. No one prevents the progressive deterioration of glycemic control FUNCTIONAL  CELL MASS AND TYPE 2 DIABETES Decrease in  cell mass in type 2 diabetic patients 40-60% Reduction compared to non diabetic patients Maclean, Ogilvie – 1955, Westermark, Wilander – 1978, Saito, et al, 1978,,,pp,1979, Klöppel, et al – 1985,,, Butler, et al – 2003,,, Yoon, et al – 2003, Deng et al - 2004 …

Functionnal  cell mass

Insulin synthesis Number of cells Insulin secretion Volume of cells

DihfilDecrease in the functional  cell mass

Progressive damage of glycemic control in type 2 diabetic patients POSSIBLE MECANISM OF  CELL FAILURE IN TYPE 2 DIABETES

Insulin resistance (b(obesit y, overf eedi ng, ph ysi cal li inacti tiitvity, geneti tifc fact ors?)

N O -cell overstimulation Primary factors of R -cell stress dysfunction (genetic) M O H G Compensatory increase of Y L functional  cell mass P Y E C R « Robust »  cell « Susceptible »  cell A G E L M Permanent sustained Intolerance to glucose Y I compensation Early T2D C A A E SdftfdftiSecondary factors of dysfunction  cell f ail ure M (metabolic environment) overt and late T2D I A POSSIBLE MECANISM OF  CELL FAILURE IN TYPE 2 DIABETES

Insulin resistance (b(obesit y, overf eedi ng, ph ysi cal li inacti tiitvity, geneti tifc fact ors?)

N O -cell overstimulation Primary factors of R -cell stress dysfunction (genetic) M O H G Compensatory increase of Y L functional  cell mass P Y E C R « Robust »  cell « Susceptible »  cell A G E L M Permanent sustained Intolerance to glucose Y I compensation Early T2D C A A E SdftfdftiSecondary factors of dysfunction  cell f ail ure M metabolic environment) overt and late T2D I A TOWARDS NEW TREATMENTS FOR TYPE 2 DIABETES: GENERAL STRATEGY To meet the uncovered medical needs…

Preventing macrovascular Preventing the progressive complications of diabetes deterioration of glycemic control

Lipid profile Vascular endothelial cells Maintining and/or restoring Cardiac function the functional -cell mass Improving -cell metabolic environment (gluco-lipo toxicity) Targeting the intra- islet mechanism of -cell function and Re duc ing i nfl ammati on, survival Oxidative and ER stress ? ? Preclinic ? APG-101.10 ARRY-403 ? Phase I AZD-6714

TTP-399 AMG-108 PSN-010 AZD-1656 PPAR  partial Adamed IL-1bQb LY-2189102 Phase II ZYH2 gevokizumab DSP-8658 chiglitazar SLV-342 SirT1 activator SLV-341 GFT-505 indeglitaza DB-959 arhalofenate Phase III MBX-2044 SirT2 activator AMG-131 balaglitazone aleglitazar SRT-2379 resveratrol, Sirtris lobeglitazone Phase IV 2245840 ZYH1 Alogliptin+ SRT-1720 pioglitazone DSP-3235 Ro-4998452 BI 44847 BI-10773 ASP-1941 dapagliflozin Exnatide ISIS-388626 TS-071 LX-4211 canagliflozinTramiprosate once weekly Remogliflozin RG7201 dapagliflozin/metformin XR etabonate albiglutide Saxagliptin+ lixisenatide dulaglutide TTP-054 metformin exendin conjugate taspoglutide linagliptin ARI-2651 ZP-2929 ROSE-010 LY-2428757 SK-0403 dutogliptin Legend CNTO-736 exenatide teneligliptin ADX-4 series semaglutide IL-1  TAK-875 gemigliptin GLP-1, Modigene SIRT-1 MBX-2982 GLP-1 analogue, Sanwa GSK-1292263 GKA AMG-222 KRP-104 nuclear receptor CAM-2036 ARI-2255 PSN-821 SYR-472 modulator APD-597 melogliptin GLP-1 RO-5312776

DPP-IV GPR40 agonists, Piramal ARI-2243 ? GPR-119 agonist, Biovitrum DSP-7238 G protein DA-1229 retagliptin XL-475 MBX-2982 follow-up xenatide-4, Oramed SGLT CNX-011 ? PSN-IV/119-1 RBx-0597 RO-5429374 ZP-2929 antidiabetics diabetes therapeutics Preclinic eprodisate prodrug CPG-23DIAB diabetes NAM, PFX-1 SMRT antisense ther metabolic disorder ther Phase I Enz-58 BMS-820132 RBP4 antisense ther RO-5095932 FPT-038 ASP-5034 THR-1474 transthyretin antisense ther LY-2405319 Legend BI-135585 ? LY-2393910 antidiabetic therapy ? AP-1170 OAP-189 Phase II A-1 polyphenols PF-04991532 SLV-337 PF-04937319 CDM-1101 LY-2409021 Kinase MKG-02 LY-2608204 PF-04971729 CNTO-3649 INGAP peptide antidiabetics KDT-500 MK-3102 RO-5027838 imeglimin Ionic Channel Ghrelin, Alize ASP-5658 BMS-770767 Cannabinoid PF-05161704 BMS-816336 EGT-0001442 Phase III Others RO-5093151 Shengke I Enclomiphene citrate Thymosin 4 AdiStem ? Phase IV Cytokin JTT-654 RG-4929 AMG-221 CNX-010 Phentermine+ Enzyme topiramate LT-ZP001 RG-7234 AZD-4017 Voglibase+ Growth factor BMS-741672 CCX-140 11-HSD1 inhibitor mitiglinide ? afresa Insulin HE-3286 cetilistat Remestemcel-1 linjeta Hormone BLX-1002 GSK-1362885 Diamyd Px-101 bromocriptine unidentifed Bardoxolone methyl MB-7803 TtTagatose FGF-21 MLR-1023 Spherix DM-71 PN-2034 TT223 SLx-4090 THCV, GW MK-0893 GSK-256073 amylin TM-38837 TTP-814PN-2034 MK-3577 BL-6010 R-256918 solabegron CIS-565C ZnT8 agonist ISI-113715 BG-8702 MB-1162 AMPK agonist

Debio-0930 R-481 Histamine H3 A-769662

pyrazolospiroketones “SELECTIVE PPAR MODULATORS“ (SPPARM) PPARs AGONISTS IN TYPE 2 DIABETES THERAPY TZD are very efficient in long-term glycemic control but … Huge limitations

Fluid retention Oedema Adipocyte proliferation

Weight gain Cardio vascular side effects

Osteoporosis

“Selective PPAR Modulator“ (SPPARM) “SELECTIVE PPAR MODULATOR“ (SPPARM)

PPAR full agonist SPPARM non tissue selective Partial agonist tissue elective

 PPAR PPAR

All tissues (1,2,3) Tissue 1 Tissue 2 Tissue 3

Differential activation or repression of genes Tissue selectivity Pharmacological profile different from that of glitazones

Increased benefitial effects/risk ratio Classification of products : Phase III

Origin License name synonym target(s) Comments

Dr Reddy's Rheoscience balaglitazone DRF2593 SPPARM positive phase III results in Jan 2010 (Nordic Bioscience)

Metabolex J&J arhalofenate MBX-102 SPPARM in Phase II Clinical Trial for gout (Hyperuricaemia) confirmed (metaglidasen) JNJ-39659100 in sept 2010; phase II/III completed in Type 2 Diabetes in 2008 and new phase II vs pioglitazone in January 2009 Chong Kun Dang Equispharm lobeglitazone CKD-501 PPAR Phase III since sept 2009 IDR-105

Zydus Cadila ZYH1 PPAR Clinical trials in India

Hoffmann-La Roche aleglitazar R-1439 PPAR Study With Aleglitazar in Patients With a Recent Acute Coronary Syndrome and Type 2 Diabetes Mellitus

Since 2007 : several phase II studie evaluate renal function Classification of products : Phase II

OOgrigin Licen se naaeme syn ony m target(s) Comme nts

Ajinomoto Boehringer Ingelheim BI-44847 BI 44847 SGLT2 inhibitor web site company

Plexxikon indeglitazar PLX-204 PPAR web site company PPM-204 pan agonist activity

Shenz hen chig litazar CS-0038 PPAR piliipeline Chipscreen CS038 pan agonist activity Biosciences Genfit GFT-505 GFT505 alpha specific PPAR 2nd phase II announced in sept 2010 pan agonist

Metabolex J&J MBX-2044 (back- SPPARM phase II in Type 2 Diabetes completed but absent from up/follow on) pipeline

Amgen InteKrin Therapeutics AMG-131 INT-131 SPPARM clinical data of phase IIb presented at ADA2010 POTENTIAL INTESTINAL DRUG TARGETS LINKED TO THE BENEFICIAL EFFECTS OF BARIATRIC SURGERY BARIATRIC SURGERY-MEDIATED EFFECTS ON SIGNALING MOLECULES

Increased delivery of food to the distal ileum and colon results in

• Increased GLP-1 (insulin secretion, beta cell survival, inhibition of gastric emptying , others) • Increased PYY (inhibition of gastric emptying, reduced appetite) • increased Adiponectin (glucose utilization and FFA oxidation) • Increased Bile-acid pool size (GLP -1 and insulin secretion, energy expenditure, others) • Decreased fasting insulin (glucose uptake, inhibition of gggluconeogenesis and lip py)olysis) • Decreased Ghrelin (stimulates GH secretion, hunger, gastric emptying) • Changes intestinal microbioata composition TGR5 ACTIVATORS BILE ACID-TGR5 OVERVIEW

Detergent-based amphipathic properties

• Solubilisation & absorption of dietary fat & lipid-soluble vitamins

• Cholesterol homeostasis

• Modulate gene transcription for enzymes & transport proteins Liver sinusoidal endothelial cells, Monocytes & macrophages, Kupffer cells GLP-1 & Insulin ( Anti-inflammatory ) secretion Glucose transport

Islet

Adipocytes

• TGR5 KO mice are more glucose intolerant than wt mice after 8 weeks of HFD. • TGR5 transgenic mice fed a high fat diet have improved glucose tolerance. TGR5 OVERVIEW

G Protein Coupled Receptor Receptor for bile acids and natural products having triterpenoidic Endogenous ligands structure Bile Acids (CDCA) Triterpppenoid compounds NH hTGR5: ~70 kD; 330 aa; no splice 2 (oleanoic acid) variants described)

7 trans-membrane protein coupled to GS protein (cAMP induction)

MditMediates cal licium i iflnflux i itnto enteroendocrine cells Gs COOH

BdtiBroad tissue expressi on Human protein homology vs mouse AC and rat is 82-91% ATP cAMP TGR5 ACTIVATION A THERAPEUTIC TARGET FOR TDM2 DIABETES

 D2 deiodinase T4→T3 Improved SK muscle  Mitochondrial biogenesis  Energy expenditure Insulin sensitivity  BW

Insulin secretion Pancreas  cell function

GLP-1 T2DM improvement Intestinal L cells GLP-1 secretion  BW

(kupffer cells) Macrophages Improved Insulin AntiAnti--inflammatoryinflammatory sensitivity (adipose tissue) TGR 5 AGONISTS

PrePre--clinicalclinical Phase I Phase IIPhase III

Takeda

Kalypsys

GSK March 2010 Terminated in phase 2a (lack of efficacy) Intercept* INT-777 IND projected for Q1 2011

Novartis

Arena

* Triterpenoïd structures ‘INCRETIN’ AGENTS

GLP-1 GLP-1 AND TYPE 2 DIABETES THERAPY

Stimulates the synthesis and secretion of Reduced risk of hypoglycemia Insulin in a glucose-dependent manner

Restoration/preservation of Incr eases th e cell m ass The functional mass

Inhibits glucagon secretion Improves fasting glycemia

•Slowers gastric emptying Decreases weight gain •Decreases appetite BIOLOGICAL EFFECTS OF GLP-1 Metabolism

GLP-1 is very rapidly inactivated by the DiPeptidyl Peptidase-IV (DPP IV) Meal Half--lifelife:1 : 1--22minmin GLP1 active 77--3636 GLP1 99--3636 inactive NNCC

LL--cellscells GLPGLP--11 DPPIV

ØSerine amino-dipeptidase ØPresent on cell membrane (110kDa) and in the plasma (100kDa) ØUbiquituous

DPPDPP--IVIV Hansen et al (Endocrinology 1998) GLP-1 AND TYPE 2 DIABETES : STRATEGIES

1 DPP IV Inhibition

PlProlonged GLP1 incretin effect Endogenous R-GLP1

DPP-IV DPP-IV inhibitor

Inactive GLP1 Vidagliptin, sitagliptin, saxagliptin, Alogliptin GLP-1 AND TYPE 2 DIABETES : STRATEGIES 2 GLP-1R Agonistes

GLP1-R agonists

GLP1 Incretin effect endogenous R-GLP1 Liraglutide Exenatide DPP-IV DPP-IV Inhibitor

GLP1 inactive Classification of products : Phase III

Origin License name synonym target(s)

Boehringer BI-10773 BI 10773 SGLT2 inhibitor Ingelheim Zealand Pharma Sanofi-Aventis lixisenatide AVE-00010 GLP-1 agonist Astellas Kotobuki PharmaceuticalASP-1941 ASP1941 SGLT2 inhibitor Ipsen Hoffmann-La Roche taspoglutide IR BIM 51077 GLP-1 agonist Mitsubishi Tanabe JohnsonTeijin & Johnson canagliflozintaspoglutide SRJNJ-24831754ITM-077 SGLT 2 inhibitor Pharma TA-7284R-1583 Human Genome GSK albiglutide 716155 GLP-1 agonist Bristol-Myers AstraZeneca dapagliflozin BMS-512148 SGLT 2 inhibitor SiSciences Albugon Squibb Syncria

DrEli Reddy'sLilly Rheoscience balaglitazonedulaglutide DRF2593LY-2189265 SPPARMGLP-1 agonist (Nordic Bioscience)

Metabolex J&J arhalofenate MBX-102 SPPARM (metaglidasen) JNJ-39659100 Phenomix Chiesi dutogliptin PHX-1149 DPP-IV inhibitor Forest Laboratories Chong Kun Dang Equispharm lobeglitazone CKD-501 PPAR Mitsubishi Tanabe teneligliptin MP-513IDR-105 DPP-IV inhibitor Pharma

ZydusBoehringer Cadila linagliptinZYH1 BI-1356 DPP-IVPPAR inhibitor Ingelheim Ondero

Hoffmann-LaSanwa Kagaku Roche Kowa SK-0403aleglitazar CWP-0403R-1439 DPP-IVPPAR inhibitor Kenkyusho Choongwae

LG Life Sciences gemigliptin LC-15-0044 DPP-IV inhibitor Launch is expected in 2013 Classification of products : Phase II

Origin License name synonym target(s)

Eli Lilly LY-2428757 GLP-1 agonist

Hanmi exendin HM-11260C GLP-1 agonist conjugate, LAPS-Exendin Hanmi Intarcia Johnson & Johnson exenatide GLP-1 agonist Therapeutics ITCA 650

Novo Nordisk semaglutide NN-9535 GLP-1 agonist

TransTech Pharma TTP-054 GLP-1 agonist

Amgen Servier AMG-222 DPP-IV inhibitor

Glenmark Merck KGaA melogliptin EMD 675992 DPP-IV inhibitor GRC 8200

Kyorin KRP-104 DPP-IV inhibitor

Takeda SYR-472 DPP-IV inhibitor ClassificationClassification of products of products : Phase: Phase I

Origin License name synonym target(s) Origin License name synonym target(s)

Kissei Dainippon Sumitomo DSP-3235 1614235 SGLT2/SGLT1 inhibitor Jiangsu Hengrui retagliptin PEX-168 DPP-IV inhibitor Medicine

Marcadia Biotech Merck & Co MAR-701 GLP-1 agonist Dong-A DA-1229 DPP-IV inhibitor

Arisaph ARI-2243 DPP-IV inhibitor Biocompatibles AstraZeneca CM3.1-AC100 GLP-1 GLP-1 agonist Pharmaceuticals analogue, CellMed Dainippon DSP-7238 DPP-IV inhibitor Novo Nordisk Emisphere Technologies NN-9924 GLP-1 agonist Sumitomo Pharma

Arena Johnson & Johnson APD-597 JNJ-28630355 GPR119 agonist Novo Nordisk NN-9925 GLP-1 agonist

Pfizer PF-4856883 CovX-096 GLP-1 agonist

Zyddildus CadilaZYOG-1ZYOG1 GLP-1 agonist

Oramed exenatide-4, ORMD-0901 GLP-1 agonist Pharmaceuticals Oramed

Altea Amylin exenatide, GLP-1 agonist Eli Lilly transdermal

Dong-A exenatide, Dong-DA-3091 GLP-1 agonist A

Marina Biotech Amylin exenatide, nasal GLP-1 agonist spray

Peptron NeoPharm exenatide SR, exenatide SR, GLP-1 agonist Peptron Neopharm PT-302 Versartis exenatide, exenatide-XTENGLP-1 agonist VRS-859 Classification of products : Preclinical Origin Name Target Origin Name Target SGLT2 ihibiinhibitor

Addex ADX-4 series GLP‐1 agonist

Johnson & Johnson CNTO-736 GLP‐1 agonist

Prolor Biotech GLP-1, Modigene GLP‐1 agonist

Sanwa Kagaku Kenkyusho GLP-1 analogue, Sanwa GLP‐1 agonist

Arisaph Pharmaceuticals ARI-2255 GLP‐1 agonist

Arisaph Pharmaceuticals ARI-2651 GLP‐1 agonist

Camurus CAM-2036 GLP‐1 agonist

Zealand Pharmaceuticals ZP-2929 GLP‐1 agonist

Astellas ASP-8497 DPP ‐IV inhibitor

Astellas PSN-IV/119-1 DPP ‐IV inhibitor GPR‐119 agonist Daiichi Sankyo RBx-0597 DPP ‐IV inhibitor GPR 119 LIGANDS GPR119 BIOLOGY

G Protein Coupled Receptor

7 trans-membrane protein Endogenous ligands coupled to GS protein (37 kD Oleyy()lethanolamide (OEA) for h uman prot ei n, 335 AA) Lysophosphatidyl choline (LPC)

NH2 Endovanilloids compounds Gene localized in Xp26.1

Human protein homology vs rat and mouse is about 80%

G s  COO H

AC ATP AMPc GPR119 MECHANISMS OF ACTION AND EXPECTED PHARMACOLOGICAL EFFECTS

Pancreatic  cells insulin secretion Glycemia Gluco-dependent GLP-1R

GPR119  cell  cell mass fuuctonction

GPR119 Diabetes agonist improvement

GPR119 GLP-1 gastric Food Body secretion emptying intake weight

Intestinal L cells

HA Overton, BJP, 2008 Classification of products : Phase II

Astellas PSN-821 GPR-119 agonist

GlaxoSmithKline GSK-1292263 GPR-119 agonist

Metabolex Sanofi-Aventis MBX-2982 SAR-260093 GPR-119 agonist

GPR-119 agonist Classification of products : Phase I GKA

GPR119 agonist Arena APD-597 GPR119 agonist JNJ-28630355 Array BioPharmaAmgenGPR-119ARRY-403 agonist AMG 151 GKA

Classification of products : Preclinical

Swedish Orphan Biovitrum GPR-119 agonist, Biovitrum GPR119 agonist

Neurocrine Biosciences GPR119 agonist

Hoffmann-La Roche RO-5312776 GPR-119 agonist

Hoffmann-La Roche RO-5429374 GPR-119 agonist

Metabolex MBX-2982 follow-ups, GPR-119 agonist

LG Life S ci ences GPR119 agon is t GLUCOKINASE (GK) ACTIVATORS Role of GK in glucose-induced insulin secretion “Glucose Sensor” of the ß-cell

K+ Glucose Ca2+  Sigmoïdal saturation curve

1.00

+ K tivity 0.75

Glucose cc 2+ GK Ca 0.50 G6P + Insulin

sis ATP/ADP

relative a relative 0250.25 lyly KK G

Krebs 0

Glyco ATP cycle 0 5 10 15 20 25 Pyruvate Glucose (mM) Acetyl Pyruvate CoA  Low affinity for glucose (Km > 5mM) mitoch ond ri a  Not inhibited by G6P or other glucose metabolites unlike the other 3 HKs ROLE OF GK IN HEPATIC GLUCOSE METABOLISM

Glucose GLYCOLYSIS Fructose-6P GKRP GK Glucose Fructose-1P PEP G3P Fructose 1,6 -di P Fructose-6 P Glucose-6 P O Phosphofructo kinase Phosphoglucose isomerase X Pyruvate kinase I D pyruvate pyruvate Oxaloacetate A Pyruvate T carboxylase PtPyruvate Glycogen synthase I dehydrogenase . O N Acetyl CoA Citrate Glycogene mitochondria

GLUCOGENOGENESIS GLUCOKINASE ACTIVATORS

Expectations Several diabetic defects potentially corrected Liver Glucose uptake and glycogen synthesis Pancreas Glucose-induced insulin secretion and ß-cell mass Gut GLP-1 secretion

Issues

Glucose dependent insulin secretion (hypoglycemia) Triglyceride accumulation by the liver COMPETITING ENVIRONMENT

PHASE II  R1440/Piragliatin (Roche) – given up in 2007 (hypoglycemia)  TTP-355 (Transtech Pharma) – probably discontinued 06/2009  TTP-399 - 08/2009  AZD 6370, AZD 1656 (Astra Zeneca) – 12/2008, 01/2009  PSN-010 (Eli Lilly) - 06/2009

PHASE I  AZD6714 – 08/2009  ARRY403 (AMG-151) - 04/2009  TAK-329 (Takeda) - 10/2009  TTP-547 - 06/2009  MK-0599 - 09/2009

Many GKAs are in preclinical development AGONISTS OF THE ZINC TRANSPORTER ZnT8 ZNT8: CRITICAL ROLE IN PANCREATIC 

CELLS Glucagon Insulin X + K 2+ Glucose Ca X Zn2+ α-cell

ΔV + K ATP Ca2+ channel channel ATP/ADP Insulin storage (hexamers)

ZnT8 Mature insulin granule Insulin biosynthesis (monomers)

ZnT8

Zn2+

Golgi apparatus RELATIONSHIP BETWEEN ZNT8 AND TYPE 2 DIABETES

• SLC30A8 variant, rs13266634

 2nd locus the most associated with type 2 diabetes in the french population

• World wild association of this locus with diabetes in other ethnic origins

• Relationship between ZnT8 and human -cell function This variant has been found to be associated with decreased  insulin secretion (Steinthorsdottir et al, Nat genet, 2007)  Impaired proinsulin conversion (Kirchhoff et al., Diabetologia, 2008)  Impaired insulin secretion under IVGTT (Boesgaard et al., Diabetologia, 2008)

• ZnT-8 has been described as a major humoral antigen in type-1 diabetes

 Circulating ZnT8 autoantibodies are highly correlated both to disease duration and to the level of c-peptide (Wenzlau et al., PNAS, 2007) IMPROVING BETA CELL FUNCTION AND SURVIVAL GENERAL STRATEGY

Preventing the progressive deterioration of glycemic control

Maintining and/or restoring the functional -cell mass

Improving -cell metabolic environment Targeting the intra- (gluco-lipo toxicity) islet mechanism of -cell function and survival Reducing inflammation, Oxidative and ER stress INTERLEUKIN 1-BETA (IL-) INHIBITORS TYPE 2 DIABETES AND THE PRO‐ INFLAMMATORY CYTOKINE IL‐1

• IL‐1β is the key initiator / mediator of the inflammatory cascade

• Elevated levels of IL‐1β are implicated in the pgypathology of both insulin resistance and impaired insulin secretion – Adipose tissue expression of IL‐1β and IL‐1β mediated cytokines (IL‐6, TNFα) is up‐regulated in obesity – Pancreatic islet cell expression of IL‐1β and IL‐1β mediated cytokines (IL‐8, MCP‐1) is up‐regulated in Type 2 Diabetes IL-1 LIGAND-RECEPTOR BINDING AND SIGNALING STRATEGIES FOR INHIBITION

Signaling 1 IL-1 2 IL-1β signaling occurs when IL-1β binds to an IL-1 Receptor IL-1R1 Recep tor IL-1 cell surface receptor (IL-1R, type I) Accessory Type I and forms a ternary Protein (AcP) (IL-1 RI) complex with the receptor’s

accessory protein (IL-1RAcP)

Chemokines Increased Pro-inflammatory expression of molecules Transduction Inhibition of signaling IL-1 antibody

IL-1Ra1 Ra INHIBITION OF IL-1 DISEASE MODIFYING POTENTIAL IN TYPE 2 DIABETES

Excess levels of IL‐1β have been shown to be directly involved in beta cell dysfunction and apoptosis

Inhibition of IL‐1β has shown disease modifying potential in T2D, improving: – beta cell survival and proliferation insulin secretion (in both animal models and human trials) – insulin resistance and lipid profile (in animal models) – glycemic control (in both animal models and human trials)

The efficacy on long‐term glycemic control and the amount of effects on HbA1c needs further investigations Classification of products : Phase II

Origin License name synonym target(s)

Eli Lilly LY-2189102 Interleukin 1b antagonist Interleukin 1 Cytos IL-1bQb CYT-013- Interleukin 1b Biotechnology IL1bQb antagonist Xoma gevokizumab Interleukin 1b XOMA-052 antagonist Amgen AMG-108 Interleukin 1 receptor anti-IL-1 Mab antagonist Classification of products : Phase I

OiOrigi n Name TtTarget Merck & Co GKA

Addex Interleukin 1 receptor antagonist

Allostera APG-101.10 Interleukin 1 receptor antagonist INHIBITORS OF THIOREDOXIN-INTERACTING PROTEIN (TxNIP) POSSIBLE MECHANISM OF DEFECTS IN CELLS SUBMITTED TO A METABOLIC STRESS

Hyperglycemia Hyperlipidemia Pancreatic  cells

ROS production +++ Stress activated transcription factors Oxidative stress (NFB, JNK/SAPK…) ER stress Superoxide dismutase Catalase Pro-inflammatory cytokines Gluthatione peroxidase Thiored oxi n (TRX) PKC activation Caspase activation

cell dysfunction cell apoptosis

Decreased  cell function and survival TXNIP: CRITICAL ROLE IN STRESS DISORDERS IN  CELLS Glucose

Proinflammatory cytokines Free fatty acids

H2O2

Antioxidant system Oxidative stress X Thiored oxi n

Mitochondrial membrane ER stress integrity TxNIP

 cell dysfunction MondoA ChREBP & apoptosis

functional  cell mass Glucose TXNIP : AN ATTRACTIVE THERAPEUTIC TARGET FOR TYPE 2 DIABETES

 Hepatic glucose Liver output

SK muscle  Glucose uptake

 TxNIP   cell function T2DM Pancreas activity and survival improvement

Adipose  Glucose uptake Potential  diabetes-related Vascular ECs vascular complications

Potential  diabetes-related renal complications

Kidney ? CONCLUSION

Stoppi ng th e d et eri orati on of gl ycemi c cont rol an d preven ting cardiovascular diseases related to type 2 diabetes are the most important challenges for new therapeutic approches for type 2 diabetes

Needs for a better understanding of the complex interplay between insulin resistance, altered lipid profile and  cell failure (alteration of the  cell micro and macro- environment)

A better understanding of the pathophysiology of type 2 diabetes is needed more than ever TxNIP over-expression induces  cell death by apoptosis In vitro

control TxNIP over-expression %) (( cells  ic tt Apopop control TNIPTxNIP over-expression dd (%) 3 activate %) ax / Bcl2 (( BB Caspase control TxNIP control TxNIP over-expression over-expression

Minn et coll., Endocrinol., 2005 TxNIP down-regulation increases functional  cell mass In vitro

Improvement of  cell function Protection against apoptosis

0.06 * Glucose (mM) 11,1 27,8 11,1 27,8 0.05 tion tion tein) ee oo 0040.04 AtitdCActivated Casp. 3 0.03 0.02 Casp.3 total ol/mg pr sulin secr mm

nn 0010.01 I (p Control siRNA TxNIP 0 2

n) tt 1.6

1.2 * U) mentation lin conten /mg protei AA

080.8 gg ( uu

Ins 0.4 (pmol DNA fra DNA 0 Glucose - + siRNA 11 mM TxNIP Glucose (mM) 11,1 27,8 11,1 27,8 Glucose 22 mM Control siRNA TxNIP TxNIP deficiency induces an increase in  cell mass IiIn vivo

normal mice Increase of  cell mass mutant mice Normal mice Mutant mice (mg) ancreas) ell mass n content ii pp cc  (µg/ Insul

Protection versus a streptozotocin-induced diabetes

Diabetic mice Mutant mice treated Glycemia 18 days with STZ post-STZ

Diabetic Mutant mice mice treated with STZ Hyperglycemia induces TxNIP up-regulation in pancreatic islets In vivo / in vitro Psammomys obesus

iiin vivo in vitro Non T2DM diabetic Glucose Glucose 4 days 2 weeks 3 weeks 3,3 mM 22,2 mM TxNIP TxNIP

Trx Thioredoxin

INS-1E cell line

2 days 5 days Glucose concentration 2,7 11,1 22,2 2,7 11,1 22,2 mM mM mM mM mM mM TxNIP

Thioredoxin TXNIP LINKS OXIDATIVE STRESS TO INFLAMMASOME ACTIVATION AND PANCREATIC --CELLCELL FAILURE IN T2T2DD ZHOU ET AL., NAT. IMMUNOL., FEVR 2010

 Prolonged hyperglycemia increases ROS, which triggers TXNIP‐dependent activation of the NLRPNLRP33inflammasome and secretion of IL ‐1

 Elevated IL ‐1 causes ‐cell death and dysfunction, exacerbating chronic hyperglycemiahyperglycemia..