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  • 1. New Agents and Technologies in thePipeline for the Treatment of Patients withDiabetesPeter Stein, MDJanssen Research and Development
  • 2. Agents in Phase 3 Development for T2DM• Long-acting GLP-1 analogues – including once-weeklyexenatide, albiglutide, dulaglutide• SGLT2 inhibitors - includingcanagliflozin, dapagliflozin, empagliflozin• GPR40 agonists - TAK875• Dual PPAR α/γ agents: aleglitazar (Phase 3 studies for post-MIuse)• Insulins– Inhaled - Afrezza®– Long-acting – Insulin degludec; LY2605541 (Lilly)2
  • 3. AHAs Sites of Action3Glucose reabsorptionKidneySGLT2 inhibitorsSU, meglitinides DPP-4GLP-1 agents+GLP-1DPP-4↓ Glucagon
  • 4. Sodium-glucose Transporter-2 (SGLT2): Key Renal TransporterReabsorbing Filtered Glucose Back into Systemic CirculationGlucoseReabsorbed toSystemicCirculationNo Glucosein UrineProximalConvoluted TubuleDistalConvoluted TubuleCollectingDuctGlomerulusSGLT1SGLT2Loop of HenleGlucose isFiltered in theGlomerulusSGLT2• Primarily expressed inkidney• Responsible for majority ofrenal glucose reabsorptionSGLT1• Responsible for smallportion of renal glucosereabsorption• Prominent role in intestinalglucose absorptionFDA Advisory Committee Sponsor Slide Presentation 10Jan2013
  • 5. SGLT2 Inhibition Leads to Improved Glucose Control inT2DMSGLT2inhibitionLessGlucoseAbsorbedGlucosuriaProximalConvoluted TubuleDistalConvoluted TubuleCollectingDuctGlomerulusGlucose isFiltered in theGlomerulusSGLT1SGLT2Loop of HenleX• Inhibition of SGLT2increases urinary glucoseexcretion (UGE)• Directly reduces plasmaglucose concentrations• Increased UGE is loss ofcalories (4 kcal per gram ofcarbohydrate)FDA Advisory Committee Sponsor Slide Presentation 10Jan2013
  • 6. Dapagliflozin: Comparator Study to Glipizide inAdd-on to Metformin6Nauck et al Diabetes Care 2011
  • 7. Dapagliflozin: Comparator Study to Glipizide in Add-onto Metformin7Safety table results extracted from Nauck et al Diabetes Care 2011 (see publication for complete results)
  • 8. Canagliflozin Active-comparator (Glimepiride) Add-on toMetforminChange in A1C (LOCF)8LSmeanchange(±SE)frombaseline(%)GLIM CANA 100 mg CANA 300 mg0 8 12LS meanchange–0.81%–0.93%–0.82%–0.01%(95% CI: –0.11, 0.09)–0.12%(95% CI: –0.22, –0.02)18 26 36 44 52Baseline (%) 7.8 7.8Time point (wk)7.8LOCF, last observation carried forward; GLIM, glimepiride; CANA, canagliflozin; LS, least squares; SE, standard error; CI, confidence interval.––0.4–0.6–0.8–1.0–1.2Cefulu et al ADA2012Hypoglycemia EventInidence:• CANA 100 mg: 5.6%• CANA 300 mg: 4.9%• GLIM: 34.2%
  • 9. Canagliflozin Active-comparator (Glimepiride) Add-on toMetforminPercent Change in Body Weight (LOCF)9LOCF, last observation carried forward; GLIM, glimepiride; CANA, canagliflozin; LS, least squares; SE, standard error.LSmean%change(±SE)frombaselineGLIM CANA 100 mg CANA 300 mgBaseline (kg)LS mean% change86.6 86.686.8–4.2% (–3.7 kg)–4.7% (–4.0 kg)1.0% (0.7 kg)–5.7% (–4.7 kg)P <0.001–5.2% (–4.4 kg)P <0.0010 4 8 12 18 26 52Time point (wk)4436–1–2–3–4–5–6012Cefalu et al ADA2012
  • 10. Canagliflozin Active-comparator (Glimepiride) Add-on toMetforminSummary of Overall Safety and Selected AEs10Subjects, n (%)GLIM(n = 482)CANA 100 mg(n = 483)CANA 300 mg(n = 485)Any AE 330 (68.5) 311 (64.4) 332 (68.5)AEs leading to discontinuation 28 (5.8) 25 (5.2) 32 (6.6)AEs related to study drug* 113 (23.4) 118 (24.4) 145 (29.9)Serious AEs 39 (8.1) 24 (5.0) 26 (5.4)Deaths 2 (0.4) 0 2 (0.4)Genital mycotic infectionMale†,Female‡,§3 (1.1)5 (2.3)17 (6.7)26 (11.3)20 (8.3)34 (13.9)UTI 22 (4.6) 31 (6.4) 31 (6.4)Osmotic diuresis-related AEsPollakiuria (increased frequency)Polyuria1 (0.2)2 (0.4)12 (2.5)4 (0.8)12 (2.5)4 (0.8)Volume-related AEsPostural dizzinessOrthostatic hypotension3 (0.6)03 (0.6)1 (0.2)2 (0.4)1 (0.2)AE, adverse event; GLIM, glimepiride; CANA, canagliflozin; UTI, urinary tract infection.*Possibly, probably, or very likely related to study drug, as assessed by investigators.†GLIM, n = 263; CANA 100 mg, n = 252; CANA 300 mg, n = 241.‡GLIM, n = 219; CANA 100 mg, n = 231; CANA 300 mg, n = 244.§Including vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovaginitis.Cefalu et al ADA2012
  • 11. SGLT2 Inhibitors – Reported ProfileEfficacy• Glucose-lowering– HbA1c, FPG, PPG• Decreases body weight• Lowers blood pressureSafety• Genital infections(vulvovaginitis, balanitis)• UTIs• Adverse events related todiuretic response (osmoticdiuresis)• Other reported adverseeffects11
  • 12. GPR40 – a new target for the treatment ofpatients with T2DM12• GPR40 – a G-proteincoupled receptor(GPCR) – withendogenous ligandsincluding free fattyacids• On pancreatic isletbeta-cells and on gutincretin secretingcells (GLP-1)• Stimulates glucose-dependent release ofinsulinAraki DOM 20122 weeksBaseline
  • 13. GPR40 Agonist: TAK875Dose-Range Finding Study Results13Burant et al Lancet 2012
  • 14. Glucose TargetPatient -DeterminedInsulin DoseInsulinDoseGlucoseCGMReadingGlucose Monitoring: Closing the Loop14JDRF CGM Study GroupDiabetes Care 2009
  • 15. 15Glucose monitoring: Closing the LoopGlucose TargetController-DeterminedInsulin DoseInsulinDoseGlucoseCGMReadingHaidar CMAJ 2013
  • 16. Stem Cell-Based TherapeuticsDifferentiation16• Stem cell basedtherapies –differentiatinginto insulin-secreting cells ex-vivo andtransplanting SC• Rejection as thekey limitation(xeno- or allo-transplantion)• One approach:encapsulation
  • 17. Immunoprotection Strategy Using anEncapsulation DeviceLoadingPortOuter CellVascularizingMembraneInsulinOxygen, Nutrients & GlucosePancreaticPrecursor CellsImmuneCellBarrierInner CellIsolationMembrane17
  • 18. “Game Changers” in the Care of Patients withDiabetes• Near term – new classes of agents that add to ourtreatment options• “Mid-term” – CV outcome studies for recent / newclasses (DPP-4, GLP-1, SGLT2 inhibitors)• Long-term - transforming how we care of patients– Closing the loop (artificial pancreas)– Stem cell approaches– Agents that restore / expand beta-cell functional mass18
  • 19. CV Outcome Study Results from New AgentClasses• GLP-1 receptor agonists– LEADER (liraglutide)– EXSCEL (once-weekly exenatide)– REWIND (Dulaglutide)– ELIXA (Lixisenatide)• DPP-4– TECOS (Sitagliptin)– SAVOR (Saxagliptin)– EXAMINE (Alogliptin)– CAROLINA (Linagliptin)• SGLT2– DECLARE (Dapagliflozin)– CANVAS (Canagliflozin)– Empagliflozin19Study Results2013-2019
  • 20. Current US Diabetes Control: NHANES20Ali NEJM 2013=<7%53% in 2007-2010 vs 44% in1999-2003
  • 21. Start metformin immediatelyConsider initial combination withanother antihyperglycemic agentStart lifestyle intervention (nutrition therapy and physical activity) +/- MetforminA1C <8.5%Symptomatic hyperglycemia withmetabolic decompensationA1C 8.5%Initiateinsulin +/-metforminIf not at glycemictarget (2-3 mos)Start / IncreasemetforminIf not at glycemic targetsLIFESTYLEAdd an agent best suited to the individual:Patient CharacteristicsDegree of hyperglycemiaRisk of hypoglycemiaOverweight or obesityComorbidities (renal, cardiac, hepatic)Preferences & access to treatmentOtherSee next page…AT DIAGNOSIS OF TYPE 2 DIABETESAgent CharacteristicsBG lowering efficacy and durabilityRisk of inducing hypoglycemiaEffect on weightContraindications & side-effectsCost and coverageOtherCanadian Diabetes Association Guidelines2013
  • 22. If not at glycemic targetFrom prior page…• Add another agent from a different class• Add/Intensify insulin regimenMake timely adjustments to attain target A1C within 3-6 monthsLIFESTYLECanadian Diabetes Association Guidelines2013
  • 23. Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596Current ADA/EASD Guidelines: Stepwise, IndividualizedTherapyThe ADA / EASDtreatment algorithm:Stepwise individualizedpatient therapy –weighing benefits andrisks
  • 24. RTG*~180 mg/dL02550751001250 50 100 150 200 250 300UrinaryGlucoseExcretion(g/day)Plasma Glucose (mg/dL)There is a Threshold Relationship Between PlasmaGlucose and UGEHealthy Subjects*Renal threshold for glucose FDA Advisory Committee Sponsor Slide Presentation 10Jan2013
  • 25. RTG*~180 mg/dLRenal Glucose Reabsorption and RTG are Elevated inT2DM02550751001250 50 100 150 200 250 300UrinaryGlucoseExcretion(g/day)Plasma Glucose (mg/dL)T2DMmean RTG~240 mg/dLT2DMHealthy Subjects*Renal threshold for glucose FDA Advisory Committee Sponsor Slide Presentation 10Jan2013
  • 26. SGLT2 Inhibition Lowers RTG Increasing UGE02550751001250 50 100 150 200 250 300UrinaryGlucoseExcretion(g/day)Plasma glucose (mg/dL)T2DMmean RTG~240 mg/dLCANAT2DM+CANARTG*~70-90 mg/dL*Renal threshold for glucose FDA Advisory Committee Sponsor Slide Presentation 10Jan2013
  • 27. Low Glucose Suspend(Reactive Shut-Off)Reactive suspension of insulindelivery at hypoglycemia withpredefined period until resumed.Hypo Minimizer(Predictive Hypo Control)Predictive suspension or reduction ofinsulin beforehypoglycemia occurs. Userinteraction required for Hyperregion.Hypo / Hyper Minimizer(Predictive Zone Control)Predictive modulation of insulindelivery when outside target rangeto limit hypo/hyper excursions.Hybrid Closed-loop(Predictive Target Control)Predictive modulation of insulin totarget with user interactionrequired to announcemeals/activity to algorithm.Automatic Closed-Loop(Automated Predictive TargetControl)Predictive modulation of insulindelivery to target with the ability atall times with no user interaction.Sources: Close Concerns, JDRF, Internal Assessment, Closed-loop insulindelivery for treatment of type 1 diabetes, BMC Medicine, Nov. 2011Automatic Closed-Loop(Automated Dual HormoneTarget Control)Predictive modulation of insulin andglucagon delivery to target at alltimes with no user interaction.1st Generation2nd Generation 3rd Generation1 2 34 5 6Evolution of Glucose Monitoring