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In the name of GOD

Learn about the latest advancements in basal insulin therapy, including formulation engineering strategies and the introduction of insulin degludec (IDeg) and gla-300. Discover the benefits of these new basal insulins for better glucose control and reduced hypoglycemic risk.

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In the name of GOD

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  1. In the name of GOD

  2. New advancement in basal insulins F.Sarvghadi MD Endocrinologist Research Institute for Endocrine sciences ShahidBeheshtiUniversityof Medical Sciences Tehran 95.11.28

  3. Agenda Introduction Basal insulin therapy: An historical overview Formulation engineering strategies for basal insulins Insulin degludec (IDeg) Gla-300 Conclusion

  4. Introduction • Type 2 diabetes is progressive in nature and many people with the condition will inevitably require insulin therapy to attain and maintain adequate glycaemic control. • Manufacturers of insulin products have long sought ways to modify the absorption rate of exogenously administered insulins in an effort to better reproduce the naturally occurring pharmacokinetics of endogenous insulin secretion. Heise et al Diabetes Obes Metab 2017; 19(1):3–12

  5. Basal insulin therapy: An historical overview 1922 1936 1946 1951 Protamine/ zinc Isophane (NPH) Lente insulin 2000 2005 Lantus/ Gla-100 Levemir

  6. Aspiration for a new basal insulin product > 24-hour coverage Long duration of action Reduced hypoglycaemic risk Flat time-action profile Stable glucose lowering High day-to-day reproducibility Dosing flexibility Flat time-action profileLong duration of action

  7. Basal insulin therapy: The next generation on the market 2013 2015 Tresiba/ IDeg 100 U/mL* Toujeo/ Gla-300 *IDeg is also approved at a 200 U/mL concentration Gla-300, insulin glargine 300 U/mL; IDeg, insulin degludec

  8. Formulation engineering strategies for basal insulins • Increased self association : NPH , Lente • Precipitation after injection : Glargine U100 • Protein bound insulin analogues : Detemir • Multihexamer chain formation : Degludec U100 • Up-concentrated formulation : Glargine U300 , Degludec U200 • PEGylation : PEGlispro Heise et al Diabetes Obes Metab 2017; 19(1):3–12

  9. Next generation basal insulins:Insulin degludec (IDeg) Heise et al Diabetes Obes Metab 2017; 19(1):3–12

  10. IDegdihexamer formation Heise et al Diabetes Obes Metab 2017; 19(1):3–12

  11. Next generation basal insulins:Insulin degludec (IDeg) Long-acting basal insulin currently approved in Europe, Japan and other markets. Upon subcutaneous injection forms soluble and stable multihexamers, that allow slow and continuous absorption of monomers into the circulation1,2 1. Owens DR, et al. Diabetes Metab Res Rev 2014;30:104–19 2. Shah VN, et al. Diabetes Technol & Ther 2013;15:727–32

  12. Half-life & Pharmacodynamicprofiles for IDeg and IGla- 100 at steady state. Heise et al. Expert Opin. Drug Metab. Toxicol. (2015) 11(8):1193-1201

  13. Long-acting profile of IDeg 5 0.8 U/kg Glucose Infusion Rate in T1DM patients at Day 6, mg/kg/min 0.6 U/kg 4 0.4 U/kg 3 2 1 0 0 4 8 12 16 20 24 Hours 1. Owens DR, et al. Diabetes Metab Res Rev 2014;30:104–19 2. Heise T , et al. Diabetes Obes Metab 2012;14:944–50 3. Heise T, et al. Diabetes Obes Metab 2012;14:859–64 A long duration of action (>42 hours), with a relatively peaklessprofile1,2 A half-life of ~25 hours, and is detectable in serum for >120 hours post-injection2 • Four times lower day-to-day variabilityin glucose lowering effect for IDegvs Gla-1003 • Consistent lower within-subject (intra) fluctuation of IDeg over time compared to Gla-1003

  14. Vora J, et al. DiabetesTher 2014;5:435–46

  15. Clinical efficacy : Degludec vs Glargine U100   Non-Inferiority achieved in all the clinical trials compared to insulin Glargine U100      No significant difference Insulin degludec significantly better extn, extension; non-inf., non-inferior; wks, weeks* Data depict results for IDeg Flexible vs. IGlar Vora J, et al. DiabetesTher 2014;5:435–46

  16. Total daily dose overview by trial 0.89 [0.84;0.93] 0.87 [0.81;0.94] 1.03 [0.97;1.10] Glycaemic control achieved at significantly lesser doses compared to insulin glargine 0.97 [0.89;1.05] 0.89 [0.82;0.98] 0.80 [0.71;0.90] 0.90 [0.82;0.99] †The ratios reported in Mathieu et al. 2013 (Table 2) deviate from those above as the publication analyses all IDeg patients (i.e. both the forced flex and standard arms)References: 1. Data on file, DOF-MA-IDeg-24APR2013-001, Novo Nordisk A/S; 2. Heller et al. Lancet 2012;379:1489–97; 3. Garber et al. Lancet 2012;379:1498–507; 4. Zinmanet al. Diabetes Care 2012;35:2464–71 (+ supplementary online data); 5. Gough et al. Diabetes Care 2013;36:2536–42; 6. Onishiet al. J Diabetes Investig2013;4:605–12 (+ supplementary online information)

  17. IDeg:: Overall hypoglycemia vs. Gla 100 • Meta analysis of phaseIII trial in T2DM patients OVERALL confirmed (BG <3.1 mmol/L) or severe hypoglycemia (Baseline to 26 or 52 weeks) (Baseline to 15 weeks) (16 weeks onwards) RR: 0.92 (0.80–1.05) Estimated RR reduction RR: 0.83 * (0.74–0.94) RR: 0.75 * (0.66–0.87) Ratner RE, et al. DiabetesObesMetab 2013;15:175–84 *Significant

  18. IDeg: Nocturnal hypoglycemia vs. Gla 100 • Meta analysis of phaseIII trial in T2DM patients Nocturnal (00:01–05:59 h) confirmed (BG <3.1 mmol/L) or severe hypoglycemia (Baseline to 26 or 52 weeks) (Baseline to 15 weeks) (16 weeks onwards) Estimated RR reduction RR: 0.81 (0.64–1.02) RR: 0.68 * (0.57–0.82) RR: 0.62 * (0.49–0.78) • For every 8 subjects initiated and treated with degludec instead of Gla-100 for 1 year,1 nocturnal confirmed episode will be avoided Clinical Implications Ratner RE, et al. DiabetesObesMetab 2013;15:175–84 *Significant

  19. IDeg: Hypoglycemia in T1DM Heller S, et al. Lancet 2012;379:1489–97 IDeg (BEGIN Basal-Bolus Type 1) • Overall hypoglycemia and severe hypoglycemia were similar in both groups. • Nocturnal hypoglycemia: 25% lower rate with IDeg compared with Gla-100.

  20. IDegvs. Gla100 :Summary • During a period of 24 hours with once-daily treatment, exposure of IDeg is evenly distributed between the first and second 12 hours. • Similar glycemic control as defined by HbA1c. • Significantly lower hypoglycaemia. • Flexibility for injection time. • Beneficial for those patients who require twice-daily dosing to maintain full basal insulin coverage. • Up- concentrated for lowervolume( IDeg U200 ). • Co-formulated with GLP-1 Analogues & rapid acting insulins.

  21. Insulin Glargine 300 (Gla-300)

  22. Insulin Glargine 300 (Gla-300) Reduction of depot surface by 1/2 1/3 of the volume Same amount of units Gla-100 Gla-300 Gla-300 Gla-100 Gla-300 contains the same insulin glargine monomer as Gla-1001 Gla-300 forms smaller subcutaneous depots than Gla-100, which results in a more gradual release of the insulin glargine monomer with Gla-300 1. Becker RHA, et al. Diabetes Care 2015;38:637–43 2. Steinstraesser A, et al. Diabetes ObesMetab 2014;16:873–6

  23. Up-concentrated formulation : Gla-300 • Half-life : 19 hours. • Steady state is reached after 3 to 4 days. • Duration of action:36 h. Heise et al Diabetes Obes Metab 2017; 19(1):3–12

  24. Pharmacokinetic Profiles of Basal Insulins

  25. More constant glucose profile with Gla-300 vs. Gla-100* Average 24-hour glucose profiles showed a more constant glucose level with Gla-300 vs Gla-100 Gla-100 11 Gla-300 10 Morning injection Average glucose (mmol/l) 9 8 7 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (h) 11 10 Evening injection Average glucose (mmol/l) 9 8 7 0 2 4 6 8 10 12 14 16 18 20 22 24 Bergenstal RM, et al. Poster presentation at EASD 2014; Abstract 949 Time (h) n=60

  26. More constant glucose profile with Gla-300 vs. Gla-100* Gla-300 11 Average glucose profiles, mean (SE), mmol/L 10 Average 24-hour glucose profiles showed a more constant glucose level with Gla-300 vs Gla-100 9 8 Morning Evening 7 0 2 4 6 8 10 12 14 16 18 20 22 24 Gla-100 11 10 9 8 Morning Evening 7 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (h) Bergenstal RM, et al. Poster presentation at EASD 2014; Abstract 949 Mean glucose profiles were more constant with Gla-300 compared with Gla-100, independent of the time of injection (morning or evening)

  27. Gla-300 : phase II results • After subcutaneous injection, Gla-300 has been shown to have smoother, more stable, and prolonged pharmacokinetic and pharmacodynamic profiles than Gla-100. • Low within-day variability (fluctuation) in insulin exposure with Gla-300. Reduce hypoglycemic risk. • Low between-day (within-subject) variability( high reproducibility). More predictable insulin exposure. Flexibility.

  28. EDITION program:Phase III trials of comparing Gla-300 vs. Gla-100 T2DM T1DM EDITION 1*1 N=807 BB Basal insulin plus mealtime bolus insulin (fast-acting analoge) EDITION 2*2 N=811 BOT Basal insulin plus OAD (excl. SU) EDITION 45 N=549 BB Basal insulin plus mealtime bolus insulin (fast-acting analog) EDITION 33 N=878 Basal Insulin Naive OAD (excl. SU) and/or GLP-1 receptor agonists EDITION JP 24 N=241 BOT Basal insulin plus OAD EDITION JP 16 N=243 BB Basal insulin plus mealtime bolus insulin (fast-acting analog) All Phase III, age of participants ≥18 years, randomization ratio 1:1 1. Riddle MC, et al. Diabetes Care 2014;37:2755–62; 2. Yki-Järvinen H, et al. Diabetes Care 2014;37:3235–43; 3. Bolli GB, et al. Diabetes Obes Metab 2015;17:386–94;4. Terauchi Y, et al. Poster presentation at EASD 2014; Abstract 976; 5. Home PD et al. Diabetes Care 2015;ePub Jun 17:pii: dc150249 6, Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975 BB, basal-bolus therapy; BOT, basal-only therapy;

  29. EDITION: study design Gla-300 ± OADs ± mealtime insulin Participants Randomized (1:1) 6-month extension period 6 months Gla-100 ± OADs ± mealtime insulin Primary endpoint: HbA1c reduction at Month 6 Main secondary endpoint*: Confirmed and/or severe nocturnal hypoglycemia in selected trials Randomized 1:1, open-label, parallel-group, multinational studies The EDITION program includes ~3,500 patients with T1DM and T2DM participating in 6 clinical trials EDITION program has similar design across studies 1. Riddle MC, et al. Diabetes Care 2014;37:2755–622. Yki-Järvinen H, et al. Diabetes Care 2014;37:3235–433. Bolli GB, et al. Diabetes Obes Metab 2015;17:386–944. Terauchi Y, et al. Poster presentation at EASD 2014; Abstract 976

  30. Primary endpoint: Gla-300 non-inferior to Gla-100 in HbA1c change at Month 6, T2DM EDITION 11 BB EDITION 22 BOT switch EDITION 33 BOT start EDITION JP 24 BOT switch LSM difference: 0.00% (–0.11 to 0.11) LSM difference: –0.01% (–0.14 to 0.12) LSM difference: 0.04% (–0.09 to 0.17) LSM difference: 0.10% (–0.08 to 0.27) LSM HbA1c change from baseline (%) Gla-300 Gla-100 1. Riddle MC, et al. Diabetes Care 2014;37:2755–62 2. Yki-Järvinen H, et al. Diabetes Care 2014;37:3235–43 3. Bolli GB, et al. Diabetes Obes Metab 2015;17:386–94 4. Terauchi Y, et al. Poster presentation at EASD 2014; Abstract 976 LSM, least square means

  31. Less or similar weight gain with Gla-300 vs. Gla-100 at Month 6, T2DM EDITION 11 EDITION 22 EDITION 33 EDITION JP 24 0.9(3.2) 0.9(3.1) 0.7(3.8) 0.7(3.0) 0.4(3.8) 0.3(2.2) 0.1(3.5) Weight change from baseline, kg (±SD) –0.6(2.0) Gla-300 Gla-100 1. Riddle MC, et al. Diabetes Care 2014;37:2755–62 2. Yki-Järvinen H, et al. Diabetes Care 2014;37:3235–43 3. Bolli GB, et al. Diabetes ObesMetab 2015;17:386–94 4. Terauchi Y, et al. Poster presentedADA 2014;Abstract 94-LB

  32. Gla-300: Participants (T2DM) reporting ≥ 1 hypoglycemic event at any time (24 hours) Participants with ≥1 confirmed (≤3.9 mmol/L) and/or severe hypoglycaemia (%) Gla-300 (n=1242) Gla-100 (n=1246) RR 0.92 (95% CI: 0.86, 0.98)† 72.0 65.5 62.5 Participants (%) 57.5 44.7 Titration period (Baseline to Week 8) Entire treatment period (Baseline to Month 6) Maintenance period (Week 9 to Month 6) Clinical Implications • For every 15 subjects initiated and treated with Gla-300 instead of Gla-100, 1 less patient will have confirmed hypoglycemia at any time (24 hours) Ritzel R, et al.Diabetes ObesMetab 2015; doi:10.1111/dom.12485.; • †Significant

  33. Gla-300: Participants (T1DM) reporting ≥ 1 hypoglycemic event at any time (24 hours) Participants with ≥1 confirmed (≤3.9 mmol/L) and/or severe hypoglycaemia (%) Gla-300 (n=1242) Gla-100 (n=1246) RR 0.75 (95% CI: 0.68, 0.83)† RR 0.80 (95% CI: 0.71, 0.91)† RR 0.69 (95% CI: 0.58, 0.81)† Participants (%) Entire treatment period (Baseline to Month 6) Titration period (Baseline to Week 8) Maintenance period (Week 9 to Month 6) • For every 10 subjects initiated and treated with Gla-300 instead of Gla-100, 1 less patient will have nocturnal confirmed hypoglycemia Clinical Implications Ritzel R, et al.Diabetes ObesMetab 2015;16 ¶Nocturnal, 00:00–05:59 h; †Significant

  34. Gla 300 vs. Gla 100: summary • Comparable HbA1c reduction in the treat-to-target RCT setting. • Slightly lower or similar weight gain. • Slightly higher dose requirement. • Lower hypoglycemia event rate. • Beneficial for those patients who require twice-daily dosing to maintain full basal insulin coverage. • Flexibility to select the timing of injections to either am or pm dosing and withina± 3 hours window when needed. • Lower volume for insulin resistance cases.

  35. Next generation basal insulin analogs offer longer duration and less variability – IDeg and Gla-300. • Gla-300 and IDeg have shown similar efficacy when compared to Gla-100. • Both of the new basal insulinsreduce the risk of hypoglycemia compared with Gla-100. • Flexibility. • Beneficial for those patients who require twice-daily dosing to maintain full basal insulin coverage. • The recent development of hepato-preferential or very long-acting (once-weekly) insulins promises the potential to achieve further clinical improvements.

  36. Thank you

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