Next Generation Basal Insulin JULIO WAINSTEIN MD 07022017

Next Generation Basal Insulin " "נופל וקם JULIO WAINSTEIN MD 07/02/2017

– התחלת טיפול מאוחרת באינסולין בזאלי מלווה בסיבוכי סוכרת נתונים מישראל • SOLVE Study - 24 -week international observational study, 10 countries, N=17, 374, T 2 DM on ≥ 1 OADs Baseline demographics - Israel Baseline Hb. A 1 c When Initiating Basal Insulin 10. 2 Hb. A 1 c (%) 9. 7 9. 2 8. 7 8. 2 7. 7 K U Tu rk ey el ra Is ly Ita rtu ga l a Po an ad ai n C Sp an y m er la nd G Po C hi n a 7. 2 adapted from : Khunti K et al. Diabetes Obes Metab. 2012; 14: 654 -61 1. Khunti K et al. Diabetes Obes Metab. 2012; 14: 654 -61

בטיפול באינסולין בזאלי נדרש איזון בין יעילות לתופעות לוואי 5 1. 2. Shar VN et al Diabetes Obes Metab. 2013 Giordana C. Minerva Endocrinol 2013

המשקל הוא חשש בקרב הסוכרתיים Medication beliefs, mean (0=fully disagree; 100=fully agree) 70 60 “I feel very anxious about my weight” 53. 7 55. 1 56. 4 “Insulin causes weight gain” 52. 7 51. 5 54. 8 52. 7 T 2 DM insulin T 1 DM 50 40 30 20 Not applicable 10 0 T 2 DM no medication T 2 DM OADs T 2 DM insulin T 1 DM T 2 DM no medication T 2 DM OADs • DAWN 2: 8, 274 patients with T 1 DM and T 2 DM from 17 countries 1. Peyrot M, Skovlund. Poster presented at ADA 2014; Abstract 56 -LB. Available at http: //ada. scientificposters. com/eps. Search. ADA. cfm Accessed July 2014

NPH to Lantus (Glargine) – A Big Leap Ahead • LANCELOT Study, n=701, 36 weeks, mean A 1 c – 8. 2% at baseline. All Day Hypoglycemia 56 mg/dl -21% Home PD et al. Diabetes Obesity and Metabolism , 2014 Nocturnal Hypoglycemia 56 mg/dl -48%

1. Yki-Jarvinen H, et al. (Poster #946) presented at EASD, Vienna, September 15– 19 2014. Available from: http: //www. easdvirtualmeeting. org/resources/19180. Date accessed: April 2015. 2. Riddle MC, et al. Diabetes Obes Metab. DOI: 10. 1111/dom. 12472. epub 2015. 3. Bergenstal R, et al. (Poster #949) presented at EASD, Vienna, September 15– 19 2014. Available from: http: //www. easdvirtualmeeting. org/resources/18574. Date accessed: April 2015. 4. Yki-Jarvinen H, et al. Diabetes Care 2014; 37: 3235– 3243. 5. Becker RH, et al. Diabetes Care 2015; 38(4): 637– 643. 6. EU, Toujeo® Summary of Product Characteristics. February 2015. 7. Ritzel R et al. (Poster #963) presented at EASD, Vienna, September 15– 19 2014. Available from: http: //www. easdvirtualmeeting. org/resources/18908. Date accessed: April 2015. 8. Gerstein HC, et al. New Eng J Med 2012; 367: 319– 328. 9. Ritzel R et al. Diabetes Obes. Metab 2015. 10. Shiramoto M et al. Diabetes Obes Metab 2015. 11. Lantus® EU SPC, June 2013; 12 Jeandidier N et al. Poster presentation at EASD 2014; Abstract 961 Available at: http: //www. easdvirtualmeeting. org/resources/18792 Accessed September 2014

Lantus הינו שליש מנפח ההזרקה של Toujeo נפח ההזרקה של Reduction of volume by 2/3 Same amount of units Lantus® Toujeo *for illustrative purposes only 1. Owens DR et al. Diabetes Metab Res Rev 2014 : 30 : 104 -119 2. Shiramoto M et al. Diabetes Obes Metab 2015 Mar 17(3): 254 -260 3. Toujeo Sm. PC February 2015

, Lantus- בהשוואה ל Toujeo פרופיל סוכר אחיד יותר עם ( ללא תלות בזמן ההזרקה )בוקר או ערב Average glucose profiles, mean (SE), mmol/L Time, h • This study was a 16 -week , multicenter , open-label , phase 2 parallel group , two period cross-over study to compare the glucose profiles following once-daily Toujeo and Lantus. • People with T 1 DM (n=59) were randomized (1: 1: 1: 1) to either Toujeo or Lantus once-daily in the evening (during 8 weeks) , then once-daily in the morning (during 8 weeks). Bergenstal RM et al. Poster presentation at EASD 2014; Abstract 949

EDITION program Testing Toujeo vs Lantus® in several populations T 2 DM T 1 DM EDITION 2 EDITION 1 N=807 BB EDITION 4 N=811 BOT N=549 BB Basal insulin plus mealtime bolus insulin (fast-acting analogue) Basal insulin plus OAD (excl. SU) EDITION 3 EDITION JP 2 EDITION JP 1 N=243 N=878 BOT Basal insulin plus OAD (excl. SU) and/or GLP-1 receptor agonists Basal insulin plus mealtime bolus insulin (fast-acting analogue) BOT BB Basal insulin plus OAD Basal insulin plus mealtime bolus insulin (fast-acting analogue) All Phase 3, ≥ 18 years BB, basal-bolus therapy; BOT, basal only therapy Riddle MC et al. Diabetes Care. 2014; 37: 2755 -62; Yki-Järvinen H et al. Diabetes Care. 2014 Sep 5. pii: DC_140990 [Epub ahead of print ]; Bolli GB et al. Poster presentation at EASD 2014; Abstract 947; Terauchi Y et al. Poster presentation at EASD 2014; Abstract 976; Home PD et al. Oral presentation at EASD 2014; Abstract 148; Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975 SAGLB. DIA. 14. 06. 0065 a(1) / 2014. 09

חודשים 6 לאחר Hb. A 1 c- ירידה דומה ברמות ה • Data were pooled from EDITION 1, 2, 3 studies conducted in patients with T 2 DM (n=2, 400). Average A 1 c – 8. 31%, BMI – 34. 7 kg/m^2, DM Duration - 12. 7 years. Mean (SE) Hb. A 1 C, % Hb. A 1 C, mmol/mol 69 8. 4 67 8. 2 65 8. 0 LS mean difference at Month 6: 0. 00 (95% CI – 0. 08 to 0. 07) % 7. 8 7. 6 61 59 7. 4 7. 2 63 57 Toujeo Lantus® 55 7. 0 53 Baseline Week 12 1. Ritzel R et al , Diabetes Obesity and Metabolism 17 : 859 -867 2015 Month 6

EDITION 1 -2 -3 T 2 DM Pooled Analysis Toujeo- בשימוש ב , במשך הלילה , פחות אירועי היפוגליקמיה Nocturnal hypoglycemia (00: 00– 05: 59 h) Cumulative mean number of confirmed* and/or severe events 3 Toujeo Lantus® Rate ratio 0. 86 (0. 77 to 0. 97) P=0. 0116 2 -31% 1 Maintenance 0 0 4 8 12 Time, weeks 1. Ritzel R et al , Diabetes Obes and Metab 17: 859 -867 , 2015 16 20 24 28 -14% *Confirmed events based on plasma glucose ≤ 70 mg/d. L (3. 9 mmol/L) Adapted from Ritzel R et al , Diabetes Obes and Metab 17: 859 -867 , 2015

EDITION 1 -2 -3 T 2 DM Pooled Analysis Toujeo- בשימוש ב , במשך כל היום , פחות אירועי היפוגליקמיה Hypoglycemia at any time (24 h) Cumulative mean number of confirmed* and/or severe events 10 Toujeo Lantus® -14% 8 6 4 2 Rate ratio 0. 69 (0. 57 to 0. 84) P=0. 0002 Maintenance 0 0 4 8 12 16 Time, weeks 1. Ritzel R et al , Diabetes Obes and Metab 17: 859 -867 , 2015 20 24 28 -14% *Confirmed events based on plasma glucose ≤ 70 mg/d. L (3. 9 mmol/L) Adapted from Ritzel R et al , Diabetes Obes and Metab 17: 859 -867 , 2015

EDITION 1 -2 -3 T 2 DM Pooled Analysis Lantus- בהשוואה ל Toujeo - עלייה פחותה במשקל בשימוש ב Mean (SE) weight change from baseline, kg 1. 5 LS mean difference at Month 6: – 0. 28 (95% CI – 0. 55 to – 0. 01) kg P=0. 039 1. 0 Toujeo Lantus® 0. 5 0. 0 – 0. 5 BL W 2 W 4 1/Ritzel R et al , Diabetes Obes and Metab 17: 859 -867 , 2015 W 8 W 12 M 4 M 6 LOV

גמישות בזמן המתן . רצוי באותה שעה בכל יום , ניתן פעם ביום Toujeo. שעות לפני או אחרי זמן הנטילה הקבוע 3 עד Toujeo ניתן להזריק את , במידת הצורך שעות 3+ שעת ההזרקה הקבועה שעות 3 - Jeandidier N et al. Poster presentation at EASD 2014; Abstract 961 Available at: http: //www. easdvirtualmeeting. org/resources/18792 Accessed September 2014

Lantus ומטופלי Toujeo פרופיל בטיחות דומה בין מטופלי Proportion of patients, % T 2 DM studies EDITION 1 BB Toujeo EDITION 2 BOT switch T 1 DM studies EDITION 3 BOT start Similar safety profiel M 1 metabolite Lantus Toujeo EDITION JP 2 BOT switch EDITION 4 EDITION JP 1 Lantus Toujeo Lantus TEAEs 56. 4 54. 2 58. 8 50. 7 56. 8 55. 9 58. 3 56. 7 60. 9 58. 2 62. 3 64. 5 Serious TEAEs 6. 4 5. 2 3. 7 5. 5 5. 9 4. 2 3. 3 6. 2 8. 0 2. 5 TEAEs leading to discontinuation 1. 5 1. 7 1. 5 1. 0 1. 1 2. 5 0. 8 1. 1 0. 8 0 Data on file, EDITION 1 CSR, pg 126; EDITION 2 CSR, pg 126; EDITION 3 CSR pg 139; EDITION JP 2 CSR pg 138; EDITION 4 CSR pg 158; EDITION JP 1 CSR pg 136

( השפעה נייטרלית על תחלואה ותמותה קרדיווסקולרית LantusToujeo) Glargine- ל 1 היא האינסולין הבזאלי Glargine היחיד עם פרופיל בטיחות קרדיווסקולרית ארוך טווח 1 -3 ומבוססת RCT, N=12, 537, T 2 DM or Pre-diabetes, Target fasting glucose level≤ 95 mg/dl. Gerstein HC, et al. N Engl J Med 2012; 367: 319– 328. 2. Lantus® EU SPC, June 2013. 3. Lantus® US SPC, October 2013. 4. Lantus® Israel SCP, March 2014

Toujeo - סיכום 1. Yki-Jarvinen H, et al. (Poster #946) presented at EASD, Vienna, September 15– 19 2014. Available from: http: // www. easdvirtualmeeting. org/resources/19180. Date accessed: April 2015. 2. Riddle MC, et al. Diabetes Obes Metab. DOI: 10. 1111/dom. 12472. epub 2015 3. Bergenstal R, et al. (Poster #949) presented at EASD, Vienna, September 15– 19 2014. Available from: http: //www. easdvirtualmeeting. org/resources/18574. Date accessed: April 2015. 4. Yki-Jarvinen H, et al. Diabetes Care 2014; 37: 3235– 3243. 5. Becker RH, et al. Diabetes Care 2015; 38(4): 637– 643. 6. EU, Toujeo® Summary of Product Characteristics. February 2015. 7. Ritzel R et al. (Poster #963) presented at EASD, Vienna, September 15– 19 2014. Available from: http: //www. easdvirtualmeeting. org/resources/18908. Date accessed: April 2015. 8. Gerstein HC, et al. New Eng J Med 2012; 367: 319– 328. 9. Ritzel R et al. Diabetes Obes Metab 2015.

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