New Insulin Formulations

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Presentation transcript:

New Insulin Formulations Guillermo Umpierrez, MD, FACP, FACE Professor of Medicine Emory University School of Medicine Part 3 1

New Insulin Formulation GLAR-300a vs GLAR-100 in Patients on Basal Plus Mealtime Insulin GLAR-100 (n = 403) Noninferior A1C change for GLAR-300 vs GLAR-100 (both groups, -0.83%) No between-group differences in adverse events Significantly fewer with nocturnal hypoglycemia (≥ 1 severe or confirmedb) with GLAR-300 (graph) GLAR-300 (n = 404) RR 0.79 (CI, 0.67-0.94) P = .0070 FXCX: Riddle 2013: abstract GLAR, glargine. a GLAR-300 is not FDA approved for clinical use. b Confirmed hypoglycemia, ≤ 70 mg/dL. Riddle M, et al. ADA 73rd Scientific Sessions. 2013;43-LB.

Meta-Analysis: U300 Glargine vs U100 Glargine: Safety and Efficacy HbA1c (%) Mean ± SE 7.6 8.4 7.0 Baseline 6 Mon Week 12 7.2 8.2 8.0 7.4 7.8 U100 U300 LS mean difference (95% CI) between groups: 000 (-0.08 to 0.07)% Nocturnal Hypo-Events* per Participant-Year 2 6 5 4 1 3 3.06 2.10 p=0.0002 RR 31% U100 U300 M6 U100 U300 Weight Change (Kg) Mean ± SE 1.5 -0.5 Base line 1.0 0.5 0.0 M4 W12 W8 W4 W2 LOV p=0.039 *Confirmed (≤70 mg/dL) or severe hypoglycemia from 00:00–05:59 h. SE = standard deviation; LOV = last on-treatment value. Ritzel R, et al. Presentation 90-LB 74th ADA Scientific Sessions June 13-17, 2014, San Francisco, CA. http://ada.scientificposters.com/epsAbstractADA.cfm?id=1. Accessed August 15, 2014.

Flexible vs Fixed Dosing U300 Glargine: Sub-Studies of Phase III Trials 6 Months (randomization, sub-study) U300 once daily every 24 ± 3h U300 once daily every 24 h 9 Months (end of sub-study) sub-study 6 Month Treatment Period (main study) 6 Month Extension Period (main study) Edition 1 Sub-Study N=109 Edition 2 Sub-Study N=89 No difference in A1C between flexible- vs fixed-dosing No difference in severe or nocturnal hypoglycemia within each sub-study 100 80 Flexible Dosing Fixed Dosing Percentage of Injections (%) 60 40 20 24 ± <1 h 24 ± 1-3 h 24 ± >3 h 24 ± <1 h 24 ± 1-3 h 24 ± >3 h Ritzel R, et al. Presentation 919-P 74th ADA Scientific Sessions June 13-17, 2014, San Francisco, CA. http://ada.scientificposters.com/epsAbstractADA.cfm?id=6. Accessed August 15, 2014.

U300 Glargine vs U100 Glargine: Meta-Analysis of 3 Phase III Trials Edition 1 Edition 2 Edition 3 Meta-Analysis Trial description and treatment U300 vs U100 (+RAI+Met) U300 vs U100 (+Met+OADs*) U300 vs U100 (+Met+OADs†) N/A No. of participants Gla-300 Gla-100 404 403 407 439 1,247 1,249 Therapy at screening Basal + mealtime insulin + OADs Basal insulin + OADs Insulin naïve + OADs Inclusion criteria Insulin dose HbA1c Age ≥42U ≥7.0%, ≤10.0% ≥18 years old ≥7.0%, ≤11.0% ≥18 years old Mean baseline characteristics BMI, kg/m2 Age, years Duration of DM, yrs HbA1c, % U300 36.6 60.1 15.6 8.15 U100 36.6 59.8 16.1 8.16 34.8 57.9 12.7 8.26 34.8 58.5 12.5 8.22 U300 32.8 58.2 10.1 8.51 33.2 57.2 9.6 8.57 34.7 58.7 12.7 8.31 34.8 58.5 12.6 8.32 *Use of sulfonylureas prohibited within 2 months prior to screening and during the study; †Except sulfonylureas, glinides and other OADs not approved for use with insulin. Ritzel R, et al. Presentation 90-LB 74th ADA Scientific Sessions June 13-17, 2014, San Francisco, CA. http://ada.scientificposters.com/epsAbstractADA.cfm?id=1. Accessed August 15, 2014.

Insulin Degludec Dihexamers form soluble multihexamers after injection CO2H H HN HO2C Dihexamers form soluble multihexamers after injection Multihexamers disassemble slowly Monomers are released rapidly after hexamers disassemble Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012 Aug;29(8):2104-14. doi: 10.1007/s11095-012-0739-z. Epub 2012 Apr 7. PubMed PMID: 22485010; PubMed Central PMCID: PMC3399081. Beals JM, et al, inventors; Eli Lilly and Company, Indianapolis, IN, assignee. Pegylated insulin lispro compounds. Patent US 2011/0105392 A1. May 5, 2011. Patent filing, fig 2 and brief explanation, p 2. Patent was published 5/5/2011. Mode of prolongation: Rosenstock ADA 2012 poster 1026-P (first column) a Polyethylene glycol (PEG) group may be attached at any of 3 points. Jonassen I, et al. Pharm Res. 2012;29:2104-2114.

Insulin Degludec* desB30 insulin acylated (16 carbon fatty acid chain) at LysB29 Duration of action >42 hours Half-life ~25 hours Detectable for at least 5 days Steady state in 2-3 days FDA denied approval in 2013, research continues FXCX: Garber page 6-7 Garber page 6 Garber page 3 Owens p107-115 *Not FDA approved Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104-19.

Pharmacodynamics of Degludec Ideg 0.4 U/kg Ideg 0.8 U/kg Ideg 0.6 U/kg 6 5 4 Glucose Lowering Effect on Day 6 (mg/kg/min) 3 2 1 FXCX: Simon pdf in Zotero Grunberger pef in Zotero 4 8 12 16 20 24 Time since Injection (hours) Josse RG and Woo V. Diabetes Obes Metab. 2013;15(12):1077-1084.

Degludec vs Glargine In Type 2 DM 16 40 28 52 4 32 20 44 12 36 24 48 8 8.6 7.8 A1C (%) 7.0 8.2 8.4 7.6 7.4 8.0 7.2 70 62 A1C (mmol/mol) 54 66 68 60 58 64 56 Insulin Degludec once-daily (N=744) Insulin Glargine once-daily (N=248) Time (weeks) 2.0 1.0 Cumulative Events per Participant 16 Time (weeks) 40 28 0.2 52 1.4 1.8 0.8 1.6 0.6 1.2 0.4 4 32 20 44 12 36 24 48 8 Nocturnal Hypoglycemia Equal Efficacy, Less Nocturnal Hypoglycemia with Degludec but no difference in severe hypoglycemia FXCX: Permissions for reuse of figures pdf in Zotero Graph A = Graph A page 1502 Graph B = Graph B (Noctural confirmed hypoglycemic episodes) Graph C = Graph C (Diurnal confirmed hypoglycemic episodes) all on page 1503 Garber AJ, et al. Lancet. 2012;379(9285):1498-1507.