Pharmacokinetics and Pharmacodynamics of Insulin VIAject TM, Insulin Lispro and Regular Human Insulin When Injected Subcutaneously Immediately Before a Meal in Patients with Type 1 Diabetes. Solomon S. Steiner, Lutz Heinemann, Roderike Pohl, Frank Flacke, Andreas Pfützner, Patrick V. Simms, Marcus Hompesch EASD September 18, 2007 1
Technology VIAject TM is a novel composition of regular recombinant human insulin and generally regarded as safe ingredients which cause insulin to: Favor the biologically active monomeric form Prevent reformation of the hexameric state Mask insulin charges, and By so doing speed insulin s absorption from subcutaneous sites 2
Presented at the ADA 2006: Phase IIa Study with Patients with Type 1 Diabetes Rapid Absorption of VIAject Compared to Regular Human Insulin 14 Patients Serum Insulin (µu/ml) 35 25 INS Tmax (min) Mean ± SEM Regular Human Insulin 112 ± 13 VIAject 33 ± 4 p<0.0001 15 5-5 0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 510 Time (min) -15 Regular Human Insulin VIAject TM 3
Phase 1 Pharmacodynamic Data: Mean Glucose Infusion Rates VIAject v. Humalog & Humulin R 12 GIR mg/kg/min baseline corrected Humulin R 12 IU 10 Humalog 12 IU 8 VIAject 12 IU 6 4 2 0 0 1 2 3 4 5 6 7 8 Time (hours) 4
Study Objective Do these improvements in PK/PD parameters translate into improved postprandial metabolic control? 5
Phase II Meal Study Patient demographics Sixteen patients (9 male, 7 female) Age 39±10 years BMI 24±2 kg Study design: Cross over with fixed treatment order Patients stabilized by glucose clamp (target BG 120 mg/dl) Glucose turned off prior to meal and insulin dosing Same patient specific dose of Regular Human Insulin (RHI, Humulin R), insulin Lispro (Humalog ) or VIAject was injected s.c. immediately before the meal by means of a syringe in the abdomen Insulin dose 11.7±0.8 IU Standardized meal consisted of 984 kcal, 28 g protein, 140 g carbohydrate and 35 g fat Postprandial glucose excursions were continuously monitored for 8 hours Glucose infusion was re-initiated if BG fell <60 mg/dl 6
Phase II Meal Study Pharmacokinetics PK- Parameters RHI Lispro VIAject p-value Early ½ Tmax (min) Ins Tmax (min) Late ½ Tmax (min) 33±4 29±4 13±1 b < 0.0001 a < 0.0001 c = n.s. 139±12 12 63±8 34±7 a < 0.001 b < 0.02 c < 0.001 267±16 217±20 20 118±12 12 b < 0.001 a < 0.001 c < 0.02 7
Mean Curves Normalized Insulin Concentration Graphs 120 Normalized Insulin Concentrations, 16 patients 100 Percent (%) 80 60 40 20 0 0 60 120 180 240 300 360 420 480 Time (min) RHI Lispro VIAject 8
Individual Curves Improved Postprandial Glycemic Control Patient 1 200 180 ADA Limit Blood Glucose (mg/dl) 160 140 120 100 80 60 40 Hyperglycemic Ideal Glycemic Control Hypoglycemic Glucose Infusion 0 1 2 3 4 5 6 Time (hours) RHI Lispro VIAject TM 9
Mean Curves Improved Postprandial Glycemic Control 180 16 Patients Average Blood Glucose 170 RHI 160 Blood Glucose (mg/dl) 150 140 130 120 110 100 90 Meal Lispro VIAject 80 70 60-240 -180-120 -60 0 60 120 180 240 300 360 420 480 Time (min) 10
Mean Curves Improved Postprandial Glycemic Control 180 170 16 Patients Average Blood Glucose 160 RHI Blood Glucose (mg/dl) 150 140 130 120 110 100 90 Meal VIAject Lispro 80 70 60 0 60 120 180 240 300 360 420 480 Time (min) 11
Phase II Meal Study Glucose Infused to Maintain BG Above 60 mg/dl Glucose Infused 180-480 min (ml) 16,000 14,000 12,000 10,000 8,000 6,000 4,000 2,000 0 Sixteen Patients mean ± SEM 10,461* 4,126 2,284* *RHI vs. VIAject p<0.05, Lispro vs. VIAject / RHI n.s. RHI Lispro VIAject 12
Phase II Meal Study Hypoglycemic Risk As Assessed by Glucose Infusion Requirements 30 Sixteen Patients # of patient hours 25 20 15 10 5 0 RHI Lispro VIAject VIAject vs. Lispro P<0.05 VIAject vs. RHI P<0.05 RHI vs. Lispro n.s. 13
Phase II Meal Study Pharmacodynamics (mg/dl) 110 100 90 80 70 60 50 40 30 20 10 0 BG Max - BG Min 91** 84* 69*,** a RHI Lispro VIAject b * RHI vs. VIAject p<0.05, **Lispro vs. VIAject p<0.0001, paired t-test 14
Summary VIAject has improved PK/PD properties compared to Lispro and Regular Human Insulin In a meal related study, postprandial glycemic excursions are reduced in patients with Type 1 diabetes after s.c. injection of VIAject in comparison to both Regular Human Insulin and Lispro Reduced risk of late postprandial hypoglycemic events compared to Regular Human Insulin Reduced risk of early and late postprandial hypoglycemic events compared to Lispro 15
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