A novel ph-neutral formulation of the monomeric insulin VIAject has a faster onset of action than insulin lispro

Transcription

1 A novel ph-neutral formulation of the monomeric insulin VIAject has a faster onset of action than insulin lispro Leszek Nosek, Tim Heise, Frank Flacke 2, Alan Krasner 2, Philip Pichotta 2, Lutz Heinemann, Solomon Steiner 2 Profil Institute for Metabolic Research, Neuss, Germany 2 Biodel, Danbury, CT, USA

2 Viaject (Linjeta ) novel formulation of recombinant human insulin currently under FDA review (PDUFA date 30 th Oct 2010) faster absorption and faster onset of action than lispro

3 Linjeta : Faster absorption through formation of monomers Zn 2+ EDTA Citric acid Monomer Human Insulin: Hexamer-Formation Linjeta : EDTA Zn chelation Linjeta : Citric acid masks charges

4 Linjeta : Faster absorption through formation of monomers Linjeta monomers Linjeta : "Ultra-fast" absorption

5 Viaject (Linjeta ) Novel formulation of recombinant human insulin Currently under FDA review (PDUFA date 30 th Oct 2010) Faster absorption and faster onset of action than lispro Previous formulation: ph 4, 25 U/ml (VJ 25) New formulation: neutral ph, 100 U/ml (VJ7) Study aims: Demonstration of bioequivalence between VJ7 and VJ25 Comparison of pharmacokinetic and pharmacodynamic characteristics of VJ7 and insulin lispro (LIS, 100 U/ml) Evaluation of safety/tolerability of VJ7, VJ25 and LIS

6 Key inclusion/exclusion criteria Inclusion criteria Type 1 diabetes mellitus for at least 1 year Age years BMI kg/m² Non-smokers Insulin antibody levels 10 µu/ml Exclusion criteria i HbA1c > 10% C-peptide > 1 ng/ml Changes in concomitant medication in the last 3 weeks Clinically significant abnormalities in safety lab C ca y s g ca t ab o a t es sa ety ab (e.g. liver enzymes >2*ULN, creatinine >ULN)

7 Study design Randomised, double-blind, crossover study Visit 1 (screening) Visit 2 (1 st dosing visit) Visit 3 (2 nd dosing visit) Visit 4 (3 rd dosing visit) Visit 5 (Final visit) VJ 7 VJ 7 VJ days VJ 25 VJ 25 VJ days LIS 3-28 days wash-out period LIS 3-28 days wash-out period LIS

8 GIR (mg/kg/min) Clamp: Important parameters Duration of action Blood glucose (mg/dl) Insulin Aspart iv (variable rate) PK-sampling VJ7, VJ25 : Immunoluminometric sandwich assay (LIAISON ) LIS :Specific radio-immunoassay for insulin lispro (Millipore) min Time (h) 12 U study insulin sc (lifted skinfold abdomen) Blood glu ucose (mmol l/l)

9 Study population (43 people p with type 1 diabetes) Parameter Gender Mean (SD) 22 male, 21 female Age (years) 42.5 (10.6) Height (m) 1.74 (0.08) Weight (kg) 73.4 (10.5) BMI (kg/m²) 24.1 (2.3) Diabetes duration (years) 21.8 (10.9) HbA1c (%) 7.5 (1.0) 3 subjects withdrew consent after the first dosing. All completed clamps were included d in the analyses.

10 Results: Pharmacokinetic profiles Insulin (Lispro) [mu/l] 80 VIAject 25 VIAject 7 Lispro Time [min]

11 Results: Bioequivalence for VJ7 and VJ25 VJ7 VJ25 Ratio VJ7 / VJ25 [90% CI] C INSmax [mu/l] [0.82; 0.96] AUC INS [mu*min/l] 10,221 10, [0.95; 1.01] Table shows geometric means and ratios with 90% confidence intervals (90% CI)

12 Time-related PK parameters (Median values) VJ7 VJ25 LIS t INS 50%early [min] 7.8* t INS 10% AUC [min] 28* t INS max [min] 23* t INS 50%late [min] *p<0.05 vs insulin lispro

13 Results: Pharmacodynamic profiles 6 GIR [mg/kg/min] VIAject 25 VIAject 7 Lispro Time [min]

14 Results: Onset of Action parameters VJ7 LIS VJ min mg/kg tgir 50%early [min] AUC GIR0-60 [mg/kg] 0

15 Pharmacodynamic parameters (Geometric means) VJ7 VJ25 LIS AUC GIR 0-60 [mg/kg] 176* GIR max [mg/kg/min] AUC GIR [mg/kg] 1263* *p<0.05 vs insulin lispro

16 Time-related PD parameters (Medians) VJ7 VJ25 LIS t GIR 50%early [min] 24.5* t GIR 10%AUC [min] t GIR max [min] t GIR 50%late [min] 274* *p<0.05 vs insulin lispro

17 Results: Safety Adverse events in 11 out of 43 patients (VJ25: 3 patients, VJ7 and Lis: 6 patients, respectively) Headache as the most frequent AE (8 patients) Adverse events mild (90%) or moderate (10%) No discontinuations because of treatment-emergent adverse events No serious adverse events

18 Conclusions A new, ph-neutral formulation of VIAject is bio-equivalent to the previously-used formulation has a faster absorption and a faster onset of action than insulin lispro adverse events were mild-moderate and did not result in discontinuation in any treatment t t condition Future clinical trials examining glycemic profiles when using more rapidly absorbed meal time insulins are under development

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20 Results: Pharmacokinetic parameters VJ7 VJ25 LIS Difference Difference VJ7 vs. VJ25 VJ7 vs. LIS [90% CI] [90% CI] t INS max [min] 23* [-10; -2.5] -30 [-35; -22.5] t INS 50%early [min] 78* 7.8* [31 [-3.1; -0.8] 08] [-17.3; -13.8] t INS 50%late [min] [-5; 23] 7 [-15; 27] t INS 10% AUC [min] 28* [-2.5; 2.5] [-15.0; -10.0] Table shows medians and differences with 90% confidence intervals. *p< vs insulin lispro

21 Results: Pharmacodynamic parameters Ratio VJ7 VJ25 LIS VJ7 / VJ25 [90% CI] Ratio VJ7 / LIS [90% CI] GIR max [mg/kg/min] [0.90; 1.06] 0.93 [0.86; 1.01] AUC GIR [mg/kg] 1263* [0.98; 1.16] 1.15 [1.06; 1.26] AUC GIR 0-60 [mg/kg] 176* [0.71; 1.19] 1.65 [1.27; 2.14] Table shows geometric means and ratios with 90% confidence intervals (90% CI). *p<0.05 vs insulin lispro

22 Results: Pharmacodynamic parameters Difference VJ7 VJ25 LIS VJ7 vs. LIS [90% CI] Difference VJ7 vs. LIS [90% CI] t GIR max [min] [13; 60] 20 [-3; 43] t GIR 50%early [min] 24.5* [-7.0; 5.9] [-25.6; -10.4] t GIR 50%late [min] 274* [13; 55] 50 [25; 73] t GIR 10%AUC [min] [-2.7; 7.0] -5.3 [-10.5; -0.8] Table shows medians and differences with 90% confidence intervals. *p<0.05 vs insulin lispro

23 Experimental design: Preparations Day prior to the clamp Last injection of basal analog Start fasting period Last injection of NPH-insulin hours Clamp day Last injection of short acting insulin Arrival in clinic Stop insulin pumps hours Connection to Biostator

24 Statistical methods Smoothing of glucose infusion rate profiles with local weighted regression technique (LOESS) Primary endpoints: C INSmax and AUC INS Bioequivalence: 90% confidence interval for ratio of VJ7 and VJ25 for both C INSmax and AUC INS within % Analysis of (log-transformed) efficacy parameters with ANOVA (fixed effect terms sequence, period, and treatment, random effect subject within sequence)