Treatment with BI 1356, a Novel and Potent DPP-4 Inhibitor, Significantly Reduces
`Glucose Excursions after an oGTT in Patients with Type 2 Diabetes
`
`ADA 22-26 June 2007, Chicago
`
`No. of pts. with any AE
`
`Tim Heise1, Renger Tiessen2, Silke Huettner3, Arne Ring3, Armin Ritzhaupt3, Ulrike Graefe-Mody3, Klaus A Dugi3
`1Profil Institut für Stoffwechselforschung, Neuss, Germany, 2PRA International, Zuidlaren, The Netherlands, 3Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
`DEMOGRAPHIC AND BASELINE
`RESULTS - PHARMACODYNAMICS
`RESULTS – SAFETY AND TOLERABILITY
`CHARACTERISTICS
`Figure 2: Arithmetic mean DPP-4 activity in plasma
`Table 3: Summary and frequency of adverse events
`Placebo
`BI 1356
`Day 1
`• 48 patients were randomised to one of 4 treatment groups with a ratio of 3:1
`Day 12
`Days 2 to 11
`N=12 (%)
`N=35 (%)
`active treatment to placebo
`• One patient was withdrawn from the study prior to first drug administration for
`9 (75.0)
`19 (54.3)
`safety reasons due to elevated blood glucose levels
`
`7 (58.3)
`
`13 (37.1)
`
`Pts. with drug-related AEs
`Patients with AEs leading
`to discontinuation
`0 (0.0)
`0 (0.0)
`Patients with SAEs
`Most frequently reported AEs by MedDRA System Organ
`Class and Preferred Term (≥3 patients in any dose group)
`Nervous system disorders
`headache
`dizziness
`Renal and urinary
`disorders
`
`0 (0.0)
`
`0 (0.0)
`
`4 (33.3)
`1 (8.3)
`
`3 (8.6)
`3 (8.6)
`
`pollakisuria
`
`3 (25.0)
`
`4 (11.4)
`
`100
`80
`60
`40
`20
`0
`
`DPP-IV activity [%]
`
`0
`
`4
`
`8
`12 16 20 24
`Time [hours]
`
`48
`
`96 144 192 240
`Time [hours]
`
`264 268 272 276 280 284 288
`Time [hours]
`
`1 mg (N=9)
`10 mg (N=9)
`
`2.5 mg (N=9)
`Placebo (N=12)
`
`5 mg (N=8)
`
`• DPP-4 activity was reduced dose dependently with increasing
`doses of BI 1356
`• At trough, DPP-4 activity was reduced by >80% in 7 patients in the
`5 mg (87.5%) and all 9 patients in the 10 mg (100%) dose group
`
`Fig. 3: DPP-4 activity in plasma versus BI 1356
`plasma concentration after administration of 1,
`2.5, 5 and 10 mg BI 1356 for 12 days
`
`DPP-IV activity versus BI 1356 plasma concentration DPP-IV activity versus BI 1356 plasma concentration
`
`
`
`100100
`
`
`
`8080
`
`
`
`6060
`
`4040
`
`Table 1: Patient characteristics at baseline
`
`Placebo
`
`BI 1356
`1 mg
`
`BI 1356
`2.5 mg
`
`BI 1356
`5 mg
`
`BI 1356
`10 mg
`
`N
`
`Age
`(years±SD)
`
`BMI
`(kg/m2±SD)
`
`12
`
`55.7
`(8.6)
`
`27.4
`(3.4)
`
`9
`
`56.1
`(8.1)
`
`28.6
`(2.2)
`
`9
`
`55.4
`(6.1)
`
`28.9
`(3.3)
`
`8
`
`54.5
`(9.0)
`
`29.9
`(2.3)
`
`9
`
`58.2
`(6.6)
`
`28.8
`(3.3)
`
`RESULTS - PHARMACOKINETICS
`
`Figure 1: Arithmetic mean (SD) plasma concentration of BI 1356
`
`Day 1
`
`Days 2 to 11
`
`Day 12
`
`Poster No. 0588P
`
`ABSTRACT
`BI 1356 is a novel, potent, and selective DPP-4 inhibitor currently in development for
`the treatment of type 2 diabetes. The safety, pharmacokinetics, and pharmacodynamic
`properties of BI 1356 were investigated in a randomised, double-blind, placebo-
`controlled study in patients with type 2 diabetes.
`Forty-seven male type 2 diabetic patients, aged 21-65 and with a BMI of 18-35 kg/m2,
`were treated once daily with 1, 2.5, 5, or 10 mg BI 1356, or placebo for 12 days.
`Treatment with BI 1356 was well tolerated. The incidence of adverse events in patients
`treated with BI 1356 (54%) was not higher when compared to placebo (75%). There
`were no serious adverse events and no episodes of hypoglycaemia.
`BI 1356 plasma concentrations and exposure increased less than proportionally with
`dose. The maximum plasma concentrations of BI 1356 at steady-state ranged from
`4.5 nmol/L (1 mg dose group) to 13.6 nmol/L (10 mg), with a median tmax of 1.5 h.
`Reductions in plasma DPP-4 activity were well correlated with plasma concentrations of
`BI 1356. Two hours after administration of 2.5 mg BI 1356, DPP-4 activity was reduced
`by >80% and remained at that level at steady-state.
`Levels of GLP-1 were increased by more than 2-fold. Following an oGTT on day 13,
`24 hrs after the last dose of BI 1356, area under the plasma glucose excursions were
`reduced by 53 (1 mg BI 1356), 106 (2.5 mg), 82 (5 mg), 111 (10 mg), and 25 (placebo)
`mg.h/dL, respectively. Despite the small group sizes, these reductions reached
`statistical significance for 2.5, 5, and 10 mg BI 1356 compared to baseline and
`compared to placebo (p<0.05 for both).
`In summary, 24 hrs after the last dose, DPP-4 inhibition was >70% after administration
`of BI 1356 doses of >1 mg, and significant improvements in glucose parameters were
`observed in patients with type 2 diabetes. Given this potency and duration of action,
`BI 1356 has the potential to be a best in class DPP-4 inhibitor.
`
`Adverse events and global tolerability
`• Incidence of AEs with BI 1356 was not higher compared to placebo,
`and there was no dose dependency
`• No adverse events associated with hypoglycaemia were observed
`Clinical laboratory tests
`• No clinically relevant changes were observed in routine blood tests
`including haematology, coagulation parameters, clinical chemistry
`parameters, and urinalysis
`12-lead ECG and vital signs
`• No clinically relevant changes in blood pressure and heart rate
`• Mean change in weight from baseline ranged from -1.5 (2.5 mg) to
`-3.2 kg (1 mg) for BI 1356 and -1.8 kg for placebo
`• Mean values of QTc for baseline, day 1 and day 12 for each of the
`dose groups and placebo were similar and no notable changes
`were detected
`
`CONCLUSIONS
`Administration of multiple rising oral doses of BI 1356 in
`patients with type 2 diabetes was well tolerated and safe
`
`The overall incidence of adverse events did not differ between
`BI 1356 and placebo, and no adverse event was seen more
`frequently with BI 1356 compared with placebo
`BI 1356 plasma concentrations correlated well with DPP-4
`activity; BI 1356 at doses of 5 and 10 mg reduced DPP-4
`activity by 80%
`Despite the small group sizes, statistically significant
`reductions of glucose excursions were observed with 2.5, 5,
`and 10 mg BI 1356 24 hrs after the last dose compared with
`baseline and compared with placebo
`BI 1356 is a potent and long-acting DPP-4 inhibitor with a
`pharmacokinetic and pharmacodynamic profile that supports a
`once-daily dosing regimen
`
`ACKNOWLEDGEMENTS
`
`We would like to thank all those who
`participated in this study and were
`involved in the preparation, conduct
`and analysis of the study.
`
`ABCD
`
`
`
`
`
`2020
`
`
`
`00
`
`DPP-IV activity [%]
`DPP-IV activity [%]
`
`
`
`0.10.1
`
`
`11
`
`1010
`
`BI 1356 plasma conc. [nmol/L]BI 1356 plasma conc. [nmol/L]
`Fig. 4: Effect of multiple oral doses of BI 1356 on 2h
`glucose levels after an oGTT after 12 days of
`treatment in patients with type 2 diabetes
`Placebo 1 mg 2.5 mg 5 mg 10 mg
`(N=12) (N=9) (N=9) (N=8) (N=9)
`
`
`
`100100
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`Day 1
`Day 13
`
`0.0
`
`-20.0
`
`-40.0
`
`-60.0
`
`-80.0
`
`-100.0
`
`-120.0
`
`-140.0
`
`Change from baseline in plasma glucose AUEC0-2h
`
`[mg.h/dL]
`
`Error bars indicate SEM; *indicates exploratory statistical significance (p<0.05) using
`an ANCOVA model
`
`Plasma glucose after oGTT
`• Treatment with multiple oral doses of BI 1356 reduced 2 hrs
`plasma glucose excursions after an oGTT administered 24 hrs after
`the last dose, both on day 1 and day 13
`• The reduction in plasma glucose excursions was dose-dependent
`and reached statistical significance (p<0.05) for the 2.5, 5, and
`10 mg doses, both compared to baseline and compared to placebo
`GLP-1
`• 24 hrs after last drug administration, levels of GLP-1 were
`increased 3 -4 fold in patients treated with 1, 2.5, 5 and 10 mg
`BI 1356
`
`0
`
`4
`
`8
`12 16 20 24
`Time [hours]
`
`48
`
`96 144 192 240
`Time [hours]
`
`264 268 272 276 280 284 288
`Time [hours]
`
`1 mg (N=9)
`
`2.5 mg (N=9)
`
`5 mg (N=8)
`
`10 mg (N=9)
`
`18
`15
`12
`
`0369
`
`BI 1356 plasma conc. [nmol/L]
`
`• Based on trough plasma concentrations, steady state of BI 1356 was
`reached between day 2 (10 mg) and day 5 (1 mg)
`• Median tmax was in the range of 1.5 hrs
`• Following multiple oral doses of BI 1356, AUC0-24 and AUCtau,ss, as well as
`Cmax and Cmax,ss increased less than proportionally
`• Approximately 3% of BI 1356 were renally excreted
`Table 2: Geometric mean (%gCV) of pharmacokinetic
`parameters after oral administration of 1, 2.5, 5
`and 10 mg BI 1356 once daily for 12 days
`
`Parameter
`AUC0-24
`[nmol·h/L]
`AUCτ,ss
`[nmol·h/L]
`Cmax
`[nmol/L]
`Cmax,ss
`[nmol/L]
`t½,ss[h]
`RA,Cmax
`RA,AUC
`
`5 mg
`2.5 mg
`1 mg
`40.2 (39.7) 85.3 (22.7) 118 (16.0)
`
`10 mg
`161 (15.7)
`
`81.7 (28.3) 117 (16.3)
`
`158 (10.1)
`
`190 (17.4)
`
`3.13 (43.2) 5.25 (24.5) 8.32 (42.4)
`
`9.69 (29.8)
`
`4.53 (29.0) 6.58 (23.0) 11.1 (21.7)
`
`13.6 (29.6)
`
`131 (17.4)
`121 (21.3) 113 (10.2)
`1.44 (25.6) 1.25 (10.6) 1.33 (30.0)
`2.03 (30.7) 1.37 (8.19) 1.33 (15.0)
`
`130 (11.7)
`1.40 (47.7)
`1.18 (23.4)
`
`INTRODUCTION
`Type 2 diabetes is characterised by insulin resistance and progressive failure in
`insulin secretion. Current oral antidiabetic agents cannot prevent the
`progressive failure of pancreatic ß-cells, leading to secondary drug failure.
`A novel approach in the treatment of type 2 diabetes targets the incretins (e.g.
`GLP-1), hormones secreted in the intestine in response to food intake. GLP-1
`regulates insulin and glucagon secretion. DPP-4 inhibitors improve glycaemic
`control by increasing plasma levels of intact GLP-1. BI 1356 is a potent, novel,
`orally available, and selective inhibitor of DPP-4 (see also Poster Nos. 0586P
`and 0594P).
`The current study was designed to evaluate the safety, tolerability,
`pharmacokinetics (PK), and efficacy of BI 1356 in men with type 2 diabetes.
`Efficacy measurements were based on pharmacodynamics (inhibition of DPP-4
`activity), and the effect of BI 1356 on post-prandial glucose excursions after an
`oGTT.
`
`OBJECTIVES
`• Safety and tolerability following administration of multiple rising oral doses
`of 1, 2.5, 5, and 10 mg BI 1356 for 12 days in men with type 2 diabetes
`• Evaluation of pharmacokinetic, including determination of renal excretion
`and pharmacodynamic parameters of BI 1356 after multiple dosing
`METHODS
`
`Subjects
`• Men with type 2 diabetes either on diet and exercise only, or treated with up to
`two oral hypoglycaemic agents, age 21 - 65 years and BMI 18.5 - 35 kg/m2
`• HbA1c ≤8.5 % at screening (≤8.0 % at screening for patients treated with two
`oral hypoglycaemic agents)
`Study design
`• Screening visit, wash-out period of previous anti-diabetic medication for 14 days
`prior to the first study drug administration, 12-day treatment period, and end-of-
`study examination
`• BI 1356 was administered orally as solution in the morning 1 h before breakfast
`• An oral glucose tolerance test (oGTT) was done at baseline, day 1 and day 13
`(24hrs after last study drug intake)
`• Pharmacokinetic profiling and pharmacodynamic measurements were
`performed on day 1 and day 12
`• DPP IV activity was measured by incubating diluted EDTA plasma with Ala-Pro-
`AFC as substrate and measuring the increase in absorbance over time
`
`MYLAN Ex. 1018