140609 Poster ADA BC Combo BC3 CT005 final vf CSE

Pharmacokinetic and Pharmacodynamic Characteristics of BioChaperone® Combo,
the First Fixed Combination of Glargine and Lispro, in Type 1 Diabetes
Ulrike Hövelmann1, Bertrand Alluis2, Grégory Meiffren2, Aymeric Ranson2, Olivier Soula*2, Gérard Soula2, Cyril Seroussi2, Birgit Kronshage1, Leszek Nosek1, Susanne Famulla1, Tim Heise1
1 Profil, Neuss, Germany; 2 Adocia, Lyon, France; * corresponding author ([email protected])
Abstract
Methods
In this double-blind, crossover study we investigated the PK/PD characteristics of BC Combo 25, a
novel formulation combining insulins lispro (25%) and glargine (75%) in a limpid pH-neutral
solution. Twenty people with type 1 diabetes participated in automated euglycemic clamps
(ClampArt®, target blood glucose (BG) 100 mg/dL, clamp duration 30h) and received 0.8 U/kg of BC
Combo or Humalog® Mix 25 (MIX). Mean glucose infusion rate (GIR) curves (Figure) illustrate an
earlier onset of action (25±11 vs. 40±13 min) consistent with earlier Tmax (2.8±0.8 vs. 3.4±0.8
h) of BC Combo vs. MIX. Likewise, the early metabolic effect (AUCGIR 0-2h 504±210 vs. 325±183
mg/kg) and the early PK exposure (AUCPK 0-1h 86±39 vs. 34±19 h*mU/L) were higher, and BC
Combo showed a more pronounced late metabolic effect (AUCGIR 12-30h 1480±900 vs. 961±553
mg/kg) consistent with a higher basal exposure (AUCPK 12-30h 563±409 vs. 286±233 h*mU/L).
Duration of action (time to BG > 118 mg/dL, 29.8±0.7 vs. 25.5±4.3 h) and half-life (17.6±8.7 vs.
7.7±3.0 h, p<0.05 for all comparisons) were longer with BC Combo indicating the potential for
once daily dosing. Both formulations were well tolerated, no local reactions occurred. Both PK and
PD demonstrate faster prandial and longer basal action for BC Combo supporting the potential for
improved BG control vs. MIX with only one daily injection.
o
This was a randomized, single-center, double-blind, two-way crossover glucose clamp study.
o
Eligible study participants: Male subjects with type 1 diabetes mellitus (T1DM), age 18 - 64 years,
body mass index (BMI) 18.0 - 28.0 kg/m2, HbA1c ≤ 9.0 %, total daily insulin dose < 1.2 U/kg/day.
o
Patients were randomly assigned to two single-dose administrations of 0.8 U/kg BioChaperone® Combo or
Humalog® Mix 25 under euglycemic clamp conditions at two separate visits.
o
After an overnight fast, patients were connected in the morning to ClampArt® (a modern clamp device
developed by Profil, Neuss, Germany). A variable intravenous infusion of insulin aspart was started to reach a
target blood glucose level (BG) of 100 mg/dl (run-in).
o
Glucose infusion rate (GIR) was automatically adjusted by ClampArt® to maintain a BG level close to target for
30 hours post-dosing. The clamp experiment was stopped earlier if BG increased to >200 mg/dl without any
glucose infusion in the past 30 min.
o Total insulin concentrations were nearly twice as high with BC Combo compared with MIX [AUCINS 0-30h, Table 2].
The difference of cross-reactivity of the assay to lispro and glargine (80 and 100%, respectively) does not fully
explain the difference in total AUC. Therefore a trend to higher bioavailability for BC Combo compared to MIX is
conceivable. That is supported by the strong trend toward a higher bio-efficacy seen in GIR (total AUC in GIR in
favour to BC Combo, p=0.05).
o
Blood samples for determination of pharmacokinetics (PK) were drawn at pre-dose and in regular intervals
until 30 h post-dose.
o Even when AUC-parameters were corrected for total insulin AUCs, parameters for duration of absorption
(AUCINS 12-30h, t½) were higher with BC Combo and were in line with the pharmacodynamic results.
o
Serum insulin concentrations were determined with an immunoradiometric sandwich assay (BI-INSULINIRMA, Cisbio Bioassays). Pre-experiment validation showed a cross-reactivity of approximately 80% to insulin
lispro and approximately 100% to insulin glargine.
Table 2: PK/PD Parameters
o Compared with MIX, BC Combo showed a significantly faster onset of action, reached maximum action (GIR tmax)
earlier and had a higher glucose-lowering effect in the first two hours post-dosing (AUCGIR 0-2h) [Table 2, Figure 2].
o Only 2 subjects on BC Combo (in contrast to 14 subjects on MIX) reached end of action (BG > 118 mg/dL without
any GIR in the last 15 min) during the 30 hour clamp duration indicating a significantly longer duration of action
of BC Combo.
o The longer duration of action of BC Combo is also supported by a better blood glucose control in the last hour of
the clamp [Table 2, Figure 5] and a significantly higher late metabolic effect (higher AUCGIR 12-30h).
PD parameters, based on glucose infusion rates (GIR)
Figure 1: Study Design
Aim
Visit 1
(Screening visit)
o To investigate the pharmacodynamic and pharmacokinetic properties and safety of BioChaperone Glargine
Lispro and HumalogMix 25 in subjects in patients with type 1 diabetes
Visit 2
(Dosing visit)
Visit 3
(Dosing visit)
Visit 4
(Follow-up visit)
BC Combo (N=19)
MIX (N=20)
p value
22 (13.8-58.8)
41 (6-61.8)
0.0017
30.0 (27.2-30)
25.7 (15.8-30.0)
0.0002
459 (42)
288 (56)
0.0012
AUCGIR 0-30h [mg/kg] ᴥ
3835 (40)
3161 (34)
0.0519
AUCGIR 12-30h [mg/kg] ᴥ
1286 (61)
823 (57)
0.0257
2.6 (2.0-4.9)
3.0 (2.5-5.0)
0.0145
100.6 (99.6-136.6)
129.6 (97.0-208.2)
0.0008
BC Combo (N=19)
MIX (N=19)
p value
77 (48-228)
26 (18-91)
<0.0001
437 (262-2082)
214 (61-1034)
<0.0001
970 (591-4182)
526 (293-2457)
<0.0001
15.9 (49.2)
7.0 (39.4)
<0.0001
0.67 (0.3-0.8)
1.50 (0.8-2.5)
<0.0001
46.3 (7.9)
38.7 (18.7)
<0.0001
a
Onset Of Action [min] #
b
BC Combo (0.8 U/kg)
End Of Action [h]
#
o To date all currently available pre-mixed insulins contain protamine-retarded insulin as basal component
which often show a peaked activity profile with rather high effects 6-12 h post-dosing and a high variability.
(Heise T, et al. Diabetes 2004; 53: 1614-20).
2−21 days
MIX (0.8 U/kg)
5−14 days
wash-out
GIR tmax [h] #
o The study insulins were given s.c. into a lifted skinfold around the umbilicus by means of an insulin syringe.
All injections were performed by a competent unblinded person not otherwise involved in the study conduct
to keep the double-blind character of the study.
o Furthermore, all these premixed insulins require at least a twice daily injection to fully cover basal insulin
requirements over 24 hours.
Statistical Analysis
o Therefore a premixed insulin combining the long-acting insulin glargine with a fast-acting insulin may provide
the option of once daily use together with improved glycaemic control (in terms of better HbA1c values) and a
reduction in hypoglycaemic episodes.
o The pharmacodynamic (PD) endpoints were derived from the individual GIR profiles which were smoothed
using a locally weighted regression technique (LOESS, smoothing factor 0.25). Time-related parameters were
derived from the smoothed curves, AUCs from the unsmoothed data.
BioChaperone Combo
o Key endpoints including early (0-1h and 0-2h) and late (12-30h) AUCs under the PK/PD curves were analyzed
using a mixed effect linear model with treatment, period and sequence as fixed effects and subjects within
sequence as random effect. Endpoints that were not normally or log normally-distributed were analyzed nonparametrically using Wilcoxon Signed Rank Test.
c
End Of Clamp BG [mg/dL] #
PK parameters, based on insulin concentrations (INS)
AUCINS 0-1h [h*mU/L] #
AUCINS 12-30h [h*mU/L]
AUCINS 0-30h [h*mU/L]
t 1/2 [h]
ᴥ
tmax [h]
#
AUCIns 12-30h/AUCIns
BioChaperone Combo 25 is an injectable combination at
pH 7 of insulin glargine (U300) and insulin lispro (U100).
This combination is made possible by the use of BioChaperone, Adocia’s proprietary platform technology.
The BioChaperone technology does not modify the physical, chemical and biological integrity of either insulin
lispro (U100) or insulin glargine (U300).
ᴥ
5−12 days
MIX (0.8 U/kg)
o Pre-mixed insulins are widely used as they provide both prandial and basal insulin coverage in one
formulation. While short-acting insulin analogues with improved pharmacodynamic characteristics for
prandial insulin coverage are available, it has not yet been possible to combine short-acting analogues with
insulin glargine, the most widely used basal insulin analogue.
ᴥ
Table 1: Baseline Characteristics (N=21*)
§
#
Characteristics
Figure 3: PD BG profiles of BioChaperone Combo and MIX
BC Combo (0.8 U/kg)
AUCGIR 0-2h [mg/kg]
Introduction
Figure 2: PD GIR profiles of BioChaperone Combo and MIX
Efficacy Results
Mean ± SD
Age (years)
42.3 ± 13.0
Height (cm)
179.1 ± 7.9
Weight (kg)
80.2 ± 8.7
BMI (kg/m2)
24.9 ± 1.4
HbA1c (%)
7.8 ± 0.6
*21 patients were exposed, 2 patients
withdrew consent, and 19 patients
completed the trial.
For the analysis of PD and PK parameters,
data from the Full Analysis Set which
included 20 subjects was used.
For safety analysis of safety data from the
Safety Analysis Set which included 21
subjects was used.
a
b
c
#
#
§
0-last [%]
Geometric means and (CV%) for log-normally distributed parameters
Arithmetic means and (CV%) for normally distributed parameters
Medians and (Min/Max) for parameters that were neither normally nor log-normally distributed
Time from dosing until blood glucose concentrations decreased by 5 mg/dL from baseline
Time from dosing until End Of Action defined as an increase in blood glucose concentrations to > 118 mg/dL without
any
glucose infusion in the last 15 min (Bolli GB, et al. Diabetes Care 2012; 35:2626-30).Duration Of Action was only reached in 2
clamps with BC Combo and 14 clamps with MIX. The p-value is based on a comparison of number of clamps reaching end of
action (Chi-Square Test)
Mean blood glucose (BG) values [mg/dL] in the last hour of the glucose clamp (29-30 hours after dosing). The p-value is based on
a non-parametric analysis
Safety
Conclusions
o This is the first study providing a "proof-of-concept" that glargine can be combined with lispro in
one insulin product at neutral pH using the BioChaperone technology.
o BioChaperone Combo 25 shows a faster onset, a more pronounced early metabolic effect as well
as a longer duration of action and a higher basal metabolic effect than Humalog® Mix25.
o BioChaperone Combo 25 has the potential to improve glycemic control compared to HumalogMix.
o The current data suggest that BioChaperone Combo 25 has the potential to be used as either
once-a-day or twice-a-day treatment.
o No safety issues were identified.
o Both insulin formulations were well tolerated and no injection site reactions occurred.
This study was funded by Adocia and performed by Profil.
NCT trial number: NCT01981031
Presented at the American Diabetes Association, 13-17 June 2014, San Francisco, USA.

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