1. LAPSInsulin 115 + LAPSCA-Exendin-4
Pharmacological Evaluation of Once-weekly Combination Of A Long-acting Insulin Analog
With A Long-acting Exendin-4 Analog In An Animal Model
P972
SC Kwon1, SY Jung1 , CK Lim1, YJ Park1, JK Kim1, IY Choi1, SH Lee1, YH Kim1, JH Kang1, M Trautmann2, M Hompesch2
1Hanmi Pharm. Co., Ltd., Seoul, South Korea, 2Profil Institute, Chula Vista, CA, USA
BACKGROUND
RESULTS
Table 1. in vitro pharmacologic activity of co-formulation
Switching from Daily Insulin to a Weekly Combination Improved Efficacy and Safety
Formulation
% Activity vs. LAPSInsulin 115
% Activity vs. LAPSCA-Exendin-4
Insulin-R
binding
Insulin-R phosphorylation
GLP-1R
cAMP accumulation
LAPSInsulin 115
100% -
LAPSCA-Exendin-4
Co-formulation
(1:0.3*)
117%
105%
106.7%
95.9%
(1:8.1*)
98.8%
129%
101.2%
104.4%
Drug Interference No
Beneficial effects of daily basal insulin and GLP-1RA combination
Superior glycemic control
Improved safety profile (BW gain ↓, Hypoglycemic risk ↓) 
Weekly Potential of LAPSInsulin LAPSCA-Exendin-4 Combination
Figure 6. ΔHbA1c (A), and relationship between ΔHbA1c and ΔBW (B) after switching from daily insulin to weekly combination in db/db mice (n=7, s.c., BID or Q2D)
Figure 1. PK comparison of weekly LAPS products vs. daily
comparator in normal rats (n=3, s.c.)
Basal Insulin
Strong FBG control
Achieve A1c target 50~60%
Body weight gain
Hypoglycemic risk ↑
GLP-1RA
Modest FBG or PPG control
Achieve A1c target 40~60%
Body weight loss
No Hypoglycemic risk
Complementary action
and insulin dose reduction
Synergistic action
Efficacy
Safety
Experimental Design 2 4
6 wk
Vehicle
db/db mice
IGlar (350U/wk as HED)
IGlar
LAPS Insulin 115
(280U/wk as HED)
* Molar ratio between LAPSCA-Exendin-4 and LAPSInsulin 115 in co-formulation
The co-formulation showed no interference with the intrinsic activity of individual drugs
IGlar
LAPSInsulin LAPSCA-Exendin-4
(280U/wk + 1mg/wk as HED)
Beneficial Effects of LAPSInsulin LAPSCA-Exendin-4 Combination
(A) Time course changes in HbA1c
(B) Relationship between ΔHbA1c and ΔBW
*Image was modified from Clin Ther. 35, (2013) and Nat Rev Endocrinol 8, (2012)
-0.8
LAPSInsulin 115
IGlar
-2.5
LAPSCombo
( LAPSInsulin LAPSCA-Exendin-4)
***
LAPSCombo
(LAPSInsulin LAPSCA-Exendin-4)
IGlar
Weekly basal insulin and GLP-1RA combination
enabled by LAPS technology
Figure 4. HbA1c (A) and Body weight changes (B) by combination
treatment in db/db mice (n=5, s.c., Q2D, 5 weeks)
-0.7
IGlar
LAPSInsulin 115
LAPSInsulin 115 [EASD Poster #933]
Low peak-to-trough ratio results in constant insulin levels
Switch
LAPSInsulin 115 and LAPSCA-Exendin-4 showed similar and prolonged PK profiles compared with daily insulin and GLP-1RA, respectively.
***
10.5
8.0
9.0
7.2 ††
Switch (Day 14)
(A) HbA1c at EOT
(B) BW changes at EOT
Figure 2. Multiple dose PK of co-formulated LAPSInsulin 115 and
LAPSCA-Exendin-4 in normal rats (n=5, s.c., Q3D) †
4 fold
reduced insulin dose
† Mean difference vs. Vehicle at EOT
BWG
Neutralization
***
† PTR : 1.6
Switching from daily basal insulin to weekly LAPSInsulin LAPSCA-Exendin-4 combination showed improved efficacy and body weight gain reduction.
† PTR : 1.4
12.1
LAPSCA-Exendin-4 [Ph2b, US & EU]
Super-Agonist [Potent A1c Reduction & BWL]
Flexible regimen from weekly to monthly
Low Immunogenicity *
Figure 7. Development plan of QUANTUM project
AIMS
7.0
Predicted PK in human
6.4
4.8
To evaluate the once-weekly potential of LAPSInsulin LAPSCA-Exendin-4 combination.
t1/2 = 153hrs, PTR = 1.4
t1/2 = 132hrs, PTR = 1.6
To evaluate the beneficial effects of LAPSInsulin LAPSCA-Exendin-4 combination in in vivo disease models.
***p<0.001 vs. vehicle by ANOVA test
†p<0.05, † † p<0.01 by ANOVA test
LAPSInsulin LAPSCA-Exendin-4 combination showed superior efficacy with BWG neutralization by insulin dose reduction.
METHODS
Figure 5. HbA1c (A) and body weight changes (B) daily vs. weekly combination in DIO/STZ rats (n=5, s.c., BID or Q3D, 4 weeks)
QUANTUM is a proprietary name of Hanmi’s diabetes & obesity pipeline
†Peak-to-Through Ratio
In vitro pharmacology of single formulation
Receptor binding affinity of LAPSInsulin 115 and LAPSCA-Exendin-4 in co-formulation was determined by SPA (scintillation proximity assay) and SPR (surface plasmon resonance) analysis, respectively. Phosphorylation of insulin receptor was determined using commercially available kit after 10min treatment of either rh-Insulin or LAPSInsulin 115 in hIR-B/CHO cells. cAMP was assayed after 10 min treatment with LAPSCA-Exendin-4 in hGLP-1R/CHO cells. All results were normalized with LAPSInsulin 115 or LAPSCA-Exendin-4.
CONCLUSIONS
LAPSInsulin 115 and LAPSCA-Exendin-4 showed well-harmonized and prolonged PK profiles compared to daily Insulin and GLP-1RA.
In a co-formulation, LAPSInsulin 115 and LAPSCA-Exendin-4 showed no PK profiles and intrinsic activity interferences.
LAPSInsulin LAPSCA-Exendin-4 combination showed superior glycemic control and reduced body weight gain in db/db mice and DIO/STZ rats.
Switching from daily basal insulin to weekly LAPSInsulin LAPSCA-Exendin-4 combination demonstrated improved glycemic and body weight control in db/db mice.
Similar and prolonged PK profiles of LAPSInsulin 115 and LAPSCA-Exendin-4 were observed in SD rat and weekly human PK simulation.
No PK and Pharmacologic Drug-Drug Interaction Between LAPSInsulin 115 and LAPSCA-Exendin-4 When Co-formulated
(A) HbA1c at EOT
(B) BW changes at EOT
PK analysis of LAPSInsulin 115 and + LAPSCA-Exendin-4 combination
Serum concentration of test articles were determined using the a modified ELISA, and PK parameters were calculated by a non-compartmental method. In multiple-dosing PK study, LAPSInsulin 115 and/or LAPSCA-Exendin-4 were administrated on a Q3D interval to mimic human QW dosing.
***
6.6
5.4
6.3
4.8 †† * 71
100 38 62 54 †
Figure 3. PK profile of co-formulation vs. individual drug
in normal rats (n=6, s.c., single)
(A)
(B)
Pharmacokinetic prediction in human
Human serum concentration vs time of LAPSInsulin 115 was predicted by Css-MRT method using PK parameters from mice, rats and dogs. Human CL was derived from rule of exponent methods, and human Vd was from allometry applied correction factor. Single-dosing PK parameter from P1 study of LAPSCA-Exendin-4 were utilized for the human PK simulation.
Efficacy study in db/db mice or DIO/STZ rats
LAPSInsulin 115 and/or LAPSCA-Exendin-4 were administrated to db/db mice or DIO/STZ rats with Q2D or Q3D dosing. HbA1c level was measured after 4~6 wk treatment. Body weight change was monitored every 2 days.
REFERENCES
Clinical Therapeutics (2013) 35: 714–23
Nature Review Endocrinology (2012) 8:
Diabetologia (2014) 50 (Suppl. 1):P933
PLoS ONE (2010) 5: e9540
***p<0.001 vs. vehicle by ANOVA test
†p<0.05, † † p<0.01 by ANOVA test
Statistical analysis
The HbA1c, body weight changes by LAPSInsulin 115, LAPSCA-Exendin-4, and their combination were analyzed by one way ANOVA with Dunnett’s post test.
LAPSInsulin 115 and LAPSCA-Exendin-4 did not show drug-drug interaction
when co-formulated.
LAPSInsulin LAPSCA-Exendin-4 combination showed superior efficacy compared with daily combination without additional BWG.
Hanmi
European Association for the Study of Diabetes 50th Annual Meeting; Vienna, Austria; September 15-19, 2014
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Hanmi Pharm. Co., Ltd.