The Long-acting Basal Insulin (LAPSInsulin 115) Offers Once-weekly Dosing Potential
With Favorable PK, PD And Mitogenic Profiles
IY Choi1, SY Hwang1, , JY Kim1, SY Jung1, DJ Kim1, YM Lee1, YH Kim1, M Trautmann2, M Hompesch2, JW Son1, SC Kwon1
1Hanmi Pharm. Co., Ltd., Seoul, South Korea, 2Profil Institute, Chula Vista, CA, USA
- PK matched with weekly GLP-1 for combination therapy
- Longer half-life
- Flat profile
- Low Variability (intra-patient)
PK/PD Correlation and Dose Sparing Effect
- Low Risk of hypos
- Flexible timing/dosing
- Little or no weight gain
Figure 3. PK in normal and renal failure model rats
- LAPSInsulin 115 as a once weekly basal insulin
In vitro Binding, Proliferation, and ex vivo T Cell Activation
(a) PK in normal rats (n=5, s.c.)
Insulin 115 analog conjugated with a constant region of a human immunoglobulin fragment via non-peptidyl linker.
Table 1. Receptor binding affinity, metabolic and mitogenic potencies relative to human insulin
4 foldreduced dose
- Excellent Device
- No CV safety concerns
- Lower peak-to-trough ratio from long duration of action
- Improved patient adherence by once-weekly administration
- Ideal combination partner with weekly GLP-1 agonist[EASD 2014 Poster #972, Combination of LAPSInsulin 115 and LAPSCA-Exendin-4]
- Key requirements for once weekly insulin
*p<0.05, **p<0.01 vs vehicle by Anova test
§Metabolic potencies were obtained from lipogenesis assay from rat primary adipocytes
- Both LAPSInsulin 115 and Insulin 115 showed reducedaffinities on IR and IGF-1R compared with human insulin. In addition, LAPSInsulin 115 and Insulin 115 showed mitogenic/metabolic potency which was comparable to human insulin.
Human PK and Developmental Plan
Figure 6. Human PK simulation of LAPSInsulin115 by weekly injection
(b) PK comparison in normal and renal failure model rats (n=5, s.c.)
Figure 7. Development plan of LAPSInsulin 115 and QUANTUM project
(172 nmol/kg, sc)
Weekly injected steady state profile
(172 nmol/kg, sc)
(22.3 nmol/kg, sc)
LAPSInsulin115, t1/2= 132 hrs
Weekly Peak-to-Trough Ratio = 1.6
Daily Peak-to-Trough Ratio =~1.1
- Investigation of in vitro receptor pharmacology, metabolic, and mitogenic activity of LAPSInsulin 115
- Evaluation of pharmacokinetics and pharmacodynamics of LAPSInsulin 115 in normal and diabetic animal models
- Prediction of human pharmacokinetic profile of LAPSInsulin 115 based on animals’ PK data
Daily Peak-to-Trough Ratio =~1.3
LAPSInsulin, t1/2= 55 hrs
Weekly Peak-to-Trough Ratio = 4.0
- QUANTUM is a proprietary name of Hanmi’s diabetes & obesity pipeline
- Pharmacokinetics in humans was predicted based on PK of three different animals. LAPSInsulin 115 demonstrated extended half-life and lower peak-to-trough ratio than LAPSInsulin. In addition, inter-day variability of LAPSInsulin 115 was ranged from 1.0-1.1.
- LAPSInsulin 115 showed extended half-life compared with LAPSInsulin and daily insulins.
- LAPSInsulin 115 showed a comparable PK profile in a renal failure rat model (4 mg/kg of cisplatin injected, ip, rats) compared with normal rats.
- Figure 1. Mitogenic signaling in MCF-7 cells
- In vitro receptor binding affinity and mitogenic signaling in MCF-7
- Binding affinity of test materials was measured in competition between unlabeled and 125I-labeled materialson the IR- or IGF-1R/CHO membrane. Mitogenic signaling was assayed in MCF-7 cells and the phosphorylation level was analyzed by Western blot.
Figure 5. Dose-sparing and glucose lowering in db/db mice (n=7, s.c.)
Figure 4. PK/PD in pigs (n=3, s.c.)
- In vitrobiological properties showed that Insulin 115 and LAPSInsulin 115 did not increase the mitogenic potency when compared with insulin.
- An extended PK profiles and prolonged glucose lowering efficacies suggest that LAPSInsulin 115 may achieve a basal insulin profile suitable for once weekly use.
- The extended human PK modeling suggests that LAPSInsulin 115 is an ideal combination partner with LAPSCA-Exendin-4 [EASD 2014 Poster #972].
- Ex vivo T cell activation (Antitope limited, UK)
- Test articles were incubated for 8 days with PBMC from 50 donors. Cell proliferation was meausred by [3H]-Thymidine incorporation and T-cell activation was identified with IL-2 secretion by Elispot assay.
LAPS Insulin 115
t1/2 = 76.6 hrs
Figure 2. Ex vivo T cell activation of Insulin 115 and LAPSInsulin 115
IGF-1 receptor signaling
(b) 4-week repeated dose
- Pharmacokinetic analysis of LAPSInsulin 115 in animal models
- Test materials were s.c. injected to normal or renal failure SD rats or normal pigs. Renal failure SD rat model was induced by 4 mpk of cisplatin. Serum concentration of test articles were determined using ELISA and PK parameters were calculated by a non-compartmental method.
t1/2 = 44.1 hrs
t1/2 = 23 hrs
- Phamacodynamic analysis of LAPSInsulin 115 in db/db mice
- In an acute study, 4-hr fasting blood glucose level was measured every day after s.c administration of test articles in db/db mice. In a chronic study, HbA1c level was measured after 4-wk administration in db/db mice with Q2D dosing interval to mimic human QW dosing.
t1/2 = 18.5 hrs
t1/2 = 2.9 hrs
20K PEG Insulin
t1/2 = 6.7 hrs
- Pharmacokinetic prediction in human
- Human serum concentration-time was predicted by Css-MRT method from PK parameters of mice, rats and dogs. Human CL was derived from rule of exponent methods, and human Vd was from allometry applied correction factor.
- LAPSInsulin 115 showed prolonged glucose lowering effect compared to LAPSInsulin in db/db mice at the same dose and even with a 6 fold lower dose.
- LAPSInsulin 115 achieved a similar HbA1c reduction with a 4 fold lower dose.
- Insulin 115 showed negligible activation of T cells from 50 human donors, which is below the immunogenic threshold. In addition, LAPSInsulin 115 completely attenuated the residual T cell activation.
1. Diabetic Medicine (2013) 30: 1293–1297., 2. Diabetes (2011) 60 (Suppl. 1):LB11 (37-LB)
3. PLoS ONE (2010) 5: e9540., 4. PLoS ONE (2012) 7: e34274.
- LAPSInsulin 115 showedPK/PD correlation in normal pigs.
- Insulin 115 triggered mitogenic signals comparable with human insulin, whereas positive controls (IGF-1 and AspB10) showed significantly higher mitogenic signals.
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Hanmi Pharm. Co., Ltd.
European Association for the Study of Diabetes 50th Annual Meeting; Vienna, Austria; September 15-19, 2014