LAPS The Longacting Basal Insulin Insulin 115 Offers
LAPS The Long-acting Basal Insulin ( Insulin 115) Offers Once-weekly Dosing Potential P 933 With Favorable PK, PD And Mitogenic Profiles IY Choi 1, SY Hwang 1, , JY Kim 1, SY Jung 1, DJ Kim 1, YM Lee 1, YH Kim 1, M Trautmann 2, M Hompesch 2, JW Son 1, SC Kwon 1 1 Hanmi Pharm. Co. , Ltd. , Seoul, South Korea, 2 Profil Institute, Chula Vista, CA, USA RESULTS BACKGROUND l Key requirements for once weekly insulin § Low Variability (intra-patient) § Little or no weight gain Test materials Insulin IGF-1 Mitogenic potency Mitogenic/Metabolic (%) potency§ ratio Sa. OS-2 MCF-7 Additional requirements Human insulin 100 100 1 1 § Excellent Device § No CV safety concerns IGF-1 0. 6 17, 984 6, 255 1, 527 2, 234 545 Insulin Asp. B 10 248 449 756 912 2. 5 3. 0 Insulin 115 86 84 119 88 <1 <1 IDeg 20 K PEG Insulin t 1/2 = 2. 9 hrs t 1/2 = 6. 7 hrs 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. Ø LAPSInsulin 115 achieved a similar Hb. A 1 c reduction with a 4 fold lower dose. PI 3 K Human PK and Developmental Plan (b) PK comparison in normal and renal failure model rats (n=5, s. c. ) Insulin 115 (172 nmol/kg, sc) LAPSInsulin 115 (22. 3 nmol/kg, sc) LAPSInsulin p-ERK 1/2 Apoptosis ERK 1/2 LAPSInsulin, ERK 1/2 Cell proliferation IGF-1 R phosphorylation , Daily Peak-to-Trough Ratio = ~1. 3 t 1/2 = 55 hrs Weekly Peak-to-Trough Ratio = 4. 0 1. 1 1. 1 Actin AKT phosphorylation ERK 1/2 phosphorylation Ø 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. Figure 7. Development plan of LAPSInsulin 115 and QUANTUM project Figure 4. PK/PD in pigs (n=3, s. c. ) Ø Insulin 115 triggered mitogenic signals comparable with human insulin, whereas positive controls (IGF-1 and Asp. B 10) showed significantly higher mitogenic signals. Insulin 115 t 1/2 = 76. 6 hrs LAPS Figure 2. Ex vivo T cell activation of Insulin 115 and LAPSInsulin 115 Ø QUANTUM is a proprietary name of Hanmi’s diabetes & obesity pipeline CONCLUSIONS § 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. 50 th 115, Daily Peak-to-Trough Ratio = ~1. 1 § In vitro receptor binding affinity and mitogenic signaling in MCF-7 § 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. 115, t 1/2 = 132 hrs AKT RAS/RAF AKT Single week Profile LAPSInsulin 115 showed extended half-life compared with LAPSInsulin and daily insulins. Ø 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. § 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, Hb. A 1 c level was measured after 4 -wk administration in db/db mice with Q 2 D dosing interval to mimic human QW dosing. Weekly injected steady state profile Weekly Peak-to-Trough Ratio = 1. 6 Ø LAPSInsulin Binding affinity of test materials was measured in competition between unlabeled and 125 I-labeled materials on the IR- or IGF-1 R/CHO membrane. Mitogenic signaling was assayed in MCF-7 cells and the phosphorylation level was analyzed by Western blot. § 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 [3 H]-Thymidine incorporation and T-cell activation was identified with IL-2 secretion by Elispot assay. Figure 6. Human PK simulation of LAPSInsulin 115 by weekly injection LAPSInsulin METHODS European Association for the Study of Diabetes Ø LAPSInsulin p-AKT SHC IRS-1/2 -3. 3 -3. 4 t 1/2 = 18. 5 hrs IGF-1 R *** -2. 6 *p<0. 05, **p<0. 01 vs vehicle by Anova test p-IGF-1 R AIMS *** LAPSInsulin B 1 0 p As la rg in e lin l ro nt Co Insulin -1. 8 reduced dose Figure 1. Mitogenic signaling in MCF-7 cells IGF-1 * ** -2. 0 ØBoth LAPSInsulin 115 and Insulin 115 showed reduced affinities on IR and IGF-1 R compared with human insulin. In addition, LAPSInsulin 115 and Insulin 115 showed mitogenic/metabolic potency which was comparable to human insulin. IGF-1 receptor signaling § 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 115 t 1/2 = 44. 1 hrs Too low to 5. 3 <1 <1 5. 4 be determined § Metabolic potencies were obtained from lipogenesis assay from rat primary adipocytes IG [EASD 2014 Poster #972, Combination of LAPSInsulin 115 and LAPSCA-Exendin-4] 1. 7 su 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 115 h. In § § § LAPSInsulin 115 analog conjugated with a constant region of a human immunoglobulin fragment via non-peptidyl linker. F- Insulin 115 as a once weekly basal insulin IG l LAPS -1. 0 LAPSInsulin 6 fold 11 5 § Flat profile Table 1. Receptor binding affinity, metabolic and mitogenic potencies relative to human insulin Receptor binding (%) 4 fold reduced dose in § Flexible timing/dosing (b) 4 -week repeated dose (a) PK in normal rats (n=5, s. c. ) ul § Longer half-life § Low Risk of hypos (a) Single dose Figure 3. PK in normal and renal failure model rats In vitro Binding, Proliferation, and ex vivo T Cell Activation In s § PK matched with weekly GLP-1 for combination therapy Figure 5. Dose-sparing and glucose lowering in db/db mice (n=7, s. c. ) PK/PD Correlation and Dose Sparing Effect § In vitro biological properties showed that Insulin 115 and LAPS Insulin Immunogenic threshold t 1/2 = 23 hrs 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. 8% § The extended human PK modeling suggests that LAPSInsulin 115 is an ideal combination partner with LAPSCA-Exendin-4 [EASD 2014 Poster #972]. 0% ØInsulin 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. Annual Meeting; Vienna, Austria; September 15 -19, 2014 REFERENCES Ø LAPSInsulin 115 showed PK/PD correlation in normal pigs. For any questions, please contact Hanmi Pharm. Co. , Ltd. , Phone: +82 -31 -371 -5141; cjchoi@hanmi. co. kr 1. Diabetic Medicine (2013) 30: 1293– 1297. , 2. Diabetes (2011) 60 (Suppl. 1): LB 11 (37 -LB) 3. PLo. S ONE (2010) 5: e 9540. , 4. PLo. S ONE (2012) 7: e 34274. Hanmi Pharm. Co. , Ltd.
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