LAPSInsulin LAPSCA-Exendin-4

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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 115 + 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 115 + LAPSCA-Exendin-4 (280U/wk + 1mg/wk as HED) Beneficial Effects of LAPSInsulin 115 + LAPSCA-Exendin-4 Combination (A) Time course changes in HbA1c (B) Relationship between ΔHbA1c and ΔBW *Image was modified from Clin Ther. 35, 714-23 (2013) and Nat Rev Endocrinol 8, 728-42 (2012) -0.8 LAPSInsulin 115 IGlar -2.5 LAPSCombo ( LAPSInsulin 115 + LAPSCA-Exendin-4) *** LAPSCombo (LAPSInsulin 115 + 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 115 + 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 115 + LAPSCA-Exendin-4 combination. t1/2 = 153hrs, PTR = 1.4 t1/2 = 132hrs, PTR = 1.6 To evaluate the beneficial effects of LAPSInsulin 115 + 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 115 + 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 115 + 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 115 + 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: 728-42 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 115 + 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 For any questions, please contact Hanmi Pharm. Co., Ltd., Phone: +82-31-371-5141; cjchoi@hanmi.co.kr Hanmi Pharm. Co., Ltd.