ADO09 is a co-formulation of PRAM and insulin A21G developed to leverage the beneficial effects of PRAM on post-prandial glucose without additional injections. This double-blind randomized cross-over trial studied pre-meal ADO09 vs. Novolog® over 24 days with degludec as basal insulin. Mixed meal tolerance test data (MMTTs) and CGM metrics of 21 T1D subjects were analyzed. Incremental plasma glucose MMTT-AUCs with ADO09 on day 24 were reduced by >100% after 1h and 2h (both p<0.001) and by 39% after 4h (not significant) vs. Novolog. Similarly, ∆PGmax was reduced by 19 mg/dL (p=0.01) and ∆PG_1h by 70 mg/dL (p<0.001)(Fig. 1). ADO09 showed improved CGM-metrics with higher 24h-time in range (TIR 70-180 mg/dL, + 51 min, p=0.01), time in tight range (80-140mg/dL, +70 min, p=0.002). Time <70 mg/dL was slightly higher (+9.6 min, p=0.046) as were hypoglycemic events (142 vs. 115) in the outpatient period. ADO09 significantly reduced body weight (-0.7kg vs. baseline, p=0.01). On the last outpatient day, mean daily bolus doses were 4 U lower with ADO09 (-21%, p=0.05). Both treatments were well tolerated with more gastrointestinal adverse events (24 vs. 6) observed with ADO09, consistent with typical effect of PRAM. In conclusion, ADO09 significantly improved CGM metrics including TIR, weight control and bolus insulin needs vs. Novolog over 24 days of use. Disclosure G. Meiffren: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. G. Andersen: Employee; Self; Profil Institute for Clinical Research. R. Eloy: Employee; Self; ADOCIA. C. Seroussi: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. C. Mégret: None. S. Famulla: None. Y. Chan: Employee; Self; ADOCIA. M. Gaudier: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. O. Soula: Board Member; Self; ADOCIA. Employee; Self; ADOCIA. Employee; Spouse/Partner; ADOCIA. Stock/Shareholder; Spouse/Partner; ADOCIA. Stock/Shareholder; Self; ADOCIA. J. DeVries: Advisory Panel; Self; Novo Nordisk A/S, Zealand Pharma A/S. Consultant; Self; Metronom Health. Employee; Self; Profil Institute for Clinical Research. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S.

Because of its physico‐chemical properties, insulin glargine is usually not mixable with rapid insulins. BioChaperone BC147 is a polyanionic amphiphilic polymer, solubilizing insulin glargine at neutral pH, and thus enabling stable glargine formulation with fast‐acting insulin lispro (BioChaperone glargine lispro co‐formulation [BC Combo]). We investigated pharmacokinetic (PK) endpoints and postprandial glucose (PPG) control after administration of BC Combo (75% insulin glargine, 25% insulin lispro), insulin lispro Mix25 (LMix) and separate injections of insulins glargine (75% total dose) and lispro (25% total dose [G + L]) immediately before ingestion of a mixed meal in people with type 2 diabetes mellitus (T2DM), using a randomized, double‐blind, double‐dummy crossover study design. Participants received individualized bolus doses (mean 0.62 U/kg) of BC Combo, LMix or G + L, together with a solid mixed meal (610 kcal, 50% carbohydrate, 30% fat, 20% protein). Insulin dosages were kept constant for each study day. Thirty‐nine participants with T2DM (mean ± SD age and glycated haemoglobin 60.8 ± 7.5 years and  64 ± 6 mmol/mol, respectively) were randomized. BC Combo improved the predefined primary endpoint, early PPG control, compared to LMix (incremental area under the blood glucose concentration–time curve from 0 to 2 hours after the meal [ΔAUCBG,0–2h] reduction of 18%; P = 0.0009) and G + L (ΔAUCBG,0–2h reduction of 10%; P = 0.0450). The number of mealtime hypoglycaemic episodes per participant was lower with BC Combo (22 episodes in 14 participants) compared to LMix (43 episodes in 20 participants; P = 0.0028), but not significantly different from G + L (28 episodes in 19 participants; P = 0.2523). BC Combo demonstrated superior early PPG control with fewer hypoglycaemic episodes compared to LMix and superior early PPG control compared to separate G + L administrations.

Pharmacokinetics oBC Combo showed an earlier onset of appearance (Early t 0.5max ) and higher early PK exposure in the first hour compared with LMx and G+L ( Fig. 1a & Table 2).o BC Combo reached similar maximum concentrations but significantly earlier than both LMx and G+L. AbstractBC Combo is a co-formulation of prandial insulin lispro (25%) and basal insulin glargine (75%) with a rapid "prandial" insulin component and prolonged flat "basal" component compared to LisproMix (LMx). In this study the effects of BC Combo on PPG vs. LMx and Glargine + Lantus (G+L) were investigated. Thirty-nine T2DM subjects (mean ± SD age 60.8 ± 7.5 years and HbA1c 8.0 ± 0.6 %) received the three insulin combinations immediately before a standardised solid meal test (MMT, 20% protein 30% fat 50% carbohydrates) in a double-blind, double-dummy, randomised crossover design. The individual insulin dose was the same for each visit day (mean 0.62 U/kg). BC Combo improved early PPG compared to LMx (reduction ∆AUC BG_0-2h of 18%, p=0.0009) and G+L (reduction ∆AUC BG_0-2h of 10%, p=0.0450) (primary endpoint). The proportion of subjects experiencing symptomatic hypoglycaemic events (plasma glucose <70 mg/mL) over 24h was lower with BC Combo (15.8%) vs. LMx (32.4%) and G+L (21.6%). The total insulin PK profile of BC Combo showed a faster time to insulin peak and a lower exposure in the late prandial phase (2-6 h) than LMx and G+L. In conclusion, BC Combo demonstrated superior PPG control in T2DM subjects with fewer subjects experiencing symptomatic hypoglycaemia compared to both LMx and separate G+L.

No abstract

Figure 4 Cumulated food consumption (n=10)o The coformulation BC Glu Exe induced a significant BW loss compared to vehicle (25%) and to exenatide alone (15%) (Figure 3). In this group the total food intake was intermediate between vehicle and exenatide without statistical significance ( Figure 4) although the BW loss was superior to both groups. This confirms the glucagon effect on weight loss in the combination. This effect can be attributed to an increase in energy expenditure. 50 60 70 80 90 100 110 120 -7 -5 -3 -1 1 3 5 7 9 11 13 15 BW (%) Study day Human formulation: BC Glu Exe in vials → Visual inspection of the formulation at 4°C and 37°C.o BC Glu Exe coformulation is a clear and colorless solution, essentially free of particle, after storage in vials at 4°C for at least 13 months and at 37°C for at least 12 weeks. → Chemical stability after 4 weeks storage at 37°C in vials. o Both glucagon and exenatide recoveries are around 90 % o Glucagon and exenatide impurity contents are of 5.4 and 7.6 % respectively (Figure 2) Mice formulation: BC Glu Exe in cartridges → Visual inspection of the formulation at 4°C and 37°C.o BC Glu Exe coformulation is a clear and colorless solution, essentially free of particle, after storage in cartridges at 4°C for at least 13 months and at 37°C for at least 12 weeks → Chemical stability after 2 weeks storage at 37°C in cartridges o Glucagon and exenatide impurity contents are of 3.6 and 5.8 % respectively (Figure 2) Figure 2. Glucagon and exenatide impurity content in BC Glu Exe coformulations designed for mice in vivo studies or human clinical trials. Animal StudyThe treatments were well tolerated in all groups without any clinical finding reported during the study.Exenatide alone, used as a refence and infused for 14 days led to a significant 10% decrease in BW compared to vehicle (Saline) (Figure 3). The total food intake in this group was significantly decreased when compared to the vehicle (Figure 4). AbstractOver the last decades, obesity and its associated consequences have become a major health issue worldwide. GLP-1 Receptor Agonists (GLP-1 RA) are one of the few treatment options currently available, but achieve limited weight loss.A combination of human glucagon (Glu) and GLP-1 RA is expected to provide a superior body weight (BW) reduction than GLP-1 RA alone. GLP-1 RA acts in the brain to induce satiety while Glu has a lipolytic and thermogenic effect in liver and adipose tissues. BioChaperone (BC) proprietary technology allows the solubilization and stabilization of poorly soluble and/or unstable peptides, such as Glu, at neutral pH and thus the combination of Glu and GLP-1 RA.A combination formulation of glucagon and exenatide (BC Glu Exe) was developed. Such combination is physically and chemically stable for at least 4 weeks at 37°C in cartridges. It was tested in vivo against reference exenatide and vehicle in diet induced obese (DIO) male mice. Mice were dosed with a subcutaneous continuous infusion of vehicle, Exe or BC Glu Exe via osmotic minipumps.After 14 ...