Pharmacodynamic Effect of Novel Oral Insulin Tregopil in Relation to Meal Composition in Type 2 Diabetes Mellitus Patients
Authors: KHEDKAR ANAND P. , JOSE VINU , LEBOVITZ HAROLD E. , CHERRINGTON ALAN D. , FLEMING GILBERT ALEXANDER , ATHALYE SANDEEP N. , VISHWESWARAMURTHY ASHWINI 
Published: June 2018

Our aim was to evaluate pharmacodynamics (PD) of insulin tregopil (IN-105) in relation to meal composition in type 2 diabetes mellitus patients in placebo-controlled, crossover study. Eighteen patients were randomised to 6 sequences and administered insulin tregopil 30 mg or placebo, 20 minutes prior to 2 meals (separated by 5 hours). Morning meal was ADA/high-fat/high-fibre meal while afternoon was ADA meal. PD sampling was done from dosing up to 180 minutes post dose. AUC0-180min (glucose exposure), Cmin (minimum glucose concentration observed) and tmin (time of peak PD effect) are presented in Table 1. Insulin tregopil administration following high-fat and high-fibre meal in morning resulted in glucose exposure (GM ratio of AUC0-180 min, baseline-corrected) of 92% and 98% compared to ADA meal, respectively; and 99% and 94%, respectively, after afternoon meal, compared to ADA meal. Maximal reduction in plasma glucose for ADA-ADA, high fibre-ADA and high fat-ADA meal groups was 42.0mg/dL, 38mg/dL and 33.4mg/dL, respectively, in morning and 29.3mg/dL, 16.7mg/dL and 37.9mg/dL, respectively, in afternoon. This peak PD effect was observed 37 to 47 minutes post dose, indicating ultra-short action profile. No clinically significant difference in PD response to insulin tregopil was observed irrespective of meal composition, in the same or subsequent meal.Table 1. Pharmacodynamic Parameters for Plasma Insulin Tregopil and PlaceboType of meal during morning and afternoonTime of mealBaseline-Corrected Plasma Glucose (Relative to time of Meal Administration)AUC0-180 min (min*mg/mL) ± SDaCmin (mg/mL) ± SDbTmin (min) ± SDcInsulin tregopil administered before both the mealsADA - ADAMorning190.68 ± 29.120.67 ± 0.1640.58 ± 8.99Afternoon216.13 ± 38.410.71± 0.1438.23 ± 14.67High-fat - ADAMorning173.81 ± 30.820.69 ± 0.1542.22 ± 11.66Afternoon215.28 ± 56.740.82 ± 0.1237.44 ± 25.29High-fibre - ADAMorning186.71 ± 30.230.73 ± 0.1546.47 ± 37.23Afternoon205.46 ± 37.860.64 ± 0.1341.17 ± 7.81Insulin tregopil administered before morning meal and placebo administered before afternoon mealADA - ADAMorning191.76 ± 27.200.70 ± 0.1338.44 ± 13.74Afternoon256.99 ± 43.380.91 ± 0.0622.77 ± 14.87High-fat - ADAMorning169.65 ± 18.630.66 ± 0.1648.82 ± 20.88Afternoon238.68 ± 31.760.92 ± 0.0724.88 ± 14.09High-fibre - ADAMorning197.49 ± 35.230.75 ± 0.1340.88 ± 37.67Afternoon257.13 ± 35.190.93 ± 0.0719.23 ± 13.27a, b, c, d, e, f Baseline corrected arithmetic mean values are presented. ADA: American diabetes association; SD: Standard deviation

Disclosure
A.P. Khedkar: None. V. Jose: None. H.E. Lebovitz: Stock/Shareholder; Self; Abbott, AbbVie Inc.. Advisory Panel; Self; Biocon. Stock/Shareholder; Self; General Electric, Gilead Sciences, Inc., IBM. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Nestlé, Novartis AG. Advisory Panel; Self; Poxel SA. A.D. Cherrington: Advisory Panel; Self; Biocon. Consultant; Self; Boston Scientific Corporation. Research Support; Self; Boston Scientific Corporation. Consultant; Self; Eli Lilly and Company. Advisory Panel; Self; Fractyl Laboratories, Inc.. Stock/Shareholder; Self; Fractyl Laboratories, Inc.. Consultant; Self; Galvani Bioelectronics Limited. Research Support; Self; Galvani Bioelectronics Limited. Consultant; Self; MedImmune. Advisory Panel; Self; Metavention. Stock/Shareholder; Self; Metavention. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Advisory Panel; Self; NuSirt Biopharma, Inc., Sensulin Labs, LLC.. Other Relationship; Self; Sensulin Labs, LLC.. Consultant; Self; Silver Lake. Research Support; Self; Silver Lake. Consultant; Self; Thermalin Diabetes, LLC., Thetis Pharmaceuticals LLC.. Stock/Shareholder; Self; Thetis Pharmaceuticals LLC.. Advisory Panel; Self; VTV Therapeutics. Consultant; Self; VTV Therapeutics. Advisory Panel; Self; Zafgen. Research Support; Self; Zafgen. Stock/Shareholder; Self; Zafgen. Consultant; Self; Abvance. Other Relationship; Self; Abvance. Consultant; Self; California Institute for Biomedical Research (Calibr). Advisory Panel; Self; These Three Medical, Inc (T3M). G. Fleming: Consultant; Self; Arisaph Pharmaceuticals, Inc., ADOCIA. Board Member; Self; Biocon. Consultant; Self; CocoaVia. Board Member; Self; Diasome Pharmaceuticals, Inc.. Consultant; Self; Dompé Pharmaceutical, InsuLine Medical Ltd., Intarcia Therapeutics, Inc., Ipsen Biopharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Mylan, Merck KGaA, Oramed Pharmaceuticals, Inc.. Board Member; Self; Orgenesis Inc., NuSirt Biopharma, Inc.. Other Relationship; Self; ProSciento. Consultant; Self; QuintilesIMS, Rhythm Pharmaceuticals Inc., Sanofi, Skyepharma PLC., Thermalin Diabetes, LLC.. Stock/Shareholder; Self; Thetis Pharmaceuticals LLC.. Consultant; Self; Xeris Pharmaceuticals, Inc., Veracyte, Inc., Versartis, Inc., VeroScience, LLC. S.N. Athalye: Employee; Self; Biocon. A. Vishweswaramurthy: Employee; Self; Biocon. Other Relationship; Self; JDRF.