Dosing Time of Insulin Tregopil, a Novel Oral Insulin, in Type 2 Diabetes Mellitus Patients and Its Pharmacodynamic Effect
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 pre-meal dosing time in type 2 diabetes mellitus (T2DM) patients in a randomized, placebo-controlled, crossover study. Fifteen patients were randomised to 5 sequences (3 patients each) and administered 4 treatments (Insulin tregopil 30 mg given 30, 20 and 10 minutes before American diabetes association (ADA) meal and placebo given 20 minutes before ADA meal) in a partial replicate crossover fashion with a washout period of 1-2 days between periods. PD sampling was done from dosing to 180 min post-meal. AUC0-180min (glucose exposure), Cmin (minimum glucose concentration observed in the sampling period) and tmin (indicating time of peak PD effect) are presented in Table 1. Maximal reduction in plasma glucose (difference between baseline [meal administration] and minimum post-meal plasma glucose concentration) was 15.7 mg/dL, 9.5 mg/dL and 9.7 mg/dL for 30, 20 and 10 minutes groups, respectively. This peak PD effect was observed 16 to 37 minutes post-meal, indicating ultra-short action profile. Insulin tregopil given orally 10-20 minutes before meals has rapid onset of action. It results in effective lowering of post-meal glucose exposure with peak PD effect early in the post-meal period, hence minimizing chances of hypoglycaemia.Table 1. Pharmacodynamic Parameters for Plasma Insulin TregopilTreatment groupsBaseline-Corrected Plasma Glucose (Relative to time of Meal Administration)AUC0-180 min (min*mg/mL) ± SDCmin (mg/mL) ± SDTmin (min) ± SDInsulin tregopil 10 min217.39 (31.58)0.86 (0.11)37.33 (59.09)Insulin tregopil 20 min227.04 (67.89)0.81 (0.10)26.00 (43.22)Insulin tregopil 30 min267.67 (46.81)0.81 (0.08)16.66 (7.23)Placebo251.96 (39.11)0.98 (0.03)33.66 (66.72)ParametersComparisonGeometric mean ratio (CI [%])AUC0-180 min (min*mg/mL)Insulin tregopil 30 min vs. placebo106.4 (87.2, 129.8)Insulin tregopil 20 min vs. placebo80.0 (65.6, 97.6)Insulin tregopil 10 min vs. placebo86.6 (71.0, 105.7)Cmin (mg/mL)Insulin tregopil 30 min vs. placebo82.7 (78.3, 87.4)Insulin tregopil 20 min vs. placebo83.0 (78.5, 87.7)Insulin tregopil 10 min vs. placebo87.8 (83.1, 92.8)Insulin tregopil was administered at 30, 20 or 10 min before the ADA meal and placebo was administered at 20 min before the ADA meal. CI-90% confidence interval; Min-minutes. Baseline-corrected arithmetic mean and geometric mean values are presented.

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.