Authors: Shashank Joshi, Vathsala Jayanth, Subramanian Loganathan, Vasan K. Sambandamurthy & Sandeep N. Athalye

Date: Aug 14th, 2023

Link: https://doi.org/10.1007/s40265-023-01925-1

Abstract –

Insulin therapy is indispensable for achieving glycemic control in all patients with type 1 diabetes mellitus and many patients with type 2 diabetes mellitus. Insulin injections are associated with negative connotations in patients owing to administration discomfort and adverse effects such as hypoglycemia and weight gain. Insulin administered orally can overcome these limitations by providing a convenient and effective mode of delivery with a potentially lower risk of hypoglycemia. Oral insulin mimics the physiologic process of insulin secretion, absorption into the portal circulation, and subsequent peripheral delivery, unlike the subcutaneous route that results in peripheral hyperinsulinemia. Insulin tregopil (IN-105), a new generation human recombinant insulin, methoxy (polyethylene glycol) hexanoyl human recombinant insulin, is developed by Biocon as an ultra-fast onset short-acting oral insulin analog. This recombinant oral insulin is a single short-chain amphiphilic oligomer modified with the covalent attachment of methoxy-triethylene-glycol-propionyl moiety at Lys-β29-amino group of the B-chain via an amide linkage. Sodium caprate, an excipient in the insulin tregopil formulation, is a permeation enhancer that increases its absorption through the gastrointestinal tract. Also, meal composition has been shown to non-significantly affect its absorption. Several global randomized, controlled clinical trials have been conducted in type 1 and type 2 diabetes patients towards the clinical development of insulin tregopil. The formulation shows post-prandial glucose control that is more effective than placebo throughout the meal period; however, compared with an active comparator insulin aspart, the post-prandial control is more effective mainly in the early post-meal period. It shows a good safety profile with a lower incidence of clinically significant hypoglycemia. This review covers the overall clinical development of insulin tregopil establishing it as an ultra-fast onset, short-acting oral insulin analog for optimizing post-prandial glucose.

Funding: This paper was funded by Biocon Limited, India.

Authors: Harold E Lebovitz, Alexander Fleming, Alan D Cherrington, Shashank Joshi, Sandeep N Athalye, Subramanian Loganathan, Ashwini Vishweswaramurthy, Jayanti Panda, Ashwani Marwah

Date: Nov 9th, 2022

Link: https://doi.org/10.1080/14656566.2022.2141569

Abstract –

Background: Efficacy and safety of ultra-rapid acting oral prandial insulin Tregopil was compared with insulin aspart (IAsp) in patients with type 2 diabetes (T2D) on insulin glargine and metformin.

Research design and methods: In this open-label, active-controlled trial, patients with T2D, HbA1c ≥7%–≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized 1:1:1 to Tregopil (30 mg, n = 30; 45 mg, n = 31) and IAsp, n = 30. Primary outcome was change from baseline (CFB) in HbA1c at week 24. Secondary outcomes included PPG excursion (PPGE) and PPG assessed from standardized test meal (STM) and 9-point self-monitored blood glucose.

Results: The observed mean HbA1c did not improve at week 24 in Tregopil groups (30 mg [0.15%], 45 mg [0.22%] vs. a reduction in IAsp group [-0.77%]). Combined Tregopil group showed better 1-h PPGE control versus IAsp following STM (CFB, estimated treatment difference, 95% CI, -45.33 mg/dL [-71.91, -18.75], p = 0.001) and 1-h PPG trended toward better control. Tregopil showed lower PPGE at 15 min versus IAsp. Clinically significant hypoglycemia was lower with Tregopil versus. IAsp (rate ratio: 0.69).

Conclusions: Tregopil demonstrated an ultrafast, short-duration prandial profile with good safety. While Tregopil’s early postprandial effects were comparable to IAsp, its late postprandial effects were inferior.

Funding: This paper was funded by Biocon Limited, India.

Authors: Anand Khedkar, Harold Lebovitz, Alexander Fleming, Alan Cherrington, Vinu Jose, Sandeep N. Athalye, and Ashwini Vishweswaramurthy

Date: Aug 7th, 2019

Link: https://doi.org/10.1002/cpdd.730

Abstract:

We evaluated the pharmacokinetics and pharmacodynamics of oral insulin tregopil in relation to premeal dosing time, between‐meal interval, and meal composition type in type 2 diabetes mellitus patients in a randomized, placebo‐controlled, crossover study consisting of 3 sequential cohorts. In Cohort 1, insulin tregopil administered 10 to 20 minutes before a meal resulted in optimal postmeal exposure and demonstrated better postprandial glucose‐lowering effect (glucose area under concentration‐time curve [AUC]) compared to the 30‐minute group. In Cohort 2, insulin tregopil pharmacokinetic exposure (plasma AUC) showed a progressive increase through 4, 5, and 6 hours of between‐meal interval. The 6‐hour between‐meal interval resulted in better absorption of insulin tregopil in comparison to 4‐ and 5‐hour intervals. However, no significant differences were observed in pharmacodynamic parameters except for higher glucose AUC0‐180min in the insulin tregopil 4‐hour group during the afternoon meal as compared to the morning meal. In Cohort 3, a high‐fiber meal had the least impact on insulin tregopil absorption and resulted in the highest reduction in plasma glucose levels in the afternoon. A high‐fat meal reduced insulin tregopil absorption in the afternoon meal; however, pharmacodynamic response was not diminished significantly. Insulin tregopil has a rapid onset of action of approximately 10 minutes and, when administered 10 to 20 minutes before a meal, demonstrated up to 13% to 18% reduction in blood glucose levels compared to baseline. A 5‐hour between‐meal interval minimizes the impact of a meal on absorption of subsequent (afternoon) insulin tregopil dose, and the pharmacodynamic response of insulin tregopil is not altered by meal composition. Insulin tregopil was well tolerated in patients with type 2 diabetes mellitus.

Authors: Anand Khedkar, Harold Lebovitz, Alexander Fleming, Alan Cherrington, Vinu Jose, Sandeep N. Athalye, and Ashwini Vishweswaramurthy

Date: Dec 28th, 2018

Link: https://doi.org/10.1111/cts.12609

Abstract:

Oral insulin tregopil (IN‐105; a new drug under development) may be coadministered with oral antidiabetic drugs, such as metformin in patients with type 2 diabetes mellitus for optimal glycemic control. IN‐105 has sodium caprate excipient, a permeation enhancer, for enhancing absorption in the stomach and increasing bioavailability via an oral route. Sodium caprate may increase bioavailability of metformin by a similar mechanism. Therefore, it was necessary to study the effect of IN‐105 on pharmacokinetics (PKs) of metformin. In this randomized, open‐label, cross‐over study, metformin was administered to healthy volunteers receiving IN‐105/placebo under fed/fasting conditions. The 90% confidence interval (CI) of the geometric mean ratio of the area under the curve from time zero to infinity (AUC 0‐inf; fasting and fed) and peak plasma concentration (Cmax; fed) of metformin were within 0.80–1.25 acceptance range. Under fasting conditions, the upper bound margin of Cmax was just beyond this range (i.e., 1.27) and was concluded as functionally not relevant. There was no clinically significant effect of sodium caprate/IN‐105 on PKs of metformin under fasting/fed conditions, and it was safe.

Author: Partha Hazra, Amarnath Chatterjee, Qais Shabandri, Laxmi Adhikary, Nitesh Dave & Madhavan Buddha

Date: March 28th, 2012

Link: https://doi.org/10.1007/s00449-012-0722-4

Abstract:

Bio-catalytic in vitro multistep reactions can be combined in a single step in one pot by optimizing multistep reactions under identical reaction condition. Using this analogy, the process of making PEGylated insulin, IN-105, was simplified. Instead of taking the purified active insulin bulk powder as the starting material for the conjugation step, an insulin process intermediate, partially purified insulin ester, was taken as starting material. Process intensification (PI) was established by performing a novel de-blocking (de-esterification) of the partially purified insulin ester and conjugation at B-29 Lys residue of B chain with a short-chain methoxy polyethylene glycol (mPEG) in a single-pot reactor. The chromatographic profile at the end of the reaction was found similar irrespective of whether both the reactions were performed sequentially or simultaneously. The conjugated product of interest, IN-105 (conjugation at LysB29), was purified from the heterogeneous mixture of conjugated products. The new manufacturing process was deduced to be more simplified and economical in making the insulin conjugates as several downstream purification steps could be circumvented. The physicochemical characteristics of IN-105 manufactured through this economic process was found to be indifferent from the product formed through the traditional process where the conjugation starting material was purified from bulk insulin.

Author: Partha Hazra, Laxmi Adhikary, Nitesh Dave, Anand Khedkar, H. S. Manjunath, Ramya Anantharaman, Harish Iyer

Date: Aug 25th, 2010

Link: https://doi.org/10.1002/btpr.487

Abstract:

To make insulin orally bioavailable, insulin was modified by covalent attachment (conjugation) of a short-chain methoxy polyethylene glycol (mPEG) derivative to the ε-amino group of a specific amino acid residue (LysB29). During the conjugation process, activated PEG can react with any of the free amino groups, the N-terminal of the B chain (PheB1), the N-terminal of the A chain (GlyA1), and the ε-amino group of amino acid (LysB29), resulting in a heterogeneous mixture of conjugated products. The abundance of the desired product (Methoxy-PEG3-propionyl—insulin at LysB29:IN-105) in the conjugation reaction can be controlled by changing the conjugation reaction conditions. Reaction conditions were optimized for maximal yield by varying the proportions of protein to mPEG molecule at various values of pH and different salt and solvent concentrations. The desired conjugated molecule (IN-105) was purified to homogeneity using RP-HPLC. The purified product, IN-105, was crystallized and lyophilized into powder form. The purified product was characterized using multiple analytical methods including ESI-TOF and peptide mapping to verify its chemical structure. In this work, we report the process development of new modified insulin prepared by covalent conjugation of short chain mPEG to the insulin molecule. The attachment of PEG to insulin resulted in a conjugated insulin derivative that was biologically active, orally bioavailable and that showed a dose-dependent glucose lowering effect in Type 2 diabetes patients. © 2010 American Institute of Chemical Engineers Biotechnol. Prog., 2010

Author: A. Khedkar, H. Iyer, A. Anand, M. Verma, S. Krishnamurthy, S. Savale, A. Atignal

Date: June 24th, 2010

Link: https://doi.org/10.1111/j.1463-1326.2010.01213.x

Abstract –

Aim: The objective of the study was to establish the dose response of IN-105 tablets and explore a possible therapeutic window in type 2 diabetes subjects poorly controlled on metformin.

Methods: The primary objective was to examine the effect of sequential single ascending doses of IN-105 on the plasma glucose concentration under fed conditions. All subjects received, sequentially, matching placebo, 10, 15, 20 and 30 mg IN-105 tablets in five consecutive periods. Tablets were administered 20 min prior to meal in all the periods. Plasma levels of immunoreactive insulin, C-peptide and glucose were measured up to 180 min from the time of dosing. The changes in postprandial glucose levels at 120 min in response to IN-105 administration were also compared against those of placebo.

Results: Changes in glucose from baseline (mean ± s.d.) at 140 min (2 h postprandial) were 94.84 ± 22.3, 79.45 ± 43.00, 70.68 ± 35.71, 63.47 ± 42.75 and 53.06 ± 47.27 mg/dL, respectively, and exhibited linear dose–response. The insulin Cmax values were found to be 50.8 ± 26.0 mU/L for placebo, 100.3 ± 66.7 with 10 mg IN-105, 177.69 ± 150.3 with 15 mg IN-105, 246.2 ± 245.2 with 20 mg IN-105 and 352.5 ± 279.3 mU/L with 30 mg of IN-105.

Conclusions: IN-105 absorption is proportional to the dose administered. The 2-h postprandial glucose excursion was reduced in a dose proportional manner. Circulating C-peptide levels were found to be suppressed in proportion to the IN-105 exposure. IN-105 reduces glucose excursion despite lower endogenous insulin secretion. IN-105 seems to have a wide therapeutic window as no clinical hypoglycaemia was observed at any of the doses studied.

Author: Harish Iyer, Anand Khedkar, Manish Verma

Date: Jan 31th, 2010

Link: https://doi.org/10.1111/j.1463-1326.2009.01150.x

Abstract:

Oral insulin is one of the most exciting areas of development in the treatment of diabetes because of its potential benefit in patient convenience, rapid insulinization of liver, adequate insulin delivery avoiding peripheral hyperinsulinaemia while potentially avoiding adverse effects of weight gain and hypoglycaemia. Growing evidence that earlier initiation of intensive insulin therapy produces sustained tight glycaemic control resulting in substantial delay in complications makes an effective oral insulin product even more vital for the management of patients with diabetes. Despite knowledge of this unmet medical need, oral delivery of insulin has been unsuccessful because of several barriers. For several decades, researchers have tried to develop oral insulin using various technologies without much clinical or commercial success. This review summarizes the development status of oral insulins which are publicly reported to be undergoing clinical studies. Currently, two oral insulin products are in an advanced stage of clinical development and first data from long-term therapy are expected to be available in the second half of 2010.

Author: Nitesh Dave, Partha Hazra, Anand Khedkar, H.S. Manjunath, Harish Iyer, Shrikumar Suryanarayanan

Date: Jan 11th, 2008

Link: https://doi.org/10.1016/j.chroma.2007.07.036

Abstract:

Oral delivery of insulin is convenient and physiologically desirable in the treatment of diabetes. However, this route of administration has presented substantial challenges as insulin is degraded enzymatically in the gut, resulting in low bioavailability. We have developed a conjugated insulin product (IN-105) that has high bioavailability and is currently undergoing clinical trials for the treatment of diabetes. A process for the manufacture of IN-105 was developed. Initially, recombinant human insulin was conjugated covalently with a monodisperse, short-chain methoxypolyethylene glycol derivative. The desired product, IN-105, was purified from its closely related species using RP-HPLC and cation exchange chromatography to a purity of 98.5%. The elution pool from cation exchange chromatography was crystallized and lyophilized into the dry active pharmaceutical ingredient.

Authors: Shrikumar Suryanarayan, Anand Khedkar, A. Vedala, Harish Iyer, K. Anil, S. Desai, Shrinivas S Savale, A. Atignal

Date: Sep, 2007

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