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Insulin Tregopil: An Ultra-Fast Oral Recombinant Human Insulin Analog: Preclinical and Clinical Development in Diabetes Mellitus

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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.

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Acknowledgements

The authors acknowledge Ashwini Vishweswaramurthy for her contributions towards the development of this monograph, Shivani Mittra and Geetanjali Tonpe for writing support and Jayanti Panda for operational support. Authors also acknowledge Molecular Connections Analytics Pvt. Ltd., Bengaluru, for providing editorial support towards its development.

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Authors and Affiliations

  1. Joshi Clinic and Lilavati Hospital, Mumbai, Maharashtra, India

    Shashank Joshi

  2. Biocon Biologics Ltd, Biocon House, Semicon Park, Electronic City Phase 2, Bengaluru, Karnataka, 560100, India

    Vathsala Jayanth, Subramanian Loganathan & Sandeep N. Athalye

  3. Biocon Ltd, Bengaluru, Karnataka, India

    Vasan K. Sambandamurthy

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  1. Shashank Joshi
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Correspondence to Subramanian Loganathan.

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Disclosures

Shashank Joshi has received Speaker/Advisory/Research Grants from Abbott, Alkem, Astra Zeneca, Bayer, Biocon, Boehringer Ingelheim, Eli Lilly, Franco Indian, Glenmark, Lupin, Marico, MSD, Novartis, Novo Nordisk, Roche, Sanofi, Serdia, Torrent Pharma, Twin Health and Zydus. Sandeep N. Athalye, Subramanian Loganathan, and Vathsala Jayanth are currently employed with Biocon Biologics Ltd and Vasan K. Sambandamurthy is previous employee of Biocon Limited.

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Biocon Limited.

Conflict of Interest

S.N.A, S.L, V.J, and V.K.S. hold stocks in Biocon. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest or financial conflict with the subject matter or materials discussed in the review apart from those disclosed. For S.J., please refer to ‘Disclosures’.

Data Availability

The data supporting the study findings are available from the corresponding author, Subramanian Loganathan, upon reasonable request.

Ethics Approval

The ethical standards of independent ethics committees or institutional review board were followed during the conduct of the clinical trials included in this review.

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All the subjects involved in the clinical trials mentioned in this review received informed consent prior to the study-related procedures, which was duly signed by the subjects and the investigators.

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Not applicable.

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Author Contributions

S.J., V.J., S.L., V.K.S., and S.N.A. designed and conceptualized the review article. All the authors were involved in writing, reviewing and approving the manuscript. As the guarantor of this work, S.L., takes full responsibility for the work, including the decision to submit and publish the manuscript.

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Joshi, S., Jayanth, V., Loganathan, S. et al. Insulin Tregopil: An Ultra-Fast Oral Recombinant Human Insulin Analog: Preclinical and Clinical Development in Diabetes Mellitus. Drugs 83, 1161–1178 (2023). https://doi.org/10.1007/s40265-023-01925-1

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