Enterically delivered insulin tregopil exhibits rapid absorption characteristics and a pharmacodynamic effect similar to human insulin in conscious dogs

Gregory, Justin M.; Lautz, Margaret; Moore, L. Merkle; Williams, Phillip E.; Reddy, P. Jagan Mohan; Cherrington, Alan D.

doi:10.1111/dom.13498

Cited by 13 publications

(7 citation statements)

References 36 publications

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“…Despite relatively high bioavailability reported in several rodent studies 7 , most of these attempts have not progressed past research or the preclinical stage and consequently there is currently no oral insulin therapy available 5 . This can at least partly be ascribed to the use of human insulin or rapid-acting insulin analogues 8 . In contrast, we rationalised that ultra-long acting basal insulin analogues can overcome this limitation by addressing the critical issue of variability due to accumulation to steady state combined with a protracted action profile.…”

Section: Introductionmentioning

confidence: 99%

Molecular engineering of safe and efficacious oral basal insulin

et al. 2020

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Recently, the clinical proof of concept for the first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered insulin glargine. Here, we report the molecular engineering as well as biological and pharmacological properties of these insulin analogues. Molecules were designed to have ultra-long pharmacokinetic profile to minimize variability in plasma exposure. Elimination plasma half-life of ~20 h in dogs and ~70 h in man is achieved by a strong albumin binding, and by lowering the insulin receptor affinity 500-fold to slow down receptor mediated clearance. These insulin analogues still stimulate efficient glucose disposal in rats, pigs and dogs during constant intravenous infusion and euglycemic clamp conditions. The albumin binding facilitates initial high plasma exposure with a concomitant delay in distribution to peripheral tissues. This slow appearance in the periphery mediates an early transient hepato-centric insulin action and blunts hypoglycaemia in dogs in response to overdosing.

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Section: Introductionmentioning

confidence: 99%

Molecular engineering of safe and efficacious oral basal insulin

et al. 2020

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“…However, major challenges in developing oral insulins, such as interference by meal ingestion, high absorption variability, low bioavailability, and resulting commercial unviability, are still a significant obstacle to success. Phase 2 and 3 studies of prandial oral insulins, including insulin tregopil (IN-105, recombinant insulin conjugated with polyethylene glycol via an acetyl chain) [ 74 ] and ORMD-0801 (enteric coated capsule containing insulin and adjuvants to protect the protein and promote intestinal uptake) [ 75 ], failed to show impressive results to date with no or negligible glucose lowering. Basal oral insulin would be more feasible in that it could avoid food effects.…”

Section: The Future Of Insulin Therapy: Noninjecting Insulinsmentioning

confidence: 99%

A Century of Progress in Diabetes Care with Insulin: A History of Innovations and Foundation for the Future

Lee

Yoon

2021

Diabetes Metab J

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The year 2021 marks the 100th anniversary of the discovery of insulin, which has greatly changed the lives of people with diabetes and become a cornerstone of advances in medical science. A rapid bench-to-bedside application of the lifesaving pancreatic extract and its immediate commercialization was the result of a promising idea, positive drive, perseverance, and collaboration of Banting and colleagues. As one of the very few proteins isolated in a pure form at that time, insulin also played a key role in the development of important methodologies and in the beginning of various fields of modern science. Since its discovery, insulin has evolved continuously to optimize the care of people with diabetes. Since the 1980s, recombinant DNA technology has been employed to engineer insulin analogs by modifying their amino acid sequence, which has resulted in the production of insulins with various profiles that are currently used. However, unmet needs in insulin treatment still exist, and several forms of future insulins are under development. In this review, we discuss the past, present, and future of insulin, including a history of ceaseless innovations and collective intelligence. We believe that this story will be a solid foundation and an unerring guide for the future.

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“…Oral insulin and insulin analogs that exhibit preferential hepatic bioavailability are another possible therapy that can confer a better insulin balance between portal and peripheral circulation. However, there are issues of limited bioavailability [ 55 ] and concerns about potential pathologic hepatic effects. Other approaches to improve insulin sensitivity in T1D include glucagon-like peptide-1 receptor agonists and liver-selective glucokinase activators.…”

Section: Implications For Therapymentioning

confidence: 99%

Autoimmune Inflammation and Insulin Resistance: Hallmarks So Far and Yet So Close to Explain Diabetes Endotypes

et al. 2021

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Purpose of Review Diabetes mellitus can be categorized into two major variants, type 1 and type 2. A number of traits such as clinical phenotype, age at disease onset, genetic background, and underlying pathogenesis distinguish the two forms. Recent Findings Recent evidence indicates that type 1 diabetes can be accompanied by insulin resistance and type 2 diabetes exhibits self-reactivity. These two previously unknown conditions can influence the progression and outcome of the disease. Unlike most conventional considerations, diabetes appears to consist of a spectrum of intermediate phenotypes that includes monogenic and polygenic loci linked to inflammatory processes including autoimmunity, beta cell impairment, and insulin resistance. Summary Here we discuss why a shift of the classical bi-modal view of diabetes (autoimmune vs. non-autoimmune) is necessary in favor of a model of an immunological continuum of endotypes lying between the two extreme “insulin-resistant” and “autoimmune beta cell targeting,” shaped by environmental and genetic factors which contribute to determine specific immune-conditioned outcomes.

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Enterically delivered insulin tregopil exhibits rapid absorption characteristics and a pharmacodynamic effect similar to human insulin in conscious dogs

Abstract: Enterically delivered tregopil is rapidly absorbed and restores a portal-to-peripheral vascular distribution. These characteristics should improve postprandial hyperglycaemia in types 1 and 2 diabetes.

Cited by 13 publications

References 36 publications

Molecular engineering of safe and efficacious oral basal insulin

Molecular engineering of safe and efficacious oral basal insulin

A Century of Progress in Diabetes Care with Insulin: A History of Innovations and Foundation for the Future

Autoimmune Inflammation and Insulin Resistance: Hallmarks So Far and Yet So Close to Explain Diabetes Endotypes

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