Insulin, discovered in 1921 and first used in 1922, has been a crucial component of diabetes management. Over the past century, numerous innovations have emerged in the insulin field, including the transition from animal-derived to human and human analogue insulins, as well as advancements in insulin administration methods, such as the shift from syringes to more convenient pens and pumps. However, the development of orally-administered insulins remains a challenge.
Despite the life-changing benefits of insulin, the requirement for parenteral administration poses barriers to patient adherence and compliance. Non-compliance with insulin therapy is associated with poorer glycemic control and an increased risk of diabetes-related complications. Additionally, insulin-related anxiety presents challenges when initiating therapy in type 2 diabetics due to the physical discomfort of injections and the associated lifestyle changes.
To address these challenges and optimise outcomes, significant interest has been devoted to the research and development of orally administered insulins, which would offer a pain-free and convenient alternative.
However, achieving this goal is challenging. Insulin, being a large protein drug, is susceptible to degradation by gastrointestinal enzymes, has limited absorption due to its high molecular weight, and faces physical mucus barriers in the gastrointestinal tract.
Recent efforts from academia and industry have focused on bringing oral insulin to reality. The most promising oral insulin candidate, nearest to commercialisation, originates from Oramed Pharmaceuticals and their partner Hefei Tianhui Biotechnology (HTIT), and is named ORMD-0801.
ORMD-0801 mimics the liver’s endogenous production of insulin and is co-formulated with a protease inhibitor and an absorption enhancer. Successful phase III clinical trials have been completed in China for type 2 diabetes, and regulatory approval from China’s National Products Administration is pending.
Interestingly, while ORMD-0801 showed success in China, the domestic phase III trial in the United States did not meet primary (ORMD-0801 vs. placebo in improving glycemic control as assessed by the mean change from baseline in A1c at 26 weeks) and secondary (mean change from baseline in fasting plasma glucose at 26 weeks) efficacy endpoints.
However, further analysis revealed that specific subpopulations of patients with particular parameters within the US trial responded well to oral insulin, showing a statistically significant reduction in HbA1c compared to placebo. Oramed notes that these respondent subpopulations in the US trial had similar characteristics to those in the Chinese trial.
Closer to home, researchers from the University of Sydney have recently established a company called Endo Axiom, receiving significant commercial backing of $2.2 million AUD.
Endo Axiom aims to develop novel therapeutics utilising nanoparticles to treat autoimmune and allergic diseases, with a current primary focus on developing a nanoparticle insulin formulation for type 1 diabetics. Early preclinical findings of their lead asset have been promising, demonstrating dose-dependent reductions in blood glucose in-vivo using mice, rats, and baboons. Endo Axiom aims to enter clinical phases in 2024.
With the remarkable innovations in insulin since its discovery almost a century ago, it is fitting that the next significant evolution for insulin in diabetes management appears to be on the horizon.
Let us know your thoughts on the potential use of oral insulins in the future. Do you think they would serve as an alternative to injectable insulin, or replace it entirely?
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