Open-label study to assess the safety and pharmacodynamics of five oral insulin formulations in healthy subjects

Aim: Orally delivered insulin is predicted to bear therapeutic advantages in diabetes management when compared to injectable insulin, because of its ability to mimic the natural route of endogenous insulin secreted by the pancreas into the portal vein and directly to the liver. Oramed Pharmaceuticals is developing an oral insulin product which consists of unmodified recombinant human insulin combined with adjuvants that protect it from enzymatic degradation in the gastrointestinal tract and promote its absorption from the gut. The aim was to determine the optimal adjuvants to insulin ratio which can provide for the best pharmacodynamic profile, while maintaining the safety of the product. Methods: Eight healthy, male volunteers participated in this open-label study which included five independent visits. During each visit, subjects were administered one of the five encapsulated oral insulin formulations which contained equal amounts of insulin but varying proportions of adjuvants. Parameters measured included safety, C-max and T-max for insulin and C-min, T-min and area under the curve (AUC) for glucose and c-peptide. Comparisons were made between formulations and between post-treatment time periods within each visit. Results: All five oral insulin formulations were well tolerated and no serious adverse events were reported. All formulations resulted in a significant response in the response period (60-300 min) in comparison to baseline (0-60 min); this was captured both in the c-peptide response and the glucose response (all five formulations p < 0.05). However, none of the formulations turned out significantly different in response over the other. Formulation 5 showed the most profound reduction in c-peptide when AUC(0-60) (baseline) was compared to AUC(60-300) (p < 0.007). Conclusions: All five oral insulin formulations resulted in glucose and c-peptide reductions, where formulation 5 demonstrated the most pronounced effect on c-peptide concentration reduction. This formulation was deemed the lead formulation to be advanced to future clinical studies. This study also reinforces the notion that oral insulin can maintain its biological activity after delivery, suggesting a potential role for this product in management of diabetes.