Oral Insulin Product Hexyl-Insulin Monoconjugate 2 (HIM2) in Type 1 Diabetes Mellitus: The Glucose Stabilization Effects of HIM2

Abstract

This study was designed to determine plasma glucose and insulin levels after administration of three escalating doses of the oral insulin product hexyl-insulin monoconjugate 2 (HIM2) in fasting, insulin-deprived adult patients with type 1 diabetes. The study was also designed to assess the safety of the product. Sixteen patients with daily insulin requirements of 27-60 units and glycosylated hemoglobin levels of 5.8-11.1% completed the study. Patients' regular insulin regimens were discontinued at bedtime, and they fasted overnight. Blood glucose levels were stabilized overnight by intravenous insulin infusion. In the morning, intravenous insulin was discontinued 30 min prior to an oral dose of HIM2 (0.6, 0.8, or 1.0 mg/kg). A second oral dose of HIM2 was administered 120 min later. Plasma glucose and insulin levels were measured during a 240-min evaluation period after the first HIM2 dose. Identical HIM2 dosing and study procedures were repeated 1 week later with the same patients. Stable or declining plasma glucose levels were observed on 31 out of a total of 32 dosing days beginning at 20 min after the initial administration of HIM2. After plasma glucose levels declined or were stable for 30 min to 2 h, increases were observed for some patients. However, for the majority of patients (68.8%), plasma glucose levels were <150% of predose levels throughout the postdose evaluation period. Similar results were observed after repeating the study procedures 1 week later. Also, plasma glucose area under the concentration-time curves (AUCs) were inversely correlated with plasma insulin AUCs. HIM2 appeared to be safe and well-tolerated in this study; no episodes of symptomatic hypoglycemia were observed. Thus, HIM2 prevented the expected rise in plasma glucose concentrations in insulin-deprived adult patients with type 1 diabetes. The lack of hypoglycemic events in this exploratory study is encouraging and suggests that there may be less risk of severe hypoglycemia associated with HIM2 when compared with injectable insulin. The promising data in this study support the hypothesis that oral HIM2 reproduces the physiological pathway of insulin secreted by the pancreas - through the portal vein directly to the liver - suggesting a therapeutic advantage in the management of type 1 diabetes mellitus.