A Single-blind, Placebo-controlled, Dose-ranging Trial of Oral Hepatic-directed Vesicle Insulin Add-on to Oral Antidiabetic Treatment in Patients With Type 2 Diabetes Mellitus

Abstract

The dose response of postprandial plasma glucose (PPG) to add-on, premeal oral hepatic-directed vesicle-insulin (HDV-I), an investigational lipid bio-nanoparticle hepatocyte-targeted insulin delivery system, was evaluated in a 3-test-meal/day model in type 2 diabetes patients. The single-blind, placebo-controlled, dose-escalating trial enrolled 6 patients with HbA(1c) 8.6 ± 2.0% (70.0 ± 21.9 mmol/mol) and on stable metformin therapy. Patients received oral HDV-I capsules daily 30 minutes before breakfast, lunch, and dinner as follows: placebo capsules, 0.05, 0.1, 0.2, and 0.4 U/kg on days 1, 2, 3, 4, and 5, respectively. Outcome measures were PPG and incremental PPG area under the concentration-time curve (AUC). All 4 doses of oral HDV-I statistically significantly lowered mean PPG (P ≤ .0110 each) and incremental PPG (P ≤ .0352 each) AUC compared to placebo. A linear dose response was not observed. The 0.05 U/kg dose was the minimum effective dose in the dosage range studied. Three adverse events unrelated to treatment were observed. Add-on oral HDV-I 0.05-0.4 U/kg significantly lowered PPG excursions and the dose response curve was flat. These results are consistent with the lack of a linear dose response between portal and systemic plasma insulin concentrations in previous animal and human studies. Oral HDV-I was safe and well tolerated.

Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials

“…HDV delivered insulin to the liver efficiently, while promoting hepatic glucose uptake with a potency that was 100-fold greater than that of the same dose of injected regular porcine or human recombinant insulin [152]. A number of small scale clinical trials were conducted for oral HDV-1 in low numbers of T1DM and T2DM patients (NCT00521378 and other non-registered trials) [153,154]. These [156].…”

Recent Advances and Future Prospects of Non-Invasive Insulin Delivery Systems

“…HDV-I comprised of hepatocyte targeting molecule (HTM) biotin-phosphatidylethanolamine with 1.1 mg of HDV-phospholipid filled in gelatin capsules for administration 30 min prior to each standardized meal. The postprandial plasma glucose (PPG) and incremental PPG area under the concentrationtime curve were significantly lower compared to placebo [13] which is clinically relevant, but a linear dose-response was not observed. The treatments did not result in any untoward effects such as hypoglycemic episodes, but a long-term randomized clinical trial is required.…”

“…This does not close the door for a futuristic smart pill technology. The idea of having HDV-I administered orally is tempting because unlike the lack of adequate glycaemic control of SC insulin injections due to marked peripheral hyperinsulinemia, the delivery of insulin directly to hepatocytes through the liver portal vein would allow better control of postprandial PGLs by directly toppling hepatic glucose production while increasing hepatic glucose uptake [13].…”

Oral delivery of macromolecular drugs: Where we are after almost 100 years of attempts

“…However, scientific publications that demonstrate the uptake and liver-targeting effect are not available. The formulation is dried using a proprietary procedure and formulated as an oral gelatin capsule [110]. In a placebo-controlled clinical trial, liposomal insulin was given 30 min before every meal as an add-on therapy to six type II diabetes patients [110].…”

“…The formulation is dried using a proprietary procedure and formulated as an oral gelatin capsule [110]. In a placebo-controlled clinical trial, liposomal insulin was given 30 min before every meal as an add-on therapy to six type II diabetes patients [110]. It was significantly more effective in lowering mean postprandial plasma glucose concentrations and AUC than the placebo but no dose-response relationship was observed [110].…”