HP-211 Safety and Proof of Concept Dose Ranging Study in Patients With Type 2 Diabetes

Blood sugar levels are controlled by insulin, a hormone made by cells in the pancreas. After a meal, carbohydrates are broken down into glucose which is absorbed from the intestine into the blood leading to a rise in glucose (blood sugar) which triggers the secretion of insulin. Insulin binds to cells in several tissues including liver, muscle, and fat, triggering cells to take up glucose and bring the blood glucose level back to normal. A high blood sugar level is known as diabetes. The most common form of diabetes, type 2 diabetes, is caused by insulin resistance; that is, a reduced ability of insulin to stimulate glucose uptake into cells. The body compensates for insulin resistance by making more insulin; type 2 diabetes occurs when the pancreas can no longer make enough insulin to control blood glucose. The high blood glucose and insulin levels lead to long-term complications such as heart attacks, kidney failure, reduced sensation and poor circulation in the feet and legs. High insulin levels also increase the incidence of cancers, stroke, and dementia. Reducing blood glucose levels with oral medications and insulin reduces risk of diabetic complications. There are several types of oral medications available for treating diabetes; however, they do not always control blood glucose adequately. In addition, these drugs have complications and are not used to treat insulin resistance and prediabetes - a condition when blood glucose is higher than normal but not high enough to be classified as diabetes. Prediabetes often progresses to diabetes over a period of months or years. Effective and safe treatments for insulin resistance may prevent the onset of diabetes or even reverse diabetes if diagnosed in its early stages before substantial damage to the pancreas has occurred. HP-211 is a botanical extract whose active ingredients are derived from herbs and vegetables present in normal diets. HP-211 has been shown in laboratory studies in cell culture, in animal studies, and in a previous Phase 1 study to enhance the ability of insulin to stimulate glucose uptake into cells. Thus, HP-211 may reduce the blood glucose and circulating insulin levels of subjects with type 2 diabetes after a meal. HP-211 may also reduce glucose and insulin responses to a greater extent in insulin-resistant as compared to insulin-sensitive subjects. Subjects will take 0, 1, 2 or 3 tablets of HP-211 in the morning and evening for 90 days. Hemoglobin A1c (HbA1c, or "A1c"), a measure of the average amount of glucose present in the blood, will be measured during the trial period.

After consumption of a meal, pancreatic secretions of various digestive enzymes result in the breakdown of carbohydrates into monosaccharides such as glucose. These sugars are subsequently absorbed through the intestinal lumen, resulting in an increased plasma glucose concentration. In response to high glucose levels, pancreatic beta cells are stimulated to release insulin, a hormone which circulates through the bloodstream and binds to insulin-responsive cells including adipocytes (fat tissue), myocytes (muscle), hepatocytes (liver), and neurons in various regions of the brain. The resulting insulin-mediated signaling cascade initiates intracellular glucose uptake within peripheral tissues leading to a corresponding decrease in circulating plasma glucose. In insulin responsive cells the stimulation of glucose uptake begins after the binding of insulin to Insulin Receptors (IR). These receptors are found on the membrane surface of cells in insulin-responsive tissues. The IR consists of an extracellular domain which binds to insulin, and an intracellular domain that has a protein tyrosine kinase activity. The binding of Insulin to the IR initiates a series of autophosphorylation events within the protein kinase domain that permit interaction and phosphorylation of downstream signaling proteins in the cell that mediate the cellular response to insulin. The resulting signaling complex includes proteins in the Insulin Receptor Substrate (IRS) family known as IRS-1 and IRS-2. These key targets of the insulin signaling pathway link IR activation to downstream signaling cascades that mediate intracellular processes including GLUT4-mediated glucose uptake. Prediabetes and Type II diabetes involve an impaired post-receptor response to insulin that hinders the glucose uptake response after meal consumption. Chronic hyperglycemia and the resulting compensatory hyperinsulinemia promote a cohort of acute and chronic sequelae including cardiovascular disease, liver complications, central nervous system degeneration, abnormal cellular growth resulting in an increased incidence of several forms of cancer, and hyperglycemic osmotic stress. HP-211 is a botanical extract containing active ingredients derived from edible plant species herbs and vegetables present in normal diets.In vitro, HP-211, has marked effects on the IRS-2 branch of the insulin signaling cascade to enhance downstream insulin signaling. HP-211 has been shown in animal models to increase glucose uptake in peripheral tissues and decrease circulating blood glucose and triglyceride concentrations. Regular supplementation of the diet with HP-211 may reduce the incidence of associated prediabetic and diabetic complications, resulting in an increased quality of life for patients without resorting to current anti-diabetic prescription drugs that may have undesirable side effects. Hypotheses HP-211 will reduce postprandial glucose and insulin levels in subjects with new onset type 2 diabetes as well trial.show_full_description

Key Inclusion Criteria: * Have type 2 diabetes for greater than 3 months and no longer than 5 years by history prior to entering the trial, based upon ADA disease diagnostic criteria. * Have an HbA1c \> 6.5% and ≤ 10% as determined by the central lab at Visit 1 (Screening). * Have been on a stable maximum dose of metformin for at least 3 months prior to entering the study or have been on stable therapy of diet and exercise only for at least 3 months. Stable treatment is defined as no change in treatment or dose in the last 3 months. Key Exclusion Criteria: * Have known type 1 diabetes. * Diabetic complications * Have taken any oral (other than metformin) or injectable treatment (insulin or GLP-1 RA classes or other) for type 2 diabetes currently or for greater than a 4 week duration previously. Previous treatment must have been stopped at least 3 months prior to screening * Systolic blood pressure greater than 150 mmHg or a diastolic blood pressure greater than 100 mmHg at Visit 1 on average after three supine measurements, or a known history of renal artery stenosis. * At baseline, the QT interval corrected by Fridericia (QTcF) ECG findings (\>450 msec for males and \>470 msec for females), left bundle branch block, or cardiac arrhythmia requiring medical or surgical treatment within 6 months prior to Visit 1 on the ECG.