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

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 as subjects with existing type 2 diabetes who are not well-controlled despite using the maximum tolerated dose of metformin. The reduction in glucose and insulin will be relatively greater in insulin-resistant than insulin-sensitive subjects. Over a 90-day treatment period, these effects will lead to a reduction in hemoglobin A1c (HbA1c), a measure of long-term blood glucose control.

Subjects will take 0, 1, 2, or 3 tablets of HP-211 in the morning and evening, preferably at least 60 minutes before a meal. Hemoglobin A1c and numerous additional measures of glucose control as well as safety studies will be determined.

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.