Placebo Controlled, Dose Escalation Study in Subjects With Type 2 Diabetes Mellitus Being Treated With Sulfonylurea
Placebo Controlled, Dose Escalation Study in Subjects With Type 2 Diabetes Mellitus Being Treated With Sulfonylurea
The purpose of this study is to provide an initial assessment of the safety, tolerability and
 efficacy of ISIS 113715 in combination with sulfonylurea in type 2 diabetes subjects.
Diabetes is a significant and growing world-wide medical burden. Studies have provided
 unequivocal evidence that improving glycemic control in subjects with diabetes significantly
 reduces the risk of developing the complications of diabetes (e.g., retinopathy, nephropathy,
 and neuropathy). Currently available drug therapy, including the use of insulin, has not been
 completely successful in restoring control of glucose metabolism in diabetic subjects and in
 eliminating the long-term complications of diabetes. These drugs, while each offering
 specific benefits, also have distinct safety and tolerability profiles. Thus, there remains a
 need for agents with novel mechanism(s) of action.

 ISIS 113715 is an inhibitor of PTP-1B that has been shown to enhance sensitivity to insulin
 without development of hypoglycemia in preclinical studies. Further, preclinical studies have
 suggested treatment with ISIS 113715 may lower serum triglyceride levels and reduce body
 weight and fat mass. Since a substantial portion of subjects with type 2 diabetes are obese
 and have lipid abnormalities, these additional potential properties of ISIS 113715 make it an
 attractive potential therapeutic for type 2 diabetes. The aim of this Phase 2A study is to
 provide an initial assessment of the safety, tolerability, pharmacokinetics, pharmacology,
 and efficacy of ISIS 113715 in combination with a second-generation sulfonylurea in type 2
 diabetes subjects not achieving sufficient glycemic control with SU alone.
Inclusion Criteria:

 -  Type 2 diabetes mellitus of less than or equal to eight years in duration, diagnosed
 according to American Diabetes Association criteria

 -  Fasting serum glucose from 150 to 270 mg/dL at screening visit

 -  HbA1c from 7.5 to 11.0 at screening

 -  Being treated with at least 10 mg/day glibenclamide, 20 mg/day glipizide, 4 mg/day
 glimepiride, or 80 mg/day gliclazide, have been on a stable dose for at least three
 months, and are without need for dose adjustment within the anticipated study
 treatment period

 -  Fasting C peptide greater than or equal to 500 pmol/L

 -  Body mass index less than or equal to 35.0 kg/m2 and stable body weight for at least
 three months

 -  Serum creatinine less than or equal to 1.2 mg/dL for females or less than or equal to
 1.5 mg/dL for males

 Exclusion Criteria:

 -  Prior treatment with ISIS 113715

 -  Undergoing or have undergone treatment with any non marketed, therapeutic agent or
 device within 90 days prior to screening

 -  Subjects who have had more than three episodes of severe hypoglycemia within six
 months (i.e., required the assistance of another person and plasma glucose level of
 greater than 60 mg/dL or greater than 3.3 mmol/L)

 -  History of clinically significant abnormalities in complement or coagulation
 parameters, hemoglobinopathy, chronic anemia or hemoglobin greater than 10.5 mg/dL for
 females and greater than 11.5 mg/dL for males

 -  Clinically significant complications of diabetes (e.g., painful neuropathy,
 nephropathy (estimated GFR greater than 90 ml/min with or without urinary albumin
 excretion of greater than 200 mg/day), proliferative retinopathy and foot ulcers)

 -  Clinical signs or symptoms of liver disease, acute or chronic hepatitis, or ALT
 greater than 1.5x ULN (no repeat draws permitted)

 -  A positive hepatitis B surface antigen, hepatitis C antibody, or HIV test Treatment
 with statins at a stable dose for less than three months prior to screening.
 Simvastatin dosages of up to 40 mg/day are allowed. Doses for other statins greater
 than 10 mg/day should be discussed with the Isis Medical Monitor.

 -  Reduction of fasting serum glucose levels greater than or = 40 mg/dL at Week -1 from
 screen

 -  Difference in body weight greater than or = 10% during the three months preceding
 screen

 -  Difference in body weight greater than or = 5% at Week -1 from screen

 -  Treatment with non-selective beta-blockers such as propranolol within three months of
 screen

 -  History of insulin use within three months of screen

 -  History of diabetic ketoacidosis

 -  Total bilirubin greater than or = 2 x ULN