Effects of Metreleptin in Type 1 Diabetes Mellitus

• Change in HgbA1c [ Time Frame: 5 months ] [ Designated as safety issue: No ]
  Improvement in HgbA1c over the course of 5 months of Leptin therapy.
• safety and tolerability of leptin in Type 1 Diabetic patients [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  To determine if adding leptin to insulin therapy will be safe and tolerated by type 1 diabetic patients.

• Mean and standard deviation of blood glucose [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  To determine if there are changes in the mean blood glucose and the standard deviation of blood glucose as assessed by continuos glucose monitoring and frequent sampling.
• change in liver and muscle fat as measured by Liver and soleus triglycerides on MRS. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Change in the soleus and liver Tg as measured by spectroscopy evaluated 4 times over the 6 months of therapy.
• Change in Glycomark [ Time Frame: Glycomark as measured at every visit from baseline until study end. ] [ Designated as safety issue: No ]
  Glycomark as a more sensitive measure of glycemic control.

• Mean and standard deviation of blood glucose [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  To determine if there are changes in the mena blood glucose and the standard deviation of blood glucose as assessed by continuos glucose monitoring and frequent sampling.
• change in liver and muscle fat as measured by Liver and soleus triglycerides on MRS. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Change in the soleus and liver Tg as measured by spectroscopy evaluated 4 times over the 6 months of therapy.
• Change in Glycomark [ Time Frame: Glycomark as measured at every visit from baseline until study end. ] [ Designated as safety issue: No ]
  Glycomark as a more sensitive measure of glycemic control.

This study will add leptin therapy to the current insulin therapy of Type 1 Diabetics with the aim of lowering the total insulin requirements and suppressing the steep fluctuations typically associated with Type 1 Diabetes.

The adipocyte hormone, leptin, has been shown to restore the health and glucoregulation of near-death, insulin deficient diabetic rodents. This makes leptin the only hormone, since the discovery of insulin in 1922, with this capability. Leptin normalizes the hyperglucagonemia of diabetes and reduces lipogenesis and cholesterologenenesis. Treatment of diabetic rodents with a combination of leptin and insulin, leads to a stable pattern of glucose control with reduced insulin requirements, as opposed to the high glucose variability that characterizes the treatment of type 1 diabetes with supraphysiologic doses of insulin alone. As such, we will initiate a pilot clinical trial to test combination leptin and insulin therapy in type 1 diabetes. Fifteen leptin sensitive patients (body mass index <27 kg/m²) with uncontrolled diabetes (HbA1c 7.0 to 10.0 %) will be treated with slightly supraphysiologic doses of recombinant human leptin (Amylin Pharmaceuticals). Subjects will be compared to themselves before and after treatment with leptin. Endpoint variables include HbA1c, change in daily insulin dose, mean and standard deviation of blood glucose from inpatient glucose monitoring and glucose meter download. We will also assess effects of leptin therapy on energy intake as assessed by 3-day food record and body weight and fat by DEXA. Intramyocellular and intrahepatic lipid concentration by 1H-MRS will be assessed before and after 3 months of metreleptin therapy. A satiety analysis will be employed. In addition, plasma hormones and inflammatory biomarkers will be assayed during the course of this study.

Inclusion Criteria:

All of the following criteria are to be fulfilled for inclusion of an individual in the study. An eligible individual:

1. Is male or female and is 18 to 50 years of age
2. Has been diagnosed with T1DM for at least 1 year. Diagnosis of T1DM will be based on clinical criteria including: insulin-dependence within 6 months of the onset, history of prior episode of ketoacidosis, previous documentation of positive serum islet cell autoantibodies or low or undetectable serum C-peptide levels.
3. Has an HbA1c 7.0 to 10.0 %, inclusive
4. Currently on insulin pump or on a combination of basal (long-acting insulin preparation) and pre-prandial (short-acting insulin preparation) insulin therapy
5. Is male, or if female of childbearing potential, is non-lactating, and has a negative pregnancy test (human chorionic gonadotropin, beta subunit [βhCG]) result at screening (Visit 1) and Visit 2 regardless of menopausal status (If female and of childbearing potential [including peri menopausal women who have had a menstrual period within one year], must practice and be willing to continue to practice appropriate birth control [defined as a method which results in a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as implants, injectables, oral contraceptives, some intrauterine contraceptive devices, sexual abstinence, tubal ligation, or a vasectomized partner] during the entire duration of the study.)
6. Has a BMI < 27 kg/m2
7. Has clinical laboratory test values (clinical chemistry, hematology, and urinalysis) judged to be not clinically significant by the investigator at screening (Visit 1)
8. Has a physical examination and electrocardiogram (ECG) with no clinically significant abnormalities as judged by the investigator

Exclusion Criteria:

1. Has a fasting serum triglyceride concentration >400 mg/dL at screening
2. Has hypoglycemia unawareness (Loss of consciousness due to hypoglycemia without preceding symptoms or recent history of blood glucose <50 mg/dl without symptoms)
3. Currently abuses drugs or alcohol, or has a history of abuse that in the investigator's opinion could cause the individual to be noncompliant with study procedures, or has a positive urine screen for drugs of abuse at screening (Visit 1)
4. Has chronic renal insufficiency with serum creatinine > 2 mg/dL
5. Has a history of weight loss (>3%) in the last 3 months
6. Is currently enrolled or plans to enroll in a diet, weight loss, or exercise program
7. Has a sitting blood pressure >160/95 mmHg (either systolic or diastolic) at screening (Visit 1)

8. Has a clinically significant history or presence of any of the following conditions:

   • Active cardio- or cerebrovascular disease
   • Active pulmonary disease

   • Hepatic disease defined as follows:

     • At screening (Visit 1), alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase > three times the upper limit of normal (elevated Liver Function Test values suggestive of obesity related non-alcoholic fatty liver disease may not be exclusionary)
   • The presence of any other co morbid disorders that, in the opinion of the investigator, would interfere with the subject's compliance of study procedures
   • Clinically significant malignancies within 5 years of screening (Visit 1)
   • Chronic infections (e.g., HIV [human immunodeficiency virus] or tuberculosis)
9. Has received any investigational drug within 30 days or within a period corresponding to five half-lives of that drug, whichever is greater, before screening (Visit 1)
10. Has had major surgery or a blood transfusion within 2 months before screening (Visit 1) or has a hematocrit < 30%
11. Has a known hypersensitivity to any of the components of the study treatment (e.g. has a known hypersensitivity to E. Coli derived proteins
12. Is an immediate family member (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study at the investigative site, or is personally directly affiliated with the study at the investigative site
13. Is employed by Amylin Pharmaceuticals, Inc., (i.e., an employee, temporary contract worker, or designee responsible for the conduct of the study)
14. Has previously received treatment with recombinant leptin (metreleptin or Fc leptin)

• Juvenile Diabetes Research Foundation
• Amylin Pharmaceuticals, LLC.