Single-dose, Dose-escalation Study of Safety, PK, and Preliminary Efficacy of XOMA 052 in Type 2 Diabetes Mellitus

• Safety
• Pharmacokinetics

• Pharmacokinetic assessments from serum samples collected at time points specified in the protocol. [ Time Frame: Dose groups 1 - 5: Day 0 pre-dose through Day 91. Dose group 6: Day 0 pre-dose through Day 364. ] [ Designated as safety issue: No ]
• Safety assessed by adverse events, vital signs measurements, clinical laboratory assessments, infusion reactions, immune responses to XOMA 052. [ Time Frame: Dose groups 1 - 5: Day 0 pre-dose through Day 91. Dose group 6: Day 0 pre-dose through Day 364. ] [ Designated as safety issue: No ]
• Assessment of inflammatory markers CRP and ESR collected at time points specified in the protocol. [ Time Frame: Dose groups 1 - 5: Day 0 pre-dose through Day 91. Dose group 6: Day 0 pre-dose through Day 364. ] [ Designated as safety issue: No ]

• Inflammatory markers (CRP and ESR)
• HbA1c

The purpose of this study is to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of XOMA 052 in subjects with active Type 2 Diabetes Mellitus (T2D).

IV administration of XOMA 052 is likely to improve glycemic control in subjects with T2D by blocking certain receptors.

• Drug: XOMA 052
  Subjects in six successive dose groups will receive a single IV infusion (mg/kg) of study drug on Day 0. The total time of the infusion will be 1 hour ± 15 minutes.
• Drug: Placebo
  Subjects in six successive dose groups will receive a single IV infusion (mg/kg) of study drug on Day 0. The total time of the infusion will be 1 hour ± 15 minutes.

• Active Comparator: 1
  Intervention: Drug: XOMA 052
• Placebo Comparator: 2
  Intervention: Drug: Placebo

• Cavelti-Weder C, Babians-Brunner A, Keller C, Stahel MA, Kurz-Levin M, Zayed H, Solinger AM, Mandrup-Poulsen T, Dinarello CA, Donath MY. Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. Diabetes Care. 2012 Aug;35(8):1654-62. Epub 2012 Jun 14.
• Cavelti-Weder C, Furrer R, Keller C, Babians-Brunner A, Solinger AM, Gast H, Fontana A, Donath MY, Penner IK. Inhibition of IL-1beta improves fatigue in type 2 diabetes. Diabetes Care. 2011 Oct;34(10):e158. No abstract available.

Inclusion Criteria:

• American Diabetes Association (ADA) diagnostic criteria for T2D: Fasting blood glucose concentration ≥ 126 mg/dL (≥ 7.0 mmol/L) (must be measured within 28 days prior to Day 0) OR Symptoms of hyperglycemia (e.g., thirst, polyuria, weight loss, visual blurring) AND a casual/random plasma glucose value of ≥ 200 mg/dL (≥ 11.1 mmol/L) (must be measured within 28 days prior to Day 0)
• HbA1c ≥ 7.5% and ≤ 12% (DCCT standard)
• Current T2D of duration > 3 months and ≤ 10 years at Screening
• T2D and other diseases must be stable. Stable disease is defined as disease that is judged stable by the investigator and which did not require a change in medications or dosing level on 4 or more consecutive days or 7 days in total within 28 days prior to Day 0.
• Age ≥ 18 and ≤ 70 at Screening
• Weight ≥ 80 lbs (36.3 kg) and ≤ 325 lbs (147.4 kg)
• BMI ≥ 23 and ≤ 36 kg/m2
• For female subjects of child-bearing age, a negative serum pregnancy test. For subjects with reproductive potential, a willingness to utilize adequate contraception and not become pregnant (or have their partner[s] become pregnant) during the study.
• Agrees not to change diet and exercise regimen during the trial

Exclusion Criteria:

• Use of the following medications: Anti-inflammatory therapy other than aspirin ≤ 100 mg/day; Immunosuppressive treatment; Beta 2 and non-selective adrenergic blockers (Note: selective beta 1 blockers are permitted); Thiazolidinediones; Glucagon-like peptide (GLP) agonists including DPP4 inhibitors
• Change in medication for diabetes within 28 days prior to Day 0, defined as a change in dosing level on 4 or more consecutive days or 7 days in total
• Fasting C-peptide < 400 pM (< 1.20 μg/L)
• Hemoglobin < 8.0 g/dL, WBC < 3.0 × 103/mm3, platelet count < 125 × 103/mm3, creatinine > 1.5 mg/dL, AST/ALT > 2 × ULN, alkaline phosphatase > 2 × ULN
• Positive for GAD65 or IA-2 auto-antibodies
• History or evidence of thyroid abnormalities, including active hyperthyroidism needing medication. Subjects with hypothyroidism will not be excluded if their TSH level has been normal during the 3 months prior to Screening.
• Abnormal T3, T4, thyroglobulin, or TSH levels
• Known HIV antibody, hepatitis B surface antigen, and/or hepatitis C antibody
• History of malignancy within 5 years prior to study entry other than carcinoma in situ of the cervix, or adequately treated, non-metastatic squamous or basal cell carcinoma of the skin
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
• History of tuberculosis, positive PPD test, active atopic disease requiring medication, or asthma
• Infectious disease: CRP > 30 mg/L, fever, or infection requiring treatment with antibiotics within 3 weeks prior to Screening; History of recurrent infection or predisposition to infection; Active leg or foot ulcer
• Immunodeficiency
• Female subjects who are pregnant, planning to become pregnant during the course of the study, or breast-feeding
• History or symptoms of a demyelinating disease
• Clinically significant diabetic macular edema and/or proliferative diabetic retinopathy by history or fundoscopy
• Receipt of a live (attenuated) vaccine within 3 months prior to Screening
• Major surgery within 28 days prior to Day 0
• Participation in an investigational drug or device trial within 30 days prior to Screening
• Use of a therapeutic monoclonal antibody within 90 days prior to Screening
• Any condition which, in the opinion of the investigator, would jeopardize the subject's safety following exposure to the study drug