safety study of amg 811 in subjects with systemic lupus erythematosus with and without glomerulonephritis

Conditions: Nephritis; Systemic Lupus Erythematosus

Summary: this is a 2-part, multi-center, randomized, double-blind, placebo-controlled, multiple dose escalation study, enrolling approximately 48 subjects. part a of the study will enroll subjects with systemic lupus erythematosus (sle) without glomerulonephritis (gn) into 3 cohorts. part b of the study will enroll sle subjects with gn into 3 cohorts. the purpose of the study is to evaluate the multiple dose of amg 811 on safety. tolerability and pharmacokinetics.

part a of the study will enroll sle without gn (non-renal) subjects into 3 cohorts (6 amg 811: 2 placebo). all subjects will receive a dose of amg 811 or placebo every 4 weeks beginning with day 1 (d1) for a total of 3 injections. subjects will be followed through to study day 197, 5 months from the last dose of study medication. part b of the study will enroll sle subjects with gn into cohorts 4, 5, and 6 (6 amg 811: 2 placebo). similar to part a, subjects in cohorts 4, 5, and 6 will be dosed every 4 weeks with amg 811 or placebo for a total of 3 injections followed by a 5 month follow-up period. for cohort 6, subjects will be followed by a 6 month follow-up period.

Eligibility criteria:
inclusion criteria: * men and women, between the ages of 18 and 70 years of age; * body mass index from 18 to 40 kg/m2 \[body weight (kg)/height2 (m2)\] at screening; * diagnosis of sle at least 6 months before randomization, including a positive antinuclear antibodies (ana) during screening; if screening ana is negative, documented historical ana with a titer of at least 1:80 will be acceptable; * any concurrent sle pharmacologic regimen (including mycophenolate mofetil, azathioprine, leflunomide, methotrexate, and anti-malarials) must be stable for at least 30 days before randomization; * prednisone ≤ 20 mg/day (or equivalent) is permitted; one increase or one decrease of ≤ 5 mg/day prednisone equivalent will be allowed within 30 days before randomization; additional inclusion criteria for part b: - active sle with gn with no other apparent cause, defined by the following: renal biopsy evidence (within 18 months) of nephritis using the who or international society of nephrology (isn)/renal pathology society (rps) classification of sle with gn (class iii or iv); urine protein/creatinine ratio (up/cr) \> 1 or 24 hour urine protein \> 1g after at least 12 weeks of treatment with mycophenolate mofetil (at least 1.5 grams/day) or azathioprine (at least 100 mg orally per day); superimposed membranous changes are allowed for those with class iii or class iv sle with gn; - prednisone ≤ 20 mg/day (or equivalent) at the time of randomization. exclusion criteria: * any disorder (including psychiatric), condition or clinically significant disease (other than a diagnosis of sle) that would, by its progressive nature and/or severity, interfere with the study evaluation, completion and/or procedures per the investigator's discretion; * creatinine clearance within the screening period of less than 50 ml/min as calculated by the cockcroft-gault method * signs or symptoms of a viral, bacterial or fungal infection within 30 days of study randomization, or recent history of repeated infections; * underlying condition other than sle or being on allowed immunosuppressants that predisposes one to infections * prior use of the following agents: * administration of an investigational biologic agent that primarily targets the immune system * administration of cyclosporine, tacrolimus, sirolimus, iv immunoglobulin, and/or plasmapheresis within 3 months of randomization; * administration of oral or iv cyclophosphamide (or any other alkylating agent) within 12 months (part a) or 3 months (part b) of randomization; * history of ethanol or drug abuse within the last one year prior to randomization; additional exclusion criteria for part b: * rapidly progressive gn (defined as a doubling of serum creatinine within the past 3 months); * evidence of significant chronicity, defined as: \> 50% glomeruli with sclerosis or \> 50% interstitial fibrosis on renal biopsy; or international society of nephrology (isn)/renal pathology society (rps) 2003 class iii (c), iv-s (c) or iv-g (c).

Keywords: lupus nephritis