Safety Study of AMG 811 in Subjects With Systemic Lupus Erythematosus With and Without Glomerulonephritis

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). Doses planed for Cohorts 1, 2, and 3 are 6, 20, and 60 mg, respectively. 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). Doses planned for Cohorts 4, 5, and 6 are 20 mg, 60, and 120 mg, respectively. 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.

• Nephritis
• Systemic Lupus Erythematosus

• Placebo Comparator: Placebo
  2 subjects of each cohort (cohort 1 to 6) will receive placebo
  Intervention: Drug: AMG 811
• AMG811
  Six subjects in each cohort (cohort 1 to 6) will receive AMG 811
  Intervention: Drug: AMG 811

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;
• Immunizations up to date with locally established guidelines, with a minimum of tetanus, diphtheria, pertussis (Td/Tdap), pneumococcal (polysaccharide) and influenza (during flu season) vaccinations, as determined by the Principal Investigator.
• Normal or clinically acceptable ECG at screening
• Women with normal Pap smear within the past 24 months before randomization;
• Able and willing to complete entire study according to study schedule.

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; SLE subjects with GN who have had either a first episode of glomerulonephritis or reactivation of nephritis that has been previously controlled (with or without maintenance therapy) are eligible;

- 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;
• History of malignancies (other than resected squamous and basal cell carcinomas of the skin);
• Subjects who, in the clinical judgment of the Investigator, have unstable or severe disease;
• Uncontrolled hypertension (> systolic 150 / diastolic 95) confirmed by repeat assessment during the screening period;
• Poorly controlled diabetes (defined as HbA1c ≥ 8.0%) during the screening period;
• Presence or history of vasculitis within the last 3 years, presence or history of active CNS lupus requiring therapy within the last 3 years;
• Creatinine clearance within the screening period of less than 50 mL/min as calculated by the Cockcroft-Gault method
• Evidence of liver disease (eg, serum ALT or AST > 2x upper limit of normal) during the screening period;
• Hemoglobin < 9 g/L during the screening period;
• Neutropenia (neutrophils < 1,500/μL) during the screening period;
• Thrombocytopenia (platelets < 75,000/μL) during the screening period;
• Total WBC < 2500 x 106/L during the screening period;
• 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
• Known residential exposure to an individual with tuberculosis (TB) (if not treated with appropriate chemoprophylaxis) or positive Quantiferon test or positive protein purified derivative (PPD) test at screening consistent with previous exposure to TB prior to or during screening. In case of prior evidence of latent infection or in case of documented BCG vaccination,
• Positive serology for HIV antibodies, hepatitis B surface antigen or hepatitis C antibodies (confirmed by PCR or RIBA) during the screening period;
• Known or suspected parasitic infestation per local incidence or prevalence of parasites;
• Positive screening test for strongyloides;
• History of valley fever or positive screening test for coccidioidomycosis;
• Known hypersensitivity to any component of the study drug;
• Receipt of a live vaccine within 3 months of study randomization;
• 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;
• Administration of another investigational drug that does not target the immune system within the previous 30 days or 5 half-lives prior to randomization, whichever time period is longest.
• Received AMG 811 previously and tested positive for the presence of anti-AMG 811 antibodies;
• Any disorder or condition that prevents the subject from providing informed consent;
• Have donated blood or experienced a loss of blood > 500 mL within 4 weeks of randomization;
• History of ethanol or drug abuse within the last one year prior to randomization;
• Unwilling to practice highly effective method of birth control during the study.
• Positive pregnancy test at screening or baseline; or females who are currently lactating;

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).