Safety, Pharmacokinetics and Preliminary Efficacy Study of CFZ533 in Patients With Lupus Nephritis.

A Randomized, Placebo-controlled, Patient and Investigator Blinded, Study Investigating the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Multiple Doses of CFZ533 in Patients With Moderately Active Proliferative Lupus Nephritis

This study was to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary therapeutic efficacy of multiple doses of CFZ533 anti-CD40 monoclonal antibody in patients with moderately active lupus nephritis.

This was a randomized, subject and investigator blind, placebo controlled multicenter study with multiple doses of CFZ533 administered by 1-hour intravenous infusion over a 24 week treatment period, as compared to matched placebo infusion. The treatment period was followed by a 24-week safety follow-up period.The duration of the study (including the screening period) for each patient was approximately 53 weeks. The investigational drug or placebo was administered on top of standard of care therapy for lupus nephritis.

Patients were screened within 29 days of the first study drug infusion. Eligibility was confirmed at the baseline visit within one week before the first dose. Eligible patients were assigned a randomization number and receive the intravenous infusion within 3 days of baseline visit.

Key Inclusion Criteria:

• Men and women with systemic lupus erythematosus (SLE) aged ≥ 18 years and ≤ 75 years at screening, fulfilling at least 4 out of 11 criteria for SLE as defined by the American College of Rheumatology (Tan at al 1982, revised by Hochberg 1997)

• Subjects must have a body mass index (BMI) within the range of 18 - 40 kg/m2 at screening visit

• Histological diagnosis of proliferative lupus nephritis World Health Organization (WHO) ISN/RPS (Weening et al 2004) Class III or IV within 5 years of screening

• Presence of antinuclear autoantibody (ANA titer ≥ 1:80) at screening

• Morning UPCR ≥ 0.5 at screening visit and baseline visit

• At least one of the following:

  1. low complement level (C3 ˂ 0.9 g/L) or (C4 ˂ 0.1 g/L), and/or
  2. elevated anti-dsDNA (≥ 30 IU/mL), and/or
  3. urine sediment consistent with active proliferative LN such as presence of cellular (granular or red blood cell) casts or hematuria ( ˃5 red blood cells per high power field) if other causes such as menstrual bleeding are excluded

• Patient must have sufficient kidney function as estimated by eGFR ˃ 30mL/min/1.73 m2 at screening and baseline visits (Levey et al 2009)

• Patient must have active disease as defined by proteinuria and additional symptoms as above despite standard of care therapy for LN as considered appropriate by the treating physician (e.g., corticosteroids and/or immunosuppressive or immunomodulatory treatments such as mycophenolate, azathioprine, methotrexate or hydroxychloroquine). For guidance, see published guidelines such as Bertsias et all 2012 and Hahn et al 2012.

• Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must use highly effective methods of contraception during dosing and until study completion.

Key Exclusion Criteria:

• Any glomerulonephritis other than WHO Class III or IV lupus nephritis. Patients with proliferative nephritis (Class III or IV) who, in addition, have overlapping histological signs for other glomerulonephritis, e.g., Class V, are eligible at the investigator´s discretion.

• Hypoalbuminemia (serum albumin of less than 2.0 g/dL)

• Patients who have received:

  1. oral or i.v. cyclophosphamide within 3 months prior to randomization
  2. i.v. corticosteroid bolus (dose ˃ 1 mg/kg) within 3 months prior to randomization
  3. rituximab or other B cell depleting agent within 12 months. for patients who received such treatment earlier, B cell count should be within normal ranges prior to randomization
  4. belimumab within 6 months prior to randomization
  5. any other biologic drug or an investigational drug within one months or five times the half-life, whichever is longer prior to randomization
  6. any calcineurin inhibitor (e.g., tacrolimus or cyclosporin A) within 3 months prior to randomization

• Patients who are at significant risk for the thromboembolic events based on the following:

  1. history of either thrombosis or 3 or more spontaneous abortions
  2. presence of lupus anticoagulant or prolonged activated partial thromboplastin time (aPTT) and no prophylactic treatment with aspirin or anticoagulants as per local standard of care

• Have had signs or symptoms of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to randomization

• Live vaccines within 4 weeks of the first study drug infusion