Active Proliferative Lupus Nephritis

Primary Objective(s)• To evaluate the safety and tolerability of 24 weeks of treatment with multiple intravenous (IV) doses of10 mg/kg CFZ533 as an add-on therapy of CFZ533 to standard of care in moderately active lupusnephritis (LN) patients• To assess the effect of CFZ533 on renal proteinuria using urinary protein creatinine ratio (UPCR) inmoderately active LN patients after 24 weeks of treatment as an add-on therapy to standard of care ascompared to placeboSecondary Objective(s)• To assess the effect of CFZ533 on relevant renal outcomes at different time points• To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of CFZ533 in LN patients aftermultiple 10 mg/kg IV doses• To evaluate the immunogenicity of CFZ533 in LN patients after multiple 10 mg/kg IV doses

CFZ533

CFZ533

Concentrate for solution for infusion

150mg/ml

• Primary endpoint(s):
• AEs/SAEs, Vital signs, ECG evaluation, Standard hematology and chemistry evaluations
• Ratio from baseline in urinary protein creatinine ratio (UPCR) at Week 25
• Secondary endpoints:
• Ratio from baseline in the following parameters:
• UPCR
• hematuria and cellular casts
• Proportion of patients who fulfill the criteria for complete renal remission (CRR) according to ACR
recommendation (Wofsy et al 2012)
• PK: Free CFZ533 concentrations in plasma.
• Parameters (free CFZ533): Ctrough,ss or Cmin,ss, Cmax,ss, and AUClast (after last dose)
• PD: Total soluble CD40 concentrations in plasma: pre-dose, during treatment and follow up. Rate,
extent and duration of target engagement.
• Anti-CFZ533 antibodies in plasma: baseline, during treatment and follow-up, incidence of ADA-positive
patients

Inclusion criteria:
Population eligible for inclusion in this study must fulfill all of the following criteria:
1. Understand the study procedures and provide written informed consent before any study-related
assessment is performed.
2. Men and women with systemic lupus erythematosus (see below), 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 et al 1982, revised by Hochberg 1997).
3. Subjects must have a body mass index (BMI) within the range of 18 - 40 kg/m2
. (BMI = Body weight (kg) /
[Height (m)]2) to participate in the study
4. Histological diagnosis of proliferative lupus nephritis World Health Organization (WHO) ISN/RPS (Weening
et al 2004) Class III or IV within 2 years of screening
5. Presence of antinuclear autoantibody (ANA titer ≥1:80 at screening)
6. First morning UPCR ≥0.5 at Screening visit and Baseline visit (at least five days apart)
7. At least one of the following at Screening visit:
a. low complement level (C3 < 0.8 g/L or C4 < 1.6 g/L), and/or
b. elevated anti-dsDNA (≥30 IU/mL), and/or
c. urine sediment consistent with active proliferative lupus nephritis 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
8. Patient must have sufficient kidney function as estimated by eGFR > 30 mL/min/1.73m2
9. Patients must have active disease as defined by proteinuria and additional symptoms as defined above
(criterion 7) despite standard of care therapy for lupus nephritis 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 by Bertsias et al 2012 and Hahn et al 2012
10. If the patient is taking oral corticosteroid treatment at screening, the dose (max. 30 mg prednisone or
equivalent per day) must be stable for at least 2 weeks prior to randomization
11. If the patient is taking immunosuppressive or immunomodulatory treatment such as mycophenolate,
azathioprine, methotrexate or hydroxychloroquine, the dose must be stable for at least 4 weeks prior to
randomization and for the duration of the study
12. If the patient is taking a medication potentially affecting renal function (such as ACE inhibitors, cholesterollowering agents) the dose must be stable for at least 4 weeks prior to randomization and for the duration of
the study
13. Vaccinations, if deemed necessary, must be up to date based on local guidelines
14. Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant)
must use highly effective methods of contraception before entering the study, during dosing and until study
completion.
Highly effective contraception methods include:
• Total abstinence from heterosexual intercourse (when this is in line with the preferred and usual
lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total
hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of
oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up
hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female subjects in the study, the
vasectomized male partner should be the sole partner for that subject.
• Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine
device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have
comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone
contraception. Women should have been stable on their chosen method of OC for a minimum of 3
months before entering the trial.
• Postmenopausal females must have had no regular menstrual bleeding for at least one (1) year prior
to initial dosing. Menopause will be confirmed by a plasma FSH level of >20 IU/L at screening.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of
natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of
vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total
hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up hormone level assessment is she
considered not of child bearing potential.
All female patients of childbearing potential must have negative pregnancy test results at Screening and
Baseline visits.

Exclusion criteria:
Eligible Population fulfilling any of the following criteria are not eligible for inclusion in this study:
1. 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
2. Hypoalbuminemia (serum albumin of less than 2.0 g/dL)
3. Patients who have received
a) oral or IV cyclophosphamide within 3 months
b) IV corticosteroid bolus (dose higher than 1 mg/kg) within 3 months
c) rituximab or other B cell depleting agent within 12 months. For patients who received such treatment
earlier, B cell count should be within normal range
d) belimumab within 6 months
e) any other biologic drug or an investigational drug within one (1) month or five times the half-life,
whichever is longer
f) calcineurin inhibitor (e.g., tacrolimus, cyclosporin A) within 3 months
4. Patients who are at significant risk for thromboembolic events based on the following:
• History of either thrombosis or 3 or more spontaneous abortions
• Presence of lupus anticoagulant or prolonged partial thromboplastin time (PTT) and no prophylactic
treatment with aspirin or anticoagulants as per local standard of care
5. History or presence of any medically significant cardiac condition which according to the investigator may
jeopardize the patient in case of participation in the study including ischemic heart disease, congestive
heart failure or cardiomyopathy, myocardial infarction or stroke
6. History of malignancy with the exception of basal cell or squamous cell carcinoma of the skin or in situ
carcinoma of the cervix within the last 3 years
7. Have had signs or symptoms of a clinically significant systemic viral, bacterial or fungal infection within 30
days prior to randomization
8. Evidence of active or latent tuberculosis as assessed by Quantiferon testing at screening (PPD is not
recommended as immunosuppression may result in false negative result)
9. Positive serology for HIV antibodies, hepatitis B surface antigen, or hepatitis C antibodies confirmed by an
appropriate licensed test at screening
10. Any other current, active or latent infection susceptible to reactivation
11. Any significant concurrent medical condition such as pulmonary or liver disease that, in the opinion of the
principal Investigator, could affect the patient's ability to tolerate or complete the study
12. Any of the following abnormal laboratory values:
a) total white blood cell count (WBC) outside the range of 1,500-15,000/mm3 (1.5-15.0 x 109/L)
b) platelets <100,000/mm3 (<100 x 109/L)
c) Hemoglobin (Hgb) <8.0 g/dL (<5mmol/L)
d) lymphocyte count <500/mm3 (<0.5 X 109/L)
e) neutrophil count <1500/mm3 (<1.5 X 109
/L)
f) Clinical evidence of liver disease or liver injury or any of the following hepatic conditions:
o known history of alcohol abuse, chronic liver or biliary disease
o conjugated bilirubin greater than the ULN
o alkaline phosphatase (AP) greater than 3 x ULN
o AST (SGOT), ALT (SGPT) greater than 3 x ULN
o γ-glutamyl-transferase (GGT) greater than 3 x ULN
13. Live vaccines within 4 weeks of study drug infusion
14. Have donated blood or experienced a loss of blood >500mL within 4 weeks of screening
15. Known allergy to human antibodies
No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.