A partially-blinded, active-controlled, multicenter, randomized study evaluating efficacy, safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) of an anti-CD40 monoclonal antibody, CFZ533, in de novo and maintenance kidney transplant recipients (CIRRUS I, CCFZ553A2201)

The purpose of this study is to investigate the safety, efficacy,
pharmacokinetics (PK) and pharmacodynamics (PD) of:

- two CFZ533 dose regimens in de novo kidney transplant recipients, in
combination with mycophenolate mofetil (MMF) and corticosteroids, compared to a
standard of care control arm of tacrolimus, MMF and corticosteroids.

- one CFZ533 dose regimen started 6-24 months post-transplantation in
maintenance kidney transplant recipients, in combination with either MMF or
EC-MPS with or without corticosteroids, compared to a standard of care control
arm of tacrolimus and MMF or EC-MPS with or without corticosteroids.

This study will allow the assessment of the ability of CFZ533 to replace CNIs
as the standard of care by potentially improving long term outcome (reduced
graft loss) while maintaining comparable short term anti-rejection efficacy,
and providing better renal function with an adequate safety and tolerability
profile, in de novo and maintenance renal transplant patients.

Primary Objective(s) (Cohort 1):
* To demonstrate that CFZ533 600 mg and/or 300 mg bi-weekly (Q2W), subcutaneous
(SC), is non-inferior to a tacrolimus-based regimen with respect to the
proportion of patients who experience composite efficacy failure event (biopsy
proven acute rejection (BPAR), graft loss, or death) over 12 months
post-transplantation.

Secondary objective (Cohort 1):
* To demonstrate that CFZ533 600 mg and/or 300 mg Q2W SC are superior to a
tacrolimus-based regimen with respect to the mean estimated glomerular
filtration rate (eGFR) over 12 months post-transplantation.
* To assess the safety and tolerability of CFZ533 regimens compared to a TAC
based-regimen.
* To assess the pharmacokinetics of CFZ533 and explore the dose-exposure
relationship during the 60 months treatment period.
* To assess the immunogenicity of CFZ533 during the 60 months treatment period.

Primary Objective(s) (Cohort 2):
* To demonstrate that CFZ533 450 mg bi-weekly (Q2W) subcutaneously (SC) is
non-inferior to a tacrolimus-based regimen with respect to the proportion of
patients who experience composite efficacy failure event (biopsy proven acute
rejection (BPAR), graft loss, or death) over 12 months post conversion

Secondary Objective(s) (Cohort 2):
* To demonstrate that CFZ533 450 mg Q2W SC is superior to a tacrolimus-based
regimen with respect to the mean change in eGFR from baseline over 12 months
post conversion.
* To assess the safety and tolerability of CFZ533 regimen compared to a
TAC-based regimen.
* To assess the pharmacokinetics of CFZ533 during the 60 months treatment
period and explore the dose-exposure relationship (together with PK data from
Cohort 1).
* To evaluate the immunogenicity of CFZ533 during the 60 months treatment
period.

Study CCFZ533A2201 is a randomized, 60-month, (5 year) study comprising of
12-months treatment for the primary analysis plus an additional 48-month
treatment period. The study is active-controlled, partially-blinded, for the
initial 12 months of treatment, multicenter, dose range finding study to
evaluate the efficacy, safety, tolerability, PK and PD of CFZ533 in 2 different
cohorts:

In adult de novo kidney transplant recipients, CFZ533 in combination with MMF
and corticosteroids as compared to standard of care comprised of tacrolimus,
MMF and corticosteroids.

In a maintenance kidney transplant population (6-24 months post-transplant),
CFZ533 in combination with MMF with or without corticosteroids, compared to a
standard of care control arm of tacrolimus and MMF with or without
corticosteroids.

Cohort 1 * de novo patients:

Arm 1: CFZ533 30 mg/kg IV (Day 1), CFZ533 15 mg/kg IV (Day 5), then CFZ533 600
mg SC Q2W (from Day 15) + MMF + corticosteroids (n=75)

Arm 2: CFZ533 30 mg/kg IV (Day 1), CFZ533 15 mg/kg IV (Day 5), then CFZ533 300
mg SC Q2W (from Day 15) CFZ533 + MMF + corticosteroids (n=75)

Arm 3: TAC + MMF + corticosteroids (n=50). All patients will receive induction
therapy: Basiliximab or Thymoglobulin (rATG)

Cohort 2 * maintenance patients:

Arm 1: CFZ533 30 mg/kg IV (Day 1) then CFZ533 450 mg SC Q2W (from Day 15) +
MMF/EC-MPS ± corticosteroids (n=75)

Arm 2: TAC + MMF/EC-MPS ± corticosteroids (n=50)

Duration of study: 5 year, 31 hospital visits, 93 home administrations.
Blood pressure, pulse, temperature: 31x
Blood and urine examination at every (hospital) visit
Pregnancy test every hospital visit and every month at home
Kidney biopsy on D1 (back-table) in cohort 1; D1 cohort 2 (if biopsy is not
available in month prior to D1); Month 12, Month 60/End of Study and if
medically required (in case of a suspected rejection).
ECG 20x
Questionnaires (1 à 2): 3x