A 12-month randomized, multiple dose, open-label, study evaluating safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and efficacy of an anti-CD40 monoclonal antibody, CFZ533, in combination with mycophenolate mofetil (MMF) and corticosteroids (CS), with and without tacrolimus (Tac), in de novo renal transplant recipients

The purpose of this adaptive, two-part study is to investigate the potential
for CFZ533 to replace calcineurin inhibitors (CNI), while providing a similar
rate of acute rejection prophylaxis and better renal function in a de novo
renal transplant population receiving an allograft from standard criteria
donors.

Part 1 of this trial will focus on profiling the multiple dose pharmacokinetics
(PK), pharmacodynamics (PD) and tolerability for both IV and SC CFZ533
administration in the setting of standard-of-care, CNI-based immunosuppression.

Part 2 will evaluate the safety and efficacy of CFZ533 in the absence of a CNI
in combination with adjunct MMF and basiliximab induction therapy for up to 12
months. Overall, results of this study will be used to inform the CFZ533 dose
and regimen selection for investigation in later phases of clinical
development.

Primary:
Part 1: PK, PD and Safety
To assess the safety, tolerability and pharmacokinetics of multiple IV and SC
doses of CFZ533 in combination with MMF, CS, and Tac (standard exposure) in de
novo renal transplant patients over the treatment and follow-up period.

Part 2: CNI-free Proof-of-Concept
To assess the potential for CFZ533 to act as the primary immunosuppressant in a
CNI-free regimen with MMF in de novo renal transplant patients as assessed by
tBPAR at Month 3 posttransplantation.

Secondary:
Part 1: PK, PD and Safety
To quantify the magnitude and duration of peripheral blood CD40 occupancy (free
CD40 and total CD40 on B cells).
To quantify the change from baseline and recovery of peripheral blood total
soluble CD40 and total soluble CD154.
To evaluate the immunogenicity of CFZ533 via the quantitative analysis of
anti-CFZ533 antibodies.

Part 2: CNI-free Proof-of-Concept
To assess the safety and tolerability of CFZ533 administered chronically in
combination with MMF and CS up to 3 months against a control.
To assess the pharmacokinetics of multiple IV doses of CFZ533 during the
12-month treatment period.
To quantify the magnitude and duration of peripheral blood CD40 occupancy (free
CD40 and total CD40 on B cells) during the treatment period following multiple
IV doses of CFZ533.
To compare renal function in CFZ533 treatment arms to control at Month 3
post-transplantation as assessed by:
Estimated GFR using MDRD
Proportion of patients with eGFR <60 mL/min/1.73m2
Proportion of patients with negative eGFR slope
To evaluate the immunogenicity of multiple IV doses of CFZ533 via the
quantitative analysis of anti-CFZ533 antibodies
To quantify the change from baseline and recovery of peripheral blood total
soluble CD40 during the treatment period following multiple IV doses of CFZ533.

A randomized, two-part, 6- or 12-month, sequential, adaptive, controlled,
open-label, multicenter, clinical proof-of-concept study to evaluate the
efficacy, safety, tolerability, PK and PD of CFZ533 + MMF + CS, with standard
exposure (Part 1) or no tacrolimus (Part 2), for initial and maintenance
prophylaxis of organ rejection in adult de novo renal transplant recipients as
compared to standard of care.

Part 1 (PK, PD and Safety):
For Arm 1, 6 patients total will be enrolled to receive IV induction (Day 1)
and SC administration on Days 15, 29, 43 and 71 of 3 mg/kg CFZ533 with
standard-exposure tacrolimus (whole blood trough concentration 4-11 ng/mL), MMF
and CS.
Following enrollment of Arm 1, if the interim review of PK/PD data confirms
predicted exposure and satisfactory tolerability, Part 2 will initiate
enrollment.
All patients enrolled into Part 1 will remain on SoC until Month 6 (EOS).
If the true treatment biopsy-proven acute rejection rate (tBPAR) in Part 1
exceeds 20% (with high probability (>90%) at any time point within three months
post-transplant, the treatment arm will be discontinued and hence the study
will be terminated.

Part 2 (CNI-free PoC):
Following 2:1 randomization, 45 patients will be enrolled in Arms 2A and 2B in
a parallel manner. Arm 2A will receive multiple
intravenous CFZ533 10 mg/kg doses with basiliximab induction, MMF and CS; Arm
2B (control) will receive standard-exposure tacrolimus (whole blood trough
concentration 4-11 ng/mL) with basiliximab induction, MMF and CS.
Primary endpoints and PoC determination will occur via interim analysis after
the Month 3 visit.

The stopping rule described for Part 1 will be in effect in Part 2.

Part 1
Arm 1, n=6: CFZ533 at 3.0 mg/kg SC (5 doses; first dose is IV, SC on
Days 15, 29, 43 and 71) + tacrolimus (4-11 ng/mL) + MMF 1.0 g BID + CS

Part 2
Arm 2A, n=30: Basiliximab 20 mg (Days 0, 4) + CFZ533 at 10 mg/kg IV
(17 doses) + MMF 1.0 g BID + CS
Arm 2B Control/Standard of Care, n=15: Basiliximab 20 mg (Days 0, 4)
+ tacrolimus (4-11 ng/mL) + MMF 1.0 g BID + CS

Study duration: 1 year, 23 visits of 2 hours
Bloodpressure, pulse, bodytemperature 16x
measurement weight 15x and length 1x
Physical examination 4x
Blood and urine tests at each visit (except Day 10)
Pregnancy test every six months
Kidney biopsy if medically necessary
ECG every six months
TB test
Optional tests: pharmacogenetic research.