A 12-month open-label, randomized, multicenter sequential cohort, dose finding study to evaluate the efficacy, safety and tolerability of oral AEB071 versus Neoral® in combination with Certican®, Simulect®, and corticosteroids in de novo adult renal transplant recipients

Over the past decades, organ allotransplantation has become a common medical
procedure with considerable impact on extending and improving the quality of
life of patients with end stage renal, cardiac, hepatic or pulmonary failure.
To maximize efficacy and minimize adverse effects, current immunosuppressant
(IS) regimens are based on the use of a combination of IS drugs. Care is taken
to achieve synergy or additive effects via the administration of sub-optimal
doses of agents with different mechanism of action while avoiding overlapping
toxicities. Consequently, most regimens are currently based on the use of the
combination of a calcineurin inhibitor (CNI) that inhibits T-cell activation,
such as Cyclosporin A (CsA, Neoral®) or tacrolimus (FK506, tacrolimus),
together with a lymphocyte
proliferation inhibitor such as drugs based on mycophenolic acid (MPA) i.e.
CellCept® (mycophenalate mofetil (MMF)); and myfortic® (MPA, as sodium salt,
gastro-resistant tablets) or mammalian target of rapamycin (mTOR) inhibitors
i.e. Rapamune® (sirolimus, rapamycin) and Certican® (everolimus (RAD001)).
CNIs demonstrate unique immunosuppressive efficacy without major risks of
overimmunosuppression, and excellent hematological tolerability. However, their
long-term benefit is limited by mechanism-based side-effects, such as renal
dysfunction, diabetogenic effects, hypertension, dyslipidemia, and
neurotoxicity. The more recently developed IS drugs (MPA; mTOR inhibitors)
effectively suppress lymphocyte proliferation, but their combination to
CNI-free IS regimen is usually associated with reduced efficacy and increased
hematological toxicity, and is therefore not ideal for the majority of
transplant recipients. A considerable need remains for safer therapeutic agents
inhibiting T-cell activation via a calcineurin-independent mechanism of action.
Mechanism of action Protein Kinase C (PKC) has been shown to play an important
role in T-lymphocyte activation. Among the various PKC isoforms expressed in T
cells, PKC * and * play a critical role. Preclinical data showed that by
knocking out these isoforms cardiac allograft survival was significantly
prolonged in mice and the results confirmed that PKC inhibitors are attractive
immunosuppressants by blocking T cell activation via a novel mechanism of
action.
AEB071 is a novel small molecular weight immunosuppressant that inhibits
PKC-dependent T-cell activation. In contrast to CsA, AEB071 potently and
selectively blocks a calcineurinindependent pathway downstream from signal 1
and signal 2 pointing towards a clear differentiation in mode of action between
AEB071 and CNIs. AEB071 potently inhibits allogeneic-stimulated T cell
proliferation in mixed lymphocyte reaction (MLR) (IC50 = 34 nM in human MLR),
but does not exhibit hematological cytotoxicity.

CAEB071A2206 will assess safety, efficacy and target trough levels for optimal
dosing of AEB071 combined with Certican in a CNI-free regimen in de novo renal
transplant recipients. This study will combine the investigational drug AEB071
with an established, effective adjunct therapy (everolimus) to provide a safe
entry into the transplant indication and a foundation for the subsequent Phase
III pivotal studies. The study will also guide the further development of
AEB071 and the selection of an appropriate target range for therapeutic drug
monitoring in de novo renal transplant patients.

This study will have 2 stages, with Stage 1 corresponding to phase IIa of drug
development (assessment of efficacy) and Stage 2 corresponding to phase IIb
(dose finding).

Each subject will be treated for 1 year. There are 2 treatment arms in Stage 1:
twothird of the subjects will be treated with AEB071 (300 mg bid) combined with
Certican. onethird of the subjects will be treated with Neoral and Certican. In
case 45 patients are included and have been treated for 3 months, an interim
analyses will be done to evaluate the efficacy and safety of AEB071. If AEB071
appears to be sufficient safe and effective, 84 new patients will be included
in the trial and after 3 months another interim analyses will be done.

In Stage 2, 180 subjects will be included. The dosing has been adapted in Stage
2, based on the results of the interim analyses. After 3 months, an interim
analyses will be done.

In Stage 1 are 2 treatment groups; twothird of the subjects will receive AEB071
(3 capsules of100 mg bid) in combination with Certican® (target dose of 4-8
ng/mL). Onethird of the subjects will be treated with Neoral® (start dose of
4-8 mg/kg/day) and Certican® (target dose of 4-8 ng/mL).

In Stage 2 are 3 treatment groups; Onethird of the subjects receives AEB071 (3
capsules of 100 mg bid) in combination with Certican® (target dose of 4-8
ng/mL). Onethird of the subjects receives Neoral® (start dose of 4-8 mg/kg/day)
and Certican® (target dose of 4-8 ng/mL). Onethird of the subjects receives
AEB071 (2 capsules of 100 mg bid) in combination with Certican® (target dose of
8-12 ng/mL).

During the transplantation and on day 4 post transplantation, the subject will
receive Simulect® via injection.
Furthermore, the subject needs to use corticosteroids to prevent infections.
The corticosteroids will be prescribed by the treating physician.

Treatment: starts after randomisation (AEB071 of Neoral) until end of treatment
in Month 12.

Patients will be monitored with help of Physical Examination, blood and urine
analyses and ECG at every visit.

A kidney biopsy will be done twice (on the day of the transplantation and on
Month 12).

Please refer to section E9 of this form for the nature and extent of the burden
and risks associated with participation.