An extension to a 12-month, open-label, randomised, 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 α 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.

The purpose of this extension is to provide continued treatment and to assess
the long term safety, efficacy and tolerability of oral AEB071 plus Certican®
vs. Neoral® plus Certican® in de novo renal transplant recipients.
The study is a continuation of a CNI-free core study. The extension will allow
continued access to AEB071 after the end of the core study to patients who were
on study treatment at the end of the core study and may provide early
notification of safety signals on AEB071 in patients during the 48 months
extension study period.

See protocol page 24 and 15 (Study design).

There are two treatment groups: 2/3 of the patients will be treated for 3
years* with AEB071 (3 capsules of 100 mg bid) in combination with Certican® (4
tablets of 0,75 mg bid). 1/3 of the patients will be treated for 3 years*with
Neoral® (starting dose of 4 mg/kg/day capsule) and Certican® (2 tablets of 0,75
mg bid).

*CAEB071A2206: 1 year treatment, CAEB071A2206E1: 2,5-5 year treatment

The patient will have to use corticosteroids to resist infections.
Cortocosteroids will be prescibed by the investigator.

Treatment: after completion of all visits in the core study, treatment will be
continued for 48 months in the extension study.

Patients will be examined during the study: physical examination, blood and
urine tests. Besides, an ECG will be performed by the patient 9x during the
extension study.