Trial Information

Randomized, Open Label, Multicenter Study of Belatacept-based Early Steroid Withdrawal Regimen With Alemtuzumab or rATG Induction Compared to Tacrolimus-based Early Steroid Withdrawal Regimen With rATG Induction in Renal Transplantation

Renal transplant is the most effective treatment for end-stage renal disease. It provides
improved survival and quality of life. Maintenance of a functioning renal transplant
mandates lifelong immunosuppressive therapy to prevent immune destruction of the graft.
Current immunosuppressive regimens yield 1-year survival rates of 89% for cadaveric and 94%
for living-donor grafts. Over time, however, there is progressive loss of both subjects and
grafts. Five-year graft survival for cadaveric and living related donor renal transplants is
67% and 80%, respectively.

The most common causes of long-term subject and graft loss in kidney transplant recipients
are cardiovascular disease and chronic allograft nephropathy (CAN), respectively.
Paradoxically, the principal immunosuppressive therapies for renal transplant, the
calcineurin inhibitors (CNIs), cyclosporine (CsA) and tacrolimus, directly contribute to
long-term allograft loss and subject death, since they are inherently nephrotoxic and can
cause or exacerbate cardiovascular risks including hypertension, hypercholesterolemia, and
diabetes mellitus.

There is, therefore, a substantial unmet medical need for new therapies in renal transplant
that can provide short-term subject and graft survival comparable to the CNIs without their
long-term nephrotoxic, cardiovascular, and metabolic effects. Because belatacept can be
administered at the time of engraftment rather than in a delayed fashion, as is frequently
necessary with CNIs - especially in those allografts with initial impaired renal function--
it affords immunosuppression in a timely manner. Unlike CNIs, the targeted mechanism of
action of belatacept should provide immunosuppression without nephrotoxicity or adverse
effects on the cardiovascular/metabolic profile.

Glucocorticoids have been a cornerstone of immunosuppressive therapy for six decades.
Although glucocorticoids provide potent suppression of allo-immune responses in humans,
their adverse effects including infection, diabetes, weight gain, hypertension,
hyperlipidemia, bone disease, dermal thinning, collagen loss in multiple tissues, and
cataracts, combined with a lack of available therapeutic monitoring all argue against their
continued use in transplantation.

Belatacept represents a potential new treatment option for renal transplant recipients,
which addresses the current unmet need for an immunosuppressive treatment that provides
short-term outcomes comparable to calcineurin inhibitors (CNIs) with the potential to avoid
their renal, cardiovascular, and metabolic toxicities. However, the initial Phase 3 studies
exhibited in higher rate of acute rejection and malignancy. The malignancies were
associated with recipients who were EBV negative at the time of transplant. All EBV
negative patients are precluded from treatment with Belatacept. Due to the limitations of
Phase 3 trial designs and the required use of basilixumab induction, it is intuitive that
the addition of a potent t cell depleting induction agent may decrease the overall acute
rejection rate in patients treated with belatacept.

The current study tests these assumptions with the following immunosuppressive regimens.
Group A and B consist of potent T-cell depleting induction agents combined with belatacept.
Group C represents the most common immunosuppressive regimen currently utilized in the
United States. Each of these regimens include early withdrawal of glucocorticoids along
with maintenance mycophenolate mofetil.

Based upon the totality of available evidence, the current study offers a favorable
benefit/risk profile to study subjects, and the potential to continue to provide important
data for the development of new immunosuppressive regimens that address important unmet
needs.

The proposed Phase 4 study is designed to determine whether belatacept, in combination with
other immunosuppressive agents (rabbit antithymocyte globulin or alemtuzumab, mycophenolate
mofetil/EC mycophenolate sodium), may provide acceptable efficacy and safety in de novo
kidney transplant recipients, in a regimen that provides simultaneous CNI freedom and early
CSWD.