An Open Label, Single-Center Pilot Study of Early Conversion From Tacrolimus to Efalizumab Maintenance Therapy in Primary Renal Transplant Recipients
Over the last two decades there have been significant improvements in renal transplantation
due in large part to the decreasing incidence of acute rejection (down to less than 20% for
first renal transplants) with the use of calcineurin inhibitors (CNI) such as cyclosporin
and tacrolimus. Though proven very effective anti-rejection medications their use is
associated with adverse side effects, including high blood pressure, post transplant
diabetes, and high cholesterol, predisposing risk factors for cardiovascular disease and
cerebrovascular disease. Chronic use of these drugs has also waged limitations to the long
term survival of transplanted kidneys and kidney recipients with an increase in the
development of chronic allograft nephropathy (CAN). There is also an increased incidence of
chronic renal failure in non renal transplant recipients receiving CNI based treatments.
The mechanism of action for these reagents is known to be imprecise and science has sought
to replace the current therapies in place with less toxic drugs more specific in their
signaling pathway targets. In recent years cell surface proteins, restricted to cells of
the immune system have been identified as mediators of the rejection response. The
activation of T cells has been seen to activate an immune response correlated clinically
with rejection. Integrins, specifically leukocyte function associated antigen LFA-1, are
cell surface molecules which play a role in T-cell activation. LFA-1 is made up of two
subunits, known as CD11 and CD18. Efalizumab is a humanized monoclonal antibody against the
CD11 molecule. By binding to CD11 on T cells the system blocks the interaction between
LFA-1 and ICAM-1, an intercellular adhesion molecule also necessary for T cell activation,
thereby diminishing an immune response. The blockade formed does not deplete the T cells.
There have been preliminary studies using efalizumab in combination with cyclosporine. A
very low incidence of rejection was observed in all groups receiving efalizumab (7.8%).
However 3 cases of post-transplant lymphoproliferative disease were seen in 38 patients.
There have been no cases of lymphomas or lymphoproliferative disease reported in clinical
trials evaluating efalizumab for the treatment of psoriasis, suggesting that the combination
of efalizumab and cyclosporine may have resulted in over immunosuppression.
As per standard of care, recipients of a kidney transplant at Emory are managed with a
combination of the calcineurin inhibitor Prograf (tacrolimus), Cellcept (an
antiproliferative agent) and Prednisone, a corticosteroid. For this study the
investigators have chosen to substitute efalizumab in place of Prograf, after 3 months post
transplant the period where the incidence of acute rejection is highest. Efalizumab, known
by its trade name Raptiva, was approved by the FDA in October 2003 for the treatment of
psoriasis. It is hypothesized that the conversion from Prograf to efalizumab will be
associated with improved renal function and not associated with an increased risk of
rejection. The investigators hope to address the challenges faced by recipients of
transplanted kidneys in the long course of their transplanted organ's management with more
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Efficacy Will be Determined by Change in Renal Function as Measured by Cold Iothalamate Glomerular Filtration Rate(GFR)3 Months After Enrollment, and Acute Rejection Episodes Within the First 6 Months Post Enrollment.
6 months from conversion
Kenneth A Newell, MD, PhD
United States: Food and Drug Administration
|Emory University||Atlanta, Georgia 30322|