FDA Approved Agents
Since the introduction of cyclosporine in the early 1980's, the biggest advances in transplantation
have been due to developments in immunosuppressive therapy, particularly with the introduction of new
agents. Increasing familiarity with these agents has led to tacrolimus currently being the calcineurin inhibitor of choice in both
kidney and liver transplantation, with over 90% of new liver transplant recipients on tacrolimus at the
time of discharge from the hospital.
Mycophenolate mofetil (MMF) has been used in
increasing frequency, often in regimens that spare corticosteroids or calcineurin inhibitors.
Corticosteroid avoidance or early elimination is also being applied with increasing frequency with the
enhanced efficacy afforded by tacrolimus and MMF.
Sirolimus (RAPA,RAD) is a macrolide antibiotic
similar in structure to tacrolimus, but with a distinct mechanism of action. Sirolimus exerts its
effects primarily as an inhibitor of mTOR (mammalian target of rapamycin), resulting in potent
antiproliferative effects. Inhibition of mTOR activity results in inhibition of cytokine (IL-2, IL-4,
IL-7, and IL-15) –driven T cell proliferation. Sirolimus inhibits progression from G1 to the S phase of
the cell cycle. mTOR is a key regulatory kinase, and its inhibition by sirolimus has several related
effects including: 1) inhibition of mRNA translation for several proteins essential for cell cycle
progression, 2) inhibition of IL-2-induced transcription of proliferating cell nuclear antigen (PCNA)
that is essential for DNA replication, 3) blocking CD28 mediated IL-2 transcription, and 4) inhibition of
cdk4/cyclinD and cdk2/cyclin E kinase activity. Sirolimus was initially developed in renal
transplantation in combination with cyclosporine and corticosteroids as a primary maintenance
immunosuppressive agent. Recently, sirolimus has been approved by the FDA for early conversion at three
months, thereby allowing calcineurin inhibitor withdrawal. Two trials in liver transplant recipients
have been initiated. The first study was a randomized study that compared sirolimus in combination with
cyclosporine and steroids to tacrolimus and steroids. Planned enrollment was 231 patients, but
enrollment was stopped at 164 patients due to increased hepatic artery thrombosis and portal vein
thrombosis in the sirolimus-treated group (3.8% v 12.6%, p = NS). Although most patients with HAT or PVT
had thrombosis risk factors, an internal decision was made by the company to discontinue the study. A
second study is currently enrolling patients in a phase 2 study comparing tacrolimus and steroids to
reduced dose tacrolimus/sirolimus/steroids.
Leflunomide is an pyrimidine synthesis
inhibitor currently FDA approved for treatment of rheumatoid arthritis. It inhibits several metabolic
pathways, of which, the enzyme dihydro-orotate dehydrogenase is thought to be the major target. The
principal drawback to its use in transplant recipients is its prolonged half-life of approximately 14
days. Anecdotal reports of its use have indicated that it may be of some use in transplant recipients
with refractory rejection, and there is also considerable interest in its use in patients with
polyomavirus nephropathy because of its reported ability to inhibit polyomavirus replication in vitro.
Agents in Development
Modified Release Tacrolimus (Prograf MR)is a
long acting tacrolimus preparation currently being developed by Fujisawa that will allow once daily
tacrolimus dosing. Unpublished, recently completed pharmacokinetic trials with Prograf MR in stable
kidney, liver, and cardiac transplant recipients have shown similar drug exposure profiles to the parent
compound, tacrolimus.
FTY 720 is a synthetic derivative of myriocin,
a compound isolated from the actinomycete Isaria sinclarii.The mechanism of action of FTY 720 is not
completely understood, however it appears that a primary mechanism of action occurs via binding to
sphingosine -1 phosphate (S1P) receptors with alterations in homing receptor expression in lymphocytes,
with a subsequent homing to lymph nodes and Peyer's patches, with peripheral lymphopenia. Phase I and
Phase II trials have been conducted with FTY 720 in combination with cyclosporine and corticosteroids and
have demonstrated efficacy similar to cyclosporine, MMF, and corticosteroids, with rejection rates in the
10-20% range. The only substantive toxicity to date is bradycardia with the first dose (probably
mediated via cardiac EDG receptors) that is easily treated with atropine. Phase I and IIA trials have
been completed and show that it is a potent adjunctive agent when used in combination with cyclosporine
and corticosteroids. Phase IIb trials are currently underway.
Malanonitrilamides (MNAs) are a group of
compounds that belong to the same family as leflunomide. Their mechanism of action is thought to be
primarily via pyrimidine synthesis inhibition. Fujisawa is currently developing one (FK 778) of several
MNAs for immunosuppression in renal transplant recipients. Several experimental studies have
demonstrated that synergy between tacrolimus and MNAs in vivo.
CP-690,550 is an antagonist of Janus Kinase 3
(JAK3), a key signaling molecule for the common gamma chain of the cytokine receptors (IL-2, IL-4, IL-7,
IL-9, IL-15, and IL-21) that are integral to lymphocyte activation and proliferation. Currently,
CP-690,550 is being developed for prevention of renal allograft rejection. The side effect profile is
also expected to be favorable, and JAK3 expression is largely restricted to cells of the immune system.
CP-690,550 was identified by screening a chemical library from Pfizer Pharmaceuticals for specific
inhibitors of JAK3. CP-690,550 is relatively specific for JAK3, and shows some crossreactivity with
other JAKs especially JAK2, a mediator of signaling pathways involving erythropoietin, thrombopoietin,
and GM-CSF receptors. Not surprisingly, therefore, anemia is a side effect of CP-690,550 in primates.
Another attractive attribute of CP-690,550 is that it is several logs more potent than other JAK3
inhibitors, especially against IL-2 driven proliferation. CP-690,550 also can be administered orally.
Recent animal studies with CP-690,550 in a murine heart transplant model and cynomologous
kidney transplant model have demonstrated in vivo efficacy. In the cynomologous kidney transplant model,
CP-690,550 monotherapy prolonged allograft survival to a median of 75 days compared to 6 days in placebo
treated animals. This is in comparison to historical experience with cyclosporine monotherapy of a
median survival of 39 days. Additional animal studies are underway to determine optimal combinations
with other immunosuppressive agents. It is expected that human studies will be initiated in 2004.
