A randomized, multicenter study to assess the efficacy on disease activity on enteric-coated mycophenolate sodium (EC-MPS, myfortic) versus continuation of azathioprine in patients with systemic lupus erythematosus on azathioprine maintenance therapy.

Systemic lupus erythematosus (SLE) is a complex and potentially
life-threatening disease that affects about 40 per 10,000 people in the general
population (Mills 1994, Brown & Schrieber 1996). SLE is a chronic inflammatory
disease characterized by auto-antibody overproduction and other distinct
immunological abnormalities (Boumpas, et al 1995, Mohan & Datta 1995). It may
affect the skin, joints, lungs, heart, serous membranes, nervous system or
other organs. Improvements in treatment over the last decade have increased
10-year survival rates in Western countries to 90% or more, and 20-year
survival rates of nearly 70% have also been reported (Abu-Shakra, et al 1995).
Newer treatment strategies include the use of novel immunosuppressive agents,
such as mycophenolate mofetil (MMF). MMF has been widely used in solid-organ
transplantation (Sollinger 1995, The Tricontinental Mycophenolate Mofetil Renal
Transplantation Study Group 1996). MMF also has been used increasingly in
autoimmune diseases (e.g., dermatomyositis, primary glomerular disease or
psoriasis (Epinette, et al 1987, Gelber, et al 2000, Choi, et al 2002)).
MMF is the morpholinoethylester prodrug of mycophenolic acid (MPA). After oral
administration MMF is well absorbed and rapidly hydrolyzed to MPA. MPA is a
noncompetitive inhibitor of inosine monophosphate (IMP) dehydrogenase (DH).
Inhibition of IMPDH leads to the depletion of deoxyguanosine triphosphate and a
consequent decrease in the level of substrate required for DNA polymerase
activity. This results in inhibition of DNA production and cell proliferation.
T and B cells are more dependent on this de novo pathway of purine synthesis
because alternative salvage pathways are unavailable. Thus, MPA is a selective
inhibitor of lymphocyte proliferation, especially in activated lymphocytes
(Allison & Eugui 2000).
In the transplant population, the high incidence of GI side effects with MMF
that leads to dose reductions or discontinuations may increase the risk of
graft failure as a result of sub-therapeutic drug exposure (Knoll, et al 2003,
Hardinger, et al 2004). Therefore, it would be useful to be able to avoid
MPA-related upper GI side effects without compromising drug exposure or
efficacy. Enteric coating has been used with several classes of drugs to reduce
the incidence of GI side effects and to protect the drug moiety from
inactivation by gastric acid. The coating delays delivery of the active
ingredient by preventing its release in the stomach; the coating disintegrates
in the intestines to allow absorption in the small intestine. Therefore, it was
suggested that enteric coating could improve the GI side-effect profile of
mycophenolates by delaying the release of MPA until the small intestine is
reached. This lead to the development of the enteric-coated formulation of
mycophenolate sodium (EC-MPS, myfortic ® ), containing MPA as the active
moiety. This drug was developed to reduce MPA-related upper GI AEs by delaying
the release of MPA while providing effective MPA immuno-protection. EC-MPS may
therefore help avoid MPA-related upper GI intolerability, potentially limiting
the number of dose reductions and rate of patient withdrawal from therapy.
Unlike MMF, EC-MPS does not contain the added molecular weight of a mofetil
ester and therefore a 720 mg dose of myfortic ® contains the same MPA content
as 1000 mg MMF (Budde, et al 2002).
A limited number of clinical studies have been performed to study the efficacy
of MMF in the treatment of SLE. Most of these studies involved the treatment of
nephritis. Chan, et al (2000) showed that the combination of MMF and
prednisolone is as effective as a regimen of cyclophosphamide and prednisolone
followed by azathioprine and prednisolone. Azathioprine and MMF as maintenance
therapy were compared to cyclophosphamide therapy (Contreras, et al 2004) and
appeared to be more efficacious and safer than long-term therapy with i.v.
cyclophosphamide. In this study, it was also noted that patients treated with
MMF had received lower doses of corticosteroids during maintenance therapy as
compared to patients treated with azathioprine.
Recent reports suggest that MMF may also be effective in systemic lupus without
severe renal involvement.(Pisoni, et al 2005) Yet, the superiority over
azathioprine in this patient group has not been established. The aim of this
study will be to show a decreased lupus activity in patients treated with
myfortic ® compared to therapy with azathioprine. Data so gathered may be
useful in planning future developments in this indication

To assess, in patients with systemic lupus erythematosus, the effect on disease
activity of a regimen with myfortic® versus continuation of azathioprine.

This is a 12 months, multi-center, 2-treatment arm, parallel-group, randomized,
open label study in patients with lupus erythematosus. The patients will be
randomized to one of the following two treatment groups:
·Maintenance of previous therapy (including azathioprine)
·Switch to a myfortic ® based regimen: myfortic ® (starting dose of 1440mg/day
instead of azathioprine)

24 patients will be switched from azathioprine to Myfortic during this study.

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