Mycophenolate mofetil (MMF), an immunosuppressive agent approved for the prevention of transplant rejection, may emerge as an effective alternative to IV cyclophosphamide (IVC), the current standard of care for lupus nephritis patients, according to new research published in the November 24, 2005, issue of the New England Journal of Medicine.¹

Induction therapy with MMF was shown to be superior to IVC in inducing remission and also appeared to be better tolerated than IVC with less severe side effects, according to the new study, which randomly assigned 140 patients with glomerulonephritis to either MMF or IVC. Sixteen of the 71 patients (22.5%) receiving MMF and four of the 69 patients receiving IVC (5.8%) on an intention-to-treat basis achieved complete remission, for an absolute difference of 16.7 percentage points (P = .005).

At 12 weeks, 56 patients receiving MMF and 42 receiving IVC showed satisfactory early responses, the study found. Partial remission occurred in 21 of the 71 patients (29.6%) taking MMF and 17 of the 69 patients (24.6%) receiving IVC. Three patients assigned to IVC died (two during protocol therapy).

Fewer severe infections and hospitalizations, but more diarrhea, occurred among those receiving MMF, the study showed. Although IVC is considered to be the standard of care for lupus nephritis, serious toxic side effects—such as bone-marrow suppression, hemorrhagic cystitis, and opportunistic infections—and limited effectiveness have led to the need for alternative therapies.

"Unresolved issues include determining the flare rate after induction with MMF, as compared to that for IVC, and determining the appropriate dose and duration of MMF therapy," states the research team, led by Ellen M. Ginzler, MD, of the division of rheumatology at State University of New York Downstate Medical Center in Brooklyn, New York.

In the 24-week, randomized, open-label, noninferiority trial of 140 patients with lupus nephritis, subjects received either an initial dose of 500 mg/bid of MMF, increased to a maximum of 1000 mg/tid (unless their white-cell count fell below 3000 mm³), or monthly IVC (0.5 g/m² of body surface area, increased to 1.0 g/m²) as induction therapy. Patients were permitted to switch to the alternative regimen at 12 weeks if they did not obtain an early response.

Of the cohort, which comprised 71 patients on MMF and 69 on IVC, over 55% were African-American, a subgroup often underrepresented in clinical trials and known to have poorer outcomes. The study protocol specified adjunctive care and the use and tapering of corticosteroids. The primary endpoint was complete remission at 24 weeks (normalization of abnormal renal measurements and maintenance of baseline normal measurements); the secondary endpoint was partial remission at 24 weeks.

Experts optimistic about use of MMF in lupus

MMF (CellCept®), an inhibitor of lymphoid/myeloid cells first approved in 1995 for use in combination therapy for the prevention of acute organ rejection in kidney transplantation, has since been approved worldwide for the prevention of organ rejection in adult heart, liver, and kidney transplants.

"CellCept has shown some very promising data in this study [of lupus nephritis] and in several other recent studies in the United States, Europe, and Asia," says Joan T. Merrill, MD, head of the clinical pharmacology research program at the Oklahoma Medical Research Foundation in Oklahoma City, Oklahoma, and medical director of the Lupus Foundation of America. "We are optimistic that it may prove to be a safer alternative to cyclophosphamide, which is problematic for risk of infections and sterility," she tells CIAOMed.

A larger multicenter study is currently evaluating the use of MMF in both the induction phase (initial higher-dose treatment) and as maintenance therapy (longer-term, lower-dose therapy), according to Dr. Merrill, an author of the present trial.

Dr. Merrill points out that the percentage of patients with full remission at 6 months in the New England Journal of Medicine study leaves a lot of room for improvement, regardless of treatment group. "We are hopeful that CellCept will be able to be combined with some of the new biologics in development for SLE, [and] perhaps soon we will be able to improve outcomes in this disease with acceptable safety."

Aspreva Pharmaceuticals Corporation, of Victoria, British Columbia, Canada, recently announced the start of patient dosing for MMF in the treatment of lupus nephritis. The two-phase induction to maintenance study will randomly assign 328 patients to an open-label comparison of MMF with IVC for the first 6 months, followed by a double-blind comparison of MMF to azathioprine for up to 3 years. Clinical results from the first phase of the study are expected in late 2006, with submission of a regulatory filing expected by late 2007. 

Reference

1. Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353:2219-2228.