FORT LAUDERDALE, FLA. — The saga of mycophenolate mofetil for lupus exemplifies the difficulties in developing new drugs for a condition with such protean manifestations and inconsistent course, for which there has not been a new drug approved for 50 years.
“An important question is whether the newer drugs don't work, or whether we're not testing them and measuring response correctly,” said Dr. Susan Manzi, director of the Lupus Center of Excellence at the University of Pittsburgh.
Only corticosteroids, hydroxychloroquine, and aspirin have FDA approval for systemic lupus erythematosus (SLE). And although current off-label therapy often also includes NSAIDs, cyclophosphamide, azathioprine, and cyclosporine, there has been considerable enthusiasm in the lupus community for the newer immunosuppressants and biologic agents that have revolutionized treatment of other rheumatic diseases. Unfortunately, results thus far have been somewhat disappointing, according to Dr. Manzi.
Mycophenylate mofetil (MMF) is an example, having been compared with cyclophosphamide in three randomized trials. Cyclophosphamide is generally considered to be effective—if toxic—by the lupus community, although randomized data are lacking and the drug is not FDA approved for SLE.
“We all got very excited about MMF when the first study came out in 2000,” she said. That study included 42 patients with diffuse proliferative lupus nephritis who were randomized to receive either oral MMF plus prednisolone for 12 months or oral cyclophosphamide plus prednisolone for 6 months, followed by azathioprine plus prednisolone for an additional 6 months. The investigators found that MMF was as effective as cyclophosphamide but less toxic, with 17 (81%) and 16 (76%) of the MMF and cyclophosphamide patients, respectively, achieving complete remission (N. Engl. J. Med. 2000;343:1156–62).
This was followed in 2005 by an open-label noninferiority trial that compared MMF in doses up to 3,000 mg/day with monthly intravenous cyclophosphamide (0.5–1.0 g/m
In this trial, too, MMF was more effective than cyclophosphamide, with 23% of MMF patients and 6% of cyclophosphamide patients achieving complete remission. More than half of patients in the trial were black, and a subanalysis determined that the nonwhite patients were those who responded best.
The safety profile also was better in the MMF group, with no cases of amenorrhea, compared with three cases in the cyclophosphamide group (N. Engl. J. Med. 2005;353:2219–28).
“Most people said MMF might be a good drug for patients without rapidly progressive disease, particularly if you are concerned about infertility or infection,” Dr. Manzi said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.
But then came the Aspreva Lupus Management Study, the largest industry-sponsored randomized trial, presented as a late-breaking abstract at the American College of Rheumatology (ACR) meeting in 2007. This trial was required by the FDA to be a superiority study, randomizing 370 patients with class III-V lupus nephritis to 24 weeks of MMF in target doses of 3 g/day or intravenous cyclophosphamide at 0.5–1.0 g/m
With 56% of MMF patients and 53% of cyclophosphamide patients responding, the study did not meet its primary efficacy end point of showing superiority for MMF. Moreover, there was no difference between the groups in terms of adverse events, which was “a double whammy,” Dr. Manzi said.
“If they had shown a much better safety profile, the company might have had a chance to go back to the FDA and see if they could move forward, but there was no difference in safety,” she said.
“Even though MMF performed the same as cyclophosphamide in this trial, the FDA's view is that it isn't good enough. Because cyclophosphamide is not approved, it is considered the same as placebo, and you have to do better than placebo, which has been a stumbling block for our trials. So even though three randomized trials have shown that efficacy and safety are equal to or better than cyclophosphamide in lupus nephritis, MMF is not approved,” she said.
Other agents also are being tested, again with mixed results. In a phase II study, belimumab did not meet the primary outcome measure, but a post hoc analysis found that many patients in the trial were not serologically positive. “They may have been enrolling the wrong patients,” she said, noting that a phase III trial is underway.
At the 2008 ACR annual meeting, results for trials of rituximab and abatacept were presented as late-breaking abstracts. In a phase II/III study that included 257 patients with moderate to severe extrarenal lupus, there were no differences between rituximab and placebo on any clinical end points, although a subgroup analysis found significant improvements in black and Hispanic patients.