DENVER—In lupus nephritis, mycophenolate mofetil (MMF) is a better maintenance therapy than azathioprine, according to results from the Aspreva Lupus Management Study (ALMS), reported here at the American Society of Nephrology Renal Week 2010 (Abstract TH-FC111).
“There have been very few lupus trials that have actually shown any one drug is superior to other drugs, and this is one of the first trials that's demonstrated there is a difference in immunosuppressants,” said lead investigator David R. W. Jayne, MD, Director of the Vasculitis & Lupus Clinic at Addenbrooke's Hospital in Cambridge, England, in an interview after his presentation of the findings.
The primary efficacy endpoint was time to treatment failure, defined as a renal flare (proteinuric or nephritic), sustained doubling of serum creatinine, initiation of rescue therapy, development of end-stage renal disease (ESRD), or death.
“The failure rate was 32 percent in the azathioprine group and 16 percent in the mycophenolate group, which provided quite a clear difference in results of this trial,” Dr. Jayne said during the presentation. “Superiority of mycophenolate was consistent regardless of induction treatment, race, or region, and in the results of key secondary endpoints.”
Glen S. Markowitz, MD, who co-moderated the session during which the data were presented and was not involved in the study, sees the results as changing clinical practice, he noted in a phone interview.
“That's a big statement, and the answer may well be yes,” said Dr. Markowitz, who is Professor of Clinical Pathology and Cell Biology at Columbia University College of Physicians and Surgeons.
“I think the data are quite impressive. This study strongly suggests that MMF is superior to azathioprine as a maintenance-phase regimen for patients with lupus nephritis.”
Renal Flares, Rescue Therapy
The Aspreva Lupus Management Study—sponsored by Vifor Pharma, which was formerly known as Aspreva—is a two-phase study that involved investigators from six continents, Dr. Jayne noted.
“The ALMS study is the largest study of lupus nephritis that's been completed,” he said. “It involved 370 patients with classes III, IV, and V within six months of their diagnostic renal biopsy.”
The first part of the trial was a 24-week, open-label induction phase, during which patients were randomized to receive 3 g/day of mycophenolate mofetil or monthly intravenous cyclophosphamide. As reported previously, this phase showed no overall difference between the two agents (Appel GB: J Am Soc Nephrol 2009;20:1103-1112).
“The proportion of patients achieving a partial or complete response was 56% in the mycophenolate group and 53% in the intravenous cyclophosphamide group, both groups being well balanced for demography and baseline characteristics, and with an adverse-event profile consistent with what was known for those drugs,” Dr. Jayne said.
Those patients who had reached a partial or complete response by the end of six months were re-randomized to receive 2 g/day of mycophenolate mofetil (116 patients) or 2 mg/kg/day of azathioprine (111 patients) in the 36-month maintenance phase. Re-randomization was stratified according to race, original biopsy class, and induction treatment assignment.
The mean achieved doses during this double-blind, double-dummy phase were 1.9 g/day of mycophenolate mofetil and 120 mg/day of azathioprine. Patients in both groups were given corticosteroids to a maximum dose of 10 mg/day.
In this maintenance phase, 85% of the participants were female, and the average age was 31, Dr. Jayne noted. “You can see there was a considerable racial distribution and ethnic distribution,” he said. Of the 227 patients randomized to this phase, 127 completed the study.
The primary endpoint of time to treatment failure was largely driven by the occurrence of renal flares or the initiation of rescue therapy, with only a small proportion of patients reaching ESRD or doubling of serum creatinine.
“In terms of safety, the pattern and frequency of adverse events were consistent with what we know well for these two drugs,” Dr. Jayne said. “Serious adverse events and withdrawals due to adverse events were more common with azathioprine than with mycophenolate, and no new safety signals were observed despite longer follow-up.”
Getting to Remission
During the question-and-answer session following the presentation, audience members asked how these results fit in with findings from previous trials like the MAINTAIN Nephritis Trial and IMPROVE (International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides).
Like ALMS, MAINTAIN compared azathioprine with mycophenolate mofetil for maintenance treatment in patients with lupus nephritis. Unlike ALMS, MAINTAIN—which included 105 patients from 27 European centers—did not show a statistically significant difference between the two treatment arms (Houssiau FA et al: Ann Rheum Dis 2010;69: 2083-2089).
“I think it's perhaps not surprising in view of the different sample size, the different ethnic group, and the differences in induction therapy,” Dr. Jayne said. “I don't think it contradicts the results of the ALMS trial.”
IMPROVE, on the other hand, compared mycophenolate mofetil with azathioprine for the prevention of relapses in 156 patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, showing mycophenolate mofetil to be less effective than azathioprine for maintaining disease remission (Hiemstra TF et al: JAMA 2010;304: 2381-2388).
“Firstly, we're dealing with two different diseases—ANCA vasculitis and lupus nephritis—and I think that's the most important thing to say,” Dr. Jayne said.
“I think the second thing to say is what we're talking about here is clinical trials, not individual patients. I think if you have a patient who is not tolerant of azathioprine then it's perfectly reasonable to give him mycophenolate mofetil in the context of ANCA vasculitis. Similarly, in lupus nephritis, if you have a patient failing on mycophenolate for whatever reason, I think it's quite reasonable to give him azathioprine. The value of the clinical trial is it really decides what should be your initial treatment decision based on the evidence.”
While this trial shows that mycophenolate mofetil should be used as that initial treatment for maintenance therapy in lupus nephritis, there are some questions left to answer, Dr. Jayne noted in the interview.
“I still think we have a little bit to learn about the optimal dosing of MMF, particularly in certain patient groups such as Asians, who seem to have high levels of toxicity on MMF. There's a question as to whether MPA [mycophenolic acid]-level monitoring, perhaps monitoring the blood levels of the active drug, may help more accurate dosing.
“I think the other point is that we still have a problem trying to get patients into remission in the first place—either MMF or cyclophosphamide still has a high failure rate—so there's a lot of work to do.”