CHICAGO—Adding abatacept to mycophenolate mofetil (MMF) and steroids does not significantly improve the time to complete renal response in patients with lupus nephritis (LN), according to the findings of a 12-month study presented at the 2011 American College of Rheumatology annual meeting.
Among nephrotic LN patients, however, researchers observed an improvement in proteinuria with abatacept, suggesting that additional exploration may be warranted to investigate potential biologic activity in this subset of patients.
“New therapies that are safer and more effective are sorely needed for patients with lupus nephritis,” investigator Richard Furie, MD, Chief of the Division of Rheumatology and Allergy-Clinical Immunology at the North Shore-Long Island Jewish Health System, Lake Success, N.Y. “Some positive signals were seen. For example, in those patients with significant proteinuria (nephrotic syndrome), there were greater reductions in proteinuria seen in those on abatacept than in those on placebo. Further analyses will be done and hopefully drug development with abatacept will continue in the area of lupus nephritis.”
Abatacept is a selective T-cell co-stimulation modulator already approved for rheumatoid arthritis. It is being evaluated at a treatment for LN. Dr. Furie and his colleagues conducted a 12-month, Phase 2/3 double-blind study in patients with active ISN/RPS Class III or IV LN. All patients received MMF (target dose 1.5–3.0 g/day depending on race) and up to 60 mg/day prednisone or equivalent (with response-guided taper after 28 days). Patients were then randomized to receive placebo or IV abatacept (either three months of abatacept 30 mg/kg followed by nine months of 10 mg/kg [30/10], or 12 months of 10 mg/kg [10/10]).
The primary efficacy endpoint was time to complete renal response (CRR) confirmed at 30 days after the first response. Secondary endpoints included time to renal improvement (RI) and rates of CRR and RI at 12 months. Exploratory endpoints included patient response and renal response.
A total of 298 LN patients were treated and 228 (76.5%) completed 12 months of treatment. The time to CRR did not differ between groups for abatacept 10/10 and 30/10 compared with placebo nor did time to RI. However, a subset analysis of 122 nephrotic patients (baseline urinary protein to creatinine ratio [UPCR] greater than 3.0 mg/mg) found an approximately 20%-30% greater reduction in UPCR in patients randomized to abatacept compared with placebo from month 6 to month 12.
Overall, the safety profile was similar in both arms. The most common adverse effects were serious infections, pneumonia, herpes zoster, gastroenteritis, and urinary tract infection. Underlying disease was the cause of death for five patients and infection was the cause of death for seven.
“As nephrologists are generally involved in the care of patients with lupus, it is important for them to keep abreast of developments in its treatment,” Dr. Furie told Renal & Urology News. “Should abatacept eventually prove to be a worthwhile addition to our treatment of lupus nephritis, extension of development to other types of glomerulonephritis may be warranted. Rheumatologists and nephrologists have been struggling with clinical trials in lupus nephritis for quite a while. The question that arises when a study fails is whether the drug was at fault or whether the study design was at fault. In this particular case, the primary endpoint as well as secondary endpoints were not met. It doesn’t necessarily mean the drug doesn’t work in lupus nephritis. Entry criteria, definitions of response, and rules for concomitant medications all need to be revisited as any or all of these items may have been responsible for the study’s failure.”