Patients with lupus nephritis who received belimumab (Benlysta) plus standard therapy were significantly more likely to have a renal response at 2 years than those given placebo plus standard care, a large randomized trial found.
At week 104, 43% of patients assigned to the belimumab group had a primary efficacy renal response compared with 32% of those in the placebo group, according to Richard Furie, MD, of the Feinstein Institutes for Medical Research and Northwell Health in Great Neck, New York, and colleagues.
The belimumab-treated patients, therefore, had an odds ratio for renal response of 1.6 (95% CI 1-2.3, P=0.03), the investigators reported in the study online in the New England Journal of Medicine.
“The positive outcome of this study positions the drug for a favorable review [for lupus nephritis] by the FDA. If approved, patients with lupus nephritis will have access to a drug that will improve their outcomes,” Furie told MedPage Today.
Nephritis develops in an estimated 25-60% of patients with systemic lupus erythematosus (SLE).
“The percentage of patients who have a renal response despite aggressive treatment remains unacceptably low, and in 10-30% of patients with lupus nephritis, this condition progresses to end-stage kidney disease. This risk has remained unchanged during the past three decades,” Furie and colleagues wrote.
Belimumab, which is a monoclonal antibody that inhibits B-cell activating factor, was approved for SLE in 2011 following two pivotal trials, BLISS-52 and BLISS-76. However, patients with severe lupus nephritis were excluded from those studies, so the investigators conducted an additional phase III trial to assess this, enrolling 448 patients from 2012 to 2017 at more than 100 sites in 21 countries. The study, which was the largest ever done in lupus nephritis, the researchers said, was sponsored by GlaxoSmithKline.
Participants were autoantibody positive and had active lesions on kidney biopsies.
Standard therapy consisted of mycophenolate mofetil (Cellcept), 1 to 3 mg/day, or intravenous cyclophosphamide, 500 mg every 2 weeks for six infusions, followed by azathioprine, 2 mg/kg/day. Oral prednisone also could be given in dosages of 0.5 to 1 mg/kg/day, but had to be tapered to 10 mg or less per day by week 24. Those randomized to belimumab were given the drug intravenously, 10 mg/kg every 28 days. A total of 59 patients in each group received the cyclophosphamide regimen.
The original primary endpoint was changed in 2017, from complete, partial, or no response at week 104, removing the partial renal response, which the investigators referred to as “an outcome of uncertain long-term clinical value.”
The revised primary efficacy renal response was defined as a ratio of urinary protein to creatinine of 0.7 or less, an estimated glomerular filtration rate (GFR) no worse than 20% below baseline or at least 60 mL/min/1.73 m2, and no rescue therapy.
A major secondary endpoint was complete renal response at week 104, defined as a ratio of urinary protein to creatinine below 0.5, an estimated GFR no worse than 10% below baseline or at least 90 ml/min/1.73 m2, and no rescue therapy.
Participants’ mean age was 33.4, the median time since the diagnosis of SLE was 3.3 years, and the median duration of nephritis was 0.2 years. The majority of patients had class III or IV nephritis. Most were Asian; only 14% were Black, and almost 90% were women.
By week 24, more patients in the belimumab group had a primary efficacy renal response, and by 1 year, 47% met this endpoint compared with 35% of the placebo group (OR 1.6, 95% CI 1.1-2.4, P=0.02).
Significantly more patients receiving belimumab met the more stringent criteria for complete renal response at week 104 (30% vs 20%, OR 1.7, 95% CI 1.1-2.7, P=0.02). Complete renal responses were more common in the belimumab group by week 12, and the likelihood of having a complete renal response sustained through week 104 was higher with belimumab treatment (HR 1.58, 95% CI 1.08-2.31).
Patients randomized to belimumab also had a significantly lower risk of almost 50% for having a renal-related event such as progression to end-stage kidney disease or death (HR 0.51, 95% CI 0.34-0.77, P=0.001).
Significantly greater likelihood for having the primary efficacy renal response was seen only among patients who received mycophenolate mofetil, with an odds ratio of 1.6 (95% CI 1-2.5), compared with an odds ratio of 1.5 (95% CI 0.7-3.5) for those given the cyclophosphamide-azathioprine regimen. Patients given cyclophosphamide may have had more resistant nephritis, the investigators suggested.
An accompanying editorial also commented on the difference in standard therapy, which was not randomized but was chosen by treating physicians. “If patients with more severe nephritis were preferentially treated with cyclophosphamide, a likely inclination among most physicians, the trial may be telling us that belimumab enhances responses only among less severely affected patients,” wrote Michael Ward, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, and Maria G. Tektonidou, MD, PhD, of the National and Kapodistrian University of Athens in Greece.
There were 11 deaths during the study, with six in the belimumab group. Three patients in each group were reported to have infection-related deaths, and none of the deaths were from lupus nephritis. Adverse events leading to treatment withdrawal were observed in 13% of both groups.
“This study in lupus nephritis on background mycophenolate or cyclophosphamide and steroids served as further confirmation of the drug’s good safety profile,” Furie said.
“Additional analyses are underway to evaluate downstream benefits related to steroid usage and comorbidities,” he said.
Limitations of the study, the researchers said, included the low number of Black patients enrolled and the lack of information on patient-reported outcomes.
“Belimumab may be added to an expanding array of adjunctive treatment options for lupus nephritis, including new calcineurin inhibitors and B cell-depleting antibodies,” Ward and Tektonidou concluded.
The study was sponsored by GlaxoSmithKline.
Furie reported financial relationships with GlaxoSmithKline, AbbVie, AstraZeneca (MedImmune), Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, EMD Serono, Equillium, Galapagos, Genentech, Glenmark Pharmaceuticals, Novartis, Reistone Biopharma, Sanofi, Takeda, and Union Chimique Belge, Alexion, Aurinia Pharmaceuticals, Daiichi Sankyo, Janssen, Kezar Life Sciences, and MorphoSys; co-authors also reported multiple relationships with industry, and several are employees of GlaxoSmithKline.