The addition of belimumab (Benlysta, GlaxoSmithKline) to standard maintenance therapy improves renal outcomes in patients with active lupus nephritis, according to the phase 3 BLISS-LN trial, the largest trial of the disease conducted to date.
Lupus nephritis "is a serious complication of systemic lupus erythematosus," said investigator Brad Rovin, MD, from Ohio State University in Columbus.
Even with aggressive treatment, renal response rates remain low, and 10% to 30% of patients progress to end-stage renal disease (ESRD), he explained during his presentation at the virtual European Renal Association–European Dialysis and Transplant Association 57th Congress.
More patients treated with belimumab — a novel monoclonal antibody that blocks B-cell activity — plus standard therapy "achieved and maintained a complete renal response and reached the primary efficacy response end point," compared with placebo plus standard therapy, he reported. "Importantly, improvement in renal outcomes was achieved on a background of sustained reduction in corticosteroid use."
For the 104-week randomized, double-blind, placebo-controlled trial, 448 patients with active lupus nephritis were randomized to intravenous belimumab 10 mg/kg a month or placebo, "but rather uniquely, investigators were allowed to choose the standard regimen," Rovin noted.
Standard therapy consisted of either high-dose corticosteroids plus cyclophosphamide induction followed by azathioprine maintenance plus low-dose corticosteroids, or high-dose corticosteroids plus mycophenolate mofetil (MMF) induction followed by MMF maintenance plus low-dose corticosteroids.
At week 24, a corticosteroid dose of 10 mg a day or less was considered a milestone.
The primary end point was primary efficacy renal response — a urine protein to creatinine ratio of 0.7 or less and an estimated glomerular filtration rate (eGFR) greater than 60 mL/min per 1.73 m² or no worse than 20% below the preflare value — at week 104.
Key secondary end points were complete renal response — a urine protein to creatinine ratio of less than 0.5 and an eGFR of at least 90 mL/min per 1.73 m² or no more than 10% below the preflare value — and time to a renal-related event or death.
Events considered renal-related were ESRD; a doubling of serum creatinine; and renal worsening, reflected by increasing levels of proteinuria, impaired renal function, or both, or renal-disease-related treatment failure.
Baseline characteristics were well matched in the two treatment groups, and most patients had preserved renal function. Median proteinuria was about 2.5 g in both groups, and about 40% of patients in each group had proteinuria in excess of 3 g per day.
Almost 80% of patients completed the study treatment, and the majority received MMF maintenance.
At week 104, patients in the belimumab group were 55% more likely than those in the placebo group to achieve primary efficacy renal response (odds ratio, 1.55) and 74% more likely to achieve complete renal response.
Time to first renal-related event or death during the 104-week study period was about half as long in the belimumab group as in the placebo group (hazard ratio, 0.51).
However, patients who were treated with cyclophosphamide induction therapy derived less benefit from belimumab than those treated with MMF induction therapy.
|Primary and Secondary End Points in the Two Treatment Groups|
|End Point at Week 104||Belimumab, % (n = 223)||Placebo, % (n = 223)||P Value|
|Primary efficacy renal response||43.0||32.3||.0311|
|Complete renal response||30.0||19.7||.0167|
|Time to first renal-related event or death||15.7||28.3||.0014|
"Very few patients had a doubling of serum creatinine or progressed to ESRD or died," Rovin said.
In fact, the majority of the renal-related events involved a worsening of renal parameters, such as serum creatinine and proteinuria, both of which were significantly more likely to occur in the placebo group than in the belimumab group.
Interestingly, both treatments groups saw an improvement in eGFR during the first 6 months.
"This was more or less sustained in the belimumab group but, over time, there was a trend toward a decline in eGFR in the placebo group," he added.
About 11% of patients in both groups experienced a serious adverse event, and about 15% of both groups developed infections of special interest, such as opportunistic infections, herpes zoster, and tuberculosis.
Rovin said he struggles with whether the 10% difference for primary efficacy and complete renal responses in the two treatment groups is clinically meaningful.
There are a lot of issues with any new drug — one of which is usually cost, another safety — and these kinds of issues need to be taken into careful consideration before making a decision to replace any regimen with a new one, he told Medscape Medical News.
"I'm a little biased, in that I thought that belimumab was going to be better for long-term outcomes. And, indeed, what we saw was that far fewer patients treated with belimumab needed rescue medications or had increases in serum creatinine or proteinuria or renal events," he noted.
"Once you get the disease under control, you have to keep it under control. When I look at the totality of the data, I think what we found is a clinically significant finding," he said.
But he acknowledged that the study was not powered to look at a difference between the two standard immunosuppressive regimens, or to assess whether outcomes were better when belimumab was used after MMF induction than after cyclophosphamide induction.
"Low-dose cyclophosphamide is a good regimen and a lot of people are using it, including myself, so my hope is that we will see further data to define the question better. But if you had to use just these data, the suggestion would be to lean toward using MMF," he said.
This study was designed to address an unmet need, which is to reduce lupus renal insults and lupus flare relapses in patients already receiving standard immunosuppressive treatment, said session cochair Denis Fouque, MD, PhD, professor of nephrology at University Claude Bernard in Lyon, France.
"Renal lupus is the most severe form of this disease and can lead to rapid loss of renal function and the need to start dialysis," he told Medscape Medical News.
"Results show that complete renal response and proteinuria control were better in the belimumab group after 2 years of follow-up, a duration that is quite acceptable, and show that there is still a chance for patients to better control their disease," Fouque added.
The study was funded by GlaxoSmithKline. Rovin reports serving as a consultant for GlaxoSmithKline. Fouque reports being a speaker for and receiving travel grants from Fresenius Kabi.
European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) 57th Congress: Abstract LB001. Presented June 7, 2020.
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Cite this: Novel Antibody Improves Renal Outcomes in Lupus Nephritis - Medscape - Jun 12, 2020.