Belimumab plus standard therapy superior to standard therapy alone for lupus nephritis
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A 2-year randomized controlled trial has found that belimumab plus standard therapy is superior to standard therapy alone in patients with lupus nephritis, according to data published in the New England Journal of Medicine.
“The greatest unmet need for systemic lupus erythematosus patients is more effective therapies for lupus nephritis, the most common severe manifestation of SLE,” Richard Furie, MD, of Northwell Health and the Donald and Barbara Zucker School of Medicine at Hofstra–Northwell, told Healio Rheumatology. “While we have come a long way with the introduction years ago of cyclophosphamide and mycophenolate, only a minority of patients currently have satisfactory responses.
“Those who don’t have good responses have worse long-term prognoses,” he added. “A poor long-term response can lead to end-stage kidney disease and the need for dialysis or kidney transplant. The BLISS-LN study not only was the largest trial ever done in lupus nephritis — 448 patients — it was successful when nearly all other phase 2 or 3 lupus nephritis studies have failed going back to the 1990s.”
To examine the efficacy and safety of intravenous belimumab (Benlysta, GlaxoSmithKline) plus standard therapy, compared with a placebo, among patients with active lupus nephritis, Furie and colleagues from the Feinstein Institutes for Medical Research conducted the phase 3 BLISS-LN study, a randomized, double-blind, 104-week trial. Investigators randomly assigned 448 adults with SLE and biopsy-confirmed lupus nephritis — recruited from 107 sites in 21 countries — to receive either 10 mg/kg of belimumab or placebo alongside standard therapy. The efficacy analysis included 223 participants in each group, while the safety analysis featured 224 in each group.
The primary endpoint was Primary Efficacy Renal Response (PERR) — defined as a urine protein creatinine ratio of 0.7 or less, an estimated glomerular filtration rate within 20% of the pre-flare value, or 60 mL/min/1.73m2 or greater, and no rescue therapy at week 104. The major secondary endpoint was complete renal response at week 104 — defined as a urinary-protein-to-creatinine ratio of less and 0.5, an eGFR that was no worse than 10% below the pre-flare value or at least 90 mL per minute per 1.73 m2, and no use of rescue therapy.
Originally, the primary endpoint was determined by the ratio of urinary protein to creatinine, urinary sediment and the calculated glomerular filtration rate. However, in order to reconcile with growing evidence on predictors of long-term kidney outcomes, the primary endpoint was changed to the PERR at week 104, which “does not include the partial renal response, an outcome of uncertain long-term clinical value,” the researchers noted.
“The primary reason for switching was because the evidence — supported by the FDA — was that partial response was of uncertain clinical significance,” Furie told Healio Rheumatology. “There was also evidence that urinary sediment added little and potentially could confound results. The endpoint changed from one that included partial response and urinary sediment to one that was driven by reduction in proteinuria with preservation of eGFR.”
Other endpoints included time to PERR or complete renal response sustained through week 104, a SLEDAI-S2K score less than 4 at week 104 and safety.
According to the researchers, 43% of patients who received belimumab alongside standard therapy achieved PERR at week 104, compared with 32% of those in the placebo group (OR = 1.6; 95% CI, 1-2.3). In addition, 30% of those in the belimumab group experienced a complete renal response, compared with 20% of those in the placebo group (OR = 1.7; 95% CI, 1.1-2.7).
Regarding safety, 95.5% of patients in the belimumab, and 94.2% of those in the placebo group, demonstrated one or more adverse event, with 25.9% and 29.9% patients, respectively, developing one or more serious adverse event. The discontinuation rate due to adverse events was 12.9% in both groups, with fatal adverse-event rates of 1.8% in the belimumab group and 1.3% in the placebo group. The risk of renal-related event or death was lower among participants who received belimumab compared with those in the placebo group (HR = 0.51; 95% CI, 0.34-0.77).
“The chance of having a good response, which was defined several different ways in the study, increased 11% on an absolute basis or 34% relative to the standard of care arm,” Furie said. “In addition, there was a unique analysis that evaluated the percentage of patients who experienced adverse renal-related events over the course of the 2-year study. A renal-related event was defined as worsening kidney function, increased proteinuria, or a renal-related treatment failure. Treatment with belimumab reduced this rate by 50%.”
Perspective
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Lupus nephritis is the most severe common complication of SLE and, if left untreated or undertreated, can lead to serious illness or death. Lupus nephritis occurs in approximately 25- 60% of patients. Despite years of recommendations of standard treatment for lupus nephritis, the renal response is still very low and 10-30% of those patients will progress to end stage kidney disease or suffer with intermittent flares after going into remission.
This study revealed how important proper and aggressive treatment is to treat lupus nephritis. It is imperative to discover safer therapies to reduce kidney inflammation, prevent flares and preserve kidney function. Black patients with lupus nephritis are more likely to have a worse prognosis than those of other racial groups. As a black health care professional, it is essential to advocate for the black community in researching compelling therapeutic pharmacological interventions for lupus nephritis.
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Furie R, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2001180.
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