BLISS-LN: Belimumab in Lupus Nephritis
Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
Furie R, Rovin BH, Houssiau F, et al.
N Engl J Med. 2020 Sep 17;383(12):1117-1128.
Summary by Amna Rana
Systemic lupus erythematosus (SLE) is a chronic autoimmune condition characterized by constitutional symptoms and variable single or multi-organ manifestations, including skin, joints, kidneys, lungs, and heart. Lupus nephritis – renal involvement in lupus – is statistically reported amongst 25-60% of SLE patients with progression of lupus nephritis to ESRD in 10-30% of patients.
Traditionally, initial treatment of lupus nephritis has consisted of high-dose steroids with initiation of mycophenolate (MMF) or cyclophosphamide for eventual tapering of steroids. Other agents, such as azathioprine, are considered after cyclophosphamide. Rituximab also has an off-label use for refractory or resistant cases. Despite these established therapies, up to 60% of patients do not achieve complete remission while 27-66% of patients in remission experience flares.
Belimumab (Benlysta) is a recombinant human monoclonal antibody which inhibits B-cell activation (via inhibiting BAFF, the B-cell activating factor, also known as BLyS) approved for SLE after 2 phase 3 clinical trials – BLISS 52 and BLISS-76; however, patients with lupus nephritis were excluded in these trials. At the time of this study in 9/2020, belimumab was the only FDA approved biologic for lupus – highlighting the importance of this trial to further study the drug in lupus nephritis patients.
Post-hoc analyses of the BLISS-52 and BLISS-76 trials showed decreased proteinuria and lower incidence of renal flares in those who received belimumab compared to those who received placebo. Thus, the Belimumab International Study in Lupus Nephritis (BLISS-LN) was initiated to assess the efficacy and safety of the belimumab (when added to standard of care of MMF, or cyclophosphamide-azathioprine) compared to current standard of care regimen (MMF or cyclophosphamide-azathioprine alone). The FDA subsequently approved belimumab for lupus nephritis in December 2020. In the interim, other treatment options have emerged. Voclosporin – a calcineurin inhibitor -has been FDA approved for treatment of lupus nephritis.
Patient population and Design
BLISS-LN was a phase 3, multinational (21 countries), multi-center, randomized, double blind, placebo controlled trial. A total of 797 patients were assessed for eligibility, out of which 448 were initially randomized and one from each group were excluded due to compliance issues. 223 patients from each group were subjected to modified intention to treat analysis.
Patients ≥18 years of age, with antibody positive SLE (≥1:80 ANA, +anti–ds DNA, or both), a urine protein to creatinine ratio (U PCr) ≥ 1, and have biopsy-proven lupus nephritis with active or active and chronic lesions on biopsy. Major exclusion criteria included dialysis within the past year, GFR <30, previous failures of cyclophosphamide or MMF induction, receipt of cyclophosphamide induction within the 3 months, or receipt of belimumab within 1 year before randomization.
In addition to standard therapy (cyclophosphamide + azathioprine or MMF) participants received belimumab or placebo on days 1 (baseline), 15, and 29 and every 28 days to week 100, with final assessments at 104 weeks. Glucocorticoids (1-3 days IV methylprednisolone pulses followed by oral prednisone @ 0.5-1.0 mg /kg / day; total ≤60 mg) where at the investigators discretion. ACE inhibitors or ARBs as well as hydroxychloroquine was encouraged for all patients.
Outcome Measures
The primary outcome was the “primary efficacy renal response” which was defined as U PCr protein ≤ 0.7, eGFR no worse than 20% below the pre-flare value or ≥ 60, and no rescue therapy by week 104. This end point was changed from the original endpoint of complete, partial, or no response, which was considered less clinically relevant relative to long term outcomes.
The secondary outcomes included complete renal response at week 104, the primary efficacy renal response at week 52, time to a renal related event or death, and ordinal renal response without urinary sediment at week 104 of complete renal response versus partial renal response.
The complete renal response at week 104 (week 100, confirmed at week 104) is defined as a ratio of U PCr ≤ 0.5, an eGFR no worse than 10% below the pre-flare value or ≥ 90, and no rescue therapy. A partial renal response includes an eGFR not worse than 10% below baseline, ≥ 50% reduction in U PCr (with U PCr < 1 if baseline ratio ≤ 3 versus U PCr < 3 if baseline was > 3), and no rescue therapy.
Renal related events would include development of ESRD, doubling of serum creatinine, increased proteinuria, impaired kidney function, or kidney disease related treatment failure.
Results
For the primary outcome, 96 of 223 patients (43%) in the belimumab arm versus 72 of 223 patients (32%) in the control arm achieved primary efficacy renal response at 104 weeks (OR 1.6, 95% CI, 1.0 to 2.3; P=0.03). Similarly the belimumab arm had a higher primary efficacy renal response at 52 weeks (47% vs. 35%, OR 1.6; 95% CI 1.1-2.4; P =.02).
The time to a renal-related event or death favored belimumab (HR 0.51; 95% CI, 0.34 to 0.77; P=0.001). More patients who received belimumab had a complete renal response at week 104 (30% vs, 20%, OR 1.7; 95% CI, 1.1 to 2.7; P=0.02). In contrast 18% belimumab versus 17% placebo achieved ordinal renal response with partial response.
Discussion
The results suggest that belimumab must be considered for treatment of lupus nephritis as it has an additive response to standard of care. Primarily, patients treated with belimumab achieved a statistically significant response in primary efficacy renal response 104 weeks, but they also saw a benefit earlier at 52 weeks. Beyond that, the decreased risk of renal related events or death in individuals treated with belimumab was also significant (HR 0.51). And finally, the safety outcomes were similar, suggesting that patients on belimumab will likely not experience an increased number of adverse events as compared to those on standard of care therapy. That the trial lasted for two years suggests the benefits are sustained as the trial time was sufficient to assess the response to therapy and assess relapses.
The trial does have limitations. There were only 446 patients with 223 allocated to each group. Initial power calculations were set for 85% but the primary endpoint was changed and thus was represented a sample with only 80% power; however this would be more of an issue had there been a negative result. Furthermore, the study endpoint was changed, though this was done prior to collecting any data. Finally, this only establishes the efficacy of belimumab as an add-on agent, as opposed to a true replacement of the current standard of care.
Belimumab has been integrated into clinical practice for treatment of lupus nephritis post FDA approval in December 2020. The FDA subsequently has approved voclosporin and anifrolumab. But it remains unknown how belimumab compares in terms of efficacy to these agents and a practiononer has little guidance how to choose between these new agents.
| F: Follow up | 104 weeks |
| R: Randomization | Yes |
| I: Intention to treat | Yes, two patients were excluded at sites with compliance issues |
| S: Similar at baseline | Yes |
| B: Blinding | Yes |
| E: Equal treatment | Yes |
| S: Source (funding) | Glaxo-Smith-Kline and other pharmaceuticals |
