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N Engl J Med. September 17, 2020 DOI: 10.1056/NEJMoa2001180
Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
Richard Furie, M.D., Brad H. Rovin, M.D., Frédéric Houssiau, M.D., Ph.D., Ana Malvar, M.D., Y.K. Onno Teng, M.D., Ph.D., Gabriel Contreras, M.D., M.P.H., Zahir Amoura, M.D., Xueqing Yu, M.D., Chi-Chiu Mok, M.D., Mittermayer B. Santiago, M.D., Amit Saxena, M.D., Yulia Green, M.D., et al.
PMID: 32937045
Introduction
Lupus nephritis (LN) is one of the most substantial causes of morbidity and mortality in systemic lupus erythematosus (SLE). It is clinically evident in 43% of Hispanics, 50.5% of African-Americans, and 14% of Caucasians (Almani et al, cJASN 2017; Bastian et al, Lupus 2002) and usually occurs within 6 months of the diagnosis of SLE. Clinically, LN is diagnosed from the presence of proteinuria, active urinary sediments, or decreased GFR. However a histological diagnosis from a kidney biopsy remains the gold standard of diagnosis and provides useful prognostic and therapeutic information.
Approximately 10–30% of patients with LN ultimately progress to end-stage kidney disease (ESKD) (Anders et al, Nat Dis Primers, 2020). Moreover, up to 60% of patients with lupus nephritis never attain complete remission, and these patients experience poor long-term outcomes. Additionally, a large fraction of (Sprangers et al, Nat Rev Nephrol 2012) of patients who achieve remission develop subsequent flares. Hence, there is a continuous search for novel safe, and efficacious therapies to achieve remission, prevent flares, and slow the progression of CKD. In addition to standard CKD treatments, LN is specifically managed with corticosteroids, cyclophosphamide (CYC), azathioprine (AZA), or mycophenolate mofetil (MMF).
B-cell activating factor (BAFF, also called B-lymphocyte stimulator, BLyS) is involved in the pathogenesis of SLE and LN. The binding of BAFF to B cells increases their survival and promotes maturation and differentiation toward autoantibody production (Baker et al, Arthr Rheum 2003). BAFF signaling also leads to an increase in anti-apoptotic proteins. Belimumab (trade name Benlysta) is a recombinant human IgG1-λ monoclonal antibody that inhibits the soluble form of BAFF, preventing activation of BAFF receptors, thus inhibiting B-cell survival and maturation.
Belimumab development has been slow, but steady. In the BLISS-52 trial, belimumab emerged as a promising agent to be used in the management of SLE (Wallace Arthritis Rheum 2009). This was a randomized controlled trial of 865 patients with moderate to severe SLE. Patients who received belimumab displayed modest but consistent improvements in various clinical outcomes through week 52. Importantly, not only was there improvement in disease activity, but it also reduced corticosteroid use. BLISS-76, was another RCT of belimumab in SLE (Furie et al, Arthritis Rheum 2016). Here it significantly improved response rate, reduced SLE disease activity as well as flares. In 2011, belimumab became the first biological medication approved by the US Food and Drug Administration (FDA) for use in SLE. (Rituximab, strangely enough, is used in SLE, but is off-label. Perhaps because no one pursued the indication?)
Unfortunately, patients with severe and active LN were excluded from these trials. A posthoc analysis by Dooley et al (Lupus, 2012) showed that patients given belimumab had reduced rates of renal flares opening the door to the notion that belimumab may offer benefits to patients with LN.
This brings us to a “Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis (BLISS-LN trial) to assess the safety and efficacy of belimumab in addition to standard therapy in patients with active lupus nephritis.
The Study
Methods
This is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, trial conducted at 107 sites in 21 countries. (NCT01639339)
Study Population
Inclusion criteria
Age of more than 18 years
Autoantibody-positive (antinuclear antibody titers ≥1:80, anti-double-stranded DNA antibodies, or both)
Clinical diagnosis of SLE by American College of Rheumatology (ACR) criteria.
Urinary protein to creatinine ratio of ≥1 (corresponding to ~ 1g/day proteinuria)
Biopsy-proven lupus nephritis. ISN-RPS class III (focal), IV (diffuse), or V (membranous) within 6 months of screening
Exclusion criteria
On dialysis within the past 1 year.
eGFR <30 ml /min/ 1.73 m2 BSA.
Treatment with belimumab within the past year.
Receipt of any B cell-targeted therapy (for example, rituximab), an investigational biological agent within the past year.
Previous failures of both cyclophosphamide (CYC) and mycophenolate mofetil (MMF) induction
Receipt of cyclophosphamide induction therapy within 3 months before the trial.
Pregnancy or breastfeeding
Intervention
Participants were randomly assigned in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg/kg) or matching placebo, on a background of standard therapy (see below). Randomization was stratified according to the induction regimen (cyclophosphamide or mycophenolate mofetil) and race group (Black or non-Black). In addition to standard therapy, patients received intravenous belimumab or placebo on days 1 (baseline), 15, and 29 and every 28 days thereafter to week 100, with final assessments at week 104.
Standard treatment
Induction therapy was chosen by the investigators and initiated within 60 days before receiving study drug. It consisted of either intravenous CYC or MMF. Patients receiving CYC (given as 500 mg every 2 weeks for 6 infusions) were then given oral azathioprine (AZA) until the trial ended. Patients started on MMF continued it until the end of the trial. Treatment regimens were based on those in ELNT (EuroLupus, Houssiau et al, Arthr Rheum 2002) and ALMS (Appel et al, JASN 2009) trial protocols.
Based on the investigator’s discretion, high-dose glucocorticoids (1 to 3 daily doses of 500-1,000 mg of IV methylprednisolone) were administered during induction, followed by oral prednisone.
ACE inhibitors or ARBs as well as hydroxychloroquine was encouraged for all patients.
Trial endpoints
Primary endpoint:
Note: The original primary endpoint was changed in 2017, from complete, partial, or no response (determined according to the ratio of urinary protein to creatinine, urinary sediment, and the calculated GFR) at week 104, removing the partial renal response.
Primary efficacy renal response at week 104, defined as
UPCR of 0.7 or less,
eGFR that was no worse than 20% below the pre-flare value or at least 60 ml /min/ 1.73 m2, and
No use of rescue therapy for treatment failure.
Secondary endpoints:
Complete renal response at week 104
UPCR <0.5
eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m2 and
No rescue therapy.
Primary efficacy renal response at week 52.
Time to a renal-related event or death.
An ordinal renal response without urinary sediment.
What does ‘ordinal renal response without urinary sediment’ mean?
Ordinal renal response could be either complete, partial, or no response. This may or may not include urinary sediment - and here they mean they used the version without a urinary sediment. So,
Complete Renal Response(CRR): as defined above
Partial Renal Response(PRR):
Estimated GFR no more than 10% below the baseline value or within normal range AND
≥ 50% decrease in the urine protein:creatinine ratio with one of the following:
a urine protein:creatinine ratio of < 1.0, if the baseline ratio was ≤3.0 OR
a urine protein:creatinine ratio of < 3.0, if the baseline ratio was >3.0
AND
No receipt of prohibited (rescue) therapy resulting in treatment failure
No Renal Response(NRR): Not meeting criteria for either CRR or PRR
Definitions of Treatment Failure
Patients had treatment failure if they violated the glucocorticoid rules ( i.e to taper glucocorticoids to 10 mg or less per day by week 24 and to not exceed this dose through week 104), or received additional immunosuppressive agents (except topical agents) beyond the induction and maintenance regimens; initiated the use of ACE inhibitors, ARBs, or antimalarial drugs after week 24; or if the standard therapy (CYC–AZA or MMF) exceeded permitted doses.
Statistics simplified
A sample of 448 patients was calculated to provide the trial with 80% power to detect a 13.6-percentage-point between-group difference and a minimum detectable difference of 9.7 percentage points in the primary endpoint. It was assumed that 40% of the patients in the placebo group would have a response.
Efficacy endpoints were analyzed in the modified intention-to-treat population, which included all the patients who underwent randomization and received at least one dose of belimumab or placebo.
Funding
The trial was sponsored by GlaxoSmithKline, which contributed to the design of the trial, the collection, analysis, and interpretation of the data and the decision to submit the manuscript for publication. Furthermore, sponsors also supported the authors in the development of the manuscript and the medical writing support. Six of the authors are employees of the sponsor.
Results
448 patients underwent randomization (224 in the belimumab group and 224 in the placebo group). About two-thirds received MMF and a third received CYC.
Figure S1 from Furie et al NEJM 2020
The mean age was 33.4±10.6 years, and the median duration of lupus nephritis was 0.2 years. Only 14% patients were Black, and almost 90% were females. 58% of the cohort had kidney-biopsy specimens suggestive of class III or IV lupus nephritis, 26% had class III or IV with class V, and 16% had isolated class V. The GFR was well preserved (100±40), and the mean proteinuria was 3.4 g/g Cr. About two-thirds were on ACEi/ARBs, hydroxychloroquine usage was not reported however.
Table 1 from Furie et al, NEJM 2020
Primary and Major Secondary Efficacy Endpoints
At week 104, primary efficacy renal response was significantly higher in patients in the belimumab group than in the placebo (43% vs. 72 of 32%; OR, 1.6; 95% [CI], 1.0 to 2.3; P=0.03). More patients in the belimumab group had a primary efficacy renal response at an earlier time point (week 52) (OR 1.6; 95% CI, 1.1 to 2.4; P=0.02) then in the placebo group and the primary efficacy renal response was sustained through week 104.
Table 2 from Furie et al, NEJM 2020
Significantly more patients had a complete renal response including a decrease in the ratio of urinary protein to creatinine to less than 0.5 and no treatment failure at week 104 in the belimumab group than placebo group (odds ratio, 1.7; 95% CI, 1.1 to 2.7; P=0.02).
Figure 1 from Furie et al, NEJM 2020. PERR: Primary efficacy renal response. CRR: Complete renal response.
Patients who received belimumab had a significantly lower risk of a renal related event or death than placebo (HR, 0.51; 95% CI, 0.34 to 0.77; P=0.001). These results were primarily because of increased proteinuria, impaired kidney function, or both or kidney-related treatment failure.
Figure 2 from Furie et al, NEJM 2020
Subgroup Analyses
In both the MMF and CYC– AZA subgroups, more patients who received belimumab had a primary efficacy renal response than patients in the placebo group (OR in MMF subgroup, 1.6; 95% CI, 1.0 to 2.5; OR in CYC– AZA subgroup, 1.5; 95% CI, 0.7 to 3.5), with the overall response driven by the results in the larger MMF subgroup.
In the CYC–AZA subgroup, there was no benefit in CRR with belimumab (OR 1.07) and the benefit was mostly seen in the MMF group, though the 95% CI do overlap.
Black patients who received belimumab appeared more likely to have a primary efficacy renal response and a complete renal response at week 104 than those who received placebo, but see the numbers below which seem to mostly overlap.
Figure S2 from Furie et al NEJM 2020
Other Efficacy Endpoints (post hoc analysis)
More patients who received belimumab had a decrease in UPCR (from ≥0.5 to <0.5) at week 104 than placebo.
The mean observed eGFR values initially increased from baseline in both trial groups; however, from week 52, eGFR values declined in the placebo group, whereas the eGFR remained stable through week 104 in the belimumab group.
Figure S4 from Furie et al NEJM 2020
Biomarker Endpoints
Patients in the belimumab group had greater reductions in ds DNA and C1q ab and greater increases in complement C3 and C4 levels and more conversions to normal levels than patients who received placebo.
Safety
Adverse events, including infections, occurred with similar frequency in the two groups.
Anti-belimumab antibodies were not detected.
Infection-associated deaths were balanced between the two groups.
No deaths were directly attributed to lupus nephritis by the investigators.
Table 3 from Furie et al, NEJM 2020
Discussion
Limitations
Interestingly, the primary endpoint of the trial was changed, 5 years after the commencement of the trial. The original endpoints categorized responses as complete, partial, or no response according to the level of proteinuria, eGFR from 24-hr urine collections, and microscopic examination of urinary sediment, although favored belimumab, were not significantly different between the belimumab and placebo groups. Whether this change in the endpoint by the investigators was independent of any data collected before the change is questionable. See below for how this data looks:
Table S2 from Furie et al NEJM 2020
The investigators permitted only 2 induction and maintenance regimens, although additional therapies for lupus nephritis, such as calcineurin inhibitors, are currently used in practice.
The induction regimen was selected by the treating physician and was not randomly assigned, making it open for unknown biases. However, the investigators were blinded to actual treatment assignments (eg belimumab or placebo), and the actual proportion of CYC was similar in both groups.
There was a low enrollment of Black patients and it's well known that black patients with lupus nephritis are more likely to have a worse prognosis than those in other racial groups.
In addition, patient-reported outcomes were not included in the trial.
The current trial still leaves us with few uncertainties for example whether the belimumab has a role in managing patients in whom induction therapy fails or those with relapse? Would the addition of belimumab be helpful in facilitating glucocorticoid tapering? And could belimumab decrease the progression to ESKD and subsequent flares in patients with severe LN? Of interest, in a recent phase 2 trial (CALIBRATE, Atisha-Fregoso et al, Arthr Rheum 2020) the addition of belimumab to rituximab and cyclophosphamide in patients with recurrent or refractory lupus nephritis, did not improve clinical efficacy compared to placebo.
Conclusion
The trial favored belimumab in enhancing renal responses in addition to standard therapy in LN management; the risk of a renal-related event - mostly proteinuria though, with little effect on clinically relevant outcomes, was almost 50% lower in patients receiving belimumab than among those who received standard therapy alone.
LN is a challenging disease that can lead to dismal complications like ESKD without proper intervention and treatment. The clinical trial depicted some kind of borderline efficacy and an adequate safety profile and has set the stage for Belimumab and B cell therapies of selective targets.
Autoreactive B cells have a key role in the pathogenesis of LN, thus BAFF antagonists are a central matter of interest and it appears as they have now have a place in the future exploration of management of LN.
Summary prepared by
Priti Meena
NSMC intern, class of 2020
Department of Nephrology, Sir Ganga Ram Hospital
New Delhi, India