Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by loss of immune tolerance, leading to multisystem inflammation and organ injury.
Lupus Nephritis (LN) is the most prevalent severe manifestation of SLE occurring in about 40% of SLE patients, most commonly within the first 5 years following diagnosis. It is associated with significant morbidity and mortality, particularly for patients who develop the end-stage renal disease (ESRD) as a result of glomerular, tubulointerstitial and vascular lesions. A local study published in 1998 discussed the development of lupus nephritis within the course of SLE for 74% of patients, with diffuse proliferative nephritis being the most common histologic picture encountered. Continue reading to learn more about Belimumab for Lupus Nephritis.
Optimal treatment of LN varies with the classification of morphological findings present on kidney biopsy and clinical care often requires an individualized approach with a goal to control disease activity, decrease the incidence of flares, avoid drug toxicity and achieve a good quality of life.
International guidelines (EULAR/ERA, KDIGO, ACR) today differ in some aspects, but generally consider immunosuppressive therapy a cornerstone for active focal (class III) or diffuse (class IV) LN with an initial approach often involving glucocorticoids in combination with either mycophenolate mofetil (MMF) or cyclophosphamide. Reasonable alternatives include MMF in combination with either a calcineurin inhibitor or Belimumab or Cyclophosphamide in combination with Belimumab.
Belimumab – Drug profile and regulatory approval evidence dossier
Belimumab is a fully human IgG1λ recombinant monoclonal antibody directed against B lymphocyte stimulator (BLyS). It was first developed as a novel biologic treatment for SLE and achieved FDA, EMA and HSA approval over 10 years ago as ‘add-on therapy in adult patients with active, autoantibody-positive SLE with a high degree of disease activity (e.g. positive anti-dsDNA and low complement) despite standard therapy. While SLE disease pathogenesis is not clear, its progression is observed to involve B cells and BLyS, two critical components responsible for mediating normal humoral immunity and autoantibody production. BLyS levels are raised in SLE patients and correlated positively with anti-dsDNA antibody titers which suggest its involvement in initiating the loss of tolerance towards self-antigens.
An extensive body of evidence assessing the efficacy and safety of the therapeutic in SLE patients has been published in the last decade. Critically, however, the trials excluded important end-organ manifestations of SLE, most notable patients with active LN. Notwithstanding, a slew of case series and post hoc results of secondary endpoints signalled renal benefits. The overwhelming indirect evidence paved the way for a randomized controlled trial (RCT) in LN patients – Phase III Efficacy and Safety of Belimumab in Patients with Active Lupus Nephritis (BLISS-LN) study. Positive findings observed in BLISS-LN subsequently informed its global regulatory indication expansion where approval of the first drug treatment ‘in combination with background immunosuppressive therapies, for the treatment of active lupus nephritis in adult patients’ was granted by the FDA in Dec 2020, EMA in Mar 2021, and locally by the HSA in Nov 2021.
BLISS-LN, the largest and longest Phase III study conducted in active LN, demonstrated that Belimumab was more effective than placebo in achieving a primary efficacy renal response (PERR) at 2 years (43% vs. 32% OR 1.6; P=0.03) when added to background therapy of glucocorticoids plus either MMF or low-dose cyclophosphamide. The PERR is a novel endpoint for LN trials and is defined as a PCD <0.7, an eGFR that was no worse than 20% below baseline or at least 60ml/min per 1.73m2, and no treatment failure. Belimumab also performed significantly better compared to placebo for other secondary endpoints evaluated which include Complete Renal Response (CRR) and time to renal-related event or death. From a safety perspective, data in the LN population was consistent with the known safety profile of Belimumab. A summary of the trial is tabled below.
| Trial Design | 104 weeks, 107 sites, 21 countries
Adults with biopsy-proven, active LN |
| Population | N=448
Mean age: 33.4±10.6 years 90% females, 50% of Asian ethnicity – 47% recruited from Asia 58% class III or IV LN; 26% class III or IV with class V; 16% isolated class V Mean proteinuria: 3.4g/g Cr Standard therapy consisted of either cyclophosphamide + azathioprine or MMF. High-dose glucocorticoids were also administered at the investigator’s discretion. ACE inhibitors or ARBs and hydroxychloroquine were encouraged for all patients Excluded: patients on dialysis in the past 1 year, eGFR<30ml/min/1.73m2 BSA, receipt of any B cell-targeted therapy (e.g. Belimumab, rituximab) in the past year, previous failures of both cyclophosphamide and MMF induction, receipt of cyclophosphamide induction therapy within 3 months of trial, pregnant, breastfeeding |
| Intervention/ Comparator | In addition to standard therapy, patients were randomized 1:1 to
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| Outcomes – Efficacy |
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| Outcomes – Safety |
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LN is a challenging disease associated with significant mortality and morbidity in the absence of adequate intervention. While questions however remain surrounding its generalizability and effects of LN classification, gender, age or race on clinical outcomes, the landmark BLISS-LN revealed the utility of Belimumab in addition to standard therapy for enhancing renal responses, achieving better control of disease, lowering the risk of progression to ESRD and relapses.
Tangentially, a number of new therapeutic targets have also recently emerged, providing hope for patients and physicians long faced with a void of targeted therapies. Daratumumab, which targets anti-CD38, was found to improve disease activity in patients with severe lupus. Success has also been observed with Anifrolumab which targets interferon (IFN) and is presently under investigation in the context of nephritis. The plethora of inflammatory mediators and molecules heralds an exciting time for the disease landscape, providing hope of better disease control, reduced damage and improved treatment tolerability. We await further studies that will inform the use of personalized medicine in LN and the stratification of patients to the most appropriate treatment.
