Table of Contents
Background on Lupus Nephritis and Current Treatment Options
Lupus nephritis (LN) is a significant complication of systemic lupus erythematosus (SLE), affecting approximately 60% of patients diagnosed with this autoimmune disorder (Anders et al., 2024). It is characterized by inflammation of the kidneys, leading to symptoms such as proteinuria, hematuria, and impaired kidney function. The severity of LN can vary, ranging from mild proteinuria to severe nephrotic syndrome or end-stage renal disease. The prognosis for patients with LN has improved in recent decades, thanks to advancements in immunosuppressive therapies; however, many patients still experience inadequate responses to current treatment options (Mok & Tang, 2004).
The standard treatment for active LN typically includes corticosteroids in combination with immunosuppressive agents like cyclophosphamide (CYC) or mycophenolate mofetil (MMF). These therapies aim to reduce inflammation and prevent kidney damage. However, not all patients achieve satisfactory control of their condition, leading to a substantial unmet need for more effective therapies (Bajema et al., 2018). Recent studies have highlighted the role of interleukin-23 (IL-23) in the pathogenesis of LN, suggesting that targeting this cytokine may represent a novel therapeutic strategy (Furie et al., 2020).
Overview of Guselkumab and Its Mechanism of Action
Guselkumab is a fully human monoclonal antibody that selectively inhibits the p19 subunit of IL-23, a cytokine involved in the inflammatory processes seen in various autoimmune diseases, including psoriasis and SLE (Humbert et al., 2024). By blocking IL-23 signaling, guselkumab aims to reduce the inflammatory response associated with LN. In preclinical models, the inhibition of the IL-23 pathway has been associated with decreased levels of inflammatory markers and improved renal function, indicating its potential utility in treating active LN (Zickert et al., 2015).
The phase 2 ORCHID-LN trial was designed to evaluate the safety and efficacy of guselkumab in patients with active LN. Participants received guselkumab alongside their standard of care, with the primary endpoint being the reduction of proteinuria at 24 weeks (Anders et al., 2024).
Study Design and Methodology of the ORCHID-LN Trial
The ORCHID-LN trial was a multicenter, randomized, double-blind, placebo-controlled study conducted across 20 centers in 9 countries (Anders et al., 2024). The study aimed to enroll 60 adults (aged 18-75 years) with active proliferative LN, specifically ISN/RPS Classes III and IV. Participants were randomized 1:1 to receive either intravenous (i.v.) guselkumab (400 mg) or placebo at weeks 0, 4, and 8, followed by subcutaneous (s.c.) injections of guselkumab (200 mg) or placebo every four weeks through week 48.
Inclusion and Exclusion Criteria
Eligible participants were required to have a kidney biopsy confirming active LN and a urine protein-to-creatinine ratio (UPCR) of ≥1 mg/mg despite standard-of-care therapy for at least eight weeks. Key exclusion criteria included the presence of other significant renal or autoimmune diseases and recent use of investigational agents. The primary endpoint was the percentage of participants achieving a ≥50% reduction in proteinuria at week 24.
Key Efficacy Outcomes: Primary and Secondary Endpoint Results
Due to early termination of the study, only 33 participants were randomized, with 17 receiving guselkumab and 16 receiving placebo. At the 24-week mark, the primary endpoint of achieving a ≥50% reduction in proteinuria was met by 56.3% of participants in the placebo group, compared to 35.3% in the guselkumab group (P = 0.891).
Table 1: Efficacy Results at Week 24
| Endpoint | Placebo (n=16) | Guselkumab (n=17) | P-Value |
|---|---|---|---|
| ≥50% Reduction in Proteinuria | 56.3% (9/16) | 35.3% (6/17) | 0.891 |
| Complete Renal Response (CRR) | 18.8% (3/16) | 17.6% (3/17) | 0.7807 |
| Sustained Reduction in Glucocorticoids | 87.5% (14/16) | 94.1% (16/17) | N/A |
| UPCR <0.5 mg/mg | 25.0% (4/16) | 29.4% (5/17) | N/A |
| UPCR <0.75 mg/mg | 37.5% (6/16) | 35.3% (6/17) | N/A |
Despite the absence of significant differences in the primary and secondary endpoints, the safety profile of guselkumab was consistent with previous studies, with no new or unexpected adverse events reported (Humbert et al., 2024).
Safety Profile and Adverse Events Associated with Guselkumab
Across both treatment groups, 75% of participants reported at least one adverse event (AE), with infections being the most common. Serious adverse events (SAEs) occurred in one participant from each group. Notably, there were no serious infections, opportunistic infections, or deaths related to the study drug in either group (Anders et al., 2024).
Table 2: Adverse Events through Study Termination
| Adverse Event | Placebo (n=16) | Guselkumab (n=17) |
|---|---|---|
| Any Adverse Event | 75.0% (12) | 70.6% (12) |
| Serious Adverse Event | 6.3% (1) | 5.9% (1) |
| Infection | 31.3% (5) | 35.3% (6) |
| Herpes Zoster | 12.5% (2) | 5.9% (1) |
| COVID-19 Related | 18.8% (3) | 0 |
This data suggests that while guselkumab did not demonstrate superior efficacy compared to placebo, its safety profile aligns with established findings in other uses of the drug (Humbert et al., 2024).
Conclusion: Implications for Future Lupus Nephritis Therapies
The ORCHID-LN trial did not meet its primary endpoint, indicating that guselkumab, when added to standard of care, did not provide a significant reduction in proteinuria compared to placebo. Nonetheless, the safety profile was consistent with existing literature. These findings highlight the challenges in treating LN and underscore the need for ongoing research into novel therapies targeting the IL-23 pathway and other mechanisms involved in the pathophysiology of lupus nephritis.
Future Directions
Further studies are required to explore the role of IL-23 inhibition in LN, potentially utilizing larger sample sizes and longer follow-up durations to assess long-term efficacy and safety.
FAQ
What is lupus nephritis?
Lupus nephritis is a kidney inflammation caused by systemic lupus erythematosus (SLE), leading to symptoms such as proteinuria and impaired kidney function.
What is guselkumab?
Guselkumab is a monoclonal antibody that targets the p19 subunit of interleukin-23 (IL-23), which is involved in inflammatory processes.
What were the results of the ORCHID-LN trial?
The trial found that guselkumab did not significantly reduce proteinuria compared to placebo, but its safety profile was consistent with previous studies.
Why is there a need for new treatments for lupus nephritis?
Many patients do not respond adequately to current therapies, highlighting the need for new and effective treatment options.
What are the next steps for research in lupus nephritis?
Future studies should focus on larger cohorts and different therapeutic approaches targeting the underlying mechanisms of lupus nephritis.
References
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Anders, H. J., Saxena, R., Zhao, M. H., et al. (2024). Efficacy and safety of guselkumab in patients with active lupus nephritis: results from a phase 2, randomized, placebo-controlled study. Rheumatology (Oxford), 10.1093/rheumatology/keae647.
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Bajema, I. M., Wilhelmus, S., Alpers, C. E., et al. (2018). Revision of the international society of nephrology/renal pathology society classification for lupus nephritis: clarification of definitions, and modified national institutes of health activity and chronicity indices. Kidney International, 93(4), 789–796.
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Furie, R., Rovin, B. H., Houssiau, F., et al. (2020). Two-year, randomized, controlled trial of belimumab in lupus nephritis. New England Journal of Medicine, 383(12), 1117–1128.
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Mok, C. C., & Tang, S. S. K. (2004). Incidence and predictors of renal disease in Chinese patients with systemic lupus erythematosus. American Journal of Medicine, 117(10), 791–795.
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Zickert, A., Amoudruz, P., Sundström, Y., et al. (2015). IL-17 and IL-23 in lupus nephritis—association to histopathology and response to treatment. BMC Immunology, 16(1), 7.
