Safety and efficacy of voclosporin-based triple immunosuppressive therapy in lupus nephritis

Voclosporin, a second-generation calcineurin inhibitor, is approved for the treatment of adults with active lupus nephritis, alongside a standard immunosuppressive regimen.¹ The phase II AURA-LV and phase III AURORA 1 trials used a combination of voclosporin with mycophenolate mofetil (MMF) and oral glucocorticoids (GCs).¹ An integrated analysis of AURA-LV/AURORA 1 demonstrated that voclosporin-based triple immunosuppressive therapy led to significantly greater and earlier reductions in proteinuria, with an acceptable safety profile compared with placebo.¹  

At the 14th European Lupus Meeting, Dall’Era et al. presented a post hoc analysis comparing safety and efficacy of voclosporin-based triple immunosuppressive therapy from the AURA-LV and AURORA 1 trials to intravenous cyclophosphamide (IVC) and MMF based double immunosuppressive therapy (IVC/MMF + high-dose GCs) from phase III ALMS trial.¹ We summarize the key findings below. 

• Mean cumulative oral GC exposure was two-fold lower in the voclosporin vs IVC and MMF groups over both 3 and 6 months (Figure 1). 

• At 6 months, 79.9%, 8.8%, and 5.7% of patients in voclosporin, IVC, and MMF groups, respectively achieved a GC dose of ≤7.5 mg/day. 

Figure 1. Cumulative glucocorticoid exposure with immunosuppressive therapies* 

GC, glucocorticoid; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil.  
*Data from Dall’Era, et al.¹ 

• Overall incidence of adverse events was lower in voclosporin compared with IVC-and MMF groups (Figure 2). 

• However, at 6 months a higher proportion of patients in the voclosporin group compared with IVC and MMF groups reported decreased glomerular filtration rate (24.6% vs 0% and 0%, respectively) and hypertension (17.3% vs 12.1% and 14.8%, respectively). 

Figure 1. Adverse events at 3 and 6 months* 

AE, adverse event; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil. 
*Data from Dall’Era, et al.¹ 

• At 3 months, a higher proportion of patients in the voclosporin group achieved a 25% reduction in urine protein creatinine ratio (91.6%) than IVC (61.5%; p < 0.0005) and MMF (77.3%; p < 0.005) groups.
• Likewise, a 50% reduction in urine protein creatinine ratio at 6 months was significantly higher in with voclosporin group (70.9%) than IVC (57.1%; p < 0.05) and MMF (56.8%; p < 0.05) groups.

Key learnings

At 6 months, voclosporin-based triple immunosuppressive therapy showed improved safety, efficacy, and reduced GC exposure compared with IVC and MMF double therapy, with noticeable effects as early as 3 months. These findings align with recent updates to treatment guidelines advocating for minimizing GC exposure and initiating combination therapy as initial therapy in patients with active lupus nephritis. However, the findings are limited by inherent bias associated with propensity matching, differences in the treatment landscape, and short follow-up period.