Objective Early reduction in proteinuria after initial treatment has been associated with improved long-term kidney outcomes in lupus nephritis (LN). The addition of voclosporin, a second generation calcineurin inhibitor, to MMF and low-dose glucocorticoids (GC)s led to greater reductions in proteinuria compared to conventional therapy in the AURA-LV and AURORA 1 studies with an acceptable safety profile. Using propensity-matched participants from the voclosporin clinical trials and ALMS, we tested the hypothesis that a voclosporin-based, triple immunosuppressive regimen results in improved safety without compromising efficacy.

Methods In AURA-LV and AURORA 1, voclosporin 23.7 mg BID was combined with MMF (2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (3 g/day) or intravenous cyclophosphamide (IVC; 0.5 to 1.0 g/m²/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS vs. AURA-LV/AURORA 1) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months.

Results A total of 179 matched pairs were identified. As expected, cumulative GC exposure was 2-fold higher in ALMS at 3 and 6 months. The incidence of adverse events (AEs) was higher in IVC- and high-dose MMF-treated participants (table 1), although more voclosporin-treated participants reported AEs of GFR decrease and hypertension; the incidence of serious AEs was similar with all treatments. At 6 months, the proportion of participants achieving >50% UPCR reduction from baseline was significantly greater in the voclosporin arm (p=0.005).

Conclusion A voclosporin-based triple immunosuppressive regimen (voclosporin, MMF, and low-dose GCs) has a better overall safety profile than double-therapy regimens, with specific AEs attributable to higher-dose GCs, higher-dose MMF and IVC in the latter. Triple therapy is also superior in achieving early proteinuria milestones. These data provide further support for use of combination therapy as initial treatment in patients with active LN and to minimizing patient exposure to GCs, as proposed by the 2023 EULAR guidelines.

Acknowledgement This study was funded by Aurinia Pharmaceuticals Inc.

In AURA-LV and AURORA 1, voclosporin 23.7 mg BID was combined with MMF (2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (3 g/day) or intravenous cyclophosphamide (IVC; 0.5 to 1.0 g/m²/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate two groups of matched patients (n=179) from the ALMS (IVC and MMF) and AURA-LV/AURORA 1 (voclosporin) studies based on the following parameters: age, duration of lupus nephritis, duration of SLE, albumin, C3, C4, creatinine, anti-dsDNA, eGFR, UPCR, biopsy class, sex, and geographical region. Adverse events (AEs) occurred on or after the first dose of study drug up to either 3 or 6 months of treatment and coded by System Organ Class and Preferred Term using MedDRA v9.1 (ALMS), v17.0 (AURA-LV) and v20.0 (AURORA 1). AEs were selected for inclusion in this table to evaluate the impact of IVC, MMF, voclosporin, and glucocorticoids on these organ systems. Assignation of AEs of ‘GFR decreased’ were based on the clinical discretion of the study investigator and were not characterized by a specified drop in eGFR from baseline. GFR, glomerular filtration rate; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil.