Comparison of a voclosporin-based triple immunosuppressive therapy to high-dose glucocorticoid-based immunosuppressive therapy: a propensity analysis of the AURA-LV and AURORA 1 studies and ALMS

Abstract

Introduction: High-dose glucocorticoid (GC)-based dual immunosuppressive treatment regimens are still frequently used in active lupus nephritis (LN) despite their known association with dose-dependent toxicities and incomplete efficacy. We hypothesised that the addition of voclosporin to low-dose GCs and mycophenolate mofetil (MMF) would reduce exposure to the toxicities of high-dose GC-based dual immunosuppressive therapy regimens, resulting in an improved safety profile without compromising efficacy.

Methods: Propensity score matching generated two groups of matched participants from the voclosporin arms (in combination with MMF (2 g/day) and low-dose GCs) of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies and the MMF (3 g/day) and intravenous cyclophosphamide (IVC) arms (both in combination with high-dose GCs) of the Aspreva Lupus Management Study (ALMS) induction study. Safety and efficacy outcomes were assessed over 6 months.

Results: There were 179 matched participants identified between the AURA-LV/AURORA 1 studies and ALMS. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS; more voclosporin-treated participants reported AEs by preferred term of glomerular filtration rate decreased, hypertension and anaemia. The incidence of serious AEs was similar across treatments. There were four (2.2%) deaths in IVC- and MMF-treated participants of ALMS compared with seven (3.9%) deaths in voclosporin-treated participants. Significantly more voclosporin-treated participants achieved a ≥25% reduction in urine protein creatinine ratio (UPCR) from baseline at 3 months and ≥50% reduction in UPCR from baseline at 6 months.

Conclusions: Compared with the high-dose GC-based regimens used in ALMS, voclosporin-based triple immunosuppressive therapy resulted in fewer AEs overall and greater and earlier reductions in proteinuria over the first 6 months of treatment. These data reinforce the feasibility of using low doses of GCs and MMF to treat LN when combined with voclosporin as a third agent.

Keywords: Glucocorticoids; Lupus Erythematosus, Systemic; Lupus Nephritis.

Figure 1. Protocol-defined GC tapering schedule. In ALMS, oral GCs were initiated at a maximum dose of 60 mg/day and the dose decreased by 10 mg/day every 2 weeks until a dose of 40 mg/day was reached, then by a further 5 mg/day every 2 weeks until 10 mg/day was reached. Reductions below 10 mg/day were allowed after 4 weeks of stable response. In AURA-LV and AURORA 1, intravenous methylprednisolone was administered on days 1 and 2. Oral GCs were initiated on day 3 with 20–25 mg/day prednisone and tapered to a target dose of 2.5 mg/day at week 16. ALMS, Aspreva Lupus Management Study; GC, glucocorticoid.

Figure 2. Corrected eGFR over 6 months by treatment arm. Propensity score methodology was used to generate two groups of matched participants (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. Only participants with available data at the specified time points are included in the analysis. To account for baseline kidney hyperfiltration known to precede chronic kidney disease, analyses of corrected eGFR (utilising the Modification of Diet in Renal Disease (ALMS) and Chronic Kidney Disease Epidemiology Collaboration (AURA-LV/AURORA 1) equations) constrained all values to a maximum of 90 mL/min/1.73 m² to mitigate the risk of false negativity. Change from baseline measures were calculated using least square means and 95% CIs calculated from a general linear model including covariates for treatment group and baseline value. ALMS, Aspreva Lupus Management Study; C, complement; dsDNA, double-stranded deoxyribonucleic acid; eGFR, estimated glomerular filtration rate; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil; SLE, systemic lupus erythematosus; UPCR, urine protein creatinine ratio.

Figure 3. Efficacy outcomes at 3 and 6 months by treatment arm. Propensity score methodology was used to generate two groups of matched participants (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. The proportion of participants achieving UPCR outcomes at 3 and 6 months was calculated using a logistic regression model with terms for treatment arm, baseline UPCR, biopsy class and region. *p<0.05; **p<0.005; ***p<0.0005. ALMS, Aspreva Lupus Management Study; C, complement; dsDNA, double-stranded deoxyribonucleic acid; eGFR, estimated glomerular filtration rate; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil; SLE, systemic lupus erythematosus; UPCR, urine protein creatinine ratio.

Figure 4. (A) Kaplan-Meier curves for probability of UPCR ≤0.5 g/g by treatment arm. (B) Kaplan-Meier curves for probability of UPCR reduction ≥50% from baseline by treatment arm. Propensity score methodology was used to generate two groups of matched participants (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. Median time to event (95% CI) calculated using Kaplan-Meier methods. Participants who did not achieve the event were censored on the day of their last available UPCR assessment. HRs and 95% CIs were derived from a Cox proportional hazards model with terms for treatment group, baseline UPCR, biopsy class, mycophenolate mofetil use at screening and region. ALMS, Aspreva Lupus Management Study; C, complement; dsDNA, double-stranded deoxyribonucleic acid; eGFR, estimated glomerular filtration rate; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil; SLE, systemic lupus erythematosus; UPCR, urine protein creatinine ratio.