Article

FC 035VOCLOSPORIN INCREASES RENAL RESPONSE AT COMMONLY USED UPCR THRESHOLDS IN PATIENTS WITH LUPUS NEPHRITIS

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Abstract

Background and Aims Voclosporin is a novel calcineurin inhibitor with a favorable metabolic profile and a consistent dose-concentration relationship, potentially eliminating the need for therapeutic drug monitoring. We have previously reported the primary endpoint of the Phase 3 AURORA trial showing the addition of voclosporin to mycophenolate mofetil (MMF) and a low-dose glucocorticoid regimen results in significantly higher renal response (RR) rates at one year of treatment compared to MMF and low-dose glucocorticoids alone in patients with lupus nephritis (LN). For the primary endpoint, RR was defined as ≤0.5 mg/mg UPCR with stable renal function in the presence of low-dose glucocorticoids and no use of rescue medication. Several studies have demonstrated that proteinuria represents the best single predictor for long-term renal outcomes.1,2 Given the efficacy of voclosporin in terms of proteinuria reduction, we conducted a sensitivity analysis evaluating RR with additional UPCR targets. Method A total of 179 participants in the voclosporin (23.7 mg BID) arm and 178 participants in the control arm from the AURORA trial were included in this analysis. All participants received MMF (target 1 g BID) and low-dose oral glucocorticoids (initiated at 20-25 mg/day and tapered to 2.5 mg/day at 16 weeks). For this post hoc analysis, the UPCR component of RR was revised to include UPCR targets at 0.2 mg/mg intervals above and below the original ≤0.5 target used for the primary endpoint in AURORA (i.e., ≤0.7 mg/mg or ≤0.3 mg/mg, respectively). Odds ratios for RR at six months and one year of treatment were analyzed using a logistic regression model with terms for treatment, baseline UPCR, biopsy class, and MMF use at baseline and region. Results RR with UPCR ≤0.7 mg/mg was achieved by 46.9% of participants in the voclosporin arm vs 32.0% of participants in the control arm at one year of treatment (OR 2.07, p<0.0014) and 39.1% of participants in the voclosporin arm vs 24.7% of participants in the control arm at six months of treatment (OR 2.10, p=0.0020). RR with UPCR ≤0.3 mg/mg was achieved by 28.5% of participants in the voclosporin arm vs 15.7% of participants in the control arm at one year (OR 2.27, p=0.0023 and 22.9% of participants in the voclosporin arm vs 14.0% of participants in the control arm at six months of treatment (OR 1.90, p=0.0238; Table 1). Conclusion Participants treated with voclosporin in addition to MMF and low-dose glucocorticoids achieved statistically significantly increased renal response rates regardless of the level of UPCR used, including at an even more stringent ≤0.3 mg/mg target. This analysis further supports the efficacy observed with voclosporin in the Phase 3 AURORA and the prior Phase 2 AURA-LV global trials.

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Article
Voclosporin (Lupkynis™), a novel calcineurin inhibitor, is approved in the USA as an add-on to background immunosuppressive therapy in adults with active lupus nephritis. Voclosporin, in combination with mycophenolate mofetil and low-dose corticosteroids, achieved higher complete renal response rates in adults with active lupus nephritis than mycophenolate mofetil and low-dose corticosteroids alone. Voclosporin treatment led to early and sustained reductions in proteinuria. Voclosporin was generally well tolerated, with no unexpected adverse events.
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Objective To update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN). Methods Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. Results The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5–0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2–3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3–0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. Conclusions We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.
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Background: Although an early decrease in proteinuria has been correlated with good long-term renal outcome in lupus nephritis (LN), studies aimed at defining a cut-off proteinuria value are missing, except a recent analysis performed on patients randomised in the Euro-Lupus Nephritis Trial, demonstrating that a target value of 0.8 g/day at month 12 optimised sensitivity and specificity for the prediction of good renal outcome. The objective of the current work is to validate this target in another LN study, namely the MAINTAIN Nephritis Trial (MNT). Methods: Long-term (at least 7 years) renal function data were available for 90 patients randomised in the MNT. Receiver operating characteristic curves were built to test the performance of proteinuria measured within the 1st year as short-term predictor of long-term renal outcome. We calculated the positive and negative predictive values (PPV, NPV). Results: After 12 months of treatment, achievement of a proteinuria <0.7 g/day best predicted good renal outcome, with a sensitivity and a specificity of 71% and 75%, respectively. The PPV was high (94%) but the NPV low (29%). Addition of the requirement of urine red blood cells ≤5/hpf as response criteria at month 12 reduced sensitivity from 71% to 41%. Conclusions: In this cohort of mainly Caucasian patients suffering from a first episode of LN in most cases, achievement of a proteinuria <0.7 g/day at month 12 best predicts good outcome at 7 years and inclusion of haematuria in the set of criteria at month 12 undermines the sensitivity of early proteinuria decrease for the prediction of good outcome. The robustness of these conclusions stems from the very similar results obtained in two distinct LN cohorts. Trial registration number: NCT00204022.
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