Comment on: “Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial” (Lancet. 2021; doi: 10.1016/S0140-6736(21)00578-X.)
Commented by: George Bertsias, Rheumatology Clinic, University of Crete School of Medicine, Greece
Despite advances in the management of lupus nephritis, still a sizeable number of patients will fail to respond adequately to first-line treatment, typically including low-dose cyclophosphamide or mycophenolate, in combination with glucocorticoids. Delayed or partial/no response of renal disease are associated with increased risks for renal damage and chronic renal insufficiency. To this end, ‘multi-target’ regimens (i.e., combinations of two or more classes of drugs) hold promise in the treatment of SLE. Rovin et al. performed a large, multi-centre, double-blind, randomized phase III trial in patients with lupus nephritis to evaluate the efficacy and safety of oral voclosporin, a novel, stable calcineurin inhibitor (23.7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1000 mg twice daily) and rapidly tapered low-dose oral glucocorticoids.
The trial included a racially-diverse group of 357 SLE patients, the majority (86%) with proliferative and 14% with pure membranous lupus nephritis, based on a kidney biopsy performed within two years of screening. Of note, patients with a kidney biopsy >6 months before screening (11% of the study sample) were required to have a doubling or greater increase in proteinuria in the 6 months before screening. At baseline, average proteinuria was approximately 4 mg/mg and 19% of patients had reduced renal function (eGFR <60 ml/min per 1.73m2). All patients received pulse intravenous methylprednisolone on days 1 and 2, followed by oral glucocorticoids at a starting dose of 20-25 mg/day and a with prespecified, quick tapering scheme.
The trial had a high completion rate (89%) and revealed superior rates of complete renal response (proteinuria ≤0.5 mg/mg, stable renal function, no administration of rescue medication, and no more than 10 mg prednisone equivalent per day) at 52 weeks in the voclosporin + mycophenolate group versus the mycophenolate alone group (41% versus 23%, odds ratio 2.65, p<0.001). At 24 weeks, the respective figures were 32% versus 20% (odds ratio 2.23, p=0.002). The median time to achieve a 50% reduction in proteinuria was significantly shorter for the voclosporin group than in the placebo group. Notably, the two groups did not differ in terms of the SELENA-SLEDAI index (overall SLE activity) and immunology serology parameters (anti-dsDNA, completement 3/4). Subgroup analysis did not reveal any significant ethnicity/race-related differences in the voclosporin efficacy. Finally, there were no specific safety signals regarding the two treatment arms, with a comparable rate of adverse events (most frequently infections and infestations) or deaths. Changes in eGFR were also similar in the two groups with 10% of patients in each arm showing a >30% decrease from baseline level.
Conclusively, this phase 3 study met its primary endpoint to demonstrate a superior (and quicker) reduction of proteinuria in patients with lupus nephritis who received the combination of mycophenolate and voclosporin over mycophenolate alone, together with background glucocorticoids. These findings reinforce the adjunct therapeutic value of calcineurin inhibitors in proliferative and membranous lupus kidney disease. Additional data on other outcomes such as prevention of flares, reduction of glucocorticoids, long-term clinical and histological improvement and safety will be useful to define the place of voclosporin in the therapeutic algorithm of lupus nephritis.