Elsevier

The Lancet

Volume 397, Issue 10289, 29 May–4 June 2021, Pages 2070-2080
The Lancet

Articles
Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(21)00578-XGet rights and content

Summary

Background

Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis.

Methods

This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1·73 m2 or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499.

Findings

Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2·65; 95% CI 1·64–4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments.

Interpretation

Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis.

Funding

Aurinia Pharmaceuticals.

Introduction

Lupus nephritis is a severe manifestation of systemic lupus erythematosus that presents with proteinuria, haematuria, and impaired kidney function. Lupus nephritis can lead to end-stage kidney disease within 10 years of diagnosis in nearly 20% of patients.1 The ultimate goals of lupus nephritis treatment are preserving kidney function and reducing mortality, while minimising treatment-related adverse events and improving quality of life.2, 3

A substantial and increasing body of evidence shows that an early reduction in proteinuria, particularly within 6–12 months from the start of treatment, is the single best predictor of improved long-term outcomes, including reduced risk of disease flares, end-stage kidney disease, and death.4, 5, 6, 7, 8 Due to the positive predictive value of proteinuria reduction in lupus nephritis, rather than other clinical or serological markers, it has become an established, objective, and reproducible endpoint for evaluating therapeutic interventions.2, 3 Consequently, lupus nephritis treatment guidelines recommend evidence of at least 25% proteinuria reduction within 3 months and at least 50% reduction by 6 months after initiating treatment, with a target proteinuria ratio of <0·5–0·7 mg/mg within the first year of treatment.3 However, up to 60% of patients are unable to achieve these treatment targets with current therapeutic options, most of which are used off label.5, 9 There is a clear need for more effective treatments eliciting an early treatment response and ideally allowing for a reduction in steroid use.2, 10, 11, 12

Research in context

Evidence before this study

Voclosporin is a novel calcineurin inhibitor (CNI) developed for the treatment of lupus nephritis. We searched PubMed for all types of papers up to Jan 15, 2021, with search terms of (“voclosporin OR tacrolimus” [All Fields]) AND (“lupus nephritis” [All Fields]) AND (“randomized clinical trial” [All Fields]) AND (“induction” [All Fields]), which yielded publications on seven randomised trials, five of which were done in China. Two trials compared tacrolimus directly with cyclophosphamide on a background of steroids and found no difference in 6-month response rates. One trial of tacrolimus compared with mycophenolate mofetil found similar 6-month response rates and another, more recent trial showed that tacrolimus is non-inferior to mycophenolate mofetil for induction therapy. Two trials compared tacrolimus plus mycophenolate mofetil with cyclophosphamide on a background of steroids and showed a significant increase in the response rate in patients treated with tacrolimus and mycophenolate mofetil. The final study was an international, phase 2b, randomised, blinded, placebo-controlled trial that compared two different doses of voclosporin with placebo on a background of mycophenolate mofetil and steroids. There was a significant increase in 6-month complete renal response rates for the voclosporin group dosed 23·7 mg twice daily compared with placebo. The 23·7 mg twice daily dose of voclosporin was studied in this phase 3 clinical trial.

Added value of this study

This was a phase 3, randomised, placebo-controlled study assessing the efficacy and safety of voclosporin in patients with lupus nephritis. All primary and hierarchical secondary endpoints were met with use of voclosporin in combination with mycophenolate mofetil and rapidly tapered low-dose steroids. The primary endpoint was complete renal response at 52 weeks, which was longer than previous trials of CNIs in lupus nephritis. The improved efficacy shown in the voclosporin group was achieved with a steroid regimen resulting in significantly lower cumulative steroid dose than in any previous study. Results from this phase 3 trial confirm the efficacy of voclosporin shown in the phase 2 trial with an improved safety profile.

Implications of all the available evidence

Most standard therapies of lupus nephritis show a disappointing complete renal response rate and are associated with considerable toxicity, much of which is due to the use of high-dose steroids during the initial phase of treatment. The totality of the data suggest that the addition of a CNI such as voclosporin to background immunosuppressive therapy as a first-line treatment will significantly increase the proportion of patients with lupus nephritis achieving compete renal response at 6 and 12 months compared with background therapy alone. The improved complete renal response rate in this study is realised with far less corticosteroid than traditionally used in the treatment of lupus nephritis, and a moderate dose of mycophenolate mofetil.

The addition of calcineurin inhibitors (CNIs) to an immunosuppressive regimen in studies of predominantly Asian patients with lupus nephritis has been shown to improve renal response rates with a lower dose of steroids and mycophenolate mofetil (MMF) than used conventionally.13, 14, 15 The general applicability of these data was not clear because the CNI regimen had not been tested in ethnically and racially diverse patients with lupus nephritis.

Voclosporin, a novel CNI developed for the treatment of lupus nephritis, has several advantages compared with traditional CNIs. These include a consistent pharmacokinetic profile eliminating the need for therapeutic drug monitoring required for other CNIs and a more favourable effect on lipids and glucose concentrations compared with other CNIs.16, 17 Additionally, voclosporin has no effect on concentrations of mycophenolic acid, the active moiety of MMF.18 Voclosporin doses of 23·7 mg twice daily and 39·5 mg twice daily were compared with placebo in a phase 2 randomised controlled trial of patients with lupus nephritis (NCT02141672; AURA-LV); the 23·7 mg dose in combination with MMF and rapidly tapered low-dose oral steroids resulted in significantly higher complete renal response rates at 24 and 48 weeks of treatment and was chosen for further evaluation.19 Here we present the results of the AURORA 1 phase 3 international, randomised controlled trial, which aimed to determine the efficacy and safety of voclosporin versus placebo added to MMF and low-dose oral steroids for the treatment of patients with active lupus nephritis in an ethnically and racially diverse patient population.

Section snippets

Study design and participants

This phase 3, multicentre, double-blind, randomised trial was done in 142 hospitals and clinics across 27 countries in North and Latin America, Europe, South Africa, and Asia. Treatment allocation remains masked for patients that subsequently enrolled into the ongoing phase 3 extension study (NCT03597464; AURORA 2).

Eligible patients had a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years

Results

Between April 13, 2017, and Oct 10, 2019, 357 patients were enrolled in the trial, of whom 179 patients were randomly assigned to the voclosporin group (intention-to-treat population) and 178 patients to the placebo group (intention-to-treat population). One patient in the voclosporin group did not start treatment because of an adverse event. 163 (91%) of 179 patients in the voclosporin group and 147 (83%) of 178 in the placebo group completed the study (figure 1). 15 (8%) of 178 patients in

Discussion

In this phase 3 trial, the primary endpoint was met with patients receiving voclosporin in combination with background MMF and low-dose steroids achieving a clinically meaningful and significantly higher complete renal response rate at 1 year compared with patients receiving MMF and low-dose steroids alone. All prespecified hierarchical secondary endpoints were significantly in favour of voclosporin, including partial renal response at weeks 24 and 52, time to UPCR of 0·5 mg/mg or less, and

Data sharing

The data underlying this Article, the study protocol, and statistical analysis plan will be shared with researchers on reasonable request to the corresponding author. Data will be shared through a secure online platform after signing a data access agreement. Data will be available at the time of publication and for a minimum of 5 years from the end of the trial.

Declaration of interests

BHR reports personal fees from Aurinia, Callidatis, ChemoCentryx, Retrophin, Novartis, Morphosys, EMD Serono, Bristol Myers Squibb, Janssen, Omeros, and AstraZeneca; non-financial support from Lupus Foundation of America; and grants from National Institutes of Health (NIH), outside the submitted work. YKOT reports consultancy fees from Aurinia, during the conduct of the study. EMG was a site primary investigator for clinical trials funded by Aurinia. CA reports personal fees from Aurinia,

References (32)

  • F Tamirou et al.

    Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis

    Ann Rheum Dis

    (2016)
  • M Dall'Era et al.

    Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the Euro-Lupus Nephritis cohort

    Arthritis Rheumatol

    (2015)
  • YE Chen et al.

    Value of a complete or partial remission in severe lupus nephritis

    Clin J Am Soc Nephrol

    (2008)
  • F Tamirou et al.

    A proteinuria cut-off level of 0·7 g/day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial

    Lupus Sci Med

    (2015)
  • JE Davidson et al.

    Renal remission status and longterm renal survival in patients with lupus nephritis: a retrospective cohort analysis

    J Rheumatol

    (2018)
  • R Furie et al.

    Two-year, randomized, controlled trial of belimumab in lupus nephritis

    N Engl J Med

    (2020)
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