AURORA 1

https://pubmed.ncbi.nlm.nih.gov/33971155/

Clinical Question

In patients with active lupus nephritis, does voclosporin in combination with mycophenolate mofetil (MMF) and low-dose corticosteroids improve renal response rates compared to placebo with mycophenolate mofetil and low-dose corticosteroids?

Bottom Line

Voclosporin, when added to standard therapy with mycophenolate mofetil and low-dose corticosteroids, significantly improves renal response rates in patients with active lupus nephritis.

Major Points

The AURORA 1 trial was a pivotal phase 3 study that evaluated the efficacy and safety of voclosporin, a novel calcineurin inhibitor, in combination with mycophenolate mofetil (MMF) and low-dose corticosteroids in patients with active lupus nephritis. The study demonstrated that the addition of voclosporin to standard therapy resulted in a statistically significant improvement in renal response rates compared to placebo, leading to the approval of voclosporin for the treatment of lupus nephritis.

Prior to this trial, standard treatment for lupus nephritis typically involved the use of MMF or cyclophosphamide in combination with corticosteroids with renal response rates typically <30%. Add-on therapies with calcineurin inhibitors, such as tacrolimus, have been investigated for the treatment of lupus nephritis with varying degrees of success. These agents work by inhibiting T-cell activation, reducing inflammation, and proteinuria, which is a significant predictor of long-term renal survival. Trials such as MAINTAIN and Euro-Lupus demonstrated the importance of reducing proteinuria to improve renal outcomes in lupus nephritis patients.

Guidelines

Following the AURORA 1 trial, voclosporin has been included in treatment guidelines as a recommended option for patients with active lupus nephritis, especially those who do not respond adequately to conventional regimens including cyclophosphamide, MMF, or low dose corticosteroid therapy.

Design

• Multicenter, double-blind, parallel-group, randomized, controlled trial
• N=357
  • Voclosporin group (n=179)
  • Placebo group (n=178)
• Setting: Multiple centers across North America, Europe, and Asia
• Enrollment: May 2017 to September 2019
• Follow-up: 52 weeks
• Analysis: Intention-to-treat
• Primary outcome: Renal response at 52 weeks

Population

Inclusion Criteria

• Adults aged 18-75 years
• Diagnosis of SLE according to the American College of Rheumatology criteria
• Biopsy-proven active lupus nephritis (Class III, IV, or V)

Exclusion Criteria

• Severe renal impairment (eGFR <45 mL/min/1.73 m²)
• Uncontrolled hypertension
• Recent use of cyclophosphamide or rituximab

Baseline Characteristics

• Mean age: 31.7 years
• Female: 88%
• Mean proteinuria: 3.92 g/day
• Mean eGFR: 81.6 mL/min/1.73 m²

Interventions

• All patients received standard therapy with MMF (2 g/day) and low-dose corticosteroids (tapered from a starting dose of 20-25 mg/day)
  • Then 179 patients were randomized to voclosporin (23.7 mg twice daily) group and 178 patients to the placebo group

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Renal response at 52 weeks

41% vs. 23% (OR 2.65; 95% CI 1.64-4.27; P<0.001)

Secondary Outcomes

Complete renal response at 52 weeks

30% vs. 20% (OR 1.79; 95% CI 1.06-3.03; P=0.03)

Time to achieve a renal response

Median 29 weeks vs. 63 weeks (HR 2.02; 95% CI 1.49-2.75; P<0.001)

Subgroup Analysis

Consistent benefits of voclosporin were observed across various subgroups, including different classes of lupus nephritis and baseline proteinuria levels.

Adverse Events

• Common adverse events included infection, gastrointestinal symptoms, and hypertension
• Serious adverse events were similar between the voclosporin and placebo groups

Criticisms

• Short duration of follow-up for a chronic disease like lupus nephritis
• Exclusion of patients with moderate-severe reductions in eGFR
• MMF dose and pre‐enrollment treatment duration were not collected such that conclusions regarding patients with new-onset lupus nephritis vs relapsed/resistant lupus nephritis were not able to be described

Funding

• The study was funded by Aurinia Pharmaceuticals Inc