Background Proteinuria is the most common manifestation of lupus nephritis (LN) and is a mediator of progressive kidney damage. Early reductions in urine protein creatinine ratio (UPCR) have shown to be predictive of improved long-term outcomes in LN. However, recent studies with monoclonal antibody therapies have demonstrated a lack of efficacy in patients with high proteinuria (UPCR ≥2 to ≥3 mg/mg), potentially due to an increase in renal excretion of drug.^[1]-[4] In a pooled analysis of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies, the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids resulted in earlier and greater reductions in proteinuria across biopsy classes, races, and ethnicities.^[5]

Objectives To further characterize the efficacy and safety of voclosporin in patients with high proteinuria, we have analyzed outcomes in various subpopulations of patients with UPCR ≥2 mg/mg using the pooled dataset.

Methods Both studies enrolled patients with biopsy-proven LN (Class III, IV, or V ± III/IV) within 6 months (or up to 2 years in AURORA 1) and proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V). Patients were randomized to voclosporin (23.7 mg BID) or placebo and treated for up to one year (48 weeks [AURA-LV], 52 weeks [AURORA 1]); all patients received MMF and low-dose steroids. For this post-hoc analysis, complete renal response (CRR) rates were evaluated in patients with baseline UPCR ≥2 mg/mg. Complete renal response was defined as UPCR ≤0.5 mg/mg with stable renal function, low-dose steroids, and no rescue medication. Subgroup analyses were based on the following: sex, age, race, ethnicity, biopsy class, and estimated glomerular filtration rate [eGFR] at baseline. Adverse events (AEs) and mean eGFR levels over time were also assessed.

Results Of the 268 and 266 patients included in the voclosporin and control arms of the pooled analysis, respectively, 217 and 215 patients had a baseline UPCR ≥2 mg/mg (mean [SD], 5.2 [3.4] vs. 4.6 [2.9] mg/mg, respectively). At one year, the change from baseline in least squares (LS) mean (SE) UPCR was -3.8 (0.1) mg/mg in the voclosporin arm compared to -3.1 (0.2) mg/mg in the control arm (difference vs. control, -0.7; p=0.0003). A significantly greater percentage of voclosporin-treated patients achieved CRR at one year compared to the control arm (41.0% vs. 21.9%; odds ratio [OR] 2.48, p<0.0001). CRR rates were numerically greater in voclosporin-treated patients in both sexes and across all ages, races, ethnicities, biopsy classes, and baseline eGFR levels assessed, with OR >1 (Figure 1). Across biopsy classes, the highest rates of CRR were observed in Class III patients treated with voclosporin (50% vs 16.1% in control, p=0.0126), followed by Class IV (44% vs. 23.8%, p=0.0019), Class V with III or IV lesions (37.7% vs. 17% p=0.0306), and Class V (31.3% vs. 28.6%, p=0.81). Similar rates of AEs were reported in both arms, and mean eGFR levels were similar and stable over one year of treatment (Figure 2).

Conclusion Consistent with results from the overall pooled study population, patients with UPCR ≥2 mg/mg at baseline treated with voclosporin achieved significantly higher renal response rates than patients treated with MMF and low-dose steroids alone regardless of baseline demographics or clinical characteristics. This is clinically relevant given the lack of safe and effective therapies for patients with high proteinuria.

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References

1. Furie RA et al. Ann Rheum Dis. 2022;81:100-107.
2. Jayne D et al. Ann Rheum Dis. 2022;81(4):496-506.
3. Liu T et al. Lupus. Apr 2022;31(4):424-432.
4. Rovin BH et al. Kidney Int. Feb 2022;101(2):403-413.
5. Arriens C et al. Arthritis Care Res. Aug 30 2022.

Acknowledgements: NIL.

Disclosure of Interests Emily Littlejohn Speakers bureau: Aurinia Pharmaceuticals Inc., Consultant of: GSK, Salem Almaani Consultant of: Chemocentryx, Aurinia Pharmaceuticals Inc., Kezar, Vanessa Birardi Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Ernie Yap Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Chris Collins Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc.

Keywords: Systemic lupus erythematosus, Clinical Trials

DOI: 10.1136/annrheumdis-2023-eular.646