Voclosporin is becoming an increasingly important weapon in the rheumatologist’s and nephrologist’s arsenal for managing lupus nephritis, since initial efficacy was demonstrated in the original AURORA program. That pivotal trial showed that combining voclosporin with mycophenolate mofetil and low-dose glucocorticoids resulted in rapid and sustained reductions in proteinuria, alongside significantly higher complete renal response (CRR) rates at 52 weeks post-induction. These compelling findings led to voclosporin’s inclusion in key treatment guidelines, such as those from the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR), and the Kidney Disease: Improving Global Outcomes (KDIGO) initiative.
Despite this progress, concerns lingered about the long-term renal safety profile of voclosporin. As a calcineurin inhibitor, voclosporin shares a drug class with older agents such as tacrolimus known for their nephrotoxic potential, especially when administered at high doses or over extended periods. This has bred some caution, underscoring the need for detailed data on how voclosporin affects renal architecture beyond the initial treatment phase.
Enter AURORA 2, the follow-up study designed to shed light on voclosporin’s safety over a medium to longer term timeframe. In this analysis by Rovin et al, renal biopsies obtained at baseline were compared with repeat biopsies performed 18 months into treatment, involving 16 patients treated with voclosporin and 10 controls drawn from the original AURORA cohort. The 2 groups were largely comparable demographically, with a notable 60% of participants of Hispanic descent. Interestingly, the voclosporin group had a higher proportion of patients with class IV nephritis (81.3% versus 30%), reflecting a potentially more severe baseline disease burden.
Adverse events prompted early discontinuation in 2 control patients and 1 voclosporin treated patient. Histological endpoints in median activity and chronicity indices, according to the revised National Institutes of Health criteria, showed no significant differences between groups either at baseline or after 18 months. Furthermore, semiquantitative evaluations of vascular and tubular lesions revealed no emerging trends suggestive of voclosporin-induced nephrotoxicity.
The authors conclude that voclosporin, when administered over an 18-month period, does not appear to increase nephrotoxicity or accelerate the progression of pre-existing kidney damage. This provides reassurance for clinicians aiming to balance efficacy and safety in treating lupus nephritis, particularly given the drug’s mechanistic overlap with earlier calcineurin inhibitors.
Nonetheless, several caveats limit the generalisability of these findings. The relatively small sample size limits the robustness and generalizability of the conclusions, and there may be selection bias as patients who poorly tolerated the drug in the initial AURORA trial likely did not continue into this extension study. Moreover, the underrepresentation of patients of African and South Asian ancestry, a demographic with a high burden of lupus nephritis, limits the applicability of these results to some of the highest-risk populations. Finally, while 18 months marks an important milestone, longer-term follow-up is imperative to fully characterize voclosporin’s renal safety profile.
In summary, AURORA 2 delivers encouraging early data suggesting that voclosporin’s safety profile holds steady beyond one year of treatment. This study represents the first double-blind investigation to directly address the long-term histopathologic impact of voclosporin and lays a valuable foundation for future research. As the rheumatology and nephrology communities continue to seek safer, more effective therapies for lupus nephritis, these findings light the way toward confident use of voclosporin, illuminating a path forward in managing lupus nephritis.
References
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Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021 29;397(10289):2070-2080. doi: 10.1016/S0140-6736(21)00578-X. Erratum in: Lancet. 2021 May 29;397(10289):2048. doi: 10.1016/S0140-6736(21)01160-0.
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Saxena A, Ginzler EM, Gibson K, et al. Safety and Efficacy of Long-Term Voclosporin Treatment for Lupus Nephritis in the Phase 3 AURORA 2 Clinical Trial. Arthritis Rheumatol. 2024 Jan;76(1):59-67. doi: 10.1002/art.42657. Epub 2023 Sep 15.