The addition of low-dose voclosporin to standard therapy led to significantly greater remission but a higher incidence of adverse events in systemic lupus erythematosus (SLE) patients with active lupus nephritis, according to a Phase 2 clinical trial.
Findings from the trial were published in the study, “A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis,” in the journal Kidney International.
Lupus nephritis is a type of kidney inflammation and is one of the most frequent and severe manifestations of SLE.
Compounds that inhibit a protein called calcineurin are used to prevent kidney transplant rejection by blocking the activation of immune T-cells. They are also believed to improve kidney responses in lupus patients.
In fact, a regimen including the calcineurin inhibitor (CNI) tacrolimus, the immunosuppressant mycophenolate mofetil, and corticosteroids increased the rate of complete renal remission in lupus nephritis patients in a randomized trial in China.
Voclosporin is a next-generation CNI intended to treat systemic, pulmonary, and dermatological autoimmune disorders. The compound, developed by Aurinia Pharmaceuticals, has shown greater potency and faster elimination of byproducts than cyclosporine A, also a CNI, as well as better dosing and tolerability than tacrolimus.
Thus, researchers developed a Phase 2 trial, called AURA-LV (NCT02141672), to determine if adding voclosporin to mycophenolate mofetil and a low dose of corticosteroids was safe and effective as a first-line treatment for lupus nephritis patients.
The study included 265 patients from 20 countries, who randomly received either a placebo, low-dose voclosporin (23.7 mg twice a day), or high-dose voclosporin (39.5 mg twice daily).
The 48 weeks of treatment were completed by 79.5% of patients in the placebo group 82% in the low-dose group, and 90.9% in the high-dose group. At 24 weeks, more patients receiving the low-dose voclosporin had achieved complete renal remission (32.6%) than those in the high-dose group (19.3%) or the placebo group (27.3%).
Both voclosporin doses enabled more rapid complete remission than placebo and earlier partial remissions — defined by a 50% or greater decrease in urine protein to creatinine ratio (UPCR) from initial values. Creatinine is an indicator of kidney function.
Patients on voclosporin also showed a significant decrease in UPCR and an increase in serum albumin — the most abundant protein in plasma and an indicator of liver function.
Indicators of SLE activity, including antibodies against double-stranded DNA and levels of complement proteins, improved over time in all treatment groups, with significant differences at 24 and 48 weeks in the low-dose group and at 12, 24 and 48 weeks in patients on the high-dose experimental therapy.
A greater improvement in SLE activity was also found in the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erthematosus Disease Activity Index (SELENA-SLEDAI) scores.
Most adverse events occurred within the first 24 weeks, with the most common being infections and gastrointestinal disorders.
The most frequent treatment-related adverse referred to the need to assess estimated glomerular filtration rate (eGFR) — a kidney function marker — mandated for any change in eGFR greater than 10%.
Patients on high-dose voclosporin had a greater incidence of adverse events and treatment-related adverse events, but serious adverse events — including five cases of acute kidney injury — were found in a greater proportion of patients on low-dose (28.1%) compared with high-dose voclosporin (25.0%) and placebo (15.9%).
Thirteen patients died during the study, 10 of whom were receiving low-dose voclosporin. Nine of these deaths occurred in Bangladesh and Sri Lanka, where two to four fold more patients received low-dose voclosporin than placebo. Three more patients on placebo – none on voclosporin – died during a safety follow-up.
Nine deaths occurred within the first two months of the study, which suggests that careful follow-up is needed early in the course of treatment, according to the researchers.
“Our trial is the first to demonstrate efficacy in a multi-ethnic global cohort, suggesting that CNI-based treatment may be applicable to all patients with [lupus nephritis],” the scientists wrote.
Early positive results of the AURA-LV trial had been reported in 2017. A Phase 3 study, called AURORA (NCT03021499), is ongoing to better determine the benefits of CNIs in patients with lupus nephritis.