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.
We are sorry that this post was not useful for you!
Let us improve this post!
Tell us how we can improve this post?