麻豆传媒

Patients with lupus nephritis who were treated with the novel calcineurin inhibitor voclosporin (Lupkynis) maintained meaningful decreases in proteinuria with no change in estimated glomerular filtration rate (eGFR) through 30 months of treatment, an investigator reported here.

In the long-term AURORA 2 extension of the , the least squares mean change in urine protein creatinine ratio from pre-treatment baseline was -3.32 mg/mg in the voclosporin arm and -2.55 mg/mg in the control arm, reported Amit Saxena, MD, of NYU Langone Health in New York City at the American College of Rheumatology virtual meeting.

In January 2021, voclosporin was for the treatment of adults with active lupus nephritis in combination with background immunosuppressive therapy. The drug has two complementary mechanisms of action pertinent to the treatment of lupus nephritis: it reduces the activation of T cells and stabilizes podocytes, reducing proteinuria.

Compared with other calcineurin inhibitors, voclosporin is associated with an improved lipid and glucose profile and no drug-drug interactions with mycophenolate mofetil (Cellcept).

"There has been some concern about long-term side effects in patients taking calcineurin inhibitors such as worsening of kidney function and high glucose and cholesterol levels. We're not seeing any of those adverse events at 30 months that we might be concerned about," Saxena said in an interview.

AURORA 1

AURORA 1 was a phase III global, double-blind, 1-year randomized trial that compared voclosporin with placebo for the achievement of complete renal response used in combination with mycophenolate and low-dose steroids. Patients had biopsy-proven lupus nephritis, eGFR of at least 45 mL/min/1.73 m², and proteinuria of 1.5 mg/mg or more. Complete renal response was defined as urine protein creatinine ratio of 0.5 mg/mg or less, stable renal function with an eGFR of 60 or higher, the ability to remain on low-dose steroids, and no use of rescue medications.

The treatment regimen included voclosporin, 23.7 mg twice daily or placebo; mycophenolate mofetil, 2 g/day; and oral steroids that were rapidly tapered to 2.5 mg/day by week 16.

AURORA 1 enrolled 357 patients, and by week 52, complete renal response was observed in 40.8% of the voclosporin group and by 22.5% of the placebo group. The odds ratio for complete renal response at week 52 was 2.65 (95% CI 1.64-4.27, P<0.001).

An expected mild early decrease in eGFR of 1.5 mL at week 2 with voclosporin treatment had returned to baseline by week 4 and remained stable for the duration of follow-up. This event is due to a well known hemodynamic change associated with reversible vasoconstriction within the nephron with calcineurin inhibition.

Overall adverse events (AEs) in AURORA 1 were similar in the voclosporin and placebo arms, with 18 serious AEs in the voclosporin group and 20 in the placebo group. There were five deaths in the placebo group and one in the voclosporin group, none of which were considered related to the study treatment.

AURORA 2

AURORA 2 is a 2-year extension study, with the current report representing an interim analysis of findings up to 30 months. Patients who completed AURORA 1 (n=216) continued in their same treatment group, with 116 in the voclosporin group and 100 in the placebo group.

Patient characteristics among patients continuing on the extension study included mean age being 34, the majority being women, with slightly fewer Asians and more Blacks in the voclosporin arm.

At the time of enrollment into AURORA 1, baseline eGFR was 79.6 in the voclosporin group and 78.9 in the control group, and at the beginning of AURORA 2, the corresponding numbers were 80.3 and 83.2. This difference in eGFR at AURORA 2 baseline was small and not clinically significant, Saxena said.

The baseline urine protein creatinine ratio for AURORA 1 was 3.9 mg/mg in both groups, and for AURORA 2 it was 0.9 and 1.5 in the voclosporin and control groups, respectively. At the start of the extension phase, the oral steroid dose in both groups was below 2.5 mg/day in 80%.

At month 30, the mean urine protein creatinine ratio was 0.58 mg/mg in the voclosporin group and 1.34 mg/mg in the control arm.

After the expected early decrease in eGFR in the first 4 weeks of AURORA 1, the eGFR remained stable through month 30.

"Complete renal response rates are not reported at this time as the components of this composite outcome will be evaluated at the end of the study," he noted.

No unexpected AEs have occurred during the 30 months of follow-up. At the time of the interim analysis, serious infections were similar in the two groups, being reported in 14 patients on voclosporin and 18 controls. Serious coronavirus infections were seen in two and six patients in the voclosporin and control groups, respectively, and three additional deaths occurred in the control group.

There was a higher number of patients developing hypertension at any time during the study in the voclosporin group (30 vs 12), but these increases were transient. No cases of QT prolongation were seen in the voclosporin group, but there were two in the control group. Similar rates in the two groups were seen for malignancy, hyperlipidemia, hyperkalemia, and hyperglycemia.

"This analysis provides further support for the positive benefit-risk profile of voclosporin seen in both phase II and III studies, representing the largest successful lupus nephritis clinical program to date," Saxena said.

"The question of how long to maintain patients on a drug like this is very much an open question," he said. "Usually when we think about treating kidney disease in lupus with agents such as mycophenolate, we think of 2 to 3 years of treatment. But we didn't have good information as to whether or not a calcineurin inhibitor could be used for that long. We now feel more comfortable saying that this can be done, and it would represent a real change in treatment," he told 麻豆传媒.

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