medwireNews: Phase 3 trial results suggest that the calcineurin inhibitor tacrolimus may represent an alternative option to cyclophosphamide for the initial treatment of lupus nephritis (LN).
Writing in JAMA Network Open, the investigators explain that “[c]ombination therapy with high-dose corticosteroids and intravenous cyclophosphamide is an established initial therapy among patients with LN,” but cyclophosphamide “is cytotoxic, and serious adverse effects have been observed during long-term treatment, including premature ovarian failure.”
The noninferiority study included 299 patients with systemic lupus erythematosus (SLE) and LN class III, IV, V, III+V, or IV+V from 35 centers in China who were randomly assigned to receive initial therapy with oral tacrolimus 4 mg/day (with adjustments to maintain trough levels of 4–10 ng/mL) or intravenous cyclophosphamide (target dose 0.5–1.0 g/m2), both given in combination with prednisone.
At the 24-week follow-up, 49.6% of participants given tacrolimus and 36.3% of those given cyclophosphamide achieved a complete response (proteinuria <0.5 g/24 hours, serum albumin ≥3.5 g/dL, and stable kidney function), while 33.3% and 38.7%, respectively, achieved a partial response (proteinuria <3.5 g/24 hours and decreased by >50% from baseline, serum albumin ≥3.0 g/dL, and stable kidney function).
The primary endpoint of complete or partial response at week 24 was met by 83.0% of patients in the tacrolimus group and 75.0% of patients in the cyclophosphamide group, with the between-group difference meeting the predefined criteria for noninferiority.
Zhangsuo Liu (The First Affiliated Hospital of Zhengzhou University, China) and colleagues report that tacrolimus-treated patients experienced a “clinically meaningful improvement” in SLE disease activity compared with those given cyclophosphamide. The least squares mean decrease in SLEDAI score from baseline to week 24 was 8.6 in the tacrolimus arm versus 6.4 points in the cyclophosphamide arm, a significant difference.
Tacrolimus was also associated with significant improvement in 24-hour proteinuria compared with cyclophosphamide, which the authors say “may suggest a more favorable long-term kidney outcome in patients with LN.”
They say that “[n]o unexpected safety findings were reported” in the trial, and that the observed treatment-emergent adverse events (TEAEs) were “expected in the patient population.” Serious TEAEs occurred in 18.5% of tacrolimus-treated patients and 24.6% of cyclophosphamide-treated patients, most commonly infections (8.9 vs 16.2%). Seven participants in each study arm discontinued treatment due to AEs.
“Overall, the findings from our study are encouraging for use of tacrolimus as LN initial therapy in clinical practice,” conclude Liu et al.
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JAMA Netw Open 2022; 5: e224492