Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis

Abstract

Objective: To assess the efficacy and safety of the type I interferon receptor antibody, anifrolumab, in patients with active, biopsy-proven, Class III/IV lupus nephritis.

Methods: This phase II double-blinded study randomised 147 patients (1:1:1) to receive monthly intravenous anifrolumab basic regimen (BR, 300 mg), intensified regimen (IR, 900 mg ×3, 300 mg thereafter) or placebo, alongside standard therapy (oral glucocorticoids, mycophenolate mofetil). The primary endpoint was change in baseline 24-hour urine protein-creatinine ratio (UPCR) at week (W) 52 for combined anifrolumab versus placebo groups. The secondary endpoint was complete renal response (CRR) at W52. Exploratory endpoints included more stringent CRR definitions and sustained glucocorticoid reductions (≤7.5 mg/day, W24-52). Safety was analysed descriptively.

Results: Patients received anifrolumab BR (n=45), IR (n=51), or placebo (n=49). At W52, 24-hour UPCR improved by 69% and 70% for combined anifrolumab and placebo groups, respectively (geometric mean ratio=1.03; 95% CI 0.62 to 1.71; p=0.905). Serum concentrations were higher with anifrolumab IR versus anifrolumab BR, which provided suboptimal exposure. Numerically more patients treated with anifrolumab IR vs placebo attained CRR (45.5% vs 31.1%), CRR with UPCR ≤0.5 mg/mg (40.9% vs 26.7%), CRR with inactive urinary sediment (40.9% vs 13.3%) and sustained glucocorticoid reductions (55.6% vs 33.3%). Incidence of herpes zoster was higher with combined anifrolumab vs placebo (16.7% vs 8.2%). Incidence of serious adverse events was similar across groups.

Conclusion: Although the primary endpoint was not met, anifrolumab IR was associated with numerical improvements over placebo across endpoints, including CRR, in patients with active lupus nephritis.

Trial registration number: NCT02547922.

Keywords: autoimmune diseases; biological therapy; immune system diseases; lupus erythematosus; lupus nephritis; systemic.

Figure 1

Patient disposition for the completed 52-week double-blind treatment period. All percentages are based on the 145 patients in the full analysis set (modified intention-to-treat population), who were included in the primary endpoint analysis. ^aOf patients not randomised, 179 did not meet the screening criteria, 7 withdrew consent, 2 experienced AEs, 1 was lost to follow-up, 1 patient was not included because of the physician’s decision, and 1 patient was not included for unspecified reason (‘other’). ^bOne patient was assigned to but did not receive ≥1 dose of each of the anifrolumab regimens and therefore was not included in the analysis. AE, adverse event; BR, basic regimen; IR, intensified regimen.

Figure 2

Key efficacy endpoints over time. Error bars represent 95% CIs. ^aGM of the ratio of the 24-hour UPCR values at each time point over the baseline value for each treatment group (values <1 indicate an improvement). ^bGMR of the relative improvement in 24-hour UPCR for anifrolumab groups vs placebo groups, where GMR <1 favours anifrolumab. A p≤0.05 for the combined anifrolumab vs placebo group was deemed significant. All other p values presented are nominal. ^cPatients from France and Italy (n=13) were excluded from the analysis (see online supplemental material). ^dProbability of obtaining a sustained CRR_0.5 was analysed post hoc using a Cox regression model controlling for stratification factors. BR, basic regimen; CRR, complete renal response; CRR_0.5, CRR with UPCR ≤0.5 mg/mg; GM, geometric mean; GMR, geometric mean ratio; IR, intensified regimen; UPCR, urine protein–creatinine ratio.

Figure 3

Measures of disease activity and IFNGS neutralisation over time. Number of patients with non-missing value at visit are presented. SLEDAI-2K, PGA and PtGA change from baseline were analysed using a mixed model for repeated measures, controlling for stratification factors, and based on observed data up to investigational product discontinuation. PD neutralisation was analysed descriptively. BR, basic regimen; IFN, interferon; IFNGS, interferon gene signature; IR, intensified regimen; LS, least squares; MAD, median absolute deviation; PD, pharmacodynamic; PGA, Physician’s Global Assessment, PtGA, Patient’s Global Assessment; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000.