POS0690\u2005RANDOMIZED, CONTROLLED, PHASE 2 TRIAL OF TYPE 1 IFN INHIBITOR ANIFROLUMAB IN PATIENTS WITH ACTIVE PROLIFERATIVE LUPUS NEPHRITIS

Abstract

Anifrolumab, a type I interferon receptor antibody, has shown efficacy in patients with systemic lupus erythematosus (SLE),1,2 >30% of whom develop lupus nephritis (LN).To evaluate the efficacy and safety of anifrolumab vs placebo alongside standard therapy in patients with active proliferative LN.TULIP-LN (NCT02547922) was a phase 2 double-blind trial in adult patients with active, biopsy-proven LN and 24-hour (h) urine protein–creatinine ratio (UPCR) >1\u2009mg/mg. Patients were randomized (1:1:1) to anifrolumab basic regimen (BR, 300\u2009mg, based on SLE dosing1,2), anifrolumab intensified regimen (IR, 900\u2009mg for 3 doses, 300\u2009mg thereafter), or placebo, intravenously every 4 weeks alongside standard therapy of oral glucocorticoids (GCs; mandatory taper ≤10\u2009mg/day by Week [W]12, ≤7.5\u2009mg/day by W24) and mycophenolate mofetil (target 2\u2009g/day by W8). The primary endpoint was the relative difference in change from baseline to W52 in 24-h UPCR, measured with a geometric mean ratio (GMR) of the change in the combined anifrolumab vs placebo groups (GMR <1 favors anifrolumab). The key secondary endpoint was complete renal response (CRR) at W52 (24-h UPCR ≤0.7\u2009mg/mg, estimated glomerular filtration rate ≥60\u2009mL/min/1.73 m2 or no decrease ≥20%, no treatment discontinuation, and no restricted medication use). Sustained GC taper (≤7.5\u2009mg/day, W24–52) was an exploratory endpoint. CRR0.5 (CRR with UPCR ≤0.5\u2009mg/mg) and time to CRR0.5 sustained to W52 were analyzed post hoc. Responder rates were calculated with a stratified Cochran–Mantel–Haenszel approach.Patients received anifrolumab BR (n=45) or IR (n=51) or placebo (n=49); demographics and baseline disease characteristics were generally balanced between groups. No difference in change from baseline to W52 in 24-h UPCR was observed for combined anifrolumab vs placebo groups (Table 1). Anifrolumab clearance was higher in patients with LN vs SLE; proteinuria in LN elicited suboptimal anifrolumab serum concentrations (early trough from BR 50%–60% lower than in SLE trials1,2), so anifrolumab IR results are presented. CRR rate at W52 was numerically higher with the IR vs placebo (45.5% vs 31.1%) (Table 1). Time to sustained CRR0.5 (Figure 1), rate of CRR0.5 at W52, and rate of sustained GC taper to ≤7.5\u2009mg/day (Table 1) were improved with the IR vs placebo. Most adverse events were nonserious, mild, or moderate and did not lead to discontinuation; rates were similar in the combined anifrolumab vs placebo groups (89.8% vs 93.8%). In the combined anifrolumab vs placebo groups, there was a higher incidence of herpes zoster (HZ, 16.7% vs 8.2%); most HZ cases were of mild to moderate intensity, cutaneous, and resolved with treatment.Although the primary endpoint was not met, the anifrolumab IR was associated with numeric improvements across clinical endpoints vs placebo; thus, intensified dosing may be required to reach clinical efficacy in LN vs SLE without active renal disease. Anifrolumab had a similar safety profile in patients with LN and SLE; despite higher frequency of HZ vs placebo, anifrolumab was well tolerated.[1]Morand EF. N Engl J Med. 2020;382:211–21.[2]Furie RA. Lancet Rheumatol. 2019;1:e208–19.Table 1.Summary of Clinical Efficacy EndpointsEndpointAnifrolumabPlaceboCombinedBasicIntensified24-hour urine protein–creatinine ratio improvement W52N91415041GMR vs placebo1.0311.1040.963–95% CI0.621, 1.7130.612, 1.9920.548, 1.693CRR rate W52n/N (%)27/87 (31.0)7/43 (16.3)20/44 (45.5)14/45 (31.1)Δ−0.08−14.8314.34–95% CI−16.92, 16.76−32.89, 3.22−5.77, 34.46CRR0.5rate W52n/N (%)25/87 (28.7)7/43 (16.3)18/44 (40.9)12/45 (26.7)Δ2.07−10.3914.24–95% CI−14.25, 18.39−28.07, 7.29−5.42, 33.90Glucocorticoid≤7.5\u2009mg/dayW24–52n/N (%)31/67 (46.3)11/31 (35.5)20/36 (55.6)11/33 (33.3)Δ12.942.1522.22–95% CI−7.26, 33.13−21.40, 25.70−0.79, 45.23Δ Percentage difference vs placebo.CI, confidence interval; CRR, complete renal response; GMR, geometric mean ratio; n, number of responders; N, number analyzed; W, Week.Writing assistance by Matilda Shackley, MPhil, of JK Associates, Inc, a member of Fishawack Health. This study was sponsored by AstraZeneca.David Jayne Grant/research support from: AstraZeneca, Aurinia, Boehringer-Ingelheim, GSK, Roche/Genentech and Sanofi-Genzyme, Brad H Rovin Consultant of: AstraZeneca, Eduardo Mysler Grant/research support from: AstraZeneca, GSK, Eli Lilly, Sandoz, Roche, AbbVie, Pfizer, Janssen, Gemma, and Amgen, Richard Furie Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Frederic Houssiau Consultant of: GSK, Teodora Trasieva Employee of: AstraZeneca, Jacob Knagenhjelm Employee of: AstraZeneca, Erik Schwetje Employee of: AstraZeneca, Yen Lin Chia Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca, Catharina Lindholm Employee of: AstraZeneca