POS0690 RANDOMIZED, CONTROLLED, PHASE 2 TRIAL OF TYPE 1 IFN INHIBITOR ANIFROLUMAB IN PATIENTS WITH ACTIVE PROLIFERATIVE LUPUS NEPHRITIS
Authors: Jayne D. , Rovin B. H. , Mysler E. , Furie R. , Houssiau F. , Trasieva T. , Knagenhjelm J. , Schwetje E. , Chia Y. L. , Tummala R. , Lindholm C. 
Published: May 2021

Background: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).Objectives:To evaluate the efficacy and safety of anifrolumab vs placebo alongside standard therapy in patients with active proliferative LN.Methods: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 mg/mg. Patients were randomized (1:1:1) to anifrolumab basic regimen (BR, 300 mg, based on SLE dosing1,2), anifrolumab intensified regimen (IR, 900 mg for 3 doses, 300 mg thereafter), or placebo, intravenously every 4 weeks alongside standard therapy of oral glucocorticoids (GCs; mandatory taper ≤10 mg/day by Week [W]12, ≤7.5 mg/day by W24) and mycophenolate mofetil (target 2 g/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 mg/mg, estimated glomerular filtration rate ≥60 mL/min/1.73 m2 or no decrease ≥20%, no treatment discontinuation, and no restricted medication use). Sustained GC taper (≤7.5 mg/day, W24–52) was an exploratory endpoint. CRR0.5 (CRR with UPCR ≤0.5 mg/mg) and time to CRR0.5 sustained to W52 were analyzed post hoc. Responder rates were calculated with a stratified Cochran–Mantel–Haenszel approach.Results: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 mg/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.Conclusion: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.References:[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 mg/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.Acknowledgements:Writing assistance by Matilda Shackley, MPhil, of JK Associates, Inc, a member of Fishawack Health. This study was sponsored by AstraZeneca.Disclosure of Interests: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