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

Background: Anifrolumab, a type I interferon receptor antibody, has shown efficacy in patients with systemic lupus erythematosus (SLE), 1,2 &gt;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) &gt;1 mg/mg. Patients were randomized (1:1:1) to anifrolumab basic regimen (BR, 300 mg, based on SLE dosing 1,2 ), 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 &lt;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 m 2 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. CRR 0.5 (CRR with UPCR ≤0.5 mg/mg) and time to CRR 0.5 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 trials 1,2 ), 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 CRR 0.5 (Figure 1), rate of CRR 0.5 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 Endpoints Endpoint Anifrolumab Placebo Combined Basic Intensified 24-hour urine protein–creatinine ratio improvement W52 N 91 41 50 41 GMR vs placebo 1.031 1.104 0.963 – 95% CI 0.621, 1.713 0.612, 1.992 0.548, 1.693 CRR rate W52 n/N (% ) 27/87 (31.0) 7/43 (16.3) 20/44 (45.5) 14/45 (31.1) Δ −0.08 −14.83 14.34 – 95% CI −16.92, 16.76 −32.89, 3.22 −5.77, 34.46 CRR 0.5 rate W52 n/N (% ) 25/87 (28.7) 7/43 (16.3) 18/44 (40.9) 12/45 (26.7) Δ 2.07 −10.39 14.24 – 95% CI −14.25, 18.39 −28.07, 7.29 −5.42, 33.90 Glucocorticoid ≤7.5 mg/day W24–52 n/N (% ) 31/67 (46.3) 11/31 (35.5) 20/36 (55.6) 11/33 (33.3) Δ 12.94 2.15 22.22 – 95% CI −7.26, 33.13 −21.40, 25.70 −0.79, 45.23 Δ 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