ObjectiveTo assess the efficacy and safety of the type I interferon receptor antibody, anifrolumab, in patients with active, biopsy-proven, Class III/IV lupus nephritis.MethodsThis 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.ResultsPatients 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.ConclusionAlthough 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 numberNCT02547922.

ObjectivesIn a post-hoc analysis, we aimed to validate the Lupus Low Disease Activity State (LLDAS) definition as an endpoint in an systemic lupus erythematosus (SLE) Phase IIb randomised controlled trial (RCT) (MUSE [NCT01438489]) and then utilize LLDAS to discriminate between anifrolumab and placebo.MethodsPatients received intravenous placebo (n=102) or anifrolumab (300 mg, n=99; 1,000 mg, n=104) Q4W plus standard of care for 48 weeks. LLDAS attainment (SLE Disease Activity Index 2000 ≤4 without major organ activity, no new disease activity, Physician’s Global Assessment ≤1, prednisolone ≤7.5 mg/d and standard immunosuppressant dosage tolerance) was assessed. Associations with endpoints and LLDAS attainment differences between treatments were explored.ResultsLLDAS attainment at Week 52 was associated with SLE Responder Index 4 (SRI[4]) and British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) (74/85[87%] and 62/84[74%] were also SRI[4] and BICLA responders, respectively; both nominal p<0.001). Only 74/159 (47%) of SRI(4) and 62/121 (51%) of BICLA responders reached LLDAS.Anifrolumab-treated patients achieved earlier LLDAS, and more spent at least half their observed time in LLDAS (OR vs. placebo; 300 mg: 3.04, 95% CI 1.34 to 6.92, nominal p=0.008; 1,000 mg: 2.17, 95% CI 0.93 to 5.03, nominal p=0.072) vs placebo-treated patients. At Week 52, 17/102 (17%), 39/99 (39%) and 29/104 (28%) of patients on placebo, anifrolumab 300 and 1,000 mg, respectively, attained LLDAS (OR vs. placebo; 300 mg: 3.41, 95% CI 1.73 to 6.76, p<0.001; 1,000 mg: 2.03, 95% CI 1.01 to 4.07, nominal p=0.046).ConclusionsLLDAS attainment represents a clinically meaningful SLE outcome measure, and anifrolumab is associated with more patients who met LLDAS criteria versus placebo. These data support LLDAS as an SLE RCT endpoint.Trial registration numberNCT1438489; Post-results.

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

The authors thank Professor Isenberg 1 for pointing out a drafting error on the manuscript reporting the use of the Lupus Low Disease Activity State (LLDAS) in the anifrolumab phase II trial data set. 2 The British Isles Lupus Assessment Group(BILAG) instrument does indeed document gastrointestinal disease activity, while Systemic Lupus Erythematosis (SLE) Disease Activity Index 2000 (SLEDAI-2K) does not. This error does not impact on the findings of the published paper, or the intended meaning of the sentence in which this error occurred, which was a discussion of the need for evidence that the physician global assessment adequately captures gastrointestinal activity in SLE.