POS0684\u2005RELATIONSHIP OF ANIFROLUMAB PK WITH EFFICACY AND SAFETY IN PATIENTS WITH SLE

Abstract

In patients with systemic lupus erythematosus (SLE), the type I interferon (IFN) receptor inhibitor anifrolumab was well tolerated and was associated with greater percentages of patients with BILAG–based Composite Lupus Assessment (BICLA) responses vs placebo in 2 phase 3 trials: TULIP-11 (secondary endpoint) and TULIP-22 (primary endpoint).To characterize the relationship of anifrolumab pharmacokinetics (PK) with BICLA response and safety using pooled data from the TULIP trials.This analysis included patients with moderate to severe SLE despite standard therapy who had ≥1 dose of investigational product and ≥1 quantifiable PK observation in the randomized, placebo-controlled, 52-week TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials of intravenous anifrolumab (every 4 weeks).1,2 The distributions of average anifrolumab serum concentrations (Cave) during treatment were similar between TULIP-1 and TULIP-2, allowing for data pooling for all analyses. For the exposure–BICLA analysis, the proportions of patients with BICLA responses at Week (W)52 (and corresponding 95% confidence intervals [CIs]) in each quartile/tertile of Cave were compared for anifrolumab 300\u2009mg and placebo groups in all patients, patients who completed treatment, and IFN gene signature (IFNGS) test–high patients who completed treatment, using average marginal effect logistic regression (stratified by SLE Disease Activity Index 2000 total score at screening, IFNGS status at screening, and Day 1 glucocorticoid dosage [mg/day]). The relationships between exposure and key safety events were similarly assessed. Analyses presented focus on the anifrolumab 300\u2009mg dose.Of the patients in TULIP-1/TULIP-2 who received anifrolumab 300\u2009mg (n=356) or placebo (n=366), 574 completed treatment, of whom 470 were IFNGS test–high at screening. In the exposure–BICLA response analyses, differences favoring anifrolumab 300\u2009mg vs placebo were observed across Cave subgroups among all patients, patients who completed treatment, and IFNGS test–high patients who completed treatment (Table 1). Among IFNGS test–high patients who completed treatment, logistic regression identified Cave as a significant covariate for BICLA response. There was no evidence that the incidence of non-opportunistic serious infections, or increased incidence of herpes zoster (HZ) or infusion-related reactions associated with anifrolumab, were exposure-driven (Figure 1); the incidence of malignancy was low in the anifrolumab 300\u2009mg and placebo groups (<1%), with no evidence that malignancy was exposure-driven through W52.Consistent benefit in favor of anifrolumab 300\u2009mg vs placebo was observed in W52 BICLA responses across Cave subgroups. Cave was a significant covariate of efficacy in IFNGS test–high patients who completed treatment. There was no evidence of exposure-driven HZ, non-opportunistic serious infections, infusion-related reactions, or malignancy during the TULIP trials.[1]Furie R. Lancet Rheumatol. 2019;1:e208–19.[2]Morand E. N Engl J Med. 2020;382:211–21.Table 1.Exposure–BICLA Analysis for Pooled TULIP DataBICLA response, W52PK subgroupaAnifrolumab 300\u2009mg,n/Nb(%)Anifrolumab vs placebo difference, % [95% CI]All patients (n=722)Q140/100 (40)9.6 [–1.0, 20.3]Q244/98 (44)13.4 [2.6, 24.2]Q343/81 (53)22.5 [10.7, 34.3]Q444/77 (58)27.4 [15.4, 39.4]Placebo112/366 (31)–Patients completing treatment (n=574)Q140/75 (54)12.7 [0.1, 25.2]Q244/74 (57)15.5 [2.7, 28.3]Q343/74 (58)17.2 [4.7, 29.8]Q444/75 (60)18.7 [6.2, 31.2]Placebo112/276 (41)–IFNGS test–high patients completing treatment (n=470)T144/81 (54)15.4 [3, 27.8]T246/81 (54)15.4 [2.8, 27.9]T352/81 (66)26.7 [14.7, 38.7]Placebo88/227 (39)–BICLA, British Isles Lupus Assessment Group–based Composite Lupus Assessment;CI, confidence interval; IFNGS, interferon gene signature; PK, pharmacokinetic; Q, quartile; T, tertile.aPK was stratified by quartiles/tertiles based on sample size.bn, number of BICLA responders; N, number of patients in the subgroup.Writing assistance by Alexus Rivas, PharmD, and Rosie Butler, PhD, of JK Associates Inc., part of Fishawack Health.This study was sponsored by AstraZeneca.Yen Lin Chia Employee of: AstraZeneca, Jianchun Zhang Employee of: Fate Therapeutics, AstraZeneca (former), Raj Tummala Employee of: AstraZeneca, Tomas Rouse Employee of: AstraZeneca, Richard Furie Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Eric F. Morand Speakers bureau: AstraZeneca, Consultant of: AstraZeneca, Grant/research support from: AstraZeneca