Relationship Between Anifrolumab Pharmacokinetics, Pharmacodynamics, and Efficacy in Patients With Moderate to Severe Systemic Lupus Erythematosus.

This study aimed to elucidate the pharmacokinetic/pharmacodynamic and pharmacodynamic/efficacy relationships of anifrolumab, a type I interferon receptor antibody, in patients with moderate to severe systemic lupus erythematosus. Data were pooled from the randomized, 52-week, placebo-controlled TULIP-1 and TULIP-2 trials of intravenous anifrolumab (150 mg/300 mg, every 4 weeks for 48 weeks). Pharmacodynamic neutralization was measured with a 21-gene type I interferon gene signature (21-IFNGS) in patients with high IFNGS. The pharmacokinetic/pharmacodynamic relationship was analyzed graphically and modeled with a nonlinear mixed-effects model. British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rates were compared across 21-IFNGS neutralization quartiles. Overall, 819 patients received ≥1 dose of anifrolumab or placebo, of whom 676 were IFNGS high. Over 52 weeks, higher average anifrolumab serum concentrations were associated with increased median 21-IFNGS neutralization, which was rapid and sustained with anifrolumab 300 mg (>80%, weeks 12-52), lower and delayed with anifrolumab 150 mg (>50%, week 52), and minimal with placebo. The proportion of patients with week 24 anifrolumab trough concentration exceeding the IC80 (3.88 µg/mL) was greater with anifrolumab 300 mg vs anifrolumab 150 mg (≈83% vs ≈27%), owing to the higher estimated median trough concentration (15.6 vs 0.2 µg/mL). BICLA response rates increased with 21-IFNGS neutralization; more patients had a BICLA response in the highest vs lowest neutralization quartiles at week 52 (58.1% vs 37.6%). In conclusion, anifrolumab 300 mg every 4 weeks rapidly, substantially, and sustainably neutralized the 21-IFNGS and was associated with clinical efficacy, supporting this dosing regimen in patients with systemic lupus erythematosus.

Relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with systemic lupus erythematosus.

OBJECTIVES: To characterize the relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with moderate to severe SLE despite standard therapy, using pooled data from two phase 3 trials. METHODS: TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (every 4 weeks for 48 weeks). For the exposure-response analysis, BILAG-based Composite Lupus Assessment (BICLA) or SLE Responder Index [SRI(4)] response rates at week 52 in each quartile/tertile of average anifrolumab serum concentration (Cave) were compared for anifrolumab and placebo in all-comers, patients who completed treatment, and IFN gene signature (IFNGS)-high patients who completed treatment, using average marginal effect logistic regression. Relationships between exposure and key safety events were assessed graphically. RESULTS: Of patients in TULIP-1/TULIP-2 who received anifrolumab (150 mg, n = 91; 300 mg, n = 356) or placebo (n = 366), 574 completed treatment, of whom 470 were IFNGS high. In the exposure-efficacy analyses, BICLA and SRI(4) treatment differences favouring anifrolumab 300 mg vs placebo were observed across Cave subgroups and all analysis populations. Logistic regression identified Cave as a significant covariate for predicted BICLA response, as higher anifrolumab Cave predicted greater efficacy. There was no evidence of exposure-driven incidence of key safety events through week 52 in patients receiving anifrolumab 150 or 300 mg. CONCLUSION: While higher Cave predicted greater efficacy, consistent positive benefit favouring anifrolumab 300 mg vs placebo was observed in BICLA and SRI(4) responses across Cave subgroups in the TULIP trials. There was no evidence of exposure-driven safety events. CLINICALTRIAL.GOV NUMBERS: NCT02446912, NCT02446899.

Pharmacokinetics, pharmacodynamics, and safety of subcutaneous anifrolumab in patients with systemic lupus erythematosus, active skin disease, and high type I interferon gene signature: a multicentre, randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: 300 mg of intravenous anifrolumab every 4 weeks added to standard-of-care treatment for patients with systemic lupus erythematosus (SLE) reduced disease activity and glucocorticoid requirement in a previous phase 3 trial. Because patients might find subcutaneous administration more convenient than intravenous delivery, we aimed to evaluate the pharmacokinetics, pharmacodynamics, safety, and efficacy of subcutaneous anifrolumab in patients with SLE, active skin disease, and a high type I interferon gene signature. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 study was done at 12 hospitals and outpatient clinics in Hungary, South Korea, Poland, and the USA. Eligible patients were aged 18-70 years, and had SLE with high type I interferon gene signature and an activity score on the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) of at least 10. Enrolled participants were randomly assigned (3:1:3:1) by use of a voice-web response system to receive either 150 mg of subcutaneous anifrolumab or corresponding placebo, or 300 mg of subcutaneous anifrolumab or corresponding placebo in addition to stable standard-of-care treatment. The study was double-blinded with respect to intervention but not dose, until 12 weeks. Doses of oral glucocorticoids were tapered after week 12. The primary pharmacokinetic endpoint was the serum concentration of anifrolumab based on the maximum concentration after the first dose and the minimum (trough) concentration before subsequent doses and was measured in all patients who received anifrolumab and had at least one quantifiable serum pharmacokinetics observation following the first dose. The primary pharmacodynamic endpoint was neutralisation of the type I interferon pharmacodynamic signature at week 12 and was assessed in all patients with a high type I interferon pharmacodynamics signature at baseline based on a 21-gene test. Safety was evaluated in the full analysis set, which included all patients who received at least one dose of anifrolumab. This trial is completed and is registered at ClinicalTrials.gov, NCT02962960. FINDINGS: Between March 14, 2017, and Oct 26, 2017, 36 patients were randomly assigned to receive 150 mg of anifrolumab (n=14), 300 mg of anifrolumab (n=13), or placebo (n=9). Two patients in the anifrolumab 150 mg group were excluded from the pharmacodynamic analysis set (n=34). Ten (71%) of 14 patients in the anifrolumab 150 mg group, ten (77%) of 13 patients in the anifrolumab 300 mg group, and nine (100%) of the nine patients in the placebo group completed 52 weeks of treatment. At week 12, pre-dose mean trough serum concentrations of anifrolumab were more than dose proportional between the anifrolumab 150 mg group (19·82 µg/mL [SD 15·01]) and the anifrolumab 300 mg group (60·28 µg/mL [43·66]), and the pharmacokinetics were non-linear. At week 12, the median percentage neutralisation of the type I interferon gene signature was higher with 150 mg (88·0% [median absolute deviation 7·4]) and 300 mg (90·7% [3·3]) of anifrolumab than with placebo (18·5% [8·1]), and more patients in the anifrolumab 150 mg group and the anifrolumab 300 mg group than in the placebo group had neutralisation of 75% or more (eight [67%] of 12 vs ten [77%] of 13 vs one [11%] of nine). At least one adverse event was reported by 23 (85%) of 27 patients in the anifrolumab groups and by seven (78%) of nine patients in the placebo group; most adverse events were of mild-to-moderate severity. Serious adverse events were reported in six (22%) of 27 patients in the anifrolumab groups (four patients in the 150 mg group and two in the 300 mg group). No serious adverse events were reported in the placebo group. Herpes zoster infection was reported by three (11%) of 27 patients in the anifrolumab groups and by one (11%) of nine patients in the placebo group. There were no treatment-related deaths. INTERPRETATION: Anifrolumab, administered subcutaneously every 2 weeks to patients with SLE and moderate-to-severe skin manifestations, had non-linear pharmacokinetics that were more than dose proportional, and neutralised the type I interferon gene signature in a dose-dependent manner. The safety profile was consistent with previous studies of intravenous anifrolumab, supporting the continued development of anifrolumab as a subcutaneously administered therapy for patients with SLE. FUNDING: AstraZeneca.

Safety, tolerability and pharmacokinetics of subcutaneous and intravenous anifrolumab in healthy volunteers.

OBJECTIVES: To compare the pharmacokinetics (PK), safety and tolerability of subcutaneous (SC) and intravenous anifrolumab, an anti-type I interferon receptor monoclonal antibody in development for SLE, in healthy volunteers. METHODS: In this Phase I randomised, placebo-controlled study, 30 adults were assigned to three treatment cohorts (anifrolumab 300 mg SC (n=6), anifrolumab 300 mg intravenous (n=6), anifrolumab 600 mg SC (n=6)) and placebo (n=4/cohort). Serial blood samples were collected up to Day 84 to measure anifrolumab concentrations and antidrug antibodies (ADAs). PK parameters were estimated by noncompartmental analysis. RESULTS: Maximum serum concentrations in SC cohorts occurred after 4-7 days. Anifrolumab serum concentrations were below the limit of detection in all individuals by Day 84. Exposure to SC anifrolumab increased dose proportionally from 300 mg to 600 mg based on area under the serum concentration-time curve. Anifrolumab 300 mg SC exposure reached 87% of the intravenous exposure. Anifrolumab 300 mg SC and placebo administration elicited minimal injection-site reactions. Transient injection-site induration occurred in five of six individuals after anifrolumab 600 mg SC and two of four individuals after placebo. Transient, mild to moderate injection-site induration and pruritus occurred simultaneously in two of six individuals after anifrolumab 600 mg SC. Adverse events were reported by 50% (n=9) of anifrolumab-treated individuals and 33% (n=4) of placebo-treated individuals. ADAs were detected in only one individual in the anifrolumab 300-mg intravenous group at the Day 84 assessment. CONCLUSION: Anifrolumab 300-mg SC exposure was 87% of intravenous administration, with single SC anifrolumab administrations well tolerated in healthy volunteers.