Background/Purpose: Anifrolumab is a fully human IgG1 monoclonal antibody directed against subunit 1 of the type I interferon receptor (IFNAR1). Anifrolumab blocks the binding of type IIFN and inhibits the biologic activity of all type I IFNs. The PD and PK effects of anifrolumab were assessed through analysis of the blood of adult patients with moderate to severe SLE enrolled in a Phase IIb study (MI-CP1013).

Methods:  Adult patients who satisfied ACR classification criteria for SLE were enrolled in a Phase IIb randomized controlled trial and received anifrolumab 300 or 1,000 mg intravenously every 4 weeks, or placebo, in addition to standard of care. Blood specimens were collected for PK and PD assessments at selected time points from pre-dosage to 422 days after initial administration. Transcript profiling was conducted through real-time quantitative reverse transcription–polymerase chain reaction (qRT–PCR) on a 21-gene type I IFN-inducible gene signature (IFNGS). Neutralization scores were calculated throughout the dosing schedule for each available time point (Days 29 to 365), based on patients’ Day-1 baseline expression IFNGS values. Percentage neutralization scores for each dosage arm were summarized (median) for all available time points.  Serum anifrolumab concentrations were measured using a validated electrochemiluminescence assay.

Results: A total of 215 of 305 patients (70.5%) were positive at baseline for the IFNGS. Expression of IFNGS in whole blood decreased following anifrolumab administration for all dosages in patients positive for the IFNGS at baseline. In the 300-mg every-4-week dosage arm, a median signature neutralization range (85.2–89.7%) was observed between Day 29 and 365. Maximum median neutralization (89.7%) was observed at Day 169. In the 1,000-mg every-4- week dosage arm, a median signature neutralization range (86.8–91.9%) was observed between Day 29 and 365. Maximum median neutralization (91.9%) was observed at Day 365, although comparable median neutralization was observed earlier, at Day 141 (91.7%). Negligible IFNGS modulation was noted for the placebo arm at each time point assessed. For all patients who received anifrolumab, near maximum median signature neutralization was observed at the first time point assessed (Day 29). As a result of target-mediated clearance, PK exposure of anifrolumab was more than dose-proportional between the 300 and 1,000 mg doses. On Day 169, mean±SD C_troughincreased more than dose proportionally from 18.8±10.9 to 115±62.9 µg/mL, when the dosage was increased from 300 mg to 1,000 mg every 4 weeks. There were no obvious differences in PK in the study between patients who were IFNGS-positive vs. IFNGS-negative. 

Conclusion: Anifrolumab demonstrated expected mechanism of action in SLE. Target engagement of anifrolumab was confirmed with near maximum and sustained inhibition of the IFNGS. These data support the selection of 300 mg every 4 weeks as the dosage for study in Phase III pivotal trials.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/target-modulation-of-a-type-i-interferon-gene-signature-and-pharmacokinetics-of-anifrolumab-in-a-phase-iib-study-of-patients-with-moderate-to-severe-systemic-lupus-erythematosus/