Background Sifalimumab is a fully human, IgG1κ monoclonal antibody in Phase IIb clinical development for systemic lupus erythematosus (SLE). Sifalimumab binds to and neutralizes the majority of IFN-α subtypes.
Objectives We assessed the pharmacokinetic and pharmacodynamic effects of sifalimumab through analysis of the blood of adult patients with moderate to severe SLE enrolled in a Phase IIb study.
Methods Adult patients who satisfied ACR classification criteria for SLE were enrolled in a Phase IIb randomized controlled trial1 and received sifalimumab 200, 600, or 1,200 mg intravenously every 4 weeks, or placebo (following starting doses at Days 1, 15, and 29). Blood specimens were collected for PK and PD assessments at several time points from pre-dosage to 516 days after initial administration. Sifalimumab drug concentrations were measured via a validated electrochemiluminescence assay, and PK parameters were determined by noncompartmental analysis. Transcript profiling was conducted through real-time quantitative reverse transcription–polymerase chain reaction (qRT–PCR) on a type I IFN-inducible gene signature (IFNGS).
Results Sifalimumab serum concentrations exhibited linear and dose-proportional PK over the 200 to 1,200 mg every 4 weeks dosage range. Mean maximum concentration (Cmax) and trough concentrations (Ctrough), respectively, ranged from 117 to 562 ug/mL and 19.9 to 150 ug/mL, respectively, at steady state. Mean clearance and half-life ranged from 0.11 to 0.14 L/day and 24 to 26 days. A total of 349 of 431 patients (81%) were positive for the IFNGS in whole blood at baseline. Expression of IFNGS in whole blood decreased following sifalimumab administration for all dosages in patients positive for the IFNGS at baseline. Neutralization scores were calculated for each available time point (Days 15 to 365), based on patients' Day-1 baseline expression IFNGS values. Percentage neutralization scores for each dosage arm were summarized (mean ± SE) for all available time points. In the 200-mg every 4 week dosage arm, a moderate mean signature neutralization (6.1–21.8%) was observed at Day 15 and maintained through Day 365. Maximum mean neutralization (21.8%) was observed at Day 15. In the 600-mg every 4 week dosage arm, moderate mean signature neutralization (8.3–27%) was observed at Day 15 and maintained through Day 365. Maximum mean neutralization (27%) was observed at Day 15. Finally, in the 1,200 mg every 4 week dosage arm, slightly more substantial mean signature neutralization (17.7–25.3%) was observed at Day 15 and maintained through Day 365. Maximum mean neutralization (25.3%) was observed at Day 15. IFNGS induction was noted for the placebo at each time point assessed. For all patients who received sifalimumab, maximum mean signature neutralization was observed at the first time point assessed (Day 15), while near-equivalent to sub-maximal neutralization magnitudes were noted at subsequent time points.
Conclusions Sifalimumab PK was linear and dose-proportional. Sifalimumab demonstrated expected mechanism of action in SLE. Target engagement of sifalimumab was confirmed with inhibition of the IFNGS. As expected, inhibition of IFN signature was less than complete over the dosage range tested.
Khamashta M, et al. Arthritis Rheumatol. 2014;66:3530–31 (Abs L4).
Acknowledgements Funded by MedImmune.
Disclosure of Interest C. Morehouse Shareholder of: AstraZeneca, Employee of: MedImmune, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune, B. Higgs Shareholder of: AstraZeneca, Employee of: MedImmune, B. Zheng Employee of: MedImmune, Y. Yao Shareholder of: AstraZeneca, Employee of: MedImmune, L. Roskos Shareholder of: AstraZeneca, Employee of: MedImmune, G. Robbie Shareholder of: AstraZeneca, Employee of: MedImmune
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