Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis.

Autor:	Boedigheimer MJ; Amgen Inc., Thousand Oaks, California, USA., Martin DA; Amgen Inc., Seattle, Washington, USA., Amoura Z; French National Reference Center for SLE, Hôpital Pitié-Salpêtrière, Paris, France., Sánchez-Guerrero J; Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico., Romero-Diaz J; Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico., Kivitz A; Altoona Center for Clinical Research, Duncansville, Pennsylvania, USA., Aranow C; Feinstein Institute for Medical Research, Manhasset, USA., Chan TM; Queen Mary Hospital, University of Hong Kong, Hong Kong., Chong YB; University Malaya Medical Centre, Kuala Lumpur, Malaysia., Chiu K; Amgen Inc., Thousand Oaks, California, USA., Wang C; Amgen Inc., Thousand Oaks, California, USA., Sohn W; Amgen Inc., Thousand Oaks, California, USA., Arnold GE; Amgen Inc., Thousand Oaks, California, USA., Damore MA; Amgen Inc., Thousand Oaks, California, USA., Welcher AA; Amgen Inc., Thousand Oaks, California, USA., Sullivan BA; Amgen Inc., Thousand Oaks, California, USA., Kotzin BL; Amgen Inc., Thousand Oaks, California, USA., Chung JB; Amgen Inc., Thousand Oaks, California, USA.
Jazyk:	angličtina
Zdroj:	Lupus science & medicine [Lupus Sci Med] 2017 Sep 14; Vol. 4 (1), pp. e000226. Date of Electronic Publication: 2017 Sep 14 (Print Publication: 2017).
DOI:	10.1136/lupus-2017-000226
Abstrakt:	Objective: To evaluate safety, pharmacokinetics and pharmacodynamics of anti-interferon (IFN)-γ monoclonal antibody AMG 811 in subjects with SLE without or with lupus nephritis (LN). Methods: In this phase Ib, randomised, multiple-dose escalation study (NCT00818948), subjects without LN were randomised to subcutaneous AMG 811 (6, 20 or 60 mg) or placebo and subjects with LN were randomised to subcutaneous AMG 811 (20, 60 or 120 mg) or placebo every four weeks for three total doses. Outcomes included incidence of adverse events (AEs); pharmacokinetics; levels of serum proteins (CXCL-10, interleukin 18, monocyte chemotactic protein-1); changes in gene transcript profiles and clinical parameters (Safety of Estrogen in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores, proteinuria, anti-double-stranded DNA (anti-dsDNA) antibodies, C3 complement, C4 complement). Results: Fifty-six subjects enrolled (28 SLE without LN; 28 with LN). Baseline mean SELENA-SLEDAI scores were 2.2 and 12.0 for SLE subjects without and with LN, respectively. Most subjects reported an AE; no meaningful imbalances were observed between AMG 811 and placebo. Pharmacokinetic profiles were similar and mostly dose-proportional in subjects without or with LN. AMG 811 treatment reduced CXCL-10 protein levels and blood-based RNA IFN-γ Blockade Signature compared with placebo. Reductions were less pronounced and not sustained in subjects with LN, even at the highest dose tested, compared with subjects without LN. No effect on SELENA-SLEDAI scores, proteinuria, C3 or C4 complement levels, or anti-dsDNA antibodies was observed. Conclusion: AMG 811 demonstrated favourable pharmacokinetics and acceptable safety profile but no evidence of clinical impact. IFN-γ-associated biomarkers decreased with AMG 811; effects were less pronounced and not sustained in LN subjects. Trial Registration Number: NCT00818948; results.
Databáze:	MEDLINE
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