FRI0383 Safety, Pharmacokinetics, and Pharmacodynamics of Epratuzumab in Japanese Patients with Moderate-To-Severe Systemic Lupus Erythematosus: Results from A Phase 1/2 Study
Authors: J. Yamamoto, R. Lledo-Garcia, T. Tsuru, Y. Tanaka, T. Koike
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Treatment with epratuzumab, a humanized monoclonal antibody targeting CD22 on B cells, has been associated with improvements in disease activity in patients (pts) with moderate-to-severe systemic lupus erythematosus (SLE) with an acceptable safety/tolerability profile and moderate reductions in B cell levels. <h3>Objectives</h3> To assess safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of epratuzumab in Japanese pts with moderate-to-severe SLE in addition to standard of care treatments. <h3>Methods</h3> Japanese pts were randomized 1:1:1:1:1 to placebo (PBO) or epratuzumab (100mg/400mg/1200mg every other week [wk] [Q2W] or 600mg every wk [QW]) for a 4-wk dosing period at the beginning of the 12-wk study. Pts had moderate-to-severe SLE (BILAG A disease activity in ≥1 or BILAG B disease activity in ≥2 body systems). Levels of plasma epratuzumab, human anti-human antibodies (HAHA) to epratuzumab, B cells, T cells and mean fluorescence intensity (MFI) of B cell CD22 were measured and results summarized using descriptive statistics. PK parameters were computed by non-compartmental methods. Adverse events (AEs) and laboratory parameters were assessed. <h3>Results</h3> 19 of 20 randomized pts (95.0%) completed the study; 1 pt (1200mg Q2W group) discontinued due to an AE. PK appeared to be linear: after first and last epratuzumab infusion C<sub>max</sub> and AUC<sub>τ</sub> increased proportionally to dose (Table). t<sub>1/2</sub> was approximately 13 days and similar across groups. No pts were HAHA positive during the study (antibody concentration &gt;2-fold the limit of quantitation; 62ng/mL). There were small-to-moderate decreases in total B cell (CD20+) counts in all epratuzumab groups (median change from baseline: -43.2% to 10.0%), no trend was seen with dose or regimen. Total T cell (CD3+) counts showed no consistent trends in any treatment group. A pharmacological effect on median CD22 MFI was observed in all epratuzumab groups: Wk1 median change from baseline was -3360 to -4092 on total B cells (CD19+CD22+) and -2147 to -2805 on memory B cells (CD19+IgD+CD27+). Decreases were maintained in 400mg Q2W/1200mg Q2W/600mg QW groups whilst increasing towards baseline in the 100mg Q2W group after Wk4 (median change on memory B cells: -954 and -674 at Wks 8 and 12, respectively). All PBO pts and 13/16 epratuzumab pts reported ≥1 AE, all mild-moderate in intensity. Most commonly reported AEs were in the system organ class of infections and infestation (7/16 pts; 43.8%). Serious AEs were reported in 2/16 pts in epratuzumab treatment groups: 1 incidence each of drug hypersensitivity and Herpes zoster. Epratuzumab was well-tolerated with no new safety signals identified. <h3>Conclusions</h3> PK of epratuzumab appeared to be linear after first and last infusions in Japanese pts with moderate-to-severe SLE. Treatment with epratuzumab was associated with downregulation of CD22 as indicated by decreased CD22 MFI, with small to moderate decreases in total B cell count. Epratuzumab was well tolerated in Japanese SLE pts. <h3>Acknowledgements</h3> The authors acknowledge Costello Medical Consulting for writing and editorial assistance which was funded by UCB Pharma. <h3>Disclosure of Interest</h3> J. Yamamoto Employee of: UCB Pharma, R. Lledo-Garcia Employee of: UCB Pharma, T. Tsuru Consultant for: UCB Pharma, Y. Tanaka Grant/research support: Bristol-Myers Squibb, Mitsubishi-Tanabe, Abbvie, MSD, Chugai, Astellas, Daiichi-Sankyo, Consultant for: Abbott Japan, Abbvie, Asahi-Kasei, Astellas, Astra-Zeneca, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly Japan, GlaxoSmithKline, Janssen, Mitsubishi-Tanabe, MSD, Pfizer, Takeda, Speakers bureau: Mitsubishi-Tanabe, Eisai, Chugai, Abbott Japan, Astellas, Daiichi-Sankyo, Abbvie, Janssen, Pfizer, Takeda, Astra-Zeneca, Eli Lilly Japan, GlaxoSmithKline, Quintiles, MSD, Asahi-Kasei, T. Koike Consultant for: Abbvie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Pfizer, Santen, Taisho-Toyama, Takeda, Teijin, UCB Pharma, Speakers bureau: UCB Pharma, Pfizer, Chugai, Abbott, Mitsubishi-Tanabe, Takeda, Eisai, Santen, Astellas, Taisho-Toyama, Bristol-Myers Squibb, Teijin and Daiichi-Sankyo <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1754