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Rozanolixizumab is a fully humanized high‐affinity anti‐human neonatal Fc receptor (FcRn) monoclonal antibody (mAb) that accelerates the removal of circulating immunoglobulin G (IgG), including pathogenic IgG autoantibodies, via the natural lysosomal degradation pathway. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model characterizing the effect of rozanolixizumab on IgG levels in cynomolgus monkeys, translate it into humans to support the first‐in‐human (FIH) rozanolixizumab clinical trial study design, and, ultimately, develop a PK/PD model in humans. Simulations from the preclinical model were performed to predict IgG responses in humans and select clinically relevant doses in the FIH study. Good alignment was observed between predicted and observed reductions in IgG, which increased with increasing dose in the FIH study. The model successfully described the PK of the 4 and 7 mg/kg intravenous (i.v.) dose groups, although the PKs were underpredicted for the 1 mg/kg i.v. dose group. Updating the model with subsequent human data identified parameters that deviated from preclinical assumptions. The updated PK/PD model was able to effectively characterize the PK FcRn‐IgG nonlinear system in response to rozanolixizumab in the FIH data.

Rozanolixizumab (UCB7665), a humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (IgG4P), has been developed to reduce pathogenic IgG in autoimmune and alloimmune diseases. We document the antibody isolation and compare rozanolixizumab with the same variable region expressed in various mono-, bi- and trivalent formats. We report activity data for rozanolixizumab and the different molecular formats in human cells, FcRn-transgenic mice, and cynomolgus monkeys. Rozanolixizumab, considered the most effective molecular format, dose-dependently and selectively reduced plasma IgG concentrations in an FcRn-transgenic mouse model (no effect on albumin). Intravenous (IV) rozanolixizumab dosing in cynomolgus monkeys demonstrated non-linear pharmacokinetics indicative of target-mediated drug disposition; single IV rozanolixizumab doses (30 mg/kg) in cynomolgus monkeys reduced plasma IgG concentration by 69% by Day 7 post-administration. Daily IV administration of rozanolixizumab (initial 30 mg/kg loading dose; 5 mg/kg daily thereafter) reduced plasma IgG concentrations in all cynomolgus monkeys, with low concentrations maintained throughout the treatment period (42 days). In a 13-week toxicology study in cynomolgus monkeys, supra-pharmacological subcutaneous and IV doses of rozanolixizumab (≤ 150 mg/kg every 3 days) were well tolerated, inducing sustained (but reversible) reductions in IgG concentrations by up to 85%, with no adverse events observed. We have demonstrated accelerated natural catabolism of IgG through inhibition of IgG:FcRn interactions in mice and cynomolgus monkeys. Inhibition of FcRn with rozanolixizumab may provide a novel therapeutic approach to reduce pathogenic IgG in human autoimmune disease. Rozanolixizumab is being investigated in patients with immune thrombocytopenia (NCT02718716) and myasthenia gravis (NCT03052751).

Objectives: This 12-week, randomized, double-blind, placebo-controlled, multicenter phase 1/2 study (NCT01449071) assessed the safety, pharmacokinetics, and pharmacodynamics of epratuzumab in Japanese patients with moderate-to-severe systemic lupus erythematosus despite standard of care.Methods: Twenty patients were randomized 1:1:1:1:1 to placebo or one of four epratuzumab dose regimens (100 mg every other week [Q2W], 400 mg Q2W, 600 mg every week [QW], or 1200 mg Q2W) administered during an initial 4-week dosing period. Adverse events (AEs), pharmacokinetics and pharmacodynamics were assessed.Results: Nineteen of 20 patients completed the study. All placebo patients and 13 of 16 epratuzumab patients reported ≥1 AE, 2 of 16 epratuzumab patients reported a serious AE. Cmax and AUCτ increased proportionally with dose after first and last infusion, t1/2 was similar across groups (∼13 days). Epratuzumab treatment was associated with decreased CD22 mean fluorescence intensity in total B cells (CD19+CD22+) and unswitched memory B cells (CD19+IgD+CD27+). Small-to-moderate decreases were observed in total B cell (CD20+) count.Conclusions: Epratuzumab was well-tolerated, with no new safety signals identified. The pharmacokinetics appeared linear after first and last infusions. Treatment with epratuzumab was associated with CD22 downregulation and with small-to-moderate decreases in total B cell count.

Pathogenic immunoglobulin G (IgG) autoantibodies characterize some human autoimmune diseases; their high concentration and long half-life are dependent on recycling by the neonatal Fc receptor (FcRn). Inhibition of FcRn is an attractive new treatment concept for IgG-mediated autoimmune diseases. Rozanolixizumab (UCB7665; CA170_01519.g57 IgG4P) is an anti-human FcRn monoclonal antibody. In cynomolgus monkeys, rozanolixizumab reduced IgG (maximum 75 to 90% by about day 10), was well tolerated, and did not increase risk of infection. We also report a first-in-human, randomized, double-blind, placebo-controlled, dose-escalating study of intravenous (IV) or subcutaneous (SC) rozanolixizumab in healthy subjects (NCT02220153). The primary objective was to evaluate safety and tolerability. Secondary objectives were assessment of rozanolixizumab pharmacokinetics and pharmacodynamics, including effects on circulating IgG concentrations. Forty-nine subjects were randomized to receive rozanolixizumab (n = 36) or placebo (n = 13) across six cohorts. The first three cohorts received IV doses, and the subsequent three cohorts received SC doses, of rozanolixizumab 1, 4, or 7 mg/kg (n = 6 for each cohort; plus n = 7 or 6 for placebo, respectively). The most frequent treatment-emergent adverse event [TEAE; headache, 14 of 36 (38.9%) subjects] was dose-dependent and more prominent after IV administration. Severe TEAEs occurred in four subjects, all in the highest-dose IV group [headache (n = 3) and back pain (n = 1)]. Rozanolixizumab pharmacokinetics demonstrated nonlinear increases with dose. There were sustained dose-dependent reductions in serum IgG concentrations (IV and SC rozanolixizumab). These data provide clinical evidence for the therapeutic potential of rozanolixizumab.

The aim of this study was to quantify the intestinal and hepatic first-pass loss of saquinavir and to assess the effect of coadministration of ritonavir on this first-pass loss. Single doses of 12, 24, and 48 mg of saquinavir and a dose of 24 mg of saquinavir/6 mg of ritonavir were orally, intravenously, or intraperitoneally administered to 94 rats. Ten groups of animals were studied. A semiphysiological pharmacokinetic model incorporating a population pharmacokinetic analysis [nonlinear mixed-effects model (NONMEM)] was developed to analyze plasma concentration-time profiles after administration via each of the three above-mentioned routes. This model confirmed that saturable metabolism in hepatocytes and enterocytes and dose-dependent precipitation in the peritoneal cavity after intraperitoneal administration characterize the pharmacokinetics of SQV. It also demonstrated that low oral bioavailability of saquinavir is due mainly to intestinal rather than to hepatic first-pass metabolism. In addition, it was shown that ritonavir diminished saquinavir clearance through competitive inhibition. The present report presents a new pharmacokinetic model applied in rats to evaluate the impact of hepatic and intestinal first-pass loss on oral bioavailability.

Background 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. Objectives 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. Methods 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. Results 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 max and AUC τ increased proportionally to dose (Table). t 1/2 was approximately 13 days and similar across groups. No pts were HAHA positive during the study (antibody concentration >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. Conclusions 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. Acknowledgements The authors acknowledge Costello Medical Consulting for writing and editorial assistance which was funded by UCB Pharma. Disclosure of Interest 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 DOI 10.1136/annrheumdis-2014-eular.1754