BACKGROUND AND OBJECTIVES:RCT-18 is a novel recombinant fusion protein that targets and neutralizes B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL). This first in-human study investigated the safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of RCT-18 in patients with rheumatoid arthritis (RA). METHODS: This was a single-center, randomized, single-blind, placebo-controlled study in 28 RA patients. Eligible patients were randomized 3:1 to receive single subcutaneous doses of RCT-18 (1.2, 6, 18, 60, 180, 360, 540 mg) or placebo. A 71-day observation period was scheduled for each patient, during which serial blood sampling for pharmacokinetic, pharmacodynamic, and immunogenicity assessments was performed. Safety was assessed throughout the study. RESULTS:RCT-18 was well tolerated, although mild infections and skin irritation occurred more frequently in patients receiving this drug. After single-dose RCT-18, the maximal serum concentration (C max) of total and free RCT-18 was reached within 1-2 days, followed by a multi-exponential decline. Mean elimination half-life for total RCT-18 and free RCT-18 was 5.7-12.8 days and 3.2-11.3 days at 6-60 mg, and 15.1-17.5 days and 18.8-36.8 days with 180-540 mg RCT-18. The formation and elimination of BLyS-RCT-18 complex were much slower, with a time to C max of 5-29 days and the elimination half-life mounting from 13.3 to 32.8 days with dose escalation. No positive reaction was detected in the immunogenicity assessments. Substantial IgM reduction was only evidenced with 540 mg RCT-18, while the response profiles of IgM/IgG were distinguishable from placebo after 180, 360, or 540 mg RCT-18. CONCLUSION:RCT-18 was safe and well tolerated up to 540-mg single doses. The serum exposure of total and free RCT-18 is linearly correlated to the weight-normalized doses of RCT-18 in dose groups receiving 180-540 mg RCT-18. The elimination half-life of BLyS-RCT-18 increased with RCT-18 doses, suggesting a shift from target-mediated disposition in 1.2-18 mg RCT-18 groups to non-specific clearance in 60-540 mg RCT-18 groups. Assuming the concentration of BLyS-RCT-18 complex and the IgM/IgG ratio are surrogate biomarkers for clinical effects of RCT-18, the dose-response relationship suggests 180-540 mg are pharmacodynamically effective doses in RCT-18 for RA patients, but the effect profile of 540 mg RCT-18 on IgM is similar to that of atacicept at pharmacodynamically effective but clinically ineffective doses.
RCT Entities:
BACKGROUND AND OBJECTIVES: RCT-18 is a novel recombinant fusion protein that targets and neutralizes B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL). This first in-human study investigated the safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of RCT-18 in patients with rheumatoid arthritis (RA). METHODS: This was a single-center, randomized, single-blind, placebo-controlled study in 28 RApatients. Eligible patients were randomized 3:1 to receive single subcutaneous doses of RCT-18 (1.2, 6, 18, 60, 180, 360, 540 mg) or placebo. A 71-day observation period was scheduled for each patient, during which serial blood sampling for pharmacokinetic, pharmacodynamic, and immunogenicity assessments was performed. Safety was assessed throughout the study. RESULTS: RCT-18 was well tolerated, although mild infections and skin irritation occurred more frequently in patients receiving this drug. After single-dose RCT-18, the maximal serum concentration (C max) of total and free RCT-18 was reached within 1-2 days, followed by a multi-exponential decline. Mean elimination half-life for total RCT-18 and free RCT-18 was 5.7-12.8 days and 3.2-11.3 days at 6-60 mg, and 15.1-17.5 days and 18.8-36.8 days with 180-540 mg RCT-18. The formation and elimination of BLyS-RCT-18 complex were much slower, with a time to C max of 5-29 days and the elimination half-life mounting from 13.3 to 32.8 days with dose escalation. No positive reaction was detected in the immunogenicity assessments. Substantial IgM reduction was only evidenced with 540 mg RCT-18, while the response profiles of IgM/IgG were distinguishable from placebo after 180, 360, or 540 mg RCT-18. CONCLUSION: RCT-18 was safe and well tolerated up to 540-mg single doses. The serum exposure of total and free RCT-18 is linearly correlated to the weight-normalized doses of RCT-18 in dose groups receiving 180-540 mg RCT-18. The elimination half-life of BLyS-RCT-18 increased with RCT-18 doses, suggesting a shift from target-mediated disposition in 1.2-18 mg RCT-18 groups to non-specific clearance in 60-540 mg RCT-18 groups. Assuming the concentration of BLyS-RCT-18 complex and the IgM/IgG ratio are surrogate biomarkers for clinical effects of RCT-18, the dose-response relationship suggests 180-540 mg are pharmacodynamically effective doses in RCT-18 for RApatients, but the effect profile of 540 mg RCT-18 on IgM is similar to that of atacicept at pharmacodynamically effective but clinically ineffective doses.
Authors: Y Wu; D Bressette; J A Carrell; T Kaufman; P Feng; K Taylor; Y Gan; Y H Cho; A D Garcia; E Gollatz; D Dimke; D LaFleur; T S Migone; B Nardelli; P Wei; S M Ruben; S J Ullrich; H S Olsen; P Kanakaraj; P A Moore; K P Baker Journal: J Biol Chem Date: 2000-11-10 Impact factor: 5.157
Authors: D Wang; Y Chang; Y Wu; L Zhang; S Yan; G Xie; Q Qin; J Jin; W Wang; J Fang; W Wei Journal: Clin Exp Immunol Date: 2010-12-13 Impact factor: 4.330
Authors: P P Tak; R M Thurlings; C Rossier; I Nestorov; A Dimic; V Mircetic; M Rischmueller; E Nasonov; E Shmidt; P Emery; A Munafo Journal: Arthritis Rheum Date: 2008-01
Authors: Richard Furie; William Stohl; Ellen M Ginzler; Michael Becker; Nilamadhab Mishra; Winn Chatham; Joan T Merrill; Arthur Weinstein; W Joseph McCune; John Zhong; Wendy Cai; William Freimuth Journal: Arthritis Res Ther Date: 2008-09-11 Impact factor: 5.156