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Pharmacokinetics, Pharmacodynamics, and Tolerability of Single Ascending Doses of RCT-18 in Chinese Patients with Rheumatoid Arthritis

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Abstract

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.

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Acknowledgments

We acknowledge all subjects for their contributions to the study. This study was funded by RC Biotechnologies, Ltd. Yantai, China. We acknowledge all subjects and investigators for their contributions to the study. The work of this study was supported by the National Program on Key Research Project of New Drug Innovation (No. 2012ZX09303006-002) to Pei Hu, the National High Technology Research and Development Program (863 Program) of China (No. 2012AA02A302) to Jianmin Fang, and the National Major Drug Innovation and Development Program (No. 2013ZX09401002) to Jianmin Fang and (No. 2013ZX09101019) to Wenxiang Wang.

Competing interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: at the time of study, Xia Chen, Ji Jiang, Qian Zhao, Wen Zhong, and Pei Hu were full-time employees of the Clinical Pharmacology Research Center in Peking Union Medical College Hospital, while Yong Hou and Fengchun Zhang were full-time employees of the Department of Rheumatology in Peking Union Medical College Hospital, both of whom received research support from RC Biotechnologies, Ltd. Yantai, China for the submitted work; Xia Chen, Ji Jiang, Qian Zhao, Wen Zhong, Pei Hu, Yong Hou, and Fengchun Zhang had no financial relationships with any organizations that might have an interest in the submitted work in the previous 5 years; Wenxiang Wang and Lin Li are full-time employees of RC Biotechnologies, Ltd. Yantai, China; Jianmin Fang and Xuejing Yao are employees of Tongji University and Jianmin Fang is a share-holder of RC Biotechnology. There are no other relationships or activities that have influenced the submitted work.

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Correspondence to Xia Chen, Jianmin Fang, Fengchun Zhang or Pei Hu.

Additional information

X. Chen and Y. Hou are parallel first authors; P. Hu, F. Zhang, and J. Fang are parallel correspondence authors.

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Chen, X., Hou, Y., Jiang, J. et al. Pharmacokinetics, Pharmacodynamics, and Tolerability of Single Ascending Doses of RCT-18 in Chinese Patients with Rheumatoid Arthritis. Clin Pharmacokinet 53, 1033–1044 (2014). https://doi.org/10.1007/s40262-014-0175-9

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