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

Chen, Xia; Hou, Yong; Jiang, Ji; Zhao, Qian; Zhong, Wen; Wang, Wenxiang; Yao, Xiaobo; Lin, Liang-In; Fang, Jianmin; Zhang, Fengchun; Hu, Pei

doi:10.1007/s40262-014-0175-9

Cited by 15 publications

(41 citation statements)

References 24 publications

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“…The implication of APRIL in B cell-mediated autoimmune diseases led to the recent development of atacicept and other drugs currently in the research stage 47 . Atacicept antagonizes APRIL as well as another cytokine, B cell activating factor (BAFF), and is currently in phase III clinical trials for the treatment of SLE 48 .…”

Section: Discussionmentioning

confidence: 99%

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Surface APRIL Is Elevated on Myeloid Cells and Is Associated with Disease Activity in Patients with Rheumatoid Arthritis

Weldon

Moldovan²,

Cabling³

et al. 2015

J Rheumatol

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Objective To assess surface APRIL (a proliferation-inducing ligand; CD256) expression by circulating myeloid cells in rheumatoid arthritis (RA) and to determine its relationship to disease activity. Methods Peripheral blood mononuclear cells (PBMC) and plasma were obtained from patients with RA and healthy donors. PBMC were stained for flow cytometry to detect surface APRIL and blood cell markers to identify circulating myeloid cell subsets. Based on CD14 and CD16 phenotypes, monocyte subsets described as classical (CD14+CD16−), intermediate (CD14+CD16+), and nonclassical (CD14loCD16+) were identified. Levels of surface APRIL expression were measured by flow cytometry and median fluorescence intensity was used for comparisons. Levels of soluble APRIL in the plasma were determined by ELISA. Disease activity was measured by the Disease Activity Score in 28 joints. Results In patients with RA, total myeloid cells showed expression of surface APRIL that correlated with disease activity and with plasma APRIL levels observed in these patients. In healthy donors, classical monocytes were composed of > 80% of circulating monocytes. However, in patients with RA, the intermediate and nonclassical subsets were elevated and made up the majority of circulating monocytes. In contrast to healthy donors, where high levels of surface APRIL were only observed in nonclassical monocytes, patients with RA showed high levels of surface APRIL expression by all circulating monocyte subsets. Conclusion Surface APRIL is elevated in circulating myeloid cells in patients with RA where it is highly correlated with disease activity. Patients with RA also showed skewing of monocytes toward subsets associated with secretion of tumor necrosis factor-α and/or interleukin 1β.

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Section: Discussionmentioning

confidence: 99%

“…Our findings suggest that surface APRIL could provide an easily detectable biomarker and be a useful selection criterion for the administration of atacicept. Surface APRIL expression, together with monocyte subset skewing, might provide a prognostic indicator of patient response to atacicept or other drugs that target APRIL 47 .…”

Section: Discussionmentioning

confidence: 99%

Surface APRIL Is Elevated on Myeloid Cells and Is Associated with Disease Activity in Patients with Rheumatoid Arthritis

Weldon

Moldovan²,

Cabling³

et al. 2015

J Rheumatol

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“…PK samples were analyzed using a validated ELISA method with a lower limit of quantification (LLOQ) of 15 ng ml ‐1 for free and total RCT‐18 and a LLOQ of 20 ng ml ‐1 for RCT‐18‐BLyS complex .…”

Section: Methodsmentioning

confidence: 99%

“…RCT‐18 is currently under clinical development. A first‐in‐human single ascending dose (SAD) study has been completed in 28 Chinese RA patients . The results suggest good safety and tolerability of RCT‐18 at subcutaneous doses up to 540 mg.…”

Section: Introductionmentioning

confidence: 99%

“…In a 52 week open label study with tabalumab, maintenance of IgM reduction was observed for at least 30 weeks after the last drug administration, although the maximum effect size on IgM was smaller than that of atacicept . As robust IgM reduction does not seem to be linked to clinical efficacy of these BLyS‐targeting agents and excessive IgM depression was found accompanied with severe infections , the highest dose of RCT‐18 (540 mg) investigated in the SAD study was not selected for this multiple dose study. Instead, 180 mg RCT‐18 and 360 mg RCT‐18 were recognized previously as the pharmacodynamically effective doses based on their effects on the ratio of IgM : IgG and were employed in the present study.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics, pharmacodynamics, short term efficacy and safety of RCT‐18, a novel BLyS/APRIL fusion protein, in patients with rheumatoid arthritis

Xia

Zhao

Hou

et al. 2016

Brit J Clinical Pharma

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AIMRCT-18 is a recombinant fusion protein that interferes with the selection and survival of mature B-lymphocytes by inhibiting B-lymphocyte stimulator and a proliferation-inducing ligand. METHODSThis single blind, randomized, placebo controlled, clinical pharmacological study explored the short term efficacy and safety of RCT-18 in 21 rheumatoid arthritis (RA) patients with three different dosing regimens. The pharmacological behaviour of RCT-18 was also characterized through a six level biomarker cascade approach to identify potential predictors for clinical responses. RESULTSNine out of 10 patients (>80%) experienced moderate to good EULAR response at the end of 3 months with once or twice weekly doses of 180 mg RCT-18, whereas weekly administration of 360 mg RCT-18 or placebo, however, only resulted in moderate improvement in one patient in each group. Absence of IgM-type rheumatoid factor reduction, recovery of IgM 2 weeks after drug cessation, lack of decrease in the count of CD27(+) B-lymphocytes and a DAS28 change from baseline <6 in 4-6 weeks after the treatment initiation may indicate poor clinical response. No anti-drug antibody of RCT-18 was detected. The active treatments were well tolerated, although more mild to moderate infections were reported in patients receiving RCT-18. CONCLUSIONThe study results support further development of RCT-18 in RA patients and provide important information for future dose selection. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The B lymphocyte stimulator (BLyS) family ligands and receptors are critical players in the selection and survival of most mature B lymphocytes.• As a BLyS-targeting recombinant fusion protein, antacicept was found to be ineffective for active RA patients who responded inadequately to MTX or a TNF-α inhibitor, despite of its pharmacodynamic effects on IgM, IgG and IgA levels.• RCT-18 has been investigated in a single ascending dose study. The doses of 180 mg and 360 mg were shown to be pharmacodynamically active based on their effects on the ratio of IgM : IgG, while the dose of 540 mg was associated with an IgMsuppressing effect similar to those reported with atacicept. WHAT THIS STUDY ADDS• RCT-18 statistically significantly reduced DAS28 score with a weekly injection of 180 mg for 3 successive weeks or twice weekly injection of 180 mg for eight times, but caused little clinical improvement with weekly injections of 360 mg for five times.• The biomarker cascade approach of this study may serve as the basis for establishing a quantitative relationship between the pharmacological effects of RCT-18 or other BLyS and/or APRIL targeting drugs and their clinical behaviours.

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Pharmacokinetic Characteristics, Safety, and Tolerability of Telitacicept, an Injectable Recombinant Human B‐Lymphocyte Stimulating Factor Receptor‐Antibody Fusion Protein, in Healthy Chinese Subjects

Xie

Fan

et al. 2022

Clinical Pharm in Drug Dev

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Telitacicept, an injectable recombinant human B‐lymphocyte stimulating factor receptor‐antibody fusion protein, is a new dual B lymphocyte stimulator (BLyS)/APRIL (a proliferation‐inducing ligand) inhibitor that effectively blocks proliferation of B lymphocytes. This study evaluates the pharmacokinetic characteristics, tolerability, and safety of a single subcutaneous injection of various doses (80, 160, and 240 mg) of telitacicept in healthy Chinese subjects. This trial is a single‐center, randomized, open‐label phase I clinical study that includes three dose groups (80, 160, and 240 mg) with 12 subjects in each dose group. The subjects were randomly assigned to different dose groups in a 1:1:1 ratio for a single subcutaneous administration trial. After a single dose, the maximum serum concentration (Cmax) of total and free telitacicept was reached within 0.5‐1 days. The elimination half‐lives of total and free telitacicept at doses of 80–240 mg were 10.9–11.9 days and 11–12.5 days, respectively. The formation and elimination of the BLyS‐telitacicept complex were much slower; the median time to Cmax was 15–57 days and was significantly prolonged with increasing dose. Only two of the 36 healthy subjects had positive antidrug antibodies with antibody titers of 1:15. The severity of adverse events was mild or moderate, and no higher treatment‐emergent adverse events were reported. In conclusion, total telitacicept within a dose range of 80–240 mg and free telitacicept within a dose range of 160–240 mg had linear pharmacokinetic characteristics.

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

Cited by 15 publications

References 24 publications

Surface APRIL Is Elevated on Myeloid Cells and Is Associated with Disease Activity in Patients with Rheumatoid Arthritis

Surface APRIL Is Elevated on Myeloid Cells and Is Associated with Disease Activity in Patients with Rheumatoid Arthritis

Pharmacokinetics, pharmacodynamics, short term efficacy and safety of RCT‐18, a novel BLyS/APRIL fusion protein, in patients with rheumatoid arthritis

Pharmacokinetic Characteristics, Safety, and Tolerability of Telitacicept, an Injectable Recombinant Human B‐Lymphocyte Stimulating Factor Receptor‐Antibody Fusion Protein, in Healthy Chinese Subjects

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