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

AIM: RCT-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. METHODS: This 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. RESULTS: Nine 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. CONCLUSION: The study results support further development of RCT-18 in RA patients and provide important information for future dose selection.

Pharmacokinetics, pharmacodynamics, and tolerability of single ascending doses of RCT-18 in Chinese patients with rheumatoid arthritis.

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.