Pharmacokinetics and immunogenicity of T0001, a newly developed anti-TNF alpha fusion protein, in healthy volunteers

Purpose T0001 was the first mutant of recombinant fusion protein of human tumor necrosis factor receptor and Fc fragment (rhTNFR:Fc) based on etanercept on a global scale. This study was carried out to investigate the pharmacokinetics (PK) and immunogenicity of T0001 in healthy Chinese volunteers. Methods This study was randomized, with a single ascending dose, and the first-in-human clinical trial of T0001. Healthy Chinese volunteers (n = 56; male: female = 1:1) were randomly assigned to receive a single subcutaneous (sc) injection of 10, 20, 35, 50, 65 or 75 mg of T0001. Blood samples were collected at designated time points after sc injection to assess immunogenicity and pharmacokinetics of T0001. Result During the study, no serious adverse events were observed. T0001 was slowly absorbed with a median T-max of 84 h and slowly eliminated with a T-1/2Z of 42.1-58.2 h. In the dose-exposure proportionality analysis, the estimated points for AUC(0-a) and C-max were 0.87 with a 90% CI of 0.76-0.98 and 0.86 with a 90% CI of 0.74-0.97 respectively. The plasma concentration of free (unbound T0001) plasma TNF alpha and total (bound and unbound T0001) TNF alpha both increased significantly after the injection of T0001. Ten out of 56 volunteers (17.9%) tested positive for anti-drug antibodies (ADAs) at a low level. Conclusions T0001 was safe and well-tolerated at doses up to 75 mg. C-max and AUC(0-infinity) had an increasing tendency with dose levels, but we could not conclude that T0001 has linear PK properties in this study.Major Project of National Science and Technology "Creation of Major New Drugs" [2009ZX090503012]; Shanghai Fudan-zhangjiang Bio-Pharmaceutical Co. Ltd. (Shanghai, China)SCI(E)ARTICLE91095-11017