A Phase 1 Dose-Escalation Study of ASP2409, a Selective T-Cell Costimulation Inhibitor, in Stable Rheumatoid Arthritis Patients on Methotrexate Therapy

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• 作者：Wenhui Zhang ; Robert M. Kernstock ; Erik E. Karrer ; Stanley B. Cohen ; Vishala L. Chindalore ; Alan J. Kivitz ; Paul C. Blahunka ; Leticia Delgado-Herrera ; Bernhardt G. Zeiher ; Nancy L. Samberg and Jay P. Garg
• 刊名：Clinical Pharmacology in Drug Development
• 出版年：2016
• 出版时间：July/August 2016
• 年：2016
• 卷：5
• 期：4
• 页码：259-268
• 全文大小：325K
• ISSN：2160-7648

文摘

ASP2409 represents a new class of CTLA4-Ig molecules with higher binding avidity and selectivity to CD86. This first-in-human study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of ASP2409 in stable rheumatoid arthritis patients on methotrexate therapy with a randomized, double-blind, placebo-controlled dose-escalation study design. Patients were enrolled and randomized in each of 8 dose-escalation cohorts ranging from 0.001 to 3.0 mg/kg to receive either ASP2409 or placebo in a sequential manner. Escalation to higher dose levels occurred in the absence of dose-limiting toxicity. A total of 57 patients completed the study. ASP2409 showed nonlinear PK over the dose range of 0.01 to 3.0 mg/kg following a single intravenous administration, indicating target-mediated drug disposition. Area under the concentration–time curve (AUC) and maximum concentration (C_max) increased at a greater than dose-proportional rate. The half-life of ASP2409 increased dose dependently and ranged from 1.57 to 6.68 days. ASP2409 showed a dose-dependent increase in the extent and duration of CD86 receptor occupancy. There were no clinically relevant safety issues up to a single dose of 3.0 mg/kg. No maximum tolerated dose was reached. The incidence and duration of antidrug antibodies did not correlate with adverse events. ClinicalTrials.gov identifier: NCT02171143