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

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 (Cmax) 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