Background/Purpose:  ASP5094 is a recombinant humanized anti-alpha-9 integrin IgG1 monoclonal antibody (mAb) under development for the treatment of rheumatoid arthritis. This first-in-human placebo‑controlled single ascending‑dose study was designed to evaluate the safety, tolerability, PK and PD of a single 30 minute intravenous (IV) infusion of ASP5094 at doses ranging from 0.002 to 10 mg/kg in healthy adult subjects.

Methods:  7 sequential cohorts consisting of any race (cohorts A to D) and non-Asian (cohorts E to G) received single increasing doses of IV administered ASP5094 or placebo. Serial Cohorts A and B consisted of 6 subjects each (4 active and 2 placebo) while cohorts C to G consisted of 8 subjects each (6 active and 2 placebo). Serial blood samples were collected for PK (ASP5094 and anti-ASP5094) and PD (alpha-9- integrin receptor occupancy (RO)).

Results: Following a 30-minute infusion of ASP5094 at doses <0.25 mg/kg most serum ASP5094 concentrations fell below the limit of detection (10 ng/mL). At doses that ranged from 0.25-10 mg/kg, mean maximum ASP5094 serum concentrations (C_max) increased nonlinearly with dose and ranged from 4742 to 277365 ng/mL. Similarly, mean ASP5094 AUC_0-infalso increased nonlinearly from 165,455 to 77,829,650 ng*h/mL with ASP5094 doses ranging from 0.25 to 10 mg/kg. ASP5094 PK exhibited nonlinear target-mediated drug disposition. Alpha-9 receptor occupancy (RO) on neutrophils remained at 100% for periods of 1, 2, 4 and 8 weeks following a single IV administration at doses of 0.25, 1, 3 and 10 mg/kg ASP5094 respectively. A direct response relationship was observed between serum ASP5094 exposure and RO. One subject dosed at 0.25 mg/kg with ASP5094 tested positive for anti-drug antibodies (ADA) on Day 90 and remained positive throughout study. The last study visit was Day 360. Drug-related adverse events (AE) were reported in 16.7% of the 0.25 mg/kg dose cohort; 33.3% of the 1 mg/kg cohort; 50% of the 3 mg/kg cohort; and 16.7% of the 10 mg/kg cohort, with no dose-dependency. There were no clinically significant abnormal ECG findings in this study.

Conclusion:  Single doses of ASP5094 (≤ 10 mg/kg IV) were safe and well tolerated in healthy subjects (any race and non-Asian). ASP5094 PK exhibited nonlinear target-mediated drug disposition. Based on these results, an additional study to explore the PK, PD and safety of multiple doses of ASP5094 in stable RA patients has been initiated.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pharmacokinetics-pk-pharmacodynamics-pd-and-safety-of-asp5094-an-anti-alpha-9-integrin-monoclonal-antibody-following-single-intravenous-doses-in-healthy-subjects/