Background/Purpose: Joint synovium is the main tissue involved in rheumatoid arthritis (RA) lesions. Alpha9 integrin is expressed by synovial tissue lining cells and has been identified as a putative key molecule in the development and exacerbation of RA (Kanayama et al. 2009). ASP5094 is a recombinant humanized anti-human alpha9 integrin IgG1 monoclonal antibody under development for the treatment of RA. A first-in-human study in healthy subjects has demonstrated that single intravenous (IV) ASP5094 doses up to 10 mg/kg had an acceptable safety profile and were well tolerated. The purpose of this study was to establish the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics of ASP5094 in patients with RA on methotrexate (MTX).

Methods: Patients (aged 18–65 years) with RA on a stable regimen (10–25 mg/week) of MTX were eligible for this phase 1, randomized, placebo-controlled, multiple ascending-dose study. Eligible patients were assigned to one of three sequential cohorts to receive increasing IV doses of ASP5094 (1, 3, 10 mg/kg) or placebo every 4 weeks for a total of three doses (Day 1, 29, and 57). A total of 10 patients were assigned to each cohort and randomized 4:1 (ASP5094, n=8; placebo, n=2). The primary objectives were to evaluate the safety, tolerability, and PK of ASP5094 in patients with RA on MTX. Exploratory objectives included the pharmacodynamics of ASP5094, assessed by the alpha9 integrin receptor occupancy rate in neutrophils as a surrogate for alpha9 integrin binding in joints at the level of synoviocytes. Formation of anti-ASP5094 antibodies was assayed using a validated method.

Results: At all dose levels, ASP5094 was well tolerated. No difference was observed between treatment groups in either the nature or frequency of treatment-emergent adverse events (TEAEs) or TEAEs considered related to ASP5094, and no dose-response relationship was observed. Two patients permanently discontinued the study due to possible treatment-related AEs: one patient treated with ASP5094 (1 mg/kg) discontinued due to a mild, intermittent tremor. The other patient, treated with placebo, discontinued due to a mild second-degree atrioventricular block, which resolved the same day. Pharmacokinetic steady state was not reached after three administrations of ASP5094 (regardless of dose level) because of slow elimination. ASP5094 exhibited nonlinear, target-mediated drug disposition pharmacokinetics. A trend of dose-dependent increase in receptor occupancy was observed. Median receptor occupancy was >90% for all ASP5094 doses on Day 1 and was maintained at >80% for approximately 2 weeks after each dose within 1 mg/kg dose cohort. For doses of 3 and 10 mg/kg, median receptor occupancy was maintained by >80% throughout the treatment period until Day 85 and Day 141, respectively. No patient had confirmed positive titers for anti-ASP5094 antibodies.

Conclusion: In this study, multiple IV doses of ASP5094 had an acceptable safety profile and were well tolerated in patients with RA on stable doses of MTX. ASP5094 exhibited a nonlinear PK disposition and demonstrated dose-dependent, high, and prolonged neutrophil alpha9 integrin receptor occupancy rates.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/multiple-dose-safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-asp5094-an-anti-alpha9-integrin-monoclonal-antibody-in-patients-with-rheumatoid-arthritis-on-methotrexate/