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Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of ASP2408, a Potent Selective T‐Cell Costimulation Modulator After Single and Multiple Ascending Doses in Healthy Volunteers and RA Patients
Author(s) -
Zhu Tong,
Keirns James,
Howieson Corrie,
Kaibara Atsunori,
Goldwater Ronald,
Kivitz Alan J.,
Chindalore Vishala,
Cohen Stanley,
Santos Vicki,
Akinlade Bolanle,
Kernstock Robert,
DelgadoHerrera Leticia,
Blahunka Paul C,
Karrer Erik E.,
Garg Jay P.,
Samberg Nancy,
Zeiher Bernhardt G.
Publication year - 2016
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.251
Subject(s) - medicine , pharmacodynamics , tolerability , pharmacology , pharmacokinetics , rheumatoid arthritis , dosing , bioavailability , adverse effect
ASP2408 is a next‐generation anti–cytotoxic T lymphocyte antigen‐4 fusion protein engineered for improved CD86 binding affinity as a treatment for rheumatoid arthritis (RA). In 72 healthy subjects (n = 6/treatment), ASP2408 was administered as single ascending doses intravenously at 0.003 to 10.0 mg/kg or subcutaneously at 0.3 to 3.0 mg/kg. It showed decreased clearance and prolonged half‐life with increasing doses, consistent with target‐mediated disposition. The apparent bioavailability was 36.3%–56.7% across single subcutaneous doses. Sixteen RA patients (n = 8/treatment) on stable methotrexate received 3 × 3.0 mg/kg subcutaneously every 4 weeks or every 2 weeks. Similar to single‐dose treatment, ASP2408 concentrations peaked 2 to 3 days postdose, with a median t 1/2 of approximately 8 days. Using CD86 receptor occupancy (RO) as a mechanistic biomarker, ASP2408 demonstrated dose‐dependent binding to its target. ASP2408 3.0 mg/kg subcutaneously every 4 weeks and every 2 weeks led to a mean %CD86 RO ≥ 74.7% and ≥ 81.5%, respectively, within each dosing interval. ASP2408 was well tolerated across studies with no evidence of dose‐limiting toxicity or clinically significant changes in clinical laboratory test results, vital signs, or 12‐lead electrocardiograms. ASP2408 elicited antidrug antibodies in the majority of patients, but with no clinical sequelae.