1. 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
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Zhu, Tong, Keirns, James, Howieson, Corrie, Kaibara, Atsunori, Goldwater, Ronald, Kivitz, Alan J., Chindalore, Vishala, Cohen, Stanley, Santos, Vicki, Akinlade, Bolanle, Kernstock, Robert, Delgado‐Herrera, Leticia, Blahunka, Paul C, Karrer, Erik E., Garg, Jay P., Samberg, Nancy, and Zeiher, Bernhardt G.
- Subjects
PHARMACODYNAMICS ,PHARMACOKINETICS ,RHEUMATOID arthritis treatment ,MEDICATION safety ,DRUG tolerance ,CHIMERIC proteins ,CD86 antigen - Abstract
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. [ABSTRACT FROM AUTHOR]- Published
- 2016
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