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
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- 作者：Tong Zhu ; James Keirns ; Corrie Howieson ; Atsunori Kaibara ; Ronald Goldwater ; Alan J. Kivitz ; Vishala Chindalore ; Stanley Cohen ; Vicki Santos ; Bolanle Akinlade ; Robert Kernstock ; Leticia Delgado-Herrera ; Paul C Blahunka ; Erik E. Karrer ; Jay P. Garg ; Nancy Samberg and Bernhardt G. Zeiher
- 刊名：Clinical Pharmacology in Drug Development
- 出版年：2016
- 出版时间：September/October 2016
- 年：2016
- 卷：5
- 期：5
- 页码：408-425
- 全文大小：927K
- ISSN：2160-7648
文摘
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 t1/2 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.