title: 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.
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 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.
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA. tong.zhu@astellas.com.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: James
authors.initials: J
authors.lastname: Keirns
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Corrie
authors.initials: C
authors.lastname: Howieson
authors.affiliation: Astellas Pharma, Inc, Tokyo, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kaibara
authors.affiliation: PAREXEL, Baltimore, MD, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Goldwater
authors.affiliation: Altoona Center for Clinical Research, Duncansville, PA, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Kivitz
authors.affiliation: Pinnacle Research Group/Anniston Medical Clinic, Anniston, AL, USA.
authors.forename: Vishala
authors.initials: V
authors.lastname: Chindalore
authors.affiliation: Metroplex Clinical Research Center, Dallas, TX, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Cohen
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Vicki
authors.initials: V
authors.lastname: Santos
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Bolanle
authors.initials: B
authors.lastname: Akinlade
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Kernstock
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Leticia
authors.initials: L
authors.lastname: Delgado-Herrera
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Blahunka
authors.affiliation: Astellas Drug Discovery Research, Northbrook, IL, USA.
authors.forename: Erik E
authors.initials: EE
authors.lastname: Karrer
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Garg
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Samberg
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Bernhardt G
authors.initials: BG
authors.lastname: Zeiher
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000276:immunology; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D051940:B7-2 Antigen / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000009:adverse effects; D007279:Injections, Subcutaneous; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: C000626017:ASP2408; D000906:Antibodies; D018501:Antirheumatic Agents; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D007074:Immunoglobulin G; D008727:Methotrexate
keywords: CD86; CTLA4-Ig; pharmacodynamics; pharmacokinetics