A Phase 1 Dose-Escalation Study of ASP2409, a Selective T-Cell Costimulation Inhibitor, in Stable Rheumatoid Arthritis Patients on Methotrexate Therapy.
ASP2409 represents a new class of CTLA4-Ig molecules with higher binding avidity and selectivity to CD86. This first-in-human study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of ASP2409 in stable rheumatoid arthritis patients on methotrexate therapy with a randomized, double-blind, placebo-controlled dose-escalation study design. Patients were enrolled and randomized in each of 8 dose-escalation cohorts ranging from 0.001 to 3.0 mg/kg to receive either ASP2409 or placebo in a sequential manner. Escalation to higher dose levels occurred in the absence of dose-limiting toxicity. A total of 57 patients completed the study. ASP2409 showed nonlinear PK over the dose range of 0.01 to 3.0 mg/kg following a single intravenous administration, indicating target-mediated drug disposition. Area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased at a greater than dose-proportional rate. The half-life of ASP2409 increased dose dependently and ranged from 1.57 to 6.68 days. ASP2409 showed a dose-dependent increase in the extent and duration of CD86 receptor occupancy. There were no clinically relevant safety issues up to a single dose of 3.0 mg/kg. No maximum tolerated dose was reached. The incidence and duration of antidrug antibodies did not correlate with adverse events. ClinicalTrials.gov identifier: NCT02171143.
Astellas Pharma Global Development, Northbrook, IL, USA.
Wenhui
W
Zhang
Astellas Pharma Global Development, Northbrook, IL, USA.
Robert M
RM
Kernstock
Astellas Pharma Global Development, Northbrook, IL, USA.
Erik E
EE
Karrer
Metroplex Clinical Research Center, Dallas, TX, USA.
Stanley B
SB
Cohen
Pinnacle Research Group, LLC/Anniston Medical Clinic, Anniston, AL, USA.
Vishala L
VL
Chindalore
Altoona Research, Duncansville, PA, USA.
Alan J
AJ
Kivitz
Astellas Pharma Global Development, Northbrook, IL, USA.
Paul C
PC
Blahunka
Astellas Pharma Global Development, Northbrook, IL, USA.
Leticia
L
Delgado-Herrera
Astellas Pharma Global Development, Northbrook, IL, USA.
Bernhardt G
BG
Zeiher
Astellas Pharma Global Development, Northbrook, IL, USA.
Nancy L
NL
Samberg
Astellas Pharma Global Development, Northbrook, IL, USA.
Jay P
JP
Garg
D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006207:Half-Life; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D008875:Middle Aged
C000619913:ASP2409; D018501:Antirheumatic Agents; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008727:Methotrexate
ASP2409; CD86 and CD80 receptor; CTLA4-Ig; nonlinear PK