A phase 1, randomized ascending single-dose study of antagonist anti-human CD40 ASKP1240 in healthy subjects.
This first-in-human, phase I study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ASKP1240 in healthy subjects. Twelve sequential groups (each 6 active and 3 placebo) were randomly assigned to placebo or single ascending doses of intravenous ASKP1240 (0.00003-10 mg/kg). ASKP1240 exhibited nonlinear pharmacokinetics, with mean maximal serum concentrations and area under the serum concentration-time curves ranging from 0.7 to 251.6 μg/mL and 6.5 to 55409.6 h·μg/mL following doses 0.1 mg/kg-10 mg/kg, respectively. CD40 receptor occupancy by ASKP1240, which was dose-dependent, reached a maximum at doses above 0.01 mg/kg. ASKP1240 was well tolerated, with no evidence of cytokine release syndrome or thromboembolic events. Treatment emergent antibodies to ASKP1240 were detected in 5/70 (7.1%) ASKP1240 recipients. In conclusion, antagonism of the CD40/CD154 interaction with ASKP1240 was safe and well tolerated at the doses tested.
PAREXEL International,  Early Phase Clinical Unit-Baltimore, Harbor Hospital, Baltimore, MD.
R
R
Goldwater
Astellas Pharma Global Development, Northbrook, IL.
J
J
Keirns
Astellas Pharma Global Development, Northbrook, IL.
P
P
Blahunka
Astellas Pharma Global Development, Northbrook, IL.
R
R
First
Astellas Pharma Global Development, Northbrook, IL.
T
T
Sawamoto
Astellas Pharma Global Development, Northbrook, IL.
W
W
Zhang
Astellas Pharma Global Development, Northbrook, IL.
D
D
Kowalski
Astellas Pharma Global Development, Northbrook, IL.
A
A
Kaibara
Astellas Pharma Global Development, Northbrook, IL.
J
J
Holman
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D055815:Young Adult
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007166:Immunosuppressive Agents