A Phase 1, Randomized Ascending Single-Dose Study of Antagonist Anti-Human CD40 ASKP1240 in Healthy Subjects

Abstract

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 lg/mL and 6.5 to 55409.6 h·lg/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. Key words: ASKP1240, anti-CD40, pharmacodynamics, pharmacokinetics, randomizedAbbreviations: AEs, adverse events; AUC inf , area under the concentration-time curve from time zero extrapolated to the infinite time; C max , maximal antibody serum concentration; INR, international normalized ratio; LLOQ, lower limit of quantification; MABEL, minimal anticipated biological effect level; MedDRA, Medical Dictionary for Regulatory Activities; MFI, mean fluorescent intensity; PD, pharmacodynamic; PDAS, pharmacodynamic analysis set; PK, pharmacokinetic; PKAS, pharmacokinetic analysis set; SAF, safety analysis set; SD, standard deviation; t 1/2 , terminal half-life; t max , time to C max ; ULN, upper limit of normal.

Long-Term Control of Diabetes in Immunosuppressed Nonhuman Primates (NHP) by the Transplantation of Adult Porcine Islets

“…An additional promising candidate would be an anti-CD40 antibody, ASKP1240 (4D11); this drug has been demonstrated to be effective in prolonging graft survival in NHP allotransplantation of kidney, liver and islets, and had an excellent safety profile in a phase I clinical trial (31)(32)(33)(34). Another promising alternative to anti-CD154 monoclonal antibody is CDP7657, which is a novel monovalent Fab' PEG anti-human CD154 antibody.…”

Effects of ASKP1240 Combined With Tacrolimus or Mycophenolate Mofetil on Renal Allograft Survival in Cynomolgus Monkeys

“…Treatment of these animals for up to 180 days was not associated with a deterioration in the general clinical observational signs (activity or appetite) nor was it associated with weight loss. A recent phase I clinical trial supports and extends these animal findings by demonstrating that ASKP1240 is well tolerated in healthy subjects and is not associated with drug-induced cytokine release or with thromboembolic events ( 34 ).…”

Targeting apoptosis to induce stable mixed hematopoietic chimerism and long-term allograft survival without myelosuppressive conditioning in mice

“…The recent report of antibodies blocking CD40 may represent an ideal solution for blocking this pathway without the thromboembolic side effect reported in primates after exposure to anti-CD154. [43][44][45][46] Importantly, in contrast to previous reports of mixed chimerism induction without myelosuppression, 29,47 our conditioning protocol was successful using a clinically relevant dose of BM cells and without additional cell-based therapy.…”