Randomized, controlled study of bleselumab (ASKP1240) pharmacokinetics and safety in patients with moderate-to-severe plaque psoriasis

Abstract

This study evaluated the pharmacokinetics (PK), efficacy, safety, and tolerability of bleselumab - a fully-human anti-CD40 monoclonal recombinant IgG4. Patients with moderate-to-severe psoriasis were randomized on day 1 to receive bleselumab or placebo on days 1, 15 and 29 in a dose-escalation of bleselumab at 0.1, 0.3, 1.0 or 3.0 mg/kg. The safety-analysis set (SAF) and full-analysis set (FAS) included all patients who received bleselumab or placebo, and the PK-analysis set (PKAS) included patients in the SAF with ≥1 quantifiable serum bleselumab concentration. Serial blood samples were collected after each dose, and the bleselumab serum concentration was measured. After each dose, the area-under-the-concentration-time curve over 336 hours (AUC₃₃₆ ) and the maximum serum concentration (C_max ), and dose proportionality of AUC₃₃₆ and C_max were determined. The psoriasis area and severity index (PASI) score, the physician static global assessment (PSGA) score, the percentage body surface area (%BSA) affected with psoriasis, adverse events and laboratory parameters were assessed. Sixty patients were randomized and included in the SAF/FAS (bleselumab, n = 49; placebo, n = 11); 48 formed the PKAS. Bleselumab C_max and AUC₃₃₆ were more than dose proportional in the range 0.1-3.0 mg/kg, suggesting nonlinear PK after single/multiple doses. No clinically significant infusion reactions, cytokine-release syndrome, or thromboembolic events were reported. Bleselumab did not improve the PASI scores, PSGA scores, or %BSA versus placebo. Transient elevation of alanine aminotransferase and aspartate aminotransferase levels by >3 × upper limit of normal were observed in four (8.2%) and two (4.1%) patients, respectively, in the 1.0 or 3.0 mg/kg groups. Patients with liver function test increases had no concurrent changes in bilirubin. Bleselumab demonstrated nonlinear PK after single and multiple doses, with few adverse reactions.

Keywords: bleselumab; moderate-to-severe plaque psoriasis; pharmacokinetics; randomized controlled trial.

Figure 1

Study design

Figure 2

Flow of patients through the study. *All randomized patients received their allocated intervention. ^†Patients who did not complete the last treatment period evaluation visit (day 29). ^‡Patients who did not complete the last study evaluation visit (day 113). AE, adverse event; FAS, full‐analysis set; PK, pharmacokinetics; PKAS, pharmacokinetics‐analysis set; SAF, safety‐analysis set

Figure 3

Mean + SD serum bleselumab concentrations (semi‐log scale) (PKAS). Mean serum concentrations of 0 were assigned a value of 0.02 × LLOQ to enable these points to appear on the plot, since the log value of 0 is undefined. A dotted line was used to connect these converted points to prior and subsequent points on the graph. Where at least half of individual data in a group at a given time point were below the LLOQ, SD was not calculated. IV, intravenous; LLOQ, lower limit of quantification; PKAS, pharmacokinetics‐analysis set; SD, standard deviation