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 (Cmax), and dose proportionality of AUC336 and Cmax 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 Cmax 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.

CD40/CD40L and Related Signaling Pathways in Cardiovascular Health and Disease—The Pros and Cons for Cardioprotection

“…As a general blockade of CD40L-signaling has, as detailed above, resulted in severe thromboembolic events in both experimental models and human trials, an antagonistic CD40 blockade has been the main focus in patients suffering from inflammatory diseases and transplant rejection. Bleselumab (ASKP1240) was shown to be effective in the treatment of psoriasis [ 109 ] while demonstrating good tolerability without producing severe side effects. The drug is currently being evaluated in a Phase II trial (ClinicalTrials NCT02921789) as part of a therapy-regimen in glomerulosclerosis after kidney transplantation.…”

Non-genotoxic conditioning facilitates hematopoietic stem cell gene therapy for hemophilia A using bioengineered factor VIII

“… 73 Since thromboembolic complications in a phase 1 trial of human CD40L mAb therapy suspended clinical development of a CD40L-targeting agent for human use, 74 newer mAbs are being developed and tested in clinical trials that disrupt CD40/CD40L signaling by instead targeting CD40 (e.g., bleselumab). 75 , 76 , 77 As an alternative to costimulatory blocking agents, basiliximab, an interleukin (IL)-2 receptor antagonist that prevents T cell replication and T cell-dependent B cell activation, has been used in combination with ATG as GVHD prophylaxis 78 and may be effective at suppressing anti-fVIII immune responses in our regimen.…”

Targeting the CD40-CD154 Signaling Pathway for Treatment of Autoimmune Arthritis

“…BIO8898 appears to intercalate between two subunits of this homotrimeric molecule and interfere with the protein’s 3-fold symmetry [110]. Another fully human anti-CD40 monoclonal recombinant IgG4, bleselumab, that failed to demonstrate efficacy in a clinical trial of 60 patients with moderate-to-severe psoriasis [111] was assessed alone or in combination with tacrolimus or mycophenolate mofetil, and appeared to provide encouraging benefits as an antirejection agent for improving renal allograft survival [112] and prolonging pancreatic islet allograft survival in cynomolgus monkeys [113]. All of these regimens may be useful for clinical evaluations of autoimmune arthritis in the future.…”