Safety, pharmacokinetics and pharmacodynamics of single rising doses of BI 655064, an antagonistic anti-CD40 antibody in healthy subjects: a potential novel treatment for autoimmune diseases

Fredrik N Albach, Frank Wagner, Andreas Hüser, Julia Igel, David Joseph, James Hilbert, Corinna Schoelch, Steven J Padula, Jürgen Steffgen, Fredrik N Albach, Frank Wagner, Andreas Hüser, Julia Igel, David Joseph, James Hilbert, Corinna Schoelch, Steven J Padula, Jürgen Steffgen

Abstract

Purpose: The CD40-CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis. The safety, pharmacokinetics and pharmacodynamics of BI 655064, a novel humanised antagonistic anti-CD40 monoclonal antibody, were investigated in this first-in-human trial.

Methods: Healthy male subjects (n = 72) were randomised 3:1, within each BI 655064 dose group, to single intravenous (IV; 0.2-120 mg) or subcutaneous (SC; 40-120 mg) doses of BI 655064 or placebo. Safety, plasma exposure, CD40 receptor occupancy and CD40L-induced CD54 upregulation were assessed over 12 weeks.

Results: Adverse events (AEs) were reported in 43% of subjects (n = 31). Frequency and intensity of AEs were generally similar between BI 655064 and placebo and showed no dose relationship. The most frequent AEs were headache and nasopharyngitis. One mild rash and one local reaction occurred with SC BI 655064; two serious AEs were reported, both judged unrelated to BI 655064. Pharmacokinetic evaluation demonstrated a more than proportional increase in plasma exposure relative to BI 655064 dose, with a terminal half-life between 4 h and 4 days IV and approximately 5 days SC; doses ≥ 20 mg IV and 120 mg SC showed > 90% CD40 receptor occupancy and inhibition of CD54 upregulation, which lasted 7 days in the 120 mg IV and SC groups.

Conclusions: Single doses up to 120 mg BI 655064 IV and SC were well tolerated and showed a high potential to block the CD40-CD40L pathway, supporting further clinical development of BI 655064 in patients with autoimmune disease.

Trial registration: ClinicalTrials.gov Identifier: NCT01510782.

Keywords: Anti-CD40; First-in-human trial; Lupus nephritis; Monoclonal antibody; Rheumatoid arthritis; Systemic lupus erythematosus.

Conflict of interest statement

The trial was approved by the local independent ethics committee (Ethik-Kommission des Landes Berlin) and by the German health authority (Paul Ehrlich Institute). It was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments and the Guidelines for Good Clinical Practice [33]. All individual participants provided written informed consent before any trial-related activities.

Figures

Fig. 1
Fig. 1
Semi-log plots for geometric BI 655064 mean plasma concentrations after IV (a) or SC (b) administration. Arithmetic mean (SD) plasma concentrations of BI 655064 are provided in online resource 1 Supplemental Tables S3 and S4. IV intravenous, LLQ lower limit of quantification, SC subcutaneous
Fig. 2
Fig. 2
Arithmetic mean percentage of CD40 receptor occupancy over time after IV (a) or SC (b) administration of BI 655064. Tabulated values (mean and SD) are provided in online resource 1 Supplemental Tables S5 and S6. IV intravenous, SC subcutaneous, SD standard deviation
Fig. 3
Fig. 3
Arithmetic mean percentage of inhibition of CD54 upregulation over time after IV (a) or SC (b) administration of BI 655064. Tabulated values (mean and SD) are provided in online resource 1 Supplemental Tables S7 and S8. IV intravenous, SC subcutaneous, SD standard deviation

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