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Anti–IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial

Published:March 12, 2015DOI:https://doi.org/10.1016/j.jaci.2015.01.018

      Background

      IL-23 is associated with plaque psoriasis susceptibility and pathogenesis. BI 655066 is a fully human IgG1 mAb specific for the IL-23 p19 subunit.

      Objective

      This first-in-human proof-of-concept study evaluated the clinical and biological effects of BI 655066 in patients with moderate-to-severe plaque psoriasis.

      Methods

      We performed a single-rising-dose, multicenter, randomized, double-blind, placebo-controlled, within-dose cohort phase I trial. Patients received 0.01, 0.05, 0.25, 1, 3, or 5 mg/kg BI 655066 intravenously, 0.25 or 1 mg/kg BI 655066 subcutaneously, or matched placebo. The primary objective was safety evaluation.

      Results

      Thirty-nine patients received single-dose BI 655066 intravenously (n = 18) or subcutaneously (n = 13) or placebo (n = 8). Adverse events were reported with similar frequency in the BI 655066 and placebo groups. Four serious adverse events (not considered treatment related) were reported among BI 655066–treated patients. BI 655066 was associated with clinical improvement from week 2 and maintained for up to 66 weeks after treatment. At week 12, 75%, 90%, and 100% decreases in the Psoriasis Area and Severity Index were achieved by 87%, 58%, and 16% of BI 655066–treated patients (any dose), respectively, versus none receiving placebo. BI 655066 treatment resulted in reduced expression of lesional skin genes associated with IL-23/IL-17 signaling pathways and normalization of psoriatic lesion gene expression profiles to a profile approaching that of nonlesional skin. Significant correlation between treatment-associated molecular changes and psoriasis area and severity index improvement was observed (r = 0.73, P = 2 × 10−6).

      Conclusions

      BI 655066 was well tolerated and associated with rapid, substantial, and durable clinical improvement in patients with moderate-to-severe psoriasis, supporting a central role for IL-23 in psoriasis pathogenesis.

      Key words

      Abbreviations used:

      AE (Adverse event), AUEC (Area under the effect curve), DC-LAMP (Dendritic cell lysosome-associated membrane glycoprotein), Emax (Maximum effect), FC (Fold change), MACE (Major adverse cardiovascular event), PASI (Psoriasis Area and Severity Index), RNA-seq (RNA sequencing), SAE (Serious adverse event), sPGA (Static Physician Global Assessment), TIA (Transient ischemic attack)
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