A series of in vitro studies have demonstrated functional similarity between ABP 654 (Wezlana), a biosimilar to ustekinumab (Stelara), and the reference products in both the European Union (EU) and the United States (US). This supports the totality of evidence for ABP 654 and its potential extrapolation to all indications of the reference product, including moderate to severe Crohn's disease.
ABP 654 is the first ustekinumab biosimilar to receive FDA approval with an interchangeable designation and is anticipated to launch in the US market by the end of January 2025. Both ABP 654 and Stelara are approved for treating moderate to severe plaque psoriasis, active psoriatic arthritis, moderate to severe active Crohn's disease (CD), and moderate to severe active ulcerative colitis. The recent publication details in vitro pharmacology studies comparing ABP 654 to the EU and US reference products, focusing on ustekinumab’s mechanism of action.
Mechanism of Action
Ustekinumab is a monoclonal antibody that targets the p40 protein subunit shared by interleukin (IL)-12 and interleukin-23 (IL-23). Dysregulation of the IL-12 and IL-23 signaling pathways is implicated in the chronic inflammation observed in various immune-mediated inflammatory diseases. Ustekinumab functions by blocking the interaction of IL-12 and IL-23 with their respective receptors, thereby preventing downstream STAT signaling and the subsequent expression of pro-inflammatory cytokines, including interferon (IFN)-γ.
While the reference product and biosimilar are manufactured using different cell types, their amino acid sequences are identical. Comprehensive analytical studies, along with human pharmacokinetic, safety, and immunogenicity studies, have confirmed that ABP 654 exhibits high similarity to the reference product.
A clinical trial (NCT04607980) is currently underway to compare the efficacy, safety, and immunogenicity of ABP 654 and the reference product in patients with moderate to severe plaque psoriasis. The in vitro study was designed to provide additional scientific rationale for extrapolating ABP 654 to other approved indications of ustekinumab. Researchers evaluated the ability of ABP 654 to inhibit the IL-23 and IL-12 signaling pathways in peripheral blood mononuclear cells (PBMCs) from both healthy donors and patients with Crohn's disease (CD).
Inhibition of IL-23-Mediated IFN-γ Release
The study found that ABP 654, the US reference product, and the EU reference product exhibited similar inhibition of IL-23-induced IFN-γ release in healthy donor PBMCs. Pairwise comparisons showed relative potency values of 102% for ABP 654 and 100% for the EU reference product, 89.5% for ABP 654 and 90.5% for the US reference product, and 89.2% for the EU reference product and 98.8% for the US reference product, all relative to the ABP 654 reference standard. Overlapping standard deviations of the mean half-maximal inhibitory concentrations (IC50) indicated no significant differences between the three ustekinumab products.
Inhibition of IL-12-Mediated IFN-γ Release
Similarly, the biosimilar and both reference products showed comparable inhibition of IL-12-induced IFN-γ release in healthy donor PBMCs. Average relative potency values compared to the ABP 654 reference standard were 100.4% for ABP 654 and 89.7% for the EU reference product, 92.7% for ABP 654 and 89.4% for the US reference product, and 109.2% for the EU reference product and 107.8% for the US reference product. No significant differences were observed in mean IC50 values among the three products.
Inhibition of IL-23-Mediated STAT3 Phosphorylation
IL-23-mediated STAT3 phosphorylation was assessed in both healthy donor and CD PBMCs. The authors reported similar inhibition of STAT3 phosphorylation between the biosimilar and reference product, noting overlapping standard deviations for all tested lots. Mean IC50 values for inhibition of STAT3 phosphorylation in healthy donor cells were not significantly different. In CD donor cells, ABP 654 and the EU reference product inhibited STAT3 phosphorylation downstream of IL-23 similarly. The US reference product was not tested in CD donor cells, as it had demonstrated similarity to the EU reference product in healthy donor cells.
Inhibition of IL-12-Mediated STAT4 Phosphorylation
ABP 654, the US reference product, and the EU reference product showed similar inhibition of IL-12-mediated STAT4 phosphorylation in healthy donor cells, with overlapping dose-response curves and overlapping standard deviations of mean IC50 values. Only the EU reference product was tested in CD donor cells, as the US reference product had been found to be similar in healthy donor cells. In donor cells from three different patients with CD, ABP 654 inhibited IL-12-induced STAT4 phosphorylation with similar mean IC50 values.
Inhibition of IL-23-Induced IL-17 Release
Finally, the study assessed inhibition of IL-23-induced IL-17 release in healthy and CD donor cells. Results indicated that ABP 654 and the EU reference product exhibited similar inhibition, with overlapping standard deviations of IC50 values.
The authors concluded that their in vitro pharmacologic assessments demonstrate similarity in the functional activity of ABP 654 compared to the reference product in inhibiting various actions of IL-12 and IL-23. These results provide additional scientific support for the extrapolation of ABP 654 to all indications of the reference ustekinumab.
