Functional Similarity Between Ustekinumab Biosimilar ABP 654, Stelara in Crohn Disease

A series of in vitro studies have confirmed functional similarity of the ustekinumab biosimilar ABP 654 (Wezlana) to the European Union (EU) and US reference products (Stelara), supporting the totality of evidence and extrapolation to all indications of the reference product.

ABP 654 (Wezlana; Amgen) is the first ustekinumab biosimilar approved by the FDA with the interchangeable designation and is set to the be the first ustekinumab biosimilar to enter the US market at the end of January 2025. | Image credit: eddows - stock.adobe.com

ABP 654 is the first ustekinumab biosimilar approved by the FDA with the interchangeable designation and is set to the be the first ustekinumab biosimilar to enter the US market at the end of January 2025. Both the reference product and biosimilar are approved to treat moderate to severe plaque psoriasis, active psoriatic arthritis, moderate to severe active Crohn disease (CD), and moderate to severe active ulcerative colitis. A recent publication described in vitro pharmacology studies relevant to ustekinumab’s mechanism of action that compared ABP 654 to the EU and US reference products.

Ustekinumab is an antibody that binds to the p40 protein subunit of both interleukin (IL)-12 and interleukin 22 (IL-23). Dysregulation of the IL-12 and IL-23 signaling pathways contributes to chronic inflammation in many immune-mediated inflammatory diseases. Ustekinumab blocks the interaction of IL-12 and IL-23 with their receptors, preventing downstream STAT signaling leading to expression of proinflammatory cytokines including interferon (IFN)-ɣ.

Although the reference product and biosimilar are manufactured in different cell types, their amino acid sequences are identical and the totality of evidence so far, including analytical studies and a human pharmacokinetic, safety, and immunogenicity study, has demonstrated that ABP 654 is highly similar to the reference product.

The authors noted that a clinical trial (NCT04607980) comparing efficacy, safety, and immunogenicity of ABP 654 and the reference product in moderate to severe plaque psoriasis is ongoing. They added the current study is intended to generate additional scientific justification for extrapolation to the additional indications of the reference product. They evaluated whether ABP 654 could inhibit the IL-23 and IL-12 signaling pathways similarly to the reference product in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with Crohn disease (CD).

Inhibition of IL-23-Mediated IFN-ɣ Release

Inhibition of IL-23-induced IFN-γ release by ABP 654, the US reference product, and the EU reference product in healthy donor PBMCs were similar. Relative potency in pairwise comparisons to the ABP 654 reference standard was 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.

The authors noted overlapping standard deviations of the mean half-maximal inhibitory concentrations (IC50), indicating no difference between the 3 ustekinumab products.

Inhibition of IL-12-mediated IFN-ɣ release

Inhibition of IL-12-induced IFN-γ release by the biosimilar and both reference products were also similar in healthy donor PBMCs. In pairwise comparisons, 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. Similarly, there were no significant differences between the 3 products in mean IC50 values.

Inhibition of IL-23-mediated STAT3 phosphorylation

IL-23-mediated STAT3 phosphorylation was assessed in both healthy donor and CD PBMCs. Similar inhibition of STAT3 phosphorylation between the biosimilar and reference product were observed, the authors said, “with overlapping standard deviations for all the lots tested.”

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, and the US reference product was not tested since it was found to be similar to the EU reference product in healthy donor cells.

Inhibition of IL-12-Mediated STAT4 Phosphorylation

Inhibition of IL-12-mediated STAT4 phosphorylation by ABP 654, the US reference product, and the EU reference product in healthy donor cells were similar 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 was found to be similar in healthy donor cells. In donor cells from 3 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 authors assessed inhibition of IL-23-induced IL-17 release in healthy and CD donor cells, which was also similar between ABP 654 and the EU reference product, with overlapping standard deviations of IC50 values.

The authors said theirin vitro pharmacologic assessments demonstrate similarity in functional activity of ABP 654 compared to the reference product in inhibiting various actions of IL-12 and IL-23. They concluded that their results provide additional scientific support for extrapolation of ABP 654 to all indications of the reference ustekinumab.

Reference

Foltz IN, Gaida K, Wong HY, Ng M, Busch M, Liu JL. assessing functional similarity of biosimilar ABP 654 and ustekinumab in samples from patients with Crohn's disease. J Inflamm Res. 2024;17:10627-10640. doi:10.2147/JIR.S478529