The authors noted that “all biologic therapeutics can be immunogenic or elicit an immune response,” and that an assessment of immunogenicity is part of the totality of evidence required for regulatory approval of biosimilars.
Pooled data from 3 randomized controlled trials on biosimilar pegfilgrastim-cbqv (Udenyca) suggested “similar immunogenicity” to the reference product (Neulasta), according to a new article in Advances in Therapy.
Pegfilgrastim is a pegylated, long-acting form of granulocyte colony-stimulating factor (G-CSF), used to prevent febrile neutropenia in patients who receiving myelosuppressive chemotherapy by stimulating neutrophil production.
The authors noted that “all biologic therapeutics can be immunogenic or elicit an immune response,” and that an assessment of immunogenicity is part of the totality of evidence required for regulatory approval of biosimilars. Anti-drug antibodies (ADAs) “may have no clinical impact or they may affect the bioavailability, efficacy, and safety of the therapeutic to various degrees,” they wrote, adding that immunogenicity of the reference product has been reported as “low with no reported clinical impact.”
The study pooled data from 3 clinical studies in healthy participants: 1 designed to evaluate immunogenicity of the biosimilar compared to the reference product, and 2 studies designed to assess pharmacokinetic (PK) and pharmacodynamic (PD) similarity.
The immunogenicity study included 303 subjects (242 evaluated for ADAs) in two treatment groups receiving either the reference product or biosimilar. The 2 PK and PD studies were crossover studies (enrolling 122 and 116 subjects) in which a single dose of the originator and biosimilar was administered to each participant on different days, spaced apart by several weeks.
Anti-drug antibodies in the immunogenicity study
The presence of ADAs, along with ADA binding specificity, titer, and neutralizing activity were evaluated. No treatment-emergent neutralizing antibodies were detected in the immunogenicity study.
In both groups, the authors reported, most ADAs reacted either with the polyethylene glycol (PEG) portion of the molecule, or both PEG and G-CSF. Three subjects (2 in biosimilar group, 1 in reference product group) had measurable anti-G-CSF titers, which the authors said were transient. They found no cases of ADAs that reacted only with G-CSF.
Overall, the incidence of treatment-emergent ADAs was 32.2% (39 subjects) in those administered the biosimilar and 23.9% (28 subjects) in those administered the reference product. Incidence of treatment-emergent, persistent ADAs with measurable titer (titer 2 or greater) was 9.8% in subjects receiving the biosimilar and 5.0% in subjects receiving the reference product. The differences between groups in ADAs was “driven by non-neutralizing, low-titer, polyethylene glycol (PEG)-reactive ADAs, which are commonly present in healthy subjects,” according to the authors.
To assess the clinical impact of ADAs, the authors compared pharmacokinetics, pharmacodynamics, and safety profiles of ADA-positive and ADA-negative participants in the immunogenicity study. They found “no apparent impact of ADAs on pharmacokinetics, pharmacodynamics or safety.”
The safety profiles of the biosimilar and reference product in this study “were consistent with the known pegfilgrastim safety profile and appeared to be unaffected by the presence of ADA,” the authors wrote. Overall, adverse events occurred in 89.7% of subjects receiving the biosimilar and 92.9% of those receiving the reference product. The most common were musculoskeletal pain and headache.
Anti-drug antibodies in the pooled analysis
The authors reported that the incidence of treatment-emergent ADAs in the pooled analysis was comparable, with ADAs detected in 31.6% (72) of subjects receiving the biosimilar and 29.3% (76) receiving the originator. In the individual PK/PD studies, treatment-emergent ADAs were detected in 28.6% compared to 33.3% and 30.0% compared to 34.6% of participants receiving the biosimilar and reference product..
Similar to the results of the immunogenicity study alone, the authors reported that in the pooled analysis, most treatment-emergent ADAs were reactive to PEG, no treatment-emergent ADAs reactive only with G-CSF were detected, and no treatment-emergent neutralizing antibodies were detected.
The authors concluded their pooled analysis “demonstrates the low immunogenic risk of pegfilgrastim-cbqv and supports the overall demonstration of similarity between pegfilgrastim-cbqv and pegfilgrastim.”
Civoli F, Finck B, Tang H, et al. Biosimilar pegfilgrastim-cbqv demonstrated similar immunogenicity to pegfilgrastim in healthy subjects across three randomized clinical studies. Adv Ther. 2022; Published online January 16, 2022. doi: 10.1007/s12325-021-02024-x.