Review: Similar Safety Profiles of Biosimilar, Reference Pegfilgrastim in Clinical Studies

Filgrastim and pegfilgrastim are recombinant human granulocyte colony-stimulating factor (G-CSF) analogs used to prevent patients with cancer from developing febrile neutropenia as a result of chemotherapy.

Pegfilgrastim biosimilars currently approved or filed for approval in the US “demonstrated a high degree of similarity and comparability” to the reference product “with no unexpected safety outcomes,” concluded the authors of review article comparing the safety profiles of pegfilgrastim biosimilars and the EU- and US-sourced reference products.

The review included 12 phase 1 studies and 4 phase 3 clinical trials comparing a pegfilgrastim biosimilar to the reference product. Across these 16 trials, 2978 participants received a biosimilar and 3787 received the reference product. The biosimilars investigated in the studies included pegfilgrastim-bmez (Ziextenzo), pegfilgrastim-fpgk (Stimufend), pegfilgrastim-apgf (Nyvepria), pegfilgrastim-jmdb (Fulphila), and pegfilgrastim-cbqv (Udenyca).

Filgrastim and pegfilgrastim are recombinant human granulocyte colony-stimulating factor (G-CSF) analogs; pegfilgrastim (reference product: Neulasta) is a longer-acting form of filgrastim. Filgrastim and pegfilgrastim bind G-CSF receptors, initiating signaling pathways leading to proliferation, differentiation, and survival of hematopoietic cells. These G-CSF biologics are used to prevent febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy.

Adverse events in phase 1 studies

In phase 1 studies, the reviewers found the majority of treatment emergent adverse events (TEAEs) were mild or moderate in severity, and the incidence of TEAEs was similar between biosimilars and reference products. Where reported, study drug-related grade 3 or higher TEAEs ranged from 0%-10% and 0%-9% of participants receiving biosimilars and reference products. The incidence of serious adverse events (SAEs) was “low” and similar between biosimilars (0%-1.4%) and reference products (0%-1.6%). TEAEs leading to study discontinuation, which was reported in six of 12 trials, occurred in 2.9% of subjects receiving biosimilars and 3% of subjects receiving reference products.

In phase 1 studies, the incidence of headache ranged from 6%-68% in biosimilar groups and 9%-71% in reference product groups. Bone pain occurred in 16%-78% of participants receiving biosimilars and 18%-75% of participants receiving reference products. According to the authors, the incidences of other musculoskeletal and connective tissue disorders were similar between groups, as were injection-site pain and bruising. The authors said changes in white blood cell counts were also common TEAEs in the phase 1 studies.

Adverse events in phase 3 studies

In 4 phase 3 trials in patients with breast cancer receiving TAC chemotherapy (docetaxel, doxorubicin, cyclophosphamide), study drug-related TEAEs occurred in 12%-34% of patients receiving the biosimilar and 14.6%-28.1% of patients receiving a reference product. Discontinuations due to TEAEs were “low” in both biosimilar (1.3%-3.2%) and reference product (0%-3.3%) groups. SAEs occurred in 1.5%-18.7% of patients treated with a biosimilar and 13%-21% of patients treated with a reference product. Twelve deaths were reported, none of which were considered related to pegfilgrastim treatment.

The incidence of headache in phase 3 trials ranged from 9%-20% in biosimilar groups and 12%-28% in reference product groups. Bone pain occurred in 40%-45% of patients treated with a pegfilgrastim biosimilar and 36%-56% of those treated with a reference product. As with phase 1 studies, the authors said that the incidences of other musculoskeletal and connective tissue disorders were similar between groups, and changes in white blood cell counts were common TEAEs. The incidence of febrile neutropenia ranged from 5%-10% in patients treated with biosimilars 2%-13% of patients treated with reference products.

Regarding adverse events of special interest, the authors said they were “seldom reported, with no notable differences between biosimilars and [reference products].” They noted that the large variability in AE incidence they observed was “expected due to the high level of clinical and methodological heterogeneity across the trials.”

Immunogenicity

In phase 1 trials the incidence of anti-drug antibodies (ADA) ranged from 6%-29% in biosimilar groups and 7%-33% in reference product groups; the incidence of neutralizing antibodies ranged from 0.2%-1.4% and 0.2%-0.5%. In phase 3 trials, the authors said the incidences of ADAs were also “low and of a similar incidence,” ranging from 1%-4.4% for biosimilars and 1%-8.3% for reference products. None of the phase 3 studies reported neutralizing antibodies.

The authors concluded that the safety profiles of biosimilar pegfilgrastims were similar to the reference products in phase 1 and phase 3 studies and consistent with the known safety profile of pegfilgrastim. They added that their conclusions aligned with a 2019 meta-analysis that found no significant differences in efficacy or safety between pegfilgrastim biosimilars and the reference products.

Reference

Loaiza-Bonilla A, Page RD. Achieving white blood cell equity: are the safety profiles of biosimilar and reference pegfilgrastims comparable? Future Oncol. 2023. doi:10.2217/fon-2023-0026