Review: Similar safety profiles of the reference pegfilgrastim biosimilar in clinical studies

Pegfilgrastim biosimilars currently approved or filed for approval in the United States have demonstrated a high degree of similarity and comparability to the reference product, with no unexpected safety findings, concluded the authors of the review article comparing the safety profiles of pegfilgrastim biosimilars and those of European and American origin. reference products.

The review included 12 phase 1 studies and 4 phase 3 clinical trials comparing a pegfilgrastim biosimilar to the reference product. In these 16 trials, 2,978 participants received a biosimilar and 3,787 received the reference product. 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 analogues of recombinant human granulocyte colony-stimulating factor (G-CSF); Pegfilgrastim (reference product: Neulasta) is a long-acting form of filgrastim. Filgrastim and pegfilgrastim bind to 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, evaluators found that 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 TEAEs of grade 3 or higher ranged from 0% to 10% and 0% to 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 were 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 between 6% and 68% in the biosimilar groups and between 9% and 71% in the reference product groups. Bone pain occurred in 16-78% of participants receiving biosimilars and in 18-75% of participants receiving reference products. According to the authors, the incidence of other musculoskeletal and connective tissue disorders was similar between the groups, as was pain and bruising at the injection site. The authors said changes in white blood cell counts were also common TEAEs in phase 1 studies.

Adverse Events in Phase 3 Studies

In 4 phase 3 trials in breast cancer patients receiving TAC chemotherapy (docetaxel, doxorubicin, cyclophosphamide), study drug-related TEAEs occurred in 12-34% of patients receiving the biosimilar and in 14.6% to 28.1% of patients receiving a reference product. . Discontinuations due to TEAEs were low in the biosimilar (1.3% to 3.2%) and reference (0% to 3.3%) groups. SAEs occurred in 1.5 to 18.7% of patients treated with a biosimilar and 13 to 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 between 9% and 20% in the biosimilar groups and between 12% and 28% in the reference product groups. Bone pain occurred in 40 to 45% of patients treated with a pegfilgrastim biosimilar and in 36 to 56% of those treated with a reference product. As with the phase 1 studies, the authors stated that the incidence of other musculoskeletal and connective tissue disorders was similar between groups and that changes in white blood cell counts were common TEAEs. The incidence of febrile neutropenia varied between 5% and 10% in patients treated with biosimilars, or between 2% and 13% of patients treated with reference products.

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

Immunogenicity

In phase 1 trials, the incidence of anti-drug antibodies (ADA) ranged between 6% and 29% in the biosimilar groups and between 7% and 33% in the reference product groups; the incidence of neutralizing antibodies varied between 0.2% and 1.4% and between 0.2% and 0.5%. In phase 3 trials, the authors said the incidence of ADAs was also low and similar, ranging from 1% to 4.4% for biosimilars and 1% to 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 those of reference products in phase 1 and phase 3 studies and consistent with the known safety profile of pegfilgrastim. They added that their findings were consistent with a 2019 meta-analysis that found no significant differences in effectiveness or safety between pegfilgrastim biosimilars and 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