Meta-analysis of Sandoz Pegfilgrastim PK/PD Studies Supports Biosimilarity

The results of a meta-analysis of 3 phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) studies of the Sandoz pegfilgrastim biosimilar Ziextenzo support PK and PD similarity of the biosimilar to both US and EU reference versions of the originator (Neulasta).

Pegfilgrastim is a pegylated, long-acting form of filgrastim. Both are granulocyte colony-stimulating factor (G-CSF) drugs, which are used to stimulate neutrophil production in patients undergoing chemotherapy to reduce the risk of febrile neutropenia.

The investigators said that “since the designs of the 3 studies were different and the sensitivity of the bioanalytical assay varied slightly among the studies,” a meta-analysis could “provide a more precise estimate of biologics comparisons than the individual studies.” With this meta-analysis, they aimed to “address all aspects of residual uncertainty regarding the biosimilarity of Sandoz pegfilgrastim.”

The First PK/PD Study Failed to Demonstrate Biosimilarity

The first study, a 3-arm (biosimilar, US reference, EU reference) parallel-group study, in which participants receive separate drugs and regimens, failed to demonstrate biosimilarity, but “revealed an unexpected high intersubject variability” in PK parameters of pegfilgrastim, according to the authors. Plus, they said, a retrospective evaluation of study 1 found it was underpowered to demonstrate biosimilarity.

The authors noted that since the publication of this study, “the high degree of intersubject variability of the PK results has since been confirmed by others with the reference biologic.”

PD parameters, in contrast, were within the equivalence margins in this study, and there were “no meaningful differences” in safety, local tolerability, and immunogenicity between the biosimilar and reference groups.

The investigators said that study 1 demonstrated that a parallel design was not suitable, and “a crossover design is more appropriate for studies involving pegfilgrastim.” In a crossover study, each participant receives both the experimental drug (biosimilar, in this case) and the control (Neulasta).

Studies 2 and 3 Demonstrated Biosimilarity Using a Crossover Design

Study 2 was conducted to address the limitations of study 1. It compared the biosimilar with the EU reference product in 1 of 2 sequences. This study used a revised sample size estimation and tighter inclusion criteria for absolute neutrophil count and body mass index to address intra-individual variability and reduce the heterogeneity of the population, respectively. No meaningful differences in safety, local tolerability, or immunogenicity were detected in this study.

Study 3 used a 3-way, 6-sequence crossover design evaluating the biosimilar vs both US and EU reference products “to circumvent the interindividual variability and take into account intra-individual variability instead.” This study also demonstrated no meaningful differences in safety, local tolerability, and immunogenicity between the 3 pegfilgrastim products

Results of the Meta-Analysis

The investigators considered biosimilarity to be demonstrated if all 90% confidence intervals (CIs) for the geometric mean ratios for treatment comparisons (comparison of biosimilar to US reference, etc) fell within the margins of 0.80 and 1.25.

They found that demographic and baseline characteristics were similar overall between the groups. They analyzed PK and PD parameters for 277 participants from study 1, 169 from study 2, and 496 from study 3. The 90% CIs of the geometric mean ratios for all 3 comparisons (biosimilar vs US reference, biosimilar vs EU reference, and biosimilar vs US reference and EU reference) were within the predefined equivalence margins, suggesting biosimilarity.

The investigators noted that their results suggest that area under the curve and maximum serum concentration were approximately 5% to 7% higher with the biosimilar compared with the 2 reference products. However, they said this “slightly higher exposure did not translate into any differences in PD effects in the present study,” adding that no clinically meaningful differences in efficacy or safety were observed in the phase 3 clinical studies.

Safety and Tolerability Found to Be Similar

The authors did not perform a meta-analysis on the safety data, but pooled data from all subjects who received at least 1 dose of the study drug in any of the 3 studies, including 781 subjects who received the biosimilar, 604 who received the US reference product, and 772 who received the EU reference product. They reported safety and tolerability were similar between the biosimilar, US reference, and EU reference in these healthy subjects.

Treatment-emergent adverse events (TEAEs) considered related to the study drug occurred in 85.8% of subjects in the biosimilar groups, 84.3% in the US reference groups, and 86.3% in the EU reference groups. The most common TEAEs included headache, back pain, bone pain, and myalgia.

There were no serious drug-related AEs in any group in any study. Six participants treated with the biosimilar and 5 treated with the EU reference product had a study drug-related TEAE leading to discontinuation of the study.

Although study 1 did not demonstrate PK biosimilarity, when combined with studies 2 and 3 in this meta-analysis, the authors said, the data support PK and PD biosimilarity as demonstrated in studies 2 and 3, with no clinically meaningful differences in safety or tolerability, adding to the totality of evidence for the Sandoz pegfilgrastim. They added, “with data from 1040 healthy subjects, this is the largest-known evaluation of PK/PD parameters and safety of a biosimilar of pegfilgrastim.”

Reference

Gattu S, Wang J, Bellon A, Schelcher C, Nakov R, Arani R. Meta-analysis of pharmacokinetic/pharmacodynamic results of 3 phase 1 studies with biosimilar pegfilgrastim. Clin Pharmacol Drug Dev. Published online August 4, 2021. doi:10.1002/cpdd.1005