Equivalent PK/PD, Noninferior Immunogenicity Reported for Pfizer's Biosimilar Filgrastim and Its Reference

Pfizer’s biosimilar filgrastim, Nivestym, was approved by the FDA in July 2018 and launched in the United States in October 2018. Among the data on which the approval was based were 3 comparative clinical assessments of the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of the biosimilar versus the US-licensed reference filgrastim (Neupogen) in both male and female healthy volunteers. Results from these studies were reported in full last week.
The Center for Biosimilars Staff
March 30, 2019
Pfizer’s biosimilar filgrastim, Nivestym, was approved by the FDA in July 2018 and launched in the United States in October 2018. Among the data on which the approval was based were 3 comparative clinical assessments of the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of the biosimilar versus the US-licensed reference filgrastim (Neupogen) in both male and female healthy volunteers. Results from these studies were reported in full last week in BioDrugs.

The first study was a randomized open-label, single-dose crossover PK/PD study conducted at a single US center. The study comprised a 21-day screening period followed by two 28-day treatment periods with 28 days between treatments. Volunteers were randomized to receive either the biosimilar followed by the reference (n = 12) or the reference followed by the biosimilar (n = 12). In each treatment period, volunteers were given a single 5-μg/kg dose of filgrastim. The primary objectives of this study were to assess the PK and PD equivalence of the biosimilar and reference based on filgrastim serum concentration and absolute neutrophil count (ANC), respectively.

In this study, the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) for primary PK end points (area under the filgrastim serum concentration–time curve from zero to infinity (AUC0–inf) and maximum observed serum filgrastim concentration [Cmax]) and PD end points (area under the effect curve [AUEC] for ANC and maximum observed concentration for ANC [ANCmax]) were contained within the acceptance limit of 0.80-1.25.

The second study was a randomized, open-label, multiple-dose, crossover PK/PD equivalence study in healthy volunteers conducted at a single US center. It comprised a 14-day screening period followed by two 33-day treatment periods with 28 days between. Patients were randomized to receive the biosimilar followed by the reference (n = 30) or the reference followed by the biosimilar (n = 30) for 5 consecutive daily doses of 5 μg/kg in each treatment period. Primary PD endpoints were AUEC for CD34+ count from day 1 through 120 hours post-dose on day 5 along with maximum observed CD34+ count. The primary PK endpoints were AUC from time zero to 24 hours post-dose (AUC0–24) and post-dose Cmax, both on day 5. All PK and PD end points fell within the same acceptance limit as the first study.

The final study was a randomized, open-label, multiple-dose, parallel-design, noninferiority, comparative immunogenicity study in healthy volunteers at 2 US centers. The study comprised a 28-day screening and 2 treatment periods of 26 (±1) days and 31 (±2) days, respectively, with approximately 1 month between treatments. Volunteers were randomized to receive either the biosimilar (n = 128) or the reference (n = 128) for 5 consecutive daily 5-μg/kg doses of filgrastim for days 1 to 5 of the first treatment period, then a single dose of the same filgrastim on the first day of the second period. The primary objective of the comparative immunogenicity study was to assess noninferiority for immunogenicity of the biosimilar and the reference based on the incidence of antidrug antibodies (ADAs) against filgrastim. In total, 7.4% of volunteers in the biosimilar arm and 4.9% of volunteers in the reference arm developed ADAs during the study period. The upper bound of the 90% CI (−2.717% to 8.096%) for the risk difference (2.560%) between treatments was within the prespecified non-inferiority margin of 10% or less, and ADAs were usually low-titer.

In terms of safety, no volunteers in the PK/PD studies experience treatment-emergent adverse events (TEAEs) that led to discontinuation. In the immunogenicity study, similar percentages of patients in each arm experienced TEAEs, with back pain, headache, pain in extremity, and injection-site hemorrhage being the most commonly reported.

According to the authors, the biosimilar and the reference showed equivalent PK and PD, and noninferiority in terms of immunogenicity, as well as similar safety, with no clinically meaningful difference observed between the products.

Reference
Yao HM, Ottery FD, Borema T, et al. PF-06881893 (Nivesym), a filgrastim biosimilar, versus US-licensed filgrastim refernce product (US Neupogen): pharmacokinetics, pharmacodynamics, immunogenicity, and safety of single or multiple subcutaneous doses in healthy volunteers [published online March 21, 2019]. BioDrugs. doi: 10.1007/s40259-019-00343-8.

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