Sandoz Resubmits Application for Pegfilgrastim Biosimilar

Mark Levick, MD, PhD

A biologics license application has been resubmitted to the FDA for the pegfilgrastim (Neulasta) biosimilar LA-EP2006 to decrease the incidence of infection from febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer therapy. The resubmission addresses a complete response letter (CRL) issued by the FDA in June 2016, according to Sandoz, the manufacturer of the agent.

Pegfilgrastim is a long-acting version of filgrastim (Neupogen), which is indicated for select patients with cancer undergoing chemotherapy to enhance the production of infection-fighting white blood cells. The indication is specific to those receiving myelosuppressive anticancer drugs associated with a clinically significance incidence of febrile neutropenia.

With the resubmission, the application includes new data from a pivotal single-dose, three-period, cross-over, pharmacokinetics (PK) and pharmacodynamics (PD) study comparing Sandoz’s pegfilgrastim biosimilar with US-sourced reference pegfilgrastim; the pegfilgrastim biosimilar with European Union—sourced reference pegfilgrastim; and US- with EU-sourced reference pegfilgrastim.

At the time of the 2016 CRL, Sandoz had stated that it was working with the FDA to address remaining questions.

"The US market is just beginning to benefit from biosimilars, as shown by the success of our filgrastim, the first approved biosimilar in the [United States],” Mark Levick, MD, PhD, global head of Development, Biopharmaceuticals, Sandoz, said in a press release. “The submission of our pegfilgrastim biosimilar application is another step for us as we continue to lead the way in creating early and expanded patient access to life-changing biologics."

The methodology of the phase I, randomized, three-way, crossover study was presented at the 2018 ESMO Congress. The study was sufficiently powered (90%) to achieve confidence intervals within margins 0.8 to 1.25 in co-primary endpoints pairwise comparisons. The investigators noted that due to historically known high intra- and inter-subject variabilities with reference biologic in area under the serum concentration-time curve (AUC)_0-inf, the study, in healthy volunteers, is appropriate and establishes the scientific bridge to demonstrate similarity of PK/PD, safety, and immunogenicity between LA-EP2006, EU reference pegfilgrastim, and US reference pegfilgrastim. As of October 2018, the trial was ongoing in in 5 US and 1 Dutch study sites.

The European Commission approved LA-EP2006, known as Ziextenzo, as a treatment to reduce the duration of neutropenia and incidence of febrile neutropenia that is associated with anticancer chemotherapy in November 2018. With that approval, the biosimilar became indicated for use in the same proposed indications as reference pegfilgrastim, which is to prevent febrile neutropenia in patients receiving myelosuppressive chemotherapy, those with acute myeloid leukemia receiving induction or consolidation chemotherapy, patients with cancer undergoing bone marrow transplantation, those undergoing autologous peripheral blood progenitor cell collection and therapy, and those with severe chronic neutropenia.

The European approval was based on comprehensive analytical, preclinical and clinical data demonstrating the similarity between Ziextenzo and pegfilgrastim regarding safety, efficacy, and quality. Part of the submitted data was from a single-dose, double-blind, randomized, two-way crossover, phase I study, in which the biosimilar demonstrated similar PD, PK, immunogenicity, and safety as reference pegfilgrastim.²

The study consisted of 2 treatment periods separated by an 8-week washout period. A total 169 patients between the ages of 18 and 45 years were randomized to either the biosimilar or pegfilgrastim. Each treatment was administered at a 6-mg subcutaneous dose on day 1 of each treatment period.

PK/PD similarity was claimed if 90% PK and 95% PD confidence intervals (CIs) for geometric mean ratios of AUC from time of dosing and extrapolated to infinity (AUC_0-inf ), or to the last measurable concentration (AUC_0-last ), maximum observed serum concentration (C_max), absolute neutrophil count (ANC) area under the effect curve from the time of dosing to the last measurable concentration (AUEC_0-last ), and ANC maximum effect attributable to the therapy under investigation (E_max ) were completely contained within the predefined margin (0.8-1.25).

Results showed that similar PK/PD data were demonstrated: 90% CIs of geometric mean ratio of proposed biosimilar/reference for PK: AUC_0-inf (1.0559-1.2244), AUC_0-last (1.0607-1.2328), C_max (1.0312-1.1909) and 95% CIs for PD (ANC): AUEC_0-last (0.9948-1.0366), E_max (0.9737-1.0169) were contained within the predefined margin.

Moreover, the biosimilar and reference pegfilgrastim demonstrated similar safety profiles and were well tolerated, and there was no detection of neutralizing or clinically relevant antibodies.

References

1. Sandoz resubmits biosimilar pegfilgrastim application to US FDA. Sandoz. Published April 2, 2019. https://bit.ly/2FQQsCu. Accessed April 2, 2019.
2. Nakov R, Schussler S, Schier-Mumzhiu S, et al. A large multi-center, randomized, double-blind, crossover study in healthy volunteers to compare pharmacokinetics and pharmacodynamics of a proposed biosimilar pegfilgrastim with EU and US reference pegfilgrastim: methodological approach. Ann Oncol. 2018;29(suppl 8; abstr 1796P). doi: 10.1093/annonc/mdy300.110.
3. Nakov R, Gattu S, Wang J, et al. Proposed biosimilar pegfilgrastim shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects [published online August 5, 2018]. Br J Clin Pharmacol. doi: 10.1111/bcp.13731.