FDA panel backs approval of filgrastim biosimilar

SILVER SPRING, MD. – With the unanimous support of a Food and Drug Administration advisory panel and a favorable review by the agency, a “biosimilar” version of filgrastim, the recombinant granulocyte colony-stimulating factor marketed as Neupogen, will likely become the first biosimilar product to be approved in the United States.

At a meeting on Jan. 7, the FDA’s Oncologic Drugs Advisory Committee voted 14-0 that the filgrastim biosimilar should be approved for the five indications approved for Neupogen in the United States, based on “the totality of the evidence,” which includes pharmacokinetic, pharmacodynamic, immunogenicity, and clinical data. With little debate, they agreed that other than minor differences in clinically inactive components, the biosimilar, currently referred to as “­EP2006,” was “highly similar” to the reference product, and that there were “no clinically meaningful differences” between EP2006 and Neupogen – the components of the definition of biosimilarity.

The meeting was considered historic, since this is the first biosimilar to be reviewed by an FDA advisory panel, and if approved, will be the first biosimilar to become available as a result of the Biologics Price Competition and Innovation Act of 2009, which was passed as part of the Affordable Care Act, creating “an abbreviated licensure pathway for biological products shown to be ‘biosimilar’ or ‘interchangeable’ with an FDA-licensed biological product,” according to the FDA.

Neupogen was approved by the FDA in 1991 and is marketed by Amgen. If approved, EP2006 would be the first biosimilar product to be approved in the United States, and, like generic drugs, is expected to provide a cheaper version of Neupogen. Sandoz, the generic pharmaceuticals arm of Novartis, plans to market the biosimilar as Zarxio in the United States. The filgrastim biosimilar was approved in 2009 in the European Union, where it is marketed as Zarzio, and it is now approved in more than 60 countries, with more than 7.5 million days of exposure, according to Sandoz.

Between 2009 and 2012, the use of filgrastim increased by 30% in Europe, and the biosimilar is now the most commonly prescribed version of filgrastim in Europe. The cost of filgrastim dropped substantially after approval because of the competition, company officials said.

EP2006 will be available in prefilled syringes containing 300 mcg/0.5 mL or 480 mcg/0.8 mL administered subcutaneously or intravenously, the same strengths as U.S.-approved Neupogen. For approval, Sandoz submitted eight studies, including two studies comparing EP2006 to U.S.-approved Neupogen conducted specifically for the U.S. approval, one of 28 healthy volunteers and another of 218 women with breast cancer, treated with myelosuppressive chemotherapy, evaluating the pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity (the breast cancer study also evaluated safety and efficacy). The remaining studies included studies in healthy volunteers and breast cancer patients, comparing the biosimilar to European-approved Neupogen, or single-arm studies.

At the meeting, Sigrid Balser, Ph.D., of the global clinical development department at Sandoz, said that in the U.S. study of healthy volunteers, there was a “high degree of similarity” between EP2006 and Neupogen in terms of the PD and PK results, and the absolute neutrophil count (ANC) and CD34+ cell responses. In the U.S. study of breast cancer patients, EP2006 and Neupogen were equivalent in terms of efficacy over the first chemotherapy cycle and had a similar safety profile over six chemotherapy cycles. There were no signs of immunogenicity associated with the biosimilar in the U.S. or European studies in patients with breast cancer or healthy volunteers.

Outside of the United States, more than 3,800 patients have been treated with Zarzio for various indications, including chemotherapy-induced neutropenia, hematopoietic stem cell mobilization, and severe chronic neutropenia, and have been monitored as part of postmarketing trials or routine pharmacovigilance. To date, there have been no signals of any differences in the safety profile of the filgrastim biosimilar, compared with Neupogen;no cases of immunogenicity; and safety and effectiveness has been “confirmed in clinical practice,” Dr. Balser added.

Based on the data, the FDA reviewers concluded that EP2006 is “highly similar to U.S.-licensed Neupogen, and that there are no clinically meaningful difference between the two products,” said Dr. Albert Deisseroth, medical officer and team leader in the division of hematology products, in the FDA’s office of hematology and oncology products.

“Clinically, they appear to really function pretty equally in terms of what you’re asking them to do,” said the panel chair, Dr. Deborah Armstrong, professor of oncology at Johns Hopkins University, Baltimore. The extensive use of the filgrastim biosimilar in other parts of the world provided evidence of “robust safety and efficacy,” which contributed to her support for approval, she added.