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Hurdles for Neulasta Biosimilars

A number of biosimilar makers have tried to obtain approval for proposed biosimilar versions of Amgen’s Neulasta (pegfilgrastim), a long-acting version of Amgen’s Neupogen (filgrastim), but have encountered hurdles so far both in the U.S. and Europe. Amgen’s Neulasta is a treatment that is used to help cancer patients on chemotherapy fight off infections. It is a blockbuster biologic medicine that has been on the U.S. and European markets since 2002.

Biosimilars of Amgen’s Neupogen, a simpler product, have been on the European market for years and Sandoz’s biosimilar of Neupogen, Zarxio, is the first U.S. biosimilar. FDA approved Zarxio in March 2015 and it has been on the U.S. market since September 2015. Neulasta, by contrast, is a bigger and more complex biologic and biosimilar makers have not succeeded in convincing FDA or the European Medicines Agency (EMA) of the biosimilarity of their proposed Neulasta biosimilars with Neulasta to date.

Neupogen (filgrastim) is made in bacteria using recombinant DNA techniques. Filgrastim is a small protein of 175 amino acids with a molecular weight of 19 kilodaltons, making it relatively easy to study and characterize. In Neulasta (pegfilgrastim), the filgrastim protein is covalently bound to a 20 kilodalton polyethylene glycol (PEG) molecule. The attachment of the PEG molecule is referred to as pegylation and it doubles the molecular weight of the medicine. Pegfilgrastim is 39 kilodaltons to filgrastim’s 19. The presence of PEG on filgrastim reduces the rate at which the medicine is removed from the body, allowing it to be given to patients less often. It is the reason that Neulasta is long-acting.

But the presence of PEG also appears to make it more difficult to develop a biosimilar product. Although Sandoz obtained approval of a biosimilar of Neupogen in Europe and in the U.S., FDA rejected Sandoz’s application for its proposed biosimilar of Neulasta in July 2016 after accepting it for review in November 2015. Sandoz has said that it plans to initiate an additional study and may be in a position to submit additional data to FDA in support of its application in 2018. Sandoz has encountered similar difficulties in Europe. Last month, Sandoz withdrew its application for a Neulasta biosimilar pending before the EMA. The EMA was concerned that Sandoz’s studies were not able to show that the concentration of its proposed product in blood was the same as that for Neulasta. In withdrawing its application, Sandoz told the EMA that it would not be able to provide the additional data required by the EMA within the permitted regulatory timeframe.

Other biosimilar makers have encountered hurdles as well. Gedeon Richter, another biosimilar maker, withdrew its application for a biosimilar of Neulasta from consideration by the EMA in November 2016. The EMA “was concerned that study results had not shown that [the proposed biosimilar] was handled by the body in the same way as the reference medicine Neulasta.” It was therefore of the opinion that the biosimilar maker “had not demonstrated that [its product] is highly similar to Neulasta.”

Apotex, another biosimilar maker, announced in December 2014 that FDA had accepted its application for a Neulasta biosimilar for review. But its proposed biosimilar has not been approved to date and no FDA advisory committee meeting has been scheduled.

Other biosimilar makers also are trying to obtain approval for a Neulasta biosimilar. In July 2016, Mylan and Biocon announced that the EMA accepted their application for a Neulasta biosimilar for review. And both FDA and EMA are evaluating Coherus’ proposed biosimilar of Neulasta. FDA accepted the application for review in October 2016 and the EMA accepted it in November 2016. It will be interesting to see how these products fair given the challenges that PEG appears to pose for demonstrating biosimilarity.

Categories: Biosimilars, BPCIA, EMA, FDA