Six years after the biosimilar pathway was enacted into law, FDA has approved three biosimilars for marketing in the US. Sandoz’s Zarxio, a biosimilar of Amgen’s Neupogen, was the first biosimilar to be approved. Zarxio, a relatively simple biologic, was approved in March 2015 under the Biologics Price Competition and Innovation Act of 2009 (BPCIA). Zarxio has now has been on the market for a year (since September 2015). This year, FDA approved two complex biologics, Celltrion and Pfizer’s Inflectra, a biosimilar of Janssen’s Remicade, and Sandoz’s Erelzi, a biosimilar of Amgen’s Enbrel. FDA staff and its arthritis advisory committee also recommended approval of Amgen’s ABP 501, a proposed biosimilar of AbbVie’s Humira. On the other hand, Sandoz’s revealed in July that its biosimilar application for Amgen’s Neulasta, a long-acting version of Neupogen, had been rejected by FDA and Hospira did the same last year for its application for Amgen’s EPO. Although the approvals (and rejections) provide significant insights as to FDA’s requirements, there are no simple lessons to be drawn.

Three Approved US Biosimilars and a Recommendation

In March 2015, FDA approved Sandoz’s Zarxio as a biosimilar of Amgen’s Neupogen (filgrastim), a biologic that boosts the ability of patients undergoing cancer treatment to fight off infections. Although Zarxio is more complex than small molecule drugs, it is a small protein that is made in bacterial cells and has no sugar molecules added to it (glycosylation). It is relatively simple compared to other biologic products and easier to characterize. FDA approved Zarxio for all five of Neupogen’s indications, even though Sandoz only submitted pivotal clinical trials for one of them. Zarxio entered the market in September 2015, after the expiration of the 180-day notice of commercial marketing period under the BPCIA. It is the only product on the US market that has been approved under the biosimilar pathway.

A year later, in April 2016, FDA approved the second US biosimilar, Celltrion and Pfizer’s Inflectra. Inflectra, a biosimilar of Janssen’s Remicade (infliximab), is a chimeric monoclonal antibody. Remicade treats rheumatoid arthritis and other inflammatory diseases, including Crohn’s disease, by blocking the activity of tumor necrosis factor alpha (TNF-alpha), a protein that plays an important role in promoting inflammation. Inflectra is made in mammalian cells, glycosylated and much more complex than Zarxio. It is the first complex biosimilar approved in the US under the biosimilar pathway and the first to provide insights into FDA’s requirements for extrapolation for a complex biologic. Despite the diversity of Remicade’s indications, Inflectra was approved for all of the requested indications by extrapolation from its clinical studies for two of them, rheumatoid arthritis and ankylosing spondylitis.

Last month, FDA approved Sandoz’s biosimilar of Enbrel (etanercept), Amgen Inc.’s treatment of moderate to severe rheumatoid arthritis and a number of other conditions. Sandoz’s biosimilar, Erelzi, is the third biologic approved under the US biosimilar pathway. Etanercept is a fusion protein that binds and neutralizes excess TNF-alpha. It is a complex biologic that is made in mammalian cells and glycosylated. FDA approved Erelzi for all of Enbrel’s indications, including rheumatoid arthritis, based on a clinical study that Sandoz conducted for one of them, plaque-type psoriasis.

Although Amgen is responsible for a number of the early innovative biologics, it now also develops biosimilar biologics. Amgen has been developing a biosimilar of a blockbuster treatment for rheumatoid arthritis, AbbVie’s Humira (adalimumab). On July 12, FDA’s arthritis advisory committee unanimously recommended approval of Amgen’s biosimilar of Humira, ABP 501. Humira, like Remicade, is a monoclonal antibody that blocks the activity of TNF-alpha. It is a complex, glycosylated biologic made in mammalian cells. The FDA advisory committee recommended approval of Amgen’s biosimilar for all of the indications of Humira based on extrapolation from Amgen’s clinical studies for two of them, plaque psoriasis and rheumatoid arthritis. Although an advisory committee recommendation is not binding on FDA, FDA generally follows the recommendation.

Notably, for each biosimilar (from the least to the most complex), FDA agreed that extrapolation from clinical studies by the biosimilar maker for one or more of the indication(s) of the reference product was justified, and that the proposed biosimilar therefore could be marketed for the other indications of the reference product as well.

New Biosimilar Filings

Two new players to the US biosimilars market have filed applications with FDA. In May 2016, Samsung Bioepis and Merck announced that FDA accepted Samsung Bioepis’s application for a proposed biosimilar of Janssen’s Remicade for review. The proposed biosimilar version was approved for marketing in Europe earlier this year.

Coherus Biosciences announced in August that it submitted an application for its proposed version of Amgen’s Neulasta to FDA. It is at least the third such application filed with FDA, with Apotex’s 2014 application and Sandoz’s 2015 application having encountered regulatory hurdles.

2014-2015 Biosimilar Filings

A number of filings from 2014-2015 have been rejected in their current form. On July 19th, Sandoz revealed that FDA rejected its application for a biosimilar of Amgen’s Neulasta (pegfilgrastim). Sandoz previously announced that FDA accepted its application for review in November 2015 (an event that typically occurs 60 days after filing of the application). FDA has a performance goal of 10 months from the filing of the application to act on it one way or the other and appears to have acted on Sandoz’s application in that timeframe.

Sandoz did not identify the reasons for FDA’s rejection, stating only that it was working with FDA “to address remaining questions.” Neulasta is a pegylated, longer-acting version of Neupogen, the reference product for Sandoz’s Zarxio. Because of the pegylation, Neulasta is a larger and more complex biologic than Neupogen.

Sandoz’s application was the second application for a biosimilar of Neulasta. The first application, filed by Apotex, has not been approved, despite being accepted for review in December 2014. Apotex’s application for a biosimilar of Neupogen, accepted for review in February 2015, also has not been approved. To date, no advisory committee meeting has been scheduled for either Apotex product. Based on FDA’s approval of significantly more complex biologics, it is clear that complexity is not the issue here.

FDA also rejected Hospira’s application for a proposed biosimilar of Amgen’s EPO, a treatment for anemia. Hospira filed its application in December 2014 and FDA accepted it for review in February 2015. In October 2015, ten months after Hospira had filed its application, FDA rejected it. Notably, FDA denied approval of the application even though Hospira’s proposed biosimilar had been approved in Europe as a biosimilar since 2007. Hospira had reported that it planned to resubmit its application during the first half of 2016. FDA has a performance goal of six months for most resubmitted applications.

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The approvals and rejections indicate that few general lessons can be drawn. Biosimilar makers cannot expect their products to sail through the regulatory process even for products with significant marketing history outside the US. FDA, however, has approved biosimilars of some of the most complex biologics, including biosimilars with no marketing history in Europe (such as Sandoz’s Erelzi). Most notably, FDA has approved biosimilars for each of a reference product’s indications based on clinical studies for one or more of them, providing a significant savings in terms of cost and time to biosimilar makers.