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Second Biosimilar Infliximab Submitted to EMA for Approval; Teva Halts Biosimilar Rituximab Clinical Trial

In late September, a second biosimilar version of Remicade® (infliximab) was submitted by an unnamed company to the EMA for review and approval. The first biosimilar version, submitted to the EMA by Celltrion in April, has since been approved by the Korean FDA. Remsima™, as it’s known, is expected to be commercially available in Korea before the end of 2012. Celltrion is preparing for approval and launch of Remsima in over 100 countries worldwide, and expects to receive marketing approval in numerous emerging markets where Remicade does not have patent protection, toward the end of the year. However, there is no imminent decision expected by EMA on either of the two biosimilar infliximab applications since the EU patents for Remicade do not expire until 2014 at the earliest in the EU.

In addition to the two pending infliximab applications, there are five other biosimilar applications currently being reviewed by EMA: three human insulins, one follitropin alfa and one filgrastim, all of which should keep EMA busy for some time. The last biosimilar to be approved by EMA was Hospira’s filgrastim back in June 2010 making us wonder whether this long period since the last biosimilar approval signals a cooling off of the biosimilar market in Europe, if the quality of applications submitted to date were inadequate for approval, or if companies are choosing other regulatory pathways entirely for approval of these products.

Consider that Teva, the world’s largest generic drugmaker, announced last week that it was suspending plans for a Phase 3 clinical trial for its biosimilar version of Roche’s Rituxan® (rituximab). Teva indicated it wants to pause to consider the best regulatory path in Europe, where patent protection expires in 2013, and the United States, where patents remain in effective until 2018. Teva has taken similarly cautious steps in their biosimilar development previously. Not wanting to wait for the regulatory haze to clear, Teva submitted a conventional BLA for its biosimilar filgrastim in the United States two years ago. Do these moves suggest that Teva is uncertain about how biosimilar monoclonal antibodies will be reviewed by EMA, and therefore, is considering a more conventional regulatory approval pathway for Europe at it has done in the US? Is this a harbinger of the regulatory challenges the infliximab developers can expect to face? The current regulatory pathway in the EU is much clearer for biosimilars than in the United States, but that doesn’t necessarily mean smooth sailing or automatic approval. As monoclonal antibodies are more complicated molecules than the already approved biosimilars, it is likely that EMA may take a more cautious approach to the review of these biosimilar marketing applications. Furthermore, approval from the EMA to extrapolate to multiple indications will be important for both companies to capture a meaningful portion of the $21 billion TNF-a antagonist market. KFDA did approve Celltrion’s Remsima for multiple indications, but it is uncertain whether EMA will follow suit. While Remicade is forecasted to be one of the top three selling drugs in 2012, it was also one of the earliest monoclonal antibodies to receive regulatory approval. Nevertheless, as a chimeric monoclonal antibody containing both human and murine sequences, it has some safety limitations associated with immunogenicity. If the biosimilar versions of infliximab are less immunogenic or have other improved quality attributes compared to the reference product, their odds of capturing a meaningful piece of the $8 billion market improve.

Even though there have only been a couple of monoclonal antibody biosimilar submissions so far, we do not believe interest in these products is cooling off because the opportunities are just too large and still untapped. We expect to see many more applications in the coming year, not only for biosimilar infliximabs, but for other monoclonal antibodies as well. We do, however, expect EMA to be cautious when reviewing this class of molecules in order to build an experience base for both regulators and manufacturers. Of course, EMA’s caution and potentially lengthy reviews of biosimilar applications may cause other companies to follow Teva’s lead and pursue the traditional novel biologic approval pathway for biosimilars. It will be interesting to track these early biosimilar monoclonal antibody submissions to see whether other companies developing biosimilars continue on their current development paths or shift gears.


Blog article by: Patti Seymour and Howard L. Levine