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The US Biosimilar Pathway: What’s Ahead

2015 was a landmark year for biosimilars.  It began with the approval of the first US biosimilar, Sandoz’s Zarxio, in March 2015 under the Biologics Price Competition and Innovation Act of 2009 (BPCIA).  Zarxio entered the US market in September, after its 180-day notice of commercial marketing under the BPCIA expired.  Many expected the floodgates to open after Zarxio’s approval but Zarxio, a relatively simple biologic, remains the only approved US biosimilar to this day.  Seven other biosimilar applications, largely to complex biologics,  were filed in 2014/2015 and are being reviewed by FDA or have to be refiled.  Other than an FDA advisory committee meeting for Zarxio, the one other meeting scheduled last year (for Celltrion/Hospira’s proposed biosimilar of Remicade) was postponed and recently rescheduled for February 9, 2016.  2016 should provide significant insights into how FDA determines biosimilarity and extrapolation for complex biologics.

First Approved US Biosimilar

On March 6, FDA approved Sandoz’s Zarxio as a biosimilar of Amgen’s Neupogen (filgrastim), a biologic for the immune systems of patients undergoing cancer treatment.  Zarxio is the first product approved under the abbreviated pathway created by the BPCIA.  The approval came after a unanimous recommendation from FDA’s Oncologic Drugs Advisory Committee on January 7, 2015 and less than ten months after Sandoz submitted its abbreviated Biologics License Application (aBLA) to FDA on May 8, 2014.  FDA accepted the aBLA for review on July 24, 2014.  It 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 under the BPCIA.  Sandoz priced it at a modest discount of 15% over Amgen’s Neupogen

Zarxio’s path to approval has provided little insight for other biosimilar products.  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 simpler to characterize.

New Biosimilar Filings

Following up on its Zarxio approval, Sandoz filed aBLAs for two other proposed biosimilar products.  On October 2, 2015, Sandoz’s announced that FDA had accepted its application for a proposed biosimilar of Amgen’s Enbrel (etanercept) for review.  Enbrel is a treatment for rheumatoid arthritis and a number of other autoimmune conditions associated with elevated levels of tumor necrosis factor alpha (TNF-alpha), a protein that plays an important role in promoting inflammation.  Sandoz is seeking approval for all of Enbrel’s indications.  It is the first biosimilar maker to submit an application for a biosimilar of Enbrel in the US.  Enbrel, a soluble dimeric receptor fusion protein made in mammalian cells, is much more complex than Neupogen.  FDA’s review of Sandoz’s proposed Enbrel biosimilar will provide important insights into the requirements for biosimilarity and extrapolation in the context of a complex biologic.  Based on FDA’s performance goal to act on most biosimilar applications within a 10-month period, those insights could come this year.

In addition, on November 18, 2015, Sandoz announced that FDA had accepted its application for a biosimilar of Amgen’s Neulasta (pegfilgrastim) for review.  Neulasta is a pegylated, longer-acting version of Neupogen.  Like Neupogen, Neulasta is indicated to decrease risk of infection in cancer patients receiving chemotherapy or radiation.  But it is larger and more complex than Neupogen due to pegylation.  On December 7, 2015, Sandoz publicly announced additional evidence from a Phase III study in support of biosimilarity to Amgen’s product.  FDA is expected to act on Sandoz’s application for its proposed biosimilar of Neulasta this year.  But Sandoz is not the first to file a biosimilar application for Neulasta.  As discussed below, Apotex filed its biosimilar application for Neulasta in 2014 but has encountered regulatory hurdles.

On November 25, 2015, Amgen, an innovator and biosimilar maker, announced that it had submitted an aBLA for a biosimilar of AbbVie’s Humira (adalimumab), an anti-TNF monoclonal antibody used to treat rheumatoid arthritis and other inflammatory diseases.  Amgen is the first to file a biosimilar application for AbbVie’s blockbuster product, a complex biologic.  Amgen is seeking approval for all indications of Humira.  FDA accepted Amgen’s biosimilar application for review on January 25 and, based on its performance goals, FDA is expected to act on the application this fall.

2014 Biosimilar Filings

In addition to Sandoz’s Zarxio, biosimilar makers filed four other regulatory applications for proposed biosimilar products in 2014.  Celltrion/Hospira filed an application for a proposed biosimilar of Janssen’s Remicade (infliximab), a blockbuster anti-TNF monoclonal antibody.  Hospira filed an application for its proposed biosimilar of Amgen’s Epogen (EPO).  And Apotex filed applications for its proposed biosimilar versions of Amgen’s Neupogen and Neulasta products.  None of these applications has been approved to date.

Celltrion/Hospira’s biosimilar application was accepted for FDA review in October, 2014, just a few months after FDA accepted Sandoz’s application for Zarxio for review on July 24, 2014.  It was the second biosimilar application accepted for review in the US but has had a much different path than Sandoz’s application for Zarxio.  FDA had initially scheduled an advisory committee meeting for March 17, 2015 but then postponed the meeting for nearly a year due to “information requests pending with the sponsor.” The meeting is now rescheduled for February 9, 2016.  On February 5, 2016, in advance of the February 9 meeting, FDA staff recommended approval of Celltrion/Hospira’s proposed biosimilar of Remicade Celltrion/Hospira for all seven of Remicade’s indications.   FDA’s Arthritis Advisory Committee will review biosimilarity and extrapolation for the proposed biosimilar.  If FDA ultimately approves this product, it will be the first complex biosimilar approved in the US under the biosimilar pathway.

Hospira filed its application for a proposed biosimilar of Amgen’s EPO on December 16, 2014.  FDA accepted it for review in February 2015.  On October 16, 2015, exactly ten months after Hospira had filed its application, FDA rejected the application, meeting its performance goal.  Notably, FDA denied approval of the application even though Hospira’s proposed product had been approved in Europe as a biosimilar (trade name Retacrit) since 2007.  While the details of FDA’s October 16, 2015 letter rejecting the application are not public, EPO is a more complex biologic product than Neupogen.  It is a larger and glycosylated protein.  It is also made in genetically engineered mammalian cells, as opposed to bacteria.  Hospira has indicated that it plans to resubmit its application during the first half of 2016 and expects FDA to act by the end of the year.  FDA has a performance goal of six months for most resubmitted applications.

Apotex’s two biosimilar applications were also filed in 2014 and have not been approved.  FDA accepted Apotex’s application for a biosimilar of Amgen’s Neulasta for review on December 17, 2014.  It accepted Apotex’s application for its proposed biosimilar of Amgen’s Neupogen on February 13, 2015.  Neither product has been scheduled for an advisory committee meeting to date.  Indeed, Apotex did not identify when FDA would approve its products in recent briefing to the Federal Circuit in an appeal involving the 180-day notice of commercial marketing under the BPCIA.

The developments for the four applications filed in 2014, other than the one for Zarxio, indicate that few lessons can be drawn from Zarxio’s approval.  Biosimilar makers cannot expect their products to sail through the regulatory process the way Zarxio did, even for products with significant marketing history outside the US.  2016 should provide insights into FDA’s requirements for biosimilarity and extrapolation for biological products in a variety of classes, including complex biologics, with at least seven biosimilar applications that are either being reviewed by FDA or have to be refiled.

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