Patent Docs: FDA approves Sandoz’s filgrastim biosimilar drug product

Many have pontificated about the benefits of a biosimilar approval pathway in the United States; those predictions have begun the process of being tested with approval of Zarxio

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Recently, the U.S. Food and Drug Administration (FDA) approved a biosimilar version of Amgen’s Neupogen (filgrastim) product for sale in the United States. This is the first biosimilar to be approved under the provisions of the Biologics Price Competition and Innovation Act (BPCIA), which was part of the healthcare reform package passed in 2010 and commonly referred to as Obamacare. Sandoz (a division of Novartis) will sell its biosimilar under the brand name Zarxio.
The drug is a recombinantly produced version of human granulocyte colony stimulating factor (methionyl-human granulocyte colony stimulating factor or r-metHuG-CSF), used to stimulate neutrophil production in patients undergoing chemotherapy. Amgen has obtained FDA approval for Neupogen for treating the following five conditions:
  • Cancer patients receiving myelosuppressive chemotherapy;
  • Cancer patients with acute myeloid leukemia receiving induction or consolidation chemotherapy;
  • Cancer patients undergoing bone marrow transplantation;
  • Patients undergoing autologous peripheral blood progenitor cell collection and therapy; and
  • Patients with severe chronic neutropenia.
Sandoz submitted its biosimilar application under Section 351(k) of the Public Health Service Act last July and provided the FDA with a wide variety of evidence of biosimilarity; this evidence included “structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data” and, importantly, an absence of immunogenicity in human subjects, together demonstrating the biosimilarity of the Sandoz product to Neupogen. In particular, Sandoz performed a head-to-head comparison between its biosimilar drug and Neupogen showing a level of biosimilarity sufficient for the FDA to approve Zarxio for all of Amgen’s approved indications.
Neupogen is a $1.2 billion to $1.4 billion per year product for Amgen, and part of the significance of the FDA approval is economic. Industry estimates have Sandoz selling Zarxio for 15 to 30 percent less than Amgen’s current price, which estimates are expected to reduce the cost of the drug by an equivalent amount once this biosimilar becomes accepted by physicians. Unlike conventional “generic,” generally small-molecule, drugs (which cause upwards of 90-percent reductions in drug prices from the innovator brand price), biosimilar drugs are both more complex than small-molecule drugs and are administered by physicians (typically by injection), and thus continue to actively involve medical personnel during a course of treatment. Consequently, physician acceptance of biosimilar drugs is much more of an issue than for generic drugs, and thus market penetrance is expected to be delayed for one to five years, even by Sandoz. These estimates are in line with industry expectations for biosimilar drugs in general; for example, Express Scripts has estimated that while U.S. healthcare costs may be reduced by about $250 million between 2015 and 2025, biosimilar sales worldwide will only increase from $1.3 billion to $35 billion by 2020, even taking into account the robust approval climate for biosimilar drugs on Europe, where the EMEA has approved 21 biosimilar drugs over the past 10 years (it should be noted that cost savings in Europe from biosimilars amount to about a 10-percent reduction).
The other basis for considering approval of Zarxio to be significant is that, as the first biosimilar approved, it will be a bellwether for how well the FDA has implemented the BPCIA and performed in its role in protecting public health. The complexity of both biologic drugs themselves (which typically comprise thousands of atoms; the chemical formula of filgrastim for example is C845H1343N223O243S9) and the methods by which they are made (typically using recombinant cells expressing genetically engineered genes transferred from one organism [here, human] to another, such as bacteria) provide much greater challenges for the agency in performing its review of safety, potency and efficacy. While the EMEA in Europe has successfully approved biosimilar drugs for a decade, in the United States, doubts are likely to remain until experience (both the agency’s and the public’s) has shown them to be unfounded.
There is one aspect of the FDA’s approval of Zarxio that remains controversial, and that is the non-proprietary (or common) name the agency has given to Sandoz’s product. The name, filgrastrim-sndz, has been called a “placeholder” by the agency because it has not yet decided whether to give different names to biosimilar versions of branded biologic drugs (as innovator biotechnology companies have advocated to ensure that any adverse events be properly ascribed to the biosimilar) or to use the same name as the innovator biologic drug (as urged by groups like the Generic Pharmaceutical Association and health organizations to minimize the chance of confusion by medical personnel).
One thing the FDA did not do was approve Zarxio as an interchangeable product, because inter alia the agency has not yet developed standards for making this determination. To be interchangeable, there must be no differences in outcomes when a patient is switched to an interchangeable biosimilar drug product than occur when the innovator’s product is administered (in addition to the absence of “no clinically meaningful differences” required to be shown between the branded [or reference product sponsor’s] product and the biosimilar drug for approval as a biosimilar). Interchangeability, when achieved, will have the advantage that switching to the interchangeable version will not require physician approval and will be eligible for at least a one-year exclusivity period for the successful interchangeable biosimilar applicant.
This is but the first of many biosimilar approvals waiting FDA action; these include applications by Apotex for its version of Neupogen (which was accepted by the FDA last month and is sold in Europe under the name Grastofil), as well as a biosimilar version of Amgen’s Neulasta (a PEGylated version of the molecule). Pundits and politicians have pontificated about the benefits to be had by adopting a biosimilar approval pathway in the United States, and those predictions have begun the process of being tested with approval of Zarxio.

Kevin Noonan is a partner with the law firm McDonnell Boehnen Hulbert & Berghoff LLP and represents biotechnology and pharmaceutical companies on a myriad of issues. A former molecular biologist, he is also the founding author of the Patent Docs weblog,

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