The approval of Sandoz’s Zarxio, a biosimilar of filgrastim, the active ingredient in Amgen’s Neupogen, in early March 2015 by the US Food and Drug Administration marked the approval of the first biosimilar product in the US.  DCAT Value Chain Insights (VCI) examines the implications and opportunities in the biosimilars market.

Since the approval of Zarxio last month, the battle in the biosimilars market has intensified. Sandoz gained two important victories to keep the drug on the market, most notably a denial by the FDA of a Citizen Petition filed by Amgen as well as a ruling by a federal court that denied Amgen’s bid for a preliminary injunction against Sandoz from marketing  filgrastim. So what are the implications for this product and the overall biosimilars market? DCAT Value Chain Insights (VCI) takes an inside look.

The FDA’s approval for Sandoz’s Zarxio (filgrastim-sndz), the first biosimilar product approved in the United State, is based on the reference product, Neupogen, marketed by Amgen, which was originally licensed in 1991. Zarxio was approved for the same indications as Neupogen, and can be prescribed by a healthcare professional for: patients with cancer receiving myelosuppressive chemotherapy; patients with acute myeloid leukemia receiving induction or consolidation chemotherapy; patients with cancer undergoing bone marrow transplantation; patients undergoing autologous peripheral blood progenitor cell collection and therapy; and patients with severe chronic neutropenia.

The regulatory pathways for biosimilars was authorized by the Biologics Price Competition and Innovation Act of 2009 (BPCIA), which was passed as part of the Affordable Care Act that was signed into law in March 2010. The BPCIA created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, called the “reference product.” This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data. A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

The FDA’s approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen. Zarxio has been approved as biosimilar, not as an interchangeable product. Under the BPCIA a biological product that that has been approved as an “interchangeable” may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. For this approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name for this product should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilar and other biological products. While the FDA has not yet issued draft guidance on how current and future biological products marketed in the United States should be named, the agency intends to do so in the near future.

Since the approval of Zarxio in early March, Sandoz has overcome two challenges by Amgen for the product. In mid-March 2015, a federal court in Northern California ruled against Amgen in its effort to obtain a preliminary injunction against Sandoz from marketing Zarxio over the companies’ dispute on conflicting interpretations of the BPCIA. At issue were disclosure and negotiation process requirements under the BPCIA that requires an applicant for a biosimilar sharing its biologics license application (BLA) and manufacturing information with the reference product sponsor within 20 days of receiving notice that the FDA has accepted the BLA for review and other provisions requiring an applicant to give the sponsor at least 180 days advance notice of the first commercial marketing of its biosimilar. The BPCIA enables a process for resolving patent disputes arising from biosimilars, whereby applicants and sponsors may participate in a series of disclosures and negotiations aimed at narrowing or eliminating the prospect of patent litigation. Under the provisions, while engagement in the process creates a temporary safe harbor from declaratory judgment actions, a party’s failure to participate permits the opposing party to commence patent litigation. Amgen had contended that Sandoz has not followed these provisions and that in doing so, it had also transgressed under California’s Unfair Competition Law (UCL). Amgen asserted that Sandoz acted unlawfully because it failed to comply with the BPCIA disclosure and negotiation procedures and intended to market its biosimilar immediately upon receiving FDA approval, rather than waiting until at least 180 days thereafter. Sandoz contended its actions comported with the letter and spirit of the BPCIA, necessitating, therefore, the denial of Amgen’s motion and dismissal of its UCL and conversion claims.

In its decision, the court sided with Sandoz. The judge ruled that it was permissible under the BPCIA for a biosimilar applicant not to provide its BLA and/or manufacturing information to the reference product sponsor, subject to the consequences set forth in the BPCIA and that such a decision alone does not offer a basis for the sponsor to obtain injunctive relief, restitution, or damages against the applicant as the BPCIA sets forth the disclosure and negotiation process for such a condition. With regard to the 180-day notice, the court ruled that: “It is therefore evident that Congress intended merely to encourage use of the statute’s dispute resolution process in favor of litigation, where practicable, with the carrot of a safe harbor for applicants who otherwise would remain vulnerable to suit. The statute contains no stick to force compliance in all instances, and Amgen does not identify any basis to impute one.” Moreover, the court said that it was not Congressional intent to provide an additional 180-days of exclusivity to a sponsor company following approval of a biosimilar. The court ruled that “because the FDA cannot license a biosimilar until 12 years after approval of a reference product, Amgen’s reading would tack an unconditional extra six months of market exclusivity onto the twelve years reference product sponsors already enjoy under 42 U.S.C. §262(k)(7)(A).7. Had Congress intended to make the exclusivity period twelve and one-half years, it could not have chosen a more convoluted method of doing so. Moreover, Congress presumably could have been far more explicit had it intended for infringement suits to commence only once a biosimilar receives FDA approval. It was, therefore, not wrongful for Sandoz to give Amgen its 180 days’ notice prior to first commercial marketing pursuant to subparagraph (l)(8)(A) in July 2014, in advance of receiving FDA approval.” Also, later in the month, the FDA denied a Citizen Petition by Amgen requesting that the FDA mandate compliance with these BPCIA information exchange provisions, citing that the BPCIA does not require the FDA to impose a certification requirement as part f the biosimilar review process.

These decisions far now bode well for biosimilar developers. Sandoz is the generics arms of Novartis.Sandoz estimates that it has a 50% volume share of biosimilars approved in North America, Europe, Japan, and Australia. It currently markets three biosimilars (somatropin, filgrastim and epoetin alfa) outside the US. Marketed as Zarzio outside of the US, the Sandoz biosimilar filgrastim is available in more than 60 countries worldwide,The Sandoz pipeline also has several biosimilars across the various stages of development, including five programs in Phase III clinical trials/filing preparation.