Court Clears First US Biosimilar for Future Marketing

An appellate court ruled that the FDA-approved biosimilar Zarxio can be marketed in the United States after September 2, 2015.

In a 2-to-1 vote, the US Court of Appeals for the Federal Circuit has ruled that the first FDA-approved biosimilar, Zarxio (filgrastim-sndz), can be marketed in the United States after September 2, 2015, according to a document from the lawsuit between Amgen and Sandoz.

Zarxio, which is manufactured by Sandoz, was approved in March 2015 under the newly initiated US biosimilar pathway, which was established under the Affordable Care Act. Biosimilars are meant to foster competition and lower prices, and are defined as biological products demonstrated to be “interchangeable” with an FDA-licensed biological product, which is Neupogen (Amgen; filgrastim) in this case.

In the ruling, the appeals court dismissed Amgen's claim that Sandoz violated information disclosure provisions in the Biologics Price Competition and Innovation Act (BPCIA) of 2009. The court confirmed that information in an abbreviated new drug application for a biosimilar should be disclosed to the original product developer 6 months prior to marketing. In this situation, the court agreed that Amgen had not received full information from Sandoz until the approval of Zarxio in March 2015.

The court sided with Sandoz on a number of other items regarding unfair competition and conversation. Additionally, the court labeled many of Amgen's appeals as moot. However, regarding Amgen’s patent infringement claim, the appeals court relied on the judgment of the district court.

"We affirm the dismissal of Amgen’s unfair competition and conversion claims, vacate the district court’s judgment on Sandoz’s counterclaims interpreting the BPCIA, and direct the district court to enter judgment on those counterclaims consistent with this opinion," according to the opinion of the court, written by Circuit Judge Alan Lourie. "We also remand for the district court to consider the patent infringement claim and counterclaims relating to the ’427 patent and any other patents properly brought into the district court action."

Amgen initiated the lawsuit in October 2014, claiming that Sandoz, which is operated by Novartis, failed to provide proper documentation on the biosimilar. Specifically, Amgen claimed to have not seen the biologics license application for Zarxio prior to filing for marketing approval. With this lawsuit pending, Novartis agreed to delay marketing Zarxio until a decision was reached, despite FDA approval.

In late March, a federal judge in San Francisco dismissed Amgen's claims, which led to an appeal in the US Court of Appeals for the Federal Circuit in Washington. This decision, which was handed down on May 5, blocked Zarxio from entering the market, until oral arguments could be heard.

The FDA based its approval for Zarxio on data Sandoz submitted from five pharmacokinetic/pharmacodynamics studies, five nonclinical studies, and two clinical studies. In the phase III PIONEER study, the cycle 1 mean duration of severe neutropenia (DSN) was 1.17 and 1.20 days, for Zarxio and Neupogen, respectively. The mean time to absolute neutrophil count recovery in cycle 1 was 1.8 days ± 0.97 in the Zarxio arm compared with 1.7 days ± 0.81 in the Neupogen arm.

"Filgrastim has proven clinical value in treating patients at increased risk of neutropenia, but it is underused in the United States for a variety of reasons, including price," explained Louis Weiner, MD, chairman of the Department of Oncology and director of the Lombardi Comprehensive Cancer Center at Georgetown University, when Zarxio was approved. "Biosimilars have the potential to increase access and the approval of Zarxio may reduce costs to the healthcare system. The comprehensive data set supports its use in clinical practice."


Zarxio was unanimously recommended for approval in early-January by the FDA's ODAC panel. The drug is manufactured using recombinant technology in E. coli host cells. The production process involves various steps that isolate and purify met-C-GSF. The drug is produced in prefilled syringes and at the same strengths (300 mcg/0.5 ml and 480 mcg/0.8 ml) as Neupogen.


Among the data Sandoz submitted, the key clinical study the FDA based its approval on was the pivotal double-blind phase III PIONEER trial (EP06-302), which compared the efficacy and safety of Zarxio and US-licensed Neupogen in patients with breast cancer treated with myelosuppressive chemotherapy.


In the study, all patients received 6 cycles of TAC chemotherapy (taxotere at 75 mg/m2 IV, Adriamycin at 50 mg/m2 IV, and Cytoxan at 500 mg/m2 on day 1 of each 21-day cycle) and were randomized to either 6 cycles of EP2006, 6 cycles of filgrastim, or one of two 6-cycle regimens that rotated between the two drugs.


Neupogen or Zarxio were administered subcutaneously at 5 mcg/kg body weight starting on day 2 of cycle 1 and given until the ANC recovered to 10 Gi/L after the nadir or a maximum of 14 days, whichever came first.


The primary endpoint was DSN, which the researchers defined as the number of consecutive days a patient’s ANC was <0.5 Gi/L after the first cycle of chemotherapy. For this analysis, which included 204 patients, the researchers combined all patients who received Zarxio (n = 101) in the first cycle and compared them with all patients who received filgrastim (n = 103) in the first cycle.


In addition to meeting the primary endpoint, the study showed that repeated switching at each cycle between the investigational biosimilar and Neupogen had no impact on efficacy, safety or immunogenicity. Moreover, there were no significant adverse event differences.


In the pharmacokinetic/pharmacodynamics studies submitted to the FDA, both Zarxio and Neupogen were found to have similar activity, when looking at the area under the curve (AUC) and peak serum concentration (Cmax). Following a single dose of either drug, the AUC and Cmax were within 80% to 125%, with a 90% confidence interval. Absolute neutrophil counts and CD34+ cell counts were within 80% and 125% of each other, following treatment (95% CI).