First FDA-Approved Biosimilar Blocked From Entering US Market

The first FDA-approved biosimilar, Zarxio (filgrastim-sndz), has been blocked from reaching US markets by an injunction from Amgen, the manufacturer of the G-CSF analog counterpart, Neupogen (filgrastim).

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, which is required under the US Biologics Price Competition and Innovation Act (BPCIA). 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. This court date is scheduled for June 3, 2015.

Zarxio was approved under the newly initiated US biosimilar pathway, which was established under the Affordable Care Act. Biosimilars are meant to foster pricing competition and lower prices, and are defined as biological products demonstrated to be “interchangeable” with an FDA-licensed biological product.

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 US 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 pre-filled 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 six 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 six cycles of EP2006, six cycles of filgrastim, or one of two six-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).