Zarxio, the first FDA-approved biosimilar, has effectively been blocked from reaching US markets by an injunction from Amgen.
Zarxio (filgrastim-sndz), the first FDA-approved biosimilar, has effectively been blocked from reaching US markets by an injunction from Amgen, the manufacturer of the G-CSF analog counterpart, Neupogen (filgrastim), according to a decision from the US Court of Appeals.
In late March, a federal judge in San Francisco dismissed Amgen's claims that Zarxio’s biologics license application was not submitted correctly. This led to an appeal in the US Court of Appeals for the Federal Circuit in Washington, with a decision handed down on May 5 that blocks 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 drug is manufactured using recombinant technology inE. colihost 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.
Prior to the approval, Zarxio was unanimously recommended for approval in early-January by the FDA's ODAC panel, based on data submitted by Sandoz, which is operated by Novartis, from five pharmacokinetic/pharmacodynamics studies, five nonclinical studies, and two clinical studies.
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/m2IV, Adriamycin at 50 mg/m2IV, and Cytoxan at 500 mg/m2on 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 absolute neutrophil count (ANC) recovered to 10 Gi/L after the nadir or a maximum of 14 days, whichever came first.
The primary endpoint was duration of severe neutropenia (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 this study, the cycle 1 mean 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.
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. ANCs and CD34+ cell counts were within 80% and 125% of each other, following treatment (95% CI).