First US Biosimilar Finally Reaches Market

Ralph Boccia, MD

The first FDA-approved biosimilar, Zarxio (filgrastim-sndz), is now available for patients in the United States, following a series of lawsuits and court decisions.

The G-CSF analog, which is manufactured by Sandoz, was approved in March 2015 for all five authorized indications for its counterpart, Neupogen (filgrastim) under the newly initiated US biosimilar pathway. 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.

The 300 µg dose of Zarxio will cost $275.66 and the 480 µg dose will cost $438.98. The historic price for Neupogen has been $324.30 and $516.45 for these same dose sizes, respectively, representing a 16.2% difference between the two drugs.

"While biologics have had a significant impact on how diseases are treated, their cost and co-pays are difficult for many patients and the healthcare budget in general," Ralph Boccia, MD, medical director of the Center for Cancer and Blood Disorders, and Chief Medical Officer for the International Oncology Network, said in a statement. "Biosimilars can help to fill an unmet need by providing expanded options, greater affordability, and increased patient access to life-saving therapies."

The FDA based its approval for Zarxio on data Sandoz submitted from five pharmacokinetic/pharmacodynamics studies, five nonclinical studies, and two clinical studies. Among all 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).

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 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.

The cycle 1 mean DSN was 1.17 and 1.20 days, for Zarxio and Neupogen, respectively. The mean time to ANC 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.

"As the pioneer and global leader in biosimilars, Sandoz has maintained a commitment to bringing high-quality biosimilar medicines to patients and healthcare professionals around the world," Richard Francis, Global Head, Sandoz, said in a statement. "With the launch of Zarxio, we look forward to increasing patient, prescriber and payer access to filgrastim in the US by offering a high-quality, more affordable version of this important oncology medicine."

Zarxio was unanimously recommended for approval in early-January 2015 by the FDA's ODAC advisory 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.

Prior to the approval, Amgen initiated a lawsuit 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.

In July, the US Court of Appeals for the Federal Circuit dismissed Amgen's claim that Sandoz violated information disclosure provisions in the Biologics Price Competition and Innovation Act of 2009. The court sided with Sandoz in a 2-to-1 vote 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.

Blackwell K, Semiglazov V, Gascon P, et al. A Comparison of Proposed Biosimilar and Originator Filgrastim for the Prevention of Neutropenia in Patients with Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Phase III, Randomized, Double-Blind Trial (The PIONEER study). Blood. 2014;124(21):5133-5133.