FDA Panel Unanimously Endorses First Biosimilar


In a unanimous 14-0 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) recommended the approval of EP2006, a biosimilar version of filgrastim (Neupogen; Amgen).



Deborah K. Armstrong, MD

In a unanimous 14-0 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) recommended the approval of EP2006, a biosimilar version of filgrastim (Neupogen; Amgen). If the FDA follows the recommendation, the drug would become the first biosimilar approved in the United States.

Filgrastim is a man-made version of granulocyte-colony stimulating factor (G-CSF), a protein that stimulates production of white blood cells known as neutrophils. When injected into the body, filgrastim has the same effect as G-CSF, increasing an individual’s ability to fight infections. With its vote, ODAC asserted that EP2006 would also have the same effect.

“I voted yes and I am willing to bet my life on it,” said temporary ODAC member and patient representative Randy Hillard, MD, from East Lansing, Michigan.

ODAC recommended approval of EP2006 for all five of filgrastim’s authorized indications. Filgrastim is approved for chemotherapy-induced febrile neutropenia in patients with nonmyeloid malignancies, for patients with acute myeloid leukemia receiving induction or consolidation chemotherapy, and for cancer patients receiving bone marrow transplants. The drug also has approved indications to treat patients with severe chronic neutropenia and patients undergoing peripheral blood progenitor cell collection and therapy.

US law definesbiosimilarsas biological products demonstrated to be “interchangeable” with an FDA-licensed biological product (the “reference product”). As part of the Affordable Care Act, an expedited approval pathway was established for biosimilars that requires less product-specific data than the FDA’s traditional regulatory channels, allowing reliance on existing efficacy and safety data for the reference product.

By voting in favor of approving EP2006, ODAC asserted that the drug met the criteria established under this biosimilar pathway. Specifically, the committee is stating that EP2006 is “highly similar” to filgrastim, “notwithstanding minor differences in clinically inactive components,” and that “there are no clinically meaningful differences between EP2006 and filgrastim in terms of [purity], safety, and effectiveness.”

“We have a lot of clinical data that these are very similar compounds and pharmacokinetics and pharmacodynamics are very comparable,” said Deborah K. Armstrong, MD, chairperson of the ODAC meeting, and professor of Oncology at the

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

EP2006, which is being developed by Sandoz Biopharmaceuticals, a unit of Novartis, 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 filgrastim.

The FDA accepted Sandoz’ application to market EP2006 as a biosimilar version of filgrastim in July 2014, making EP2006 the first drug to be reviewed under the new US biosimilar pathway.

To support its regulatory filing, Sandoz submitted data from five pharmacokinetic/pharmacodynamics studies, five nonclinical studies, and two clinical studies.

Sandoz used European Union (EU)-approved Neupogen as a comparator in some of these studies, and thus the FDA required that the company establish the biosimilarity of US-licensed Neupogen, (EU)—approved Neupogen, and EP2006. ODAC determined that through pair-wise comparisons of the three products, Sandoz established an adequate “bridge” showing that the treatments met the predetermined criteria for analytical similarity.

Among all the data Sandoz submitted, the key clinical study ODAC considered was the pivotal double-blind phase III PIONEER trial (EP06-302), which compared the efficacy and safety of EP2006 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.

Filgrastim or EP2006 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&rsquo;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 EP2006 (N = 101) in the first cycle and compared them with all patients who received filgrastim (N = 103) in the first cycle.

The results showed that the study met its primary endpoint, with a cycle 1 mean DSN of 1.17 and 1.20 days, respectively, for patients receiving EP2006 and filgrastim. The filgrastim minus EP2006 DSN difference was 0.04 days (90% CI, -0.21-0.28).

The data also showed that repeated switching at each cycle between the investigational biosimilar and Neupogen had no impact on efficacy, safety or immunogenicity.

There were no significant adverse event differences.

In explaining her &ldquo;yes&rdquo; vote, Ginna G. Laport, MD, clinical research director in the Division of Blood & Marrow Transplantation at Stanford University Medical Center, said the data supplied by Sandoz was convincing. &ldquo;What really moved me was the very strong evidence shown by the sponsor for biosimilarity in numerous studies.&rdquo;

Sandoz already manufactures a biosimilar version of filgrastim under the brand name Zarzio in more than 40 countries. According to Sandoz, Zarzio is the leading daily G-GSF used daily in Europe.

Biosimilars have reduced healthcare costs in some of these countries and it is hoped that it will have a similar impact in the United States. One analysis estimates that increased use of biosimilars could reduce US spending on biologics by $44 billion over the next 10 years.1

Though biosimilars typically cost less than the original drugs, this will not always be the case; however, healthcare savings with biosimilars will likely be manifested in other areas, such as copay reductions and formulary decisions.

&ldquo;Let me say we cannot say that the price [of EP2006] would be less [than filgrastim]—in some situations it might be a parity because of other relative terms that will come into existence&hellip;but the cost will be less to the consumer, to the payer, to the healthcare economy&mdash;otherwise it does not make sense,&rdquo; Mark McCamish, MD, PhD, global head of development at Sandoz, said at the ODAC hearing.


1. The RAND Corporation. Biosimilar medications could create billions in health care savings. http://bit.ly/1xG2vt4. Accessed January 7, 2014.

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