Product Profile: Zarxio

Product Profile:

Filgrastim-sndz (Zarxio)

Drug Category: Granulocyte Colony–Stimulating Factor

Target Indications: Decreasing the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs; reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia;  reducing the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g.‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation; mobilizing autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; reduce the incidence and duration of sequelae of neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.

Manufactured and marketed by Sandoz

Summary: Zarxio is a biosimilar version of filgrastim (reference product, Neupogen, Amgen) manufactured and marketed by Sandoz. A biologic license application for approval via the 351(k) biosimilar pathway was submitted to the Food and Drug Administration (FDA) in May 2014, and it was the first biosimilar approved in the United States on March 6, 2015, launching six months later.

About the Manufacturer

Sandoz, although established as a division of Novartis in 2003, has its origins as an active player in the pharmaceutical industry in 1886. It has a considerable portfolio of biosimilar products approved by the FDA and in various stages of filing. These include Erelzi (etanercept-szzs), pegfilgrastim, adalimumab (awaiting FDA approval), and rituximab. The latter two have been approved for use in Europe, as has Erelzi and Zarxio (under the brand name Zarzio), and a biosimilar form of epoetin alfa.

News, Commentary, and Intelligence

Competitor Products and Manufacturer Analysis

Company

Product name

Brand name

Innovator product

Filing Date

Stage of development

Filgrastim

Pfizer

Filgrastim-aafi

Nevistym

Neupogen

Q4 2017 (est)

FDA approved July 20, 2018; marketed

Teva

Tbo-filgrastim*

Granix*

N/A

2009

FDA approved  August 30, 2012

Adello Biologics

TBD

Neupogen

September 2017

FDA decision expected Q4 2018

Tanvex Biologics

TX-01

TBD

Neupogen

October 2018

FDA decision expected Q3 2019

Apotex (Apobiologix)

TBD

Neupogen

February 2015

No public information on FDA action (CRL issued?)

Pegfilgrastim

Adello Biologics

TPI-120

TBD

Neulasta

Application possible in 2018

Apotex (Apobiologix)

Lapelga

Neulasta

December 2014

No public information on FDA action reported (CRL issued?)

Coherus Biosciences

CHS-1701

Udenyca

Neulasta

August 2016

Received a CRL in June 2017. Refiled application in May 2018. FDA will review by November 3, 2018

Sandoz

LA-EP2006

TBD

Neulasta

December 2015

CRL issued June/July 2016; withdrew EMA application January 2017; new application possible 2019

*Filed as a 351a product (prior to implementation of 351[k] pathway). Not technically a biosimilar.  CRL = complete response letter.

An Update From BBCIC: A Conversation With Cate Lockhart, Program Director—Part 2

(October 12, 2018)  At the recent AAM meeting, Hillel Cohen from Sandoz said that of 69 adverse drug reports for filgrastim since 2015, all but four were filed without the four-letter suffix, and they were able to identify the correct brand, whether it was Zarxio, Granix, or Neupogen.

Tidal Wave of Pegfilgrastim Biosimilars About to Hit Europe

(September 27, 2018) The European Medicines Agency (EMA) has had an extremely busy week in the pegfilgrastim biosimilars arena, granting marketing authorization to two companies’ products. In addition, the EMA’s Committee for Medicinal Products for Human Use has also recommended aprpoval for three others.

Scaling the Mountains to Create a Biosimilar Market Success

(September 11, 2018) The only biosimilar market success story to date, Zarxio®, may be as much the result of a certain set of preconditions as that of Sandoz’s marketing efforts.

Part B to Part D and Other Questions: How CMS’s Plans Could Affect Biosimilars

(August 10, 2018)  Some of these tactics are a bit late to the party, as commercial insurers and health plans have been employing them for years. To the extent that an injectable treatment can be managed through the pharmacy benefit rather than the medical benefit, the drug can be easily subjected to prior authorization, step therapy, quantity limits, and other tools routinely used.

Pfizer Gets FDA’s Green Light on Its Filgrastim Biosimilar

(July 21, 2018) The originator product, Amgen’s Neupogen®, has steep competition from two other products (Sandoz’s Zarxio®[filgrastim-sndz] and Teva’s Granix® (tbo-filgrastim]). Granix was approved as a follow-on biologic, before the biosimilar pathway was implemented.

A Test for Adello and for FDA’s Biosimilar Approval Pathway

(March 29, 2018) Adello Biologic’s 351(k) application for filgrastim comprises the physiochemical biosimilarity evidence, but in terms of clinical data, only phase 1 studies were performed..

Evidence to Support Zarxio Use Presented at AMCP

(October 27, 2017) Two posters presented at the Academy of Managed Care Pharmacy bolstered the case for moving away from the use of the originator filgrastim product Neupogen.

Coverage Uptake: Zarxio Covered by 94% of Employer-Sponsored Plans

(July 11, 2017) An analysis released by Avalere on July 11 showed that coverage of biosimilar filgrastim is the rule, not the exception, by employer-sponsored plans.

How to Self-Inject Zarxio

Lessons Learned by Sandoz in Its Launch of Zarxio

Clinical Trials of Renflexis

Published Trial Results

Pivotal Trial for Approval:

Comparison of EP2006, a filgrastim biosimilar, to the reference: A Phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy.

Study EP06-302 was a randomized, double-blind comparison of EP2006 and US-licensed Neupogen for prevention of severe neutropenia in patients with breast cancer being treated with up to 6 cycles of combination chemotherapy using docetaxel, doxorubicin, and cyclophosphamide (TAC). Chemotherapy was administered on day 1 of each 21-day cycle, and EP2006 or US-licensed Neupogen 5 μg/kg/day subcutaneously was given from day 2 until neutrophil recovery.

A total of 218 subjects were randomized to one of four groups to receive EP2006 for all cycles, US-licensed Neupogen for all cycles, EP2006 then US-licensed Neupogen in alternate cycles, or US-licensed Neupogen then EP2006 in alternate cycles. The primary endpoint was duration of severe neutropenia (DSN) in cycle 1. The between-group analysis of the primary endpoint of Cycle 1 DSN included 101 subjects treated with EP2006 and 103 subjects treated with US-licensed Neupogen.

The DSN was 1.17 ± 1.11 for the biosimilar (N = 101 days) and 1.20 ± 1.02 for the reference product (N = 1030 days). The results indicated a maximum of 3% increase or decrease in the incidence of febrile neutropenia compared with the reference product, and this was considered clinically insignificant.

Key secondary endpoints, including febrile neutropenia, days of fever, absolute neutrophil count (ANC) nadir, and time to ANC recovery in cycle 1 and across all cycles were all reported to be comparable between the study drug and the reference product. Episodes of fever were reported in 6.6% of patients receiving the biosimilar and 2.8% receiving the US-licensed reference product. Maximum duration of fever in any patient was 2 days, with most resolving within a day. One patient in both treatment groups were hospitalized. Researchers indicated 82 patients in the EP2006 arm experienced grade 3/4 neutropenia, compared with 85 patients in the Neupogen arm.

The incidence of the adverse events, including musculoskeletal pain (25% vs 29%) and injection site reaction (2% vs 1%), were deemed similar between subjects treated with EP2006 or US-licensed Neupogen in cycle 1. The researchers also found little variance in safety for the next five treatment cycles. Common treatment emergent adverse events were similar in incidence when compared between subjects treated with EP2006 or US-licensed Neupogen in Cycle 1 or across Cycles 1-6, and when compared within subjects who alternated treatments. There were too few grade > 3 TEAE or grade > 3 laboratory abnormalities for a meaningful comparison. There were no related TEAE with allergic reaction event terms specifically.

This study demonstrated the noninferiority of EP2006 to the reference agent Neupogen, without clinically meaningful differences in efficacy and safety in prevention of severe neutropenia.

 

Phase I Trial:

Comparability of biosimilar filgrastim with originator filgrastim: protein characterization, pharmacodynamics, and pharmacokinetics

 

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