Ten Years of Data Support Safety of Biosimilar Filgrastim for Donor Mobilization

A 10-year prospective surveillance study of healthy stem cell donors who received the Sandoz biosimilar filgrastim (Zarzio, marketed as Filgrastim Hexal in Germany) for hematopoietic stem and progenitor cell (HSPC) mobilization reported no evidence of long-term safety concerns, providing reassurance for the continued use of granulocyte colony-stimulating factors (G-CSFs) in donor mobilization.

The noninterventional EP06-501 (SMART; NCT01766934) study enrolled 244 adult, healthy, unrelated stem cell donors from the Deutsche Stammzellspenderdatei registry at 2 German centers. Participants received at least 1 dose of Sandoz’s filgrastim biosimilar, Zarzio, administered subcutaneously for up to 5 days to mobilize stem cells for collection by leukapheresis. Median donor age was 34 years (mean [SD], 35.8 [9.8] years; range, 19-60 years), and approximately three-fourths of participants were male. Median body mass index was 26.9 kg/m², placing the cohort in the overweight category.

Follow-up included structured assessments of physical and mental health, self-reported outcomes via the SF-12 questionnaire, and adverse event (AE) reporting at baseline, 1, 6, and 12 months after apheresis, and annually for 10 years.

Nearly all donors (95%) reported at least 1 AE during the initial mobilization period, with bone pain being the most common. After this period, a total of 564 AEs were documented, with median onset occurring about 4 years after mobilization (3.86 years for women and 4.02 years for men).

The majority of AEs were musculoskeletal or connective tissue disorders (n = 134) and infections or infestations (n = 130). Other categories included gastrointestinal (n = 29), endocrine (n = 18), and vascular disorders (n = 16). A total of 98 serious AEs were reported in 56 donors, but none were deemed related to biosimilar filgrastim.

Age and sex differences emerged: younger donors had significantly lower AE rates compared with older donors (rate ratio, 0.64; 95% CI, 0.43–0.95; P = .026). Female donors experienced higher annual AE rates than male donors (0.40 vs 0.21 AEs/year; rate ratio, 1.87; 95% CI, 1.32–2.64; P < .001).

Twelve women reported 13 pregnancies following donation, resulting in 14 live births. Pregnancy-related AEs—such as gestational diabetes, cervical incompetence, and gestational hypertension—occurred only once each, with no clustering or suspected relationship to prior biosimilar filgrastim exposure. No miscarriages, congenital anomalies, or neonatal complications were reported.

Well-Being and Long-Term Safety

SF-12 assessments indicated that donors maintained superior average physical health scores compared with the general German population, even after 10 years (53.0 [6.9] vs 43.1 [6.9]; P < .0001). Mental health scores remained comparable to population averages. Neither long-term declines in health nor increased incidence of malignancies were observed. Importantly, the COVID-19 pandemic did not appear to affect donor well-being during follow-up.

Sandoz, the developer of Zarzio, funded the study. Authors concluded that the findings confirm the established safety profile of filgrastim biosimilars and provide critical long-term reassurance for donor safety in the context of allogeneic transplantation.

“No new or excessive adverse events were identified during a 10-year follow-up of mobilized stem cell donors and therefore reassure about the overall safety of stem cell mobilization with G-CSF in healthy volunteers,” wrote the investigators.

The results bolster confidence in biosimilar filgrastim products as safe, cost-effective alternatives to reference filgrastim for HSPC mobilization, supporting their continued integration into transplantation practice and managed care formularies.

A Brief History of Zarzio/Zarxio in the EU and US

Sandoz’s filgrastim biosimilar was first approved in Europe in 2009 under the brand name Zarzio.2 Approval was based on phase 3 confirmatory clinical data—the most sensitive population being patients with breast cancer undergoing myelosuppressive chemotherapy—and regulatory extrapolation of other indications such as stem cell mobilization and chronic neutropenia. Over the subsequent decade, real-world evidence, including the MONITOR-GCSF study (NCT01459653) across 12 European countries (n = 1447), supported Zarzio’s efficacy and safety in oncology treatments.

In the US, Sandoz’s biosimilar (filgrastim-sndz, branded as Zarxio) became the first FDA-approved biosimilar on March 6, 2015, under the Biologics Price Competition and Innovation Act pathway.3 Its approval was grounded in a robust "totality of evidence," which included structural/functional characterization, nonclinical and clinical comparability, and the PIONEER trial data (NCT01519700) showing equivalent reductions in severe neutropenia durations vs the reference product.4 The product launched in the US in September 2015 and offered patient support through Sandoz One Source.

Zarxio’s transatlantic approval signified a major biosimilar milestone, leveraging its extensive EU track record (>7.5 million patient-days of exposure) to facilitate FDA acceptance.

References
1. Heyn J, Bräuninger S, Becker P, et al. Healthy volunteer stem cell donors followed up 10 years after stimulation with biosimilar filgrastim. Transfusion. 2025;65(8):1418-1426. doi:10.1111/trf.18317

2. Davio K. A decade of biosimilar filgrastim experience highlights the scientific basis for extrapolation, study says. The Center for Biosimilars®. September 17, 2019. Accessed August 21, 2025. https://www.centerforbiosimilars.com/view/a-decade-of-biosimilar-filgrastim-experience-highlights-the-scientific-basis-for-extrapolation-study-says

3. Jeremias S. From Amjevita to Zarxio: a decade of US biosimilar approvals. The Center for Biosimilars. March 6, 2025. Accessed August 21, 2025. https://www.centerforbiosimilars.com/view/from-amjevita-to-zarxio-a-decade-of-us-biosimilar-approvals

4. FDA approves first biosimilar Zarxio (filgrastim-sndz) from Sandoz. News release. Sandoz. March 6, 2015. Accessed August 21, 2025. https://www.novartis.com/news/media-releases/fda-approves-first-biosimilar-zarxiotm-filgrastim-sndz-from-sandoz