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Review: 15 Years of Real-world Data Demonstrates Safety of Epoetin Alfa Biosimilar HX575


Authors of a review of safety results across indications and study designs on the epoetin alfa biosimilar HX575 concluded that HX575 “has repeatedly demonstrated long-term safety” in all approved indications in both clinical trials and real-world studies.

Authors of a review of safety results across indications and study designs on the epoetin alfa biosimilar HX575 concluded that HX575 “has repeatedly demonstrated long-term safety” in all approved indications in both clinical trials and real-world studies.

Erythropoietin is the “main hormonal regulator responsible for stimulating red blood cell production,” the reviewers said, and erythropoietin-stimulating agents (ESAs) such as epoetin alfa, promote red blood cell production by regulating their differentiation. Janssen’s reference epoetin alfa was approved in 1989 by the European Medicines Agency (EMA) and in 1999 by the FDA. The main indications for ESAs are anemia associated with impaired red blood cell production, such as anemia associated with chronic renal failure or chronic kidney disease (CKD) and chemotherapy-induced anemia (CIA).

HX575 (Sandoz; Binocrit, HEXAL) was the first epoetin alfa biosimilar approved for anemia associated with CKD and CIA in August 2007. Another biosimilar, SB309 (Retacrit, Silapo) was approved in December of the same year by the EMA and in 2018 by the FDA. Myelodysplastic anemia (MDS) was added as an indication of HX575 in 2017. HX575 is not currently authorized in the United States.

According to the reviewers, as of 2021, there have been 1.3 million patient-years of experience with HX575 across its indications, with 3400 patients receiving HX575 in clinical trials. After 15 years of clinical experience with HX575, they said, “data have highlighted no new safety concerns or identified risks.”

Immunogenicity Associated With Subcutaneous Epoetin Alfa

A sudden increase in anti-erythropoietin antibody-mediated pure red cell aphasia (PRCA), a rare adverse effect of erythropoietin treatment, in patients receiving the subcutaneous reference epoetin alfa led to contraindication of subcutaneous administration by the EMA from 2002 to 2006. The cause was traced to polysorbate-80 in rubber vial stoppers holding the subcutaneous formulation. After a switch to new teflon stoppers, EMA approval was reinstated in 2006. No PRCA cases have been reported since.

Since the clinical development of HX575 was going on during this time, intravenous HX575 was compared to the intravenous reference product in its original phase 3 trials. Once the subcutaneous reference product was re-authorized, studies compared the subcutaneous administration route of HX575 and the reference product. In one of these studies, immunogenicity concerns were raised about subcutaneous HX575. Therapeutic equivalence was demonstrated in this study.

However 2 patients in the HX575 group developed neutralizing antibodies and the study was terminated early. Here, the cause was traced to some pre-filled syringes with unusually high aggregation, likely caused by high tungsten levels. Low-tungsten syringes were used in a new open-label single-arm phase 3 study (SENSE). In this study, no neutralizing antibodies were detected, and the EMA approved HX575 for subcutaneous delivery.

Real-world Evidence in CKD

The authors discussed 2 key real-world studies on HX575 for treatment of anemia associated with CKD, MONITOR-CKD5 and ESAVIEW. In MONITOR-CKD5, a single-arm study that followed patients with stage 5 CKD and renal anemia for up to 24 months, the safety profile was “consistent” with previous studies of HX575 and the reference product, no anti-erythropoietin antibodies were detected, and there were no cases of PRCA. In ESAVIEW, after adjustment for baseline factors, the risk of any safety outcome was not significantly different between groups.

Switching in CKD

A large (14,400 patients) Italian real-world observational study (ItaBioNet) assessed the safety of switching between ESAs: the reference product, epoetin alfa biosimilars, short-acting erythropoietin biosimilars, and long-acting erythropoietin biosimilars. The incidence of adverse events in this study was similar in patients who switched from reference epoetin alfa to a biosimilar ESA and patients who switched from a biosimilar ESA to the reference product.

Switching to HX575 was well-tolerated in a study in Germany, with no unexpected serious adverse events (SAEs) or neutralizing antibodies detected, and only one SAE related to study treatment among the 326 patients. Another German study found no dose increases following a switch from the reference product to a biosimilar.

Real-world Evidence in Chemotherapy-induced Anemia (CIA)

A post-approval retrospective study of HX575 in CIA collected data from 152 patients from 5 centers across Europe in clinical practice and found no serious unexpected treatment-emergent adverse events (TEAEs) and no unexpected safety concerns. In another real-world study evaluating the relative effectiveness of HX575 and darbepoetin alfa in Spain and Germany, with 116 and 95 patients, respectively, treated with HX575, there were no serious TEAEs in either cohort.

In OncoBOS, a prospective observational study in multiple centers in France, in 563 patients with lymphoid malignancies and CIA, no TEAEs were reported. In the German cohort of OncoBOS, among 196 patients, 35% of whom had breast cancer, there were 5 thromboembolic events, 1 of which was suspected to be treatment-related. In this cohort, the authors added, red blood cell transfusions were reduced by 59% and quality of life improved by 67%. An analysis of patients in OncoBOS with colorectal cancer found no TEAEs, and in multiple myeloma, 1 TEAE was reported, which was not considered serious.

In the ANEMONE study, a retrospective observational study in Italy, among 215 patients receiving HX575 for CIA, 13.5% experienced at least 1 AE, 12.5% of which were considered severe. Two patients had AEs (venous thrombosis) considered possibly related to treatment.

In another 65 patients with chronic lymphoid neoplasms treated with HX575, the biosimilar was well-tolerated and “allowed patients with non-Hodgkin lymphoma or chronic lymphoproliferative disorders to continue their course of chemotherapy by effectively increasing and maintaining adequate concentrations of hemoglobin,” the reviewers said.

Collectively, according to the reviewers, these studies “highlight the post-approval long-term safety of HX575 in real-world settings for patients with CIA.”

Real-world Evidence in Myelodysplastic Syndrome (MDS)

MDS are malignancies that develop from hematopoietic stem cells, are characterized by ineffective hematopoiesis, and lead to peripheral blood cytopenias, the most common of which is anemia. MDS was added as an approved indication for HX575 in 2017 in Europe. According to the reviewers there have been multiple studies since HX575’s approval “that further support the use in this indication.”

In 24 patients with anemia and MDS in a retrospective study, after initiating treatment with HX575, 15 became transfusion independent for 3 months or longer, and 2 patients had reduced need for transfusions. No SAEs were reported. In another real-world retrospective study of 92 patients receiving epoetin alfa or a biosimilar for refractory anemia, disease progression was comparable between groups. SAEs were reported in 1 patient treated with the reference product, and 2 treated with a biosimilar. Five patients in the reference group required transfusions, compared to 7 in the biosimilar group. The reviewers noted biosimilars were found to be more cost effective in this study.

According to the reviewers, “the data collected in the 15-year post-approval period of HX575 highlight its long-term safety and effectiveness in all approved indications.” Additionally, they said, the growing clinical experience with EMA-approved epoetin alfa biosimilars “should offer additional reassurance to healthcare professionals and patients that these agents are as effective and well tolerated as other biologics in the therapeutic class.”


Gascón P, Goldsmith D, Aapro M, Dellanna F, Esmael A, Zabransky M. Epoetin alfa biosimilar (HX575): A review of 15 years' post-approval clinical experience. Crit Rev Oncol Hematol. 2023;181:103894. doi:10.1016/j.critrevonc.2022.103894

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