The Journey of Biosimilar Epoetin Alfa Serves as Example of Approval Pathway Integrity

Erythropoiesis-stimulating agents (ESAs), such as recombinant human erythropoietin, are commonly used to treat anemia in patients with chronic kidney disease (CKD). In May 2017, the FDA’s Oncologic Drugs Advisory Committee voted favorably following its review of the proposed epoetin alfa biosimilar, Epoetin Hospira.

In Europe, however, the first biosimilar (HX575, Binocrit) to originator epoetin alfa (Epogen, Procrit) was approved by the European Medicines Agency (EMA) in 2007. Thus, there are already 10 years of clinical experience of this biosimilar to epoetin alfa. Frank Dellanna, MD, and colleagues reviewed the journey of HX575 from development to approval in Europe, and describe a decade of clinical experience in patients with CKD, as the history and experience with this biosimilar provides an excellent example of a successful demonstration of biosimilarity.

The review, first presented in abstract form at the European Society for Medical Oncology’s 2017 meeting, appears in the December 2017 issue of Drug Design, Development and Therapy.

Like all biosimilar drugs in the research and development pipeline, HX575 (Sandoz GmbH, Kundl, Austria) proceeded through the many steps of an approval pathway in which it demonstrated biosimilarity through the totality of the evidence obtained in a comprehensive comparability exercise that involved extensive analytical characterization, nonclinical studies, and clinical studies—phase 1, phase 2, and phase 3 trials of the compound’s pharmacokinetics (PK), pharmacodynamics (PD), as well as confirmatory studies. Extensive clinical experience with HX575 over the last decade also confirms that it provides an effective treatment for anemia related to CKD, with a safety profile similar to those of other ESAs.

HX575 has generated more than 400,000 patient-years of experience worldwide in CKD and chemotherapy-induced anemia; with more widespread adoption, patient exposure and experience continues to increase.

The approval pathway for HX575 was as follows:

1. Analytic and characterization studies were the first important part of the “evidence dossier” on which any approval of a biosimilar is based. The studies were performed using an array of techniques to assess each molecular attribute. HX575 and the reference epoetin alfa have an identical amino acid sequence and therefore the same primary structure, as demonstrated by the analyses.
2. The clinical development program and initial EMA approval of HX5757 were based on 3 open-label, randomized, parallel-group phase 1 studies that compared the pharmacological properties of HX575 with those of the existing epoetins following administration in health volunteers. HX575 and comparator epoetins were found to be bioequivalent with respect to their pharmacologic profiles. The clinical development program provided sufficient confirmatory evidence for biosimilarity to be established, and intravenous HX575 was approved by the EMA for all indications that the reference drug had at the time.
3. Further clinical development and further clinical testing led to the recent EU approval of subcutaneous HX5757.
4. A large-scale post-approval safety study was conducted in 10 European countries in patients with renal anemia. The study covered 770 patient-years, and no unexpected safety findings were reported over the treatment period. The overall adverse event profile was in line with the expectations for this CKD population, and was consistent with the results of previous studies with ESAs in general as well as HX575 and the reference medication.
5. Since the approval of HX575, a wealth of real-world data on the effectiveness and safety of biosimilar epoetins has accrued in a variety of multi- and single-center studies. The continuing collection of this data serves patients, physicians, and researchers.

In conclusion, the successful approval and clinical use of more than 20 biosimilars in the European Union over the last decade affirms the integrity of the EMA’s biosimilar pathway, the researchers conclude.

Comparability exercises and extensive clinical experience over the last decade also confirm that HX575 provides an effective treatment for anemia related to CKD and its safety profile is similar to that of other ESAs. Growing clinical experience with EMA-approved biosimilars should offer additional reassurance to healthcare professionals and patients that these agents are as effective and well-tolerated as others in the therapeutic class.