A 40-week comparative study conducted in multiple sites across Malaysia and Korea demonstrated that efficacy and safety of the epoetin alfa biosimilar candidate PDA10 (PanGen Biotech) was comparable to the reference product (Eprex/Epogen) in patients with end-stage kidney disease (ESKD).

Anemia is a common complication of chronic kidney disease, and as renal function declines, the risk of anemia increases. In patients with ESKD, anemia can compromise the quality of life, require blood transfusions, and increase the risk of heart failure and mortality.

Erythropoietin-stimulating agents (ESAs), which promote survival, differentiation, proliferation, and maturation of red blood cells, are the standard of care for anemia associated with kidney disease. Up to 80% to 90% of patients on dialysis require ESAs, according to the authors of the study. However, access to ESAs is “limited” due to cost, which leads to suboptimal dosage. Biosimilars are a cost-effective alternative, they said.

Study Methodology

PDA10 is a proposed epoetin alfa biosimilar. The only epoetin alfa biosimilar now available in the United States is Pfizer’s Retacrit, approved by the FDA in 2018. Based on the results of phase 1 nonclinical studies and analytical similarity studies, the requirement for a phase 2 clinical study for PDA10 was waived by Korean regulatory authorities. This phase 3 study compared the safety and efficacy of PDA10 with the reference product in renal anemia in patients on hemodialysis. The study was conducted over 40 weeks at 29 sites in Malaysia and Korea. Patients ranged in age from 18 to 75 years, had ESKD, and were undergoing regular hemodialysis and erythropoietin therapy.

After a 12-week titration phase to assess disease stability and establish baseline characteristics, 296 patients were randomized to the reference product or biosimilar for a 28-week treatment phase, which was followed by a 24-week open-label extension phase. The investigators did not report on the open-label phase in the current publication.

Findings

The change in hemoglobin (Hb) levels, dose of epoetin alfa, and proportion of patients out of target Hb range were similar between groups

The investigators found baseline characteristics were similar between the originator and biosimilar groups. Differences in the primary efficacy end points were not significantly different between groups: the mean (SD) change in Hb was –0.176 (0.914) g/dL in the biosimilar group and –0.118 (1.114) g/dL in the originator group. The mean (SD) weekly dose change was 10.01 (44.64) IU/kg in the biosimilar group and –10.30 (56.09) IU/kg in the reference product group, a difference that was not statistically significant.

Secondary end points examined by the authors included change in hematocrit (proportion of red blood cells in blood), the proportion of patients with Hb levels within or out of the target range (10-12 g/dL), and safety and immunogenicity indicators. These were also comparable between groups.

The mean (SD) change in hematocrit from baseline to treatment phase was –0.71% (2.944) in the PDA10 group and –0.007% (3.498) in the reference group. During the treatment phase, 111 (81.62%) patients in the biosimilar group and 108 (90.0%) patients in the reference group had an Hb level outside the target range of 10 to 12 g/dL.

In this 28-week randomized controlled study, PDA10 was shown to be therapeutically equivalent to the originator Eprex in terms of absolute change in hemoglobin levels and comparable safety profile in treating renal anemia for patients undergoing maintenance hemodialysis.

The investigators noted the “high proportion” of patients with Hb out of the target range, saying “these Hb fluctuations are not uncommon and have been well described in the use of ESA in renal anemia. However, with the appropriate epoetin dosage adjustment, these fluctuations did not increase occurrence of AEs secondary to high Hb level, such as worsening hypertension, stroke, and vascular access thrombosis,” they wrote.

Immunogenicity and Safety

No anti-epoetin antibodies were observed in either group at baseline or in the treatment phase.

There were no differences between groups in the number of patients who experienced treatment-emergent adverse events (TEAEs). The most common were respiratory tract infections, affecting 14.0% and 16.4% in the biosimilar and reference groups, respectively, and gastrointestinal infections, affecting 4.0% and 2.7%. Although there were more TEAEs leading to death in the originator group than the biosimilar group, the authors wrote “all TEAEs leading to death were considered unrelated to the products.”

The investigators concluded PDA10 and the reference product were “therapeutically equivalent,” with no significant differences in change in Hb, change in weekly dose, or safety parameters between groups. They also noted the dose required to maintain stable Hb levels was similar for the biosimilar and originator, saying “this biosimilar epoetin alfa may offer a more cost-effective erythropoietin therapy and improve the access of ESA therapy for patients undergoing hemodialysis treatment.”

Reference

Lim SK, Goh BL, Visvanathan R, et al. A multicentre, multi-national, double-blind, randomised, active-controlled, parallel-group clinical study to assess the safety and efficacy of PDA10 (epoetin-alpha) vs. Eprex in patients with anaemia of chronic renal failure. BMC Nephrol. 2021;22(1):391. doi:10.1186/s12882-021-02601-w