Phase 3 Study Finds Therapeutic Equivalence Between Pegfilgrastim and Withdrawn Biosimilar Candidate

Drug maker Gedeon Richter’s RGB-02 is undergoing development as a proposed biosimilar to the reference pegfilgrastim, Neulasta, and researchers recently reported on the results of a phase 3 clinical study of the drug versus its reference in patients with breast cancer who were receiving chemotherapy.

The study, newly published in BMC Cancer, reports on a trial in 239 patients who were randomized to receive either the biosimilar (n = 121) or the reference (n = 118) pegfilgrastim as a once-per-chemotherapy-cycle fixed dose of 6 mg administered approximately 24 hours after chemotherapy was initiated. The study was conducted in a double-blind fashion for 2 cycles, after which patients in the reference arm were switched to the proposed biosimilar in an open-label extension for up to 6 cycles in total.

The study’s primary end point was the duration of severe neutropenia in cycle 1, defined as the number of consecutive days on which a patient had an absolute neutrophil count of less than 0.5 x 10⁹/L. The predetermined limits were —1 day and 1 day; if the upper limit of the 95% CI for the difference in means was 1 day or less, and the lower bound of the CI for the difference in means was –1 day or more, then the means in the 2 arms were considered equivalent.

The mean duration of severe neutropenia in cycle 1 in the biosimilar arm was 1.7 days (±1.14 days), versus 1.6 days (±1.31 days) in the reference arm. The least squares means (95% CI) were 1.5 (range, 1.2-1.8) and 1.4 (range, 1.1-1.7) days, respectively. With the least squares mean difference of 0.1 days (95% CI, —0.2 to 0.4) falling within the prespecified equivalence margin, the investigators concluded that equivalence had been established.

In total, 87.2% of patients treated with the biosimilar experienced at least 1 adverse event (AE) during the study. During the 2-week double-blinded period, 80.2% of patients in the biosimilar arm reported AEs, versus 93.2% of patients in the reference arm. The most frequently reported AE was bone pain. Serious AEs were reported in 8.3% of patients in the biosimilar arm and 6.8% of patients in the reference arm, and the most commonly reported serious AE was febrile neutropenia.

The investigators report that an antidrug antibody (ADA) screening assay was negative in 96.1% of samples during the double-blind period, and that all samples that tested positive later tested negative in a confirmatory test. In the open-label period, again, all positive tests were negative upon confirmatory testing. No neutralizing ADA assays were performed.

The study’s authors concluded that therapeutic equivalence had been demonstrated between the biosimilar and the reference, that the 2 products had similar safety profiles, and that no immunogenicity was detected.

Results of the trial notwithstanding, the European Medicines Agency (EMA) recently announced that Gedeon Richter has withdrawn its marketing authorization for the drug, which it had hoped to sell under the brand name Efgratin.

According to the EMA, Gedeon Richter’s data package included results of 2 studies in healthy volunteers as well as the phase 3 study, and upon reviewing the data, the EMA “had some concerns and was of the provisional opinion that Efgratin could not have been approved for reducing neutropenia. The CHMP [Committee for Medicinal Products for Human Use] was concerned about the validity of results from studies on how the body handles Efgratin compared with Neulasta.” Additionally, the EMA indicated that the study lacked information on immunogenicity.

“Therefore, at the time of the withdrawal, the CHMP was of the opinion that the company had not demonstrated that Efgratin was highly similar to Neulasta,” wrote the EMA in a February 1 notice of the marketing authorization application’s withdrawal.

Reference

Kahan Z, Grecea D, Smakal M, et al. Efficacy and safety of RGB-02, a pegfilgrastim biosimilar to prevent chemotherapy-induced neutropenia: results of a randomized, double-blind, phase 3 clinical study vs reference pegfilgrastim in patients with breast cancer receiving chemotherapy. BMC Cancer. 2019;19(1): 122. doi: 10.1186/s12885-019-5329-6.