The makers of eflapegrastim received a complete response letter from the FDA due to concerns over manufacturing.
A biologics license application for the novel long-acting granulocyte-colony stimulating factor (G-CSF) agent eflapegrastim (Rolontis) was issued a complete response letter by the FDA due to deficiencies in manufacturing, as reported by the company responsible for the agent, Spectrum Pharmaceuticals.1
The FDA indicated that a reinspection will be necessary and further clarification regarding these plans are being discussed between the 2 entities.
“We are disappointed with this outcome and look forward to fully understanding the remediation timelines for the program,” Joe Turgeon, president and CEO of Spectrum Pharmaceuticals, said in a press release. “We continue to believe in Rolontis and plan to diligently complete the regulatory process to bring Rolontis to market.”
Eflapegrastim is intended for use alongside myelosuppressive anticancer drugs and, if approved, would be the first novel G-CSF agent to become available to clinicians and their patients in over a decade. The BLA was supported by data from 2 phase 3 clinical trials investigating the safety and efficacy of the agent in patients with early-stage breast cancer receiving chemotherapy for their disease.
In the ADVACNE trial (NCT02643420), eflapegrastim was compared with pegfilgrastim in patients with early breast cancer who were receiving docetaxel and cyclophosphamide with a primary end point of severe neutropenia duration in cycle 1. In 406 patients in the intent-to-treat population, the mean duration of severe neutropenia (DSN) was 0.19 days (standard deviation [SD], 0.478) in the experimental arm vs 0.34 days (SD, 0.668) with pegfilgrastim and met the threshold for non-inferiority (95% CI, -0.260 to -0.035; P <.0001). Noninferiority was maintained across all 4 cycles.2
The RECOVER trial (NCT02953340) was conducted in a similar fashion to ADVANCE in 237 intent to treat patients, for which the mean DSN was 0.31 days (SD, 0.688) for eflapegrastim compared with 0.39 days (SD, 0.949) with standard pegfilgrastim (95% CI, -0.292 to 0.129; P <.0001), with noninferiority maintained across 4 cycles of therapy.3
In either trial, the statistical significance for additional end points such as time to absolute neutrophil count (ANC) recovery, depth of ANC nadir, and incidence of febrile neutropenia at cycle 1 were noted.
This BLA for eflapegrastim was initially submitted in October 2019, which was an update to a previously withdrawn application for this indication. The new BLA had additional information in the Chemistry, Manufacturing and Controls (CMC) section regarding the manufacturing process.4 In December 2019, the company announced that the new BLA had been accepted by the FDA with a prescription drug user fee act (PDUFA) date of October 24, 2020.5
1. Spectrum Pharmaceuticals receives complete response letter from FDA for Rolontis (eflapegrastim). News release. Spectrum Pharmaceuticals. August 6, 2021. Accessed August 6, 2021. https://bit.ly/3AiXbj2
2. Schwartzberg LS, Yang Z, Peguero JA, et al. Safety and efficacy of eflapegrastim in reducing severe neutropenia in patients treated with myelosuppressive chemotherapy in a phase 3 randomized controlled trial compared to pegfilgrastim (ADVANCE trial). J Clin Oncol. 2018;36(suppl 15):e12513. doi:10.1200/JCO.2018.36.15_suppl.e12513
3. Schwartzberg LS, Bhat G, Mezei K, et al. Efficacy and safety of eflapegrastim confirmed in reducing severe neutropenia in breast cancer patients treated with myelosuppressive chemotherapy in the second phase 3 randomized controlled multinational trial compared to pegfilgrastim (RECOVER trial). Cancer Res. 2019;79(suppl 4):P1-13-05. doi: 10.1158/1538-7445.SABCS18-P1-13-05.
4. Spectrum Pharmaceuticals announces submission to the U.S. Food and Drug Administration of updated biologics license application for Rolontis. News release. Spectrum Pharmaceuticals. Published October 24, 2019. Accessed August 6, 2021. https://bit.ly/3fDAhv0
5. Spectrum Pharmaceuticals provides pipeline update on late stage programs. News release. Spectrum Pharmaceuticals. Published December 26, 2019. Accessed August 6, 2021. https://bit.ly/2VtM8EF