ODAC Recommends Approval of Epoetin Alfa Biosimilar

FDA

The FDA’s Oncologic Drugs Committee voted (ODAC) 14-1 today to recommend approving a biologics license application (BLA) for epoetin hospira (Retacrit), an epoetin alfa (Epogen/Procrit) biosimilar manufactured by Hospira.

The BLA will now go to the FDA for consideration. The agency denied Hospira’s application for an abbreviated Biologics License Application in 2015.

ODAC staff recommended approval, concluding that epoetin hospira is “highly similar to US-licensed Epogen/Procrit.” In evaluating the request from Hospira, a division of Pfizer, committee members kept coming back to the same conclusion: “The totality of the analytical similarity data supports the conclusion that epoetin hospira is highly similar to US-licensed Epogen/Procrit, notwithstanding minor differences in clinically inactive components. The clinical data, including pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety and immunogenicity data support a finding of no clinically relevant differences.”

Hospira was seeking approval for 4 indications:

• to treat anemia due to chronic kidney disease, including patients on dialysis and not on dialysis to decrease the need for red blood cell transfusion
• to treat anemia in HIV-infected patients being treated with zidovudine
• to treat chronic renal failure, specifically anemia caused by concomitant myelosuppressive chemotherapy in patients with non-myeloid malignancy
• to reduce the need for allogeneic red blood cell transfusions in patients with perioperative hemoglobin from >10 g/dL to ≤13 g/dL who are at high risk for perioperative blood loss from elective noncardiac, nonvascular surgery

Although the vote was nearly unanimous, many committee members expressed concern about immunogenicity, especially in patients with HIV or cancer. Those patient populations were not as extensively studied when epoetin alfa was first approved in 1989.

“The immunogenicity questions are legitimate,” said Gary Gordon, MD, PhD, vice president of oncology development at AbbVie. It’s unfortunate that there could not be more integration, if you will, around the data from Europe.”

Epoetin hospira has been available in Europe since 2008 for the treatment of anemia associated with chronic renal failure, but committee members were instructed not to take those experiences into account.

While Gordon ultimately voted to approve, Thomas Uldrick, MD, clinical director of the HIV & AIDS Malignancy Branch at the National Cancer Institute’s Center for Cancer Research, was the lone holdout. He said he could not support the application for 2 of the indications.

“I do not support approval for indications 1 and 4 based on the clinical data,” he said. “As previously stated, I have residual concerns about the lack of data for immunogenicity and safety in patients with HIV and cancer.”

Hospira submitted the application based on results from 2 single center, randomized, open label studies, EPOE-12-02 and EPOE-14-01. The first was aimed to establish the PK and PD (reticulocyte count) of epoetin hospira following a single subcutaneous dose of 100 u/kg in healthy participants (N = 81). EPOE-14-01 was designed to determine the drug’s PK and PD (hemoglobin level) following multiple doses of subcutaneous 100 u/kg epoetin hospira 3 times weekly for 4 weeks in healthy participants (N = 129). Epoetin hospira was compared with epoetin alfa in both studies.

In EPOE-12-02, researchers found that epoetin hospira met the prespecified acceptance criteria for PK similarity, the geometric mean of AUC_0-INF (1.06 mIU-h/mL; 90% CI, 1.01-1.11), AUC_0-T (1.03 mIU-h/mL; 90% CI, 0.97-1.09), and C_MAX (1.09 mIU-h/mL; 90% CI, 1.01, 1.18). The same was true of PD for AUEC_0-456 (1.01%-h; 90% CI, 0.98-1.05) and E_MAX (1.02%-h; 90% CI, 0.99-1.05).

In EPOE-14-01, epoetin hospira also met prespecified acceptance criteria for PD similarity of geometric mean of hemoglobin level AEUC _0-28d (1.00 g-h/dL; 90% CI, 0.99-1.02) and E_MAX (1.00 g/dL; 90% CI, 0.99-1.02).

ODAC recommended approval of a biosimilar for the first time in January 2015, when it voted unanimously in favor of filgrastim-sndz (Zarxio), a biosimilar version of the G-CSF analog filgrastim (Neupogen). The FDA made filgrastim-sndz the first biosimilar approved in the United States in March of that year. The treatment is approved for patients with cancer who are receiving myelosuppressive chemotherapy, patients with acute myeloid leukemia receiving induction or consolidation chemotherapy, patients with cancer undergoing bone marrow transplantation, patients undergoing autologous peripheral blood progenitor cell collection and therapy, and those with severe chronic neutropenia.