FDA advisory committee supports biosimilar for anemia

An FDA advisory panel today supported approval of a biosimilar version of Amgen’s epoetin alfa for the treatment of anemia from various causes.

The Oncologic Drugs Advisory Committee (ODAC) voted 14-1 in favor of Pfizer’s biologics license application for “epoetin Hospira.” The biosimilar is proposed for the following indications:

anemia due to chronic kidney disease (CKD), including patients on and not on dialysis, to decrease the need for red blood cell transfusion;
anemia due to zidovudine administered at less than 4,200 mg/week for patients with HIV who have endogenous serum erythropoietin levels less than 500 milliunits/mL;
anemia in patients with nonmyeloid malignancies who develop anemia from concomitant myelosuppressive chemotherapy; and
to reduce the need for allogeneic red blood cell transfusions for patients with perioperative hemoglobin levels between 10 g/dL and 13 g/dL at high risk for perioperative blood loss from noncardiac, nonvascular surgery.

A biosimilar is an agent highly similar to a reference biological product. To gain approval, the biosimilar must demonstrate no clinically meaningful differences in terms of safety, purity and potency of product.

“The totality of evidence supports the conclusion that the biologic product is biosimilar to the reference product,” Donald E. Mager, PharmD, PhD, associate professor of pharmaceutical sciences at University of Buffalo, State University of New York, and an ODAC committee member, said after the vote. “The minor differences weren’t clinically meaningful. ... Based on determination of the biosimilar product, I think there is a strong scientific basis.”

The panel reviewed data from multiple parallel-arm studies that included 849 patients with CKD (EPOE-10-01, EPOE-10-13) and 129 healthy volunteers (EPOE-14-01) that evaluated the similarities and differences between epoetin Hospira and epoetin alfa (Epogen/Procrit, Amgen).

In EPOE-10-01, patients with CKD received either epoetin Hospira (n = 301; mean age 55 years; 48% women) or epoetin alfa (n = 304; mean age 57 years; 43% women) in variable IV doses one to three times per week up to 24 weeks. In EPOE-10-13, patients with CKD received titration therapy with either epoetin Hospira (n = 80; mean age 57 years; 48% women) or epoetin alfa (n = 86; mean age 57 years; 54% women) in variable subcutaneous doses one to three times per week up to 24 weeks, or maintenance therapy with either epoetin Hospira (n = 122) or epoetin alfa (n = 122) in variable subcutaneous doses up to 16 weeks.

In terms of immunogenicity — which, for erythropoietin, is linked to the development of life-threatening pure red cell aplasia — the studies showed similar rates and titers of antidrug antibodies for both drugs.

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The rates of treatment-induced antidrug antibodies were 0.4% for both arms of EPOE-10-01, 0% for EPOE-10-13, and 3% for the epoetin Hospira arm and 3.2% for the epoetin alfa arm of EPOE-14-01.

During the maintenance period of EPOE-10-13, rates of treatment-induced antidrug antibodies appeared similar between both products (1% vs. 0.9%).

“These data show no increase in immunogenicity risk and support a conclusion that there are no clinical meaningful differences between epoetin Hospira and [Amgen’s epoetin alfa],” Steven Bowen, PhD, immunogenicity reviewer for the FDA, said during his presentation.

Two clinical studies among healthy individuals (EPOE-12-02 and EPOE-14-01) evaluated the pharmacokinetics and pharmacodynamics — which include reticulocyte count and hemoglobin levels — following single and multiple doses of both products. In EPOE-12-02, 81 healthy individuals received either 100 U/kg subcutaneous dose of epoetin Hospira or epoetin alfa. In EPOE-14-01, 129 healthy individuals received multiple 100 U/kg doses of epoetin Hospira or epoetin alfa three times a week for 4 weeks. Analyses showed this dose increased hemoglobin level by approximately 0.086 g/dL per day.

Both studies met various pharmacodynamics and pharmacokinetics similarity prespecified margins.

“Hospira demonstrated pharmacokinetics and pharmacodynamics equivalence to reference product using measures under strict concerning,” Nancy Martin, MD, PharmD, FCP, consultant for Pfizer, said during her presentation. “Hemoglobin were completely contained within the acceptance limits, demonstrating pharmacodynamic equivalents under multiple dose conditions.”

The committee evaluated primary evidence of efficacy and safety derived from pooled data from EPOE-10-13 and EPOE-10-01. Adverse events appeared similar between the products; 75% of patients in both groups experienced at least one adverse event. Common adverse events included nausea, vomiting and muscle spasms.

“Patients remained clinically stable throughout treatment and no cases of [patient-controlled analgesia] were reported,” Martin said.

There were differences in the levels of some glycosylation species and Cys29-Cys33 trisulfide species between the two products, according to a presentation by Chao Wang, PhD, chemistry, manufacturing and controls statistical reviewer from the office of biostatistics at the FDA.

Epoetin Hospira contained 4.5% more Cys29-Cys33 trisulfide than epoetin alfa. More than 10% Cys29-Cys33 trisulfide did not lead to differences in the in vivo or in vitro activity.

“Based on in vivo and in vitro biological activity data and our statistical analysis, we do not expect the minor differences in glycosylation to have an impact on safety,” Wang said.

Although a majority of panel members voted yes based on the established comparability, concerns over immunogenicity and patient populations remained.

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“I voted yes but with some hesitation,” Courtney J. Preusse, MA, research administrator in the pathology program at Fred Hutchinson Cancer Research Center and ODAC committee member, said after the vote. “Although I see the cost-effectiveness benefit, I am still concerned and uneasy with the fact that the patient population in which this drug was tested is very small in the United States.”

Thomas S. Uldrick, MD, MS, clinical director of the NCI’s HIV & AIDS Malignancy Branch at the Center for Cancer Research, cast the lone dissenting vote.

“I do not support indications one and four based on the clinical data as previously stated, and I have residual concerns about lack of data of immunogenicity and safety data in patients with HIV,” Uldrick said after the vote.

Members of the panel expressed interest in seeing further data to address immunogenicity and hypersensitivity concerns among certain patients.

The FDA accepted the application for review in February 2015. However, FDA initially denied the application approval and issued a complete response letter to Pfizer later that year.

The FDA often follows the guidance of ODAC when making its final decision about an agent’s approval, but the agency is not obligated to do so. – by Melinda Stevens