Fresenius Kabi Pegfilgrastim Shows Matching Safety, Immunogenicity

Fresenius Kabi, which launched an adalimumab biosimilar (Idacio), an arthritis product, in Germany a year ago, has demonstrated that its proposed pegfilgrastim biosimilar (MSB11455) has similar safety and immunogenicity profiles to the reference product (Neulasta).

Pegfilgrastim is the long-acting form of filgrastim, a recombinant human granulocyte colony‐stimulating factor (G‐CSF). It is administered to patients undergoing myelosuppressive chemotherapy to reduce the risk of developing febrile neutropenia, a serious adverse effect of chemotherapy characterized by a high body temperature and low neutrophil count. Additionally, this condition can force patients to reduce the dose of chemotherapy or discontinue it entirely.

G-CSF is a hematopoietic growth factor that stimulates proliferation, differentiation, and activation of neutrophils. The use of filgrastim or pegfilgrastim reduces the risk of febrile neutropenia, which improves the likelihood of patients completing chemotherapy.

Fresenius Kabi is headquartered in Germany and last year announced the expansion of its biosimilar activities in a new center in Eysins, Switzerland, where the company hopes to conduct biosimilar research in immunology and oncology. The company also has a tocilizumab biosimilar, for rheumatoid arthritis, in its development pipeline.

Biosimilars to pegfilgrastim have previously been approved and launched, such as Sandoz’s Ziextenzo in the United States and Mylan and Biocon’s Fulphila in Australia and Canada. According to a recent conference abstract from Sandoz, the use of pegfilgrastim biosimilars has the potential to prevent more cases of febrile neutropenia by expanding access to patients who are not generally treated (those at intermediate risk for febrile neutropenia) because of the high cost of the reference product.

Immunogenicity Concerns

There is potential for any biologic drug to provoke an immunogenic response, and immunogenicity is a major concern regarding biosimilars, because the “ability to stimulate antibody formation can differ between structurally closely related molecules, with even minor changes affecting immunogenicity,” as stated by the authors. The development of antidrug antibodies (ADAs) can negatively affect the therapeutic action of the drug or predispose the patient to adverse reactions.

Because pegfilgrastim is a recombinant human protein, immunogenicity is particularly concerning, because ADAs could cross-react with the endogenous human protein and interfere with the function of that protein in the body.

Analytical similarity and pharmacokinetic and pharmacodynamic equivalence have previously been demonstrated for the proposed pegfilgrastim biosimilar, and the current study was designed to evaluate immunogenicity and safety in healthy volunteers compared with the reference product.

Safety and Immunogenicity of the Proposed Biosimilar

The immunogenicity results demonstrated noninferiority of MSB11455 based on the prespecified margins. Treatment-induced ADA-positive rates were 8.9% in the MSB11455 group and 9.5% in the reference product group.

Most ADAs were specific to the polyethylene glycol (PEG) portion of pegfilgrastim rather than filgrastim. No filgrastim-specific neutralizing antibodies were reported, but 3 patients in the MSB11455 group and 1 in the reference product group had at least 1 sample with pegfilgrastim-neutralizing activity. The authors noted that “no relevant differences in ADA characteristics such as onset, titer, and specificity were found between the treatment groups.”

Safety and tolerability were similar between groups. Most patients (99.4%) in each group experienced some treatment-emergent adverse event (TEAE); the most common were headache and bone pain, which are known adverse effects of pegfilgrastim. Just 1 patient of the 168 in the MSB11455 group and 2 of 168 in the Neulasta group experienced a serious TEAE.

There were no significant differences in the pattern of TEAEs reported for ADA-positive subjects compared with ADA-negative patients, and similar TEAE frequency was found in anti-PEG positive patients between groups. The results provide support for the biosimilarity of the proposed biosimilar MSB11455 to pegfilgrastim, investigators concluded.