FDA modifies immunogenicity language in final bispecific antibody guidance

Regulatory NewsRegulatory News | 25 May 2021 |  By 

A newly finalized guidance on bispecific antibodies from the US Food and Drug Administration (FDA) notes that although bispecific antibodies can generally be characterized in the same ways as standard monoclonal antibodies and manufacturing processes may be similar, some scientific and regulatory considerations are unique to bispecifics.
According to a 24 May agency announcement, while the regulatory pathway for evaluating monoclonal antibodies is “well established,” developers needed additional guidance for antibody-based therapies that target more than one antigen. The final guidance addresses challenges that may arise in developing these products and recommends the type of data necessary to support approval.
The guidance notes that “therapeutic monoclonal antibodies, first commercialized in 1986, have become a vital component of therapy for various diseases and conditions, including cancer, autoimmune and infectious diseases, and inflammatory conditions.”  Bispecific antibodies are genetically engineered, recombinant antibodies that consist of two distinct binding domains capable of binding two different antigens or two different epitopes of the same antigen.
So far, the FDA has approved three bispecific antibodies while over a hundred more are in development. The latest approval was for Janssen’s Rybrevant (Amivantamab-vmjw), the first treatment for adult patients with non-small cell lung cancer, approved on 21 May. The others are Amgen’s Blincyto (blinatumomab ) and Roche’s Hemlibra (emicizumab-kxwh) for patients with hemophilia.
The guidance has been revised from the draft guideline issued in April 2019 to put more emphasis on the quality, nonclinical and clinical development programs for these drugs; to clarify  considerations in assessing immunogenicity; and to  clarify clinical assessments comparing a bipecific antibody and an approved monospecific product. (RELATED: Bispecific Antibodies: FDA drafts guidance for developers, Regulatory Focus, 18 April 2019).
In terms of the regulatory considerations, the guidance says that FDA may in some cases request a comparison of the bispecific antibody to an approved monospecific product directed against the same antigenic target to “inform the benefit-risk assessment of the bispecific antibody.”
Bispecific antibodies can exist in many different formats, including tandem monovalent binding fragments as well as immunoglobin G (IgG) based antibodies, and “unique development considerations may be relevant for each of these formats, such as quality, stability, and production yields,” according to the guidance. In general, however, these products “should be characterized and the manufacturing process should be developed in accordance with standard monoclonal antibody development practices.”
FDA also encourages sponsors to discuss plans with the appropriate clinical review division for their products “early in development.”
In June 2019, FDA received pushback on its assertion that one of the challenges in developing bispecific antibodies is “significant immunogenicity caused by novel epitopes.” (RELATED: Drugmakers seek tweaks to FDA guidance on bispecific antibodies, Regulatory Focus, 19 June 2019).
Pfizer, which called on FDA to delete that line in the guidance, noted that“Emerging clinical data suggest that the risk of immunogenicity of bispecific antibodies are likely to be similar to that of monoclonal bodies against one antigen.” Pfizer noted that blinatumomab anti-drug antibody was reported in very few subjects through the entire program (<1%). “Given the lack of evidence that the risk of immunogenicity is necessarily high for a bispecific antibody, we suggest deleting the latter part of the statement,” wrote Pfizer in its commentary on the guidance.

The final guidance deletes the statement.
FDA final guidance on bispecifics


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