Bispecific Antibodies: FDA Drafts Guidance for Developers

Regulatory NewsRegulatory News | 18 April 2019 |  By 

With more than two dozen companies developing bispecific antibodies, the next frontier of cancer therapy may well involve these genetically engineered, recombinant antibodies, which is why the US Food and Drug Administration (FDA) on Thursday released new draft guidance to help developers of these products.

In explaining why bispecific antibodies could be advantageous, FDA notes that they “can target multiple disease-modifying molecules with one drug, with possible advantages over combination therapy or the use of antibody mixtures. The possibility of immune cell retargeting through the delivery of an effector or effector cell to a specific target or the possibility of synergistic efficacy through engagement of multiple targets gives bispecific antibodies the potential to advance the development of antibody-based therapies.”

Examples of bispecific antibodies marketed in the US include Amgen’s Blincyto (blinatumomab), which brought in $230 million in worldwide sales in 2018, up 31% from 2017, and Roche’s hemophilia medicine Hemlibra (emicizumab-kxwh). But others are coming, and recent safety concerns, such as a partial clinical hold initiated by FDA after Xencor reported two patient deaths from a Phase 1 study of a bispecific antibody in February, may have triggered the need for more FDA guidance.

“There are a number of challenges in developing bispecific antibodies, one of which may be significant immunogenicity caused by novel epitopes. This draft guidance addresses these considerations and provides recommendations regarding the type of data necessary to support the approval of bispecific antibodies,” FDA said.

The seven-page draft guidance discusses unique aspects for chemistry, manufacturing and controls (CMC); nonclinical and clinical pharmacology; and the clinical development of bispecific antibodies, while noting how bispecific antibody development programs will be similar to monoclonal antibody development programs.

Under the section on clinical studies, the draft notes that FDA may request a “clinical trial comparing a bispecific antibody to an approved monospecific product(s) directed against the same antigenic target(s) may inform the risk-benefit assessment of the bispecific antibody.”

The draft adds: “For example, if both targets are anticipated to be immunosuppressive based on the animal/early human trials suggesting unique or greater safety concerns, a trial comparing the bispecific antibody to the approved monospecific product(s) may be appropriate. Also, if there is a concern that only one of the bispecific antibody’s targets was driving the efficacy results, it may be useful to conduct a comparison trial with the relevant monospecific product(s).”

Under the CMC quality consideration section, the draft also explains how, “The relative amounts of homodimers should be assessed. This is particularly important for effector cell engaging constructs where homodimers of the anti-CD3 or anti-Fc engaging arm may lead to cytokine release. Also, the molecular structure, such as novel epitopes or intact antibody structures with additional domains, could potentially lead to increased immunogenicity.”

Those looking to comment on the draft guidance have 60 days to do so.

Bispecific Antibody Development Programs: Draft Guidance for Industry


© 2022 Regulatory Affairs Professionals Society.

Discover more of what matters to you

No taxonomy