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FDA draft guidance on bispecific antibodies still has some kinks

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The comment period for a Food and Drug Administration draft guidance on bispecific monoclonal antibodies closed earlier this week. But while the guidance marks the first time the agency has taken a close look at this class of drugs, an expert said it contains a number of flaws.

The FDA put out the draft guidance, “Bispecific Antibody Development Programs,” in April, and the comment period closed Tuesday. Whereas most monoclonal antibodies on the market bind to one antigen or epitope, bispecific antibodies work by binding to two.

Currently, there are two such antibodies on the market, namely Amgen’s Blincyto (blinatumomab), for acute lymphoblastic leukemia, and Roche’s Hemlibra (emicizumab-kxwh), for hemophilia A. Despite both falling under the category of “bispecific,” the two drugs have significantly different mechanisms of action. Blincyto works by binding to CD19, an antigen on the surface of leukemia cells, and CD3, on the surface of immune T cells, in order to act as a “bridge” between the two cells allowing the latter to kill the former. Hemlibra is designed to promote blood clotting by mimicking Factor VIII and bringing together activated Factor IX and Factor X.

It’s bispecific antibodies’ differing mechanisms of action that result in one of the flaws in the FDA’s guidance, said Christopher Betti, an intellectual property lawyer and partner at the global law firm Morgan Lewis, in a phone interview. “To assume that all these bispecific formats are going to function in the same manner is an incorrect assumption,” he said. “And the way the FDA was jamming all these molecules into one hole is not realistic, given the structure of these molecules.”

Related to that issue were some of the manufacturer comments critiquing the guidance’s focus on immunogenicity, meaning the ability of a drug to trigger an immune system response. On the one hand, part of that is a knee-jerk reaction from some companies that simply don’t want associated with their products, Betti said. But it also is related to the conflation of different mechanisms of action, given that drugs designed to bind to immune cells are likelier to carry a risk of immunogenicity than drugs that don’t, he added.

Another criticism was of a suggestion that the FDA might want to see comparisons between a bispecific antibody and a monospecific antibody that is already approved, which would create an extra burden of cost and time for drugmakers and thus hinder development. “The issue there is not whether those studies can be performed – it’s really an issue of cost and time to add another layer onto clinical studies and trials like that,” Betti said. “That takes a lot of time and effort, given that you’re talking about full-blown clinical studies that are gong to have to involve two other antibody targets.”

For the time being, development of bispecific antibodies has taken off. According to a paper published in Nature earlier this month, there are 85 in clinical development. Oncology is the hottest area, though Betti said other areas like rheumatoid arthritis are attractive for the class as well.

Bispecific antibodies currently in development include Amgen’s AMG 420, which targets BCMA and CD3 in multiple myeloma, and several bispecifics under development by MacroGenics for cancers and also HIV.

Several manufacturers also weighed in, including Johnson & Johnson, Regeneron Pharmaceuticals, Biocon, Eli Lilly & Co., AstraZeneca, Novartis and Pfizer.

Photo: Food and Drug Administration, Flickr (free from all copyright)

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