Potential liver-related side effects have led to the FDA placing a partial clinical hold on a MacroGenics-developed bispecific antibody for cancer.

The regulator sent Rockville, Maryland-based MacroGenics a letter last week placing the hold on a phase 1 trial of MGD009 as a monotherapy as well as a combination study with Incyte’s anti-PD-1 candidate MGA012.

MacroGenics insists the development isn’t a big setback, pointing out that the block only applies to recruiting new subjects, and existing patients in both studies can continue on treatment under the assigned protocol. Nevertheless, shares in the company fell more than 15% after hours as investors reacted to the update.

It isn’t the first setback for the biotech’s bispecific program. The news comes after Johnson & Johnson's Janssen division decided not to continue a partnership on a CD19- and CD3-targeting bispecific called duvortuxizumab last year after seeing treatment-related neurotoxicity in trials. Janssen is, however, still partnering another MacroGenics’ bispecific targeting CD3 and an undisclosed target.

MacroGenics notes that the hold was introduced after it reported liver-related adverse events in some patients in the monotherapy trial, including "reversible elevations of transaminases with or without concurrent elevations of bilirubin."

While the side effects tended to be mild and short-lived, they were sufficiently concerning to the company that it has amended the protocol for the MGD009 studies with "additional supportive care to mitigate these events." The FDA is currently reviewing those amendments and the company is hopeful that the hold will be lifted soon.

MGD009 is one of MacroGenics’ humanized DART bispecific drug candidates which combines CD3 and B7-H3 targeting and is being developed for solid tumors. B7-H3 is a member of a family of molecules involved in immune regulation and is over-expressed on a wide variety of cancer cells, while CD3 is an antigen on T cells. The drug is designed to redirect T cells to kill B7-H3-expressing cells.

"As we’ve identified to the FDA, we believe that transaminitis observed in patients administered MGD009 was likely a cytokine-mediated event," said MacroGenics CEO Scott Koenig, M.D., Ph.D.

"We are working with the FDA and will provide an update when we have additional information," he continued, adding that the hold has no implications on other B7-H3 programs which include enoblituzumab in phase 2 and antibody-drug conjugate (ADC) MGC018 in preclinical development.

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