The US FDA has placed a partial clinical hold on MacroGenics’ CD3 bispecific candidate MGD009 following reports of hepatic adverse events.

On December 6, the US Food and Drug Administration (FDA) sent Maryland-based clinical-stage biopharmaceutical company MacroGenics a letter indicating that a partial clinical hold has been placed on its Phase I monotherapy study of MGD009 and a combination study of MGD009 and MGA012 (anti-PD-1). No new patients will be enrolled in either study until the partial hold is lifted by the FDA.

The reason was cited as hepatic adverse events on the MGD009 monotherapy trial, including reversible elevations of transaminases.

“Although these events have been otherwise uncomplicated and short-lived in duration, MacroGenics also communicated to the FDA the company’s plans to amend the existing MGD009 studies with additional supportive care to mitigate these events,” MacroGenics said in a statement.

No new patients will be enrolled in either study until the partial hold is lifted by the FDA.

The (bi)specifics

MGD009 is a humanized, Dual-Affinity Re-Targeting (DART) molecule that recognizes both B7-H3 and CD3, molecules expressed on a wide variety of cancer cells. The mechanism of action of MGD009 is to redirect T cells, via their CD3 component, to kill B7-H3-expressing cells.

Evercore ISI analysts Umer Raffat and Jonathan Miller said that while the program is not critical in isolation, it is a CD3 bispecific antibody and the clinical hold could raise concerns on other CD3-engaging bispecific candidates.

“Although the company says B7-H3 expression is high in solid tumors and minimal in normal tissues, other sources suggest B7-H3 has medium to high expression in various tissues, including the liver. If normal cells also express B7-H3, then this DART may induce more immune activation than expected, in non-tumor environments like the liver,” they said in a note.

While they said there is a need to see further clinical data on safety, they added that while this is a negative development for the MGD009 program, “we don’t see widespread implications for the broader antibody design platform, and even readthrough to the CD3 bispecific platform should be cautious.”