Xencor’s bispecific hold reignites debates over approach and target

Yesterday’s clinical hold on XmAb14045 marked the second time one of Xencor’s CD123-targeting assets has hit the buffers. A study of talacotuzumab was earlier scrapped by partner Johnson & Johnson after this naked anti-CD123 MAb failed to show an acceptable risk/benefit profile. The hold on XmAb14045, a Novartis-partnered bispecific that might have been responsible for two patient deaths, was therefore a blow for Xencor, for followers of bispecific approaches, and for other groups focused on the CD123 antigen. The bispecific field has been beset with problems, with clinical holds on projects including those targeting CD19 (Affimed’s AFM11) and B7-H3 (Macrogenics’ MGD009). And a separate J&J anti-CD123 bispecific, JNJ-63709178, now has two clinical holds under its belt. Though CD123 is a troublesome target it has resulted in one approval in Stemline’s Elzonris, for blastic plasmacytoid dendritic cell neoplasm, and at last year’s Ash conference Macrogenics’ flotetuzumab generated promising early data in AML. Nevertheless, the debate about whether CD123 can be targeted relatively cleanly will continue.