Xencor’s bispecific hold reignites debates over approach and target

Snippets

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.

Selected CD123-targeting projects
Project  Company  Mechanism  Notes 
Approved
Elzonris Stemline Therapeutics Protein/drug conjugate  Two deaths in BPDCN cohort despite protocol modification
Phase III 
Talacotuzumab Xencor/J&J MAb  Trial scrapped; J&J evaluating data to determine further steps
Phase I 
UCART123   Cellectis/Allogene Allogeneic CAR-T   Clinical hold after patient death (Sep 2017), now lifted
MB-102   Fortress Biotech/Mustang  Bio Autologous CAR-T    
MIH911   Novartis   Autologous CAR-T   Study terminated for "lack of funding"
SGN-CD123A   Seattle Genetics  Antibody-drug conjugate   
Flotetuzumab   Macrogenics   Bispecific MAb   
JNJ-63709178   Genmab/J&J Bispecific MAb  Two clinical holds (Sep 2016 & Aug 2018), both lifted
XmAb14045   Xencor/Novartis Bispecific MAb  Clinical hold after 2 patient deaths (Feb 2019)
KHK2823   Kyowa Hakko Kirin   MAb   
Source: EvaluatePharma. 

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