Phase 1 ORM-1153 CD123-directed degrader-antibody conjugate delivers a GSPT1-degrading payload in hematologic malignancies

Orum Therapeutics USA is running this first-in-human, multicenter Phase 1 study of ORM-1153 in relapsed or refractory acute myeloid leukemia and other protocol-eligible CD123-expressing hematologic malignancies. ORM-1153 is a degrader-antibody conjugate: an anti-CD123 antibody delivers a cereblon-recruiting molecular-glue payload designed to degrade GSPT1, a protein involved in translation termination, inside targeted cells.

The open-label dose-escalation study evaluates intravenous dosing, safety, pharmacokinetics, and pharmacodynamic measures such as receptor occupancy and GSPT1 degradation. Unlike a conventional ADC payload that disrupts microtubules or damages DNA, this approach uses targeted protein degradation. CD123 is expressed on many AML cells but also on some normal hematopoietic cells, so antibody targeting does not guarantee a wide safety margin. The trial explores a new strategy for heavily pretreated disease, where salvage treatment, mutation-directed drugs, and transplantation are selected according to leukemia biology, prior therapy, and patient fitness.