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Seattle Genetics, Inc. announced that it has received notice from the U.S. Food and Drug Administration (FDA) that a clinical hold or partial clinical hold has been placed on several early stage trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML). The clinical holds were initiated to evaluate the potential risk of hepatotoxicity in patients who were treated with SGN-CD33A and received allogeneic stem cell transplant either before or after treatment. Six patients have been identified with hepatotoxicity, including several cases of veno-occlusive disease, with four fatal events. Overall, more than 300 patients have been treated with SGN-CD33A in clinical trials across multiple treatment settings. Seattle Genetics is working diligently with the FDA to determine whether there is any association between hepatotoxicity and treatment with SGN-CD33A, to promptly identify appropriate protocol amendments for patient safety and to enable continuation of these trials.
The phase 1/2 trial of SGN-CD33A monotherapy in pre- and post-allogeneic transplant AML patients has been placed on full clinical hold. Two phase 1 trials have been placed on partial clinical hold (no new enrollment, existing patients may continue treatment with re-consent). These studies are SGN-CD33A monotherapy, including a subset of older AML patients in combination with hypomethylating agents, and SGN-CD33A combination treatment with 7+3 chemotherapy in newly diagnosed younger AML patients. No new studies will be initiated until the clinical holds are lifted.
Vadastuximab talirine is a novel investigational ADC targeted to CD33 utilizing Seattle Genetics’ proprietary ADC technology. CD33 is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its potent cell-killing PBD agent upon internalization into CD33-expressing cells.
