The U.S. Food and Drug Administration (FDA) confirmed today that it has lifted the clinical hold on phase 1 trials of vadastuximab talirine (SGN-CD33A; 33A) in acute myeloid leukemia (AML). The clinical hold was announced on December 27, 2016.

Vadastuximab talirine is a novel investigational antibody-drug conjugate or ADC targeted to CD33 utilizing Seattle Genetics’ proprietary technology. CD33 is expressed on most acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) blast cells. The CD33 engineered cysteine antibody is stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine or 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.

Orphan Drug Designation
Vadastuximab talirine was granted Orphan Drug Designation by both the FDA and the European Commission for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.

“The clinical hold on early-stage vadastuximab talirine clinical trials has been resolved through a comprehensive analysis of the clinical data from over 300 patients treated to date, evaluation by an independent committee of clinical experts, collaborative interactions with the FDA, and protocol amendments designed to further enhance patient safety,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

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“We will resume two phase I trials in AML and plan to initiate a randomized phase II trial during 2017 evaluating vadastuximab talirine in combination with standard of care chemotherapy in frontline, younger AML patients. In addition, we are continuing to enroll our ongoing phase 3 randomized CASCADE trial in frontline older AML patients and our phase I/II trial in frontline high-risk myelodysplastic syndrome (MDS).”

Resuming trials
Following the lifting of the clinical hold, Seattle Genetics will resume two phase I trials of vadastuximab talirine. The first is combination treatment with standard of care, or 7+3, chemotherapy in newly diagnosed younger AML patients. The second is monotherapy and combination treatment with hypomethylating agents in both newly diagnosed and relapsed AML patients.

However, the company will not resume the phase I/II trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant AML patients given the challenges of developing therapies in this specific setting.

The randomized global phase III CASCADE trial in frontline older AML and phase I/II trial in frontline MDS were not placed on clinical hold and have continued to enroll patients. Planned studies include a randomized phase II trial of vadastuximab talirine in combination with 7+3 chemotherapy in frontline younger AML patients.

As part of resuming the clinical trial program, additional risk mitigation measures will be implemented in all vadastuximab talirine clinical studies, including revised eligibility criteria and stopping rules for veno-occlusive disease (VOD), which occurs when the small blood vessels that lead into and are inside the liver become blocked.