FDA Places Clinical Hold on Kura Oncology’s Acute Myeloid Leukemia Therapeutic

Kura Oncology is a clinical-stage biopharma focused on precision medicines for cancers. On November 23rd, the San-Diego company announced that the FDA has placed a partial clinical hold on the administration of its KO-539 to patients with relapsed or refractory acute myeloid leukemia (AML) in the KOMET-001 Phase 1b study.

The hold was triggered by a patient death associated with differentiation syndrome, a Grade 5 serious adverse event, which is a known side-effect relevant to differentiating agents in the treatment of AML. Although the existing cohort of patients in the study may continue to receive KO-539, the enrollment of new participants will be halted until the partial clinical hold is lifted.

In addition, Kura suspended guidance on the completion of enrollment in the KOMET-001 Phase 1b study and the determination of the recommended Phase 2 dose of KO-539. The ensuing news led to shares falling by 29% in pre-market trading after closing on November 23rd at $16.

“We share the FDA’s commitment to patient safety, and we appreciate our ongoing dialogue as we work diligently to address their questions,” said Troy Wilson, Ph.D., J.D., President and CEO of Kura Oncology.

“Differentiation syndrome is known to be an on-target effect associated with therapeutic agents that induce differentiation, and we want to ensure physicians are fully informed and prepared to address these events if they occur. Based on the totality of preclinical and clinical data, we continue to believe that KO-539 has the potential to address the significant unmet medical need of AML patients, including those with NPM1 mutations and KMT2A rearrangements.”

Causation of Menin-MLL

MLL-rearranged leukemias are induced by chromosomal translocations of the KMT2A gene, mainly found in patients with AML and acute lymphoblastic leukemia (ALL). The translocations overexpress in a broader subset of AMLs characterized by oncogenic driver mutations in genes like NPM1, as they form oncogenes encoding MLL fusion proteins which are accountable for the onset, development, and progression of MLL-rearranged leukemias. More so, such mutations are dependent on the interaction between menin and MLL, and thus the design of KO-539 is to inhibit the menin-MLL protein-protein interaction.

KO-539 is a potent, selective, and first-in-class small molecule inhibitor of the menin-mixed lineage leukemia (menin-MLL). In preclinical studies, KO-539 demonstrated promising anti-tumor activity in multiple in vivo models of AML characterized by MLL-rearrangements or oncogenic driver mutations in genes such as NPM1.

“The preliminary first-in-human data generated by KO-539 for the treatment of patients with relapsed or refractory AML is encouraging,” said Eunice Wang, M.D., CHief of the Leukemia Service at Roswell Park Comprehensive Cancer Center and principal investigator of the trial.

“In addition to a favorable safety and tolerability profile, we have observed evidence of biologic activity in each dose-escalation cohort treated to date. I am delighted to observe evidence of clinical activity in patients with adverse genetic backgrounds, including patients with NPM1 mutations. The preliminary clinical data for KO-539 suggest it has the potential to be effective for multiple genetically defined AML subgroups of high unmet need.”

KOMET-001 Study

KOMET-001 study is a first-in-human, open-label, dose-escalation, and dose-validation/expansion study that assesses the safety and activity of KO-539 as a qualified menin-MLL inhibitor. A total of 90 patients who are at least 18 years old with relapsed or refractory AML, an ECOG performance status of zero to two, adequate kidney and liver function, and peripheral white blood cell count less than 30,000 per microliter were enrolled in the study.

The co-primary endpoints of the study are to determine the maximum tolerated dose of the agent, the number of patients who experience adverse events and figure out the minimal biologically effective dose. The secondary endpoints are the number of patients with any levels of adverse events, complete response rate, duration of response, relapse-free survival, overall survival, and transfusion independence. Kura will be hoping that the partial hold is lifted and the study resumes to meet the needs of the victims of acute myeloid leukemia.

Author

Judy Ya-Hsuan Lin

Success is the ability to go from one failure to another with no loss of enthusiasm.