Ziftomenib Earns FDA Priority Review for R/R NPM1-Mutrant AML

Ziftomenib was observed to be well-tolerated among patients with NPM1 mutations, showing limited myelosuppression; 3% of patients experienced treatment discontinuations.

The FDA has granted priority review to a new drug application (NDA) for ziftomenib (KO-539) as a treatment for patients with NPM1-mutant relapsed/refractory acute myeloid leukemia (AML), according to a news release from the drug’s developers, Kura Oncology and Kyowa Kirin Co.¹

The FDA named a Prescription Drug User Fee Act (PDUFA) target action date of November 30, 2025, for this indication.

Support for the FDA decision came from results from the phase 2 KOMET-001 trial (NCT04067336). According to the news release, the trial met its primary endpoint of complete remission (CR) and CR with partial hematological recovery (CRh). Furthermore, ziftomenib was observed to be well-tolerated among patients with NPM1 mutations, showing limited myelosuppression; 3% of patients experienced treatment discontinuations. In addition, ziftomenib’s safety and tolerability in the trial were consistent with its known profile.

The FDA previously granted breakthrough therapy status to ziftomenib in patients with relapsed/refractory NPM1-mutant AML in April 2024.²

“Adult [patients with relapsed/refractory] NPM1-mutant AML [have] a significantly poor prognosis, highlighting the urgent need for innovative treatment options that can improve their outcomes,” Takeyoshi Yamashita, PhD, executive vice president and chief medical officer of Kyowa Kirin, stated in the news release.¹ “The acceptance of this NDA is a crucial step in our ongoing efforts to explore and evaluate various therapeutic strategies for AML through our comprehensive clinical trials….Kura Oncology and Kyowa Kirin are fully committed to working tirelessly to ensure that, once approved, ziftomenib is made available to patients [with AML] as quickly as possible.”

In the phase 1b dose-validation/dose-expansion portion of the KOMET-001 trial, patients were randomly assigned 1:1 to receive 2 potential recommend phase 2 doses (RP2Ds) of ziftomenib: 200 mg and 600 mg.³ Patients in the dose-validation phase were assigned to receive 200 mg or 600 mg of the agent orally once daily in 28-day cycles. In the expansion phase, all patients received 600 mg of ziftomenib.

Patients with NPM1 mutations treated with 200 mg or 600 mg had a median age of 60.5 years (IQR, 44.0-73.0) vs 70.5 years (IQR, 48.0-75.0), 67% vs 70% were female, and 83% vs 65% were White. The median number of previous regimens in each arm was 2.5 (IQR, 2.0-9.0) vs 3 (IQR, 2.0-4.0), and 50% vs 65% of patients received prior venetoclax (Venclexta) treatment.

The primary end points of the phase 1b trial were safety, remission rates, pharmacokinetics, and pharmacodynamics supporting the RP2D. Key secondary end points included duration of response, transfusion independence, measurable residual disease, event-free survival, and overall survival.

Patients 18 years and older with relapsed/refractory AML, an ECOG performance status of0 to 2, and adequate renal and hepatic function were eligible for enrollment on the trial.

Safety data from phase 1 of the trial revealed that among all patients treated with ziftomenib (n = 83), including those with KMT2A rearrangements, treatment-emergent adverse effects (TEAEs) occurred in 82 (99%) patients. The most common TEAEs included diarrhea (31%), nausea (29%), anemia (25%), febrile neutropenia (23%), hypokalemia (23%), differentiation syndrome (22%), and epistaxis (21%). Additionally, the most common grade 3 or higher AEs included anemia (24%), febrile neutropenia (22%), pneumonia (19%), differentiation syndrome (15%), and thrombocytopenia (13%).

A total of 60 on-study deaths were observed. Most deaths occurred due to disease progression, with 1 treatment-related death and 1 cardiac arrest related to a grade 4 differentiation syndrome event. Furthermore, the 30- and 60-day mortality rates were 24% and 28%.

References

1. Kura Oncology and Kyowa Kirin announce FDA acceptance and priority review of new drug application for ziftomenib in adults with relapsed or refractory NPM1-mutant AML. News release. Kura Oncology Inc., Kyowa Kirin Co. June 2, 2025. Accessed June 3, 2025. https://tinyurl.com/yca5675t
2. Kura Oncology receives breakthrough therapy designation for ziftomenib in NPM1-mutant AML. News release. Kura Oncology, Inc. April 22, 2024. Accessed June 3, 2025. https://tinyurl.com/muzr3bye
3. Wang ES, Issa GC, Erba HP, et al. Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial [published correction appears in Lancet Oncol. 2024;25(11):e542. doi:10.1016/S1470-2045(24)00584-9. Lancet Oncol. 2024;25(10):1310-1324. doi:10.1016/S1470-2045(24)00386-3