FDA Grants Priority Review to NDA of Ziftomenib in NPM1-Mutant AML

• The new drug application (NDA) seeking full approval of ziftomenib (KO-539) in relapsed/refractory acute myeloid leukemia (AML) harboring an NPM1 mutation has received FDA priority review.
• A target action date of November 30, 2025, under the Prescription Drug User Fee Act (PDUFA), has been set by the FDA.
• Findings from the phase 1/2 KOMET-001 trial (NCT04067336) support this regulatory decision.

The FDA has granted priority review to the NDA seeking full approval of ziftomenib for the treatment of patients with relapsed/refractory AML that harbors an NPM1 mutation, and a PDUFA target action date of November 30, 2025, has been set.¹

Data from the phase 1/2 KOMET-001 trial support this FDA decision, as the study previously met its primary end point of complete remission (CR) plus CR with partial hematologic recovery (CRi) rate. This showed a favorable risk-benefit profile and safety findings that were consistent with earlier data. In the phase 1b portion of KOMET-001, 35% of patients with NPM1 mutations (n = 20) treated at the recommended phase 2 dose (600 mg) achieved CR.^2,3

The Menin inhibitor was well tolerated, and treatment-emergent grade 3 or greater adverse events included anemia (24%), febrile neutropenia (22%), pneumonia (19%), differentiation syndrome (15%), and more. Differentiation syndrome led to the cessation of enrollment for patients with KMT2A rearrangements due to safety concerns.

“The FDA’s acceptance of our NDA marks a significant milestone for Kura [Oncology], Kyowa Kirin, and, more importantly, for patients living with this genetic subset of AML, who face an aggressive form of the disease with few treatment options,” said Troy Wilson, PhD, JD, president and chief executive officer of Kura Oncology, in a press release. “This achievement reflects the strength of the clinical data for ziftomenib as well as the incredible commitment of our teams. Along with our partners at Kyowa Kirin, we look forward to continuing to work closely with the FDA throughout the review process and to prepare for the anticipated launch of this treatment, which holds potential to meaningfully impact the lives of patients and their families.”

If approved, this would become the first Menin inhibitor to be granted FDA approval for the treatment of adult patients with relapsed/refractory AML with an NPM1 mutation. Full data from the first-in-human, open-label, dose-escalation and -validation/expansion KOMET-001 trial were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Enrollment in the trial was open to patients aged 18 years and older with relapsed/refractory AML, which was defined as the reemergence of a bone marrow blast level of at least 5%.⁴ All patients were required to have disease that progressed on or was ineligible for standard-of-care therapies. This included hematopoietic stem cell transplant (HSCT). Further, patients must have had an ECOG performance status of 0 to 2, a life expectancy of 2 months or more, and adequate liver and kidney function. Phase 1b of the study enrolled patients with AML that harbored KMT2A rearrangements or NPM1 mutations, while phase 2 only included those with NPM1 mutations.

Phase 1a was the dose-escalation portion of the trial. Phase 1b was the dose-validation/expansion portion. In phase 2 of the study, patients with NMP1-mutant relapsed/refractory AML were given ziftomenib at the recommended phase 2 dose (RP2D) that was established in phase 1.

For phase 1a, the primary end point was to determine the maximum tolerated dose/RP2D. In phase 1b, primary end points included safety and determining the minimal biologically effective dose. For phase 2, CR/CRi rate was the primary end point.

“Adult [patients with] relapsed/refractory, NPM1-mutant AML face 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, added 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. Our dedicated teams at Kyowa Kirin and Kura are fully committed to working tirelessly to ensure that, once approved, ziftomenib is made available to [patients with] AML as quickly as possible. We recognize the importance of this endeavor and are excited about the possibility of making a meaningful impact on the lives of those affected by this challenging disease,” Yamashita concluded.

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. June 1, 2025. Accessed June 3, 2025. https://tinyurl.com/42pup9zu

2. Kura Oncology and Kyowa Kirin announce positive ziftomenib monotherapy registrational trial and positive FDA feedback for upcoming frontline combination trial designs. News release. Kura Oncology. February 5, 2025. Accessed June 3, 2025. https://tinyurl.com/534aspw5

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. Lancet Oncol. 2024;25(10):1310-1324. doi:10.1016/S1470-2045(24)00386-3

4. First in human study of ziftomenib in relapsed or refractory acute myeloid leukemia. ClinicalTrials.gov. Updated April 18, 2025. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT04067336