FDA Grants Breakthrough Therapy Designation to Ziftomenib in NPM1-Mutant AML


The FDA has granted breakthrough therapy designation to ziftomenib for the treatment of NPM1-mutant acute myeloid leukemia.



The FDA has granted breakthrough therapy designation to ziftomenib for the treatment of heavily pretreated patients with relapsed/refractory NPM1-mutant acute myeloid leukemia (AML), marking this agent as the first investigational treatment to be granted breakthrough therapy designation for NPM1-mutant AML.1

Ziftomenib is a once-daily, oral drug that targets the menin-KMT2A/MLL protein-protein interaction to treat genetically defined patients AML with high unmet need. In the phase 1/2 KOMET-001 trial (NCT04067336), treatment with the novel drug was safe and tolerable, with optimal efficacy of the treatment observed at the 600-mg daily dose.

Data shared from the phase 1b portion of the trial, which supported the breakthrough therapy designation, were presented at the 2023 EHA Congress and showed a 35% complete remission (CR) rate in 20 patients with NPM1-mutant AML at the 600-mg dose, as well as a composite CR rate and an overall response rate of 40% and 45%, respectively. Additionally, CR rates of 33% and 50% were seen in patients with co-mutations of FLT3 (n = 6) and IDH (n = 8).1,2

Notably, ziftomenib received an orphan drug designation from the FDA in July 2019 for the treatment of patients with AML.1,3

“We are highly encouraged by FDA’s decision to grant breakthrough therapy designation to ziftomenib, recognizing its potential as an innovative medicine for patients with relapsed/refractory NPM1-mutant AML,” Troy Wilson, PhD, JD, president and chief executive officer of Kura Oncology, stated in a press release.1NPM1-mutant AML represents approximately 30% of new AML cases annually, and this designation reflects that NPM1-mutant AML is a disease of significant unmet need for which there is no approved targeted therapy as well as the fact that ziftomenib offers potential to demonstrate substantial improvement over available therapies.”

AML is the most common acute leukemia in adults, and despite available treatments, patient prognosis remains bleak with significant unmet needs. The menin pathway, particularly NPM1 mutations, is a major driver in AML. Although frontline therapy yields high response rates, relapse rates are high, resulting in poor survival outcomes; co-occurring mutations also worsen prognosis. Furthermore, patients with NPM1-mutant AML and additional mutations, as well as relapsed/refractory disease, face low survival rates.1

The ongoing KOMET-001 trial is designed to evaluate the safety, tolerability, pharmacokinetics, and clinical activity of ziftomenib in patients with relapsed/refractory NPM1-mutant AML.2 The primary end point of the study is CR, and secondary end points include duration of CR, transfusion independence, CR minimal residual disease negativity, and adverse effects (AEs).

Safety data from KOMET-001 showed that treatment-emergent AEs (TEAEs) of any grade occurred in 19 patients (95%), including diarrhea (45%), hypokalemia (40%), nausea (30%), anemia (30%), back pain (30%), and epistaxis (25%). Furthermore, 85% of patients experienced grade 3 or higher TEAEs, including anemia (25%) and thrombocytopenia (20%).2

Additionally, the registration-directed trial of ziftomenib in patients with relapsed/refractory NPM1-mutant AML is on track to complete by mid-2024. Ongoing trials of ziftomenib are also evaluating the agent in combination with current standards of care for the treatment of patients with AML. The phase 1 KOMET-007 trial (NCT05735184) is evaluating the agent in combination with venetoclax (Venclexta) plus azacitidine (Vidaza) or standard induction cytarabine/daunorubicin chemotherapy in patients with NPM1-mutant or KMT2A-rearranged AML. The phase 1 KOMET-008 trial (NCT06001788) is investigating the agent plus gilteritinib (Xospata), FLAG-IDA (fludarabine, cytarabine, granulocyte-colony stimulating factor, and idarubicin), or low-dose cytarabine in the same patient population.1

“We remain committed to bringing ziftomenib to the market as quickly as possible and look forward to working more closely with FDA to bring our ziftomenib program to patients in urgent need of effective treatments,” Wilson added in the press release.1


  1. Kura Oncology receives breakthrough therapy designation for ziftomenib in NPM1-mutant AML. News release. Kura Oncology. April 22, 2024. Accessed April 22, 2024. https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-receives-breakthrough-therapy-designation
  2. Fathi AT, Wang ES, Issa GC, et al. Activity, tolerability, and resistance profile of the menin inhibitor ziftomenib in adults with relapsed or refractory NPM1-mutated AML. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LB2713.
  3. Kura Oncology’s menin-MLL inhibitor KO-539 receives orphan drug designation from FDA for treatment of acute myeloid leukemia. News release. Kura Oncology. July 24, 2019. Accessed April 22, 2024. https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-doses-first-patient-phase-1-clinical-trial-menin
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