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FDA Grants Ziftomenib with Breakthrough Therapy Designation for NPM1-Mutant Acute Myeloid Leukemia

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Kura Oncology’s ziftomenib has been granted Breakthrough Therapy Designation (BTD) by the FDA for heavily pretreated patients with relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML) based on data from the Phase I/II KOMET-001 trial (NCT04067336). The regulatory action makes ziftomenib the first novel therapy granted BTD for NPM1-mutant AML. The FDA previously granted ziftomenib with orphan drug designation in 2019 to treat AML.2

“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,” said Troy Wilson, PhD, JD, president and CEO of Kura Oncology, in a press release. “NPM1-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. 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.”1

AML is the most commonly diagnosed form of acute leukemia and has a patient population with significant unmet needs and a poor prognosis. The menin pathway is a significant driver of multiple genetic AML alterations, of which NPM1 is the most common, comprising approximately 30% of total AML cases.

Despite the high response rates observed with frontline therapy, the disease has high relapse rates and poor survival outcomes. Further, co-occurring mutations have been found to worsen prognosis and R/R patients with NPM1-mutant AML and additional mutations have low survival rates.1

Ziftomenib is a once-daily, oral treatment that targets the menin-KMT2A/MLL protein-protein interaction in genetically defined patients with AML. The BTD was granted based on findings from the Phase Ib portion of the KOMET-001 trial.

The ongoing, global, open-label KOMET-001 trial is analyzing the safety, tolerability, pharmacokinetics, and clinical activity of ziftomenib in patients with R/R NPM1-mutant AML.3 The trial’s primary endpoint is complete remission (CR) rate, with secondary endpoints that include duration of CR, transfusion independence, CR minimal residual disease negativity, and adverse effects (AEs).

Data from the KOMET-001 trial presented at the 2023 EHA Congress showed ziftomenib has a favorable tolerability profile, with optimal efficacy achieved at a daily dose of 600 mg.3 Among 20 patients with NPM1-mutant AML administered the 600-mg dose, investigators observed a 35% CR rate, a composite CR rate of 40%, and an overall response rate of 45%. Further, the CR rate was 33% in patients with co-mutations of FLT3 (n = 6) and 50% in patients with co-mutations of IDH (n = 8).1,3

In terms of safety, treatment-emergent AEs (TEAEs) of any grade were reported in 19 patients (95%). The most commonly reported TEAEs were diarrhea (45%), hypokalemia (40%), nausea (30%), anemia (30%), back pain (30%), and epistaxis (25%), with 85% of patients reporting grade 3 or higher TEAEs, which included anemia (25%) and thrombocytopenia (20%).3


  1. Kura Oncology receives breakthrough therapy designation for ziftomenib in NPM1-mutant AML. News release. Kura Oncology. April 22, 2024. Accessed April 23, 2024.
  2. 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 23, 2024.
  3. 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.