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Target Overview
Prognosis of acute leukemias with rearrangements in the MLL1 (KMT2A) gene is poor (5-year OS <25%). MLL-rearrangements (MLL-r) account for 80% of infant ALL and 5-15% of children and adults with acute leukemias. Mutated nucleophosmin 1 gene (NPM1), known as NPM1c, occurs in up to 30% of AML patients. NPM1c adult patients achieve high response rates 80-90%, however 37-50% eventually relapse. mOS in R/R NPM1c patients poor: 2nd line 7.8 mo, 3rd line 5.4 mo, 4th line 3.5 mo. Menin mediates pro-leukemic gene expression in acute leukemias & high risk MDS with genetic alterations in KMT2A, NPM1, or other loci promoting HOX gene over-expression.1,2
Compound Overview
AZD3632 is a next-generation small-molecule that binds to the protein menin and blocks its interaction with the protein KMT2A, thereby suppressing pro-leukemic gene expression in acute leukemias and high-risk myelodysplastic syndromes with specific genetic alterations, including KMT2A gene rearrangements (KMT2Ar) and NPM1 gene mutations (NPM1m).1,3
AZD3632 is being evaluated in a Phase I clinical study of participants with advanced haematologic malignancies harboring KMT2Ar, NPM1m, or other genotypes associated with homeobox (HOX) gene overexpression.
Mechanism of Action
References
1. Issa GC, et al. Leukemia. 2021;35(9):2482–2495. 2. Döhner H, Weisdorf DJ, Bloomfield CD. New England Journal of Medicine. 2015;373(12):1136-1152. 3. Bruin G, et al. Abstract presented at: ACS; August 26, 2026; Chicago, Illinois. Abs 4525231.
Target Overview
Prognosis of acute leukemias with rearrangements in the MLL1 (KMT2A) gene is poor (5-year OS <25%). MLL-rearrangements (MLL-r) account for 80% of infant ALL and 5-15% of children and adults with acute leukemias. Mutated nucleophosmin 1 gene (NPM1), known as NPM1c, occurs in up to 30% of AML patients. NPM1c adult patients achieve high response rates 80-90%, however 37-50% eventually relapse. mOS in R/R NPM1c patients poor: 2nd line 7.8 mo, 3rd line 5.4 mo, 4th line 3.5 mo. Menin mediates pro-leukemic gene expression in acute leukemias & high risk MDS with genetic alterations in KMT2A, NPM1, or other loci promoting HOX gene over-expression.1,2
Compound Overview
AZD3632 is a next-generation small-molecule that binds to the protein menin and blocks its interaction with the protein KMT2A, thereby suppressing pro-leukemic gene expression in acute leukemias and high-risk myelodysplastic syndromes with specific genetic alterations, including KMT2A gene rearrangements (KMT2Ar) and NPM1 gene mutations (NPM1m).1,3
AZD3632 is being evaluated in a Phase I clinical study of participants with advanced haematologic malignancies harboring KMT2Ar, NPM1m, or other genotypes associated with homeobox (HOX) gene overexpression.
Mechanism of Action
References
1. Issa GC, et al. Leukemia. 2021;35(9):2482–2495. 2. Döhner H, Weisdorf DJ, Bloomfield CD. New England Journal of Medicine. 2015;373(12):1136-1152. 3. Bruin G, et al. Abstract presented at: ACS; August 26, 2026; Chicago, Illinois. Abs 4525231.
Clinical trial information
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MOMENTUM trial overview
Abbreviations
ALL
Acute lymphoblastic leukemia
AML
Acute myeloid leukemia
HOX
Homeobox
KMT2A
Lysine methyltransferase 2A; formerly MLL1
KMT2Ar / MLL-r
KMT2A rearrangement / MLL rearrangement
MDS
Myelodysplastic syndromes
mOS
Median overall survival
mo
Months
NPM1
Nucleophosmin 1
NPM1c
Cytoplasmic NPM1 mutant
NPM1m
NPM1 mutation
OS
Overall survival
R/R
Relapsed/refractory