What menin inhibitors are FDA-approved?

Revumenib (SNDX-5613, Syndax Pharmaceuticals) received FDA accelerated approval in November 2023 for relapsed/refractory acute leukemia with a KMT2A rearrangement in adults and children aged 1 year and older — the first menin inhibitor approval. It is marketed as Revuforj. Approval was based on AUGMENT-101 Phase 1/2 data showing a 23% complete remission (CR/CRh) rate in heavily pretreated patients.

What is ziftomenib and how does it differ from revumenib?

Ziftomenib (KO-539) is Kura Oncology's menin inhibitor in Phase 3 development for NPM1-mutated AML (KOMET-007, NCT07007312). Unlike revumenib, which targets KMT2A-rearranged leukemia (where menin-KMT2A fusion drives aberrant gene expression), ziftomenib's Phase 3 program focuses on NPM1-mutated AML, where NPM1 mutations also cause menin-dependent transcriptional activation of HOX/MEIS1 oncogenes. NPM1 mutations are the most common AML mutation (~30% of cases), making this a larger potential market than KMT2A rearrangements (~10%).

How do menin inhibitors work?

Menin inhibitors block the protein-protein interaction between menin (encoded by MEN1) and the KMT2A (MLL1) histone methyltransferase complex. In leukemias with KMT2A rearrangements or NPM1 mutations, this menin-KMT2A interaction drives aberrant expression of HOX and MEIS1 genes — a transcriptional program normally active in early hematopoiesis but pathological when locked on in leukemic stem cells. By disrupting menin-KMT2A binding, menin inhibitors cause downregulation of HOXA9, HOXA10, and MEIS1, forcing leukemic blasts to differentiate and die.

What are the key biomarkers for menin inhibitor response?

The two primary biomarkers predictive of menin inhibitor response are KMT2A rearrangements (also called MLL rearrangements, present in ~10% of adult AML and ~70-80% of infant ALL) and NPM1 mutations (present in ~30% of adult AML). Both result in menin-dependent transcriptional addiction to HOX/MEIS1 programs. Biomarker testing — specifically cytogenetics/FISH for KMT2A rearrangements and PCR/NGS for NPM1 mutations — is therefore mandatory for patient selection in menin inhibitor trials.

How does DataLookout monitor menin inhibitor competitive intelligence?

DataLookout monitors ClinicalTrials.gov daily for new menin inhibitor trial registrations, enrollment status changes, and sponsor updates. With three companies running Phase 3 programs (Syndax, Kura Oncology, Janssen) and AstraZeneca in Phase 1/2, the menin inhibitor landscape is evolving rapidly. Daily alerts notify pharma BD teams of new trial registrations, enrollment openings, and competitive program changes.

Menin Inhibitor Clinical Trials — Revumenib, Ziftomenib, Bleximenib Pipeline 2026

Active Trials

Phase 3 Programs

Drug Candidates

2023

First FDA Approval

FDA Approval: Revumenib (Revuforj, Syndax Pharmaceuticals) received FDA accelerated approval in November 2023 for relapsed/refractory acute leukemia with a KMT2A rearrangement — the first menin inhibitor to reach the market. Approval was based on AUGMENT-101 data: 23% CR/CRh rate in patients with median 4 prior lines of therapy.

Phase 3 Trials: The Competitive Landscape

Trial / NCT	Drug	Regimen	Sponsor	Setting	Status
NCT07211958	Revumenib	+ Intensive chemo (7+3 backbone)	Syndax Pharmaceuticals	Newly diagnosed AML (KMT2Ar or NPM1-mut)	Recruiting Phase 3
NCT07007312 KOMET-007	Ziftomenib	+ Ven+Aza or 7+3	Kura Oncology	NPM1-mutated AML (newly diagnosed or R/R)	Recruiting Phase 3
NCT06852222	Bleximenib	+ Venetoclax + Azacitidine	Janssen (J&J)	Newly diagnosed AML (NPM1-mut or KMT2Ar)	Recruiting Phase 3
NCT05327894 Interfant-21	Standard chemo ± menin inhibitor	Chemotherapy backbone	Princess Maxima Center	Infant ALL with KMT2A rearrangement	Recruiting Phase 3

Key Phase 1/2 Trials

Trial / NCT	Drug	Combination	Sponsor	Status
NCT04065399 AUGMENT-101	Revumenib	Monotherapy → FDA registration	Syndax Pharmaceuticals	Recruiting Phase 1/2
NCT04811560 cAMeLot-1	Bleximenib	Monotherapy + combinations	Janssen	Active Phase 1/2
NCT07155226	AZD3632	Monotherapy + combinations	AstraZeneca	Recruiting Phase 1/2
NCT06177067	Revumenib	+ Azacitidine + Venetoclax (pediatric)	St. Jude Children's Research Hospital	Recruiting Phase 1
NCT06313437	Revumenib	+ 7+3 + Midostaurin (FLT3+NPM1 AML)	Richard Stone / DFCI	Recruiting Phase 1
NCT05735184	Ziftomenib	+ Venetoclax + Azacitidine	Kura Oncology	Recruiting Phase 1
NCT06440135	Ziftomenib	Maintenance post-allogeneic HCT	Massachusetts General Hospital	Recruiting Phase 1

What Are Menin Inhibitors?

Menin inhibitors are a new class of targeted therapy that block the protein-protein interaction between menin (the MEN1 gene product) and the KMT2A (MLL1) histone methyltransferase complex. This interaction is the molecular linchpin of transcriptional programs that drive leukemogenesis in two distinct genetic subsets:

KMT2A-rearranged (KMT2Ar) leukemia: Chromosomal translocations create KMT2A fusion proteins (e.g., KMT2A-AFF1, KMT2A-MLLT3) that depend on menin as an obligate cofactor to activate HOXA9/HOXA10/MEIS1. Present in ~10% of adult AML and 70–80% of infant ALL — where it confers the worst prognosis in pediatric oncology.
NPM1-mutant AML: Mutant NPM1 mislocalizes to the cytoplasm, indirectly causing menin-dependent overexpression of HOXA/MEIS1. NPM1 mutations are the most common genetic alteration in AML (~30% of cases), making this the larger commercial opportunity.

Both pathways converge on the same HOX/MEIS1 oncogenic transcriptional program. Menin inhibitors disrupt this program regardless of the upstream driver, causing leukemic blasts to differentiate and undergo programmed cell death — a mechanism entirely distinct from chemotherapy, hypomethylating agents, or BCL-2 inhibition.

Revumenib (Revuforj): The First Approval

Syndax Pharmaceuticals developed revumenib (SNDX-5613) as the first-in-class menin inhibitor. The AUGMENT-101 Phase 1/2 trial enrolled heavily pretreated patients with KMT2A-rearranged or NPM1-mutated acute leukemia, generating the data set that supported FDA accelerated approval in November 2023 for KMT2A-rearranged leukemia.

Key AUGMENT-101 efficacy data (KMT2A-r cohort):

Overall response rate (ORR): ~63% in the overall population
CR/CRh rate: 23% (the endpoint supporting accelerated approval) in patients with ≥1 prior therapy
MRD negativity: Many complete responders achieved measurable residual disease (MRD) negativity — the deepest response category
Bridge to transplant: A meaningful fraction of patients who responded proceeded to allogeneic stem cell transplantation

Differentiation syndrome risk: Menin inhibitors can cause differentiation syndrome — a potentially life-threatening inflammatory reaction arising as leukemic blasts mature rapidly. This is mechanistically analogous to differentiation syndrome with IDH inhibitors (ivosidenib, enasidenib). All menin inhibitor trials require monitoring protocols for fever, respiratory distress, fluid retention, and rapid corticosteroid initiation.

Ziftomenib (KOMET-007): Targeting NPM1-Mutant AML at Scale

Kura Oncology's ziftomenib (KO-539) is advancing through Phase 3 in what may be the most commercially significant menin inhibitor program: NPM1-mutated AML, present in approximately one-third of all adult AML cases. KOMET-007 (NCT07007312) randomizes patients to ziftomenib plus venetoclax+azacitidine or ziftomenib plus 7+3 intensive chemotherapy.

The strategic rationale is compelling: if ziftomenib can improve outcomes in NPM1-mutant AML on top of standard backbones, it would represent the first molecularly targeted agent validated specifically for this mutation — in a population 3x larger than the KMT2A-rearranged cohort. Kura is also studying ziftomenib in combination with imatinib in GIST (NCT06655246) — an exploratory program testing menin inhibition outside of leukemia.

BD Intelligence: Three independent Phase 3 programs (Syndax, Kura Oncology, Janssen) running simultaneously in overlapping patient populations creates an unusual competitive dynamic: each sponsor is racing to establish standard-of-care position before others read out. Watch enrollment pace — the first positive Phase 3 will reshape prescribing patterns for all three drugs.

Bleximenib (cAMeLot): Janssen's Ven+Aza Integration Strategy

Janssen (Johnson & Johnson) is developing bleximenib (JNJ-75276617) with a differentiated positioning: integrating menin inhibition directly into the ven+aza backbone that is already standard of care for newly diagnosed AML patients ineligible for intensive chemotherapy. The Phase 3 trial (NCT06852222) tests bleximenib+venetoclax+azacitidine — a triplet — in NPM1-mutant and KMT2A-rearranged newly diagnosed AML.

The cAMeLot-1 Phase 1/2 trial (NCT04811560) provided dose-finding and early efficacy data. The Phase 3 design reflects Janssen's hypothesis that adding menin inhibition to the established ven+aza platform will produce deeper and more durable responses, particularly in the biomarker-selected population, without requiring patients to choose between the two complementary mechanisms.

AZD3632: AstraZeneca Enters the Race

AstraZeneca's AZD3632 entered Phase 1/2 in 2025 (NCT07155226), adding a fourth company to the competitive field. AstraZeneca's oncology pipeline breadth — acalabrutinib in CLL, olaparib in BRCA-mutant cancers, osimertinib in EGFR-mutant NSCLC — suggests potential for bleximenib combinations with existing AZ assets, particularly in AML where AZ has existing presence through acalabrutinib's CLL franchise and enasidenib (IDH2 inhibitor, developed with Celgene).

The Infant ALL Problem: Menin Inhibition's Most Urgent Application

Infant ALL (acute lymphoblastic leukemia in children under 1 year) is characterized by KMT2A rearrangements in approximately 75–80% of cases and carries the worst prognosis in pediatric oncology — historically less than 30% long-term survival with intensive chemotherapy. The Interfant-21 trial (NCT05327894, Princess Maxima Center) is testing whether adding menin inhibition to the established Interfant chemotherapy backbone can improve outcomes in this population.

The St. Jude trial (NCT06177067) evaluates revumenib combined with azacitidine and venetoclax in pediatric patients, addressing the question of whether the combination mechanisms — menin inhibition + BCL-2 inhibition + DNA methylation targeting — can be combined safely in younger patients.

Combination Strategy: Menin + BCL-2 + Hypomethylating Agents

The most active combination strategy in current trials pairs menin inhibition with venetoclax+azacitidine, reasoning that these mechanisms are mechanistically complementary:

Menin inhibitors force differentiation — they reduce the self-renewal capacity of leukemic stem cells
BCL-2 inhibitors (venetoclax) remove the survival advantage of differentiated blasts — they restore apoptosis sensitivity
Hypomethylating agents (azacitidine) reactivate silenced tumor suppressor genes and augment differentiation signals

Early Phase 1 data from ziftomenib+ven+aza (Kura, NCT05735184) and revumenib+aza+ven (St. Jude, NCT06177067) suggest the combination is tolerable and active, supporting the Phase 3 programs. The differentiation syndrome risk requires careful management protocols in triplet combinations.

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Frequently Asked Questions

What are KMT2A rearrangements and why do they matter for menin inhibitors?

KMT2A (formerly MLL1) rearrangements are chromosomal translocations that fuse the KMT2A gene to one of 80+ fusion partners, creating oncogenic fusion proteins (e.g., KMT2A-AFF1 in t(4;11), KMT2A-MLLT3 in t(9;11)). The resulting fusion protein recruits menin as an obligate cofactor to drive HOXA/MEIS1 transcription. This menin dependence is what makes KMT2A-rearranged leukemia sensitive to menin inhibitors. KMT2Ar accounts for ~10% of adult AML, ~3% of adult ALL, and ~75% of infant ALL.

Is revumenib approved for NPM1-mutated AML?

The initial November 2023 FDA accelerated approval was specifically for KMT2A-rearranged acute leukemia. AUGMENT-101 also enrolled NPM1-mutated patients, with the NPM1 cohort showing high response rates that are expected to support a label expansion. Syndax's Phase 3 program (NCT07211958) includes both KMT2Ar and NPM1-mutant patients to enable full approval and potential label expansion. Prescribers use revumenib off-label in NPM1-mutant patients based on AUGMENT-101 NPM1 cohort data, pending formal approval in this indication.

How do menin inhibitors fit into AML treatment sequencing after venetoclax+azacitidine?

The current standard of care for newly diagnosed AML in transplant-ineligible patients is venetoclax+azacitidine. When patients relapse or become refractory, there is no validated second-line standard. Menin inhibitors are being studied both as upfront additions to ven+aza (the triplet approach) and as single-agent or combination therapy in the relapsed/refractory setting. The Phase 3 readouts will establish whether menin inhibition belongs in the frontline (improving initial remission depth) or salvage (rescuing ven+aza failures) setting — or both.

What is the QTc prolongation concern with menin inhibitors?

Revumenib and other menin inhibitors have shown dose-dependent QTc interval prolongation in clinical trials. AUGMENT-101 required ECG monitoring and dose modifications or interruptions in some patients. This cardiac monitoring requirement is carried into Phase 3 trials. Importantly, QTc prolongation management is incorporated into trial protocols and is not expected to preclude commercial use, but does require monitoring infrastructure — a consideration for combination trial designs.

Menin Inhibitor Clinical Trial Tracker