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Drugmoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q47-swi-snf

FHD-286 - the dual BRG1/BRM inhibitor that carries every SWI/SNF therapeutic claim in this disease, with a minimum enrolment age of 16

also called dual SMARCA2/SMARCA4 ATPase inhibitor · Foghorn FHD-286

FHD-286 is an oral drug that blocks both motors of the SWI/SNF machine. In the laboratory it kills MLL-rearranged leukaemia cells, works together with menin inhibitors, and is in a phase 1 trial in adults with relapsed leukaemia - but no trial of it admits children under sixteen.

The same thing, for a scientist

FHD-286 is an orally bioavailable, selective inhibitor of the BRG1 (SMARCA4) and BRM (SMARCA2) ATPases, in clinical development in AML [E1]. Preclinically it induces differentiation and lethality in AML with MLL1 rearrangement or mutant NPM1, perturbs chromatin accessibility, represses c-Myc, PU.1 and CDK4/6, reduces burden and improves survival in patient-derived xenografts, and attenuates the AML-initiating potential of stem-progenitor cells; it synergises with decitabine, a BET inhibitor, a menin inhibitor or venetoclax [E1]. In derived menin-inhibitor-resistant cells it is one of two agents that restore lethality, including against the menin M327I mutant and against patient-derived cells with ex vivo menin-inhibitor resistance [E2]. **Against this: a 2025 preprint reports KMT2A-R B-ALL lines resistant to FHD-286 and BRM014 while Ph-like B-ALL is sensitive [E3].** Clinically: NCT04891757, phase 1 in R/R AML/MDS/CMML, Foghorn, estimated n=144, minimum age **16 years**, monotherapy arm closed to enrolment, combination arms with low-dose cytarabine or decitabine, active but not recruiting as of the 2025-07 registry update [E4]. A separate uveal melanoma study was **terminated** with `whyStopped` reading *"Sponsor terminated the study for business reasons"* [E5]. An investigator-initiated study of FHD-286 with low-dose weekly decitabine/venetoclax in AML is recruiting at Montefiore [E6].

Go deeper
What the drug does and does not select for

Neither registered leukaemia study restricts enrolment by KMT2A rearrangement; NCT04891757's inclusion criteria are R/R AML, MDS or CMML with at most four prior lines, ECOG <=2, WBC <=20x10^9/L and standard organ function, with no molecular selection 4. So although every preclinical argument in this beat is about MLL1-rearranged disease, the clinical programme is a general R/R myeloid programme.

That matters twice over. First, a trial not enriched for the biology cannot confirm it. Second, the strongest preclinical rationale - synergy with a menin inhibitor - is not what either leukaemia protocol tests; the combinations on protocol are with low-dose cytarabine, decitabine and venetoclax 46.

The paediatric gap, stated as a fact rather than a complaint

Minimum age on NCT04891757 is 16 years 4. Infant KMT2A-rearranged ALL - the population this graph exists for - is therefore outside every current protocol for this drug class, and so is essentially all of paediatric KMT2A-rearranged AML.

The preclinical package is also myeloid. Every FHD-286 result cited here is AML; the only B-lineage data in the literature is the preprint reporting KMT2A-R B-ALL resistance 3. So for the disease this lab studies, the evidence base for this drug class is: one preprint, and it is negative.

Facts and figures
targetgene-smarca4
secondary targetgene-smarca2
modalitysmall molecule, oral, dual ATPase inhibitor (not a degrader)
statusphase 1 in R/R AML/MDS/CMML (NCT04891757, active not recruiting); investigator-initiated combination study recruiting (NCT07283094); uveal melanoma study terminated for business reasons (NCT04879017)
minimum age leukaemia trial16 years
molecular selectionnone; no KMT2A-rearrangement enrichment in eligibility
key aenot established from the registry; no results posted for NCT04891757 as of 2026-09-20
trials
[
  "NCT04891757",
  "NCT07283094",
  "NCT04879017"
]
combinations preclinical
[
  "decitabine",
  "BET inhibitor (OTX015/birabresib)",
  "menin inhibitor (revumenib, SNDX-50469)",
  "venetoclax"
]
combinations on protocol
[
  "low-dose cytarabine",
  "decitabine",
  "decitabine + venetoclax"
]
resistance
[
  "reported resistance of KMT2A-R B-ALL lines (preprint)",
  "paralogue-slot restoration is a theoretical route with no published assay"
]
How this could bite us back
  • Resistance: the target is an ATPase module with two interchangeable subunits; restoration of module function by either paralogue, or by a binding-site mutation in either, is an obvious escape route with no clinical assay.
  • Essential-function toxicity: SMARCA4 and SMARCB1 loss are oncogenic in other tissues and SWI/SNF is required for normal haematopoiesis and development; chronic inhibition in a child carries a second-malignancy and developmental question that no published study addresses.
  • Compensation: the drug induces differentiation, so differentiation syndrome is foreseeable, and it would be combined with menin inhibitors which carry the same liability.
  • Delivery and population: minimum age 16 excludes the infant population entirely, and every preclinical dataset is myeloid while the index disease here is B-lineage.
  • Biomarker: the one B-lineage dataset in existence reports KMT2A-R resistance, so a rearrangement-selected trial could be selecting for non-responders.
Still open
  1. Has any KMT2A-rearranged patient received FHD-286, and with what response? The registry does not stratify and no results are posted.
  2. Will the menin-inhibitor combination, which is the best-evidenced preclinical pairing, ever be tested clinically? Neither registered leukaemia protocol includes it.
  3. What is the minimum age at which this class could be studied, and is there a juvenile-animal toxicology package? SWI/SNF is required for normal development, so this is not a formality.
Every source behind this entry (6)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    FHD-286 is an orally bioavailable selective BRG1/BRM inhibitor under clinical development in AML that induces differentiation and lethality in AML cells with MLL1 rearrangement or mutant NPM1, represses c-Myc, PU.1 and CDK4/6, reduces burden and improves survival in patient-derived xenografts, and synergises with decitabine, BET inhibitor, menin inhibitor or venetoclax.

    PMID 38437498DOI
    What this evidence cannot show

    Preclinical; single laboratory for the combination matrix; 'without inducing significant toxicity' is a mouse observation in immune-depleted animals and does not address marrow reserve in a treated child.

    Evidence that argues against this (1)
    • The compound inhibits both ATPases, so none of these results attributes activity to SMARCA4; and DepMap gives SMARCA4 knockout no KMT2A selectivity at all, which means the genetic and pharmacological pictures do not agree. Oncofusion knowledge graph et al. 2026
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In menin-inhibitor-resistant AML cells derived without menin mutations, CRISPR screening identifies SMARCA4 among druggable co-enrichments, and menin inhibitor plus FHD-286 synergistically kills those cells, cells expressing menin M327I, and patient-derived MLL1-rearranged or mutant-NPM1 AML cells with ex vivo menin-inhibitor resistance; revumenib plus FHD-286 reduces in vivo burden and improves survival.

    PMID 41734382DOI
    What this evidence cannot show

    Resistance was derived in MV4-11 and OCI-AML3 by repeated SNDX-50469 shocks; no samples from patients who progressed clinically on a menin inhibitor. Same laboratory as E1.

    Evidence that argues against this (1)
    • A co-dependency identified by CRISPR in a resistant line is a property of that derived state; resistance arising in a patient on revumenib may take a different route, and none has been profiled. Xiu Y et al. 2018
  3. E3weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.preprint

    KMT2A-R B-ALL cell lines are resistant to FHD-286 and BRM014 while Ph-like B-ALL lines are markedly sensitive, and FHD-286 prolongs survival of NSG mice engrafted with Ph-like B-ALL.

    Selective Sensitivity of Ph-like B-ALL to BRG1 Inhibition Reveals a Novel Targeted Therapy Strategy. · Abhinav Ayyadevara VSS, Gaur S, Paik A, Perencsik R, et al. · bioRxiv 2025
    PMID 40672274DOI
    What this evidence cannot show

    bioRxiv preprint, not peer-reviewed; read from the abstract only; the number and identity of the resistant KMT2A-R lines are not stated there. Deliberately graded weak, and flagged for re-checking on publication.

    Evidence that argues against this (1)
    • All the positive FHD-286 data are myeloid; a B-lineage negative and a myeloid positive are not in contradiction, and the simplest reading is that lineage rather than rearrangement determines sensitivity. Fiskus W et al. 2024
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry

    NCT04891757 is a Foghorn Therapeutics phase 1 study of FHD-286 as monotherapy or with low-dose cytarabine or decitabine in R/R AML, MDS and CMML, estimated enrolment 144, minimum age 16 years, monotherapy arm closed to enrolment, status active-not-recruiting, started 2021-06-14, registry updated 2025-07-07; eligibility contains no molecular selection for KMT2A rearrangement.

    FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies · ClinicalTrials.gov, raw API v2 read 2026-09-20 · ClinicalTrials.gov 2026
    NCT04891757
    What this evidence cannot show

    Read from the raw ClinicalTrials.gov API v2 on 2026-09-20 including the eligibility, arms and status modules. A registry record states the protocol as filed, not what was done; enrolment is estimated, and no results are posted.

    Evidence that argues against this (1)
    • Absence of molecular selection in the eligibility criteria does not mean molecular data were not collected; a biomarker analysis could still exist in the sponsor's dataset and be invisible to the registry. ClinicalTrials.gov et al. 2026
  5. E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry

    Foghorn's phase 1 FHD-286 study in metastatic uveal melanoma (NCT04879017, actual enrolment 76) is TERMINATED with whyStopped reading 'Sponsor terminated the study for business reasons.'

    FHD-286 in Subjects With Metastatic Uveal Melanoma · ClinicalTrials.gov, raw API v2 read 2026-09-20 · ClinicalTrials.gov 2026
    NCT04879017
    What this evidence cannot show

    The whyStopped string was read from the raw API, which the MCP tool does not return. 'Business reasons' is a sponsor characterisation; it neither confirms nor excludes a safety or efficacy signal, and the registry offers nothing further.

    Evidence that argues against this (1)
    • A business-reasons termination in a different indication says nothing about the leukaemia programme, and reading it as a safety signal would be an error; it is recorded because portfolio decisions, not data, frequently decide whether a paediatric programme ever exists. ClinicalTrials.gov et al. 2026
  6. E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry

    An investigator-initiated phase 1 study at Montefiore Medical Center (NCT07283094, estimated n=33) of FHD-286 with low-dose weekly decitabine and venetoclax in AML and MDS is recruiting.

    FHD-286 With Low-Dose Weekly Decitabine/Venetoclax in Patients With Acute Myeloid Leukemia · ClinicalTrials.gov, raw API v2 read 2026-09-20 · ClinicalTrials.gov 2026
    NCT07283094
    What this evidence cannot show

    Read from the raw ClinicalTrials.gov API v2 on 2026-09-20; status and enrolment are as registered. Eligibility detail beyond condition and phase was not pulled for this record.

    Evidence that argues against this (1)
    • The combination on protocol is with hypomethylating agent and venetoclax, not with a menin inhibitor, so the combination with the strongest preclinical rationale in KMT2A-rearranged disease remains untested clinically. Fiskus W et al. 2024
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