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Drugweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q6-therapeutics

Bleximenib (JNJ-75276617) — menin inhibitor with a cleaner cardiac profile, and the only one with a 2-year-old floor

also called JNJ-75276617 · JNJ-75276617-AAA

Bleximenib is an experimental menin-blocking pill from Johnson & Johnson. It is interesting for two reasons: in early trials it did not prolong the heart's QT interval the way the approved drug does, and its first-in-human trial has a paediatric cohort open from age two — though that cohort sits in the phase 1 part, while both phase 3 studies that could support approval enrol adults only, so children will again get the drug after adults do.

The same thing, for a scientist

Bleximenib is an investigational oral inhibitor of the menin–KMT2A interaction (C32H50FN7O3, MW 599.80, aLogP 4.57, ChEMBL CHEMBL5314509). Structurally it is a close analogue of the revumenib chemotype — same N-ethyl-N-isopropyl fluorobenzamide head and spirocyclic diamine core — but with a 1,2,4-triazine replacing revumenib's pyrimidine and a methoxyethyl-methylamino-isopropyl tail in place of the ethanesulfonamide-cyclohexyl group. In the first-in-human cAMeLot-1 study (NCT04811560) it produced dose-dependent responses (ORR 36.4%/47.6%/55.0% at 45/90-100/150 mg) with no QTc prolongation reported and grade 3/4 differentiation syndrome in only ~6.5% at the RP2D. It is not approved anywhere. Its eligibility floor of 2 years, and its inclusion of NUP98/NUP214-altered leukaemia, make it the most paediatrically accessible menin inhibitor in the class today — though still not open to infants.

Go deeper
Chemistry — a same-pocket, different-periphery analogue of revumenib

Side by side, bleximenib and revumenib share the distinctive N-ethyl-N-isopropyl-2-aryloxy-5-fluorobenzamide head group and a spiro-fused azetidine/pyrrolidine-piperidine core. Bleximenib swaps revumenib's pyrimidin-4-yl ether for a 1,2,4-triazin-3-yl ether and replaces the polar ethanesulfonamido-cyclohexyl arm with a lipophilic, basic 1-(methoxyethyl-methylamino)propyl-isobutyl chain 14.

Why this matters mechanistically: both molecules occupy the same MBM1 pocket, so they are likely to share the M327I/G331D vulnerability. But the periphery differs enough that the hERG liability profile differs markedly in the clinic — which is exactly the kind of structure–toxicity separation the lab should be looking for when it asks whether the interface or the chemotype is the limiting factor.

Clinical data (cAMeLot-1, NCT04811560) — dose–response and the QTc difference1 deeper

As of an October 2024 data cut, 146 patients with R/R acute leukaemia had been treated (AML n=132, ALL n=7, other n=7); median age 60; 56.8% KMT2A-rearranged, 39.7% NPM1-mutant 2.

DoseORRCR/CRh
45 mg36.4%18.2%
90/100 mg47.6%33.3%
150 mg55.0%40.0%

In the 90/100 mg group, composite CR was 44.4% in KMT2A-r (n=9) and 33.3% in NPM1m (n=12) 2. These are tiny subgroups — 9 and 12 patients — and should be read as hypothesis-generating, not as a comparison with revumenib's 104-patient registration cohort.

The safety observation that matters: at the recommended phase 2 dose there was no QTc prolongation, and grade 3/4 differentiation syndrome was ~6.5% 2. If replicated in a registration-sized dataset, that would be a genuine advance for paediatric use, because it decouples menin inhibition from the azole/QT interaction problem that constrains revumenib.

Why the trial design tells you about the class's fear of differentiation syndrome

cAMeLot-1 excludes patients with WBC above 20 x 10^9/L and excludes active CNS disease, and it excludes QTcF ≥450 ms (male) / ≥470 ms (female) and any family history of long QT syndrome 3. The WBC cap is a differentiation-syndrome risk-management device: high blast burden is the main driver of DS severity. It also means the published response rates come from a lower-burden population than the one a clinician faces at relapse, and the CNS exclusion is a serious limitation for infant KMT2A-r ALL, where CNS involvement is common.

Combination programme

Bleximenib is in phase 1b combination with intensive chemotherapy in newly diagnosed AML with KMT2A or NPM1 alterations 5 and in phase 1b with venetoclax in KMT2A/NPM1-altered AML 6. The frontline-intensive-chemotherapy design is notable because it is one of the few menin combinations aimed at preventing resistance rather than treating it after the fact — the strategy the PI's 'comes back to bite us' concern actually demands.

Facts and figures
chembl IDCHEMBL5314509
targetgene-men1
target interactionmenin–KMT2A (MBM1) protein–protein interface
modalitysmall molecule (oral, reversible PPI inhibitor)
chemical class1,2,4-triazinyl-ether N-ethyl-N-isopropyl fluorobenzamide on a spiro azetidine-pyrrolidine core (revumenib-like head, different tail)
molecular formulaC32H50FN7O3
mw freebase da599.8
alogp4.57
ro5 violations1
statusInvestigational — not approved. Phase 1/2 (cAMeLot-1) recruiting; phase 1b combinations with intensive chemotherapy and with venetoclax ongoing.
sponsorJanssen Research & Development / Johnson & Johnson
pediatric eligibletrue
pediatric floor2 years (phase 1 paediatric cohort 2 to <18 years); infants under 2 not eligible
notablealso enrols NUP98/NUP214-altered acute leukaemia, extending the menin-dependency hypothesis beyond KMT2A-r and NPM1m
dosing
{
  "route": "oral",
  "doses_studied_mg": [
    45,
    90,
    100,
    150
  ],
  "schedule": "daily (dose optimisation ongoing)"
}
trials
[
  "NCT04811560"
]
efficacy
[
  {
    "population": "R/R acute leukaemia, 45 mg",
    "orr_pct": 36.4,
    "cr_crh_pct": 18.2
  },
  {
    "population": "R/R acute leukaemia, 90/100 mg",
    "orr_pct": 47.6,
    "cr_crh_pct": 33.3
  },
  {
    "population": "R/R acute leukaemia, 150 mg",
    "orr_pct": 55,
    "cr_crh_pct": 40
  },
  {
    "population": "KMT2A-r at 90/100 mg",
    "n": 9,
    "composite_cr_pct": 44.4
  },
  {
    "population": "NPM1m at 90/100 mg",
    "n": 12,
    "composite_cr_pct": 33.3
  }
]
key ae
[
  "differentiation syndrome grade 3/4 ~6.5% at RP2D",
  "no QTc prolongation reported at RP2D",
  "myelosuppression"
]
resistance
[
  "expected to share the MEN1 MBM1-pocket escape mutations of the class (untested)"
]
registry verified
{
  "nct": "NCT04811560",
  "sponsor": "Janssen Research & Development, LLC",
  "overall_status": "RECRUITING",
  "phases": "Phase 1/2",
  "target_enrolment": 420,
  "minimum_age": "2 Years",
  "std_ages": [
    "CHILD",
    "ADULT",
    "OLDER_ADULT"
  ],
  "why_stopped": null,
  "retrieved": "2026-09-19",
  "source": "https://clinicaltrials.gov/api/v2/studies/NCT04811560"
}
How this could bite us back
  • Same pocket as revumenib means probably the same on-target resistance mutations; a favourable safety profile does not buy durability.
  • The WBC cap of 20 x 10^9/L and the active-CNS-disease exclusion select a population unlike relapsed infant KMT2A-r ALL, so the reported response rates will likely not transfer.
  • All current bleximenib efficacy data are conference abstracts with subgroups of 9-12 patients; the confidence interval around 44% composite CR in 9 KMT2A-r patients is enormous.
  • Venetoclax and intensive-chemotherapy combinations will add myelosuppression on top of a drug whose main benefit is differentiation — the two effects can work against each other in count recovery.
Still open
  1. Is bleximenib's apparent absence of QTc prolongation a real chemotype property (off-target hERG avoidance) or an artefact of stricter baseline QTc exclusion in cAMeLot-1? A thorough QT study or a head-to-head would settle it.
  2. Does bleximenib retain activity against MEN1 M327I and G331D, which defeat both revumenib and ziftomenib? Nobody has published this, and it is a cheap, high-value experiment.
  3. Would a 2-years-and-up agent with a clean cardiac profile support the first genuine infant (under 12 months) menin-inhibitor trial, and what formulation and PK work is needed first?
Every source behind this entry (7)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Bleximenib is a small molecule of formula C32H50FN7O3 (MW 599.80, aLogP 4.57, 1 Lipinski violation) carrying the USAN '-menib' stem denoting a menin-MLL(KMT2A) interaction inhibitor, currently at max clinical phase 2.

    ChEMBL compound record: BLEXIMENIB (CHEMBL5314509) · EMBL-EBI ChEMBL Database · ChEMBL 2025
    What this evidence cannot show

    Database record; max_phase reflects ChEMBL curation lag and may understate current development stage.

    Evidence that argues against this (1)
    • The ChEMBL max_phase of 2 is stale and understates the programme by a full phase. Raw ClinicalTrials.gov v2 API query on intervention 'bleximenib', retrieved 2026-09-19, returns TWO recruiting PHASE 3 studies: cAMeLot-2 (NCT06852222, sponsor study id 75276617AML3001, bleximenib + venetoclax + azacitidine in newly diagnosed AML, estimated n=600, actual start 2025-06-04) and HOVON 181 AML (NCT07223814, bleximenib with standard induction/consolidation and maintenance, estimated n=875, actual start 2026-03-01). Neither carries a whyStopped value. Citing a database max_phase as a statement about a live development programme will be wrong on a timescale of months. Janssen Research & Development et al. 2025
  2. E2weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.news

    In the first-in-human cAMeLot-1 study (146 patients treated as of October 2024), bleximenib produced dose-dependent responses (ORR 36.4%, 47.6% and 55.0% at 45, 90/100 and 150 mg; CR/CRh 18.2%, 33.3% and 40.0%), with no QTc prolongation and grade 3/4 differentiation syndrome in about 6.5% at the recommended phase 2 dose.

    Menin inhibitors for AML: Current status and insights from ASH 2024 (bleximenib cAMeLot-1 dose optimisation data) · AML Hub editorial team (reporting Jabbour E et al., ASH 2024) · AML Hub 2024
    What this evidence cannot show

    Conference-abstract-level data reported through a secondary medical-education source, not a peer-reviewed primary publication. Subgroups are very small (KMT2A-r n=9, NPM1m n=12 at 90/100 mg). Data cut is October 2024 and may be superseded. No independent verification of the QTc claim in a registration-sized dataset. CONFERENCE-SOURCED (flagged 2026-09-19): this figure traces to a meeting abstract or meeting report and has not been verified against a peer-reviewed primary source. Abstract-stage response rates move on full publication and the denominators are often not comparable across trials.

    Evidence that argues against this (1)
    • A scoping review of menin-inhibitor safety across agents cautions that cross-agent safety comparisons from early-phase single-arm trials are confounded by differing eligibility (e.g. WBC caps, QTc exclusions) and monitoring intensity. Canichella M et al. 2025
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry

    cAMeLot-1 (NCT04811560) is a recruiting phase 1/2 Janssen study with planned enrolment 420, admitting patients from age 2 years into a phase-1-only paediatric cohort (2 to under 18) while the phase 2 part is adult, enrolling R/R acute leukaemia with KMT2A, NPM1 or NUP98/NUP214 alterations, and excluding WBC above 20 x 10^9/L, active CNS disease and baseline QTcF prolongation.

    NCT04811560
    What this evidence cannot show

    Registry record reflects the current protocol version; eligibility has been amended over the study's life, and the paediatric cohort is limited to phase 1.

    Evidence that argues against this (1)
    • 'Open from age 2' overstates paediatric access at the PROGRAMME level, which is what determines a label. Every bleximenib study that can generate registrational evidence enrols adults only: cAMeLot-2 (NCT06852222, phase 3, minimum age 18 years) and HOVON 181 AML (NCT07223814, phase 3, minimum age 18 years); the largest completed combination study, NCT05453903 (phase 1, actual enrolment 196, ACTIVE_NOT_RECRUITING), has a 12-year floor. All checked against the raw ClinicalTrials.gov v2 API on 2026-09-19. Paediatric and infant evidence will therefore arrive after adult approval, as it did for both approved menin inhibitors — and the phase 1/2 paediatric cohort in cAMeLot-1 is capped at phase 1, so it cannot by design produce a registrational paediatric efficacy estimate. Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON) 2026
  4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.review

    Bleximenib is one of six menin inhibitors in clinical evaluation (with revumenib, ziftomenib, enzomenib, DS-1594 and BMF-219/icovamenib) and is among the four most extensively studied.

    Therapeutic Implications of Menin Inhibitors in the Treatment of Acute Leukemia: A Critical Review · Canichella M, Papayannidis C, Mazzone C, de Fabritiis P · Diseases (Basel) 2025
    PMID 40710017DOI
    What this evidence cannot show

    Review; landscape snapshot as of mid-2025 and does not capture programmes discontinued since.

    Evidence that argues against this (1)
    • A mid-2025 landscape enumeration cannot support a present-tense claim about this class, and this one is out of date on both edges. On the contracting edge: the raw ClinicalTrials.gov v2 API (retrieved 2026-09-19) shows BOTH oncology studies of one of the six named agents, BMF-219/icovamenib, TERMINATED — NCT05153330 (acute leukaemia/lymphoid, actual n=55, completion 2025-05-02) and NCT05631574 (KRAS-driven solid tumours, actual n=13, completion 2025-01-15) — each carrying the identical whyStopped string 'Biomea Fusion, Inc., is no longer pursuing oncology indications for BMF-219. No safety concerns or efficacy observations led to this study closure.' On the expanding edge: bleximenib has since opened two phase 3 registration studies. The review's own count is a snapshot, and this entry should not carry it as a current fact. Biomea Fusion Inc. 2025
  5. E5weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.preprint

    Bleximenib is being tested in combination with intensive chemotherapy in newly diagnosed AML with KMT2A or NPM1 alterations in a phase 1b study reported at ASH 2025.

    Bleximenib in combination with intensive chemotherapy: A phase 1b study in newly diagnosed Acute Myeloid Leukemia with KMT2A or NPM1 alterations · Johnson & Johnson / cAMeLot investigators · Blood 146 (Supplement 1), ASH Annual Meeting abstract 2025
    DOI
    What this evidence cannot show

    Conference abstract, not peer-reviewed; no mature efficacy or survival data; abstracts of this kind are frequently revised before full publication.

    Evidence that argues against this (1)
    • A conference abstract is a selected sample, and the selection runs in the direction of the claim. Pooling 425 reports covering 307,028 biomedical meeting abstracts, only 37.3% (95% CI 35.3-39.3) were ever published in full, and abstracts reporting a 'positive' result were significantly more likely to reach full publication (RR 1.31, 95% CI 1.23-1.40; RR 1.17, 95% CI 1.07-1.28 for results favouring the experimental arm). So the probability that an ASH abstract describing encouraging combination activity is the one that surfaces is inflated relative to the underlying data, and roughly six in ten such abstracts never produce a peer-reviewable record at all. Scherer RW et al. 2018
  6. E6weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.preprint

    A separate phase 1b study is evaluating bleximenib plus venetoclax in AML with KMT2A or NPM1 alterations.

    Phase 1b study of bleximenib in combination with venetoclax in Acute Myeloid Leukemia with KMT2A or NPM1 alterations · Johnson & Johnson / cAMeLot investigators · Blood 146 (Supplement 1), ASH Annual Meeting abstract 5200 2025
    What this evidence cannot show

    Conference abstract; small n; myelosuppression from the combination is the predictable limiting toxicity and is not yet quantified in a mature dataset. CONFERENCE-SOURCED (flagged 2026-09-19): this figure traces to a meeting abstract or meeting report and has not been verified against a peer-reviewed primary source. Abstract-stage response rates move on full publication and the denominators are often not comparable across trials.

    Evidence that argues against this (1)
    • The bleximenib + venetoclax signal has not been replicated in any peer-reviewed dataset, and the study designed to test it will not answer the question for this lab's population. cAMeLot-2 (NCT06852222) randomises bleximenib + venetoclax + azacitidine in NEWLY DIAGNOSED AML, phase 3, estimated n=600, minimum age 18 years, recruiting since 2025-06-04 (raw ClinicalTrials.gov v2 API, retrieved 2026-09-19). It is adults-only, myeloid-only and frontline, so it can neither confirm the R/R combination abstract nor extend it to KMT2A-r infant ALL. Until it reports, the myelosuppression that is the predictable limiting toxicity of this pairing has no controlled estimate. Janssen Research & Development et al. 2025
  7. E_registry_verifiedestablished confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.registry

    A Phase 1/2 Study of Bleximenib in Participants With Acute Leukemia (cAMeLot-1) is registered as NCT04811560, sponsored by Janssen Research & Development, LLC, Phase 1/2, status RECRUITING with a target enrolment of 420. Eligibility opens at 2 Years and the registered standard age groups are CHILD, ADULT, OLDER_ADULT - i.e. the trial explicitly enrols children. No whyStopped value is recorded.

    NCT04811560
    What this evidence cannot show

    Fetched from the RAW ClinicalTrials.gov v2 API by the coordinator on 2026-09-19; the Clinical_Trials MCP tool does not return whyStopped and was not used. Registry fields are sponsor-reported and change without notice - enrolment is a target, not an accrual, and a registered minimum age is not evidence that children have actually been enrolled or dosed.

    Evidence that argues against this (1)
    • A registered paediatric minimum age is the weakest form of the paediatric-access claim. Registration permits enrolment; it does not show that any child was enrolled, that paediatric cohorts opened, or that sites activated for them. This project has already found the registry contradicting the adults-only framing in the other direction, so the registry is worth reading, but an age field is not an outcome. ClinicalTrials.gov v2 API 2026
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