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Drugweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q6-therapeutics

Enzomenib (DSP-5336) — menin inhibitor with the highest reported KMT2A-r response rate and little differentiation syndrome

also called DSP-5336 · DSP5336

Enzomenib is an experimental menin-blocking pill from Sumitomo Pharma. In early trials it produced the highest response rate so far in KMT2A-rearranged leukaemia while causing much less of the dangerous differentiation reaction — but the numbers come from small, early-phase cohorts, not a full trial.

The same thing, for a scientist

Enzomenib (DSP-5336) is an investigational oral menin–KMT2A interaction inhibitor being developed by Sumitomo Pharma in the phase 1/2 Horizen-1 study (NCT04988555, planned n=606, recruiting). Reported phase 1 monotherapy activity at the 300 mg BID RP2D in KMT2A-rearranged disease is ORR 73.3% with CR+CRh 40% (n=39), and CR+CRh 44% in NPM1-mutant patients at 200 mg BID or above (n=25). Grade 3 or higher differentiation syndrome was 7.8% and QTc prolongation 2.6%, with no DS prophylaxis used and no DS-related deaths or permanent discontinuations. It has FDA orphan drug designation in ALL. Horizen-1 includes combination arms with venetoclax/azacitidine, gilteritinib and 7+3 intensive chemotherapy. Age floor is 12 years and 40 kg; not approved anywhere.

Go deeper
The efficacy claim and why to hold it loosely

At the 300 mg twice-daily recommended phase 2 dose, KMT2A-rearranged patients (n=39) had an ORR of 73.3% and CR+CRh of 40%; NPM1-mutant patients at 200 mg BID or higher (n=25) had CR+CRh 44% 12. On face value that is roughly double revumenib's registration CR+CRh of 21.2% in 104 patients.

Three reasons not to take the comparison at face value:

  1. Cohort size and selection. n=39 in a dose-expansion cohort, not a registration cohort with central genotype confirmation and a prespecified efficacy-evaluable population.
  2. Menin-inhibitor-naive population. Horizen-1 phase 2 explicitly excludes prior menin-inhibitor exposure 3; the revumenib registration cohort was accrued before the class existed but in a more heavily pretreated, later-line population.
  3. WBC caps and CYP3A4 restrictions. Horizen-1 caps WBC at 30,000/µL for monotherapy (25,000/µL for combinations) and excludes ketoconazole, isavuconazole and itraconazole; QTcF above 480 ms and any history of Torsades de Pointes are exclusions 3. That is a healthier-heart, lower-burden population than the one the drug will eventually face.

The honest summary: enzomenib's safety differentiation (low DS, low QTc, no prophylaxis needed) is the more credible signal, because safety rates are less sensitive to cohort selection than response rates are.

Combination architecture — the most complete of any menin programme

Horizen-1 has monotherapy plus four distinct combination strategies in one protocol 3:

  • Venetoclax + azacitidine (non-intensive SOC), in both R/R and newly diagnosed KMT2A-r/NPM1m AML.
  • 7+3 cytarabine/daunorubicin (intensive SOC) in newly diagnosed KMT2A-r/NPM1m AML.
  • Gilteritinib in KMT2A-r or NPM1m AML that also carries FLT3-ITD or FLT3-TKD (D835/I836) — a direct test of whether pre-empting the FLT3 escape route improves durability.
  • An azole co-administration arm to characterise the CYP3A4 interaction prospectively.

The gilteritinib arm is the one this lab should watch. FLT3 and RAS-pathway signalling is a recognised bypass under menin inhibition, and this is the first clinical test of blocking it up front rather than at relapse.

Paediatric reach

The registry lists a minimum age of 12 years, and the protocol permits acute leukaemia patients 12 years and older weighing at least 40 kg on monotherapy in countries where approved 3. It also excludes active CNS leukaemia (prophylactic intrathecal chemotherapy allowed). So enzomenib is less paediatrically accessible than bleximenib (from 2 years) or revumenib (labelled from 1 year), and is of no direct use in infant KMT2A-r ALL today. FDA orphan drug designation in ALL 4 signals intent, not access.

Facts and figures
targetgene-men1
target interactionmenin–KMT2A (MBM1) protein–protein interface
modalitysmall molecule (oral, reversible PPI inhibitor)
chemical classnot disclosed in peer-reviewed literature as of this cycle; no ChEMBL record found
statusInvestigational — not approved. Phase 1/2 Horizen-1 recruiting. FDA orphan drug designation in ALL.
sponsorSumitomo Pharma America
pediatric eligibletrue
pediatric floor12 years and 40 kg (monotherapy, where permitted) — not applicable to infant ALL
dosing
{
  "route": "oral",
  "rp2d_mg": 300,
  "schedule": "twice daily"
}
trials
[
  "NCT04988555"
]
efficacy
[
  {
    "population": "KMT2A-r, 300 mg BID",
    "n": 39,
    "orr_pct": 73.3,
    "cr_crh_pct": 40
  },
  {
    "population": "NPM1m, 200 mg BID or higher",
    "n": 25,
    "cr_crh_pct": 44
  }
]
key ae
[
  "differentiation syndrome grade 3+ 7.8% (no prophylaxis used, no deaths or permanent discontinuations)",
  "QTc prolongation grade 3+ 2.6%",
  "no dose-limiting toxicities or treatment-related deaths reported"
]
combination arms
[
  "venetoclax + azacitidine",
  "7+3 cytarabine/daunorubicin",
  "gilteritinib (FLT3-mutant KMT2A-r/NPM1m)",
  "azole co-administration cohort"
]
resistance
[
  "not yet reported; assume shared MBM1-pocket vulnerability until tested"
]
registry verified
{
  "nct": "NCT04988555",
  "sponsor": "Sumitomo Pharma America, Inc.",
  "overall_status": "RECRUITING",
  "phases": "Phase 1/2",
  "target_enrolment": 606,
  "minimum_age": "12 Years",
  "std_ages": [
    "CHILD",
    "ADULT",
    "OLDER_ADULT"
  ],
  "why_stopped": null,
  "retrieved": "2026-09-19",
  "source": "https://clinicaltrials.gov/api/v2/studies/NCT04988555"
}
How this could bite us back
  • A 73.3% ORR in 39 selected, menin-inhibitor-naive, low-blast-burden patients is the kind of number that regresses sharply in a registration cohort; planning around it would be a mistake.
  • Low differentiation syndrome could in principle mean weaker on-target pharmacodynamics rather than a safer drug — the class's efficacy and its DS are the same biology.
  • The 12-year / 40-kg floor and the active-CNS-leukaemia exclusion put enzomenib furthest from the infant KMT2A-r ALL population of all four leading agents.
  • Excluding itraconazole/isavuconazole/ketoconazole is workable in adult AML but collides with paediatric antifungal practice.
Still open
  1. Is enzomenib's low differentiation-syndrome rate a property of the molecule (slower onset of differentiation, different PK) or of the population (WBC cap of 30,000/µL, hydroxyurea cytoreduction allowed)? Matched-cohort analysis would separate these.
  2. The gilteritinib combination arm is the first clinical test of pre-emptively blocking the FLT3/RAS bypass under menin inhibition. Does adding a FLT3 inhibitor up front change the mutational spectrum at relapse?
  3. Does enzomenib retain potency against MEN1 M327I and G331D? If its chemotype is sufficiently distinct, it could be the class member that covers the mutants that defeat both approved drugs.
Every source behind this entry (5)
  1. E1weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.preprint

    In the phase 1 monotherapy portion of Horizen-1, enzomenib at the 300 mg twice-daily RP2D gave an ORR of 73.3% and CR+CRh of 40% in KMT2A-rearranged patients (n=39), and CR+CRh of 44% in NPM1-mutant patients at 200 mg BID or higher (n=25), with grade 3+ differentiation syndrome in 7.8% and QTc prolongation in 2.6%.

    Monotherapy update from the Phase 1 portion of the Phase 1/2 trial of the menin-MLL inhibitor enzomenib (DSP-5336) in patients with relapsed or refractory acute leukemia · Horizen-1 investigators / Sumitomo Pharma America · Blood 146 (Supplement 1): 763, ASH Annual Meeting abstract 2025
    What this evidence cannot show

    Conference abstract, not peer reviewed. Dose-expansion cohorts of 25-39 patients; no central genotype confirmation reported; menin-inhibitor-naive, WBC-capped, QTc-screened population; sponsor-reported. The 73.3% ORR should not be compared directly with revumenib's registration numbers. 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 critical review of the class cautions that cross-agent efficacy comparisons from early-phase single-arm cohorts with differing eligibility are not valid, and that no head-to-head data exist. Canichella M et al. 2025
  2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.review

    Enzomenib is one of six menin inhibitors in clinical development and one of the four most extensively studied, with a reported safety profile notable for low rates of differentiation syndrome.

    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 synthesising conference-level data; not primary.

    Evidence that argues against this (1)
    • Cross-study differentiation-syndrome rates are not comparable, so 'notably low rates of differentiation syndrome' may be an artefact of mitigation rules and grading rather than a property of enzomenib. Within a SINGLE programme the number moves: KOMET-001 phase 1 reported grade 3 or worse differentiation syndrome in 12/83 (15%) with two treatment-related deaths, while the phase 2 of the same trial, run with protocol-defined mitigation, reported differentiation syndrome in 25% overall but 15% grade 3, no grade 4-5 events, and only 3% discontinuation for drug-related adverse events. A compound studied later, with prophylaxis and cytoreduction rules already written, inherits a lower apparent rate. Wang ES et al. 2025
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry

    Horizen-1 (NCT04988555) is a recruiting phase 1/2 Sumitomo Pharma America study with planned enrolment 606, minimum age 12 years (monotherapy, 40 kg or more), started 2022-02-28, testing enzomenib as monotherapy and in combination with venetoclax/azacitidine, gilteritinib and 7+3 intensive chemotherapy; phase 2 requires a documented KMT2A fusion and excludes prior menin-inhibitor exposure.

    NCT04988555
    What this evidence cannot show

    Registry snapshot; arm-level enrolment and status vary by country and site; primary completion projected 2027-06-30.

    Evidence that argues against this (1)
    • An open eligibility floor does not produce data in young children, so Horizen-1's 12-year/40-kg floor understates rather than overstates the infant evidence gap only if one assumes lower floors work. They do not: AUGMENT-101 phase 2 enrolled from age 30 DAYS and the youngest patient actually treated was 1.3 years, across 22 sites in five countries over nearly two years. A 12-year floor therefore guarantees zero paediatric KMT2A-r ALL evidence from this trial, and the class's experience shows that even removing the floor would not by itself deliver infants. Issa GC et al. 2025
  4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.news

    Enzomenib has received FDA orphan drug designation for acute lymphoblastic leukaemia.

    Menin Inhibitor Enzomenib Gains FDA Orphan Drug Designation in ALL · Targeted Oncology editorial staff · Targeted Oncology 2025
    What this evidence cannot show

    Trade press reporting of a sponsor announcement; orphan designation confers development incentives only and says nothing about efficacy or eventual approval.

    Evidence that argues against this (1)
    • The orphan designation names ALL, but the trial that would generate ALL evidence cannot study the ALL population that matters here. The raw ClinicalTrials.gov v2 record for Horizen-1 (NCT04988555, retrieved 2026-09-19) lists conditions AML, ALL, multiple myeloma and MDS, with a minimum age of 12 years and no maximum, phase 1 inclusion requiring relapsed/refractory disease after available standard therapy and — in regions where regulators require it — a documented KMT2A(MLL) fusion or NPM1 mutation. KMT2A-rearranged ALL is overwhelmingly a disease of infants and young children, so a designation in 'ALL' supported by a 12-years-and-40-kg trial is an incentive award attached to a population the protocol excludes. A trade-press report of the designation is also two removes from the primary record: it reports a sponsor announcement, not an FDA document. Sumitomo Pharma America et al. 2022
  5. 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 Enzomenib (DSP-5336) in Patients With Acute Leukemia (Horizen-1) is registered as NCT04988555, sponsored by Sumitomo Pharma America, Inc., Phase 1/2, status RECRUITING with a target enrolment of 606. Eligibility opens at 12 Years and the registered standard age groups are CHILD, ADULT, OLDER_ADULT - i.e. the trial explicitly enrols children. No whyStopped value is recorded.

    NCT04988555
    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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