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Explainerstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q8-impact

Orphan drug designation: what it actually gives a KMT2A programme, and what it bends

also called ODD · Orphan Drug Act · orphan designation · ODE · orphan drug exclusivity

If a drug treats a disease affecting fewer than 200,000 Americans, its maker gets seven years where nobody else can sell the same drug for that use, a tax break on trial costs, and a waiver of a $4.7 million filing fee. Revumenib, the first drug approved for KMT2A-rearranged leukaemia, holds three of these orphan exclusivities, all running to 15 November 2031.

The same thing, for a scientist

Orphan drug designation under FDCA sections 526-528 (21 U.S.C. 360bb-360dd; 21 CFR part 316) is granted pre-approval on a plausible-medical-use showing for a disease affecting fewer than 200,000 persons in the US (or one for which development costs are not recoverable). It is a designation, not an approval, and carries three concrete benefits: seven years of marketing exclusivity for the approved orphan indication upon approval (FDCA 527), a 25% federal tax credit on qualified clinical testing expenses (26 U.S.C. 45C, halved from 50% by the Tax Cuts and Jobs Act of 2017 for tax years beginning after 2017), and exemption from the PDUFA application fee under FDCA 736(a)(1)(F), worth $4,682,003 in FY2026 for an application requiring clinical data. The KMT2A field has used it: FDA's Orange Book records three orphan drug exclusivities for Revuforj (revumenib, NDA 218944) expiring 2031-11-15 alongside five-year NCE exclusivity to 2029-11-15, and the European Commission granted revumenib orphan designation EU/3/21/2569 for AML on 2022-01-14. The Consolidated Appropriations Act, 2026 narrowed the exclusivity to the approved use rather than the whole designated condition, reversing Catalyst Pharms. v. Becerra.

Go deeper
What the programme requires

Designation is requested from FDA's Office of Orphan Products Development before the marketing application, and is granted on two showings 1:

  1. Prevalence or cost-recovery. The disease or condition affects fewer than 200,000 persons in the United States, or affects 200,000 or more but there is no reasonable expectation that US sales will recover development costs (FDCA 526; 21 U.S.C. 360bb). The regulations are at 21 CFR part 316.
  2. Scientific rationale. A plausible medical hypothesis, supported by some data (in vitro, animal or clinical), that the drug may be effective in the designated condition. The bar sits far below the approval standard.

Designation attaches to a disease or condition, not to a drug in the abstract, and one molecule may carry several. Revumenib is reported to hold separate US designations covering AML, ALL and acute leukaemias of ambiguous lineage; the three distinct orphan exclusivity codes on its Orange Book entry (ODE-502, ODE-504, ODE-505) are consistent with three designated conditions each converting to exclusivity at approval 5.

KMT2A-rearranged acute leukaemia clears the prevalence test by orders of magnitude. Infant KMT2A-r ALL alone is on the order of tens of US cases per year; all-ages KMT2A-rearranged acute leukaemia remains far inside 200,000. Rarity was never the binding constraint here - trial feasibility was.

What it is worth, in numbers
BenefitValueAuthority
US marketing exclusivity7 years from approval, for the approved orphan indicationFDCA 527 (21 U.S.C. 360cc) 2
Federal tax credit25% of qualified clinical testing expenses26 U.S.C. 45C 3
PDUFA application fee exemption$4,682,003 avoided (FY2026, application requiring clinical data)FDCA 736(a)(1)(F); FY2026 fee notice 4
EU market exclusivity10 years, extendable to 12 with a completed PIPRegulation (EC) No 141/2000; see reg-eu-paediatric-investigation-plan 6

Three things about that table deserve saying out loud, as of 2026-09-18.

The tax credit was halved. Section 13401 of the Tax Cuts and Jobs Act of 2017 cut the orphan drug credit from 50% to 25% of qualified clinical testing expenses, effective for tax years beginning after 2017 3. For a paediatric leukaemia trial - small, slow-accruing, expensive per patient - that is the largest single change to orphan development economics in a decade, and it cut hardest against exactly the trials that are hardest to fund.

The fee waiver is conditional. The exemption under FDCA 736(a)(1)(F) is lost if the application includes an indication other than the rare disease or condition 4. The FY2026 PDUFA programme (establishment) fee of $442,213 per approved product still applies regardless.

Seven years of exclusivity is narrower than it was. Section 6605 of the Consolidated Appropriations Act, 2026 (signed 2026-02-03) codified FDA's long-standing reading that orphan exclusivity attaches to the approved use or indication, not to the entire designated rare disease, reversing the effect of Catalyst Pharms., Inc. v. Becerra (11th Cir. 2021) 9. A sponsor designated for "acute myeloid leukaemia" but approved only in the KMT2A-translocated relapsed/refractory slice now blocks competitors only in that slice.

Has it actually been used for a KMT2A indication? Yes - and the Orange Book proves it

This question is usually answered from press releases. It does not have to be.

Revumenib (Revuforj, Syndax; NDA 218944; approved 2024-11-15 for relapsed or refractory acute leukaemia with a KMT2A translocation in patients 1 year and older). FDA's Orange Book patent-and-exclusivity record for NDA 218944, retrieved 2026-09-18 5, lists:

  • NCE - new chemical entity exclusivity, expiring 2029-11-15
  • ODE-502 - orphan drug exclusivity, expiring 2031-11-15
  • ODE-504 - orphan drug exclusivity, expiring 2031-11-15
  • ODE-505 - orphan drug exclusivity, expiring 2031-11-15

Three ODE codes, each exactly seven years from the 2024-11-15 approval. That is FDA's own primary record and it settles the question: revumenib holds US orphan drug exclusivity arising from the KMT2A approval.

In the EU, the European Commission granted revumenib orphan designation EU/3/21/2569 for the treatment of acute myeloid leukaemia to Syndax Europe B.V. on 2022-01-14 6. The EMA record identifies the active substance by full chemical name rather than by INN, which is why keyword searches for "revumenib" miss it.

Ziftomenib (Komzifti, Kura Oncology / Kyowa Kirin; NDA 220305; approved 2025-11-13 for adults with relapsed or refractory NPM1-mutant AML). Kura and Kyowa Kirin state that FDA granted orphan drug designation alongside breakthrough therapy, fast track and priority review 8. But the Orange Book entry for NDA 220305, checked 2026-09-18, lists only NCE exclusivity expiring 2030-11-13 and no ODE code 7. Designation is not exclusivity, and Orange Book entries can lag; neither reading is established here. Note also that ziftomenib's approved indication is NPM1-mutant, not KMT2A-rearranged - its KMT2A programme (KOMET-017) is still in trials. On the narrow question asked, ziftomenib has no KMT2A indication at all, orphan or otherwise.

Status of the programme, dated

The orphan drug programme itself is stable and, unlike the rare paediatric disease voucher (see reg-rare-pediatric-disease-prv), was never at risk of lapsing. The live changes as of 2026-09-18 are:

  • 2026-02-03: Consolidated Appropriations Act, 2026, section 6605 - orphan exclusivity codified as indication-specific 9.
  • FY2026 fees (1 Oct 2025 - 30 Sep 2026): application fee with clinical data $4,682,003; without clinical data $2,341,002; programme fee $442,213 4. FY2027 rates were published 2026-07-30 and take effect 2026-10-01; this node has not verified the FY2027 figures.
  • The 25% section 45C credit rate is unchanged since 2018 3.

One verification failure to record honestly: FDA's Orphan Drug Designations and Approvals search database at accessdata.fda.gov/scripts/opdlisting/oopd/ is served behind a bot filter that rejects programmatic POST queries, so the designation dates and conditions for revumenib and ziftomenib could not be read from the agency's own designation register. The Orange Book exclusivity record (E5, E7) was used instead, which is a stronger fact (exclusivity actually granted) about a narrower question (it does not name the condition).

Facts and figures
programmeorphan drug designation
us statuteFDCA 526-528 (21 U.S.C. 360bb-360dd); 21 CFR part 316
us prevalence threshold200000
exclusivity years7
eu market exclusivity years10
eu market exclusivity years with completed pip12
tax credit PCT25
tax credit PCT before 201850
tax credit statute26 U.S.C. 45C
pdufa fy2026 application fee usd clinical data4682003
pdufa fy2026 application fee usd no clinical data2341002
pdufa fy2026 program fee usd442213
used for kmt2atrue
revumenib us nce expiry2029-11-15
revumenib us ode expiry2031-11-15
revumenib eu orphan designationEU/3/21/2569
revumenib eu orphan designation date2022-01-14
ziftomenib us nce expiry2030-11-13
ziftomenib ode in orange bookfalse
ziftomenib has kmt2a indicationfalse
indication specific exclusivity codified2026-02-03
as of2026-09-18
jurisdiction
[
  "US",
  "EU"
]
revumenib us exclusivity codes
[
  "NCE",
  "ODE-502",
  "ODE-504",
  "ODE-505"
]
How this could bite us back
  • Designation is granted for a disease; exclusivity is now granted for an indication. A sponsor can designate broadly (AML, ALL, ALAL) on a cheap plausible-mechanism showing and then approve in whichever slice is fastest and most commercially attractive. Nothing in the programme obliges anyone to carry the hardest slice - infants - through to approval, and holding the designation costs nothing.
  • The salami-slicing critique applies directly here. Orphan status is set by the prevalence of a molecularly-defined subset, not of the parent disease. Any common cancer can be partitioned by biomarker until each partition is an orphan, and each partition earns its own seven years and its own fee exemption. AML is roughly 20,000 US cases a year; NPM1-mutant AML is its single largest molecular subset, and it is an orphan indication. The rarity the Orphan Drug Act was written to subsidise is not the rarity being subsidised.
  • The 25% tax credit is proportional to spend, not to unmet need or to who is enrolled. A sponsor running a 100-patient adult cohort claims four times the credit of one running a 25-patient infant cohort in the same indication. The incentive is neutral at best, and regressive in practice, with respect to the youngest and rarest patients - who cost the most per head to enrol.
  • The Tax Cuts and Jobs Act halved the credit in 2017 for reasons that had nothing to do with rare disease, and the paediatric-heavy, slow-accruing, small-n trial is exactly the design whose economics that cut damages first. This is the clearest case in the whole regulatory stack of a purely fiscal decision, taken elsewhere, changing which children get dosed.
  • Seven years of orphan exclusivity for revumenib runs to 2031-11-15 - two years past NCE expiry and, in practice, past the window in which a second-generation menin inhibitor with better CNS penetration or a better resistance profile might otherwise enter the same indication. Exclusivity that rewards being first can also delay being better, and when the approved CR+CRh rate is 21.2%, being better matters more than being first.
Still open
  1. Which three designated conditions do ODE-502, ODE-504 and ODE-505 on NDA 218944 correspond to? The Orange Book gives codes and dates but not conditions, and FDA's orphan designation search interface blocks programmatic queries.
  2. Does ziftomenib in fact hold US orphan drug exclusivity? The sponsor claims designation; the Orange Book showed no ODE code on 2026-09-18.
  3. What was the dollar value of the section 45C credit actually claimed against the revumenib paediatric cohort, versus what the pre-2018 50% credit would have been? Sponsors do not disclose this, and it is the cleanest natural experiment on the TCJA change available in this field.
Every source behind this entry (9)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    US orphan drug designation requires a disease affecting fewer than 200,000 persons in the United States (or a cost-recovery showing) plus a scientific rationale for plausible medical use, under FDCA section 526 and 21 CFR part 316.

    Designating an Orphan Product: Drugs and Biological Products · US Food and Drug Administration, Office of Orphan Products Development · FDA 2026
    What this evidence cannot show

    FDA guidance page; the operative legal text is 21 U.S.C. 360bb and 21 CFR part 316, which this page summarises.

    Evidence that argues against this (1)
    • A statute or a programme page states what the law PERMITS, not how the agency exercises the discretion the law gives it. Every operative term here — serious condition, substantial improvement, unmet need, plausible medical use — is applied case by case and the reasoning is not published, so the text bounds the outer edge of what could happen and predicts nothing about a particular application. The 200,000-person threshold is also a US prevalence test, which interacts oddly with a disease defined by a molecular lesion: KMT2A-rearranged leukaemia across all ages, and NPM1-mutant AML, are separate designations for the same molecule. U.S. Food and Drug Administration 2026
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Approval of a designated orphan drug confers seven years of marketing exclusivity for the approved orphan indication under 21 U.S.C. 360cc.

    21 U.S.C. 360cc - Protection for drugs for rare diseases or conditions · United States Code · Office of the Law Revision Counsel, US House of Representatives 2026
    What this evidence cannot show

    Statutory text. The scope of the exclusivity was amended by the Consolidated Appropriations Act, 2026 (see E9); the prelim US Code text may lag that amendment.

    Evidence that argues against this (1)
    • Seven years of orphan exclusivity blocks approval of the SAME drug for the SAME orphan indication and does not block a different molecule, a different indication, or a clinically superior version of the same molecule. The protection it confers is narrower than the headline number suggests. U.S. Food and Drug Administration 2026
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.news

    The orphan drug tax credit under 26 U.S.C. 45C is 25% of qualified clinical testing expenses, reduced from 50% by the Tax Cuts and Jobs Act of 2017 for tax years beginning after 2017.

    What this evidence cannot show

    Accounting-firm summary, not a primary IRS or statutory source. The underlying authority is section 13401 of Pub. L. 115-97 amending 26 U.S.C. 45C. The 50-to-25 percent change is uncontested across multiple independent summaries.

    Evidence that argues against this (1)
    • A tax advisory firm's insight piece is secondary. The primary record is 26 U.S.C. 45C as amended by the Tax Cuts and Jobs Act of 2017 (Public Law 115-97), and the rate reduction from 50% to 25% is in the statutory text. Advisory summaries also go stale silently as later Acts amend the provision. BDO Insights 2018
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    For FY2026 (1 October 2025 to 30 September 2026) the PDUFA application fee is $4,682,003 for an application requiring clinical data, $2,341,002 for one not requiring clinical data, and the prescription drug programme fee is $442,213.

    Prescription Drug User Fee Rates for Fiscal Year 2026 · US Food and Drug Administration · Federal Register, doc. 2025-14413, 30 July 2025 2025
    What this evidence cannot show

    The fee figures come from the FY2026 notice. The orphan exemption itself is in FDCA 736(a)(1)(F) and FDA's user-fee waiver guidance, not in this notice. FY2027 rates were published 2026-07-30 and were not verified for this node.

    Evidence that argues against this (1)
    • A fee, an exclusivity date or a programme status is a dated fact with a short shelf life: fee schedules are reset every fiscal year, exclusivity dates move on paediatric extension or litigation, and programme sunsets have been extended by Congress before. Anything planned on these has to re-query them. PDUFA fees are also waived or reduced for small businesses and for the first application from a qualifying applicant, so the list price is not what every sponsor pays. U.S. Food and Drug Administration 2026
  5. E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    As of 2026-09-18 FDA's Orange Book lists for Revuforj (revumenib citrate, NDA 218944) an NCE exclusivity expiring 2029-11-15 and three orphan drug exclusivities (ODE-502, ODE-504, ODE-505) each expiring 2031-11-15.

    Patent and Exclusivity Information, NDA 218944 (REVUFORJ, revumenib citrate) · US Food and Drug Administration, Orange Book · Approved Drug Products with Therapeutic Equivalence Evaluations 2026
    What this evidence cannot show

    Retrieved 2026-09-18. Orange Book exclusivity codes establish that an orphan exclusivity exists and when it expires but do not name the designated condition; mapping ODE-502/504/505 to AML, ALL and ALAL is inferred from sponsor statements, not from this record.

    Evidence that argues against this (1)
    • A fee, an exclusivity date or a programme status is a dated fact with a short shelf life: fee schedules are reset every fiscal year, exclusivity dates move on paediatric extension or litigation, and programme sunsets have been extended by Congress before. Anything planned on these has to re-query them. Orange Book exclusivity dates are additionally extendable by six months of paediatric exclusivity under FDCA 505A, which is directly in play for a product with a paediatric programme. U.S. Food and Drug Administration 2026
  6. E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    The European Commission granted orphan designation EU/3/21/2569 for the treatment of acute myeloid leukaemia to Syndax Europe B.V. on 14 January 2022, for the active substance corresponding to revumenib.

    EU/3/21/2569 - orphan designation for treatment of acute myeloid leukaemia · European Medicines Agency · EMA orphan designation register 2022
    What this evidence cannot show

    The EMA record identifies the substance by full chemical name (a diazaspirononane pyrimidinyloxy benzamide sesquifumarate) and by the menin-KMT2A mechanism rather than by the INN; the identification rests on sponsor, mechanism and date rather than on the name 'revumenib' appearing in the record.

    Evidence that argues against this (1)
    • This is the same EU designation cited in the paediatric-plan entry, so it is one fact appearing twice across the beat rather than two lines of evidence, and a designation is separate from and does not imply a marketing authorisation. European Medicines Agency 2026
  7. E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

    As of 2026-09-18 FDA's Orange Book lists only NCE exclusivity (expiring 2030-11-13) for Komzifti (ziftomenib, NDA 220305) and no orphan drug exclusivity code.

    Patent and Exclusivity Information, NDA 220305 (KOMZIFTI, ziftomenib) · US Food and Drug Administration, Orange Book · Approved Drug Products with Therapeutic Equivalence Evaluations 2026
    What this evidence cannot show

    This is an absence of a record, not a positive finding. Orange Book exclusivity entries can lag an approval, and the sponsor states that orphan designation was granted (E8). Confidence is moderate because an absent code is weak evidence in either direction.

    Evidence that argues against this (1)
    • Designation is not exclusivity, and the Orange Book records only the latter. Kura Oncology and Kyowa Kirin state FDA granted ziftomenib orphan drug designation (E8), and the Adis review of the approval (PMID 41653248, fetched 2026-09-20) attributes that FDA designation to a Kura media release of 24 July 2019 and to no agency document, so the FDA-side designation has no public regulator-issued source. An independent regulator's record does exist on the European side and is cited here: EMA designated ziftomenib an orphan medicine for acute myeloid leukaemia on 12 January 2024 under EU/3/23/2881 (page fetched 2026-09-20). FDA's own orphan designation search was re-tried on 2026-09-20 by HTTP POST to OOPD_Results.cfm and again returned a redirect with no result rows, so the absence of an FDA-side record here is a tooling limit, not a finding about the designation. European Medicines Agency et al. 2024
  8. E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.news

    Kura Oncology and Kyowa Kirin state that FDA granted ziftomenib breakthrough therapy, fast track and orphan drug designations as well as priority review, and approved Komzifti on 13 November 2025 for adults with relapsed or refractory NPM1-mutant AML.

    What this evidence cannot show

    Company press release, not an agency source. Designation claims in press releases are usually accurate but could not be independently confirmed here because FDA's orphan designation search interface blocks automated queries. The approval date and indication are separately corroborated by FDA's Drug Trials Snapshot for KOMZIFTI.

    Evidence that argues against this (1)
    • A joint sponsor press release is a primary record of the sponsors' statement about their own designations. FDA's designation databases are the independent check and are searchable, so a designation claim sourced only to a press release is verifiable and has not been verified here. Kura Oncology investor relations 2025
  9. E9strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.news

    Section 6605 of the Consolidated Appropriations Act, 2026, signed 3 February 2026, restored FDA's indication-specific interpretation of orphan drug exclusivity, reversing the effect of Catalyst Pharmaceuticals, Inc. v. Becerra.

    Congress Extends Rare Pediatric Disease Priority Review Voucher Program Through 2029 · Spencer Fane LLP · Spencer Fane client insight 2026
    What this evidence cannot show

    Law-firm client alert, corroborated independently by a Wilson Sonsini alert covering the same provisions. The statutory text of section 6605 was not read directly for this node.

    Evidence that argues against this (1)
    • A law firm alert again, and this claim is the most volatile kind: it describes a statutory interpretation RESTORED by a 2026 Act. Provisions of this sort are amended, sunset and re-enacted repeatedly, so the primary record — the Consolidated Appropriations Act, 2026, section 6605 — governs and the alert may already describe a superseded state. Spencer Fane client insight 2026
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