Zileuton

證據等級: L5

預測適應症: 10 個

Zileuton: From Asthma to Chronic Obstructive Pulmonary Disease (COPD)

One-Sentence Summary

Zileuton is a 5-lipoxygenase (5-LOX) inhibitor already established for asthma management (marketed in the US as Zyflo/Zyflo CR), though it is currently not marketed in this jurisdiction and holds no active local license. The TxGNN model’s raw top hit (“bronchitis”) had zero supporting evidence, so this report focuses on the highest-scoring candidate that is actually backed by real data: Obstructive Lung Disease (COPD), supported by 8 clinical trials (including one Phase 3 COPD-exacerbation trial) and 20 publications, though evidence remains preliminary (L2) and a critical safety data gap blocks any safety screening.

Quick Overview

Item	Content
Original Indication	Asthma (established off-pack via trial descriptions confirming FDA-approved use; not present in the formal license registry because the drug is unmarketed here)
Predicted New Indication	Obstructive Lung Disease (COPD)
TxGNN Prediction Score	99.87%
Evidence Level	L2
Market Status	✗ Not Marketed (未上市)
Number of NDAs	0
Recommended Decision	Hold

Note on indication selection: TxGNN’s #1 raw-score prediction was “bronchitis” (99.99%), but that candidate has no clinical trials or literature at all (L5, flagged in the model’s own rationale as “僅為知識圖譜高分預測” — a high score with no supporting evidence). We instead lead with COPD/Obstructive Lung Disease, the strongest evidence-backed new-indication candidate in this pack.

Why is This Prediction Reasonable?

Zileuton is a selective inhibitor of 5-lipoxygenase (5-LOX), the enzyme responsible for the first committed step in converting arachidonic acid into leukotrienes (LTB4 and the cysteinyl leukotrienes LTC4/D4/E4). These leukotrienes drive bronchoconstriction, airway inflammation, mucus hypersecretion, and eosinophil recruitment — the mechanism underlying zileuton’s established use in asthma. (This mechanistic detail is drawn from the evidence pack’s literature and trial rationale text, since the structured original_moa field itself is a data gap.)

Asthma and COPD are both obstructive airway diseases sharing the leukotriene inflammatory pathway, which is why the model surfaces COPD as a plausible extension. However, the pack’s own rationale flags an important caveat: COPD inflammation is predominantly neutrophil-driven, while asthma is predominantly eosinophil-driven — a mechanistic difference that weakens the strength of direct extrapolation. This is consistent with the clinical evidence: a Phase 3 trial testing zileuton specifically for COPD exacerbations (NCT00493974) was terminated, leaving the COPD hypothesis mechanistically plausible but clinically unconfirmed.

For context, the same evidence pack shows asthma itself re-emerging as a top TxGNN candidate with the strongest evidence of any indication in the set (L1, multiple completed Phase 2–4 RCTs) — effectively validating that the 5-LOX/leukotriene mechanism captured by the model matches zileuton’s known real-world use. Two other exploratory signals are also worth noting at lower confidence: lung cancer chemoprevention in patients with bronchial dysplasia (L2, including a completed Phase 2 chemoprevention trial, NCT00056004) and atopic dermatitis (L3, small pilot studies). Several other top-ranked predictions (bronchitis, “asthma-related traits, susceptibility to,” Laubry-Pezzi syndrome, interventricular septum aneurysm, Pierre Robin syndrome) have no supporting evidence whatsoever and are assessed as likely knowledge-graph noise.

Clinical Trial Evidence

(Evidence for Obstructive Lung Disease / COPD)

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00493974	Phase 3	Terminated	119	Direct test of zileuton for reducing hospital stay in COPD exacerbations; trial stopped early, efficacy inconclusive
NCT00486343	Phase 4	Terminated	400	Zileuton CR vs. placebo in poorly controlled asthma on moderate-dose ICS; terminated
NCT00575861	Phase 4	Completed	19	Additive effect of zileuton to Advair on exhaled/bronchial/alveolar nitric oxide in asthmatics
NCT00595114	N/A	Completed	43	Ancillary study of oxidative stress and anti-inflammatory lipids in airway disease (COPD and asthma)
NCT00299065	Phase 1/2	Completed	60	Safety, tolerability, and PK of IV zileuton in asthma patients
NCT00723021	Phase 2a	Completed	15	Bronchodilatory action, safety, and PK of PF-04191834 vs. zileuton in asthmatics
NCT00534625	Phase 2	Completed	36	Pulmonary function, safety, and PK of IV zileuton in chronic stable asthma
NCT01805687	Phase 4	Completed	25	Duration and extent of bronchodilation with Zyflo CR 1200 mg in stable chronic asthma

Literature Evidence

(Evidence for Obstructive Lung Disease / COPD, prioritized by relevance)

PMID	Year	Type	Journal	Key Findings
10421833	1999	Review	Clin Exp Allergy	Reviews leukotriene pathway inhibitors, including zileuton, across both asthma and COPD
33446622	2020	Review	Medical Letter on Drugs and Therapeutics	Overview of current asthma drug classes including leukotriene modifiers
8826571	1996	Review	Ann Pharmacother	Introduces zileuton as the first 5-LOX inhibitor approved for asthma
31841698	2020	Clinical Study	Pulm Pharmacol Ther	Zileuton response varies by asthma phenotype; modest overall response rates
37253655	2023	Preclinical	Am J Physiol Lung Cell Mol Physiol	5-LOX pathway elevated in severe/fungal-associated asthma; zileuton is an FDA-approved therapeutic targeting this pathway
26385352	2015	Review	Curr Allergy Asthma Rep	Reviews antileukotriene efficacy across upper/lower airway inflammatory diseases
11527015	2001	Review	Curr Opin Investig Drugs	Discusses zileuton’s successor compound (ABT-761), context on 5-LOX inhibition potency
9042024	1997	Review	Chest	Leukotrienes’ role in airflow obstruction mechanisms relevant to both asthma and COPD
32000655	2020	Review	Recent Pat Inflamm Allergy Drug Discov	Role of leukotriene inhibitors across chronic inflammatory diseases
16894531	2007	Review	Med Res Rev	Critical update on cysteinyl-leukotrienes and receptors in asthma and other inflammatory diseases

Market Information

No license records are available — taiwan_regulatory.licenses is empty and total_licenses = 0. Zileuton is currently not marketed in this jurisdiction; any repurposing pathway would require a new market authorization filing rather than a label extension.

Safety Considerations

Please refer to the package insert for safety information.

Important note: The evidence pack flags a Blocking-severity data gap (DG001) — TFDA label warnings/contraindications are unavailable, which means this candidate cannot yet enter S1 safety screening. This gap must be resolved before any further evaluation stage is attempted.

Conclusion and Next Steps

Decision: Hold

Rationale: The pivotal COPD-specific trial (NCT00493974) was terminated, evidence level is only L2, and — critically — a Blocking data gap in label warnings/contraindications prevents even a basic safety screening (S1). The drug is also not currently marketed in this jurisdiction, so a new indication would require a full new filing rather than a label extension.

To proceed, the following is needed:

TFDA-equivalent package insert / warnings and contraindications (resolve DG001, currently Blocking)
Confirmed mechanism-of-action documentation via DrugBank API (resolve DG002)
Clarification of why NCT00493974 was terminated, and whether any completed/ongoing COPD trials exist elsewhere
A market-entry assessment, since the drug currently holds zero local licenses
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.