Macitentan

證據等級: L5

預測適應症: 10 個

Macitentan: From Pulmonary Arterial Hypertension to PAH Associated with Congenital Heart Disease

One-Sentence Summary

Macitentan is a dual endothelin receptor antagonist (ERA), originally developed and approved for pulmonary arterial hypertension (PAH, WHO Group 1). The TxGNN model predicts continued benefit in Pulmonary Arterial Hypertension Associated with Congenital Heart Disease (CHD-PAH), a recognized WHO Group 1 subtype, with 2 clinical trials and 18 publications currently supporting this direction — including a completed Phase III RCT (MAESTRO) in the Eisenmenger syndrome subgroup.

Note: TxGNN generated several other candidate indications for macitentan (e.g. pulmonary arteriovenous malformation, schistosomiasis-associated PAH). Those carry no clinical trial or literature support (Evidence Level L5, decision stage S0, recommendation “Hold”) and are not covered below. This report focuses on the best-evidenced candidate, CHD-PAH.

Quick Overview

Item	Content
Original Indication	Pulmonary arterial hypertension (WHO Group 1) — per international labeling context in the evidence pack; no Danish marketing authorisation on file
Predicted New Indication	Pulmonary Arterial Hypertension Associated with Congenital Heart Disease (CHD-PAH)
TxGNN Prediction Score	98.75%
Evidence Level	L2 (1 completed Phase III RCT — MAESTRO, in Eisenmenger syndrome)
Denmark Market Status	Not marketed
Number of Marketing Authorisations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

A formal DrugBank mechanism-of-action record has not yet been retrieved for this candidate (flagged as data gap DG002). Based on the clinical evidence assembled in this pack, macitentan is established as a dual endothelin receptor antagonist (ERA), blocking ET-1-mediated pulmonary vasoconstriction and vascular remodeling — the core pathophysiology of WHO Group 1 pulmonary arterial hypertension.

CHD-PAH (including Eisenmenger syndrome) is itself classified under WHO Group 1 PAH, sharing the same vascular remodeling pathology as idiopathic/heritable PAH — macitentan’s original indication. This is therefore not a mechanistic extrapolation across disease categories, but an indication-class expansion within the same approved pharmacological target.

This is directly supported by clinical data: the Phase III, double-blind, randomized, placebo-controlled MAESTRO study (PMID 30586694) evaluated macitentan specifically in Eisenmenger syndrome, a CHD-PAH subtype, and multiple real-world cohorts (OPUS/OrPHeUS, Asian post-marketing surveillance, pediatric multicenter series) report consistent safety and effectiveness in CHD-PAH populations already receiving macitentan off-label or under expanded indications elsewhere.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT05731492	Phase 1	Withdrawn	0	Planned PK/safety study of macitentan and its active metabolite (aprocitentan) in children aged 1 month to <2 years with PAH; withdrawn with no participants enrolled
NCT05179876	Phase 3	Recruiting	280	Open-label long-term follow-up platform study allowing PAH patients (multiple etiologies, including CHD) to continue study intervention after parent-trial closure; assesses long-term safety

Literature Evidence

PMID	Year	Type	Journal	Key Findings
30586694	2019	RCT (Phase III, MAESTRO)	Circulation	Multicenter, double-blind, randomized, placebo-controlled 16-week trial of macitentan in Eisenmenger syndrome (CHD-PAH subtype)
39585521	2024	Real-World/Retrospective	Cardiology and Therapy	OPUS/OrPHeUS real-world data on patients with CHD-PAH newly initiating macitentan
40616677	2026	Cohort (multicenter)	Pediatric Cardiology	Multicenter experience of oral macitentan in pediatric PAH (Spanish Registry), safety and efficacy outcomes
36329372	2023	Real-World/Retrospective	Drugs - Real World Outcomes	Prospective multicenter post-marketing surveillance of macitentan safety/outcomes in Asian PAH patients
36196862	2022	Cohort	Anatolian Journal of Cardiology	Single-center comparison of macitentan efficacy/safety across idiopathic and CHD-associated PAH
35514768	2022	Prospective Cohort	Pulmonary Circulation	POTENT study: prospective assessment of PAH patients switched from bosentan to macitentan
28867027	2017	Cohort	Heart, Lung & Circulation	Macitentan use in PAH associated with congenital heart defects
38276220	2023	Review	Journal of Personalized Medicine	Current management and future directions for PAH-CHD
31096477	2019	Systematic Review/Meta-analysis	Medicine	Position of PAH-specific drug therapy in Eisenmenger syndrome
30545978	2019	Review	European Respiratory Journal	Updated definition, classification, diagnostics and management of paediatric PAH

Denmark Market Information

Currently no marketing authorisation is on file for Denmark. Macitentan’s market status in this evidence pack is recorded as Not marketed, with 0 registered licences (national Laegemiddelstyrelsen or centralised EMA).

Safety Considerations

Please refer to the approved Summary of Product Characteristics (SmPC) for safety information. Key warnings, contraindications, and drug-drug interaction data are not yet available in this evidence pack (data gap DG001, flagged Blocking — required before this candidate can proceed past the initial safety screening stage).

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale:

Mechanistic fit is direct (same WHO Group 1 PAH pathology and ERA target as the original indication), and is corroborated by a completed Phase III RCT (MAESTRO, Eisenmenger syndrome) plus multiple real-world cohorts (Evidence Level L2). However, a blocking safety data gap (DG001 — TFDA/local label warnings and contraindications) prevents a full “Go” decision.

To proceed, the following is needed:

Danish/EU SmPC warnings, contraindications, and drug-drug interaction data (resolves DG001, blocking)
Confirmed DrugBank mechanism-of-action record (resolves DG002)
Formal review of whether Denmark market entry (currently “Not marketed”) is planned or required before this indication can be pursued locally
Disclaimer

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