Riociguat

Evidence Level: L1

Predicted Indications: 10

Riociguat
Riociguat: From Pulmonary Arterial Hypertension to PAH Associated with Connective Tissue Disease

## Pharmacist Assessment Report

Using the drug-repurposing report template to produce the evaluation for Riociguat.

Note on indication selection: the evidence pack’s own annotations flag the raw top-5 TxGNN hits (Ambras hypertrichosis, odontal malformation syndrome, Dandy-Walker syndrome, hair-shaft abnormality, isolated hypertrichosis) as “embedding-space noise” with no mechanistic link and zero clinical/literature support (all L5/Hold). I selected the highest-quality, evidence-triaged candidate instead — pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH), rank 9, which carries L1 evidence and a “Proceed with Guardrails” recommendation from the pack’s own scoring — because reporting the raw #1 hit would be clinically misleading.

Riociguat: From Pulmonary Arterial Hypertension to PAH Associated with Connective Tissue Disease

One-Sentence Summary

Riociguat is a soluble guanylate cyclase (sGC) stimulator originally used for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension. The evidence-triaged TxGNN analysis supports extending its use to PAH associated with connective tissue disease (CTD-PAH), a recognized WHO Group 1 PAH subtype, with a dedicated Phase 3 subgroup analysis (PATENT-1/2) and 12 supporting publications currently backing this direction. No dedicated CTD-PAH interventional trial (with registered NCT number) currently exists.

Quick Overview

Item	Content
Original Indication	Not specified in the regulatory data provided (0 licenses on file); trial context indicates riociguat is an approved sGC stimulator for pulmonary arterial hypertension
Predicted New Indication	Pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH)
TxGNN Prediction Score	91.55%
Evidence Level	L1
EU Market Status	Not marketed (per available regulatory data)
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Detailed formal mechanism-of-action data was not available in the regulatory record (flagged as a blocking data gap). However, the supporting evidence in this pack consistently describes riociguat as an sGC stimulator acting on the sGC–cGMP vasodilatory pathway — the same mechanism underlying its established efficacy in idiopathic/heritable PAH, as demonstrated in the pivotal PATENT-1 (Phase 3, randomized, double-blind, placebo-controlled) and PATENT-2 (long-term open-label extension) trials.

CTD-PAH is classified as a WHO Group 1 PAH subtype, sharing the same underlying pulmonary vascular remodeling pathophysiology as idiopathic PAH. Because PATENT-1/2 pre-specified CTD-PAH as a subgroup, dedicated subgroup efficacy and safety data already exist (Humbert et al., Ann Rheum Dis 2017), directly supporting mechanistic and clinical plausibility rather than relying on TxGNN embedding similarity alone.

A second candidate identified through the same evidence-triage process — PAH associated with congenital heart disease (CHD-PAH, rank 6) — is also a WHO Group 1 subtype with L1-level PATENT subgroup evidence (Rosenkranz et al., Heart 2015), reinforcing that riociguat’s mechanism generalizes reasonably across Group 1 PAH etiologies. By contrast, the raw top-5 TxGNN outputs (hypertrichosis syndromes, dental/periodontal malformation syndrome, Dandy-Walker malformation) have no plausible vascular mechanism, no clinical trials, and largely disease-cluster/topic-overlap literature unrelated to riociguat — these were excluded from further consideration despite higher raw model scores.

Clinical Trial Evidence

Currently no dedicated interventional clinical trials registered specifically for CTD-PAH with riociguat as the primary study drug (all supporting clinical data derive from the pre-specified PATENT-1/2 subgroup analysis, documented as literature below rather than as a distinct registered trial).

For reference, the mechanistically related CHD-PAH subtype (rank 6) has one ongoing Phase 4 trial:

Trial Number	Phase	Status	Enrollment	Key Findings
NCT07356778	Phase 4	Recruiting	36	Sotatercept add-on vs. standard PAH pulmonary vasodilator therapy (riociguat as background/comparator therapy) in adults with PAH from unrepaired congenital shunts, including Eisenmenger syndrome

Literature Evidence

PMID	Year	Type	Journal	Key Findings
27457511	2017	RCT (subgroup analysis)	Ann Rheum Dis	PATENT-1/2 prospective subgroup analysis: efficacy and safety of riociguat specifically in PAH-CTD patients
38378970	2024	Systematic Review / Meta-analysis	Intern Emerg Med	Meta-analysis of RCTs (incl. riociguat) in CTD-PAH: functional class, survival, 6MWD outcomes
28671485	2017	Cohort (open-label switch)	Pulm Circ	Case series switching PDE-5 inhibitor to riociguat in CTD-PAH (incl. systemic sclerosis) patients
40331647	2025	Cohort (prospective observation)	Kardiologiia	Long-term survival analysis in PAH associated with immune-mediated rheumatic disease, including riociguat-treated patients
33131480	2020	Review	Kardiologiia	Role of riociguat in treatment of PAH associated with systemic connective tissue diseases
37765060	2023	Review	Pharmaceuticals (Basel)	Recent advances in treatment of CTD-associated PAH, including sGC stimulator class
35412560	2022	Review	JAMA	General diagnosis/treatment review of PAH, contextualizing sGC-stimulator class
27941129	2017	Guideline	Ann Rheum Dis	EULAR recommendations for systemic sclerosis treatment, incl. PAH management
40592721	2025	Review	RMD Open	New horizons in systemic sclerosis treatment, including PAH-directed therapy
39985455	2025	Preclinical	Rheumatology (Oxford)	Characterization of avenciguat, a novel sGC activator (successor class to riociguat) with antifibrotic effects in SSc preclinical models

EU Market Information

No marketing authorization records are present in the regulatory data provided (0 licenses; market status: not marketed). Real-world regulatory context indicates riociguat is approved elsewhere as Adempas® for PAH and CTEPH, but this could not be independently confirmed from the supplied evidence pack.

Safety Considerations

Please refer to the SmPC for safety information. Key warnings, contraindications, and drug-drug interaction data were not available in this evidence pack (flagged as a blocking data gap — DG001).

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: CTD-PAH is a WHO Group 1 PAH subtype with a pre-specified, Phase 3 pivotal-trial subgroup analysis (PATENT-1/2) directly supporting riociguat’s efficacy and safety, giving this prediction L1-level evidence — substantially stronger than the raw TxGNN top-ranked outputs, which lack any mechanistic or clinical support. However, this remains subgroup-level evidence rather than a dedicated primary indication trial, and critical safety/regulatory data gaps remain unresolved.

To proceed, the following is needed:

TFDA/EMA SmPC warnings, contraindications, and DDI data (currently blocking — DG001)
Formal, structured mechanism-of-action documentation from DrugBank (currently high-severity gap — DG002)
Consideration of a dedicated CTD-PAH interventional trial (current evidence is a pre-specified subgroup analysis, not a primary-endpoint trial for this indication)
Regulatory confirmation of riociguat’s EU marketing/authorization status, which could not be verified from the supplied data
Disclaimer

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