Bosentan
| Evidence Level: L5 | Predicted Indications: 9 |
Table of Contents
Bosentan: From Pulmonary Arterial Hypertension to Rheumatoid Arthritis
One-Sentence Summary
Bosentan is an oral endothelin receptor antagonist, best known for treating pulmonary arterial hypertension (PAH). The TxGNN model predicts it may be effective for rheumatoid arthritis, but the support is thin: 1 registered trial (which studies giant cell arteritis, not RA) and 15 publications, almost none showing human RA efficacy.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Pulmonary arterial hypertension (approved indication text is not supplied in the US license records; inferred from the literature) |
| Predicted New Indication | Rheumatoid arthritis |
| TxGNN Prediction Score | 99.80% |
| Evidence Level | L4 (preclinical and mechanistic studies only) |
| US Market Status | ✓ Marketed |
| Number of NDAs | 14 US licenses (NDA and ANDA) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data are not available in the Evidence Pack. Bosentan is known to block endothelin receptors A and B (ETA/ETB), which regulate vasoconstriction and vascular remodelling. Its efficacy in PAH is well established.
The link to rheumatoid arthritis runs through inflammation. Endothelin-1 levels are raised in the plasma and synovial membrane of RA patients. Two mouse studies suggest that blocking endothelin reduces arthritis severity, partly via TNF-α and related mediators. One used collagen-induced arthritis (PMID 22249931), the other zymosan-induced arthritis (PMID 18515326). Rheumatic diseases also overlap with PAH clinically, since connective-tissue-disease-associated PAH is a common reason bosentan is used in rheumatology patients.
The evidence stops at animal models. No human RA efficacy data were provided, and the high TxGNN score is a graph-based prediction, not clinical evidence.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT06957002 | Phase 2 | Not yet recruiting | 40 | Bosentan plus glucocorticoids versus glucocorticoids alone in giant cell arteritis (not RA). It tests whether 3 months of bosentan improves failure-free survival at 12 months. It has no results and offers no direct RA evidence. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 22249931 | 2012 | Preclinical (animal model) | Inflamm Res | Bosentan ameliorated collagen-induced arthritis in mice; TNF-α drives induction of endothelin system genes |
| 18515326 | 2008 | Preclinical (animal model) | J Leukoc Biol | Endothelin receptor blockade modulated inflammation in zymosan-induced arthritis (LTB4, TNF-α, CXCL-1) |
| 16766656 | 2006 | Preclinical (not bosentan-specific) | PNAS | IL-15-induced joint hypernociception was inhibited by dual ETA/ETB antagonism |
| 24268012 | 2014 | Review | Rheum Dis Clin North Am | PAH related to connective tissue disease: poor prognosis, more treatment options available |
| 16218473 | 2005 | Review | Lupus | PAH in connective tissue diseases, including (less often) RA |
| 19487226 | 2009 | Review | Rheumatology (Oxford) | Vasculopathy and PAH in SLE, Sjögren’s syndrome and vasculitides |
| 21165350 | 2010 | Not classified | Can Respir J | Pulmonary hypertension therapy in connective tissue disease with interstitial lung disease |
| 20054770 | 2009 | Case report | Kardiol Pol | Child with Eisenmenger syndrome on bosentan who later developed juvenile RA; the RA was treated with naproxen, so this shows no bosentan effect on RA |
| 16766376 | 2006 | Not classified | Scand J Rheumatol | Endothelin receptor antagonist in primary Sjögren’s syndrome with PAH (no abstract available) |
| 19969421 | 2010 | Preclinical (not bosentan-specific) | Pain | IL-17 mediates joint hypernociception in antigen-induced arthritis in mice |
US Market Information
Approved indication text was not included in the US license records.
| Authorization Number | Product Name | Dosage Form |
|---|---|---|
| NDA209279 | Tracleer (Actelion) | Tablet, for suspension |
| ANDA213154 | Bosentan (Lupin) | Tablet, for suspension |
| ANDA209324 | Bosentan (Sun Pharma) | Tablet, film coated |
| ANDA207760 | Bosentan (Zydus) | Tablet |
| ANDA207110 | Bosentan (Actavis) | Tablet, film coated |
All listed forms are oral. Nine further licenses are not shown.
Safety Considerations
- Hepatotoxicity: liver function monitoring is a key guardrail for bosentan.
- Teratogenicity: contraception requirements apply.
Both points come from the candidate’s rationale notes, not from the package insert. Please refer to the package insert for full warnings, contraindications and drug interactions.
Conclusion and Next Steps
Decision: Hold
Rationale: The RA prediction rests on animal-model data and a plausible endothelin-inflammation mechanism. No human RA efficacy data were provided, and the only registered trial studies giant cell arteritis. This is a research question, not a development-ready candidate.
To proceed, the following is needed:
- Human evidence in RA, such as a pilot or Phase 2 trial with clinical endpoints.
- Mechanism-of-action data and the package insert warnings and contraindications.
- A comparison with the same drug’s other predicted indications. Limited systemic sclerosis (rank 3) has much stronger support (L3). It has an observational study of digital ulcers (NCT05168215) and a systematic review and meta-analysis (PMID 36974107), although one small study (PMID 19350343) found no microvascular effect. If that review pools RCTs, a narrow digital-ulcer indication could move toward Proceed with Guardrails.
This report is for research reference only and does not constitute medical advice. Predicted repurposing candidates require clinical validation before any use.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.