Teriflunomide
| Evidence Level: L1 | Predicted Indications: 10 |
Table of Contents
- Teriflunomide
- Teriflunomide: From No Documented Original Indication to Relapsing-Remitting Multiple Sclerosis
Teriflunomide: From No Documented Original Indication to Relapsing-Remitting Multiple Sclerosis
One-Sentence Summary
This evidence pack records no approved indication or authorization for teriflunomide in the regulatory dataset (0 licenses on file, market status “not marketed”), and the original mechanism-of-action field is also a data gap. The TxGNN model’s top-ranked prediction is Relapsing-Remitting Multiple Sclerosis (RRMS), supported by 27 clinical trials and 20 publications — including several completed Phase 3 RCTs. Important caveat: the literature evidence in this pack itself (e.g. PMID 26758290) states that teriflunomide (Aubagio®) has been licensed in the EU since 2013 specifically for RRMS. This means the “predicted new indication” is very likely the drug’s already-known, already-approved indication, not a genuine repurposing signal — the empty regulatory license data appears to be a data gap rather than a reflection of clinical reality.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not documented in the regulatory license dataset (0 licenses on file) |
| Predicted New Indication | Relapsing-Remitting Multiple Sclerosis |
| TxGNN Prediction Score | 99.24% |
| Evidence Level | L1 |
| EU Market Status | ✗ Not Marketed (per dataset — see discrepancy note below) |
| Number of Authorizations | 0 |
| Recommended Decision | Proceed with Guardrails |
Data discrepancy note: The regulatory record shows 0 EU authorizations and “not marketed,” yet the literature evidence in this same pack (PMID 26758290) explicitly states teriflunomide has been EU-licensed for RRMS since August 2013, with the SmPC later expanded (Sept 2014) to include first clinical demyelinating events. This inconsistency should be reconciled against the EMA/EU register before any downstream decision relies on the “not marketed” status.
Why is This Prediction Reasonable?
Detailed structured mechanism-of-action data is not available in this dataset (original_moa = data gap). However, the evidence pack’s own repurposing rationale supplies substantive mechanistic information: teriflunomide is a dihydroorotate dehydrogenase (DHODH) inhibitor that blocks de novo pyrimidine synthesis, selectively suppressing proliferation of rapidly dividing, activated T and B lymphocytes. This anti-proliferative, immunomodulatory action is the accepted core mechanism underlying its use in autoimmune-mediated demyelinating disease.
Multiple Sclerosis — specifically the relapsing-remitting subtype — is an immune-mediated, T/B-lymphocyte-driven neurodegenerative disease. Given teriflunomide’s selective lymphocyte-proliferation-blocking mechanism, its applicability to RRMS is mechanistically direct rather than a distant cross-indication inference.
The critical interpretive point, however, is that this mechanistic fit is not novel: it reflects teriflunomide’s well-established, already-approved use (as Aubagio®) for RRMS in the EU since 2013, corroborated by multiple pivotal trials (TEMSO, TENERE) and head-to-head Phase 3 comparator trials against newer agents (ofatumumab, ublituximab, tolebrutinib, ponesimod, evobrutinib). In other words, this TxGNN output functions here as a validation case — correctly recovering a known drug-disease relationship — rather than as a genuine repurposing candidate. Within this same evidence pack, a secondary, more novel signal is visible at a lower rank: teriflunomide combined with dexamethasone for primary immune thrombocytopenia (ITP), which has active Phase 2 RCTs (e.g. NCT07065968) testing a use outside its known label — that candidate would warrant separate, dedicated evaluation as a true repurposing opportunity.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00134563 | Phase 3 | Completed | 1,088 | TEMSO pivotal trial: randomized, double-blind, placebo-controlled study establishing teriflunomide’s effect on relapse frequency and disability accumulation in relapsing MS; the key trial underpinning original approval |
| NCT00803049 | Phase 3 | Completed | 742 | Long-term extension of the TEMSO trial documenting sustained safety, tolerability, and durability of efficacy on disability, relapse rate, and MRI outcomes |
| NCT00883337 | Phase 3 | Completed | 324 | TENERE trial: rater-blinded comparison of teriflunomide vs interferon beta-1a on time to treatment failure, relapse frequency, and patient-reported outcomes |
| NCT03302442 | N/A | Completed | 3,000 | Large real-world observational comparison (French MS Observatory) of dimethyl fumarate vs teriflunomide on clinical and MRI outcomes in RRMS |
| NCT03535298 | Phase 4 | Active, not recruiting | 800 | DELIVER-MS: compares early intensive high-efficacy therapy vs escalation strategy to inform overall treatment philosophy in RRMS |
| NCT06663189 | Phase 3 | Not yet recruiting | 200 | TWINS trial: randomized, open-label study evaluating disease-modifying therapy withdrawal in inactive RRMS patients aged ≥55 |
| NCT06843382 | N/A | Not yet recruiting | 100 | ROOF-MS: real-world prospective cohort comparing teriflunomide vs dimethyl fumarate on physical and cognitive fatigability in MS |
| NCT00228163 | Phase 2 | Completed | 147 | Long-term extension study assessing durability of teriflunomide’s safety and efficacy in relapsing MS |
| NCT04129736 | Phase 4 | Completed | 12 | Determined teriflunomide 14 mg concentration in serum and cerebrospinal fluid in RRMS patients |
| NCT03464448 | N/A | Completed | 30 | Phase 4 open-label mechanistic study identifying regulatory B lymphocytes as central mediators of teriflunomide’s therapeutic effect |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 32757523 | 2020 | RCT | N Engl J Med | ASCLEPIOS trials: compared anti-CD20 ofatumumab against teriflunomide in relapsing MS |
| 36001711 | 2022 | RCT | N Engl J Med | ULTIMATE trials: evaluated ublituximab (B-cell depleting antibody) versus teriflunomide in relapsing MS |
| 40202623 | 2025 | RCT | N Engl J Med | Compared BTK inhibitor tolebrutinib against teriflunomide for efficacy and safety in relapsing MS |
| 26758290 | 2016 | RCT | CNS Drugs | Reviews the EU SmPC for teriflunomide, confirming EU licensure since August 2013 for RRMS, with key clinical/safety outcomes and prescribing considerations |
| 38174776 | 2024 | Network Meta-analysis | Cochrane Database Syst Rev | Compares relative benefits of immunomodulators, immunosuppressants, and biologics (including teriflunomide) in RRMS |
| 33779698 | 2021 | RCT | JAMA Neurology | OPTIMUM trial: first Phase 3 active-comparator study of ponesimod vs teriflunomide in relapsing MS |
| 39307151 | 2024 | RCT | Lancet Neurology | evolutionRMS1/2: Phase 3 trials comparing BTK inhibitor evobrutinib against teriflunomide in relapsing MS |
| 35266417 | 2022 | RCT | Mult Scler | ASCLEPIOS I/II subgroup analysis: ofatumumab showed superior clinical and MRI outcomes vs teriflunomide in newly diagnosed, treatment-naive patients |
| 33620411 | 2021 | Review | JAMA | General review of MS diagnosis and treatment, summarizing the evidence base for current disease-modifying therapies |
| 31098896 | 2019 | Review | Drugs | Comprehensive review of teriflunomide’s efficacy and tolerability in RRMS, based on RCT and real-world evidence |
EU Market Information
Currently no EU marketing authorization records are available in this dataset (0 licenses on file). This conflicts with literature evidence (PMID 26758290) indicating EU licensure since 2013; the regulatory database should be verified/reconciled.
Safety Considerations
Please refer to the SmPC for safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale:
- Multiple completed Phase 3 RCTs (TEMSO, TENERE, and several active-comparator trials) provide L1-level evidence for teriflunomide’s efficacy in RRMS, but this evidence supports a known, already-approved indication rather than a novel repurposing candidate. Regulatory and safety data gaps prevent this from being treated as a validated new-use decision at this stage.
To proceed, the following is needed:
- Product label warnings/contraindications (source: TFDA website; blocking gap — required before any safety pre-screening/S1 stage can proceed)
- Detailed mechanism-of-action data (source: DrugBank API; high-priority gap — needed to properly assess mechanistic linkage for lower-ranked, more novel candidates)
- Reconciliation of the “not marketed / 0 licenses” regulatory status against the EU approval history cited in the literature evidence
- If genuine repurposing value is the goal, separate dedicated evaluation of the immune thrombocytopenia (ITP) signal (rank 5 in this pack), which has active Phase 2 RCTs testing teriflunomide outside its known indication
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.