Dimethyl Fumarate
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Dimethyl Fumarate
- Dimethyl Fumarate: From Relapsing-Remitting Multiple Sclerosis to Progressive Multiple Sclerosis
Dimethyl Fumarate: From Relapsing-Remitting Multiple Sclerosis to Progressive Multiple Sclerosis
One-Sentence Summary
Dimethyl fumarate (DMF) is an oral disease-modifying therapy originally used for relapsing-remitting multiple sclerosis. The TxGNN model predicts it may be effective for progressive multiple sclerosis, with 3 clinical trials and 19 publications compiled for this direction. However, the only Phase 3 trial was terminated early with a small enrollment, so clinical efficacy remains unproven.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Relapsing-remitting multiple sclerosis (the Singapore licence records contain no approved indication text) |
| Predicted New Indication | Progressive multiple sclerosis |
| TxGNN Prediction Score | 90.67% |
| Evidence Level | L1 per the pre-computed scoring, but see the note below (L1 requires ≥2 completed Phase 3 RCTs; only 1 terminated Phase 3 trial exists, so the evidence is closer to L2 or lower) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Proceed with Guardrails (as a research question, not a treatment recommendation) |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on general knowledge, DMF is thought to activate the Nrf2 pathway and to have antioxidant, cytoprotective and immunomodulatory effects.
These actions overlap with the inflammatory and neurodegenerative processes in progressive MS. The drug is already established in relapsing MS, and progressive forms share the same underlying disease, which makes the TxGNN prediction biologically plausible.
Two studies support this link: a Phase 2 trial in primary progressive MS (NCT02959658) and a Phase 4 mechanistic study of indirect neuroprotection (NCT03092544). The only Phase 3 RCT (NCT02430532) was terminated early, so it cannot establish efficacy. One open-label extension study of the primary progressive MS trial notes that the placebo-controlled phase did not meet its primary endpoint (a reduction in cerebrospinal fluid neurofilament concentrations).
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02430532 | Phase 3 | Terminated | 58 | Randomized, double-blind, placebo-controlled study of DMF (BG00012) to delay disability progression in secondary progressive MS. Terminated early, so underpowered and likely inconclusive. |
| NCT02959658 | Phase 2 | Completed | 54 | DMF vs placebo in primary progressive MS, assessing safety and efficacy. Most direct completed study, but small. |
| NCT03092544 | Phase 4 | Unknown | 57 | Mechanistic study of indirect neuroprotection (including gut bacteria) in relapsing-remitting and progressive MS. Provides biomarker and mechanistic support, not efficacy data. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 38174776 | 2024 | Network meta-analysis | Cochrane Database Syst Rev | Compares immunomodulators and immunosuppressants in relapsing-remitting MS; update of a 2015 review |
| 36586351 | 2023 | Open-label extension | Mult Scler Relat Disord | Extension of the primary progressive MS trial; the placebo-controlled phase did not meet its primary endpoint |
| 33996142 | 2021 | Cohort | Mult Scler J Exp Transl Clin | Effectiveness and safety of DMF in progressive MS, where data are limited |
| 33773271 | 2021 | PK/biomarker study | Mult Scler Relat Disord | Cerebrospinal fluid penetration and exploratory biomarker effects of DMF in secondary progressive MS |
| 25900414 | 2015 | Cochrane review | Cochrane Database Syst Rev | DMF for multiple sclerosis; immunomodulatory and neuroprotective activity |
| 29686116 | 2018 | Guideline | Neurology | American Academy of Neurology recommendations on disease-modifying therapies for MS |
| 33091427 | 2021 | Review | Pharmacol Ther | DMF-induced lymphopenia and its link to progressive multifocal leukoencephalopathy (PML) |
| 32808554 | 2022 | Cohort | Mult Scler | Nine PML cases in DMF-treated patients; incidence 0.02 per 1000 patients |
| 38321317 | 2024 | Meta-analysis | Drug Saf | Systematic review of drug-induced PML |
| 27433310 | 2016 | Review | Ther Adv Chronic Dis | Real-world experience and place in therapy of DMF in relapsing-remitting MS |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN15054P | TECFIDERA Gastro-Resistant Hard Capsules 240 mg | Enteric-coated capsule | Not stated in the compiled data |
| SIN15053P | TECFIDERA Gastro-Resistant Hard Capsules 120 mg | Enteric-coated capsule | Not stated in the compiled data |
Both registrations are valid single-ingredient oral products.
Safety Considerations
- Drug Interactions: 100 interactions were identified, and the 20 listed in the compiled data are all rated Moderate. They include:
- Corticosteroids: hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, budesonide, triamcinolone
- Immunosuppressive or cytotoxic agents: mercaptopurine, trimetrexate, dexrazoxane, levamisole
- Radiopharmaceuticals: ibritumomab tiuxetan, tositumomab, iobenguane (I-131)
- Others: naltrexone, roflumilast, dupilumab
- Literature-based safety signals: Sustained lymphopenia is a recognized concern with DMF and is linked to rare cases of PML (incidence 0.02 per 1000 patients in one cohort).
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: DMF is marketed in Singapore and has a plausible mechanistic link to progressive MS, supported by a completed Phase 2 trial. However, the Phase 3 trial was terminated early and the Phase 2 placebo-controlled phase missed its primary endpoint, so efficacy is unproven. This should be treated as a research question, not a basis for clinical use.
To proceed, the following is needed:
- Package insert warnings and contraindications from the Health Sciences Authority (HSA), which are currently missing and block safety screening
- Detailed mechanism of action data (for example, from DrugBank)
- Published results of NCT02959658, and the reasons for termination of NCT02430532
- A lymphocyte-count and PML monitoring plan
- A larger, adequately powered randomized trial in progressive MS
Other predicted indications (ranks 2 to 10, such as jugular foramen schwannoma, cervical neuroblastoma and benign oral neoplasms) rest on model prediction alone or on a single preclinical oral squamous cell carcinoma study. They should be held.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.