Folic Acid
| Evidence Level: L4 | Predicted Indications: 1 |
Table of Contents
Folic Acid: From an Unrecorded Original Indication to Biotin Metabolic Disease
One-Sentence Summary
Folic acid is a marketed B-vitamin (DrugBank DB00158), but the record does not list its approved indication. The TxGNN model predicts it may be relevant to biotin metabolic disease, with a very high score (99.49%). The supporting evidence is weak: 14 clinical trials and 20 publications were retrieved, but none tests folic acid in this disease, so the prediction remains model-only (L4).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded (all retrieved US labels have empty indication text) |
| Predicted New Indication | Biotin metabolic disease |
| TxGNN Prediction Score | 99.49% |
| Evidence Level | L4 |
| US Market Status | ✓ Marketed |
| Number of NDAs | 20 (the sampled entries are ANDA generics) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available for folic acid, and no original indication is recorded. The score therefore cannot be tied to a specific pathway from the data supplied.
A plausible link is that folate and biotin are both B-vitamin cofactors in one-carbon and carboxylase-related metabolism. Reviews often group them together as “vitamin-responsive disorders” (for example PMID 23622402). Biotin metabolic diseases, such as biotinidase or holocarboxylase synthetase deficiency, are treated by replacing biotin itself. No source in this pack shows that folic acid corrects the underlying defect.
The high score most likely reflects vitamin-class proximity in the knowledge graph rather than a validated repurposing mechanism.
Clinical Trial Evidence
None of the trials tests folic acid in a biotin metabolic disorder. The table lists the 10 most relevant of the 14 retrieved; NCT01643187 and NCT01173315 are the only two graded B, and the rest were graded C.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01643187 | Phase 2 | Unknown | 1000 | Fortified food vs. milk on nutritional and micronutrient status (including serum and erythrocyte folate) in malnourished children. Closest to a deficiency context, but folic acid is not isolated. |
| NCT01173315 | Phase 2 | Completed | 75 | Vitamin and mineral supplementation for neuropathy and nephropathy complications in type 2 diabetes. Multivitamin intervention. |
| NCT03360435 | N/A | Completed | 99 | Transdermal vitamin patch absorption after bariatric surgery. Measures absorption, not disease treatment. |
| NCT03444155 | N/A | Completed | 30 | Natural vs. synthetic vitamin B complexes, comparing bioavailability in healthy volunteers. |
| NCT01474486 | N/A | Completed | 40 | Multi-micronutrient feasibility study in congestive heart failure. |
| NCT00572741 | N/A | Completed | 39 | Nutritional intervention targeting oxidative stress and methylation in autism. |
| NCT04312152 | N/A | Unknown | 200 | Q10 ubiquinol plus B and E vitamins in autism and Phelan-McDermid syndrome. |
| NCT05687474 | N/A | Completed | 6824 | Genomic newborn screening for 126 treatable genetic diseases. Diagnostic, no drug tested. |
| NCT04067921 | N/A | Unknown | 1963 | General platform for nutrition and health trials. Not indication-specific. |
| NCT01558193 | N/A | Completed | 202 | Multivitamin/mineral supplementation, with and without fatty acids, on impulsivity and aggression. |
Literature Evidence
All retrieved publications are reviews or background articles; there are no RCTs. The table shows the 10 most relevant of the 20.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 23622402 | 2013 | Review | Handbook of Clinical Neurology | Vitamin-responsive disorders (cobalamin, folate, biotin, B1, E). Many enzymes need vitamins as cofactors, and rare inborn errors of vitamin absorption, transport and metabolism are described. |
| 30557456 | 2019 | Review | Movement Disorders | Movement disorders in treatable inborn errors of metabolism. |
| 7027768 | 1981 | Review | Acta Vitaminologica et Enzymologica | Vitamins in metabolic diseases through malabsorption, errors of vitamin metabolism and vitamin-dependent syndromes. Pharmacological doses of the specific vitamin may be needed. |
| 779426 | 1976 | Not classified | Advances in Human Genetics | Vitamin-responsive inherited metabolic disorders (title only, no abstract available). |
| 11031989 | 2000 | Not classified | Ryoikibetsu Shokogun Shirizu | Vitamin dependency syndrome (title only, no abstract available). |
| 958746 | 1976 | Not classified | Pediatric Clinics of North America | Megavitamin-responsive aminoacidopathies. B-complex vitamins act as coenzymes. Therapeutic trials of the specific cofactor are advised because response cannot be predicted. |
| 38203763 | 2024 | Review | International Journal of Molecular Sciences | Vitamin B12 deficiency and the nervous system. Mentions the B12-dependent link between biotin, folate and homocysteine pathways. |
| 37123774 | 2023 | Review | Cureus | Vitamins and type 2 diabetes. Thiamine, pyridoxine and biotin levels are lower in diabetes. |
| 25388747 | 2015 | Review | Endocrine, Metabolic & Immune Disorders Drug Targets | Vitamins and type 2 diabetes. Reports the same low levels of B-group vitamins, including biotin. |
| 29173522 | 2017 | Review | Gastroenterology Clinics of North America | Vitamins and minerals in inflammatory bowel disease. Patients should be monitored and their deficiencies corrected. |
US Market Information
Twenty US authorizations are on record. The five below are the main ones, and none of them has indication text in the data. Other forms on record are solution and injection solution.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ANDA040796 | Folic Acid (Aphena Pharma Solutions) | Tablet | Not stated in the record |
| ANDA211064 | Folic Acid (A-S Medication Solutions) | Tablet | Not stated in the record |
| ANDA211064 | Folic Acid (Preferred Pharmaceuticals) | Tablet | Not stated in the record |
| ANDA040625 | Folic Acid (Cardinal Health 107) | Tablet | Not stated in the record |
| ANDA211064 | Folic Acid (Bryant Ranch Prepack) | Tablet | Not stated in the record |
Safety Considerations
Please refer to the package insert for safety information. No drug-interaction records were found for this drug in the queried source.
Conclusion and Next Steps
Decision: Hold
Rationale: The TxGNN score is very high, but no trial or publication tests folic acid in biotin metabolic disease. The standard treatment for these disorders is biotin replacement, and the signal likely reflects vitamin-class similarity rather than a real mechanism. Safety screening cannot start without label warnings and contraindications.
To proceed, the following is needed:
- Package insert warnings and contraindications (blocking gap), parsed from the FDA label
- Mechanism of action from DrugBank, to test whether any pathway links folic acid to biotin-dependent enzymes
- The approved indication text, to establish the original use
- Any direct preclinical or clinical evidence of folic acid in biotinidase or holocarboxylase synthetase deficiency
- A check of whether the biotin metabolic disease label in the model maps to a clinically meaningful population
This report is for research reference only and does not constitute medical advice. 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.