Cholesterol

證據等級: L5

預測適應症: 10 個

Cholesterol: From No Approved Therapeutic Indication to Homozygous Familial Hypercholesterolemia

One-Sentence Summary

Cholesterol (DB04540) is an endogenous lipid molecule with no approved therapeutic indication in any jurisdiction. The TxGNN model predicts it may be effective for Homozygous Familial Hypercholesterolemia (HoFH), however all 50 clinical trials and 20 publications identified relate to drugs that lower cholesterol in HoFH — directly contradicting the hypothesis of administering cholesterol as a treatment. This prediction represents a classic reverse false positive driven by strong pathological (not therapeutic) associations in the knowledge graph.

Quick Overview

Item	Content
Original Indication	None — cholesterol is an endogenous biological molecule with no approved therapeutic use
Predicted New Indication	Homozygous Familial Hypercholesterolemia (HoFH)
TxGNN Prediction Score	98.76%
Evidence Level	L5 (Model prediction only; no supportive therapeutic evidence)
UK Market Status	Not marketed
Number of Marketing Authorisations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

It is not. This prediction is a well-characterised failure mode of knowledge-graph-based drug repurposing models. Cholesterol is the central pathological molecule in HoFH — the disease is defined by the inability to clear LDL cholesterol from the bloodstream due to bi-allelic mutations in the LDL receptor pathway. TxGNN has identified the exceptionally strong association between cholesterol and HoFH within its knowledge graph, but it has mistakenly interpreted this pathological relationship as a potential therapeutic one.

All clinical evidence points in the opposite direction: every registered clinical trial for HoFH aims to reduce cholesterol levels (via PCSK9 inhibitors, ANGPTL3 antibodies, MTP inhibitors, antisense oligonucleotides, CETP inhibitors, or LDL apheresis). Administering exogenous cholesterol to patients with HoFH would be expected to worsen the disease, not treat it.

Furthermore, cholesterol has no established mechanism of action as a therapeutic agent. It is not formulated as a medicine, holds no marketing authorisation in the UK or any other regulatory jurisdiction, and has no SmPC or BNF entry. The remaining nine predicted indications in this evidence pack (multiple endocrine neoplasia, HIV, platelet disorders, HER2+ breast cancer, and several veterinary diseases) are similarly implausible, with several representing animal diseases entirely inapplicable to human medicine.

Clinical Trial Evidence

All identified trials investigate drugs that lower cholesterol in HoFH patients. None investigate cholesterol itself as a therapeutic agent.

Trial Number	Phase	Status	Enrolment	Key Findings
NCT05611528	Phase 3	Completed	10	Evinacumab (anti-ANGPTL3) real-world safety/efficacy in HoFH in Canada
NCT03851705	Phase 3	Completed	56	ORION-5: Inclisiran (PCSK9 siRNA) safety/tolerability/efficacy in HoFH
NCT04659863	Phase 3	Completed	13	ORION-13: Inclisiran in adolescents with HoFH
NCT03156621	Phase 3	Completed	69	Alirocumab (anti-PCSK9) vs placebo in HoFH — LDL-C reduction at 12 weeks
NCT00607373	Phase 3	Completed	51	Mipomersen (apoB antisense) as add-on therapy in HoFH
NCT00730236	Phase 3	Completed	29	Lomitapide (MTP inhibitor) long-term LDL-C lowering in HoFH
NCT04034485	Phase 3	Completed	65	LIB003 vs evolocumab cross-over in HoFH
NCT02226198	Phase 3	Completed	20	Rosuvastatin in children/adolescents with HoFH
NCT00263081	Phase 3	Terminated	44	TAK-475 (squalene synthase inhibitor) — programme terminated
NCT01841684	Phase 3	Terminated	2	Anacetrapib (CETP inhibitor) in HoFH — terminated, only 2 enrolled

Key interpretation: Every trial listed above tests a cholesterol-lowering intervention. The therapeutic direction is diametrically opposite to administering cholesterol.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
32813947	2020	RCT	N Engl J Med	Evinacumab significantly reduced LDL-C in HoFH patients including those with null-null LDLR variants
37860863	2024	Clinical Trial	Circulation	Evinacumab efficacy and safety in paediatric HoFH patients
37850379	2024	Clinical Trial	Circulation	ORION-5: Inclisiran produced durable LDL-C reduction in HoFH
40391436	2025	Clinical Trial	Circulation	ORION-13: Inclisiran in adolescents with genetically confirmed HoFH
38695169	2024	Outcomes Study	Arterioscler Thromb Vasc Biol	Evinacumab demonstrated durable LDL-C response and improved CV outcomes
37130090	2023	Consensus Statement	Eur Heart J	EAS 2023 update: pragmatic recommendations for HoFH diagnosis and treatment
39751968	2025	Review	Curr Atheroscler Rep	Review of novel LDL-C lowering pharmacotherapies for HoFH
35101175	2022	Retrospective Cohort	Lancet	Worldwide HoFH experience: clinical, genetic characteristics and outcomes
38353972	2024	Cohort Study	JAMA Cardiol	Sex differences in HoFH diagnosis, treatment, and CV outcomes
27246162	2016	Consensus Statement	Lancet Diabetes Endocrinol	IAS panel defining severe FH and implications for management

Key interpretation: All publications concern the disease HoFH and its management via cholesterol-lowering strategies. None provide evidence supporting cholesterol as a therapeutic agent.

UK Market Information

Cholesterol holds no marketing authorisation in the United Kingdom. There are no MHRA-licensed products, no NICE technology appraisals, and no BNF entries for cholesterol as a therapeutic agent.

Safety Considerations

Please refer to the SmPC and BNF for safety information. Report suspected adverse reactions via the Yellow Card Scheme.

As cholesterol has no marketing authorisation, no SmPC exists. Exogenous cholesterol administration would be expected to elevate serum LDL-C levels and could accelerate atherosclerotic cardiovascular disease, particularly in patients with pre-existing lipid metabolism disorders.

Conclusion and Next Steps

Decision: Hold

Rationale: This prediction is a classic reverse false positive. Cholesterol is the causative pathological molecule in HoFH, not a treatment for it. The TxGNN knowledge graph correctly identifies the strong association between cholesterol and HoFH but incorrectly interprets this pathological relationship as a therapeutic one. All 50 clinical trials and 20 publications identified in the evidence pack concern drugs designed to lower cholesterol — the opposite therapeutic direction. Additionally, cholesterol is not a licensed medicine in any jurisdiction, has no established mechanism of action as a therapeutic agent, and 4 of the 10 predicted indications are veterinary diseases (infectious bovine rhinotracheitis, malignant catarrh, feline AIDS, simian immunodeficiency virus) inapplicable to human medicine.

This candidate should not proceed further in the evaluation pipeline.

If future review is warranted, the following would be needed:

Fundamental re-evaluation of TxGNN scoring methodology to distinguish pathological associations from therapeutic relationships
Implementation of a “directionality filter” to flag cases where the drug is a known causative factor for the predicted disease
Exclusion of veterinary diseases from the predicted indications output
Verification that candidate molecules hold at least one marketing authorisation as a therapeutic agent before entering the evaluation pipeline

Disclaimer: This report is generated for research purposes only and does not constitute medical advice. Drug repurposing candidates require rigorous clinical validation before any therapeutic application. Report suspected adverse reactions via the Yellow Card Scheme.

Disclaimer

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