Becaplermin

證據等級: L5

預測適應症: 10 個

Becaplermin: From Diabetic Foot Ulcers to Amenorrhea

One-Sentence Summary

Becaplermin (Regranex) is a recombinant human platelet-derived growth factor BB (PDGF-BB) originally approved for the topical treatment of lower extremity diabetic neuropathic ulcers. The TxGNN model predicts it may be effective for Amenorrhea as the top-ranked new indication (score 99.86%); however, no clinical trials and no publications currently support this specific direction. Across all five uniquely predicted indications, mechanistic analysis consistently reveals that PDGF-BB agonism is either biologically implausible or directionally contraindicated — a Hold decision is recommended for all candidates pending fundamental safety and mechanistic review.

Quick Overview

Item	Content
Original Indication	Lower extremity diabetic neuropathic ulcers
Predicted New Indication (Rank 1)	Amenorrhea
TxGNN Prediction Score	99.86%
Evidence Level	L5
Denmark Market Status	Not marketed
Number of Marketing Authorisations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Becaplermin is a recombinant human PDGF-BB that acts as a PDGF receptor agonist, primarily stimulating cell proliferation, chemotaxis, and extracellular matrix synthesis in tissues expressing PDGF receptors (PDGFRα and PDGFRβ). Its established clinical role is topical promotion of granulation tissue formation in chronic diabetic wounds.

Detailed mechanism of action data was not available in the Evidence Pack. Based on known pharmacology, becaplermin is a PDGF-BB receptor agonist; its efficacy in diabetic foot ulcers has been clinically proven, and it acts through growth factor signalling pathways involved in tissue repair and cell proliferation. PDGF signalling has been reported to play an auxiliary role in folliculogenesis and ovarian stromal cell proliferation, which may have led the TxGNN knowledge graph to generate an indirect association with the female reproductive axis.

However, the mechanistic link to amenorrhea is very weak. Amenorrhea is predominantly caused by hypothalamic-pituitary-gonadal (HPG) axis dysregulation, hyperprolactinaemia, or structural uterine pathology — none of which involve PDGF-BB as a primary mediator. This prediction most likely reflects an indirect node-level association in the TxGNN graph rather than a clinically plausible biological pathway.

Clinical Trial Evidence

Currently no related clinical trials registered.

Literature Evidence

Currently no related literature available.

Denmark Market Information

Becaplermin is not currently marketed in Denmark. The Danish Medicines Agency (Lægemiddelstyrelsen) holds no active national marketing authorisations for this product.

Regulatory note: Becaplermin (Regranex 0.01% gel) holds a centralised European Marketing Authorisation (EU/1/99/095) granted by the EMA for the treatment of lower limb neuropathic diabetic ulcers in adults. Although the EU authorisation is technically valid across all EU/EEA member states, the product appears to have no active distribution or supply in Denmark. Healthcare professionals wishing to prescribe it may need to arrange individual import through the Lægemiddelstyrelsen’s compassionate use or named-patient import pathway.

Safety Considerations

Please refer to the approved Summary of Product Characteristics (SmPC) for complete safety information.

⚠️ Critical safety signal — Black Box Warning: Becaplermin carries an FDA Black Box Warning for increased risk of cancer mortality, based on post-marketing pharmacovigilance data showing a higher incidence of malignant neoplasms in diabetic foot ulcer patients who received three or more tubes. This warning has direct and serious implications for any proposed oncology-adjacent repurposing (see Additional Predicted Indications below).

Additional Predicted Indications — Overview and Safety Assessment

The TxGNN model returned five unique predicted indications (each appearing twice in the ranked list). All five received a Hold recommendation. The table below summarises each, followed by the key mechanistic concern.

Rank	Predicted Indication	TxGNN Score	Evidence Level	Literature	Recommendation
1	Amenorrhea	99.86%	L5	0	Hold
3	Erectile Dysfunction	99.72%	L4	1	Hold
5	HER2+ Breast Carcinoma	99.70%	L4	1	Hold
7	PR– Breast Cancer	99.50%	L4	2	Hold
9	Pulmonary Hypertension	99.49%	L4	20	Hold

Erectile Dysfunction — Literature Evidence

PMID	Year	Type	Journal	Key Findings
28245285	2017	Basic science (cell/molecular)	PLoS One	PDGFR/STAT3 signalling regulates phenotypic transition of corpus cavernosum smooth muscle cells (CCSMCs) in rats; hypoxia-driven phenotypic switch implicated in ED pathogenesis

Mechanistic concern: PDGFR/STAT3 signalling is involved in CCSMC phenotypic transition (contractile → synthetic), which is pathologically relevant to erectile dysfunction. However, becaplermin as a PDGF-BB agonist may promote smooth muscle cell proliferation and synthetic phenotype transition, theoretically worsening fibrotic remodelling rather than reversing it. The mechanistic direction requires very careful evaluation before any further investigation.

HER2+ Breast Carcinoma — Literature Evidence

PMID	Year	Type	Journal	Key Findings
19298655	2009	Basic science (cell model)	Breast Cancer Research	PPARγ protects ERBB2-positive breast cancer cells from palmitate toxicity via lipid metabolism regulation; de novo fatty acid synthesis is critical for ERBB2+ cell survival

Mechanistic concern — direction reversed: PDGF signalling in the tumour microenvironment generally acts as a pro-tumorigenic driver (activating cancer-associated fibroblasts, promoting angiogenesis and tumour invasion). Combined with the existing Black Box Warning for increased cancer incidence, using a PDGF-BB agonist in HER2+ breast carcinoma carries a significant theoretical risk of accelerating tumour growth. The mechanistic rationale directly conflicts with the treatment objective.

PR– Breast Cancer — Literature Evidence

PMID	Year	Type	Journal	Key Findings
24577164	2016	Biomarker study (clinical)	American Journal of Clinical Oncology	High circulating Tie2 associated with pathological complete response to chemotherapy and anti-angiogenic therapy (bevacizumab) in breast cancer; angiogenic pathway profiling
21733044	2011	Basic science (animal model)	Cancer Science	Soluble PDGFRβ (decoy receptor) inhibits intraosseous growth of breast cancer cells in nude mice; blocking PDGF-BB/PDGFRβ signalling reduces bone metastasis

Mechanistic concern — direction directly reversed: PMID 21733044 explicitly demonstrates that reducing PDGF-BB/PDGFRβ signalling inhibits breast cancer bone metastasis. Becaplermin, as a PDGF-BB agonist, acts in the exact opposite direction. PR– breast cancer carries higher aggressiveness, and PDGF pathway activation is associated with promoting epithelial-mesenchymal transition (EMT) and metastatic spread. This prediction should not be pursued.

Pulmonary Hypertension — Literature Evidence

PMID	Year	Type	Journal	Key Findings
33591958	2021	Animal model + human tissue	JCI Insight	Macrophage-derived PDGF-B directly induces pulmonary arteriole muscularisation in murine and human PAH; clodronate-mediated macrophage depletion attenuates disease
18420966	2008	Mechanistic study	Am J Respir Crit Care Med	PDGF promotes PASMC proliferation and migration; overexpression demonstrated in idiopathic PAH lesions
18382765	2008	Animal model + human SMCs	J Clin Invest	BMP-2/PPARγ/apoE axis prevents PDGF-BB–induced PASMC proliferation; BMP-RII mutations linked to PAH
17339547	2007	Animal model	Circulation	Enhanced PDGF signalling in apoE-deficient mice linked to PAH; PPARγ activation reverses disease
19324949	2009	Clinical study	European Respiratory Journal	Elevated circulating PDGF-BB levels across pulmonary circulation in PAH patients; correlates with haemodynamic severity
39360410	2024	Basic science (non-coding RNA)	Arteriosclerosis, Thrombosis, Vascular Biology	PDGF signalling activation promotes PASMC hyperproliferation and pulmonary vascular remodelling in PAH
39901736	2025	Multi-omics, animal model	American Journal of Hypertension	PDGF-BB–induced PASMC model used to map transcriptomic and metabolomic changes in PAH pathogenesis
41213438	2026	Basic science (animal model)	Free Radical Biology & Medicine	TRIB2 promotes PASMC proliferation via SERCA2 ubiquitination; PDGF-BB stimulation used as disease model
39551320	2024	Basic science (non-coding RNA)	Int J Biological Macromolecules	miR-34a-3p/DUSP1 axis inhibits PDGF-BB–induced hPASMC proliferation; MEG3 lncRNA aggravates APE-induced PAH
38614383	2024	Pharmacological study	European Journal of Pharmacology	Corosolic acid attenuates PDGF signalling in macrophages and SMCs; anti-PAH effect via PDGF pathway inhibition

Mechanistic concern — critically reversed, high patient safety risk: This is the most clinically significant safety flag in the entire analysis. The overwhelming consensus across 20 publications is that PDGF-B/PDGFRβ signalling drives pulmonary arterial smooth muscle cell (PASMC) hyperproliferation and vascular remodelling — the defining pathological process of pulmonary arterial hypertension (PAH). Importantly, the PDGF receptor inhibitor imatinib (Gleevec) has been studied in Phase 3 clinical trials for PAH precisely by blocking this pathway. Administering becaplermin (a PDGF-BB agonist) to a patient with pulmonary hypertension would theoretically directly accelerate vascular remodelling. This indication must not be pursued.

Conclusion and Next Steps

Decision: Hold (All Predicted Indications)

Rationale: For the highest-ranked prediction (amenorrhea), the evidence level is L5 — model prediction only, with zero supporting clinical trials or published literature, and no biologically plausible mechanistic link between PDGF-BB agonism and the condition. More broadly, across all five predicted indications, mechanistic analysis consistently shows that becaplermin’s mode of action (PDGF-BB agonism) is either directionally inconsistent with therapeutic benefit or poses active safety risk — most critically in pulmonary hypertension, where the existing literature establishes PDGF-BB as a key disease driver, and in oncology-related indications where the existing Black Box Warning must be treated as a blocking signal.

To proceed with any further investigation, the following is required:

MOA data gap resolution: Obtain full DrugBank mechanism-of-action profile to characterise receptor binding specificity, downstream signalling cascades, and tissue distribution
Danish regulatory and safety data: Obtain the approved EMA SmPC for Regranex (EU/1/99/095), paying particular attention to the oncology Black Box Warning and its implications for any proposed new indication
Route compatibility assessment: The current approved formulation is a topical gel (0.01%). For all predicted indications (amenorrhea, erectile dysfunction, breast cancer, pulmonary hypertension), systemic or alternative delivery would be required — a separate formulation development programme would be necessary
Preclinical biological plausibility work for amenorrhea: Before any clinical consideration, in vitro and in vivo studies demonstrating PDGF-BB–mediated effects on HPG axis regulation or endometrial function would be required
Formal safety risk assessment for oncology-adjacent indications: Before any investigation in breast cancer subtypes, a structured benefit-risk analysis addressing the Black Box Warning and the pro-tumorigenic role of PDGF signalling must be completed and reviewed by a multidisciplinary team
Definitive exclusion of pulmonary hypertension: Given the weight of evidence demonstrating PDGF-BB as a direct contributor to PAH pathogenesis, this indication should be formally excluded from further repurposing consideration without extraordinary new mechanistic evidence

This report is generated for research reference purposes only and does not constitute medical advice. All drug repurposing candidates require clinical validation before any therapeutic application. Please refer to the full approved Summary of Product Characteristics (SmPC) for all prescribing decisions.

Disclaimer

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